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Peripartum cardiomyopathy: Causes, diagnosis, and treatment

Article Type
Article
Changed
Wed, 02/28/2018 - 15:05
Display Headline
Peripartum cardiomyopathy: Causes, diagnosis, and treatment
Author(s)
Radhakrishnan Ramaraj, MD
Vincent L. Sorrell, MD

Heart failure during pregnancy was recognized as early as 1849, but it was first described as a distinctive form of cardiomyopathy only in the 1930s.1 In 1971, Demakis et al2 described 27 patients who presented during the puerperium with cardiomegaly, abnormal electrocardiographic findings, and congestive heart failure, and named the syndrome peripartum cardiomyopathy.

The European Society of Cardiology3 recently defined peripartum cardiomyopathy as a form of dilated cardiomyopathy that presents with signs of heart failure in the last month of pregnancy or within 5 months of delivery.

Peripartum cardiomyopathy is relatively rare but can be life-threatening. The National Hospital Discharge Survey (1990–2002) estimated that it occurs in 1 in every 2,289 live births in the United States.4 The disease appears to be more common in African American women.1 The rate varies in other populations: it is highest in Haiti, with 1 case in 300 live births, which is nearly 10 times higher than in the United States.5 The reason for such a variation remains unclear.

Although early reports suggested the death rate was nearly 50%, more recent reports show it to be 0 to 5% in the United States, and the higher numbers in the earlier reports likely represented publication bias.5,6–9

WHAT CAUSES IT?

Peripartum cardiomyopathy is generally considered a form of idiopathic primary myocardial disease associated with the pregnant state. Although several plausible etiologic mechanisms have been suggested, none of them is definite. Some are discussed below.

Myocarditis

Myocarditis has been found on endomyocardial biopsy of the right ventricle in patients with peripartum cardiomyopathy,10,11 with a dense lymphocytic infiltrate and variable amounts of myocyte edema, necrosis, and fibrosis. The prevalence of myocarditis in patients with peripartum cardiomyopathy ranged from 8.8% to 78% in different studies.12,13 On the other hand, the presence or absence of myocarditis alone does not predict the outcome of peripartum cardiomyopathy.7

Cardiotropic viral infections

After a viral infection, a pathologic immune response might occur that is inappropriately directed against native cardiac tissue proteins, leading to ventricular dysfunction.

Bultmann et al14 found parvovirus B19, human herpes virus 6, Epstein-Barr virus, or cytomegalovirus DNA in endomyocardial biopsy specimens from 8 (31%) of 26 patients with peripartum cardiomyopathy that was associated immunohistologically with interstitial inflammation.

Kühl et al15 found, in patients with viral infection confirmed by endomyocardial biopsy, that the median left ventricular ejection fraction improved in those in whom the virus was cleared (from 50.2% before to 58.1% afterward, P < .001), whereas it decreased in those in whom the virus persisted (from 54.3% before to 51.4% afterward, P < .01).

Lyden and Huber16 found that mice developed worse myocarditis if they were experimentally infected with coxsackievirus and echovirus during pregnancy than if they were infected while not pregnant.

Chimerism

In a phenomenon called chimerism, cells from the fetus take up residence in the mother (or vice versa), sometimes provoking an immune response.17,18

As reviewed by Ansari et al,19 the serum from patients with peripartum cardiomyopathy has been found to contain autoantibodies in high titers, which are not present in serum from patients with idiopathic cardiomyopathy. Most of these antibodies are against normal human cardiac tissue proteins of 37, 33, and 25 kD. The peripheral blood in these patients has a high level of fetal microchimerism in mononuclear cells, an abnormal cytokine profile, and low levels of CD4+ CD25lo regulatory T cells.

Warraich et al,20 in a study from South Africa, Mozambique, and Haiti, found that the frequencies and reactivities of immunoglobulins were similar in distribution in patients with peripartum cardiomyopathy, irrespective of the geographic location.

Apoptosis and inflammation

Apoptosis (programmed cell death) of cardiac myocytes occurs in heart failure and may contribute to progressive myocardial dysfunction. 21 Experiments in mice suggest that apoptosis of cardiac myocytes has a role in peripartum cardiomyopathy.22

Fas and Fas ligand are cell surface proteins that play a key role in apoptosis. Sliwa et al,23 in a single-center, prospective, longitudinal study from South Africa, followed 100 patients with peripartum cardiomyopathy for 6 months. During this time 15 patients died, and those who died had significantly higher plasma levels of Fas/Apo-1 (P < .05). In the same study, plasma levels of C-reactive protein and tumor necrosis factor alpha (markers of inflammation) were elevated and correlated with higher left ventricular dimensions and lower left ventricular ejection fractions at presentation.

In the Studies of Left Ventricular Dysfunction,24 circulating levels of tumor necrosis factor alpha and interleukin 6 increased in patients as their functional heart failure classification deteriorated.

An abnormal hemodynamic response

During pregnancy, blood volume and cardiac output increase. In addition, afterload decreases because of relaxation of vascular smooth muscle. The increases in volume and cardiac output during pregnancy cause transient and reversible hypertrophy of the left ventricle to meet the needs of the mother and fetus. Cardiac output reaches its maximum at around 20 weeks of pregnancy.25

The transient left ventricular systolic dysfunction during the third trimester and early postpartum period returns to baseline once the cardiac output decreases.26,27

Other possible factors

Other possible etiologic factors include prolactin,28,29 relaxin,30 immune complexes,31 cardiac nitric oxide synthase,32 immature dendritic cells,33 cardiac dystrophin,34 and toll-like receptors.35

 

 

WHO IS AT RISK?

Demakis and colleagues2 suggest the following risk factors for peripartum cardiomyopathy:

  • Multiparity
  • Advanced maternal age (although the disease can occur at any age, the incidence is higher in women over age 3036)
  • Multifetal pregnancy
  • Preeclampsia
  • Gestational hypertension
  • African American race.

CLINICAL FEATURES

Peripartum cardiomyopathy involves left ventricular systolic dysfunction in women with no history of heart disease. It can be diagnosed only if other causes of cardiomyopathy are absent.2

Diagnostic criteria for peripartum cardiomyopathy (all must be present) are37:

  • Cardiac failure developing in the last month of pregnancy or within 5 months of delivery
  • No identifiable cause of the cardiac failure
  • No recognizable heart disease before the last month of pregnancy
  • An ejection fraction of less than 45%, or the combination of an M-mode fractional shortening of less than 30% and an end-diastolic dimension greater than 2.7 cm/m2.

Symptoms of heart failure such as dyspnea, dizziness, pedal edema, and orthopnea can occur even in normal pregnancies. Therefore, a pregnant woman in whom peripartum cardiomyopathy is developing may consider her symptoms to be normal. The dyspnea during normal pregnancy is thought to be due to hyperventilation caused by the effects of progesterone, and also due to pressure on the diaphragm from the growing uterus.38 Peripheral edema occurs in approximately two-thirds of healthy pregnant women.39 Nevertheless, if swelling and other heart failure symptoms develop suddenly in an otherwise normal pregnancy, this should prompt further investigation.40

Pulmonary edema was a presenting symptom in all 106 patients in a 2007 study in China. 41 The clinical presentation was similar to that of congestive heart failure but was highly variable; 17% of cases were diagnosed antepartum and 83% postpartum. The mean age at diagnosis was 28 ± 6 years. Left ventricular function almost completely normalized in 51% of surviving patients. These findings were similar to those in earlier studies.2,36 Interestingly, the left ventricular ejection fraction normalized only in 23% of an African cohort.23

Thromboembolism can be a presentation of peripartum cardiomyopathy. Hemoptysis and pleuritic chest pain may be presenting symptoms of pulmonary embolism.42

Cardiac arrhythmias and sudden cardiac arrest have also been reported.43

A latent form of peripartum cardiomyopathy without significant clinical signs and symptoms has been reported.8

Preeclampsia should be excluded on the basis of history and physical examination, as its management is different. Preeclampsia occurs after 20 weeks of gestation and is characterized by high blood pressure, protein in the urine, swelling, sudden weight gain, headaches, and changes in vision.

Delayed diagnosis may be associated with higher rates of illness and death; therefore, physicians should consider peripartum cardiomyopathy in any peripartum patient with unexplained symptoms. Although the symptoms of heart failure can be difficult to differentiate from those of late pregnancy, a heightened suspicion can help.44

The aims during the diagnosis are to exclude other causes of cardiomyopathy and to confirm left ventricular systolic dysfunction by echocardiography. Whether endomyocardial biopsy should be done in this setting is still controversial, and recent guidelines do not recommend it.45,46

Role of cardiac MRI

Magnetic resonance imaging (MRI) may be used as a complementary tool to diagnose peripartum cardiomyopathy, and it may prove to be important in identifying the mechanisms involved. It can measure global and segmental myocardial contraction, and it can characterize the myocardium.47

Furthermore, delayed contrast enhancement (with gadolinium) can help differentiate the type of myocyte necrosis, ie, myocarditis vs ischemia. Myocarditis has a nonvascular distribution in the subepicardium with a nodular or band-like pattern, whereas ischemia has a vascular distribution in a subendocardial or transmural location.48

Kawano et al49 described a patient with peripartum cardiomyopathy whose myocardial damage was demonstrated by delayed contrast enhancement of the left ventricle. This measure improved after she was treated with a beta-blocker, an angiotensin receptor blocker (ARB), and spironolactone (Aldactone), and her cardiac function recovered.

Leurent et al50 advocate using cardiac MRI to guide biopsy to the abnormal area, which may be much more useful than blind biopsy.

Questions remaining about MRI include the pathologic and prognostic implications of late gadolinium enhancement.

 

 

MANAGEMENT OF POSTPARTUM CARDIOMYOPATHY

Heart failure treatment during pregnancy

When considering tests or treatments in pregnancy, the welfare of the fetus is always considered along with that of the mother. Coordinated management with specialists (an obstetrician and maternal-fetal medicine team) is essential, with fetal heart monitoring.

Angiotensin-converting enzyme (ACE) inhibitors and ARBs are contraindicated in pregnancy because they can cause birth defects, although they are the main treatments for postpartum women with heart failure. The teratogenic effects occur particularly in the second and third trimester, with fetopathy characterized by fetal hypotension, oligohydramnios-anuria, and renal tubular dysplasia.51,52 However, a recent study suggested a risk of malformations even after firsttrimester exposure to ACE inhibitors.53

Digoxin, beta-blockers, loop diuretics, and drugs that reduce afterload such as hydralazine and nitrates have been proven to be safe and are the mainstays of medical therapy of heart failure during pregnancy.44 Beta-blockers have strong evidence of efficacy in patients with heart failure, but they have not been tested in peripartum cardiomyopathy. Nevertheless, beta-blockers have long been used in pregnant women with hypertension without any known adverse effects on the fetus, and patients taking these agents prior to diagnosis can continue to use them safely.46,54

Heart failure treatment postpartum

After delivery, the treatment is identical to that for nonpregnant women with dilated cardiomyopathy.

ACE inhibitors and ARBs. The target dose is one-half the maximum antihypertensive dose.

Diuretics are given for symptom relief.

Spironolactone or digoxin is used in patients who have New York Heart Association class III or IV symptoms. The goal with spironolactone is 25 mg/day after dosing of other drugs is maximized. The goal with digoxin is the lowest daily dose to obtain a detectable serum digoxin level, which should be kept at less than 1.0 ng/mL. In the Digitalis Investigation Group trial,55 serum digoxin levels of 0.5 to 0.8 ng/mL (0.6–1.0 nmol/L) were most beneficial, and levels of 1.1 to 1.5 ng/mL (1.4–1.9 nmol/L) were associated with an increase in deaths related to heart failure.

Beta-blockers are recommended for peripartum cardiomyopathy,44 as they improve symptoms, ejection fraction, and survival. Nonselective beta-blockers such as carvedilol (Coreg) and selective ones such as metoprolol succinate (Toprol XL) have shown benefit. The goal dosage is carvedilol 25 mg twice a day (50 mg twice a day for larger patients) or metoprolol succinate 100 mg once a day.

Anticoagulation treatment

During pregnancy, the risk of thromboembolic complications increases due to higher concentrations of coagulation factors II, VII, VIII, and X, and of plasma fibrinogen. The risk may persist up to 6 weeks postpartum.1 Cases of arterial, venous, and cardiac thrombosis have been reported in women with peripartum cardiomyopathy, and the risk may be related to the degree of chamber enlargement and systolic dysfunction and the presence of atrial fibrillation.56,57

Patients with evidence of systemic embolism, with severe left ventricular dysfunction or documented cardiac thrombosis, should receive anticoagulation.56–58 Anticoagulation should be continued until a return of normal left ventricular function is documented.

We await the results of the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial, which should determine which drug will best prevent death or stroke in patients with ejection fractions of less than 35%.

Warfarin can cause spontaneous fetal cerebral hemorrhage in the second and third trimesters and therefore is generally contraindicated during pregnancy.59,60 However, guidelines from the American College of Cardiology and the American Heart Association on the management of patients with heart valve disease say that “warfarin is probably safe during the first 6 weeks of gestation, but there is a risk of embryopathy if the warfarin is taken between 6 and 12 weeks of gestation.”61 The guidelines also say warfarin is “relatively safe” during the second and third trimesters but must be stopped and switched to a heparin several weeks before delivery. Unfractionated heparin or low-molecular-weight heparin can be used during pregnancy. However, should warfarin be needed for any reason, we believe a cesarian section should be performed to reduce the risk to the infant.

Cardiac transplantation

Patients with severe heart failure despite maximal drug therapy need cardiac transplantation to survive and to improve their quality of life. However, fewer than 3,000 hearts are available for transplantation worldwide per year. Therefore, ventricular assist devices are indicated as a bridge to transplantation.62

Patients with symptomatic ventricular arrhythmias should be considered for defibrillator implantation.63

New treatments

Pentoxifylline improved outcomes, left ventricular function, and symptoms when added to conventional therapy in a small prospective study.64

Intravenous immunoglobulin improved the ejection fraction in several studies65,66 and also markedly reduced the levels of inflammatory cytokines, namely thioredoxin.67

Immunosuppressive therapy does not yet have a fully proven role, but it could be considered in patients with proven myocarditis. Given the various etiologic mechanisms of peripartum cardiomyopathy, it is unlikely that immunosuppression will help all patients. Furthermore, without a large randomized trial, treatment successes may merely reflect the natural course of the disease.

Investigators have emphasized the need to rule out viral infection before starting immunosuppressive treatment, as the treatment may activate a latent virus, with subsequent deterioration in myocardial function.28,68

Bromocriptine (Parlodel). Peripartum cardiomyopathy develops in mice bred to have a cardiomyocyte-specific deletion of stat3, leading to enhanced expression and activity of cardiac cathepsin D and promoting the formation of a 16-kD proaptotic form of prolactin.29 Therefore, drugs that inhibit prolactin secretion may represent a novel therapy for peripartum cardiomyopathy. Based on this concept, two patients with peripartum cardiomyopathy were treated with bromocriptine, an inhibitor of prolactin secretion, and they showed a good recovery.69 We require large prospective randomized controlled studies to prove the beneficial effect of blocking prolactin in patients with peripartum cardiomyopathy.

Other proposed therapies are calcium channel antagonists,70 statins,71 monoclonal antibodies,72 interferon beta,73 immunoadsorption, 74 therapeutic apheresis,75 and cardiomyoplasty.76

How long to treat?

Patients with peripartum cardiomyopathy who recover normal left ventricular function at rest or with low-dose dobutamine (Dobutrex) can be allowed to taper and then discontinue heart failure treatment in 6 to 12 months.46

 

 

NATURAL COURSE

In a study of patients with various types of cardiomyopathy, those with peripartum cardiomyopathy had a substantially better prognosis, with a 94% survival rate at 5 years.7

Although various reports have shown that the clinical course of peripartum cardiomyopathy is usually related to the return of heart size to normal within 6 months, it is possible that left ventricular function may continue to recover beyond 6 months, and further studies are needed to determine the reasons for this.54

Elkayam et al36 reported that, of 100 patients with peripartum cardiomyopathy in the United States, at the end of 2 years, 9 had died and 4 had received a heart transplant. However, 54 had recovered normal left ventricular function, and recovery was more likely in those with an ejection fraction greater than 30% at diagnosis. The incidence of gestational hypertension was 43%, and the rate of twin pregnancy was 13%. The rate of cesarean delivery was 40%, compared with the national rate of 30.2%.

In contrast, in 98 patients in Haiti, the death rate was 15.3% during a mean follow-up of 2.2 years, and only about 28% had regained normal left ventricular function at 6 months.5

PROGNOSTIC FACTORS

Troponin T. Hu et al41 reported that the serum cardiac troponin T concentration measured 2 weeks after the onset of peripartum cardiomyopathy correlated inversely with the left ventricular ejection fraction at 6 months. However, the sensitivity was low: a troponin T concentration of more than 0.04 ng/mL predicted persistent left ventricular dysfunction with a sensitivity of only 55%. The specificity was 91%.

QRS duration of 120 ms or more has been identified as a predictor of death. Prolonged QRS duration has been shown to be an independent risk factor for death and sudden death in a large series of patients with ischemic and nonischemic cardiac failure.77

Heart dimensions and ejection fraction had prognostic value in several studies.

Factors predicting normalization of left ventricular function were an initial left ventricular end-systolic dimension of 5.5 cm or less78 and a left ventricular ejection fraction greater than 27%78 or 30%.36

In a retrospective study,79 a fractional shortening of 20% or more and a left ventricular end-diastolic dimension of 6 cm or more at the time of diagnosis increased the risk of persistent left ventricular dysfunction threefold. Other factors at initial assessment associated with lack of recovery were a left ventricular end-diastolic dimension greater than 5.6 cm, left ventricular thrombus, and African American race.6

RISK OF RELAPSE

Even after full recovery of left ventricular function, subsequent pregnancies carry a risk of relapse of peripartum cardiomyopathy. A study in Haiti followed 99 patients, 15 of whom became pregnant again. Eight of the women who became pregnant again experienced worsening heart failure and long-term systolic dysfunction.80

Of six South African women who had New York Heart Association class I symptoms who became pregnant again, two died within 8 weeks of delivery, and the other four continued to have heart failure symptoms.81

In the United States, Elkayam et al82 identified 44 women with peripartum cardiomyopathy who became pregnant again. Of these, 28 had recovered systolic function, with ejection fractions of 50% or higher before becoming pregnant again, and 16 had not. The ejection fraction fell in both groups during the subsequent pregnancy, but in the first group it fell by more than 20% in only 6 (21%), and none died. In contrast, in the second group it fell by more than 20% in 5 (31%), and 3 (19%) died.

Patients who recover normal left ventricular function and have normal left ventricular contractile reserve after dobutamine challenge may undertake another pregnancy safely, but they should be warned of the risk of recurrence even with fully recovered left ventricular function.46,82

Dorbala et al83 performed dobutamine stress echocardiography to measure maximal inotropic contractile reserve in six women presenting with peripartum cardiomyopathy, and it correlated accurately with subsequent recovery of left ventricular function.

Based on these data, our recommendations for further pregnancies are the following:

  • If left ventricular function has recovered fully, subsequent pregnancy is not contraindicated, but the patient should be told that, although the risk is low, it is not absent.
  • If left ventricular function has recovered partially, perform dobutamine stress echocardiography. If the left ventricular inotropic response to dobutamine is normal, then patients can be counseled as above; if the left ventricular inotropic response to dobutamine is abnormal, then the risk is moderate and pregnancy is not recommended.
  • If left ventricular function has not recovered at all, the risk is high, and subsequent pregnancy is not recommended.
References
  1. Lampert MB, Lang RM. Peripartum cardiomyopathy. Am Heart J 1995; 130:860–870.
  2. Demakis JG, Rahimtoola SH, Sutton GC, et al. Natural course of peripartum cardiomyopathy. Circulation 1971; 44:1053–1061.
  3. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29:270–276.
  4. Mielniczuk LM, Williams K, Davis DR, et al. Frequency of peripartum cardiomyopathy. Am J Cardiol 2006; 97:1765–1768.
  5. Fett JD, Christie LG, Carraway RD, Murphy JG. Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo Clin Proc 2005; 80:1602–1606.
  6. Amos AM, Jaber WA, Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 2006; 152:509–513.
  7. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342:1077–1084.
  8. Fett JD, Christie LG, Carraway RD, Ansari AA, Sundstrom JB, Murphy JG. Unrecognized peripartum cardiomyopathy in Haitian women. Int J Gynaecol Obstet 2005; 90:161–166.
  9. Pulerwitz TC, Cappola TP, Felker GM, Hare JM, Baughman KL, Kasper EK. Mortality in primary and secondary myocarditis. Am Heart J 2004; 147:746–750.
  10. Melvin KR, Richardson PJ, Olsen EG, Daly K, Jackson G. Peripartum cardiomyopathy due to myocarditis. N Engl J Med 1982; 307:731–734.
  11. Sanderson JE, Olsen EG, Gatei D. Peripartum heart disease: an endomyocardial biopsy study. Br Heart J 1986; 56:285–291.
  12. Midei MG, DeMent SH, Feldman AM, Hutchins GM, Baughman KL. Peripartum myocarditis and cardiomyopathy. Circulation 1990; 81:922–928.
  13. Rizeq MN, Rickenbacher PR, Fowler MB, Billingham ME. Incidence of myocarditis in peripartum cardiomyopathy. Am J Cardiol 1994; 74:474–477.
  14. Bultmann BD, Klingel K, Nabauer M, Wallwiener D, Kandolf R. High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol 2005; 193:363–365.
  15. Kühl U, Pauschinger M, Seeberg B, et al. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005; 112:1965–1970.
  16. Lyden DC, Huber SA. Aggravation of coxsackievirus, group B, type 3-induced myocarditis and increase in cellular immunity to myocyte antigens in pregnant Balb/c mice and animals treated with progesterone. Cell Immunol 1984; 87:462–472.
  17. Artlett CM, Smith JB, Jimenez SA. Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med 1998; 338:1186–1191.
  18. Nelson JL. Microchimerism: expanding new horizon in human health or incidental remnant of pregnancy? Lancet 2001; 358:2011–2012.
  19. Ansari AA, Fett JD, Carraway RE, Mayne AE, Onlamoon N, Sundstrom JB. Autoimmune mechanisms as the basis for human peripartum cardiomyopathy. Clin Rev Allergy Immunol 2002; 23:301–324.
  20. Warraich RS, Sliwa K, Damasceno A, et al. Impact of pregnancy-related heart failure on humoral immunity: clinical relevance of G3-subclass immunoglobulins in peripartum cardiomyopathy. Am Heart J 2005; 150:263–269.
  21. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996; 335:1182–1189.
  22. Hayakawa Y, Chandra M, Miao W, et al. Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation 2003; 108:3036–3041.
  23. Sliwa K, Forster O, Libhaber E, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. Eur Heart J 2006; 27:441–446.
  24. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996; 27:1201–1206.
  25. Mabie WC, DiSessa TG, Crocker LG, Sibai BM, Arheart KL. A longitudinal study of cardiac output in normal human pregnancy. Am J Obstet Gynecol 1994; 170:849–856.
  26. Julian DG, Szekely P. Peripartum cardiomyopathy. Prog Cardiovasc Dis 1985; 27:223–240.
  27. Mone SM, Sanders SP, Colan SD. Control mechanisms for physiological hypertrophy of pregnancy. Circulation 1996; 94:667–672.
  28. Zimmermann O, Kochs M, Zwaka TP, et al. Myocardial biopsy based classification and treatment in patients with dilated cardiomyopathy. Int J Cardiol 2005; 104:92–100.
  29. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007; 128:589–600.
  30. Coulson CC, Thorp JM, Mayer DC, Cefalo RC. Central hemodynamic effects of recombinant human relaxin in the isolated, perfused rat heart model. Obstet Gynecol 1996; 87:610–612.
  31. Fairweather D, Frisancho-Kiss S, Njoku DB, et al. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart. J Immunol 2006; 176:3516– 3524.
  32. Szalay G, Sauter M, Hald J, Weinzierl A, Kandolf R, Klingel K. Sustained nitric oxide synthesis contributes to immunopathology in ongoing myocarditis attributable to interleukin-10 disorders. Am J Pathol 2006; 169:2085–2093.
  33. Ellis JE, Ansari AA, Fett JD, et al. Inhibition of progenitor dendritic cell maturation by plasma from patients with peripartum cardiomyopathy: role in pregnancy-associated heart disease. Clin Dev Immunol 2005; 12:265–273.
  34. Xu HF, Li YH, Chen Y, Cheng LB. [The expression of dystrophin in human viral myocarditis and dilated cardiomyopathy]. Fa Yi Xue Za Zhi 2006; 22:12–14.
  35. Thomas JA, Haudek SB, Koroglu T, et al. IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. Am J Physiol Heart Circ Physiol 2003; 285:H597–H606.
  36. Elkayam U, Akhter MW, Singh H, et al. Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation. Circulation 2005; 111:2050–2055.
  37. Hibbard JU, Lindheimer M, Lang RM. A modified definition for peripartum cardiomyopathy and prognosis based on echocardiography. Obstet Gynecol 1999; 94:311–316.
  38. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990; 142:1009–1014.
  39. Cho S, Atwood JE. Peripheral edema. Am J Med 2002; 113:580–586.
  40. Brown MA, Mackenzie C, Dunsmuir W, et al. Can we predict recurrence of pre-eclampsia or gestational hypertension? BJOG 2007; 114:984–993.
  41. Hu CL, Li YB, Zou YG, et al. Troponin T measurement can predict persistent left ventricular dysfunction in peripartum cardiomyopathy. Heart 2007; 93:488–490.
  42. Desai D, Moodley J, Naidoo D. Peripartum cardiomyopathy: experiences at King Edward VIII Hospital, Durban, South Africa and a review of the literature. Trop Doct 1995; 25:118–123.
  43. Diao M, Diop IB, Kane A, et al. [Electrocardiographic recording of long duration (Holter) of 24 hours during idiopathic cardiomyopathy of the peripartum]. Arch Mal Coeur Vaiss 2004; 97:25–30.
  44. Pearson GD, Veille JC, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000; 283:1183–1188.
  45. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J 2007; 28:3076–3093.
  46. Baughman KL. Peripartum cardiomyopathy. Curr Treat Options Cardiovasc Med 2001; 3:469–480.
  47. Di Bella G, de Gregorio C, Minutoli F, et al. Early diagnosis of focal myocarditis by cardiac magnetic resonance. Int J Cardiol 2007; 117:280–281.
  48. Laissy JP, Hyafil F, Feldman LJ, et al. Differentiating acute myocardial infarction from myocarditis: diagnostic value of early- and delayed-perfusion cardiac MR imaging. Radiology 2005; 237:75–82.
  49. Kawano H, Tsuneto A, Koide Y, et al. Magnetic resonance imaging in a patient with peripartum cardiomyopathy. Intern Med 2008; 47:97–102.
  50. Leurent G, Baruteau AE, Larralde A, et al. Contribution of cardiac MRI in the comprehension of peripartum cardiomyopathy pathogenesis. Int J Cardiol 2009; 132:e91–e93. Epub 2008 Feb 6.
  51. Andrade SE, Raebel MA, Brown J, et al. Outpatient use of cardiovascular drugs during pregnancy. Pharmacoepidemiol Drug Saf 2008; 17:240–247.
  52. Ray JG, Vermeulen MJ, Koren G. Taking ACE inhibitors during early pregnancy: is it safe? Can Fam Physician 2007; 53:1439–1440.
  53. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354:2443–2451.
  54. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006; 368:687–693.
  55. Rathore SS, Curtis JP, Wang Y, Birstow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289:871–888.
  56. Shimamoto T, Marui A, Oda M, et al. A case of peripartum cardiomyopathy with recurrent left ventricular apical thrombus. Circ J 2008; 72:853–854.
  57. Nishi I, Ishimitsu T, Ishizu T, et al. Peripartum cardiomyopathy and biventricular thrombi. Circ J 2002; 66:863–865.
  58. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1. J Am Coll Cardiol 2000; 35:701–705.
  59. Clark NP, Delate T, Witt DM, Parker S, McDuffie R. A descriptive evaluation of unfractionated heparin use during pregnancy. J Thromb Thrombolysis 2008epub March 8.
  60. Narin C, Reyhanoglu H, Tulek B, et al. Comparison of different dose regimens of enoxaparin in deep vein thrombosis therapy in pregnancy. Adv Ther 2008; 25:585–594.
  61. Bonow RO, Carabello BA, Chatterjee K, et al; 2006 Writing Committee Members. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008; 118:e523–e661.
  62. Rose EA, Gelijns AC, Moskowitz AJ, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001; 345:1435–1443.
  63. Jessup M, Brozena S. Heart failure. N Engl J Med 2003; 348:2007–2018.
  64. Sliwa K, Skudicky D, Candy G, Bergemann A, Hopley M, Sareli P. The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy. Eur J Heart Fail 2002; 4:305–309.
  65. Bozkurt B, Villaneuva FS, Holubkov R, et al. Intravenous immune globulin in the therapy of peripartum cardiomyopathy. J Am Coll Cardiol 1999; 34:177–180.
  66. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001; 103:2254–2259.
  67. Kishimoto C, Shioji K, Kinoshita M, et al. Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress. Int J Cardiol 2003; 91:173–178.
  68. Fett JD. Inflammation and virus in dilated cardiomyopathy as indicated by endomyocardial biopsy. Int J Cardiol 2006; 112:125–126.
  69. Hilfiker-Kleiner D, Meyer GP, Schieffer E, et al. Recovery from postpartum cardiomyopathy in 2 patients by blocking prolactin release with bromocriptine. J Am Coll Cardiol 2007; 50:2354–2355.
  70. Yuan Z, Kishimoto C, Shioji K. Beneficial effects of low-dose benidipine in acute autoimmune myocarditis: suppressive effects on inflammatory cytokines and inducible nitric oxide synthase. Circ J 2003; 67:545–550.
  71. Li WM, Liu W, Gao C, Zhou BG. Immunoregulatory effects of atorvastatin on experimental autoimmune myocarditis in Lewis rats. Immunol Cell Biol 2006; 84:274–280.
  72. Yuan HT, Liao YH, Wang Z, et al. Prevention of myosin-induced autoimmune myocarditis in mice by anti-L3T4 monoclonal antibody. Can J Physiol Pharmacol 2003; 81:84–88.
  73. Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003; 107:2793–2798.
  74. Felix SB, Staudt A. Non-specific immunoadsorption in patients with dilated cardiomyopathy: mechanisms and clinical effects. Int J Cardiol 2006; 112:30–33.
  75. Bosch T. Therapeutic apheresis—state of the art in the year 2005. Ther Apher Dial 2005; 9:459–468.
  76. Liu Z, Yuan J, Yanagawa B, Qiu D, McManus BM, Yang D. Coxsackievirus-induced myocarditis: new trends in treatment. Expert Rev Anti Infect Ther 2005; 3:641–650.
  77. Yu CM, Abraham WT, Bax J, et al; PROSPECT Investigators. Predictors of response to cardiac resynchronization therapy (PROSPECT)—study design. Am Heart J 2005; 149:600–605.
  78. Duran N, Gunes H, Duran I, Biteker M, Ozkan M. Predictors of prognosis in patients with peripartum cardiomyopathy. Int J Gynaecol Obstet 2008; 101:137–140.
  79. Chapa JB, Heiberger HB, Weinert L, Decara J, Lang RM, Hibbard JU. Prognostic value of echocardiography in peripartum cardiomyopathy. Obstet Gynecol 2005; 105:1303–1308.
  80. Fett JD, Christie LG, Murphy JG. Brief communication: Outcomes of subsequent pregnancy after peripartum cardiomyopathy: a case series from Haiti. Ann Intern Med 2006; 145:30–34.
  81. Sliwa K, Forster O, Zhanje F, Candy G, Kachope J, Essop R. Outcome of subsequent pregnancy in patients with documented peripartum cardiomyopathy. Am J Cardiol 2004; 93:1441–1443,A10.
  82. Elkayam U, Tummala PP, Rao K, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy. N Engl J Med 2001; 344:1567–1571.
  83. Dorbala S, Brozena S, Zeb S, et al. Risk stratification of women with peripartum cardiomyopathy at initial presentation: a dobutamine stress echocardiography study. J Am Soc Echocardiogr 2005; 18:45–48.
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Address: Radhakrishnan Ramaraj, MD, Department of Internal Medicine, University of Arizona College of Medicine, 1501 North Campbell Avenue, Tucson, AZ 85724; E-mail [email protected]

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Address: Radhakrishnan Ramaraj, MD, Department of Internal Medicine, University of Arizona College of Medicine, 1501 North Campbell Avenue, Tucson, AZ 85724; E-mail [email protected]

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Vincent L. Sorrell, MD
Professor of Clinical Medicine, Pediatrics, and Radiology, The Allan C. Hudson and Helen Lovaas Endowed Chair of Cardiovascular Imaging, Section of Cardiology, University of Arizona Sarver Heart Center, Tucson, AZ

Address: Radhakrishnan Ramaraj, MD, Department of Internal Medicine, University of Arizona College of Medicine, 1501 North Campbell Avenue, Tucson, AZ 85724; E-mail [email protected]

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Related Articles
Enigmas of a mother’s heart

Heart failure during pregnancy was recognized as early as 1849, but it was first described as a distinctive form of cardiomyopathy only in the 1930s.1 In 1971, Demakis et al2 described 27 patients who presented during the puerperium with cardiomegaly, abnormal electrocardiographic findings, and congestive heart failure, and named the syndrome peripartum cardiomyopathy.

The European Society of Cardiology3 recently defined peripartum cardiomyopathy as a form of dilated cardiomyopathy that presents with signs of heart failure in the last month of pregnancy or within 5 months of delivery.

Peripartum cardiomyopathy is relatively rare but can be life-threatening. The National Hospital Discharge Survey (1990–2002) estimated that it occurs in 1 in every 2,289 live births in the United States.4 The disease appears to be more common in African American women.1 The rate varies in other populations: it is highest in Haiti, with 1 case in 300 live births, which is nearly 10 times higher than in the United States.5 The reason for such a variation remains unclear.

Although early reports suggested the death rate was nearly 50%, more recent reports show it to be 0 to 5% in the United States, and the higher numbers in the earlier reports likely represented publication bias.5,6–9

WHAT CAUSES IT?

Peripartum cardiomyopathy is generally considered a form of idiopathic primary myocardial disease associated with the pregnant state. Although several plausible etiologic mechanisms have been suggested, none of them is definite. Some are discussed below.

Myocarditis

Myocarditis has been found on endomyocardial biopsy of the right ventricle in patients with peripartum cardiomyopathy,10,11 with a dense lymphocytic infiltrate and variable amounts of myocyte edema, necrosis, and fibrosis. The prevalence of myocarditis in patients with peripartum cardiomyopathy ranged from 8.8% to 78% in different studies.12,13 On the other hand, the presence or absence of myocarditis alone does not predict the outcome of peripartum cardiomyopathy.7

Cardiotropic viral infections

After a viral infection, a pathologic immune response might occur that is inappropriately directed against native cardiac tissue proteins, leading to ventricular dysfunction.

Bultmann et al14 found parvovirus B19, human herpes virus 6, Epstein-Barr virus, or cytomegalovirus DNA in endomyocardial biopsy specimens from 8 (31%) of 26 patients with peripartum cardiomyopathy that was associated immunohistologically with interstitial inflammation.

Kühl et al15 found, in patients with viral infection confirmed by endomyocardial biopsy, that the median left ventricular ejection fraction improved in those in whom the virus was cleared (from 50.2% before to 58.1% afterward, P < .001), whereas it decreased in those in whom the virus persisted (from 54.3% before to 51.4% afterward, P < .01).

Lyden and Huber16 found that mice developed worse myocarditis if they were experimentally infected with coxsackievirus and echovirus during pregnancy than if they were infected while not pregnant.

Chimerism

In a phenomenon called chimerism, cells from the fetus take up residence in the mother (or vice versa), sometimes provoking an immune response.17,18

As reviewed by Ansari et al,19 the serum from patients with peripartum cardiomyopathy has been found to contain autoantibodies in high titers, which are not present in serum from patients with idiopathic cardiomyopathy. Most of these antibodies are against normal human cardiac tissue proteins of 37, 33, and 25 kD. The peripheral blood in these patients has a high level of fetal microchimerism in mononuclear cells, an abnormal cytokine profile, and low levels of CD4+ CD25lo regulatory T cells.

Warraich et al,20 in a study from South Africa, Mozambique, and Haiti, found that the frequencies and reactivities of immunoglobulins were similar in distribution in patients with peripartum cardiomyopathy, irrespective of the geographic location.

Apoptosis and inflammation

Apoptosis (programmed cell death) of cardiac myocytes occurs in heart failure and may contribute to progressive myocardial dysfunction. 21 Experiments in mice suggest that apoptosis of cardiac myocytes has a role in peripartum cardiomyopathy.22

Fas and Fas ligand are cell surface proteins that play a key role in apoptosis. Sliwa et al,23 in a single-center, prospective, longitudinal study from South Africa, followed 100 patients with peripartum cardiomyopathy for 6 months. During this time 15 patients died, and those who died had significantly higher plasma levels of Fas/Apo-1 (P < .05). In the same study, plasma levels of C-reactive protein and tumor necrosis factor alpha (markers of inflammation) were elevated and correlated with higher left ventricular dimensions and lower left ventricular ejection fractions at presentation.

In the Studies of Left Ventricular Dysfunction,24 circulating levels of tumor necrosis factor alpha and interleukin 6 increased in patients as their functional heart failure classification deteriorated.

An abnormal hemodynamic response

During pregnancy, blood volume and cardiac output increase. In addition, afterload decreases because of relaxation of vascular smooth muscle. The increases in volume and cardiac output during pregnancy cause transient and reversible hypertrophy of the left ventricle to meet the needs of the mother and fetus. Cardiac output reaches its maximum at around 20 weeks of pregnancy.25

The transient left ventricular systolic dysfunction during the third trimester and early postpartum period returns to baseline once the cardiac output decreases.26,27

Other possible factors

Other possible etiologic factors include prolactin,28,29 relaxin,30 immune complexes,31 cardiac nitric oxide synthase,32 immature dendritic cells,33 cardiac dystrophin,34 and toll-like receptors.35

 

 

WHO IS AT RISK?

Demakis and colleagues2 suggest the following risk factors for peripartum cardiomyopathy:

  • Multiparity
  • Advanced maternal age (although the disease can occur at any age, the incidence is higher in women over age 3036)
  • Multifetal pregnancy
  • Preeclampsia
  • Gestational hypertension
  • African American race.

CLINICAL FEATURES

Peripartum cardiomyopathy involves left ventricular systolic dysfunction in women with no history of heart disease. It can be diagnosed only if other causes of cardiomyopathy are absent.2

Diagnostic criteria for peripartum cardiomyopathy (all must be present) are37:

  • Cardiac failure developing in the last month of pregnancy or within 5 months of delivery
  • No identifiable cause of the cardiac failure
  • No recognizable heart disease before the last month of pregnancy
  • An ejection fraction of less than 45%, or the combination of an M-mode fractional shortening of less than 30% and an end-diastolic dimension greater than 2.7 cm/m2.

Symptoms of heart failure such as dyspnea, dizziness, pedal edema, and orthopnea can occur even in normal pregnancies. Therefore, a pregnant woman in whom peripartum cardiomyopathy is developing may consider her symptoms to be normal. The dyspnea during normal pregnancy is thought to be due to hyperventilation caused by the effects of progesterone, and also due to pressure on the diaphragm from the growing uterus.38 Peripheral edema occurs in approximately two-thirds of healthy pregnant women.39 Nevertheless, if swelling and other heart failure symptoms develop suddenly in an otherwise normal pregnancy, this should prompt further investigation.40

Pulmonary edema was a presenting symptom in all 106 patients in a 2007 study in China. 41 The clinical presentation was similar to that of congestive heart failure but was highly variable; 17% of cases were diagnosed antepartum and 83% postpartum. The mean age at diagnosis was 28 ± 6 years. Left ventricular function almost completely normalized in 51% of surviving patients. These findings were similar to those in earlier studies.2,36 Interestingly, the left ventricular ejection fraction normalized only in 23% of an African cohort.23

Thromboembolism can be a presentation of peripartum cardiomyopathy. Hemoptysis and pleuritic chest pain may be presenting symptoms of pulmonary embolism.42

Cardiac arrhythmias and sudden cardiac arrest have also been reported.43

A latent form of peripartum cardiomyopathy without significant clinical signs and symptoms has been reported.8

Preeclampsia should be excluded on the basis of history and physical examination, as its management is different. Preeclampsia occurs after 20 weeks of gestation and is characterized by high blood pressure, protein in the urine, swelling, sudden weight gain, headaches, and changes in vision.

Delayed diagnosis may be associated with higher rates of illness and death; therefore, physicians should consider peripartum cardiomyopathy in any peripartum patient with unexplained symptoms. Although the symptoms of heart failure can be difficult to differentiate from those of late pregnancy, a heightened suspicion can help.44

The aims during the diagnosis are to exclude other causes of cardiomyopathy and to confirm left ventricular systolic dysfunction by echocardiography. Whether endomyocardial biopsy should be done in this setting is still controversial, and recent guidelines do not recommend it.45,46

Role of cardiac MRI

Magnetic resonance imaging (MRI) may be used as a complementary tool to diagnose peripartum cardiomyopathy, and it may prove to be important in identifying the mechanisms involved. It can measure global and segmental myocardial contraction, and it can characterize the myocardium.47

Furthermore, delayed contrast enhancement (with gadolinium) can help differentiate the type of myocyte necrosis, ie, myocarditis vs ischemia. Myocarditis has a nonvascular distribution in the subepicardium with a nodular or band-like pattern, whereas ischemia has a vascular distribution in a subendocardial or transmural location.48

Kawano et al49 described a patient with peripartum cardiomyopathy whose myocardial damage was demonstrated by delayed contrast enhancement of the left ventricle. This measure improved after she was treated with a beta-blocker, an angiotensin receptor blocker (ARB), and spironolactone (Aldactone), and her cardiac function recovered.

Leurent et al50 advocate using cardiac MRI to guide biopsy to the abnormal area, which may be much more useful than blind biopsy.

Questions remaining about MRI include the pathologic and prognostic implications of late gadolinium enhancement.

 

 

MANAGEMENT OF POSTPARTUM CARDIOMYOPATHY

Heart failure treatment during pregnancy

When considering tests or treatments in pregnancy, the welfare of the fetus is always considered along with that of the mother. Coordinated management with specialists (an obstetrician and maternal-fetal medicine team) is essential, with fetal heart monitoring.

Angiotensin-converting enzyme (ACE) inhibitors and ARBs are contraindicated in pregnancy because they can cause birth defects, although they are the main treatments for postpartum women with heart failure. The teratogenic effects occur particularly in the second and third trimester, with fetopathy characterized by fetal hypotension, oligohydramnios-anuria, and renal tubular dysplasia.51,52 However, a recent study suggested a risk of malformations even after firsttrimester exposure to ACE inhibitors.53

Digoxin, beta-blockers, loop diuretics, and drugs that reduce afterload such as hydralazine and nitrates have been proven to be safe and are the mainstays of medical therapy of heart failure during pregnancy.44 Beta-blockers have strong evidence of efficacy in patients with heart failure, but they have not been tested in peripartum cardiomyopathy. Nevertheless, beta-blockers have long been used in pregnant women with hypertension without any known adverse effects on the fetus, and patients taking these agents prior to diagnosis can continue to use them safely.46,54

Heart failure treatment postpartum

After delivery, the treatment is identical to that for nonpregnant women with dilated cardiomyopathy.

ACE inhibitors and ARBs. The target dose is one-half the maximum antihypertensive dose.

Diuretics are given for symptom relief.

Spironolactone or digoxin is used in patients who have New York Heart Association class III or IV symptoms. The goal with spironolactone is 25 mg/day after dosing of other drugs is maximized. The goal with digoxin is the lowest daily dose to obtain a detectable serum digoxin level, which should be kept at less than 1.0 ng/mL. In the Digitalis Investigation Group trial,55 serum digoxin levels of 0.5 to 0.8 ng/mL (0.6–1.0 nmol/L) were most beneficial, and levels of 1.1 to 1.5 ng/mL (1.4–1.9 nmol/L) were associated with an increase in deaths related to heart failure.

Beta-blockers are recommended for peripartum cardiomyopathy,44 as they improve symptoms, ejection fraction, and survival. Nonselective beta-blockers such as carvedilol (Coreg) and selective ones such as metoprolol succinate (Toprol XL) have shown benefit. The goal dosage is carvedilol 25 mg twice a day (50 mg twice a day for larger patients) or metoprolol succinate 100 mg once a day.

Anticoagulation treatment

During pregnancy, the risk of thromboembolic complications increases due to higher concentrations of coagulation factors II, VII, VIII, and X, and of plasma fibrinogen. The risk may persist up to 6 weeks postpartum.1 Cases of arterial, venous, and cardiac thrombosis have been reported in women with peripartum cardiomyopathy, and the risk may be related to the degree of chamber enlargement and systolic dysfunction and the presence of atrial fibrillation.56,57

Patients with evidence of systemic embolism, with severe left ventricular dysfunction or documented cardiac thrombosis, should receive anticoagulation.56–58 Anticoagulation should be continued until a return of normal left ventricular function is documented.

We await the results of the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial, which should determine which drug will best prevent death or stroke in patients with ejection fractions of less than 35%.

Warfarin can cause spontaneous fetal cerebral hemorrhage in the second and third trimesters and therefore is generally contraindicated during pregnancy.59,60 However, guidelines from the American College of Cardiology and the American Heart Association on the management of patients with heart valve disease say that “warfarin is probably safe during the first 6 weeks of gestation, but there is a risk of embryopathy if the warfarin is taken between 6 and 12 weeks of gestation.”61 The guidelines also say warfarin is “relatively safe” during the second and third trimesters but must be stopped and switched to a heparin several weeks before delivery. Unfractionated heparin or low-molecular-weight heparin can be used during pregnancy. However, should warfarin be needed for any reason, we believe a cesarian section should be performed to reduce the risk to the infant.

Cardiac transplantation

Patients with severe heart failure despite maximal drug therapy need cardiac transplantation to survive and to improve their quality of life. However, fewer than 3,000 hearts are available for transplantation worldwide per year. Therefore, ventricular assist devices are indicated as a bridge to transplantation.62

Patients with symptomatic ventricular arrhythmias should be considered for defibrillator implantation.63

New treatments

Pentoxifylline improved outcomes, left ventricular function, and symptoms when added to conventional therapy in a small prospective study.64

Intravenous immunoglobulin improved the ejection fraction in several studies65,66 and also markedly reduced the levels of inflammatory cytokines, namely thioredoxin.67

Immunosuppressive therapy does not yet have a fully proven role, but it could be considered in patients with proven myocarditis. Given the various etiologic mechanisms of peripartum cardiomyopathy, it is unlikely that immunosuppression will help all patients. Furthermore, without a large randomized trial, treatment successes may merely reflect the natural course of the disease.

Investigators have emphasized the need to rule out viral infection before starting immunosuppressive treatment, as the treatment may activate a latent virus, with subsequent deterioration in myocardial function.28,68

Bromocriptine (Parlodel). Peripartum cardiomyopathy develops in mice bred to have a cardiomyocyte-specific deletion of stat3, leading to enhanced expression and activity of cardiac cathepsin D and promoting the formation of a 16-kD proaptotic form of prolactin.29 Therefore, drugs that inhibit prolactin secretion may represent a novel therapy for peripartum cardiomyopathy. Based on this concept, two patients with peripartum cardiomyopathy were treated with bromocriptine, an inhibitor of prolactin secretion, and they showed a good recovery.69 We require large prospective randomized controlled studies to prove the beneficial effect of blocking prolactin in patients with peripartum cardiomyopathy.

Other proposed therapies are calcium channel antagonists,70 statins,71 monoclonal antibodies,72 interferon beta,73 immunoadsorption, 74 therapeutic apheresis,75 and cardiomyoplasty.76

How long to treat?

Patients with peripartum cardiomyopathy who recover normal left ventricular function at rest or with low-dose dobutamine (Dobutrex) can be allowed to taper and then discontinue heart failure treatment in 6 to 12 months.46

 

 

NATURAL COURSE

In a study of patients with various types of cardiomyopathy, those with peripartum cardiomyopathy had a substantially better prognosis, with a 94% survival rate at 5 years.7

Although various reports have shown that the clinical course of peripartum cardiomyopathy is usually related to the return of heart size to normal within 6 months, it is possible that left ventricular function may continue to recover beyond 6 months, and further studies are needed to determine the reasons for this.54

Elkayam et al36 reported that, of 100 patients with peripartum cardiomyopathy in the United States, at the end of 2 years, 9 had died and 4 had received a heart transplant. However, 54 had recovered normal left ventricular function, and recovery was more likely in those with an ejection fraction greater than 30% at diagnosis. The incidence of gestational hypertension was 43%, and the rate of twin pregnancy was 13%. The rate of cesarean delivery was 40%, compared with the national rate of 30.2%.

In contrast, in 98 patients in Haiti, the death rate was 15.3% during a mean follow-up of 2.2 years, and only about 28% had regained normal left ventricular function at 6 months.5

PROGNOSTIC FACTORS

Troponin T. Hu et al41 reported that the serum cardiac troponin T concentration measured 2 weeks after the onset of peripartum cardiomyopathy correlated inversely with the left ventricular ejection fraction at 6 months. However, the sensitivity was low: a troponin T concentration of more than 0.04 ng/mL predicted persistent left ventricular dysfunction with a sensitivity of only 55%. The specificity was 91%.

QRS duration of 120 ms or more has been identified as a predictor of death. Prolonged QRS duration has been shown to be an independent risk factor for death and sudden death in a large series of patients with ischemic and nonischemic cardiac failure.77

Heart dimensions and ejection fraction had prognostic value in several studies.

Factors predicting normalization of left ventricular function were an initial left ventricular end-systolic dimension of 5.5 cm or less78 and a left ventricular ejection fraction greater than 27%78 or 30%.36

In a retrospective study,79 a fractional shortening of 20% or more and a left ventricular end-diastolic dimension of 6 cm or more at the time of diagnosis increased the risk of persistent left ventricular dysfunction threefold. Other factors at initial assessment associated with lack of recovery were a left ventricular end-diastolic dimension greater than 5.6 cm, left ventricular thrombus, and African American race.6

RISK OF RELAPSE

Even after full recovery of left ventricular function, subsequent pregnancies carry a risk of relapse of peripartum cardiomyopathy. A study in Haiti followed 99 patients, 15 of whom became pregnant again. Eight of the women who became pregnant again experienced worsening heart failure and long-term systolic dysfunction.80

Of six South African women who had New York Heart Association class I symptoms who became pregnant again, two died within 8 weeks of delivery, and the other four continued to have heart failure symptoms.81

In the United States, Elkayam et al82 identified 44 women with peripartum cardiomyopathy who became pregnant again. Of these, 28 had recovered systolic function, with ejection fractions of 50% or higher before becoming pregnant again, and 16 had not. The ejection fraction fell in both groups during the subsequent pregnancy, but in the first group it fell by more than 20% in only 6 (21%), and none died. In contrast, in the second group it fell by more than 20% in 5 (31%), and 3 (19%) died.

Patients who recover normal left ventricular function and have normal left ventricular contractile reserve after dobutamine challenge may undertake another pregnancy safely, but they should be warned of the risk of recurrence even with fully recovered left ventricular function.46,82

Dorbala et al83 performed dobutamine stress echocardiography to measure maximal inotropic contractile reserve in six women presenting with peripartum cardiomyopathy, and it correlated accurately with subsequent recovery of left ventricular function.

Based on these data, our recommendations for further pregnancies are the following:

  • If left ventricular function has recovered fully, subsequent pregnancy is not contraindicated, but the patient should be told that, although the risk is low, it is not absent.
  • If left ventricular function has recovered partially, perform dobutamine stress echocardiography. If the left ventricular inotropic response to dobutamine is normal, then patients can be counseled as above; if the left ventricular inotropic response to dobutamine is abnormal, then the risk is moderate and pregnancy is not recommended.
  • If left ventricular function has not recovered at all, the risk is high, and subsequent pregnancy is not recommended.

Heart failure during pregnancy was recognized as early as 1849, but it was first described as a distinctive form of cardiomyopathy only in the 1930s.1 In 1971, Demakis et al2 described 27 patients who presented during the puerperium with cardiomegaly, abnormal electrocardiographic findings, and congestive heart failure, and named the syndrome peripartum cardiomyopathy.

The European Society of Cardiology3 recently defined peripartum cardiomyopathy as a form of dilated cardiomyopathy that presents with signs of heart failure in the last month of pregnancy or within 5 months of delivery.

Peripartum cardiomyopathy is relatively rare but can be life-threatening. The National Hospital Discharge Survey (1990–2002) estimated that it occurs in 1 in every 2,289 live births in the United States.4 The disease appears to be more common in African American women.1 The rate varies in other populations: it is highest in Haiti, with 1 case in 300 live births, which is nearly 10 times higher than in the United States.5 The reason for such a variation remains unclear.

Although early reports suggested the death rate was nearly 50%, more recent reports show it to be 0 to 5% in the United States, and the higher numbers in the earlier reports likely represented publication bias.5,6–9

WHAT CAUSES IT?

Peripartum cardiomyopathy is generally considered a form of idiopathic primary myocardial disease associated with the pregnant state. Although several plausible etiologic mechanisms have been suggested, none of them is definite. Some are discussed below.

Myocarditis

Myocarditis has been found on endomyocardial biopsy of the right ventricle in patients with peripartum cardiomyopathy,10,11 with a dense lymphocytic infiltrate and variable amounts of myocyte edema, necrosis, and fibrosis. The prevalence of myocarditis in patients with peripartum cardiomyopathy ranged from 8.8% to 78% in different studies.12,13 On the other hand, the presence or absence of myocarditis alone does not predict the outcome of peripartum cardiomyopathy.7

Cardiotropic viral infections

After a viral infection, a pathologic immune response might occur that is inappropriately directed against native cardiac tissue proteins, leading to ventricular dysfunction.

Bultmann et al14 found parvovirus B19, human herpes virus 6, Epstein-Barr virus, or cytomegalovirus DNA in endomyocardial biopsy specimens from 8 (31%) of 26 patients with peripartum cardiomyopathy that was associated immunohistologically with interstitial inflammation.

Kühl et al15 found, in patients with viral infection confirmed by endomyocardial biopsy, that the median left ventricular ejection fraction improved in those in whom the virus was cleared (from 50.2% before to 58.1% afterward, P < .001), whereas it decreased in those in whom the virus persisted (from 54.3% before to 51.4% afterward, P < .01).

Lyden and Huber16 found that mice developed worse myocarditis if they were experimentally infected with coxsackievirus and echovirus during pregnancy than if they were infected while not pregnant.

Chimerism

In a phenomenon called chimerism, cells from the fetus take up residence in the mother (or vice versa), sometimes provoking an immune response.17,18

As reviewed by Ansari et al,19 the serum from patients with peripartum cardiomyopathy has been found to contain autoantibodies in high titers, which are not present in serum from patients with idiopathic cardiomyopathy. Most of these antibodies are against normal human cardiac tissue proteins of 37, 33, and 25 kD. The peripheral blood in these patients has a high level of fetal microchimerism in mononuclear cells, an abnormal cytokine profile, and low levels of CD4+ CD25lo regulatory T cells.

Warraich et al,20 in a study from South Africa, Mozambique, and Haiti, found that the frequencies and reactivities of immunoglobulins were similar in distribution in patients with peripartum cardiomyopathy, irrespective of the geographic location.

Apoptosis and inflammation

Apoptosis (programmed cell death) of cardiac myocytes occurs in heart failure and may contribute to progressive myocardial dysfunction. 21 Experiments in mice suggest that apoptosis of cardiac myocytes has a role in peripartum cardiomyopathy.22

Fas and Fas ligand are cell surface proteins that play a key role in apoptosis. Sliwa et al,23 in a single-center, prospective, longitudinal study from South Africa, followed 100 patients with peripartum cardiomyopathy for 6 months. During this time 15 patients died, and those who died had significantly higher plasma levels of Fas/Apo-1 (P < .05). In the same study, plasma levels of C-reactive protein and tumor necrosis factor alpha (markers of inflammation) were elevated and correlated with higher left ventricular dimensions and lower left ventricular ejection fractions at presentation.

In the Studies of Left Ventricular Dysfunction,24 circulating levels of tumor necrosis factor alpha and interleukin 6 increased in patients as their functional heart failure classification deteriorated.

An abnormal hemodynamic response

During pregnancy, blood volume and cardiac output increase. In addition, afterload decreases because of relaxation of vascular smooth muscle. The increases in volume and cardiac output during pregnancy cause transient and reversible hypertrophy of the left ventricle to meet the needs of the mother and fetus. Cardiac output reaches its maximum at around 20 weeks of pregnancy.25

The transient left ventricular systolic dysfunction during the third trimester and early postpartum period returns to baseline once the cardiac output decreases.26,27

Other possible factors

Other possible etiologic factors include prolactin,28,29 relaxin,30 immune complexes,31 cardiac nitric oxide synthase,32 immature dendritic cells,33 cardiac dystrophin,34 and toll-like receptors.35

 

 

WHO IS AT RISK?

Demakis and colleagues2 suggest the following risk factors for peripartum cardiomyopathy:

  • Multiparity
  • Advanced maternal age (although the disease can occur at any age, the incidence is higher in women over age 3036)
  • Multifetal pregnancy
  • Preeclampsia
  • Gestational hypertension
  • African American race.

CLINICAL FEATURES

Peripartum cardiomyopathy involves left ventricular systolic dysfunction in women with no history of heart disease. It can be diagnosed only if other causes of cardiomyopathy are absent.2

Diagnostic criteria for peripartum cardiomyopathy (all must be present) are37:

  • Cardiac failure developing in the last month of pregnancy or within 5 months of delivery
  • No identifiable cause of the cardiac failure
  • No recognizable heart disease before the last month of pregnancy
  • An ejection fraction of less than 45%, or the combination of an M-mode fractional shortening of less than 30% and an end-diastolic dimension greater than 2.7 cm/m2.

Symptoms of heart failure such as dyspnea, dizziness, pedal edema, and orthopnea can occur even in normal pregnancies. Therefore, a pregnant woman in whom peripartum cardiomyopathy is developing may consider her symptoms to be normal. The dyspnea during normal pregnancy is thought to be due to hyperventilation caused by the effects of progesterone, and also due to pressure on the diaphragm from the growing uterus.38 Peripheral edema occurs in approximately two-thirds of healthy pregnant women.39 Nevertheless, if swelling and other heart failure symptoms develop suddenly in an otherwise normal pregnancy, this should prompt further investigation.40

Pulmonary edema was a presenting symptom in all 106 patients in a 2007 study in China. 41 The clinical presentation was similar to that of congestive heart failure but was highly variable; 17% of cases were diagnosed antepartum and 83% postpartum. The mean age at diagnosis was 28 ± 6 years. Left ventricular function almost completely normalized in 51% of surviving patients. These findings were similar to those in earlier studies.2,36 Interestingly, the left ventricular ejection fraction normalized only in 23% of an African cohort.23

Thromboembolism can be a presentation of peripartum cardiomyopathy. Hemoptysis and pleuritic chest pain may be presenting symptoms of pulmonary embolism.42

Cardiac arrhythmias and sudden cardiac arrest have also been reported.43

A latent form of peripartum cardiomyopathy without significant clinical signs and symptoms has been reported.8

Preeclampsia should be excluded on the basis of history and physical examination, as its management is different. Preeclampsia occurs after 20 weeks of gestation and is characterized by high blood pressure, protein in the urine, swelling, sudden weight gain, headaches, and changes in vision.

Delayed diagnosis may be associated with higher rates of illness and death; therefore, physicians should consider peripartum cardiomyopathy in any peripartum patient with unexplained symptoms. Although the symptoms of heart failure can be difficult to differentiate from those of late pregnancy, a heightened suspicion can help.44

The aims during the diagnosis are to exclude other causes of cardiomyopathy and to confirm left ventricular systolic dysfunction by echocardiography. Whether endomyocardial biopsy should be done in this setting is still controversial, and recent guidelines do not recommend it.45,46

Role of cardiac MRI

Magnetic resonance imaging (MRI) may be used as a complementary tool to diagnose peripartum cardiomyopathy, and it may prove to be important in identifying the mechanisms involved. It can measure global and segmental myocardial contraction, and it can characterize the myocardium.47

Furthermore, delayed contrast enhancement (with gadolinium) can help differentiate the type of myocyte necrosis, ie, myocarditis vs ischemia. Myocarditis has a nonvascular distribution in the subepicardium with a nodular or band-like pattern, whereas ischemia has a vascular distribution in a subendocardial or transmural location.48

Kawano et al49 described a patient with peripartum cardiomyopathy whose myocardial damage was demonstrated by delayed contrast enhancement of the left ventricle. This measure improved after she was treated with a beta-blocker, an angiotensin receptor blocker (ARB), and spironolactone (Aldactone), and her cardiac function recovered.

Leurent et al50 advocate using cardiac MRI to guide biopsy to the abnormal area, which may be much more useful than blind biopsy.

Questions remaining about MRI include the pathologic and prognostic implications of late gadolinium enhancement.

 

 

MANAGEMENT OF POSTPARTUM CARDIOMYOPATHY

Heart failure treatment during pregnancy

When considering tests or treatments in pregnancy, the welfare of the fetus is always considered along with that of the mother. Coordinated management with specialists (an obstetrician and maternal-fetal medicine team) is essential, with fetal heart monitoring.

Angiotensin-converting enzyme (ACE) inhibitors and ARBs are contraindicated in pregnancy because they can cause birth defects, although they are the main treatments for postpartum women with heart failure. The teratogenic effects occur particularly in the second and third trimester, with fetopathy characterized by fetal hypotension, oligohydramnios-anuria, and renal tubular dysplasia.51,52 However, a recent study suggested a risk of malformations even after firsttrimester exposure to ACE inhibitors.53

Digoxin, beta-blockers, loop diuretics, and drugs that reduce afterload such as hydralazine and nitrates have been proven to be safe and are the mainstays of medical therapy of heart failure during pregnancy.44 Beta-blockers have strong evidence of efficacy in patients with heart failure, but they have not been tested in peripartum cardiomyopathy. Nevertheless, beta-blockers have long been used in pregnant women with hypertension without any known adverse effects on the fetus, and patients taking these agents prior to diagnosis can continue to use them safely.46,54

Heart failure treatment postpartum

After delivery, the treatment is identical to that for nonpregnant women with dilated cardiomyopathy.

ACE inhibitors and ARBs. The target dose is one-half the maximum antihypertensive dose.

Diuretics are given for symptom relief.

Spironolactone or digoxin is used in patients who have New York Heart Association class III or IV symptoms. The goal with spironolactone is 25 mg/day after dosing of other drugs is maximized. The goal with digoxin is the lowest daily dose to obtain a detectable serum digoxin level, which should be kept at less than 1.0 ng/mL. In the Digitalis Investigation Group trial,55 serum digoxin levels of 0.5 to 0.8 ng/mL (0.6–1.0 nmol/L) were most beneficial, and levels of 1.1 to 1.5 ng/mL (1.4–1.9 nmol/L) were associated with an increase in deaths related to heart failure.

Beta-blockers are recommended for peripartum cardiomyopathy,44 as they improve symptoms, ejection fraction, and survival. Nonselective beta-blockers such as carvedilol (Coreg) and selective ones such as metoprolol succinate (Toprol XL) have shown benefit. The goal dosage is carvedilol 25 mg twice a day (50 mg twice a day for larger patients) or metoprolol succinate 100 mg once a day.

Anticoagulation treatment

During pregnancy, the risk of thromboembolic complications increases due to higher concentrations of coagulation factors II, VII, VIII, and X, and of plasma fibrinogen. The risk may persist up to 6 weeks postpartum.1 Cases of arterial, venous, and cardiac thrombosis have been reported in women with peripartum cardiomyopathy, and the risk may be related to the degree of chamber enlargement and systolic dysfunction and the presence of atrial fibrillation.56,57

Patients with evidence of systemic embolism, with severe left ventricular dysfunction or documented cardiac thrombosis, should receive anticoagulation.56–58 Anticoagulation should be continued until a return of normal left ventricular function is documented.

We await the results of the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial, which should determine which drug will best prevent death or stroke in patients with ejection fractions of less than 35%.

Warfarin can cause spontaneous fetal cerebral hemorrhage in the second and third trimesters and therefore is generally contraindicated during pregnancy.59,60 However, guidelines from the American College of Cardiology and the American Heart Association on the management of patients with heart valve disease say that “warfarin is probably safe during the first 6 weeks of gestation, but there is a risk of embryopathy if the warfarin is taken between 6 and 12 weeks of gestation.”61 The guidelines also say warfarin is “relatively safe” during the second and third trimesters but must be stopped and switched to a heparin several weeks before delivery. Unfractionated heparin or low-molecular-weight heparin can be used during pregnancy. However, should warfarin be needed for any reason, we believe a cesarian section should be performed to reduce the risk to the infant.

Cardiac transplantation

Patients with severe heart failure despite maximal drug therapy need cardiac transplantation to survive and to improve their quality of life. However, fewer than 3,000 hearts are available for transplantation worldwide per year. Therefore, ventricular assist devices are indicated as a bridge to transplantation.62

Patients with symptomatic ventricular arrhythmias should be considered for defibrillator implantation.63

New treatments

Pentoxifylline improved outcomes, left ventricular function, and symptoms when added to conventional therapy in a small prospective study.64

Intravenous immunoglobulin improved the ejection fraction in several studies65,66 and also markedly reduced the levels of inflammatory cytokines, namely thioredoxin.67

Immunosuppressive therapy does not yet have a fully proven role, but it could be considered in patients with proven myocarditis. Given the various etiologic mechanisms of peripartum cardiomyopathy, it is unlikely that immunosuppression will help all patients. Furthermore, without a large randomized trial, treatment successes may merely reflect the natural course of the disease.

Investigators have emphasized the need to rule out viral infection before starting immunosuppressive treatment, as the treatment may activate a latent virus, with subsequent deterioration in myocardial function.28,68

Bromocriptine (Parlodel). Peripartum cardiomyopathy develops in mice bred to have a cardiomyocyte-specific deletion of stat3, leading to enhanced expression and activity of cardiac cathepsin D and promoting the formation of a 16-kD proaptotic form of prolactin.29 Therefore, drugs that inhibit prolactin secretion may represent a novel therapy for peripartum cardiomyopathy. Based on this concept, two patients with peripartum cardiomyopathy were treated with bromocriptine, an inhibitor of prolactin secretion, and they showed a good recovery.69 We require large prospective randomized controlled studies to prove the beneficial effect of blocking prolactin in patients with peripartum cardiomyopathy.

Other proposed therapies are calcium channel antagonists,70 statins,71 monoclonal antibodies,72 interferon beta,73 immunoadsorption, 74 therapeutic apheresis,75 and cardiomyoplasty.76

How long to treat?

Patients with peripartum cardiomyopathy who recover normal left ventricular function at rest or with low-dose dobutamine (Dobutrex) can be allowed to taper and then discontinue heart failure treatment in 6 to 12 months.46

 

 

NATURAL COURSE

In a study of patients with various types of cardiomyopathy, those with peripartum cardiomyopathy had a substantially better prognosis, with a 94% survival rate at 5 years.7

Although various reports have shown that the clinical course of peripartum cardiomyopathy is usually related to the return of heart size to normal within 6 months, it is possible that left ventricular function may continue to recover beyond 6 months, and further studies are needed to determine the reasons for this.54

Elkayam et al36 reported that, of 100 patients with peripartum cardiomyopathy in the United States, at the end of 2 years, 9 had died and 4 had received a heart transplant. However, 54 had recovered normal left ventricular function, and recovery was more likely in those with an ejection fraction greater than 30% at diagnosis. The incidence of gestational hypertension was 43%, and the rate of twin pregnancy was 13%. The rate of cesarean delivery was 40%, compared with the national rate of 30.2%.

In contrast, in 98 patients in Haiti, the death rate was 15.3% during a mean follow-up of 2.2 years, and only about 28% had regained normal left ventricular function at 6 months.5

PROGNOSTIC FACTORS

Troponin T. Hu et al41 reported that the serum cardiac troponin T concentration measured 2 weeks after the onset of peripartum cardiomyopathy correlated inversely with the left ventricular ejection fraction at 6 months. However, the sensitivity was low: a troponin T concentration of more than 0.04 ng/mL predicted persistent left ventricular dysfunction with a sensitivity of only 55%. The specificity was 91%.

QRS duration of 120 ms or more has been identified as a predictor of death. Prolonged QRS duration has been shown to be an independent risk factor for death and sudden death in a large series of patients with ischemic and nonischemic cardiac failure.77

Heart dimensions and ejection fraction had prognostic value in several studies.

Factors predicting normalization of left ventricular function were an initial left ventricular end-systolic dimension of 5.5 cm or less78 and a left ventricular ejection fraction greater than 27%78 or 30%.36

In a retrospective study,79 a fractional shortening of 20% or more and a left ventricular end-diastolic dimension of 6 cm or more at the time of diagnosis increased the risk of persistent left ventricular dysfunction threefold. Other factors at initial assessment associated with lack of recovery were a left ventricular end-diastolic dimension greater than 5.6 cm, left ventricular thrombus, and African American race.6

RISK OF RELAPSE

Even after full recovery of left ventricular function, subsequent pregnancies carry a risk of relapse of peripartum cardiomyopathy. A study in Haiti followed 99 patients, 15 of whom became pregnant again. Eight of the women who became pregnant again experienced worsening heart failure and long-term systolic dysfunction.80

Of six South African women who had New York Heart Association class I symptoms who became pregnant again, two died within 8 weeks of delivery, and the other four continued to have heart failure symptoms.81

In the United States, Elkayam et al82 identified 44 women with peripartum cardiomyopathy who became pregnant again. Of these, 28 had recovered systolic function, with ejection fractions of 50% or higher before becoming pregnant again, and 16 had not. The ejection fraction fell in both groups during the subsequent pregnancy, but in the first group it fell by more than 20% in only 6 (21%), and none died. In contrast, in the second group it fell by more than 20% in 5 (31%), and 3 (19%) died.

Patients who recover normal left ventricular function and have normal left ventricular contractile reserve after dobutamine challenge may undertake another pregnancy safely, but they should be warned of the risk of recurrence even with fully recovered left ventricular function.46,82

Dorbala et al83 performed dobutamine stress echocardiography to measure maximal inotropic contractile reserve in six women presenting with peripartum cardiomyopathy, and it correlated accurately with subsequent recovery of left ventricular function.

Based on these data, our recommendations for further pregnancies are the following:

  • If left ventricular function has recovered fully, subsequent pregnancy is not contraindicated, but the patient should be told that, although the risk is low, it is not absent.
  • If left ventricular function has recovered partially, perform dobutamine stress echocardiography. If the left ventricular inotropic response to dobutamine is normal, then patients can be counseled as above; if the left ventricular inotropic response to dobutamine is abnormal, then the risk is moderate and pregnancy is not recommended.
  • If left ventricular function has not recovered at all, the risk is high, and subsequent pregnancy is not recommended.
References
  1. Lampert MB, Lang RM. Peripartum cardiomyopathy. Am Heart J 1995; 130:860–870.
  2. Demakis JG, Rahimtoola SH, Sutton GC, et al. Natural course of peripartum cardiomyopathy. Circulation 1971; 44:1053–1061.
  3. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29:270–276.
  4. Mielniczuk LM, Williams K, Davis DR, et al. Frequency of peripartum cardiomyopathy. Am J Cardiol 2006; 97:1765–1768.
  5. Fett JD, Christie LG, Carraway RD, Murphy JG. Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo Clin Proc 2005; 80:1602–1606.
  6. Amos AM, Jaber WA, Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 2006; 152:509–513.
  7. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342:1077–1084.
  8. Fett JD, Christie LG, Carraway RD, Ansari AA, Sundstrom JB, Murphy JG. Unrecognized peripartum cardiomyopathy in Haitian women. Int J Gynaecol Obstet 2005; 90:161–166.
  9. Pulerwitz TC, Cappola TP, Felker GM, Hare JM, Baughman KL, Kasper EK. Mortality in primary and secondary myocarditis. Am Heart J 2004; 147:746–750.
  10. Melvin KR, Richardson PJ, Olsen EG, Daly K, Jackson G. Peripartum cardiomyopathy due to myocarditis. N Engl J Med 1982; 307:731–734.
  11. Sanderson JE, Olsen EG, Gatei D. Peripartum heart disease: an endomyocardial biopsy study. Br Heart J 1986; 56:285–291.
  12. Midei MG, DeMent SH, Feldman AM, Hutchins GM, Baughman KL. Peripartum myocarditis and cardiomyopathy. Circulation 1990; 81:922–928.
  13. Rizeq MN, Rickenbacher PR, Fowler MB, Billingham ME. Incidence of myocarditis in peripartum cardiomyopathy. Am J Cardiol 1994; 74:474–477.
  14. Bultmann BD, Klingel K, Nabauer M, Wallwiener D, Kandolf R. High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol 2005; 193:363–365.
  15. Kühl U, Pauschinger M, Seeberg B, et al. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005; 112:1965–1970.
  16. Lyden DC, Huber SA. Aggravation of coxsackievirus, group B, type 3-induced myocarditis and increase in cellular immunity to myocyte antigens in pregnant Balb/c mice and animals treated with progesterone. Cell Immunol 1984; 87:462–472.
  17. Artlett CM, Smith JB, Jimenez SA. Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med 1998; 338:1186–1191.
  18. Nelson JL. Microchimerism: expanding new horizon in human health or incidental remnant of pregnancy? Lancet 2001; 358:2011–2012.
  19. Ansari AA, Fett JD, Carraway RE, Mayne AE, Onlamoon N, Sundstrom JB. Autoimmune mechanisms as the basis for human peripartum cardiomyopathy. Clin Rev Allergy Immunol 2002; 23:301–324.
  20. Warraich RS, Sliwa K, Damasceno A, et al. Impact of pregnancy-related heart failure on humoral immunity: clinical relevance of G3-subclass immunoglobulins in peripartum cardiomyopathy. Am Heart J 2005; 150:263–269.
  21. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996; 335:1182–1189.
  22. Hayakawa Y, Chandra M, Miao W, et al. Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation 2003; 108:3036–3041.
  23. Sliwa K, Forster O, Libhaber E, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. Eur Heart J 2006; 27:441–446.
  24. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996; 27:1201–1206.
  25. Mabie WC, DiSessa TG, Crocker LG, Sibai BM, Arheart KL. A longitudinal study of cardiac output in normal human pregnancy. Am J Obstet Gynecol 1994; 170:849–856.
  26. Julian DG, Szekely P. Peripartum cardiomyopathy. Prog Cardiovasc Dis 1985; 27:223–240.
  27. Mone SM, Sanders SP, Colan SD. Control mechanisms for physiological hypertrophy of pregnancy. Circulation 1996; 94:667–672.
  28. Zimmermann O, Kochs M, Zwaka TP, et al. Myocardial biopsy based classification and treatment in patients with dilated cardiomyopathy. Int J Cardiol 2005; 104:92–100.
  29. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007; 128:589–600.
  30. Coulson CC, Thorp JM, Mayer DC, Cefalo RC. Central hemodynamic effects of recombinant human relaxin in the isolated, perfused rat heart model. Obstet Gynecol 1996; 87:610–612.
  31. Fairweather D, Frisancho-Kiss S, Njoku DB, et al. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart. J Immunol 2006; 176:3516– 3524.
  32. Szalay G, Sauter M, Hald J, Weinzierl A, Kandolf R, Klingel K. Sustained nitric oxide synthesis contributes to immunopathology in ongoing myocarditis attributable to interleukin-10 disorders. Am J Pathol 2006; 169:2085–2093.
  33. Ellis JE, Ansari AA, Fett JD, et al. Inhibition of progenitor dendritic cell maturation by plasma from patients with peripartum cardiomyopathy: role in pregnancy-associated heart disease. Clin Dev Immunol 2005; 12:265–273.
  34. Xu HF, Li YH, Chen Y, Cheng LB. [The expression of dystrophin in human viral myocarditis and dilated cardiomyopathy]. Fa Yi Xue Za Zhi 2006; 22:12–14.
  35. Thomas JA, Haudek SB, Koroglu T, et al. IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. Am J Physiol Heart Circ Physiol 2003; 285:H597–H606.
  36. Elkayam U, Akhter MW, Singh H, et al. Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation. Circulation 2005; 111:2050–2055.
  37. Hibbard JU, Lindheimer M, Lang RM. A modified definition for peripartum cardiomyopathy and prognosis based on echocardiography. Obstet Gynecol 1999; 94:311–316.
  38. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990; 142:1009–1014.
  39. Cho S, Atwood JE. Peripheral edema. Am J Med 2002; 113:580–586.
  40. Brown MA, Mackenzie C, Dunsmuir W, et al. Can we predict recurrence of pre-eclampsia or gestational hypertension? BJOG 2007; 114:984–993.
  41. Hu CL, Li YB, Zou YG, et al. Troponin T measurement can predict persistent left ventricular dysfunction in peripartum cardiomyopathy. Heart 2007; 93:488–490.
  42. Desai D, Moodley J, Naidoo D. Peripartum cardiomyopathy: experiences at King Edward VIII Hospital, Durban, South Africa and a review of the literature. Trop Doct 1995; 25:118–123.
  43. Diao M, Diop IB, Kane A, et al. [Electrocardiographic recording of long duration (Holter) of 24 hours during idiopathic cardiomyopathy of the peripartum]. Arch Mal Coeur Vaiss 2004; 97:25–30.
  44. Pearson GD, Veille JC, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000; 283:1183–1188.
  45. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J 2007; 28:3076–3093.
  46. Baughman KL. Peripartum cardiomyopathy. Curr Treat Options Cardiovasc Med 2001; 3:469–480.
  47. Di Bella G, de Gregorio C, Minutoli F, et al. Early diagnosis of focal myocarditis by cardiac magnetic resonance. Int J Cardiol 2007; 117:280–281.
  48. Laissy JP, Hyafil F, Feldman LJ, et al. Differentiating acute myocardial infarction from myocarditis: diagnostic value of early- and delayed-perfusion cardiac MR imaging. Radiology 2005; 237:75–82.
  49. Kawano H, Tsuneto A, Koide Y, et al. Magnetic resonance imaging in a patient with peripartum cardiomyopathy. Intern Med 2008; 47:97–102.
  50. Leurent G, Baruteau AE, Larralde A, et al. Contribution of cardiac MRI in the comprehension of peripartum cardiomyopathy pathogenesis. Int J Cardiol 2009; 132:e91–e93. Epub 2008 Feb 6.
  51. Andrade SE, Raebel MA, Brown J, et al. Outpatient use of cardiovascular drugs during pregnancy. Pharmacoepidemiol Drug Saf 2008; 17:240–247.
  52. Ray JG, Vermeulen MJ, Koren G. Taking ACE inhibitors during early pregnancy: is it safe? Can Fam Physician 2007; 53:1439–1440.
  53. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354:2443–2451.
  54. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006; 368:687–693.
  55. Rathore SS, Curtis JP, Wang Y, Birstow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289:871–888.
  56. Shimamoto T, Marui A, Oda M, et al. A case of peripartum cardiomyopathy with recurrent left ventricular apical thrombus. Circ J 2008; 72:853–854.
  57. Nishi I, Ishimitsu T, Ishizu T, et al. Peripartum cardiomyopathy and biventricular thrombi. Circ J 2002; 66:863–865.
  58. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1. J Am Coll Cardiol 2000; 35:701–705.
  59. Clark NP, Delate T, Witt DM, Parker S, McDuffie R. A descriptive evaluation of unfractionated heparin use during pregnancy. J Thromb Thrombolysis 2008epub March 8.
  60. Narin C, Reyhanoglu H, Tulek B, et al. Comparison of different dose regimens of enoxaparin in deep vein thrombosis therapy in pregnancy. Adv Ther 2008; 25:585–594.
  61. Bonow RO, Carabello BA, Chatterjee K, et al; 2006 Writing Committee Members. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008; 118:e523–e661.
  62. Rose EA, Gelijns AC, Moskowitz AJ, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001; 345:1435–1443.
  63. Jessup M, Brozena S. Heart failure. N Engl J Med 2003; 348:2007–2018.
  64. Sliwa K, Skudicky D, Candy G, Bergemann A, Hopley M, Sareli P. The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy. Eur J Heart Fail 2002; 4:305–309.
  65. Bozkurt B, Villaneuva FS, Holubkov R, et al. Intravenous immune globulin in the therapy of peripartum cardiomyopathy. J Am Coll Cardiol 1999; 34:177–180.
  66. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001; 103:2254–2259.
  67. Kishimoto C, Shioji K, Kinoshita M, et al. Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress. Int J Cardiol 2003; 91:173–178.
  68. Fett JD. Inflammation and virus in dilated cardiomyopathy as indicated by endomyocardial biopsy. Int J Cardiol 2006; 112:125–126.
  69. Hilfiker-Kleiner D, Meyer GP, Schieffer E, et al. Recovery from postpartum cardiomyopathy in 2 patients by blocking prolactin release with bromocriptine. J Am Coll Cardiol 2007; 50:2354–2355.
  70. Yuan Z, Kishimoto C, Shioji K. Beneficial effects of low-dose benidipine in acute autoimmune myocarditis: suppressive effects on inflammatory cytokines and inducible nitric oxide synthase. Circ J 2003; 67:545–550.
  71. Li WM, Liu W, Gao C, Zhou BG. Immunoregulatory effects of atorvastatin on experimental autoimmune myocarditis in Lewis rats. Immunol Cell Biol 2006; 84:274–280.
  72. Yuan HT, Liao YH, Wang Z, et al. Prevention of myosin-induced autoimmune myocarditis in mice by anti-L3T4 monoclonal antibody. Can J Physiol Pharmacol 2003; 81:84–88.
  73. Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003; 107:2793–2798.
  74. Felix SB, Staudt A. Non-specific immunoadsorption in patients with dilated cardiomyopathy: mechanisms and clinical effects. Int J Cardiol 2006; 112:30–33.
  75. Bosch T. Therapeutic apheresis—state of the art in the year 2005. Ther Apher Dial 2005; 9:459–468.
  76. Liu Z, Yuan J, Yanagawa B, Qiu D, McManus BM, Yang D. Coxsackievirus-induced myocarditis: new trends in treatment. Expert Rev Anti Infect Ther 2005; 3:641–650.
  77. Yu CM, Abraham WT, Bax J, et al; PROSPECT Investigators. Predictors of response to cardiac resynchronization therapy (PROSPECT)—study design. Am Heart J 2005; 149:600–605.
  78. Duran N, Gunes H, Duran I, Biteker M, Ozkan M. Predictors of prognosis in patients with peripartum cardiomyopathy. Int J Gynaecol Obstet 2008; 101:137–140.
  79. Chapa JB, Heiberger HB, Weinert L, Decara J, Lang RM, Hibbard JU. Prognostic value of echocardiography in peripartum cardiomyopathy. Obstet Gynecol 2005; 105:1303–1308.
  80. Fett JD, Christie LG, Murphy JG. Brief communication: Outcomes of subsequent pregnancy after peripartum cardiomyopathy: a case series from Haiti. Ann Intern Med 2006; 145:30–34.
  81. Sliwa K, Forster O, Zhanje F, Candy G, Kachope J, Essop R. Outcome of subsequent pregnancy in patients with documented peripartum cardiomyopathy. Am J Cardiol 2004; 93:1441–1443,A10.
  82. Elkayam U, Tummala PP, Rao K, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy. N Engl J Med 2001; 344:1567–1571.
  83. Dorbala S, Brozena S, Zeb S, et al. Risk stratification of women with peripartum cardiomyopathy at initial presentation: a dobutamine stress echocardiography study. J Am Soc Echocardiogr 2005; 18:45–48.
References
  1. Lampert MB, Lang RM. Peripartum cardiomyopathy. Am Heart J 1995; 130:860–870.
  2. Demakis JG, Rahimtoola SH, Sutton GC, et al. Natural course of peripartum cardiomyopathy. Circulation 1971; 44:1053–1061.
  3. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29:270–276.
  4. Mielniczuk LM, Williams K, Davis DR, et al. Frequency of peripartum cardiomyopathy. Am J Cardiol 2006; 97:1765–1768.
  5. Fett JD, Christie LG, Carraway RD, Murphy JG. Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo Clin Proc 2005; 80:1602–1606.
  6. Amos AM, Jaber WA, Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 2006; 152:509–513.
  7. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342:1077–1084.
  8. Fett JD, Christie LG, Carraway RD, Ansari AA, Sundstrom JB, Murphy JG. Unrecognized peripartum cardiomyopathy in Haitian women. Int J Gynaecol Obstet 2005; 90:161–166.
  9. Pulerwitz TC, Cappola TP, Felker GM, Hare JM, Baughman KL, Kasper EK. Mortality in primary and secondary myocarditis. Am Heart J 2004; 147:746–750.
  10. Melvin KR, Richardson PJ, Olsen EG, Daly K, Jackson G. Peripartum cardiomyopathy due to myocarditis. N Engl J Med 1982; 307:731–734.
  11. Sanderson JE, Olsen EG, Gatei D. Peripartum heart disease: an endomyocardial biopsy study. Br Heart J 1986; 56:285–291.
  12. Midei MG, DeMent SH, Feldman AM, Hutchins GM, Baughman KL. Peripartum myocarditis and cardiomyopathy. Circulation 1990; 81:922–928.
  13. Rizeq MN, Rickenbacher PR, Fowler MB, Billingham ME. Incidence of myocarditis in peripartum cardiomyopathy. Am J Cardiol 1994; 74:474–477.
  14. Bultmann BD, Klingel K, Nabauer M, Wallwiener D, Kandolf R. High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol 2005; 193:363–365.
  15. Kühl U, Pauschinger M, Seeberg B, et al. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005; 112:1965–1970.
  16. Lyden DC, Huber SA. Aggravation of coxsackievirus, group B, type 3-induced myocarditis and increase in cellular immunity to myocyte antigens in pregnant Balb/c mice and animals treated with progesterone. Cell Immunol 1984; 87:462–472.
  17. Artlett CM, Smith JB, Jimenez SA. Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med 1998; 338:1186–1191.
  18. Nelson JL. Microchimerism: expanding new horizon in human health or incidental remnant of pregnancy? Lancet 2001; 358:2011–2012.
  19. Ansari AA, Fett JD, Carraway RE, Mayne AE, Onlamoon N, Sundstrom JB. Autoimmune mechanisms as the basis for human peripartum cardiomyopathy. Clin Rev Allergy Immunol 2002; 23:301–324.
  20. Warraich RS, Sliwa K, Damasceno A, et al. Impact of pregnancy-related heart failure on humoral immunity: clinical relevance of G3-subclass immunoglobulins in peripartum cardiomyopathy. Am Heart J 2005; 150:263–269.
  21. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996; 335:1182–1189.
  22. Hayakawa Y, Chandra M, Miao W, et al. Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation 2003; 108:3036–3041.
  23. Sliwa K, Forster O, Libhaber E, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. Eur Heart J 2006; 27:441–446.
  24. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996; 27:1201–1206.
  25. Mabie WC, DiSessa TG, Crocker LG, Sibai BM, Arheart KL. A longitudinal study of cardiac output in normal human pregnancy. Am J Obstet Gynecol 1994; 170:849–856.
  26. Julian DG, Szekely P. Peripartum cardiomyopathy. Prog Cardiovasc Dis 1985; 27:223–240.
  27. Mone SM, Sanders SP, Colan SD. Control mechanisms for physiological hypertrophy of pregnancy. Circulation 1996; 94:667–672.
  28. Zimmermann O, Kochs M, Zwaka TP, et al. Myocardial biopsy based classification and treatment in patients with dilated cardiomyopathy. Int J Cardiol 2005; 104:92–100.
  29. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007; 128:589–600.
  30. Coulson CC, Thorp JM, Mayer DC, Cefalo RC. Central hemodynamic effects of recombinant human relaxin in the isolated, perfused rat heart model. Obstet Gynecol 1996; 87:610–612.
  31. Fairweather D, Frisancho-Kiss S, Njoku DB, et al. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart. J Immunol 2006; 176:3516– 3524.
  32. Szalay G, Sauter M, Hald J, Weinzierl A, Kandolf R, Klingel K. Sustained nitric oxide synthesis contributes to immunopathology in ongoing myocarditis attributable to interleukin-10 disorders. Am J Pathol 2006; 169:2085–2093.
  33. Ellis JE, Ansari AA, Fett JD, et al. Inhibition of progenitor dendritic cell maturation by plasma from patients with peripartum cardiomyopathy: role in pregnancy-associated heart disease. Clin Dev Immunol 2005; 12:265–273.
  34. Xu HF, Li YH, Chen Y, Cheng LB. [The expression of dystrophin in human viral myocarditis and dilated cardiomyopathy]. Fa Yi Xue Za Zhi 2006; 22:12–14.
  35. Thomas JA, Haudek SB, Koroglu T, et al. IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. Am J Physiol Heart Circ Physiol 2003; 285:H597–H606.
  36. Elkayam U, Akhter MW, Singh H, et al. Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation. Circulation 2005; 111:2050–2055.
  37. Hibbard JU, Lindheimer M, Lang RM. A modified definition for peripartum cardiomyopathy and prognosis based on echocardiography. Obstet Gynecol 1999; 94:311–316.
  38. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990; 142:1009–1014.
  39. Cho S, Atwood JE. Peripheral edema. Am J Med 2002; 113:580–586.
  40. Brown MA, Mackenzie C, Dunsmuir W, et al. Can we predict recurrence of pre-eclampsia or gestational hypertension? BJOG 2007; 114:984–993.
  41. Hu CL, Li YB, Zou YG, et al. Troponin T measurement can predict persistent left ventricular dysfunction in peripartum cardiomyopathy. Heart 2007; 93:488–490.
  42. Desai D, Moodley J, Naidoo D. Peripartum cardiomyopathy: experiences at King Edward VIII Hospital, Durban, South Africa and a review of the literature. Trop Doct 1995; 25:118–123.
  43. Diao M, Diop IB, Kane A, et al. [Electrocardiographic recording of long duration (Holter) of 24 hours during idiopathic cardiomyopathy of the peripartum]. Arch Mal Coeur Vaiss 2004; 97:25–30.
  44. Pearson GD, Veille JC, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000; 283:1183–1188.
  45. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J 2007; 28:3076–3093.
  46. Baughman KL. Peripartum cardiomyopathy. Curr Treat Options Cardiovasc Med 2001; 3:469–480.
  47. Di Bella G, de Gregorio C, Minutoli F, et al. Early diagnosis of focal myocarditis by cardiac magnetic resonance. Int J Cardiol 2007; 117:280–281.
  48. Laissy JP, Hyafil F, Feldman LJ, et al. Differentiating acute myocardial infarction from myocarditis: diagnostic value of early- and delayed-perfusion cardiac MR imaging. Radiology 2005; 237:75–82.
  49. Kawano H, Tsuneto A, Koide Y, et al. Magnetic resonance imaging in a patient with peripartum cardiomyopathy. Intern Med 2008; 47:97–102.
  50. Leurent G, Baruteau AE, Larralde A, et al. Contribution of cardiac MRI in the comprehension of peripartum cardiomyopathy pathogenesis. Int J Cardiol 2009; 132:e91–e93. Epub 2008 Feb 6.
  51. Andrade SE, Raebel MA, Brown J, et al. Outpatient use of cardiovascular drugs during pregnancy. Pharmacoepidemiol Drug Saf 2008; 17:240–247.
  52. Ray JG, Vermeulen MJ, Koren G. Taking ACE inhibitors during early pregnancy: is it safe? Can Fam Physician 2007; 53:1439–1440.
  53. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354:2443–2451.
  54. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006; 368:687–693.
  55. Rathore SS, Curtis JP, Wang Y, Birstow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289:871–888.
  56. Shimamoto T, Marui A, Oda M, et al. A case of peripartum cardiomyopathy with recurrent left ventricular apical thrombus. Circ J 2008; 72:853–854.
  57. Nishi I, Ishimitsu T, Ishizu T, et al. Peripartum cardiomyopathy and biventricular thrombi. Circ J 2002; 66:863–865.
  58. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1. J Am Coll Cardiol 2000; 35:701–705.
  59. Clark NP, Delate T, Witt DM, Parker S, McDuffie R. A descriptive evaluation of unfractionated heparin use during pregnancy. J Thromb Thrombolysis 2008epub March 8.
  60. Narin C, Reyhanoglu H, Tulek B, et al. Comparison of different dose regimens of enoxaparin in deep vein thrombosis therapy in pregnancy. Adv Ther 2008; 25:585–594.
  61. Bonow RO, Carabello BA, Chatterjee K, et al; 2006 Writing Committee Members. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008; 118:e523–e661.
  62. Rose EA, Gelijns AC, Moskowitz AJ, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001; 345:1435–1443.
  63. Jessup M, Brozena S. Heart failure. N Engl J Med 2003; 348:2007–2018.
  64. Sliwa K, Skudicky D, Candy G, Bergemann A, Hopley M, Sareli P. The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy. Eur J Heart Fail 2002; 4:305–309.
  65. Bozkurt B, Villaneuva FS, Holubkov R, et al. Intravenous immune globulin in the therapy of peripartum cardiomyopathy. J Am Coll Cardiol 1999; 34:177–180.
  66. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001; 103:2254–2259.
  67. Kishimoto C, Shioji K, Kinoshita M, et al. Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress. Int J Cardiol 2003; 91:173–178.
  68. Fett JD. Inflammation and virus in dilated cardiomyopathy as indicated by endomyocardial biopsy. Int J Cardiol 2006; 112:125–126.
  69. Hilfiker-Kleiner D, Meyer GP, Schieffer E, et al. Recovery from postpartum cardiomyopathy in 2 patients by blocking prolactin release with bromocriptine. J Am Coll Cardiol 2007; 50:2354–2355.
  70. Yuan Z, Kishimoto C, Shioji K. Beneficial effects of low-dose benidipine in acute autoimmune myocarditis: suppressive effects on inflammatory cytokines and inducible nitric oxide synthase. Circ J 2003; 67:545–550.
  71. Li WM, Liu W, Gao C, Zhou BG. Immunoregulatory effects of atorvastatin on experimental autoimmune myocarditis in Lewis rats. Immunol Cell Biol 2006; 84:274–280.
  72. Yuan HT, Liao YH, Wang Z, et al. Prevention of myosin-induced autoimmune myocarditis in mice by anti-L3T4 monoclonal antibody. Can J Physiol Pharmacol 2003; 81:84–88.
  73. Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003; 107:2793–2798.
  74. Felix SB, Staudt A. Non-specific immunoadsorption in patients with dilated cardiomyopathy: mechanisms and clinical effects. Int J Cardiol 2006; 112:30–33.
  75. Bosch T. Therapeutic apheresis—state of the art in the year 2005. Ther Apher Dial 2005; 9:459–468.
  76. Liu Z, Yuan J, Yanagawa B, Qiu D, McManus BM, Yang D. Coxsackievirus-induced myocarditis: new trends in treatment. Expert Rev Anti Infect Ther 2005; 3:641–650.
  77. Yu CM, Abraham WT, Bax J, et al; PROSPECT Investigators. Predictors of response to cardiac resynchronization therapy (PROSPECT)—study design. Am Heart J 2005; 149:600–605.
  78. Duran N, Gunes H, Duran I, Biteker M, Ozkan M. Predictors of prognosis in patients with peripartum cardiomyopathy. Int J Gynaecol Obstet 2008; 101:137–140.
  79. Chapa JB, Heiberger HB, Weinert L, Decara J, Lang RM, Hibbard JU. Prognostic value of echocardiography in peripartum cardiomyopathy. Obstet Gynecol 2005; 105:1303–1308.
  80. Fett JD, Christie LG, Murphy JG. Brief communication: Outcomes of subsequent pregnancy after peripartum cardiomyopathy: a case series from Haiti. Ann Intern Med 2006; 145:30–34.
  81. Sliwa K, Forster O, Zhanje F, Candy G, Kachope J, Essop R. Outcome of subsequent pregnancy in patients with documented peripartum cardiomyopathy. Am J Cardiol 2004; 93:1441–1443,A10.
  82. Elkayam U, Tummala PP, Rao K, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy. N Engl J Med 2001; 344:1567–1571.
  83. Dorbala S, Brozena S, Zeb S, et al. Risk stratification of women with peripartum cardiomyopathy at initial presentation: a dobutamine stress echocardiography study. J Am Soc Echocardiogr 2005; 18:45–48.
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Cleveland Clinic Journal of Medicine - 76(5)
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Cleveland Clinic Journal of Medicine - 76(5)
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KEY POINTS

  • Heightened suspicion is important when a pregnant woman presents with signs of heart failure, because early diagnosis allows proven treatment to be started.
  • Standard heart failure therapy should be started in postpartum patients with this disease, using available local protocols.
  • Pregnant women should not receive angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or warfarin because of potential teratogenic effects.
  • An initial left ventricular end-systolic dimension less than 5.5 cm, a left ventricular ejection fraction greater than 30%, and a low cardiac troponin level may predict a better outcome.
  • Subsequent pregnancies carry a high risk of relapse, even in women who have fully recovered left ventricular function.
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Proceedings of the 2008 Heart-Brain Summit

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Proceedings of the 2008 Heart-Brain Summit

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Preface
Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)

Introduction: Heart-brain medicine: Update 2008
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)

Bakken Lecture: The brain, the heart, and therapeutic hypothermia
Patrick M. Kochanek, MD

 

Session 1: Pathways Involved in Neuromodulation of Risks in Coronary Artery Disease

Depression and heart rate variability in patients with coronary heart disease
Robert M. Carney, PhD, and Kenneth E. Freedland, PhD

Autonomic function and prognosis
Michael S. Lauer, MD

Vagal tone and the inflammatory reflex
Julian F. Thayer, PhD

Inflammation, atherosclerosis, and arterial thrombosis: Role of the scavenger receptors CD36
Roy L. Silverstein, MD

Pioneer Award Address: Ignorance isn't biased: Comments on receiving the Pioneer Award
David S. Goldstein, MD, PhD

 

Session II: Measures and Strategies for Modulation of Heart-Brain Interactions

Heart rate variability with deep breathing as a clinical test of cardiovagal function
Robert W. Shields, Jr, MD

Basic research models for the study of underlying mechanisms of electrical neuromodulation and ischemi heart-brain interactions
Mike J.L. DeJongste, MD, PhD, FESC; Gert J. TerHorst, PhD; and Robert D. Foreman, PhD

 

Session III: Annual Review of Key Papers in Heart-Brain Medicine

Key papers in the field published during the year prior to the Summit were discussed; two of those papers are reported here.

Cardiac sympathetic denervation preceding motor signs in Parkinson disease
David S. Goldstein, MD, PhD; Yehonatan Sharabi, MD; Barbara I. Karp, MD; Oladi Bentho; Ahmed Saleem, MD; Karel Pacak, MD, PhD; and Graeme Eisenhofer, PhD

Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation
Jeffrey P. Moak, MD; David S. Goldstein, MD, PhD; Basil A. Eldadah, MD, PhD; Ahmed Saleem, MD; Courtney Holmes, CMT; Sandra Pechnik, RN; and Yehonatan Sharabi, MD

 

Session IV: Code Lavender—Strategies for Implementing Heart-Brain Medicine

Is posttraumatic stress disorder related to development of heart disease? An update
Laura D. Kubzansky, PhD, and Karestan C. Koenen, PhD

Creating a healing environment: Rationale and research overview
Jone Geimer-Flanders, DO

Redesigning the neurocritical care unit to enhance family participation and improve outcomes
Owen Samuels, MD

 

Session V: Insights into Neuromodulation of Cardiovascular Function

Neuromodulation of cardiac pain and cerebral vasculature: Neural mechanisms
Robert D. Foreman, PhD, and Chao Qin, MD, PhD

Pinacidil induces vascular dilation and hyperemia in vivo and does not impact biophysical properties of neurons and astrocytes in vitro
Rosa Cao; Bryan T. Higashikubo; Jessica Cardin; Ulf Knoblich; Raddy Ramos, PhD; Mark T. Nelson, PhD; Christopher I. Moore, PhD; and Joshua C. Brumberg, PhD

The polyvagal theory: New insights into adaptive reactions of the autonomic nervous system
Stephen W. Porges, PhD

 

Poster Abstracts

Abstract 1: Insulin use does not protect against restenosis in diabetic patients presenting with acute coronary syndrome or symptomatic angina
Matthew C. Becker, MD; John M. Galla, MD; Saif Anwaruddin, MD; Samir Kapadia, MD; and Richard A. Krasuski, MD

Abstract 2: Postoperative statin use and lower LDL cholesterol concentration are associated with reduced incidence of stroke
Matthew C. Becker, John M. Galla, Ryan P. Daly, Femi Philip, Peter Zimbwa, Stephen O. Chen, Chen H. Chow, Tingfei Hu, Richard A. Krasuski, and Arman T. Askari

Abstract 3: Brain edema and blood-brain barrier leakage influence antiepileptic drug levels
Giulia Betto, Vincent Fazio, Damir Janigro, and Chaitali Ghosh

Abstract 4: CPAP treatment vs conservative treatment in mild obstructive sleep apnea: Implications on cardiovascular morbidity
Kumar Budur, MD, and Nattapong Jaimchariyatam, MD

Abstract 5: New bioinformatics program identifies behavioral medicine interventions for epidemic cardiovascular disease in the developing world: Analysis of multidisciplinary findings for launching a new global public health initiative in heart-brain medicine
William C. Bushell, PhD

Abstract 6: Do systemic inflammation and blood-brain barrier failure play a role in pediatric psychosis?
Erin Carlton, Tatiana Falcone, Ayush Batra, Vince Fazio, Kathleen Franco, and Damir Janigro

Abstract 7: Brain, heart, and education
Linda Bryant Caviness, PhD

Abstract 8: Tobacco smoke mediates a monocytic and endothelial proinflammatory activation that synergistically affects BBB integrity
L. Cucullo, T. Sathe, M. Hossain, and D. Janigro

Abstract 9: Dynamic changes in ECG predict poor outcome after aneurysmal subarachnoid hemorrhage (aSAH)
H.A. Elsharkawy, MD; S.M. El Hadi, MD, PhD; J.E. Tetzlaff, MD; and J.J. Provencio, MD, FCCM

Abstract 10: Mechanism studies of malformation of cortical development by prenatal exposure of combined methylazoxymethanol and thalidomide
Q. Fan, S. Ramakrishna, N. Marchi, V. Fazio, K. Hallene, and D. Janigro

Abstract 11: Proapolipoprotein A1 demonstrates improved potential as a serum marker for brain metastases without vascular disease interference
Vince Fazio, Peter Mazzone, Nicola Marchi, Thomas Masaryk, and Damir Janigro

Abstract 12: Biofeedback-assisted stress management training to reverse myocardial remodeling in patients with end-stage heart failure
Dana L. Frank, BS; Mary E. Klecka, BA; Jerry Kiffer, MA; Heather Henrickson, PhD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 13: Nitric oxide and arginine metabolism in depression: Effect of a serotonin-norepinephrine reuptake inhibitor
Angelos Halaris, John Piletz, Omer Iqbal, Debra Hoppensteadt, Jawed Fareed, He Zhu, James Sinacore, and C. Lindsay DeVane

Abstract 14: Association between excessive daytime sleepiness and oxygen desaturation in obstructive sleep apnea syndrome: Nadir oxygen saturation vs mean oxygen saturation vs time spent below 90% oxygen saturation—which is important?
Nattapong Jaimchariyatam, MD, and Kumar Budur, MD

Abstract 15: Endotoxin preconditioning of the CNS: Microglia activation and neuroprotection
Walid Jalabi, Ranjan Dutta, Yongming Jin, Gerson Criste, Xinghua Yin, Grahame J. Kidd, and Bruce D. Trapp

Abstract 16: Pilot of stress reduction strategies for patients after a coronary event
R. Lindquist, D. Windenburg, K. Savik, and U. Bronas

Abstract 17: Cerebrovascular substrates of seizures after cardiopulmonary bypass
Rebecca O’Dwyer, Tim Wehner, Dileep Nair, Giulia Betto, Nicola Marchi, and Damir Janigro

Abstract 18: Depression and whole blood serotonin in patients with coronary heart disease from the heart and soul study
Lawson Wulsin, Dominique Musselman, Christian Otte, Erica Bruce, Sadia Ali, and Mary Whooley

Abstract 19: Gender differences prominent in linking anxiety to long-term mortality among the elderly
Jianping Zhang, MD, PhD; Boaz Kahana, PhD; Eva Kahana, PhD; Bo Hu, PhD; and Leo Pozuelo, MD

Abstract 20: Temporal lobe and sinus node: A case report provides evidence for bidirectional effects
Rebecca O’Dwyer, MD; Andreas Alexopoulos, MD, MPH; Walid Saliba, MD; Imad Najm, MD; and Richard Burgess, MD, PhD

Article PDF
heart-brain_summit_iii_final.pdf
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Cleveland Clinic Journal of Medicine - 76(4)
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Cleveland Clinic Journal of Medicine
Topics
Cardiology
Neurology
Page Number
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Article PDF
heart-brain_summit_iii_final.pdf
Article PDF
heart-brain_summit_iii_final.pdf

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Preface
Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)

Introduction: Heart-brain medicine: Update 2008
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)

Bakken Lecture: The brain, the heart, and therapeutic hypothermia
Patrick M. Kochanek, MD

 

Session 1: Pathways Involved in Neuromodulation of Risks in Coronary Artery Disease

Depression and heart rate variability in patients with coronary heart disease
Robert M. Carney, PhD, and Kenneth E. Freedland, PhD

Autonomic function and prognosis
Michael S. Lauer, MD

Vagal tone and the inflammatory reflex
Julian F. Thayer, PhD

Inflammation, atherosclerosis, and arterial thrombosis: Role of the scavenger receptors CD36
Roy L. Silverstein, MD

Pioneer Award Address: Ignorance isn't biased: Comments on receiving the Pioneer Award
David S. Goldstein, MD, PhD

 

Session II: Measures and Strategies for Modulation of Heart-Brain Interactions

Heart rate variability with deep breathing as a clinical test of cardiovagal function
Robert W. Shields, Jr, MD

Basic research models for the study of underlying mechanisms of electrical neuromodulation and ischemi heart-brain interactions
Mike J.L. DeJongste, MD, PhD, FESC; Gert J. TerHorst, PhD; and Robert D. Foreman, PhD

 

Session III: Annual Review of Key Papers in Heart-Brain Medicine

Key papers in the field published during the year prior to the Summit were discussed; two of those papers are reported here.

Cardiac sympathetic denervation preceding motor signs in Parkinson disease
David S. Goldstein, MD, PhD; Yehonatan Sharabi, MD; Barbara I. Karp, MD; Oladi Bentho; Ahmed Saleem, MD; Karel Pacak, MD, PhD; and Graeme Eisenhofer, PhD

Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation
Jeffrey P. Moak, MD; David S. Goldstein, MD, PhD; Basil A. Eldadah, MD, PhD; Ahmed Saleem, MD; Courtney Holmes, CMT; Sandra Pechnik, RN; and Yehonatan Sharabi, MD

 

Session IV: Code Lavender—Strategies for Implementing Heart-Brain Medicine

Is posttraumatic stress disorder related to development of heart disease? An update
Laura D. Kubzansky, PhD, and Karestan C. Koenen, PhD

Creating a healing environment: Rationale and research overview
Jone Geimer-Flanders, DO

Redesigning the neurocritical care unit to enhance family participation and improve outcomes
Owen Samuels, MD

 

Session V: Insights into Neuromodulation of Cardiovascular Function

Neuromodulation of cardiac pain and cerebral vasculature: Neural mechanisms
Robert D. Foreman, PhD, and Chao Qin, MD, PhD

Pinacidil induces vascular dilation and hyperemia in vivo and does not impact biophysical properties of neurons and astrocytes in vitro
Rosa Cao; Bryan T. Higashikubo; Jessica Cardin; Ulf Knoblich; Raddy Ramos, PhD; Mark T. Nelson, PhD; Christopher I. Moore, PhD; and Joshua C. Brumberg, PhD

The polyvagal theory: New insights into adaptive reactions of the autonomic nervous system
Stephen W. Porges, PhD

 

Poster Abstracts

Abstract 1: Insulin use does not protect against restenosis in diabetic patients presenting with acute coronary syndrome or symptomatic angina
Matthew C. Becker, MD; John M. Galla, MD; Saif Anwaruddin, MD; Samir Kapadia, MD; and Richard A. Krasuski, MD

Abstract 2: Postoperative statin use and lower LDL cholesterol concentration are associated with reduced incidence of stroke
Matthew C. Becker, John M. Galla, Ryan P. Daly, Femi Philip, Peter Zimbwa, Stephen O. Chen, Chen H. Chow, Tingfei Hu, Richard A. Krasuski, and Arman T. Askari

Abstract 3: Brain edema and blood-brain barrier leakage influence antiepileptic drug levels
Giulia Betto, Vincent Fazio, Damir Janigro, and Chaitali Ghosh

Abstract 4: CPAP treatment vs conservative treatment in mild obstructive sleep apnea: Implications on cardiovascular morbidity
Kumar Budur, MD, and Nattapong Jaimchariyatam, MD

Abstract 5: New bioinformatics program identifies behavioral medicine interventions for epidemic cardiovascular disease in the developing world: Analysis of multidisciplinary findings for launching a new global public health initiative in heart-brain medicine
William C. Bushell, PhD

Abstract 6: Do systemic inflammation and blood-brain barrier failure play a role in pediatric psychosis?
Erin Carlton, Tatiana Falcone, Ayush Batra, Vince Fazio, Kathleen Franco, and Damir Janigro

Abstract 7: Brain, heart, and education
Linda Bryant Caviness, PhD

Abstract 8: Tobacco smoke mediates a monocytic and endothelial proinflammatory activation that synergistically affects BBB integrity
L. Cucullo, T. Sathe, M. Hossain, and D. Janigro

Abstract 9: Dynamic changes in ECG predict poor outcome after aneurysmal subarachnoid hemorrhage (aSAH)
H.A. Elsharkawy, MD; S.M. El Hadi, MD, PhD; J.E. Tetzlaff, MD; and J.J. Provencio, MD, FCCM

Abstract 10: Mechanism studies of malformation of cortical development by prenatal exposure of combined methylazoxymethanol and thalidomide
Q. Fan, S. Ramakrishna, N. Marchi, V. Fazio, K. Hallene, and D. Janigro

Abstract 11: Proapolipoprotein A1 demonstrates improved potential as a serum marker for brain metastases without vascular disease interference
Vince Fazio, Peter Mazzone, Nicola Marchi, Thomas Masaryk, and Damir Janigro

Abstract 12: Biofeedback-assisted stress management training to reverse myocardial remodeling in patients with end-stage heart failure
Dana L. Frank, BS; Mary E. Klecka, BA; Jerry Kiffer, MA; Heather Henrickson, PhD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 13: Nitric oxide and arginine metabolism in depression: Effect of a serotonin-norepinephrine reuptake inhibitor
Angelos Halaris, John Piletz, Omer Iqbal, Debra Hoppensteadt, Jawed Fareed, He Zhu, James Sinacore, and C. Lindsay DeVane

Abstract 14: Association between excessive daytime sleepiness and oxygen desaturation in obstructive sleep apnea syndrome: Nadir oxygen saturation vs mean oxygen saturation vs time spent below 90% oxygen saturation—which is important?
Nattapong Jaimchariyatam, MD, and Kumar Budur, MD

Abstract 15: Endotoxin preconditioning of the CNS: Microglia activation and neuroprotection
Walid Jalabi, Ranjan Dutta, Yongming Jin, Gerson Criste, Xinghua Yin, Grahame J. Kidd, and Bruce D. Trapp

Abstract 16: Pilot of stress reduction strategies for patients after a coronary event
R. Lindquist, D. Windenburg, K. Savik, and U. Bronas

Abstract 17: Cerebrovascular substrates of seizures after cardiopulmonary bypass
Rebecca O’Dwyer, Tim Wehner, Dileep Nair, Giulia Betto, Nicola Marchi, and Damir Janigro

Abstract 18: Depression and whole blood serotonin in patients with coronary heart disease from the heart and soul study
Lawson Wulsin, Dominique Musselman, Christian Otte, Erica Bruce, Sadia Ali, and Mary Whooley

Abstract 19: Gender differences prominent in linking anxiety to long-term mortality among the elderly
Jianping Zhang, MD, PhD; Boaz Kahana, PhD; Eva Kahana, PhD; Bo Hu, PhD; and Leo Pozuelo, MD

Abstract 20: Temporal lobe and sinus node: A case report provides evidence for bidirectional effects
Rebecca O’Dwyer, MD; Andreas Alexopoulos, MD, MPH; Walid Saliba, MD; Imad Najm, MD; and Richard Burgess, MD, PhD

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Preface
Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)

Introduction: Heart-brain medicine: Update 2008
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)

Bakken Lecture: The brain, the heart, and therapeutic hypothermia
Patrick M. Kochanek, MD

 

Session 1: Pathways Involved in Neuromodulation of Risks in Coronary Artery Disease

Depression and heart rate variability in patients with coronary heart disease
Robert M. Carney, PhD, and Kenneth E. Freedland, PhD

Autonomic function and prognosis
Michael S. Lauer, MD

Vagal tone and the inflammatory reflex
Julian F. Thayer, PhD

Inflammation, atherosclerosis, and arterial thrombosis: Role of the scavenger receptors CD36
Roy L. Silverstein, MD

Pioneer Award Address: Ignorance isn't biased: Comments on receiving the Pioneer Award
David S. Goldstein, MD, PhD

 

Session II: Measures and Strategies for Modulation of Heart-Brain Interactions

Heart rate variability with deep breathing as a clinical test of cardiovagal function
Robert W. Shields, Jr, MD

Basic research models for the study of underlying mechanisms of electrical neuromodulation and ischemi heart-brain interactions
Mike J.L. DeJongste, MD, PhD, FESC; Gert J. TerHorst, PhD; and Robert D. Foreman, PhD

 

Session III: Annual Review of Key Papers in Heart-Brain Medicine

Key papers in the field published during the year prior to the Summit were discussed; two of those papers are reported here.

Cardiac sympathetic denervation preceding motor signs in Parkinson disease
David S. Goldstein, MD, PhD; Yehonatan Sharabi, MD; Barbara I. Karp, MD; Oladi Bentho; Ahmed Saleem, MD; Karel Pacak, MD, PhD; and Graeme Eisenhofer, PhD

Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation
Jeffrey P. Moak, MD; David S. Goldstein, MD, PhD; Basil A. Eldadah, MD, PhD; Ahmed Saleem, MD; Courtney Holmes, CMT; Sandra Pechnik, RN; and Yehonatan Sharabi, MD

 

Session IV: Code Lavender—Strategies for Implementing Heart-Brain Medicine

Is posttraumatic stress disorder related to development of heart disease? An update
Laura D. Kubzansky, PhD, and Karestan C. Koenen, PhD

Creating a healing environment: Rationale and research overview
Jone Geimer-Flanders, DO

Redesigning the neurocritical care unit to enhance family participation and improve outcomes
Owen Samuels, MD

 

Session V: Insights into Neuromodulation of Cardiovascular Function

Neuromodulation of cardiac pain and cerebral vasculature: Neural mechanisms
Robert D. Foreman, PhD, and Chao Qin, MD, PhD

Pinacidil induces vascular dilation and hyperemia in vivo and does not impact biophysical properties of neurons and astrocytes in vitro
Rosa Cao; Bryan T. Higashikubo; Jessica Cardin; Ulf Knoblich; Raddy Ramos, PhD; Mark T. Nelson, PhD; Christopher I. Moore, PhD; and Joshua C. Brumberg, PhD

The polyvagal theory: New insights into adaptive reactions of the autonomic nervous system
Stephen W. Porges, PhD

 

Poster Abstracts

Abstract 1: Insulin use does not protect against restenosis in diabetic patients presenting with acute coronary syndrome or symptomatic angina
Matthew C. Becker, MD; John M. Galla, MD; Saif Anwaruddin, MD; Samir Kapadia, MD; and Richard A. Krasuski, MD

Abstract 2: Postoperative statin use and lower LDL cholesterol concentration are associated with reduced incidence of stroke
Matthew C. Becker, John M. Galla, Ryan P. Daly, Femi Philip, Peter Zimbwa, Stephen O. Chen, Chen H. Chow, Tingfei Hu, Richard A. Krasuski, and Arman T. Askari

Abstract 3: Brain edema and blood-brain barrier leakage influence antiepileptic drug levels
Giulia Betto, Vincent Fazio, Damir Janigro, and Chaitali Ghosh

Abstract 4: CPAP treatment vs conservative treatment in mild obstructive sleep apnea: Implications on cardiovascular morbidity
Kumar Budur, MD, and Nattapong Jaimchariyatam, MD

Abstract 5: New bioinformatics program identifies behavioral medicine interventions for epidemic cardiovascular disease in the developing world: Analysis of multidisciplinary findings for launching a new global public health initiative in heart-brain medicine
William C. Bushell, PhD

Abstract 6: Do systemic inflammation and blood-brain barrier failure play a role in pediatric psychosis?
Erin Carlton, Tatiana Falcone, Ayush Batra, Vince Fazio, Kathleen Franco, and Damir Janigro

Abstract 7: Brain, heart, and education
Linda Bryant Caviness, PhD

Abstract 8: Tobacco smoke mediates a monocytic and endothelial proinflammatory activation that synergistically affects BBB integrity
L. Cucullo, T. Sathe, M. Hossain, and D. Janigro

Abstract 9: Dynamic changes in ECG predict poor outcome after aneurysmal subarachnoid hemorrhage (aSAH)
H.A. Elsharkawy, MD; S.M. El Hadi, MD, PhD; J.E. Tetzlaff, MD; and J.J. Provencio, MD, FCCM

Abstract 10: Mechanism studies of malformation of cortical development by prenatal exposure of combined methylazoxymethanol and thalidomide
Q. Fan, S. Ramakrishna, N. Marchi, V. Fazio, K. Hallene, and D. Janigro

Abstract 11: Proapolipoprotein A1 demonstrates improved potential as a serum marker for brain metastases without vascular disease interference
Vince Fazio, Peter Mazzone, Nicola Marchi, Thomas Masaryk, and Damir Janigro

Abstract 12: Biofeedback-assisted stress management training to reverse myocardial remodeling in patients with end-stage heart failure
Dana L. Frank, BS; Mary E. Klecka, BA; Jerry Kiffer, MA; Heather Henrickson, PhD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 13: Nitric oxide and arginine metabolism in depression: Effect of a serotonin-norepinephrine reuptake inhibitor
Angelos Halaris, John Piletz, Omer Iqbal, Debra Hoppensteadt, Jawed Fareed, He Zhu, James Sinacore, and C. Lindsay DeVane

Abstract 14: Association between excessive daytime sleepiness and oxygen desaturation in obstructive sleep apnea syndrome: Nadir oxygen saturation vs mean oxygen saturation vs time spent below 90% oxygen saturation—which is important?
Nattapong Jaimchariyatam, MD, and Kumar Budur, MD

Abstract 15: Endotoxin preconditioning of the CNS: Microglia activation and neuroprotection
Walid Jalabi, Ranjan Dutta, Yongming Jin, Gerson Criste, Xinghua Yin, Grahame J. Kidd, and Bruce D. Trapp

Abstract 16: Pilot of stress reduction strategies for patients after a coronary event
R. Lindquist, D. Windenburg, K. Savik, and U. Bronas

Abstract 17: Cerebrovascular substrates of seizures after cardiopulmonary bypass
Rebecca O’Dwyer, Tim Wehner, Dileep Nair, Giulia Betto, Nicola Marchi, and Damir Janigro

Abstract 18: Depression and whole blood serotonin in patients with coronary heart disease from the heart and soul study
Lawson Wulsin, Dominique Musselman, Christian Otte, Erica Bruce, Sadia Ali, and Mary Whooley

Abstract 19: Gender differences prominent in linking anxiety to long-term mortality among the elderly
Jianping Zhang, MD, PhD; Boaz Kahana, PhD; Eva Kahana, PhD; Bo Hu, PhD; and Leo Pozuelo, MD

Abstract 20: Temporal lobe and sinus node: A case report provides evidence for bidirectional effects
Rebecca O’Dwyer, MD; Andreas Alexopoulos, MD, MPH; Walid Saliba, MD; Imad Najm, MD; and Richard Burgess, MD, PhD

Issue
Cleveland Clinic Journal of Medicine - 76(4)
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Cleveland Clinic Journal of Medicine - 76(4)
Page Number
S1-S99
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Cleveland Clinic Journal of Medicine
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Neurology
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Barium esophagography

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Barium esophagography
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To the Editor: I would like to comment on the excellent review article on barium esophagography by Drs. Allen, Baker, and Falk in your February 2009 issue. In their opening clinical vignette, they describe a 55-year-old female patient with gastroesophageal reflux disease (GERD) and slowly worsening dysphagia for solids. The patient was sent for barium esophagography, which disclosed an obstructing mucosal ring in the distal esophagus. The patient was then sent for endoscopy so that the ring could be treated with dilation. The authors present this case as an example of the type of patient who could obtain benefit from barium esophagography as the initial study. I disagree. In this patient’s case, the barium procedure accomplished nothing, but it did unnecessarily cost the patient money, time, and radiation exposure. The patient would have been better served by being sent directly for endoscopy at the start of her workup, so that her condition could be diagnosed and treated with a single procedure. In her case, this would have spared her any need for the barium procedure. I believe that patients with dysphagia and GERD are best served by initial endoscopy, since GERD is associated with esophageal strictures, dysplasia, and cancer. Barium esophagography can be reserved for those who have had a normal or nondiagnostic endoscopy. For example, a patient with dysphagia and a normal endoscopy might then be sent for esophagography to diagnose a motility disorder.

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In reply: Barium esophagography

To the Editor: I would like to comment on the excellent review article on barium esophagography by Drs. Allen, Baker, and Falk in your February 2009 issue. In their opening clinical vignette, they describe a 55-year-old female patient with gastroesophageal reflux disease (GERD) and slowly worsening dysphagia for solids. The patient was sent for barium esophagography, which disclosed an obstructing mucosal ring in the distal esophagus. The patient was then sent for endoscopy so that the ring could be treated with dilation. The authors present this case as an example of the type of patient who could obtain benefit from barium esophagography as the initial study. I disagree. In this patient’s case, the barium procedure accomplished nothing, but it did unnecessarily cost the patient money, time, and radiation exposure. The patient would have been better served by being sent directly for endoscopy at the start of her workup, so that her condition could be diagnosed and treated with a single procedure. In her case, this would have spared her any need for the barium procedure. I believe that patients with dysphagia and GERD are best served by initial endoscopy, since GERD is associated with esophageal strictures, dysplasia, and cancer. Barium esophagography can be reserved for those who have had a normal or nondiagnostic endoscopy. For example, a patient with dysphagia and a normal endoscopy might then be sent for esophagography to diagnose a motility disorder.

To the Editor: I would like to comment on the excellent review article on barium esophagography by Drs. Allen, Baker, and Falk in your February 2009 issue. In their opening clinical vignette, they describe a 55-year-old female patient with gastroesophageal reflux disease (GERD) and slowly worsening dysphagia for solids. The patient was sent for barium esophagography, which disclosed an obstructing mucosal ring in the distal esophagus. The patient was then sent for endoscopy so that the ring could be treated with dilation. The authors present this case as an example of the type of patient who could obtain benefit from barium esophagography as the initial study. I disagree. In this patient’s case, the barium procedure accomplished nothing, but it did unnecessarily cost the patient money, time, and radiation exposure. The patient would have been better served by being sent directly for endoscopy at the start of her workup, so that her condition could be diagnosed and treated with a single procedure. In her case, this would have spared her any need for the barium procedure. I believe that patients with dysphagia and GERD are best served by initial endoscopy, since GERD is associated with esophageal strictures, dysplasia, and cancer. Barium esophagography can be reserved for those who have had a normal or nondiagnostic endoscopy. For example, a patient with dysphagia and a normal endoscopy might then be sent for esophagography to diagnose a motility disorder.

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Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)

I started the study of heart-brain medicine with a symposium in Miami on June 19–20, 1978, entitled “Cerebral Manifestations of Episodic Cardiac Dysrhythmias.” One of the participants, Dr. Shlomo Stern, said, “I believe that this meeting was the first of its kind, focusing as it did on the brain/heart relationship. I do not know of a previous meeting that has been directly devoted to the subject, and I consider this as important as the discussions on the areas that we do not know much about.”

It was a very successful meeting, but little happened after we all went home. Since that time, I have felt strongly that we need to study the whole body—not just the individual “organs”—when someone has a disease. Doctors who look at the whole body (such as internists and general practitioners) do better, most of the time, at being correct in their diagnoses, whereas those who specialize in a single organ tend to be less accurate. This approach of looking at the whole body helps us all with the use of “integrated” medicine, which is more complete at “healing” at much lower cost. Healing is 20% science and 80% alternative (complementary and alternative medicine).

I am pleased with what is happening at the Heart-Brain Summits, and pleased with the great research that is ongoing at Cleveland Clinic and around the world in the area of heart-brain medicine. But I am even more pleased that patients everywhere are receiving better care because better diagnosis is taking place when the whole person is considered—body, brain, heart, spirit, and, very importantly, the mind. (See my “10 points” from the proceedings of the first Heart-Brain Summit, held in 2006.1)

The mind is separate from the brain and yet can have major effects on our health. Professional journals on the mind are becoming more pervasive. More and more, I am encountering doctors, educators, and researchers who want to discuss the mind—how the mind takes over when the brain shuts off. The mind is in us, and much is around us, and quite possibly there is some part of it connected to the cosmos.

It is interesting, and hard to understand, how the mind reacts to a placebo and causes the same change in the brain as a chemical or medication does. We have much to learn about the internal workings of the body. Many of these ideas relating to these complex connections will be covered at the 4th Annual Heart-Brain Summit, to be held in October 2009.

Although I wasn’t able to attend the 2008 Summit, I stay updated and involved with the Bakken Heart-Brain Institute and the world of knowledge that continues to emerge on the significance and importance of these multiple connections—30 years after the first meeting of this kind.

References
  1. Bakken EE. The dream behind the summit. Cleve Clin J Med 2007; 74(suppl 1):S7.
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I started the study of heart-brain medicine with a symposium in Miami on June 19–20, 1978, entitled “Cerebral Manifestations of Episodic Cardiac Dysrhythmias.” One of the participants, Dr. Shlomo Stern, said, “I believe that this meeting was the first of its kind, focusing as it did on the brain/heart relationship. I do not know of a previous meeting that has been directly devoted to the subject, and I consider this as important as the discussions on the areas that we do not know much about.”

It was a very successful meeting, but little happened after we all went home. Since that time, I have felt strongly that we need to study the whole body—not just the individual “organs”—when someone has a disease. Doctors who look at the whole body (such as internists and general practitioners) do better, most of the time, at being correct in their diagnoses, whereas those who specialize in a single organ tend to be less accurate. This approach of looking at the whole body helps us all with the use of “integrated” medicine, which is more complete at “healing” at much lower cost. Healing is 20% science and 80% alternative (complementary and alternative medicine).

I am pleased with what is happening at the Heart-Brain Summits, and pleased with the great research that is ongoing at Cleveland Clinic and around the world in the area of heart-brain medicine. But I am even more pleased that patients everywhere are receiving better care because better diagnosis is taking place when the whole person is considered—body, brain, heart, spirit, and, very importantly, the mind. (See my “10 points” from the proceedings of the first Heart-Brain Summit, held in 2006.1)

The mind is separate from the brain and yet can have major effects on our health. Professional journals on the mind are becoming more pervasive. More and more, I am encountering doctors, educators, and researchers who want to discuss the mind—how the mind takes over when the brain shuts off. The mind is in us, and much is around us, and quite possibly there is some part of it connected to the cosmos.

It is interesting, and hard to understand, how the mind reacts to a placebo and causes the same change in the brain as a chemical or medication does. We have much to learn about the internal workings of the body. Many of these ideas relating to these complex connections will be covered at the 4th Annual Heart-Brain Summit, to be held in October 2009.

Although I wasn’t able to attend the 2008 Summit, I stay updated and involved with the Bakken Heart-Brain Institute and the world of knowledge that continues to emerge on the significance and importance of these multiple connections—30 years after the first meeting of this kind.

I started the study of heart-brain medicine with a symposium in Miami on June 19–20, 1978, entitled “Cerebral Manifestations of Episodic Cardiac Dysrhythmias.” One of the participants, Dr. Shlomo Stern, said, “I believe that this meeting was the first of its kind, focusing as it did on the brain/heart relationship. I do not know of a previous meeting that has been directly devoted to the subject, and I consider this as important as the discussions on the areas that we do not know much about.”

It was a very successful meeting, but little happened after we all went home. Since that time, I have felt strongly that we need to study the whole body—not just the individual “organs”—when someone has a disease. Doctors who look at the whole body (such as internists and general practitioners) do better, most of the time, at being correct in their diagnoses, whereas those who specialize in a single organ tend to be less accurate. This approach of looking at the whole body helps us all with the use of “integrated” medicine, which is more complete at “healing” at much lower cost. Healing is 20% science and 80% alternative (complementary and alternative medicine).

I am pleased with what is happening at the Heart-Brain Summits, and pleased with the great research that is ongoing at Cleveland Clinic and around the world in the area of heart-brain medicine. But I am even more pleased that patients everywhere are receiving better care because better diagnosis is taking place when the whole person is considered—body, brain, heart, spirit, and, very importantly, the mind. (See my “10 points” from the proceedings of the first Heart-Brain Summit, held in 2006.1)

The mind is separate from the brain and yet can have major effects on our health. Professional journals on the mind are becoming more pervasive. More and more, I am encountering doctors, educators, and researchers who want to discuss the mind—how the mind takes over when the brain shuts off. The mind is in us, and much is around us, and quite possibly there is some part of it connected to the cosmos.

It is interesting, and hard to understand, how the mind reacts to a placebo and causes the same change in the brain as a chemical or medication does. We have much to learn about the internal workings of the body. Many of these ideas relating to these complex connections will be covered at the 4th Annual Heart-Brain Summit, to be held in October 2009.

Although I wasn’t able to attend the 2008 Summit, I stay updated and involved with the Bakken Heart-Brain Institute and the world of knowledge that continues to emerge on the significance and importance of these multiple connections—30 years after the first meeting of this kind.

References
  1. Bakken EE. The dream behind the summit. Cleve Clin J Med 2007; 74(suppl 1):S7.
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In reply: Barium esophagography

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In Reply: We thank Dr. Keller for his kind remarks and feedback. However, we do not necessarily agree that the case presented was a bad example of a patient to be evaluated with a barium study. While a significant distal mucosal ring was identified on the study as the cause of the patient’s symptoms, this was not known before the examination. This patient could easily have had a subtle peptic stricture as the cause of the dysphagia. It is well known that subtle strictures can be missed with endoscopy. Further, if we knew that the patient had a significant distal mucosal ring before any testing, one could argue that all that was necessary was a dilation. When one knows, after the fact, what the cause of a patient’s symptoms are, one can always retrospectively determine which tests were necessary and which tests were not.

In our experience, we find that a well-performed barium study can identify many abnormalities that further direct a patient’s care. This examination, when performed correctly, provides both functional and anatomic information about the esophagus. We believe that too many patients undergo unnecessary endoscopic procedures and that endoscopy is not necessarily the initial examination in patients with dysphagia. As a result, the barium examination of the esophagus is underused. Furthermore, we view the barium examination and endoscopy as complementary examinations. We realize this is in many respects a philosophy. But Dr. Keller is also expressing a philosophy when he states, “I believe that patients with dysphagia and GERD are best served by initial endoscopy.” We, including most of our gastroenterologists and esophageal surgeons, believe that the barium examination is an important and often the best initial examination in patients with dysphagia.

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In Reply: We thank Dr. Keller for his kind remarks and feedback. However, we do not necessarily agree that the case presented was a bad example of a patient to be evaluated with a barium study. While a significant distal mucosal ring was identified on the study as the cause of the patient’s symptoms, this was not known before the examination. This patient could easily have had a subtle peptic stricture as the cause of the dysphagia. It is well known that subtle strictures can be missed with endoscopy. Further, if we knew that the patient had a significant distal mucosal ring before any testing, one could argue that all that was necessary was a dilation. When one knows, after the fact, what the cause of a patient’s symptoms are, one can always retrospectively determine which tests were necessary and which tests were not.

In our experience, we find that a well-performed barium study can identify many abnormalities that further direct a patient’s care. This examination, when performed correctly, provides both functional and anatomic information about the esophagus. We believe that too many patients undergo unnecessary endoscopic procedures and that endoscopy is not necessarily the initial examination in patients with dysphagia. As a result, the barium examination of the esophagus is underused. Furthermore, we view the barium examination and endoscopy as complementary examinations. We realize this is in many respects a philosophy. But Dr. Keller is also expressing a philosophy when he states, “I believe that patients with dysphagia and GERD are best served by initial endoscopy.” We, including most of our gastroenterologists and esophageal surgeons, believe that the barium examination is an important and often the best initial examination in patients with dysphagia.

In Reply: We thank Dr. Keller for his kind remarks and feedback. However, we do not necessarily agree that the case presented was a bad example of a patient to be evaluated with a barium study. While a significant distal mucosal ring was identified on the study as the cause of the patient’s symptoms, this was not known before the examination. This patient could easily have had a subtle peptic stricture as the cause of the dysphagia. It is well known that subtle strictures can be missed with endoscopy. Further, if we knew that the patient had a significant distal mucosal ring before any testing, one could argue that all that was necessary was a dilation. When one knows, after the fact, what the cause of a patient’s symptoms are, one can always retrospectively determine which tests were necessary and which tests were not.

In our experience, we find that a well-performed barium study can identify many abnormalities that further direct a patient’s care. This examination, when performed correctly, provides both functional and anatomic information about the esophagus. We believe that too many patients undergo unnecessary endoscopic procedures and that endoscopy is not necessarily the initial examination in patients with dysphagia. As a result, the barium examination of the esophagus is underused. Furthermore, we view the barium examination and endoscopy as complementary examinations. We realize this is in many respects a philosophy. But Dr. Keller is also expressing a philosophy when he states, “I believe that patients with dysphagia and GERD are best served by initial endoscopy.” We, including most of our gastroenterologists and esophageal surgeons, believe that the barium examination is an important and often the best initial examination in patients with dysphagia.

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Heart-brain medicine: Update 2008

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Investigators involved in heart-brain medicine are dedicated to defining the physiology associated with interactions of the neurological and cardiovascular systems. In 2004 the Bakken Heart-Brain Institute was founded at Cleveland Clinic because we believed that furthering our understanding of this physiology could lead to a better understanding of chronic disease, define novel therapies, and improve patient outcomes.

Reprinted from Cleveland Clinic Journal of Medicine (Penn MS, Bakken EE. Heart-brain medicine: update 2007. Cleve Clin J Med 2008; 75(suppl 2):S3–S4).
Figure 1. Proposed pathways involved in psychiatrically mediated states altering cardiovascular disease and outcomes.
The 2008 Bakken Heart-Brain Summit, held last June in Cleveland, further demonstrated real progress in our understanding of the importance of heart-brain interactions in health and disease. The opening session of the 2008 Summit focused on reviewing the evidence linking psychiatric disorders—specifically depression—to increased inflammation and plaque rupture associated with worsening outcomes in patients with atherosclerotic heart disease. These pathways linking psychiatric disorders to acute coronary syndrome were proposed after the 2007 Bakken Heart-Brain Summit (Figure 1)1:

  • Depression leads to decreased vagal tone
  • Decreased vagal tone leads to increased inflammation
  • Increased inflammation leads to acute coronary syndrome.

Speakers at the 2008 Summit offered insights into the physiology, clinical measures, and molecular pathways involved in linking the heart and the brain, including:

  • Measures of heart rate variability in depression
  • The utility of heart rate variability and heart rate recovery in quantifying vagal tone and outcome in patients with and without coronary artery disease
  • Pathways of inflammation involved in acute coronary syndrome.

MOUNTING CLINICAL EVIDENCE LINKING DEPRESSION WITH CARDIAC OUTCOMES

The 2007 and 2008 Summits highlighted the link between depression and outcomes in patients with atherosclerosis (2007)1 and the potential associated mechanisms (2008). Just as exciting are the developments since last June: numerous papers have been published demonstrating this link in clinical populations, and depression screening has been included in recommendations from the American Heart Association on the treatment of patients with coronary artery disease—recommendations that are endorsed by the American Psychiatric Association.2

The studies published since June 2008 demonstrate clear links between depression and morbidity and mortality from cardiovascular causes. A recent paper from the Nurses’ Health Study showed that individuals with depression had a higher incidence of cardiovascular death.3 Notably, subjects in the Nurses’ Health Study had no clinical evidence of atherosclerotic heart disease at enrollment. In another recent study, depression was associated with worse outcomes in patients following coronary stenting.4 Finally, and most interestingly, depression was recently associated with endothelial dysfunction in patients with atypical angina and angiographically normal coronary arteries.5 Thus, regardless of the degree of underlying atherosclerosis, depression is associated with cardiovascular morbidity or mortality.

Less clear is the relationship between depression and inflammation as measured by surrogate inflammatory markers. An analysis of the Canadian Nova Scotia Health Survey [NSHS95] Prospective Population Study suggested that increased inflammatory markers accounted for only a small portion of the risk of coronary heart disease associated with depression.6 Conversely, a recent analysis of patients with stable coronary artery disease demonstrated a strong correlation between major depressive disorders and highsensitivity C-reactive protein.7

Clearly, significant work has yet to be done to fully elucidate the molecular pathways that link depression and adverse outcomes in patients at risk for coronary artery disease. That said, it is very encouraging that professional societies are beginning to recognize the value and importance of heart-brain medicine in identifying novel strategies for improving patient outcomes.

 

 

STILL ELUSIVE: EVIDENCE THAT DEPRESSION THERAPY IMPROVES CARDIAC OUTCOMES

At the 2008 Summit there was clear enthusiasm among attendees and faculty for advances in our understanding of the pathways discussed above. Since then, as reviewed above, significant publications have furthered the link between heart and brain in the setting of atherosclerotic heart disease. That said, the missing piece—the demonstration that treating depression leads to improved outcomes in patients with coronary artery disease—remains missing.

Some advances in this regard have been made. A recent study from the Enhancing Recovery In Coronary Heart Disease (ENRICHD) clinical trial demonstrated that major depression in any patient who survived myocardial infarction decreased survival over 2.5 years.8 Interestingly, and perhaps critical for an event-driven treatment trial in the future, this analysis showed an even worse outcome in patients who experienced their initial episode of major depression after their myocardial infarction.8 The need, ethics, and design of clinical trials to determine whether treatment of depression leads to improved outcomes in patients with coronary artery disease will be a major topic of the 4th Annual Heart-Brain Summit, to be held in Chicago on October 15–16, 2009.

OTHER HIGHLIGHTS, INCLUDING ROLE OF THE HEALING ENVIRONMENT

While much of the early focus of the 2008 Heart-Brain Summit was on the interaction of depression, inflammation, and outcomes in patients with coronary artery disease, a significant portion of the Summit identified other disease states and opportunities. The disease states discussed can be divided into primary cardiac, primary psychiatric, and primary neurologic. Cardiac topics under continued investigation include the role of vagal tone on the inflammatory response that regulates left ventricular remodeling following acute myocardial infarction9 as well as the role of spinal stimulation for treatment of refractory myocardial ischemia. Psychiatric disorders of interest that have been shown to modulate vagal tone include post-traumatic stress disorder,10 which has also been shown to increase the risk for coronary heart disease.11,12 Neurologically, advances concerning the polyvagal theory of autonomic nervous system control and cardiac control were discussed.13,14

On the Summit’s final day, the discussions of neuropathways, inflammation, and cardiac control gave way to presentations on the role of the healing environment. Following discussions of how depression can have significant ramifications on systemic inflammation and acute coronary syndrome, it was interesting to review data on how the presence of family and the patient environment can improve patient outcomes.

Many of the topics touched on above are discussed in greater detail in the following pages of this proceedings of the 2008 Bakken Heart-Brain Summit. We are gratified to see the advancements in the field of heartbrain medicine over the past 5 years, and especially to see the recognition the discipline is receiving in our attempt to improve patient outcomes.

FAR MORE QUESTIONS REMAIN

Without a doubt there are more questions than answers at this time. That said, by continuing the rigorous multidisciplinary approach that has served this field well to date, many questions will be answered. We hope you will join us in Chicago on October 15–16, 2009, for the 4th Annual Heart-Brain Summit, which will be jointly hosted by the Society of Heart-Brain Medicine and the Bakken Heart-Brain Institute.

References
  1. Penn MS, Bakken EE. Heart-brain medicine: update 2007. Cleve Clin J Med 2008; 75( suppl 2):S3–S4.
  2. Lichtman JH, Bigger JT, Blumenthal JA, et al. Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research. Endorsed by the American Psychiatric Association. Circulation 2008; 118:1768–1775.
  3. Whang W, Kubzansky LD, Kawachi I, et al. Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study. J Am Coll Cardiol 2009; 53:950–958.
  4. Frazier L, Vaughn W, Willerson J, Ballantyne C, Boerwinkle E Inflammatory protein levels and depression screening after coronary stenting predict major adverse coronary events [published online ahead of print February 26, 2009]. Biol Res Nurs. doi:10.1177/1099800409332801.
  5. Kim JH, Kim JW, Ko YH, et al Coronary endothelial dysfunction associated with a depressive mood in patients with atypical angina but angiographically normal coronary artery [published online ahead of print March 7, 2009]. Int J Cardiol. doi:10.1016/j.ijcard.2009.02.004.
  6. Davidson KW, Schwartz JE, Kirkland SA, et al. Relation of inflammation to depression and incident coronary heart disease (from the Canadian Nova Scotia Health Survey [NSHS95] Prospective Population Study). Am J Cardiol 2009; 103:755–761.
  7. Bankier B, Barajas J, Martinez-Rumayor A, Januzzi JL. Association between major depressive disorder and C-reactive protein levels in stable coronary heart disease patients. J Psychosom Res 2009; 66:189–194.
  8. Carney RM, Freedland KE, Steinmeyer B, et al History of depression and survival after acute myocardial infarction [published online ahead of print February 27, 2009]. Psychosom Med. doi:10.1097/PSY.0b013e31819b69e3.
  9. Vasilyev N, Williams T, Brennan ML, et al. Myeloperoxidase-generated oxidants modulate left ventricular remodeling but not infarct size after myocardial infarction. Circulation 2005; 112:2812–2820.
  10. Sack M, Hopper JW, Lamprecht F. Low respiratory sinus arrhythmia and prolonged psychophysiological arousal in posttraumatic stress disorder: heart rate dynamics and individual differences in arousal regulation. Biol Psychiatry 2004; 55:284–290.
  11. Kubzansky LD, Koenen KC, Jones C, Eaton WW. A prospective study of posttraumatic stress disorder symptoms and coronary heart disease in women. Health Psychol 2009; 28:125–130.
  12. Kubzansky LD, Koenen KC, Spiro A, Vokonas PS, Sparrow D. Prospective study of posttraumatic stress disorder symptoms and coronary heart disease in the Normative Aging Study. Arch Gen Psychiatry 2007; 64:109–116.
  13. Porges SW. The polyvagal perspective. Biol Psychol 2007; 74:116–143.
  14. Porges SW. The polyvagal theory: phylogenetic substrates of a social nervous system. Int J Psychophysiol 2001; 42:123–146.
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Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)
Founder and Director Emeritus, Medtronic, Inc., Minneapolis, MN Founder, The Earl and Doris Bakken Heart-Brain Institute

Correspondence: Marc S. Penn, MD, PhD, Director, Bakken Heart-Brain Institute, Cleveland Clinic, 9500 Euclid Avenue, J2-4, Cleveland, OH 44195; [email protected]

Author and Disclosure Information

Marc S. Penn, MD, PhD
Director, The Earl and Doris Bakken Heart-Brain Institute, Cleveland Clinic, Cleveland, OH

Earl E. Bakken, MD, HonC, Hon DSc (3), Hon DHL (2)
Founder and Director Emeritus, Medtronic, Inc., Minneapolis, MN Founder, The Earl and Doris Bakken Heart-Brain Institute

Correspondence: Marc S. Penn, MD, PhD, Director, Bakken Heart-Brain Institute, Cleveland Clinic, 9500 Euclid Avenue, J2-4, Cleveland, OH 44195; [email protected]

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Investigators involved in heart-brain medicine are dedicated to defining the physiology associated with interactions of the neurological and cardiovascular systems. In 2004 the Bakken Heart-Brain Institute was founded at Cleveland Clinic because we believed that furthering our understanding of this physiology could lead to a better understanding of chronic disease, define novel therapies, and improve patient outcomes.

Reprinted from Cleveland Clinic Journal of Medicine (Penn MS, Bakken EE. Heart-brain medicine: update 2007. Cleve Clin J Med 2008; 75(suppl 2):S3–S4).
Figure 1. Proposed pathways involved in psychiatrically mediated states altering cardiovascular disease and outcomes.
The 2008 Bakken Heart-Brain Summit, held last June in Cleveland, further demonstrated real progress in our understanding of the importance of heart-brain interactions in health and disease. The opening session of the 2008 Summit focused on reviewing the evidence linking psychiatric disorders—specifically depression—to increased inflammation and plaque rupture associated with worsening outcomes in patients with atherosclerotic heart disease. These pathways linking psychiatric disorders to acute coronary syndrome were proposed after the 2007 Bakken Heart-Brain Summit (Figure 1)1:

  • Depression leads to decreased vagal tone
  • Decreased vagal tone leads to increased inflammation
  • Increased inflammation leads to acute coronary syndrome.

Speakers at the 2008 Summit offered insights into the physiology, clinical measures, and molecular pathways involved in linking the heart and the brain, including:

  • Measures of heart rate variability in depression
  • The utility of heart rate variability and heart rate recovery in quantifying vagal tone and outcome in patients with and without coronary artery disease
  • Pathways of inflammation involved in acute coronary syndrome.

MOUNTING CLINICAL EVIDENCE LINKING DEPRESSION WITH CARDIAC OUTCOMES

The 2007 and 2008 Summits highlighted the link between depression and outcomes in patients with atherosclerosis (2007)1 and the potential associated mechanisms (2008). Just as exciting are the developments since last June: numerous papers have been published demonstrating this link in clinical populations, and depression screening has been included in recommendations from the American Heart Association on the treatment of patients with coronary artery disease—recommendations that are endorsed by the American Psychiatric Association.2

The studies published since June 2008 demonstrate clear links between depression and morbidity and mortality from cardiovascular causes. A recent paper from the Nurses’ Health Study showed that individuals with depression had a higher incidence of cardiovascular death.3 Notably, subjects in the Nurses’ Health Study had no clinical evidence of atherosclerotic heart disease at enrollment. In another recent study, depression was associated with worse outcomes in patients following coronary stenting.4 Finally, and most interestingly, depression was recently associated with endothelial dysfunction in patients with atypical angina and angiographically normal coronary arteries.5 Thus, regardless of the degree of underlying atherosclerosis, depression is associated with cardiovascular morbidity or mortality.

Less clear is the relationship between depression and inflammation as measured by surrogate inflammatory markers. An analysis of the Canadian Nova Scotia Health Survey [NSHS95] Prospective Population Study suggested that increased inflammatory markers accounted for only a small portion of the risk of coronary heart disease associated with depression.6 Conversely, a recent analysis of patients with stable coronary artery disease demonstrated a strong correlation between major depressive disorders and highsensitivity C-reactive protein.7

Clearly, significant work has yet to be done to fully elucidate the molecular pathways that link depression and adverse outcomes in patients at risk for coronary artery disease. That said, it is very encouraging that professional societies are beginning to recognize the value and importance of heart-brain medicine in identifying novel strategies for improving patient outcomes.

 

 

STILL ELUSIVE: EVIDENCE THAT DEPRESSION THERAPY IMPROVES CARDIAC OUTCOMES

At the 2008 Summit there was clear enthusiasm among attendees and faculty for advances in our understanding of the pathways discussed above. Since then, as reviewed above, significant publications have furthered the link between heart and brain in the setting of atherosclerotic heart disease. That said, the missing piece—the demonstration that treating depression leads to improved outcomes in patients with coronary artery disease—remains missing.

Some advances in this regard have been made. A recent study from the Enhancing Recovery In Coronary Heart Disease (ENRICHD) clinical trial demonstrated that major depression in any patient who survived myocardial infarction decreased survival over 2.5 years.8 Interestingly, and perhaps critical for an event-driven treatment trial in the future, this analysis showed an even worse outcome in patients who experienced their initial episode of major depression after their myocardial infarction.8 The need, ethics, and design of clinical trials to determine whether treatment of depression leads to improved outcomes in patients with coronary artery disease will be a major topic of the 4th Annual Heart-Brain Summit, to be held in Chicago on October 15–16, 2009.

OTHER HIGHLIGHTS, INCLUDING ROLE OF THE HEALING ENVIRONMENT

While much of the early focus of the 2008 Heart-Brain Summit was on the interaction of depression, inflammation, and outcomes in patients with coronary artery disease, a significant portion of the Summit identified other disease states and opportunities. The disease states discussed can be divided into primary cardiac, primary psychiatric, and primary neurologic. Cardiac topics under continued investigation include the role of vagal tone on the inflammatory response that regulates left ventricular remodeling following acute myocardial infarction9 as well as the role of spinal stimulation for treatment of refractory myocardial ischemia. Psychiatric disorders of interest that have been shown to modulate vagal tone include post-traumatic stress disorder,10 which has also been shown to increase the risk for coronary heart disease.11,12 Neurologically, advances concerning the polyvagal theory of autonomic nervous system control and cardiac control were discussed.13,14

On the Summit’s final day, the discussions of neuropathways, inflammation, and cardiac control gave way to presentations on the role of the healing environment. Following discussions of how depression can have significant ramifications on systemic inflammation and acute coronary syndrome, it was interesting to review data on how the presence of family and the patient environment can improve patient outcomes.

Many of the topics touched on above are discussed in greater detail in the following pages of this proceedings of the 2008 Bakken Heart-Brain Summit. We are gratified to see the advancements in the field of heartbrain medicine over the past 5 years, and especially to see the recognition the discipline is receiving in our attempt to improve patient outcomes.

FAR MORE QUESTIONS REMAIN

Without a doubt there are more questions than answers at this time. That said, by continuing the rigorous multidisciplinary approach that has served this field well to date, many questions will be answered. We hope you will join us in Chicago on October 15–16, 2009, for the 4th Annual Heart-Brain Summit, which will be jointly hosted by the Society of Heart-Brain Medicine and the Bakken Heart-Brain Institute.

Investigators involved in heart-brain medicine are dedicated to defining the physiology associated with interactions of the neurological and cardiovascular systems. In 2004 the Bakken Heart-Brain Institute was founded at Cleveland Clinic because we believed that furthering our understanding of this physiology could lead to a better understanding of chronic disease, define novel therapies, and improve patient outcomes.

Reprinted from Cleveland Clinic Journal of Medicine (Penn MS, Bakken EE. Heart-brain medicine: update 2007. Cleve Clin J Med 2008; 75(suppl 2):S3–S4).
Figure 1. Proposed pathways involved in psychiatrically mediated states altering cardiovascular disease and outcomes.
The 2008 Bakken Heart-Brain Summit, held last June in Cleveland, further demonstrated real progress in our understanding of the importance of heart-brain interactions in health and disease. The opening session of the 2008 Summit focused on reviewing the evidence linking psychiatric disorders—specifically depression—to increased inflammation and plaque rupture associated with worsening outcomes in patients with atherosclerotic heart disease. These pathways linking psychiatric disorders to acute coronary syndrome were proposed after the 2007 Bakken Heart-Brain Summit (Figure 1)1:

  • Depression leads to decreased vagal tone
  • Decreased vagal tone leads to increased inflammation
  • Increased inflammation leads to acute coronary syndrome.

Speakers at the 2008 Summit offered insights into the physiology, clinical measures, and molecular pathways involved in linking the heart and the brain, including:

  • Measures of heart rate variability in depression
  • The utility of heart rate variability and heart rate recovery in quantifying vagal tone and outcome in patients with and without coronary artery disease
  • Pathways of inflammation involved in acute coronary syndrome.

MOUNTING CLINICAL EVIDENCE LINKING DEPRESSION WITH CARDIAC OUTCOMES

The 2007 and 2008 Summits highlighted the link between depression and outcomes in patients with atherosclerosis (2007)1 and the potential associated mechanisms (2008). Just as exciting are the developments since last June: numerous papers have been published demonstrating this link in clinical populations, and depression screening has been included in recommendations from the American Heart Association on the treatment of patients with coronary artery disease—recommendations that are endorsed by the American Psychiatric Association.2

The studies published since June 2008 demonstrate clear links between depression and morbidity and mortality from cardiovascular causes. A recent paper from the Nurses’ Health Study showed that individuals with depression had a higher incidence of cardiovascular death.3 Notably, subjects in the Nurses’ Health Study had no clinical evidence of atherosclerotic heart disease at enrollment. In another recent study, depression was associated with worse outcomes in patients following coronary stenting.4 Finally, and most interestingly, depression was recently associated with endothelial dysfunction in patients with atypical angina and angiographically normal coronary arteries.5 Thus, regardless of the degree of underlying atherosclerosis, depression is associated with cardiovascular morbidity or mortality.

Less clear is the relationship between depression and inflammation as measured by surrogate inflammatory markers. An analysis of the Canadian Nova Scotia Health Survey [NSHS95] Prospective Population Study suggested that increased inflammatory markers accounted for only a small portion of the risk of coronary heart disease associated with depression.6 Conversely, a recent analysis of patients with stable coronary artery disease demonstrated a strong correlation between major depressive disorders and highsensitivity C-reactive protein.7

Clearly, significant work has yet to be done to fully elucidate the molecular pathways that link depression and adverse outcomes in patients at risk for coronary artery disease. That said, it is very encouraging that professional societies are beginning to recognize the value and importance of heart-brain medicine in identifying novel strategies for improving patient outcomes.

 

 

STILL ELUSIVE: EVIDENCE THAT DEPRESSION THERAPY IMPROVES CARDIAC OUTCOMES

At the 2008 Summit there was clear enthusiasm among attendees and faculty for advances in our understanding of the pathways discussed above. Since then, as reviewed above, significant publications have furthered the link between heart and brain in the setting of atherosclerotic heart disease. That said, the missing piece—the demonstration that treating depression leads to improved outcomes in patients with coronary artery disease—remains missing.

Some advances in this regard have been made. A recent study from the Enhancing Recovery In Coronary Heart Disease (ENRICHD) clinical trial demonstrated that major depression in any patient who survived myocardial infarction decreased survival over 2.5 years.8 Interestingly, and perhaps critical for an event-driven treatment trial in the future, this analysis showed an even worse outcome in patients who experienced their initial episode of major depression after their myocardial infarction.8 The need, ethics, and design of clinical trials to determine whether treatment of depression leads to improved outcomes in patients with coronary artery disease will be a major topic of the 4th Annual Heart-Brain Summit, to be held in Chicago on October 15–16, 2009.

OTHER HIGHLIGHTS, INCLUDING ROLE OF THE HEALING ENVIRONMENT

While much of the early focus of the 2008 Heart-Brain Summit was on the interaction of depression, inflammation, and outcomes in patients with coronary artery disease, a significant portion of the Summit identified other disease states and opportunities. The disease states discussed can be divided into primary cardiac, primary psychiatric, and primary neurologic. Cardiac topics under continued investigation include the role of vagal tone on the inflammatory response that regulates left ventricular remodeling following acute myocardial infarction9 as well as the role of spinal stimulation for treatment of refractory myocardial ischemia. Psychiatric disorders of interest that have been shown to modulate vagal tone include post-traumatic stress disorder,10 which has also been shown to increase the risk for coronary heart disease.11,12 Neurologically, advances concerning the polyvagal theory of autonomic nervous system control and cardiac control were discussed.13,14

On the Summit’s final day, the discussions of neuropathways, inflammation, and cardiac control gave way to presentations on the role of the healing environment. Following discussions of how depression can have significant ramifications on systemic inflammation and acute coronary syndrome, it was interesting to review data on how the presence of family and the patient environment can improve patient outcomes.

Many of the topics touched on above are discussed in greater detail in the following pages of this proceedings of the 2008 Bakken Heart-Brain Summit. We are gratified to see the advancements in the field of heartbrain medicine over the past 5 years, and especially to see the recognition the discipline is receiving in our attempt to improve patient outcomes.

FAR MORE QUESTIONS REMAIN

Without a doubt there are more questions than answers at this time. That said, by continuing the rigorous multidisciplinary approach that has served this field well to date, many questions will be answered. We hope you will join us in Chicago on October 15–16, 2009, for the 4th Annual Heart-Brain Summit, which will be jointly hosted by the Society of Heart-Brain Medicine and the Bakken Heart-Brain Institute.

References
  1. Penn MS, Bakken EE. Heart-brain medicine: update 2007. Cleve Clin J Med 2008; 75( suppl 2):S3–S4.
  2. Lichtman JH, Bigger JT, Blumenthal JA, et al. Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research. Endorsed by the American Psychiatric Association. Circulation 2008; 118:1768–1775.
  3. Whang W, Kubzansky LD, Kawachi I, et al. Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study. J Am Coll Cardiol 2009; 53:950–958.
  4. Frazier L, Vaughn W, Willerson J, Ballantyne C, Boerwinkle E Inflammatory protein levels and depression screening after coronary stenting predict major adverse coronary events [published online ahead of print February 26, 2009]. Biol Res Nurs. doi:10.1177/1099800409332801.
  5. Kim JH, Kim JW, Ko YH, et al Coronary endothelial dysfunction associated with a depressive mood in patients with atypical angina but angiographically normal coronary artery [published online ahead of print March 7, 2009]. Int J Cardiol. doi:10.1016/j.ijcard.2009.02.004.
  6. Davidson KW, Schwartz JE, Kirkland SA, et al. Relation of inflammation to depression and incident coronary heart disease (from the Canadian Nova Scotia Health Survey [NSHS95] Prospective Population Study). Am J Cardiol 2009; 103:755–761.
  7. Bankier B, Barajas J, Martinez-Rumayor A, Januzzi JL. Association between major depressive disorder and C-reactive protein levels in stable coronary heart disease patients. J Psychosom Res 2009; 66:189–194.
  8. Carney RM, Freedland KE, Steinmeyer B, et al History of depression and survival after acute myocardial infarction [published online ahead of print February 27, 2009]. Psychosom Med. doi:10.1097/PSY.0b013e31819b69e3.
  9. Vasilyev N, Williams T, Brennan ML, et al. Myeloperoxidase-generated oxidants modulate left ventricular remodeling but not infarct size after myocardial infarction. Circulation 2005; 112:2812–2820.
  10. Sack M, Hopper JW, Lamprecht F. Low respiratory sinus arrhythmia and prolonged psychophysiological arousal in posttraumatic stress disorder: heart rate dynamics and individual differences in arousal regulation. Biol Psychiatry 2004; 55:284–290.
  11. Kubzansky LD, Koenen KC, Jones C, Eaton WW. A prospective study of posttraumatic stress disorder symptoms and coronary heart disease in women. Health Psychol 2009; 28:125–130.
  12. Kubzansky LD, Koenen KC, Spiro A, Vokonas PS, Sparrow D. Prospective study of posttraumatic stress disorder symptoms and coronary heart disease in the Normative Aging Study. Arch Gen Psychiatry 2007; 64:109–116.
  13. Porges SW. The polyvagal perspective. Biol Psychol 2007; 74:116–143.
  14. Porges SW. The polyvagal theory: phylogenetic substrates of a social nervous system. Int J Psychophysiol 2001; 42:123–146.
References
  1. Penn MS, Bakken EE. Heart-brain medicine: update 2007. Cleve Clin J Med 2008; 75( suppl 2):S3–S4.
  2. Lichtman JH, Bigger JT, Blumenthal JA, et al. Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research. Endorsed by the American Psychiatric Association. Circulation 2008; 118:1768–1775.
  3. Whang W, Kubzansky LD, Kawachi I, et al. Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study. J Am Coll Cardiol 2009; 53:950–958.
  4. Frazier L, Vaughn W, Willerson J, Ballantyne C, Boerwinkle E Inflammatory protein levels and depression screening after coronary stenting predict major adverse coronary events [published online ahead of print February 26, 2009]. Biol Res Nurs. doi:10.1177/1099800409332801.
  5. Kim JH, Kim JW, Ko YH, et al Coronary endothelial dysfunction associated with a depressive mood in patients with atypical angina but angiographically normal coronary artery [published online ahead of print March 7, 2009]. Int J Cardiol. doi:10.1016/j.ijcard.2009.02.004.
  6. Davidson KW, Schwartz JE, Kirkland SA, et al. Relation of inflammation to depression and incident coronary heart disease (from the Canadian Nova Scotia Health Survey [NSHS95] Prospective Population Study). Am J Cardiol 2009; 103:755–761.
  7. Bankier B, Barajas J, Martinez-Rumayor A, Januzzi JL. Association between major depressive disorder and C-reactive protein levels in stable coronary heart disease patients. J Psychosom Res 2009; 66:189–194.
  8. Carney RM, Freedland KE, Steinmeyer B, et al History of depression and survival after acute myocardial infarction [published online ahead of print February 27, 2009]. Psychosom Med. doi:10.1097/PSY.0b013e31819b69e3.
  9. Vasilyev N, Williams T, Brennan ML, et al. Myeloperoxidase-generated oxidants modulate left ventricular remodeling but not infarct size after myocardial infarction. Circulation 2005; 112:2812–2820.
  10. Sack M, Hopper JW, Lamprecht F. Low respiratory sinus arrhythmia and prolonged psychophysiological arousal in posttraumatic stress disorder: heart rate dynamics and individual differences in arousal regulation. Biol Psychiatry 2004; 55:284–290.
  11. Kubzansky LD, Koenen KC, Jones C, Eaton WW. A prospective study of posttraumatic stress disorder symptoms and coronary heart disease in women. Health Psychol 2009; 28:125–130.
  12. Kubzansky LD, Koenen KC, Spiro A, Vokonas PS, Sparrow D. Prospective study of posttraumatic stress disorder symptoms and coronary heart disease in the Normative Aging Study. Arch Gen Psychiatry 2007; 64:109–116.
  13. Porges SW. The polyvagal perspective. Biol Psychol 2007; 74:116–143.
  14. Porges SW. The polyvagal theory: phylogenetic substrates of a social nervous system. Int J Psychophysiol 2001; 42:123–146.
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Bakken Lecture: The brain, the heart, and therapeutic hypothermia

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Bakken Lecture: The brain, the heart, and therapeutic hypothermia
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Patrick M. Kochanek, MD

Therapeutic hypothermia has been a central focus of research at the Safar Center for Resuscitation Research since the center was founded—as the International Resuscitation Research Center—at the University of Pittsburgh School of Medicine in 1979. In this article, which is based on my 2008 Bakken Lecture, I will discuss historical, contemporary, and futuristic applications of therapeutic hypothermia. Given that the key mission of the Safar Center is “to save hearts and brains too good to die,” the basis of my discussion will consist of how therapeutic hypothermia impacts both heart and brain—and the lessons that can be learned in each case.

THERAPEUTIC HYPOTHERMIA: A HISTORICAL PERSPECTIVE

Reprinted, with permission, from Journal of the Iowa Medical Society (Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc 1964; 54:629–635).
Figure 1. Classic publication of the “first ABCs of resuscitation” by the late Dr. Peter Safar. As shown, therapeutic hypothermia was recommended for use in comatose patients who achieve restoration of spontaneous circulation, even in the 1960s.3
The late Dr. Peter Safar and his colleague, the late Dr. Hubert Rosomoff, played an instrumental role in the use of therapeutic hypothermia in the early 1960s in patients with acute neurological insults. Their classic 1965 publication, “Management of the comatose patient,”1 contained recommendations that in many ways outline the current use of mild therapeutic hypothermia as recommended by the American Heart Association and the International Liaison Committee on Resuscitation.2 In addition, in 1964, Dr. Safar recommended in his historic “first ABCs of resuscitation” that hypothermia be used in patients who remain comatose after successful restoration of spontaneous circulation (Figure 1).3 That recommendation holds true in today’s guidelines.2 However, therapeutic hypothermia in acute resuscitation medicine has a remarkably long history.

Baron Dominique Jean Larrey, surgeon-in-chief of the Napoleonic armies and the father of modern military medicine, observed in 1814 that the wounded “privileged” soldiers lying closer to the campfire died sooner than those in more remote, colder areas.4 Similarly, Dr. Charles Phelps, surgeon to the New York City Police Department, in 1897 recommended the use of the “ice cap” for traumatic brain injury.5

In the 1980s, however, therapeutic hypothermia began to fall out of favor. This resulted, in part, from overzealous application in some patients, who were treated for durations longer than a week and at temperatures in the moderate (28°C to 32°C) rather than mild (33°C to 35°C) range. This led to an increase in complications.6 Laboratory studies in a rat model of global cerebral ischemia by Busto et al 7 in 1987 and in a canine model of cardiac arrest by Leonov et al8 in 1990 demonstrated that benefit could be produced using mild cooling after the insult. This and parallel work in neonatology led to the ultimate breakthrough that translated into improved outcomes with the use of mild therapeutic hypothermia in adults with cardiac arrest9,10 and in newborns with hypoxic-ischemic encephalopathy.11

Clinicians and scientists familiar with hypothermia might suggest that its potential therapeutic benefit has been known for decades, given the use of hypothermic circulatory arrest for neuroprotection and cardioprotection in open heart surgery. However, one of the most interesting aspects of neuroprotection provided by mild therapeutic hypothermia is that it is not clearly linked to attenuation of energy failure.7 Unlike the setting of deep hypothermic circulatory arrest—where the induction of hypothermia occurs before the insult, and levels of hypothermia are such that energy failure is prevented—mild cooling, applied after cardiac arrest, appears to confer benefit by other mechanisms. Effects on cell signaling, oxidative and nitrative stress, apoptosis, excitotoxicity, and other mechanisms appear to mediate this benefit.12,13

THERAPEUTIC HYPOTHERMIA: CONTEMPORARY APPLICATION

Use in cardiac arrest

Compared with normothermia, mild therapeutic hypothermia, induced immediately after restoration of spontaneous circulation in comatose survivors of ventricular fibrillation cardiac arrest, leads to 1 additional patient with intact neurological outcome for every 6 patients treated.9 This is a remarkable effect given the extremely poor overall outcomes observed after out-of-hospital cardiac arrest. Studies in animal models, however, suggest that the therapeutic potential of mild hypothermia can be maximized with application either during or as early as possible after the insult.14 However, clinicians in the field of cardiology appropriately have cause for concern about the possibility that even mild cooling could reduce that potential for successful defibrillation or lead to re-arrest. In 2005, an important paper by Boddicker et al15 explored the impact of mild hypothermia on defibrillation success in experimental ventricular fibrillation in pigs and found, remarkably, that the success rate actually improved with mild or moderate hypothermia! That report opened the door for a number of studies that are now focused on rapid cooling during cardiopulmonary resuscitation (CPR) and on the rapid induction of mild hypothermia using intravenous cooling.16,17

Support for the use of intra-arrest cooling came initially from work in animal models of cardiac arrest—first from the work of Abella et al18 in a mouse model of potassium-induced cardiac arrest, and later from a canine model in work by Nozari et al.19 In the latter study, delaying the onset of mild hypothermia during advanced cardiac life support markedly worsened both multisystem organ failure and survival. Cardiovascular function in that model appeared to be substantively improved by early intra-arrest cooling.

The potential for the use of intravenous cooling in patients with a bolus of crystalloid to induce mild hypothermia was pioneered in a seminal paper by Bernard et al.16 In that report, an approximately 2°C reduction in core temperature could be achieved with infusion of about 30 mL/kg of fluid over 30 minutes. Mean arterial blood pressure increased mildly, and the intervention was well tolerated when applied early after restoration of spontaneous circulation. Kim and colleagues20 built upon that initial work and demonstrated the feasibility of the use of intravenous iced normal saline to induce mild hypothermia by paramedics in the prehospital setting. This approach, and its impact on neurological outcome and survival, is currently being evaluated in a randomized controlled trial. Combining intra-arrest cooling with the use of intravenous fluids is the obvious next step. This could facilitate rapid induction, which could then be maintained with commercially available surface cooling devices.21

 

 

Cardiac arrest vs traumatic brain injury

One of the interesting aspects of the beneficial effects of mild therapeutic hypothermia in the setting of cardiac arrest relates to the following question: Why is hypothermia effective in improving neurological outcome after cardiac arrest while it has been more difficult to demonstrate benefit in other acute neurological insults, such as traumatic brain injury?22

Application of hypothermia in cardiac arrest may represent something of a “perfect storm.” First, a recent study by Berger et al23 provides some insight into the time course of neuronal death after cardiac arrest versus traumatic brain injury. In that study of children who suffered either cardiac arrest or severe traumatic brain injury requiring management in the intensive care unit, peak levels of the serum biomarker of neuronal death, neuron-specific enolase (NSE), occurred days after cardiac arrest, whereas they occurred generally within a few hours of traumatic brain injury. This suggests a broader therapeutic window for the application of mild hypothermia in cardiac arrest as opposed to traumatic brain injury. In addition, the only neuroprotective therapy used in cardiac arrest is mild hypothermia. In contrast, in traumatic brain injury, myriad therapies are part of standard of care, including intracranial pressure monitoring and cerebrospinal fluid drainage, mannitol, hypertonic saline, barbiturates, and surgical interventions such as decompressive craniectomy.24 These intracranial pressure–directed therapies in traumatic brain injury may confer a variety of neuroprotective actions, thus raising the bar for hypothermia to show benefit. A similar case could be made regarding the surgical treatment of subarachnoid hemorrhage, where hypothermia has been ineffective.25

Efforts to optimize hypothermia

Given the benefit of mild therapeutic hypothermia in cardiac arrest, we and other investigative teams are actively pursuing ways to further optimize its effects beyond the use of a more rapid induction, as discussed above.

One of the most overlooked areas of study relates to hypothermia’s profound effects on drug metabolism; despite the need for many drugs in critically ill patients after cardiac arrest, knowledge of how hypothermia alters drug metabolism and how best to adjust drug doses is limited. Therapeutic hypothermia has recently been shown, during cooling, to directly inhibit binding of drugs to the active site of the key drug-metabolizing enzyme, cytochrome P450.26 In contrast, in the setting of experimental cardiac arrest and resuscitation, mild hypothermia also protects against induction of cytokines such as interleukin-6, which downregulates cytochrome P450. Thus, mild hypothermia reduces drug metabolism during cooling but leads to a better recovery of drug metabolism after rewarming. This dichotomous effect will need to be studied at the bedside. Hypothermia can also reduce drug effects.26 Thus, until we know how to optimally dose various therapies in patients treated with hypothermia, it is probably best to carefully monitor levels (when possible) and also drug effects. The best example of this at the bedside is the use of monitoring neuromuscular blockade in patients treated with vecuronium or pancuronium during mild hypothermia.

Another interesting area of study involves defining the best anesthetics or sedatives to use with cooling. For example, a recent report by Statler et al27 showed that hypothermia was much less effective as a neuroprotectant after experimental traumatic brain injury in rats anesthetized with fentanyl than with isoflurane. In that study, fentanyl was unable to blunt the stress response to cooling. Given the variety of sedatives and analgesics used at the beside in both neurointensive care units and coronary care units, understanding which agents work best with hypothermia could further enhance hypothermia’s therapeutic benefit.

There is also a search for agents that may promote induction of hypothermia or create a poikilothermic state, thereby facilitating tolerance of the hypothermic state without a stress response. One agent that has shown some promise in the setting of experimental cardiac arrest is the endogenous peptide neurotensin, which has direct effects on temperature regulation at the hypothalamic level. In an experimental model of asphyxial cardiac arrest in rats, Katz et al28 reported that the neurotensin analog NT69L facilitated induction of hypothermia and improved outcome. Another agent that has been touted to induce a state of “hibernation on demand” is hydrogen sulfide gas. A recent experiment by Blackstone et al29 demonstrated induction of deep hypothermia and a hibernation-like state in mice allowed to breathe hydrogen sulfide gas at 80 parts per million. This state was completely reversible upon discontinuation of the agent. Unfortunately, studies in large animal models have not been able to demonstrate induction of hypothermia with this approach.30 Nevertheless, these drugs represent prototypes for future exploration; if the right agent is found, it could lead, in theory, to markedly enhanced efficacy of cooling.

 

 

FUTURISTIC APPLICATIONS OF THERAPEUTIC HYPOTHERMIA

Emergency preservation and resuscitation

Exsanguination cardiac arrest is one of the most refractory types of cardiac arrest, with mortality rates generally greater than 95%.31 Obviously, therapies such as CPR are ineffective in the absence of an adequate circulating blood volume.

Figure 2. Schematic of aortic cold flush for the induction of emergency preservation and resuscitation (EPR) to rapidly create a transient state of hypothermic preservation in otherwise lethally injured victims of exsanguination cardiac arrest. After damage-control surgery, resuscitation is performed via cardiopulmonary bypass (see text for details).
In 1984, Dr. Peter Safar and military expert Col Ronald Bellamy pioneered a new approach to exsanguination cardiac arrest that they called suspended animation for delayed resuscitation. The concept was a logical one—namely, in the setting of otherwise lethal trauma-induced exsanguination cardiac arrest, a transient state of preservation would be induced to buy time for damage-control surgery, and then a delayed resuscitation would be carried out using cardiopulmonary bypass. Our center has worked on this concept since 1988 in studies funded initially by the US Navy and later by the US Congress. Ultimately, we coined the phrase emergency preservation and resuscitation (EPR) for this method. Using a canine model of exsanguination cardiac arrest, we first demonstrated the feasibility of this approach by inducing a state of preservation via an aortic flush of iced saline.32 A schematic of the protocol is presented in Figure 2.

In initial reports,32–34 we targeted relatively brief insults ranging from 15 to 60 minutes. We determined that for insults at or beyond 60 minutes, profound levels of hypothermia (tympanic temperature of ~10°C) were most effective.34 In subsequent studies, we demonstrated that pharmacologic adjuncts to hypothermia were relatively ineffective. Indeed, only one agent, the brain-penetrating antioxidant Tempol, enhanced the efficacy of profound hypothermia.35 We also demonstrated that the prolonged use (36 to 48 hours) of mild hypothermia after the acute application of EPR further enhanced neurological outcomes as compared with more rapid rewarming.36 Similarly, unlike drugs, the addition of energy substrates (namely, dissolved oxygen and 2.5% dextrose) to the flush facilitated the ability to achieve remarkably long EPR durations in experimental exsanguination cardiac arrest—as long as 3 hours of preservation at approximately 10°C.37 These findings could also have important implications for optimizing conventional use of deep hypothermia circulatory arrest in cardiac or neurological surgery. We also have recently developed a rat model of EPR using a miniaturized cardiopulmonary bypass system. It is used to screen novel therapeutic adjuncts to EPR and to study mechanisms of neuroprotection in this special paradigm.38,39

Two other investigative teams, one at Harvard University and another at the Vienna General Hospital, have also been exploring the use of EPR-related technologies—and observing similar success. Alam et al40 have used a low-flow EPR approach in pigs to facilitate damage-control surgery after otherwise lethal traumatic insults. Janata et al41 have successfully used EPR in the setting of refractory normovolemic cardiac arrest, simulating the typical cardiac arrest victim who cannot be resuscitated in either the field or the emergency department.

Finally, the EPR concept recently received funding to proceed to a clinical trial in civilian trauma. The study, to be led by Dr. Samuel Tisherman, one of the pioneers of this approach at the Safar Center, will include several trauma centers in the United States and target otherwise lethally injured trauma victims with exsanguination cardiac arrest.

References
  1. Rosomoff HL, Safar P. Management of the comatose patient. In:Safar P, ed. Respiratory Therapy. Philadelphia, PA: FA Davis Co; 1965:244–258.
  2. Storm C, Schefold JC, Nibbe L, et al. Therapeutic hypothermia after cardiac arrest—the implementation of the ILCOR guidelines in clinical routine is possible! Crit Care 2006; 10:425.
  3. Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc 1964:629–635.
  4. Larrey DJ. Memoirs of Military Surgery and Campaigns of the French Armies. Baltimore, MD: Joseph Cushing/University Press of Sergeant Hall;1814.
  5. Phelps C. Traumatic injuries of the brain and its membranes. In:Phelps C, ed. Traumatic Injuries of the Brain and Its Membranes. New York, NY: D Appleton & Co; 1897:223–224.
  6. Bohn DJ, Biggar WD, Smith CR, Conn AW, Barker GA. Influence of hypothermia, barbiturate therapy, and intracranial pressure monitoring on morbidity and mortality after near-drowning. Crit Care Med 1986; 14:529–534.
  7. Busto R, Dietrich WD, Globus MY, Valdés I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987; 7:729–738.
  8. Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab 1990; 10:57–70.
  9. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549–556.
  10. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557–563.
  11. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:1574–1584.
  12. Kochanek PM, Jenkins LW, Clark RSB. Traumatic brain injury: laboratory studies. In:Tisherman SA, Sterz F, eds. Therapeutic Hypothermia. New York, NY: Springer; 2005:63–86.
  13. Zhao H, Steinberg GK, Sapolsky RM. General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage. J Cereb Blood Flow Metab 2007; 27:1879–1894.
  14. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 1993; 21:1348–1358.
  15. Boddicker KA, Zhang Y, Zimmerman MB, Davies LR, Kerber RE. Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation. Circulation 2005; 111:3195–3201.
  16. Bernard S, Buist M, Monteiro O, Smith K. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 2003; 56:9–13.
  17. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med 2005; 33:2744–2751.
  18. Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation 2004; 109:2786–2791.
  19. Nozari A, Safar P, Wu X, et al. Suspended animation can allow survival without brain damage after traumatic exsanguination cardiac arrest of 60 minutes in dogs. J Trauma 2004; 57:1266–1275.
  20. Kim F, Olsufka M, Longstreth WT, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007; 115:3064–3070.
  21. Haugk M, Sterz F, Grassberger M, et al. Feasibility and efficacy of a new non-invasive surface cooling device in post-resuscitation intensive care medicine. Resuscitation 2007; 75:76–81.
  22. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008; 358:2447–2456.
  23. Berger RP, Adelson PD, Richichi R, Kochanek PM. Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the biochemical response of the pediatric brain to inflicted brain injury. Dev Neurosci 2006; 28:327–335.
  24. , et al., Brain Trauma Foundation. Guidelines for the management of severe traumatic brain injury:. Introduction. J Neurotrauma 2007; 24( suppl 1):S1–S2.
  25. Todd MM, Hindman BJ, Clarke WR, Torner JCIntraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005; 352:135–145.
  26. Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med 2007; 35:2196–2204.
  27. Statler KD, Alexander HL, Vagni VA, et al. Moderate hypothermia may be detrimental after traumatic brain injury in fentanylanesthetized rats. Crit Care Med 2003; 31:1134–1139.
  28. Katz LM, Wang Y, McMahon B, Richelson E. Neurotensin analog NT69L induces rapid and prolonged hypothermia after hypoxic ischemia. Acad Emerg Med 2001; 8:1115–1121.
  29. Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science 2005; 308:518.
  30. Li J, Zhang G, Cai S, Redington AN. Effect of inhaled hydrogen sulfide on metabolic responses in anesthetized, paralyzed, and mechanically ventilated piglets. Pediatr Crit Care Med 2008; 9:110–112.
  31. Rhee PM, Acosta J, Bridgeman A, Wang D, Jordan M, Rich N. Survival after emergency department thoracotomy: review of published data from the past 25 years. J Am Coll Surg 2000; 190:288–298.
  32. Behringer W, Prueckner S, Kentner R, et al. Rapid hypothermic aortic flush can achieve survival without brain damage after 30 minutes cardiac arrest in dogs. Anesthesiology 2000; 93:1491–1499.
  33. Behringer W, Kentner R, Wu X, et al. Fructose-1,6-bisphosphate and MK-801 by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 min in dogs: an exploratory study. Resuscitation 2001; 50:205–216.
  34. Behringer W, Safar P, Wu X, et al. Survival without brain damage after clinical death of 60–120 mins in dogs using suspended animation by profound hypothermia. Crit Care Med 2003; 31:1523–1531.
  35. Behringer W, Safar P, Kentner R, et al. Antioxidant Tempol enhances hypothermic cerebral preservation during prolonged cardiac arrest in dogs. J Cereb Blood Flow Metab 2002; 22:105–117.
  36. Wu X, Drabek T, Kochanek PM, et al. Induction of profound hypothermia for emergency preservation and resuscitation allows intact survival after cardiac arrest resulting from prolonged lethal hemorrhage and trauma in dogs. Circulation 2006; 113:1974–1982.
  37. Wu X, Drabek T, Tisherman SA, et al. Emergency preservation and resuscitation with profound hypothermia, oxygen, and glucose allows reliable neurological recovery after 3 h of cardiac arrest from rapid exsanguination in dogs. J Cereb Blood Flow Metab 2008; 28:302–311.
  38. Drabek T, Stezoski J, Garman RH, et al. Emergency preservation and delayed resuscitation allows normal recovery after exsanguination cardiac arrest in rats: a feasibility trial. Crit Care Med 2007; 35:532–537.
  39. Drabek T, Stezoski J, Garman RH, et al. Exsanguination cardiac arrest in rats treated by 60 min, but not 75 min, emergency preservation and delayed resuscitation is associated with intact outcome. Resuscitation 2007; 75:114–123.
  40. Alam HB, Chen Z, Honma K, et al. The rate of induction of hypothermic arrest determines the outcome in a swine model of lethal hemorrhage. J Trauma 2004; 57:961–969.
  41. Janata A, Bayegan K, Weihs W, et al. Emergency preservation and resuscitation improve survival after 15 minutes of normovolemic cardiac arrest in pigs. Crit Care Med 2007; 35:2785–2791.
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Patrick M. Kochanek, MD
Department of Critical Care Medicine, Department of Pediatrics, Safar Center for Resuscitation Research, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA

Correspondence: Patrick M. Kochanek, MD, Director, Safar Center for Resuscitation Research; Professor and Vice Chairman, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3434 Fifth Avenue, Pittsburgh, PA 15260; [email protected]

Dr. Kochanek reported that he has no financial interests or relationships that pose a potential conflict of interest with this article.

Dr. Kochanek is a co-holder of the patent on the Emergency Preservation and Resuscitation Method. He is supported by grants from the National Institutes of Health (NS38087, NS30318, HD04686), the United States Army (PRMRP PR054755 W81XWH-06-1-0247), the Defense Advanced Research Projects Agency, the Centers for Disease Control and Prevention, and the Laerdal Foundation.

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Department of Critical Care Medicine, Department of Pediatrics, Safar Center for Resuscitation Research, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA

Correspondence: Patrick M. Kochanek, MD, Director, Safar Center for Resuscitation Research; Professor and Vice Chairman, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3434 Fifth Avenue, Pittsburgh, PA 15260; [email protected]

Dr. Kochanek reported that he has no financial interests or relationships that pose a potential conflict of interest with this article.

Dr. Kochanek is a co-holder of the patent on the Emergency Preservation and Resuscitation Method. He is supported by grants from the National Institutes of Health (NS38087, NS30318, HD04686), the United States Army (PRMRP PR054755 W81XWH-06-1-0247), the Defense Advanced Research Projects Agency, the Centers for Disease Control and Prevention, and the Laerdal Foundation.

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Patrick M. Kochanek, MD
Department of Critical Care Medicine, Department of Pediatrics, Safar Center for Resuscitation Research, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA

Correspondence: Patrick M. Kochanek, MD, Director, Safar Center for Resuscitation Research; Professor and Vice Chairman, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3434 Fifth Avenue, Pittsburgh, PA 15260; [email protected]

Dr. Kochanek reported that he has no financial interests or relationships that pose a potential conflict of interest with this article.

Dr. Kochanek is a co-holder of the patent on the Emergency Preservation and Resuscitation Method. He is supported by grants from the National Institutes of Health (NS38087, NS30318, HD04686), the United States Army (PRMRP PR054755 W81XWH-06-1-0247), the Defense Advanced Research Projects Agency, the Centers for Disease Control and Prevention, and the Laerdal Foundation.

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Therapeutic hypothermia has been a central focus of research at the Safar Center for Resuscitation Research since the center was founded—as the International Resuscitation Research Center—at the University of Pittsburgh School of Medicine in 1979. In this article, which is based on my 2008 Bakken Lecture, I will discuss historical, contemporary, and futuristic applications of therapeutic hypothermia. Given that the key mission of the Safar Center is “to save hearts and brains too good to die,” the basis of my discussion will consist of how therapeutic hypothermia impacts both heart and brain—and the lessons that can be learned in each case.

THERAPEUTIC HYPOTHERMIA: A HISTORICAL PERSPECTIVE

Reprinted, with permission, from Journal of the Iowa Medical Society (Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc 1964; 54:629–635).
Figure 1. Classic publication of the “first ABCs of resuscitation” by the late Dr. Peter Safar. As shown, therapeutic hypothermia was recommended for use in comatose patients who achieve restoration of spontaneous circulation, even in the 1960s.3
The late Dr. Peter Safar and his colleague, the late Dr. Hubert Rosomoff, played an instrumental role in the use of therapeutic hypothermia in the early 1960s in patients with acute neurological insults. Their classic 1965 publication, “Management of the comatose patient,”1 contained recommendations that in many ways outline the current use of mild therapeutic hypothermia as recommended by the American Heart Association and the International Liaison Committee on Resuscitation.2 In addition, in 1964, Dr. Safar recommended in his historic “first ABCs of resuscitation” that hypothermia be used in patients who remain comatose after successful restoration of spontaneous circulation (Figure 1).3 That recommendation holds true in today’s guidelines.2 However, therapeutic hypothermia in acute resuscitation medicine has a remarkably long history.

Baron Dominique Jean Larrey, surgeon-in-chief of the Napoleonic armies and the father of modern military medicine, observed in 1814 that the wounded “privileged” soldiers lying closer to the campfire died sooner than those in more remote, colder areas.4 Similarly, Dr. Charles Phelps, surgeon to the New York City Police Department, in 1897 recommended the use of the “ice cap” for traumatic brain injury.5

In the 1980s, however, therapeutic hypothermia began to fall out of favor. This resulted, in part, from overzealous application in some patients, who were treated for durations longer than a week and at temperatures in the moderate (28°C to 32°C) rather than mild (33°C to 35°C) range. This led to an increase in complications.6 Laboratory studies in a rat model of global cerebral ischemia by Busto et al 7 in 1987 and in a canine model of cardiac arrest by Leonov et al8 in 1990 demonstrated that benefit could be produced using mild cooling after the insult. This and parallel work in neonatology led to the ultimate breakthrough that translated into improved outcomes with the use of mild therapeutic hypothermia in adults with cardiac arrest9,10 and in newborns with hypoxic-ischemic encephalopathy.11

Clinicians and scientists familiar with hypothermia might suggest that its potential therapeutic benefit has been known for decades, given the use of hypothermic circulatory arrest for neuroprotection and cardioprotection in open heart surgery. However, one of the most interesting aspects of neuroprotection provided by mild therapeutic hypothermia is that it is not clearly linked to attenuation of energy failure.7 Unlike the setting of deep hypothermic circulatory arrest—where the induction of hypothermia occurs before the insult, and levels of hypothermia are such that energy failure is prevented—mild cooling, applied after cardiac arrest, appears to confer benefit by other mechanisms. Effects on cell signaling, oxidative and nitrative stress, apoptosis, excitotoxicity, and other mechanisms appear to mediate this benefit.12,13

THERAPEUTIC HYPOTHERMIA: CONTEMPORARY APPLICATION

Use in cardiac arrest

Compared with normothermia, mild therapeutic hypothermia, induced immediately after restoration of spontaneous circulation in comatose survivors of ventricular fibrillation cardiac arrest, leads to 1 additional patient with intact neurological outcome for every 6 patients treated.9 This is a remarkable effect given the extremely poor overall outcomes observed after out-of-hospital cardiac arrest. Studies in animal models, however, suggest that the therapeutic potential of mild hypothermia can be maximized with application either during or as early as possible after the insult.14 However, clinicians in the field of cardiology appropriately have cause for concern about the possibility that even mild cooling could reduce that potential for successful defibrillation or lead to re-arrest. In 2005, an important paper by Boddicker et al15 explored the impact of mild hypothermia on defibrillation success in experimental ventricular fibrillation in pigs and found, remarkably, that the success rate actually improved with mild or moderate hypothermia! That report opened the door for a number of studies that are now focused on rapid cooling during cardiopulmonary resuscitation (CPR) and on the rapid induction of mild hypothermia using intravenous cooling.16,17

Support for the use of intra-arrest cooling came initially from work in animal models of cardiac arrest—first from the work of Abella et al18 in a mouse model of potassium-induced cardiac arrest, and later from a canine model in work by Nozari et al.19 In the latter study, delaying the onset of mild hypothermia during advanced cardiac life support markedly worsened both multisystem organ failure and survival. Cardiovascular function in that model appeared to be substantively improved by early intra-arrest cooling.

The potential for the use of intravenous cooling in patients with a bolus of crystalloid to induce mild hypothermia was pioneered in a seminal paper by Bernard et al.16 In that report, an approximately 2°C reduction in core temperature could be achieved with infusion of about 30 mL/kg of fluid over 30 minutes. Mean arterial blood pressure increased mildly, and the intervention was well tolerated when applied early after restoration of spontaneous circulation. Kim and colleagues20 built upon that initial work and demonstrated the feasibility of the use of intravenous iced normal saline to induce mild hypothermia by paramedics in the prehospital setting. This approach, and its impact on neurological outcome and survival, is currently being evaluated in a randomized controlled trial. Combining intra-arrest cooling with the use of intravenous fluids is the obvious next step. This could facilitate rapid induction, which could then be maintained with commercially available surface cooling devices.21

 

 

Cardiac arrest vs traumatic brain injury

One of the interesting aspects of the beneficial effects of mild therapeutic hypothermia in the setting of cardiac arrest relates to the following question: Why is hypothermia effective in improving neurological outcome after cardiac arrest while it has been more difficult to demonstrate benefit in other acute neurological insults, such as traumatic brain injury?22

Application of hypothermia in cardiac arrest may represent something of a “perfect storm.” First, a recent study by Berger et al23 provides some insight into the time course of neuronal death after cardiac arrest versus traumatic brain injury. In that study of children who suffered either cardiac arrest or severe traumatic brain injury requiring management in the intensive care unit, peak levels of the serum biomarker of neuronal death, neuron-specific enolase (NSE), occurred days after cardiac arrest, whereas they occurred generally within a few hours of traumatic brain injury. This suggests a broader therapeutic window for the application of mild hypothermia in cardiac arrest as opposed to traumatic brain injury. In addition, the only neuroprotective therapy used in cardiac arrest is mild hypothermia. In contrast, in traumatic brain injury, myriad therapies are part of standard of care, including intracranial pressure monitoring and cerebrospinal fluid drainage, mannitol, hypertonic saline, barbiturates, and surgical interventions such as decompressive craniectomy.24 These intracranial pressure–directed therapies in traumatic brain injury may confer a variety of neuroprotective actions, thus raising the bar for hypothermia to show benefit. A similar case could be made regarding the surgical treatment of subarachnoid hemorrhage, where hypothermia has been ineffective.25

Efforts to optimize hypothermia

Given the benefit of mild therapeutic hypothermia in cardiac arrest, we and other investigative teams are actively pursuing ways to further optimize its effects beyond the use of a more rapid induction, as discussed above.

One of the most overlooked areas of study relates to hypothermia’s profound effects on drug metabolism; despite the need for many drugs in critically ill patients after cardiac arrest, knowledge of how hypothermia alters drug metabolism and how best to adjust drug doses is limited. Therapeutic hypothermia has recently been shown, during cooling, to directly inhibit binding of drugs to the active site of the key drug-metabolizing enzyme, cytochrome P450.26 In contrast, in the setting of experimental cardiac arrest and resuscitation, mild hypothermia also protects against induction of cytokines such as interleukin-6, which downregulates cytochrome P450. Thus, mild hypothermia reduces drug metabolism during cooling but leads to a better recovery of drug metabolism after rewarming. This dichotomous effect will need to be studied at the bedside. Hypothermia can also reduce drug effects.26 Thus, until we know how to optimally dose various therapies in patients treated with hypothermia, it is probably best to carefully monitor levels (when possible) and also drug effects. The best example of this at the bedside is the use of monitoring neuromuscular blockade in patients treated with vecuronium or pancuronium during mild hypothermia.

Another interesting area of study involves defining the best anesthetics or sedatives to use with cooling. For example, a recent report by Statler et al27 showed that hypothermia was much less effective as a neuroprotectant after experimental traumatic brain injury in rats anesthetized with fentanyl than with isoflurane. In that study, fentanyl was unable to blunt the stress response to cooling. Given the variety of sedatives and analgesics used at the beside in both neurointensive care units and coronary care units, understanding which agents work best with hypothermia could further enhance hypothermia’s therapeutic benefit.

There is also a search for agents that may promote induction of hypothermia or create a poikilothermic state, thereby facilitating tolerance of the hypothermic state without a stress response. One agent that has shown some promise in the setting of experimental cardiac arrest is the endogenous peptide neurotensin, which has direct effects on temperature regulation at the hypothalamic level. In an experimental model of asphyxial cardiac arrest in rats, Katz et al28 reported that the neurotensin analog NT69L facilitated induction of hypothermia and improved outcome. Another agent that has been touted to induce a state of “hibernation on demand” is hydrogen sulfide gas. A recent experiment by Blackstone et al29 demonstrated induction of deep hypothermia and a hibernation-like state in mice allowed to breathe hydrogen sulfide gas at 80 parts per million. This state was completely reversible upon discontinuation of the agent. Unfortunately, studies in large animal models have not been able to demonstrate induction of hypothermia with this approach.30 Nevertheless, these drugs represent prototypes for future exploration; if the right agent is found, it could lead, in theory, to markedly enhanced efficacy of cooling.

 

 

FUTURISTIC APPLICATIONS OF THERAPEUTIC HYPOTHERMIA

Emergency preservation and resuscitation

Exsanguination cardiac arrest is one of the most refractory types of cardiac arrest, with mortality rates generally greater than 95%.31 Obviously, therapies such as CPR are ineffective in the absence of an adequate circulating blood volume.

Figure 2. Schematic of aortic cold flush for the induction of emergency preservation and resuscitation (EPR) to rapidly create a transient state of hypothermic preservation in otherwise lethally injured victims of exsanguination cardiac arrest. After damage-control surgery, resuscitation is performed via cardiopulmonary bypass (see text for details).
In 1984, Dr. Peter Safar and military expert Col Ronald Bellamy pioneered a new approach to exsanguination cardiac arrest that they called suspended animation for delayed resuscitation. The concept was a logical one—namely, in the setting of otherwise lethal trauma-induced exsanguination cardiac arrest, a transient state of preservation would be induced to buy time for damage-control surgery, and then a delayed resuscitation would be carried out using cardiopulmonary bypass. Our center has worked on this concept since 1988 in studies funded initially by the US Navy and later by the US Congress. Ultimately, we coined the phrase emergency preservation and resuscitation (EPR) for this method. Using a canine model of exsanguination cardiac arrest, we first demonstrated the feasibility of this approach by inducing a state of preservation via an aortic flush of iced saline.32 A schematic of the protocol is presented in Figure 2.

In initial reports,32–34 we targeted relatively brief insults ranging from 15 to 60 minutes. We determined that for insults at or beyond 60 minutes, profound levels of hypothermia (tympanic temperature of ~10°C) were most effective.34 In subsequent studies, we demonstrated that pharmacologic adjuncts to hypothermia were relatively ineffective. Indeed, only one agent, the brain-penetrating antioxidant Tempol, enhanced the efficacy of profound hypothermia.35 We also demonstrated that the prolonged use (36 to 48 hours) of mild hypothermia after the acute application of EPR further enhanced neurological outcomes as compared with more rapid rewarming.36 Similarly, unlike drugs, the addition of energy substrates (namely, dissolved oxygen and 2.5% dextrose) to the flush facilitated the ability to achieve remarkably long EPR durations in experimental exsanguination cardiac arrest—as long as 3 hours of preservation at approximately 10°C.37 These findings could also have important implications for optimizing conventional use of deep hypothermia circulatory arrest in cardiac or neurological surgery. We also have recently developed a rat model of EPR using a miniaturized cardiopulmonary bypass system. It is used to screen novel therapeutic adjuncts to EPR and to study mechanisms of neuroprotection in this special paradigm.38,39

Two other investigative teams, one at Harvard University and another at the Vienna General Hospital, have also been exploring the use of EPR-related technologies—and observing similar success. Alam et al40 have used a low-flow EPR approach in pigs to facilitate damage-control surgery after otherwise lethal traumatic insults. Janata et al41 have successfully used EPR in the setting of refractory normovolemic cardiac arrest, simulating the typical cardiac arrest victim who cannot be resuscitated in either the field or the emergency department.

Finally, the EPR concept recently received funding to proceed to a clinical trial in civilian trauma. The study, to be led by Dr. Samuel Tisherman, one of the pioneers of this approach at the Safar Center, will include several trauma centers in the United States and target otherwise lethally injured trauma victims with exsanguination cardiac arrest.

Therapeutic hypothermia has been a central focus of research at the Safar Center for Resuscitation Research since the center was founded—as the International Resuscitation Research Center—at the University of Pittsburgh School of Medicine in 1979. In this article, which is based on my 2008 Bakken Lecture, I will discuss historical, contemporary, and futuristic applications of therapeutic hypothermia. Given that the key mission of the Safar Center is “to save hearts and brains too good to die,” the basis of my discussion will consist of how therapeutic hypothermia impacts both heart and brain—and the lessons that can be learned in each case.

THERAPEUTIC HYPOTHERMIA: A HISTORICAL PERSPECTIVE

Reprinted, with permission, from Journal of the Iowa Medical Society (Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc 1964; 54:629–635).
Figure 1. Classic publication of the “first ABCs of resuscitation” by the late Dr. Peter Safar. As shown, therapeutic hypothermia was recommended for use in comatose patients who achieve restoration of spontaneous circulation, even in the 1960s.3
The late Dr. Peter Safar and his colleague, the late Dr. Hubert Rosomoff, played an instrumental role in the use of therapeutic hypothermia in the early 1960s in patients with acute neurological insults. Their classic 1965 publication, “Management of the comatose patient,”1 contained recommendations that in many ways outline the current use of mild therapeutic hypothermia as recommended by the American Heart Association and the International Liaison Committee on Resuscitation.2 In addition, in 1964, Dr. Safar recommended in his historic “first ABCs of resuscitation” that hypothermia be used in patients who remain comatose after successful restoration of spontaneous circulation (Figure 1).3 That recommendation holds true in today’s guidelines.2 However, therapeutic hypothermia in acute resuscitation medicine has a remarkably long history.

Baron Dominique Jean Larrey, surgeon-in-chief of the Napoleonic armies and the father of modern military medicine, observed in 1814 that the wounded “privileged” soldiers lying closer to the campfire died sooner than those in more remote, colder areas.4 Similarly, Dr. Charles Phelps, surgeon to the New York City Police Department, in 1897 recommended the use of the “ice cap” for traumatic brain injury.5

In the 1980s, however, therapeutic hypothermia began to fall out of favor. This resulted, in part, from overzealous application in some patients, who were treated for durations longer than a week and at temperatures in the moderate (28°C to 32°C) rather than mild (33°C to 35°C) range. This led to an increase in complications.6 Laboratory studies in a rat model of global cerebral ischemia by Busto et al 7 in 1987 and in a canine model of cardiac arrest by Leonov et al8 in 1990 demonstrated that benefit could be produced using mild cooling after the insult. This and parallel work in neonatology led to the ultimate breakthrough that translated into improved outcomes with the use of mild therapeutic hypothermia in adults with cardiac arrest9,10 and in newborns with hypoxic-ischemic encephalopathy.11

Clinicians and scientists familiar with hypothermia might suggest that its potential therapeutic benefit has been known for decades, given the use of hypothermic circulatory arrest for neuroprotection and cardioprotection in open heart surgery. However, one of the most interesting aspects of neuroprotection provided by mild therapeutic hypothermia is that it is not clearly linked to attenuation of energy failure.7 Unlike the setting of deep hypothermic circulatory arrest—where the induction of hypothermia occurs before the insult, and levels of hypothermia are such that energy failure is prevented—mild cooling, applied after cardiac arrest, appears to confer benefit by other mechanisms. Effects on cell signaling, oxidative and nitrative stress, apoptosis, excitotoxicity, and other mechanisms appear to mediate this benefit.12,13

THERAPEUTIC HYPOTHERMIA: CONTEMPORARY APPLICATION

Use in cardiac arrest

Compared with normothermia, mild therapeutic hypothermia, induced immediately after restoration of spontaneous circulation in comatose survivors of ventricular fibrillation cardiac arrest, leads to 1 additional patient with intact neurological outcome for every 6 patients treated.9 This is a remarkable effect given the extremely poor overall outcomes observed after out-of-hospital cardiac arrest. Studies in animal models, however, suggest that the therapeutic potential of mild hypothermia can be maximized with application either during or as early as possible after the insult.14 However, clinicians in the field of cardiology appropriately have cause for concern about the possibility that even mild cooling could reduce that potential for successful defibrillation or lead to re-arrest. In 2005, an important paper by Boddicker et al15 explored the impact of mild hypothermia on defibrillation success in experimental ventricular fibrillation in pigs and found, remarkably, that the success rate actually improved with mild or moderate hypothermia! That report opened the door for a number of studies that are now focused on rapid cooling during cardiopulmonary resuscitation (CPR) and on the rapid induction of mild hypothermia using intravenous cooling.16,17

Support for the use of intra-arrest cooling came initially from work in animal models of cardiac arrest—first from the work of Abella et al18 in a mouse model of potassium-induced cardiac arrest, and later from a canine model in work by Nozari et al.19 In the latter study, delaying the onset of mild hypothermia during advanced cardiac life support markedly worsened both multisystem organ failure and survival. Cardiovascular function in that model appeared to be substantively improved by early intra-arrest cooling.

The potential for the use of intravenous cooling in patients with a bolus of crystalloid to induce mild hypothermia was pioneered in a seminal paper by Bernard et al.16 In that report, an approximately 2°C reduction in core temperature could be achieved with infusion of about 30 mL/kg of fluid over 30 minutes. Mean arterial blood pressure increased mildly, and the intervention was well tolerated when applied early after restoration of spontaneous circulation. Kim and colleagues20 built upon that initial work and demonstrated the feasibility of the use of intravenous iced normal saline to induce mild hypothermia by paramedics in the prehospital setting. This approach, and its impact on neurological outcome and survival, is currently being evaluated in a randomized controlled trial. Combining intra-arrest cooling with the use of intravenous fluids is the obvious next step. This could facilitate rapid induction, which could then be maintained with commercially available surface cooling devices.21

 

 

Cardiac arrest vs traumatic brain injury

One of the interesting aspects of the beneficial effects of mild therapeutic hypothermia in the setting of cardiac arrest relates to the following question: Why is hypothermia effective in improving neurological outcome after cardiac arrest while it has been more difficult to demonstrate benefit in other acute neurological insults, such as traumatic brain injury?22

Application of hypothermia in cardiac arrest may represent something of a “perfect storm.” First, a recent study by Berger et al23 provides some insight into the time course of neuronal death after cardiac arrest versus traumatic brain injury. In that study of children who suffered either cardiac arrest or severe traumatic brain injury requiring management in the intensive care unit, peak levels of the serum biomarker of neuronal death, neuron-specific enolase (NSE), occurred days after cardiac arrest, whereas they occurred generally within a few hours of traumatic brain injury. This suggests a broader therapeutic window for the application of mild hypothermia in cardiac arrest as opposed to traumatic brain injury. In addition, the only neuroprotective therapy used in cardiac arrest is mild hypothermia. In contrast, in traumatic brain injury, myriad therapies are part of standard of care, including intracranial pressure monitoring and cerebrospinal fluid drainage, mannitol, hypertonic saline, barbiturates, and surgical interventions such as decompressive craniectomy.24 These intracranial pressure–directed therapies in traumatic brain injury may confer a variety of neuroprotective actions, thus raising the bar for hypothermia to show benefit. A similar case could be made regarding the surgical treatment of subarachnoid hemorrhage, where hypothermia has been ineffective.25

Efforts to optimize hypothermia

Given the benefit of mild therapeutic hypothermia in cardiac arrest, we and other investigative teams are actively pursuing ways to further optimize its effects beyond the use of a more rapid induction, as discussed above.

One of the most overlooked areas of study relates to hypothermia’s profound effects on drug metabolism; despite the need for many drugs in critically ill patients after cardiac arrest, knowledge of how hypothermia alters drug metabolism and how best to adjust drug doses is limited. Therapeutic hypothermia has recently been shown, during cooling, to directly inhibit binding of drugs to the active site of the key drug-metabolizing enzyme, cytochrome P450.26 In contrast, in the setting of experimental cardiac arrest and resuscitation, mild hypothermia also protects against induction of cytokines such as interleukin-6, which downregulates cytochrome P450. Thus, mild hypothermia reduces drug metabolism during cooling but leads to a better recovery of drug metabolism after rewarming. This dichotomous effect will need to be studied at the bedside. Hypothermia can also reduce drug effects.26 Thus, until we know how to optimally dose various therapies in patients treated with hypothermia, it is probably best to carefully monitor levels (when possible) and also drug effects. The best example of this at the bedside is the use of monitoring neuromuscular blockade in patients treated with vecuronium or pancuronium during mild hypothermia.

Another interesting area of study involves defining the best anesthetics or sedatives to use with cooling. For example, a recent report by Statler et al27 showed that hypothermia was much less effective as a neuroprotectant after experimental traumatic brain injury in rats anesthetized with fentanyl than with isoflurane. In that study, fentanyl was unable to blunt the stress response to cooling. Given the variety of sedatives and analgesics used at the beside in both neurointensive care units and coronary care units, understanding which agents work best with hypothermia could further enhance hypothermia’s therapeutic benefit.

There is also a search for agents that may promote induction of hypothermia or create a poikilothermic state, thereby facilitating tolerance of the hypothermic state without a stress response. One agent that has shown some promise in the setting of experimental cardiac arrest is the endogenous peptide neurotensin, which has direct effects on temperature regulation at the hypothalamic level. In an experimental model of asphyxial cardiac arrest in rats, Katz et al28 reported that the neurotensin analog NT69L facilitated induction of hypothermia and improved outcome. Another agent that has been touted to induce a state of “hibernation on demand” is hydrogen sulfide gas. A recent experiment by Blackstone et al29 demonstrated induction of deep hypothermia and a hibernation-like state in mice allowed to breathe hydrogen sulfide gas at 80 parts per million. This state was completely reversible upon discontinuation of the agent. Unfortunately, studies in large animal models have not been able to demonstrate induction of hypothermia with this approach.30 Nevertheless, these drugs represent prototypes for future exploration; if the right agent is found, it could lead, in theory, to markedly enhanced efficacy of cooling.

 

 

FUTURISTIC APPLICATIONS OF THERAPEUTIC HYPOTHERMIA

Emergency preservation and resuscitation

Exsanguination cardiac arrest is one of the most refractory types of cardiac arrest, with mortality rates generally greater than 95%.31 Obviously, therapies such as CPR are ineffective in the absence of an adequate circulating blood volume.

Figure 2. Schematic of aortic cold flush for the induction of emergency preservation and resuscitation (EPR) to rapidly create a transient state of hypothermic preservation in otherwise lethally injured victims of exsanguination cardiac arrest. After damage-control surgery, resuscitation is performed via cardiopulmonary bypass (see text for details).
In 1984, Dr. Peter Safar and military expert Col Ronald Bellamy pioneered a new approach to exsanguination cardiac arrest that they called suspended animation for delayed resuscitation. The concept was a logical one—namely, in the setting of otherwise lethal trauma-induced exsanguination cardiac arrest, a transient state of preservation would be induced to buy time for damage-control surgery, and then a delayed resuscitation would be carried out using cardiopulmonary bypass. Our center has worked on this concept since 1988 in studies funded initially by the US Navy and later by the US Congress. Ultimately, we coined the phrase emergency preservation and resuscitation (EPR) for this method. Using a canine model of exsanguination cardiac arrest, we first demonstrated the feasibility of this approach by inducing a state of preservation via an aortic flush of iced saline.32 A schematic of the protocol is presented in Figure 2.

In initial reports,32–34 we targeted relatively brief insults ranging from 15 to 60 minutes. We determined that for insults at or beyond 60 minutes, profound levels of hypothermia (tympanic temperature of ~10°C) were most effective.34 In subsequent studies, we demonstrated that pharmacologic adjuncts to hypothermia were relatively ineffective. Indeed, only one agent, the brain-penetrating antioxidant Tempol, enhanced the efficacy of profound hypothermia.35 We also demonstrated that the prolonged use (36 to 48 hours) of mild hypothermia after the acute application of EPR further enhanced neurological outcomes as compared with more rapid rewarming.36 Similarly, unlike drugs, the addition of energy substrates (namely, dissolved oxygen and 2.5% dextrose) to the flush facilitated the ability to achieve remarkably long EPR durations in experimental exsanguination cardiac arrest—as long as 3 hours of preservation at approximately 10°C.37 These findings could also have important implications for optimizing conventional use of deep hypothermia circulatory arrest in cardiac or neurological surgery. We also have recently developed a rat model of EPR using a miniaturized cardiopulmonary bypass system. It is used to screen novel therapeutic adjuncts to EPR and to study mechanisms of neuroprotection in this special paradigm.38,39

Two other investigative teams, one at Harvard University and another at the Vienna General Hospital, have also been exploring the use of EPR-related technologies—and observing similar success. Alam et al40 have used a low-flow EPR approach in pigs to facilitate damage-control surgery after otherwise lethal traumatic insults. Janata et al41 have successfully used EPR in the setting of refractory normovolemic cardiac arrest, simulating the typical cardiac arrest victim who cannot be resuscitated in either the field or the emergency department.

Finally, the EPR concept recently received funding to proceed to a clinical trial in civilian trauma. The study, to be led by Dr. Samuel Tisherman, one of the pioneers of this approach at the Safar Center, will include several trauma centers in the United States and target otherwise lethally injured trauma victims with exsanguination cardiac arrest.

References
  1. Rosomoff HL, Safar P. Management of the comatose patient. In:Safar P, ed. Respiratory Therapy. Philadelphia, PA: FA Davis Co; 1965:244–258.
  2. Storm C, Schefold JC, Nibbe L, et al. Therapeutic hypothermia after cardiac arrest—the implementation of the ILCOR guidelines in clinical routine is possible! Crit Care 2006; 10:425.
  3. Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc 1964:629–635.
  4. Larrey DJ. Memoirs of Military Surgery and Campaigns of the French Armies. Baltimore, MD: Joseph Cushing/University Press of Sergeant Hall;1814.
  5. Phelps C. Traumatic injuries of the brain and its membranes. In:Phelps C, ed. Traumatic Injuries of the Brain and Its Membranes. New York, NY: D Appleton & Co; 1897:223–224.
  6. Bohn DJ, Biggar WD, Smith CR, Conn AW, Barker GA. Influence of hypothermia, barbiturate therapy, and intracranial pressure monitoring on morbidity and mortality after near-drowning. Crit Care Med 1986; 14:529–534.
  7. Busto R, Dietrich WD, Globus MY, Valdés I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987; 7:729–738.
  8. Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab 1990; 10:57–70.
  9. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549–556.
  10. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557–563.
  11. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:1574–1584.
  12. Kochanek PM, Jenkins LW, Clark RSB. Traumatic brain injury: laboratory studies. In:Tisherman SA, Sterz F, eds. Therapeutic Hypothermia. New York, NY: Springer; 2005:63–86.
  13. Zhao H, Steinberg GK, Sapolsky RM. General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage. J Cereb Blood Flow Metab 2007; 27:1879–1894.
  14. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 1993; 21:1348–1358.
  15. Boddicker KA, Zhang Y, Zimmerman MB, Davies LR, Kerber RE. Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation. Circulation 2005; 111:3195–3201.
  16. Bernard S, Buist M, Monteiro O, Smith K. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 2003; 56:9–13.
  17. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med 2005; 33:2744–2751.
  18. Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation 2004; 109:2786–2791.
  19. Nozari A, Safar P, Wu X, et al. Suspended animation can allow survival without brain damage after traumatic exsanguination cardiac arrest of 60 minutes in dogs. J Trauma 2004; 57:1266–1275.
  20. Kim F, Olsufka M, Longstreth WT, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007; 115:3064–3070.
  21. Haugk M, Sterz F, Grassberger M, et al. Feasibility and efficacy of a new non-invasive surface cooling device in post-resuscitation intensive care medicine. Resuscitation 2007; 75:76–81.
  22. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008; 358:2447–2456.
  23. Berger RP, Adelson PD, Richichi R, Kochanek PM. Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the biochemical response of the pediatric brain to inflicted brain injury. Dev Neurosci 2006; 28:327–335.
  24. , et al., Brain Trauma Foundation. Guidelines for the management of severe traumatic brain injury:. Introduction. J Neurotrauma 2007; 24( suppl 1):S1–S2.
  25. Todd MM, Hindman BJ, Clarke WR, Torner JCIntraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005; 352:135–145.
  26. Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med 2007; 35:2196–2204.
  27. Statler KD, Alexander HL, Vagni VA, et al. Moderate hypothermia may be detrimental after traumatic brain injury in fentanylanesthetized rats. Crit Care Med 2003; 31:1134–1139.
  28. Katz LM, Wang Y, McMahon B, Richelson E. Neurotensin analog NT69L induces rapid and prolonged hypothermia after hypoxic ischemia. Acad Emerg Med 2001; 8:1115–1121.
  29. Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science 2005; 308:518.
  30. Li J, Zhang G, Cai S, Redington AN. Effect of inhaled hydrogen sulfide on metabolic responses in anesthetized, paralyzed, and mechanically ventilated piglets. Pediatr Crit Care Med 2008; 9:110–112.
  31. Rhee PM, Acosta J, Bridgeman A, Wang D, Jordan M, Rich N. Survival after emergency department thoracotomy: review of published data from the past 25 years. J Am Coll Surg 2000; 190:288–298.
  32. Behringer W, Prueckner S, Kentner R, et al. Rapid hypothermic aortic flush can achieve survival without brain damage after 30 minutes cardiac arrest in dogs. Anesthesiology 2000; 93:1491–1499.
  33. Behringer W, Kentner R, Wu X, et al. Fructose-1,6-bisphosphate and MK-801 by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 min in dogs: an exploratory study. Resuscitation 2001; 50:205–216.
  34. Behringer W, Safar P, Wu X, et al. Survival without brain damage after clinical death of 60–120 mins in dogs using suspended animation by profound hypothermia. Crit Care Med 2003; 31:1523–1531.
  35. Behringer W, Safar P, Kentner R, et al. Antioxidant Tempol enhances hypothermic cerebral preservation during prolonged cardiac arrest in dogs. J Cereb Blood Flow Metab 2002; 22:105–117.
  36. Wu X, Drabek T, Kochanek PM, et al. Induction of profound hypothermia for emergency preservation and resuscitation allows intact survival after cardiac arrest resulting from prolonged lethal hemorrhage and trauma in dogs. Circulation 2006; 113:1974–1982.
  37. Wu X, Drabek T, Tisherman SA, et al. Emergency preservation and resuscitation with profound hypothermia, oxygen, and glucose allows reliable neurological recovery after 3 h of cardiac arrest from rapid exsanguination in dogs. J Cereb Blood Flow Metab 2008; 28:302–311.
  38. Drabek T, Stezoski J, Garman RH, et al. Emergency preservation and delayed resuscitation allows normal recovery after exsanguination cardiac arrest in rats: a feasibility trial. Crit Care Med 2007; 35:532–537.
  39. Drabek T, Stezoski J, Garman RH, et al. Exsanguination cardiac arrest in rats treated by 60 min, but not 75 min, emergency preservation and delayed resuscitation is associated with intact outcome. Resuscitation 2007; 75:114–123.
  40. Alam HB, Chen Z, Honma K, et al. The rate of induction of hypothermic arrest determines the outcome in a swine model of lethal hemorrhage. J Trauma 2004; 57:961–969.
  41. Janata A, Bayegan K, Weihs W, et al. Emergency preservation and resuscitation improve survival after 15 minutes of normovolemic cardiac arrest in pigs. Crit Care Med 2007; 35:2785–2791.
References
  1. Rosomoff HL, Safar P. Management of the comatose patient. In:Safar P, ed. Respiratory Therapy. Philadelphia, PA: FA Davis Co; 1965:244–258.
  2. Storm C, Schefold JC, Nibbe L, et al. Therapeutic hypothermia after cardiac arrest—the implementation of the ILCOR guidelines in clinical routine is possible! Crit Care 2006; 10:425.
  3. Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc 1964:629–635.
  4. Larrey DJ. Memoirs of Military Surgery and Campaigns of the French Armies. Baltimore, MD: Joseph Cushing/University Press of Sergeant Hall;1814.
  5. Phelps C. Traumatic injuries of the brain and its membranes. In:Phelps C, ed. Traumatic Injuries of the Brain and Its Membranes. New York, NY: D Appleton & Co; 1897:223–224.
  6. Bohn DJ, Biggar WD, Smith CR, Conn AW, Barker GA. Influence of hypothermia, barbiturate therapy, and intracranial pressure monitoring on morbidity and mortality after near-drowning. Crit Care Med 1986; 14:529–534.
  7. Busto R, Dietrich WD, Globus MY, Valdés I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987; 7:729–738.
  8. Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab 1990; 10:57–70.
  9. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549–556.
  10. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557–563.
  11. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:1574–1584.
  12. Kochanek PM, Jenkins LW, Clark RSB. Traumatic brain injury: laboratory studies. In:Tisherman SA, Sterz F, eds. Therapeutic Hypothermia. New York, NY: Springer; 2005:63–86.
  13. Zhao H, Steinberg GK, Sapolsky RM. General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage. J Cereb Blood Flow Metab 2007; 27:1879–1894.
  14. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 1993; 21:1348–1358.
  15. Boddicker KA, Zhang Y, Zimmerman MB, Davies LR, Kerber RE. Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation. Circulation 2005; 111:3195–3201.
  16. Bernard S, Buist M, Monteiro O, Smith K. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 2003; 56:9–13.
  17. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med 2005; 33:2744–2751.
  18. Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation 2004; 109:2786–2791.
  19. Nozari A, Safar P, Wu X, et al. Suspended animation can allow survival without brain damage after traumatic exsanguination cardiac arrest of 60 minutes in dogs. J Trauma 2004; 57:1266–1275.
  20. Kim F, Olsufka M, Longstreth WT, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007; 115:3064–3070.
  21. Haugk M, Sterz F, Grassberger M, et al. Feasibility and efficacy of a new non-invasive surface cooling device in post-resuscitation intensive care medicine. Resuscitation 2007; 75:76–81.
  22. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008; 358:2447–2456.
  23. Berger RP, Adelson PD, Richichi R, Kochanek PM. Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the biochemical response of the pediatric brain to inflicted brain injury. Dev Neurosci 2006; 28:327–335.
  24. , et al., Brain Trauma Foundation. Guidelines for the management of severe traumatic brain injury:. Introduction. J Neurotrauma 2007; 24( suppl 1):S1–S2.
  25. Todd MM, Hindman BJ, Clarke WR, Torner JCIntraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005; 352:135–145.
  26. Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med 2007; 35:2196–2204.
  27. Statler KD, Alexander HL, Vagni VA, et al. Moderate hypothermia may be detrimental after traumatic brain injury in fentanylanesthetized rats. Crit Care Med 2003; 31:1134–1139.
  28. Katz LM, Wang Y, McMahon B, Richelson E. Neurotensin analog NT69L induces rapid and prolonged hypothermia after hypoxic ischemia. Acad Emerg Med 2001; 8:1115–1121.
  29. Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science 2005; 308:518.
  30. Li J, Zhang G, Cai S, Redington AN. Effect of inhaled hydrogen sulfide on metabolic responses in anesthetized, paralyzed, and mechanically ventilated piglets. Pediatr Crit Care Med 2008; 9:110–112.
  31. Rhee PM, Acosta J, Bridgeman A, Wang D, Jordan M, Rich N. Survival after emergency department thoracotomy: review of published data from the past 25 years. J Am Coll Surg 2000; 190:288–298.
  32. Behringer W, Prueckner S, Kentner R, et al. Rapid hypothermic aortic flush can achieve survival without brain damage after 30 minutes cardiac arrest in dogs. Anesthesiology 2000; 93:1491–1499.
  33. Behringer W, Kentner R, Wu X, et al. Fructose-1,6-bisphosphate and MK-801 by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 min in dogs: an exploratory study. Resuscitation 2001; 50:205–216.
  34. Behringer W, Safar P, Wu X, et al. Survival without brain damage after clinical death of 60–120 mins in dogs using suspended animation by profound hypothermia. Crit Care Med 2003; 31:1523–1531.
  35. Behringer W, Safar P, Kentner R, et al. Antioxidant Tempol enhances hypothermic cerebral preservation during prolonged cardiac arrest in dogs. J Cereb Blood Flow Metab 2002; 22:105–117.
  36. Wu X, Drabek T, Kochanek PM, et al. Induction of profound hypothermia for emergency preservation and resuscitation allows intact survival after cardiac arrest resulting from prolonged lethal hemorrhage and trauma in dogs. Circulation 2006; 113:1974–1982.
  37. Wu X, Drabek T, Tisherman SA, et al. Emergency preservation and resuscitation with profound hypothermia, oxygen, and glucose allows reliable neurological recovery after 3 h of cardiac arrest from rapid exsanguination in dogs. J Cereb Blood Flow Metab 2008; 28:302–311.
  38. Drabek T, Stezoski J, Garman RH, et al. Emergency preservation and delayed resuscitation allows normal recovery after exsanguination cardiac arrest in rats: a feasibility trial. Crit Care Med 2007; 35:532–537.
  39. Drabek T, Stezoski J, Garman RH, et al. Exsanguination cardiac arrest in rats treated by 60 min, but not 75 min, emergency preservation and delayed resuscitation is associated with intact outcome. Resuscitation 2007; 75:114–123.
  40. Alam HB, Chen Z, Honma K, et al. The rate of induction of hypothermic arrest determines the outcome in a swine model of lethal hemorrhage. J Trauma 2004; 57:961–969.
  41. Janata A, Bayegan K, Weihs W, et al. Emergency preservation and resuscitation improve survival after 15 minutes of normovolemic cardiac arrest in pigs. Crit Care Med 2007; 35:2785–2791.
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Bakken Lecture: The brain, the heart, and therapeutic hypothermia
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Depression and heart rate variability in patients with coronary heart disease

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Depression and heart rate variability in patients with coronary heart disease
Author(s)
Robert M. Carney, PhD
Kenneth E. Freedland, PhD

Depression is a common psychiatric disorder in patients with coronary heart disease (CHD). Whereas the lifetime prevalence of major depression in the United States is estimated to be about 16%,1 with an annual rate of about 7%, approximately 20% of patients with CHD have major depression at any point in time.2–5 About the same proportion have minor depression.3 During the 12 months following an acute coronary event, as many as 30% of patients may develop major depression;6 the prevalence of minor depression during this 12-month period has not been reported but is also estimated to be about 30%. Thus, up to 60% of patients with an acute coronary event experience symptoms of depression within the 12 months following the event.

In addition to being highly comorbid with CHD, depression is also a significant risk factor for cardiac morbidity and mortality in patients with CHD. This risk is present from the time of initial diagnosis of CHD by cardiac catheterization and angiography7,8 as well as after an acute myocardial infarction (MI),6,9–11 an episode of unstable angina,12 or coronary artery bypass graft surgery.13–15 A recent meta-analysis of more than 20 studies of depression following acute MI found that major depression more than doubles the risk of mortality in the months following the acute event.16 Another meta-analysis found that just having symptoms of depression at various times in the course of CHD doubles the risk of death, and that clinical depression is associated with an even higher risk.17

Depression has been associated with many behavioral and biological abnormalities that could help explain the increased mortality risk in depressed patients with cardiac disease, including reduced adherence to treatment regimens, increased prevalence of smoking and diabetes, platelet dysfunction and coagulant processes, inflammatory processes, and alterations in hypothalamic-pituitary-adrenal axis and autonomic nervous system (ANS) function.18,19 Any or all of these might contribute to the increased risk for cardiac morbidity and mortality in depressed patients. Of all these possibilities, however, ANS dysfunction probably has received the most attention.20 Excessive sympathetic or reduced parasympathetic nervous system activity in patients with CHD may promote myocardial ischemia, ventricular tachycardia, ventricular fibrillation, and even sudden cardiac death.21–23

Studies dating back to the 1960s have found plasma and urinary catecholamine levels and resting heart rate (HR) to be elevated in medically well psychiatric patients with major depression compared with nondepressed controls.24–30 Studies of patients with CHD have also found elevated resting and 24-hour HRs in depressed compared with nondepressed patients.31,32 Additional evidence of ANS dysfunction in depressed CHD patients includes increased HR response to orthostatic challenge;32 increased QT interval variability, reflecting abnormal ventricular repolarization;33 abnormal HR response to ventricular arrhythmias (turbulence);34 and an increased incidence of ventricular tachycardia.35 All of these factors have been related to ANS dysfunction, and all are predictors of mortality in cardiac patients.

Many, though not all, studies of medically well depressed psychiatric patients have also found reduced HR variability (HRV), reflecting abnormal ANS modulation of HR. Low HRV is an excellent predictor of cardiac-related mortality36–39 and thus may further help to explain the relationship of depression to increased risk of mortality.

MEASUREMENT OF HEART RATE VARIABILITY

Analysis of HRV is a widely used method for studying cardiac autonomic modulation of HR.36 Low HRV generally reflects excessive sympathetic and/or inadequate parasympathetic modulation of HR36 and is a strong predictor of mortality in patients with CHD.37–39

Three methods of deriving HRV

In large prognostic or epidemiologic studies, HRV is usually measured over a 24-hour period and is derived from electrocardiographic (ECG) data by one of three methods: time domain analysis, frequency domain analysis, and nonlinear statistical models.

Time domain indices are based on descriptive statistical analyses of the HR time series. These include the standard deviation of all normal-to-normal intervals (SDNN) and the root mean square of successive N-N differences (rMSSD).

Frequency domain indices. Fast Fourier transforms and spectral analyses of ECG data are used to characterize HRV in the frequency domain. Frequency domain indices are defined by specific frequency ranges:

  • Ultra low frequency (ULF;
  • Very low frequency (VLF; 0.0033 to 0.04 Hz)
  • Low frequency (LF; 0.04 to 0.15 Hz)
  • High frequency (HF; 0.15 to 0.4 Hz).

These indices are usually log-transformed to produce approximately normal distributions. Efferent vagal activity is largely responsible for the HF component, whereas LF power seems to reflect both sympathetic and parasympathetic activity.36 There is less certainly about the contributions to ULF.36 While not completely understood, VLF power is known to be unaffected by beta-blockade but nearly abolished by atropine, suggesting that the parasympathetic nervous system is the predominant determinant of VLF.40

Nonlinear statistical models. HRV has also been characterized by nonlinear mathematical models, such as those based on chaos theory and fractals. Nonlinear methods quantify the structure of the HR time series, including its regularity and self-similarity. These indices include the short-term fractal scaling exponent and approximate entropy.

 

 

HEART RATE VARIABILITY AND DEPRESSION IN CHD

Some studies have assessed HRV and depression following acute MI,41–45 whereas others have focused on HRV in medically stable patients with CHD. 46–49 Most of the studies have used frequency domain indices to calculate HRV.

HRV in post-MI patients with depression

In the largest study of depressed post-MI patients published to date,41 24-hour HRV levels were compared between 380 patients with a recent MI who had either major or minor depression and 425 post-MI patients who were not depressed. In univariate analyses, the four frequency domain indices of HRV (ULF, VLF, LF, and HF) were significantly lower in the depressed than in the nondepressed patients. After adjustment for possible confounders, all the indices except HF remained significantly lower in depressed patients than in nondepressed patients.

HRV in depressed patients with stable coronary disease

Most46–48 but not all49 studies have also found HRV to be lower in depressed than in nondepressed patients with stable CHD. The one exception was reported by Gehi et al,49 who assessed participants from the Heart and Soul Study cohort who had stable CHD at the time HRV was determined. Of the 873 outpatients with stable CHD who received 24-hour ambulatory ECG monitoring, 195 were found to have major depression. No differences between depressed and nondepressed patients were found on any time domain or frequency domain measure of HRV. This is the largest study to date of medically stable CHD patients assessed for depression and HRV, but its results differ from those of most smaller studies. The authors noted that although there was no difference in HRV between depressed and nondepressed patients, HRV in the nondepressed patients was similar to that in depressed patients in other samples.50 They speculated that the participants in their study, who were largely recruited from a Veterans Affairs hospital, may have been sicker than most participants in other studies and that this might have obscured depression-related differences in HRV.50

What is the clinical significance of HRV differences?

When evaluating differences in HRV between depressed and nondepressed patients, it is important to look past statistical comparisons and consider the clinical significance of these differences—ie, whether they are large enough to affect clinical outcomes or to be responsible for the depressed patients’ increased risk of death.

In the Cardiac Arrhythmia Pilot Study, HRV was assessed 1 year after acute MI in 331 patients.51 All measured indices of HRV were strong predictors of mortality. Patients with VLF power of less than 600 ms2 (natural logarithm of VLF power [LnVLF] 51 In a study of a similar group of medically stable (ie, eventfree for ≥6 months) patients with CHD,48 47% of those who were moderately to severely depressed, 29% of those who were mildly depressed, and 13% of those who were not depressed had VLF power below this cutpoint.

In the Multicenter Post-Infarction Program study, which evaluated patients in the immediate post–acute MI period, an LnVLF less than 5.2 was associated with a relative risk of 4.7 for cardiac mortality over the next 2.5 years.37 In our own study of post-MI patients, 7% of the nondepressed participants and 16% of the depressed participants had VLF power below this value, a difference that was significant even after adjusting for covariates (P = .006).41 Thus, mean 24-hour HRV is low enough in depressed patients with medically stable CHD and in those with recent acute MI to have prognostic significance.

How much of depression’s effect is due to low HRV?

In an attempt to determine whether low HRV accounts for at least part of the effect of depression on mortality, a statistical mediation model was applied to data collected in a follow-up study of the 311 depressed patients with recent acute MI described above,41 who were enrolled in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial,52 and 367 patients who met the ENRICHD medical inclusion criteria but were without depression.53 VLF was selected as the index of HRV for this study because of its prognostic importance in post-MI patients. As noted earlier, VLF was significantly lower in the depressed patients.41 During a median follow-up of 24 months, there were 47 deaths within the overall study population of 766 patients (6.1%).53 Consistent with earlier studies, the depressed patients were at higher risk for all-cause mortality, even after adjusting for potential confounders (hazard ratio = 2.8; 95% confidence interval [CI], 1.4 to 5.4; P P = .03), indicating that the LnVLF accounted for about one-quarter of the total mortality risk. Thus, the study results suggest that low HRV at least partially mediates the effect of depression on survival after acute MI.

A role for premature ventricular contractions

In one of the first prognostic studies of depression following acute MI, Frasure-Smith et al reported an interaction between depression and premature ventricular contractions (VPCs) on subsequent mortality.6 Specifically, they found that depressed patients who had 10 or more VPCs per hour after an MI were at considerably higher risk of death than were either depressed post-MI patients without VPCs or nondepressed post-MI patients with 10 or more VPCs per hour. One interpretation of these data is that depressed patients may be at greater risk for death due to an abnormal response to VPCs or other arrhythmias.

HR turbulence analysis is a method for quantifying HR response to VPCs. In most individuals, when a VPC occurs, HR first accelerates and then decelerates. HR responses that differ from this pattern have been found to be even better predictors of post-MI mortality than more traditional measures of HRV in these patients.54,55

A total of 498 patients from the study reported above53 were found to have VPCs during 24-hour ambulatory monitoring.34 Of these patients, 260 had normal HR turbulence, 152 had equivocal HR turbulence, and 86 had abnormal HR turbulence. The depressed patients were more likely than their nondepressed counterparts to have abnormal HR turbulence (risk factor–adjusted odds ratio [OR] = 1.8; 95% CI, 1.0 to 3.0; P = .03). The patients were followed for a median of 24 months. Consistent with earlier studies, depressed patients had worse survival (OR for death = 2.4; 95% CI, 1.2 to 4.6; P = .02) than the nondepressed patients. When HR turbulence was added to the statistical model, the adjusted hazard ratio for depression decreased to 1.9 (95% CI, 0.9 to 3.8; P = .08). When the LnVLF was added to this model, the adjusted hazard ratio decreased further, to 1.6 (95% CI, 0.8 to 3.4; P = .18). Thus, the combination of VLF and HR response to VPCs explained about half of the effect of depression on survival in these patients.

Causality not proven, but further study warranted

Obviously, these results do not prove that there is a causal relationship between depression, low HRV, and mortality. However, they are consistent with the interpretation that HRV, especially when combined with measures of HR response to VPCs, may account for a significant proportion of depression’s association with mortality following an MI. Future studies of these risk markers should explore their potential interrelationships to clarify how they may jointly contribute to the risk of death in patients with depression.

 

 

RELATIONSHIP AMONG HRV AND OTHER POSSIBLE BIOLOGICAL PATHWAYS

As discussed earlier, other biological pathways that may link depression to increased mortality have been reported. The two that have received the most support are proinflammatory and procoagulant processes. 18,19 Studies of medically healthy depressed psychiatric patients and of depressed CHD patients have found depression to be associated with higher levels of the inflammatory risk markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor–alpha (TNF-α) and with inflammatory-procoagulant markers such as fibrinogen,56–60 as well as with platelet activation. Low HRV and elevations in proinflammatory or procoagulant markers generally have been described as though they are independent pathways. However, both inflammatory and coagulant responses can be modulated by ANS activity,61,62 and a cholinergic anti-inflammatory pathway was recently proposed in which there is vagal efferent inhibition of proinflammatory cytokine release, thereby reducing systemic inflammation.62,63 Low HRV, reflecting reduced vagal activity, should therefore be associated with higher levels of both proinflammatory and procoagulant markers. Recent studies have found a relationship between HRV activity and increased markers of inflammation in other high-risk patients, including those with heart failure64,65 and with acute coronary syndrome.66

In a recent study of 44 patients with major depression, moderate negative correlations were found between fibrinogen and four measures of HRV.67 IL-6 was also negatively correlated with one measure of HRV (total power) and was marginally related to two others (VLF and LF power). On the other hand, neither CRP nor TNF-α was significantly related to any measure of HRV. The finding that fibrinogen and IL-6 are moderately related to HRV suggests a link between these factors in depressed CHD patients. Thus, these risk markers, which are commonly found in patients with depression, may be related and contribute to the increased mortality associated with depression. This possibility should be investigated in larger mechanistic studies of depression and cardiac morbidity and mortality.

SUMMARY AND FUTURE DIRECTIONS

Low HRV and other markers of cardiac ANS dysfunction in depressed patients are likely to contribute to the elevated risk associated with depression in patients with CHD. More work is needed to clarify the physiologic and behavioral mechanisms underlying depression’s role as a risk factor for mortality in patients with CHD. Work is also needed to identify treatments that improve both depression and HRV, and to determine whether such treatments might also improve survival in these patients.68

References
  1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289:3095–3105.
  2. Carney RM, Rich MW, teVelde A, et al. Major depressive disorder in coronary artery disease. Am J Cardiol 1987; 60:1273–1275.
  3. Hance M, Carney RM, Freedland KE, Skala J. Depression in patients with coronary heart disease: a 12-month follow-up. Gen Hosp Psychiatry 1996; 18:61–65.
  4. Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003; 54:227–240.
  5. Thombs BD, Bass EB, Ford DE, et al. Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 2006; 21:30–38.
  6. Frasure-Smith N, Lespérance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995; 91:999–1005.
  7. Carney RM, Rich MW, Freedland KE, et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Med 1988; 50:627–633.
  8. Herrmann C, Brand-Driehorst S, Buss U, Rüger U. Effects of anxiety and depression on 5-year mortality in 5,057 patients referred for exercise testing. J Psychosom Res 2000; 48:455–462.
  9. Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001; 88:337–341.
  10. Carney RM, Blumenthal JA, Catellier D, et al. Depression as a risk factor for mortality after acute myocardial infarction. Am J Cardiol 2003; 92:1277–1281.
  11. Ladwig KH, Kieser M, König J, Breithardt G, Borggrefe M. Affective disorders and survival after acute myocardial infarction: results from the post-infarction late potential study. Eur Heart J 1991; 12:959–964.
  12. Lespérance F, Frasure-Smith N, Juneau M, Théroux P. Depression and 1-year prognosis in unstable angina. Arch Intern Med 2000; 160:1354–1360.
  13. Blumenthal JA, Lett HS, Babyak MA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.
  14. Burg MM, Benedetto C, Rosenberg R, Soufer R. Depression prior to CABG predicts 6-month and 2-year morbidity and mortality. Psychosom Med 2001; 63:103. Abstract 1175.
  15. Connerney I, Shapiro PA, McLaughlin JS, Sloan RP. In-hospital depression after CABG surgery predicts 12-month outcome. Psychosom Med 2000; 62:106. Abstract 1195.
  16. van Melle JP, de Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 2004; 66:814–822.
  17. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a metaanalysis. Psychosom Med 2004; 66:802–813.
  18. Carney RM, Freedland KE, Miller GE, Jaffe AS. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res 2002; 53:897–902.
  19. Carney RM, Freedland KE. Depression, mortality, and medical morbidity in patients with coronary heart disease. Biol Psychiatry 2003; 54:241–247.
  20. Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med 2005; 67( suppl 1):S29–S33.
  21. Kliks BR, Burgess MJ, Abildskov JA. Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Am J Cardiol 1975; 36:45–49.
  22. Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation 1990; 82( 2 suppl):I103–I113.
  23. Schwartz PJ, Vanoli E. Cardiac arrhythmias elicited by interaction between acute myocardial ischemia and sympathetic hyperactivity: a new experimental model for the study of antiarrhythmic drugs. J Cardiovasc Pharmacol 1981; 3:1251–1259.
  24. Esler M, Turbott J, Schwarz R, et al. The peripheral kinetics of norepinephrine in depressive illness. Arch Gen Psychiatry 1982; 39:295–300.
  25. Lake CR, Pickar D, Ziegler MG, Lipper S, Slater S, Murphy DL. High plasma norepinephrine levels in patients with major affective disorder. Am J Psychiatry 1982; 139:1315–1318.
  26. Roy A, Pickar D, De Jong J, Karoum F, Linnoila M. Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression. Arch Gen Psychiatry 1988; 45:849–857.
  27. Veith RC, Lewis N, Linares OA, et al. Sympathetic nervous system activity in major depression: basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch Gen Psychiatry 1994; 51:411–422.
  28. Dawson ME, Schell AM, Catania JJ. Autonomic correlates of depression and clinical improvement following electroconvulsive shock therapy. Psychophysiology 1977; 14:569–578.
  29. Lahmeyer HW, Bellur SN. Cardiac regulation and depression. J Psychiatr Res 1987; 21:1–6.
  30. Wyatt RJ, Portnoy B, Kupfer DJ, Snyder F, Engelman K. Resting plasma catecholamine concentrations in patients with depression and anxiety. Arch Gen Psychiatry 1971; 24:65–70.
  31. Carney RM, Rich MW, teVelde A, et al. The relationship between heart rate, heart rate variability and depression in patients with coronary artery disease. J Psychosom Res 1988; 32:159–164.
  32. Carney RM, Freedland KE, Veith RC, et al. Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease. Biol Psychiatry 1999; 45:458–463.
  33. Carney RM, Freedland KE, Stein PK, et al. Effects of depression on QT interval variability after myocardial infarction. Psychosom Med 2003; 65:177–180.
  34. Carney RM, Howells WB, Blumenthal JA, et al. Heart rate turbulence, depression, and survival after acute myocardial infarction. Psychosom Med 2007; 69:4–9.
  35. Carney RM, Freedland KE, Rich MW, Smith LJ, Jaffe AS. Ventricular tachycardia and psychiatric depression in patients with coronary artery disease. Am J Med 1993; 95:23–28.
  36. Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996; 93:1043–1065.
  37. Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 1992; 85:164–171.
  38. Kleiger RE, Miller JP, Bigger JT, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987; 59:256–262.
  39. Vaishnav S, Stevenson R, Marchant B, Lagi K, Ranjadayalan K, Timmis AD. Relation between heart rate variability early after acute myocardial infarction and long-term mortality. Am J Cardiol 1994; 73:653–657.
  40. Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation 1998; 98:547–555.
  41. Carney RM, Blumenthal JA, Stein PK, et al. Depression, heart rate variability, and acute myocardial infarction. Circulation 2001; 104:2024–2028.
  42. Guinjoan SM, de Guevara MS, Correa C, et al. Cardiac parasympathetic dysfunction related to depression in older adults with acute coronary syndromes. J Psychosom Res 2004; 56:83–88.
  43. Pitzalis MV, Iacoviello M, Todarello O, et al. Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction. Am Heart J 2001; 141:765–771.
  44. van den Berg MP, Spijkerman TA, van Melle JP, et al. Depression as an independent determinant of decreased heart rate variability in patinets post myocardial infarction. Neth Heart J 2005; 13:1365–1369.
  45. Vigo DE, Nicola Siri L, Ladrón De Guevara MS, et al. Relation of depression to heart rate nonlinear dynamics in patients ≥60 years of age with recent unstable angina pectoris or acute myocardial infarction. Am J Cardiol 2004; 93:756–760.
  46. Carney RM, Saunders RD, Freedland KE, Stein P, Rich MW, Jaffe AS. Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol 1995; 76:562–564.
  47. Krittayaphong R, Cascio WE, Light KC, et al. Heart rate variability in patients with coronary artery disease: differences in patients with higher and lower depression scores. Psychosom Med 1997; 59:231–235.
  48. Stein PK, Carney RM, Freedland KE, et al. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J Psychosom Res 2000; 48:493–500.
  49. Gehi A, Mangano D, Pipkin S, Browner WS, Whooley MA. Depression and heart rate variability in patients with stable coronary heart disease: findings from the Heart and Soul Study. Arch Gen Psychiatry 2005; 62:661–666.
  50. Gehi A, Whooley M. Heart rate variability and depression [reply to letter]. Arch Gen Psychiatry 2006; 63:1052.
  51. Bigger JT, Fleiss JL, Rolnitzky LM, Steinman RC. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am Coll Cardiol 1993; 21:729–736.
  52. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 2003; 289:3106–3116.
  53. Carney RM, Blumenthal JA, Freedland KE, et al. Low heart rate variability and the effect of depression on post-myocardial infarction mortality. Arch Intern Med 2005; 165:1486–1491.
  54. Ghuran A, Reid F, La Rovere MT, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and Reflexes After Myocardial Infarction substudy). Am J Cardiol 2002; 89:184–190.
  55. Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 1999; 353:1390–1396.
  56. Dentino AN, Pieper CF, Rao MK, et al. Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc 1999; 47:6–11.
  57. Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 1995; 34:301–309.
  58. Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997; 9:853–858.
  59. Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 2002; 90:1279–1283.
  60. von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med 2001; 63:531–544.
  61. März P, Cheng JG, Gadient RA, et al. Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci USA 1998; 95:3251–3256.
  62. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853–859.
  63. Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun 2005; 19:493–499.
  64. Aronson D, Mittleman MA, Burger AJ. Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure. J Cardiovasc Electrophysiol 2001; 12:294–300.
  65. Malave HA, Taylor AA, Nattama J, Deswal A, Mann DL. Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure. Chest 2003; 123:716–724.
  66. Lanza GA, Sgueglia GA, Cianflone D, et al. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2006; 97:1702–1706.
  67. Carney RM, Freedland KE, Stein PK, et al. Heart rate variability and markers of inflammation and coagulation in depressed patients with coronary heart disease. J Psychosom Res 2007; 62:463–467.
  68. Carney RM, Freedland KE, Stein PK, et al. Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease. Psychosom Med 2000; 62:639–647.
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Robert M. Carney, PhD
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO

Kenneth E. Freedland, PhD
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO

Correspondence: Robert M. Carney, PhD, Behavioral Medicine Center, 4320 Forest Park Boulevard, Suite 301, St. Louis, MO 63108; [email protected]

This manuscript was supported in part by grant RO1 HL76808 from the National Heart, Lung, and Blood Institute and by the Lewis and Jean Sachs Charitable Lead Trust.

Both authors reported that they have no financial interests or relationships that pose a potential conflict of interest with this article.

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Correspondence: Robert M. Carney, PhD, Behavioral Medicine Center, 4320 Forest Park Boulevard, Suite 301, St. Louis, MO 63108; [email protected]

This manuscript was supported in part by grant RO1 HL76808 from the National Heart, Lung, and Blood Institute and by the Lewis and Jean Sachs Charitable Lead Trust.

Both authors reported that they have no financial interests or relationships that pose a potential conflict of interest with this article.

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Department of Psychiatry, Washington University School of Medicine, St. Louis, MO

Correspondence: Robert M. Carney, PhD, Behavioral Medicine Center, 4320 Forest Park Boulevard, Suite 301, St. Louis, MO 63108; [email protected]

This manuscript was supported in part by grant RO1 HL76808 from the National Heart, Lung, and Blood Institute and by the Lewis and Jean Sachs Charitable Lead Trust.

Both authors reported that they have no financial interests or relationships that pose a potential conflict of interest with this article.

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Depression is a common psychiatric disorder in patients with coronary heart disease (CHD). Whereas the lifetime prevalence of major depression in the United States is estimated to be about 16%,1 with an annual rate of about 7%, approximately 20% of patients with CHD have major depression at any point in time.2–5 About the same proportion have minor depression.3 During the 12 months following an acute coronary event, as many as 30% of patients may develop major depression;6 the prevalence of minor depression during this 12-month period has not been reported but is also estimated to be about 30%. Thus, up to 60% of patients with an acute coronary event experience symptoms of depression within the 12 months following the event.

In addition to being highly comorbid with CHD, depression is also a significant risk factor for cardiac morbidity and mortality in patients with CHD. This risk is present from the time of initial diagnosis of CHD by cardiac catheterization and angiography7,8 as well as after an acute myocardial infarction (MI),6,9–11 an episode of unstable angina,12 or coronary artery bypass graft surgery.13–15 A recent meta-analysis of more than 20 studies of depression following acute MI found that major depression more than doubles the risk of mortality in the months following the acute event.16 Another meta-analysis found that just having symptoms of depression at various times in the course of CHD doubles the risk of death, and that clinical depression is associated with an even higher risk.17

Depression has been associated with many behavioral and biological abnormalities that could help explain the increased mortality risk in depressed patients with cardiac disease, including reduced adherence to treatment regimens, increased prevalence of smoking and diabetes, platelet dysfunction and coagulant processes, inflammatory processes, and alterations in hypothalamic-pituitary-adrenal axis and autonomic nervous system (ANS) function.18,19 Any or all of these might contribute to the increased risk for cardiac morbidity and mortality in depressed patients. Of all these possibilities, however, ANS dysfunction probably has received the most attention.20 Excessive sympathetic or reduced parasympathetic nervous system activity in patients with CHD may promote myocardial ischemia, ventricular tachycardia, ventricular fibrillation, and even sudden cardiac death.21–23

Studies dating back to the 1960s have found plasma and urinary catecholamine levels and resting heart rate (HR) to be elevated in medically well psychiatric patients with major depression compared with nondepressed controls.24–30 Studies of patients with CHD have also found elevated resting and 24-hour HRs in depressed compared with nondepressed patients.31,32 Additional evidence of ANS dysfunction in depressed CHD patients includes increased HR response to orthostatic challenge;32 increased QT interval variability, reflecting abnormal ventricular repolarization;33 abnormal HR response to ventricular arrhythmias (turbulence);34 and an increased incidence of ventricular tachycardia.35 All of these factors have been related to ANS dysfunction, and all are predictors of mortality in cardiac patients.

Many, though not all, studies of medically well depressed psychiatric patients have also found reduced HR variability (HRV), reflecting abnormal ANS modulation of HR. Low HRV is an excellent predictor of cardiac-related mortality36–39 and thus may further help to explain the relationship of depression to increased risk of mortality.

MEASUREMENT OF HEART RATE VARIABILITY

Analysis of HRV is a widely used method for studying cardiac autonomic modulation of HR.36 Low HRV generally reflects excessive sympathetic and/or inadequate parasympathetic modulation of HR36 and is a strong predictor of mortality in patients with CHD.37–39

Three methods of deriving HRV

In large prognostic or epidemiologic studies, HRV is usually measured over a 24-hour period and is derived from electrocardiographic (ECG) data by one of three methods: time domain analysis, frequency domain analysis, and nonlinear statistical models.

Time domain indices are based on descriptive statistical analyses of the HR time series. These include the standard deviation of all normal-to-normal intervals (SDNN) and the root mean square of successive N-N differences (rMSSD).

Frequency domain indices. Fast Fourier transforms and spectral analyses of ECG data are used to characterize HRV in the frequency domain. Frequency domain indices are defined by specific frequency ranges:

  • Ultra low frequency (ULF;
  • Very low frequency (VLF; 0.0033 to 0.04 Hz)
  • Low frequency (LF; 0.04 to 0.15 Hz)
  • High frequency (HF; 0.15 to 0.4 Hz).

These indices are usually log-transformed to produce approximately normal distributions. Efferent vagal activity is largely responsible for the HF component, whereas LF power seems to reflect both sympathetic and parasympathetic activity.36 There is less certainly about the contributions to ULF.36 While not completely understood, VLF power is known to be unaffected by beta-blockade but nearly abolished by atropine, suggesting that the parasympathetic nervous system is the predominant determinant of VLF.40

Nonlinear statistical models. HRV has also been characterized by nonlinear mathematical models, such as those based on chaos theory and fractals. Nonlinear methods quantify the structure of the HR time series, including its regularity and self-similarity. These indices include the short-term fractal scaling exponent and approximate entropy.

 

 

HEART RATE VARIABILITY AND DEPRESSION IN CHD

Some studies have assessed HRV and depression following acute MI,41–45 whereas others have focused on HRV in medically stable patients with CHD. 46–49 Most of the studies have used frequency domain indices to calculate HRV.

HRV in post-MI patients with depression

In the largest study of depressed post-MI patients published to date,41 24-hour HRV levels were compared between 380 patients with a recent MI who had either major or minor depression and 425 post-MI patients who were not depressed. In univariate analyses, the four frequency domain indices of HRV (ULF, VLF, LF, and HF) were significantly lower in the depressed than in the nondepressed patients. After adjustment for possible confounders, all the indices except HF remained significantly lower in depressed patients than in nondepressed patients.

HRV in depressed patients with stable coronary disease

Most46–48 but not all49 studies have also found HRV to be lower in depressed than in nondepressed patients with stable CHD. The one exception was reported by Gehi et al,49 who assessed participants from the Heart and Soul Study cohort who had stable CHD at the time HRV was determined. Of the 873 outpatients with stable CHD who received 24-hour ambulatory ECG monitoring, 195 were found to have major depression. No differences between depressed and nondepressed patients were found on any time domain or frequency domain measure of HRV. This is the largest study to date of medically stable CHD patients assessed for depression and HRV, but its results differ from those of most smaller studies. The authors noted that although there was no difference in HRV between depressed and nondepressed patients, HRV in the nondepressed patients was similar to that in depressed patients in other samples.50 They speculated that the participants in their study, who were largely recruited from a Veterans Affairs hospital, may have been sicker than most participants in other studies and that this might have obscured depression-related differences in HRV.50

What is the clinical significance of HRV differences?

When evaluating differences in HRV between depressed and nondepressed patients, it is important to look past statistical comparisons and consider the clinical significance of these differences—ie, whether they are large enough to affect clinical outcomes or to be responsible for the depressed patients’ increased risk of death.

In the Cardiac Arrhythmia Pilot Study, HRV was assessed 1 year after acute MI in 331 patients.51 All measured indices of HRV were strong predictors of mortality. Patients with VLF power of less than 600 ms2 (natural logarithm of VLF power [LnVLF] 51 In a study of a similar group of medically stable (ie, eventfree for ≥6 months) patients with CHD,48 47% of those who were moderately to severely depressed, 29% of those who were mildly depressed, and 13% of those who were not depressed had VLF power below this cutpoint.

In the Multicenter Post-Infarction Program study, which evaluated patients in the immediate post–acute MI period, an LnVLF less than 5.2 was associated with a relative risk of 4.7 for cardiac mortality over the next 2.5 years.37 In our own study of post-MI patients, 7% of the nondepressed participants and 16% of the depressed participants had VLF power below this value, a difference that was significant even after adjusting for covariates (P = .006).41 Thus, mean 24-hour HRV is low enough in depressed patients with medically stable CHD and in those with recent acute MI to have prognostic significance.

How much of depression’s effect is due to low HRV?

In an attempt to determine whether low HRV accounts for at least part of the effect of depression on mortality, a statistical mediation model was applied to data collected in a follow-up study of the 311 depressed patients with recent acute MI described above,41 who were enrolled in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial,52 and 367 patients who met the ENRICHD medical inclusion criteria but were without depression.53 VLF was selected as the index of HRV for this study because of its prognostic importance in post-MI patients. As noted earlier, VLF was significantly lower in the depressed patients.41 During a median follow-up of 24 months, there were 47 deaths within the overall study population of 766 patients (6.1%).53 Consistent with earlier studies, the depressed patients were at higher risk for all-cause mortality, even after adjusting for potential confounders (hazard ratio = 2.8; 95% confidence interval [CI], 1.4 to 5.4; P P = .03), indicating that the LnVLF accounted for about one-quarter of the total mortality risk. Thus, the study results suggest that low HRV at least partially mediates the effect of depression on survival after acute MI.

A role for premature ventricular contractions

In one of the first prognostic studies of depression following acute MI, Frasure-Smith et al reported an interaction between depression and premature ventricular contractions (VPCs) on subsequent mortality.6 Specifically, they found that depressed patients who had 10 or more VPCs per hour after an MI were at considerably higher risk of death than were either depressed post-MI patients without VPCs or nondepressed post-MI patients with 10 or more VPCs per hour. One interpretation of these data is that depressed patients may be at greater risk for death due to an abnormal response to VPCs or other arrhythmias.

HR turbulence analysis is a method for quantifying HR response to VPCs. In most individuals, when a VPC occurs, HR first accelerates and then decelerates. HR responses that differ from this pattern have been found to be even better predictors of post-MI mortality than more traditional measures of HRV in these patients.54,55

A total of 498 patients from the study reported above53 were found to have VPCs during 24-hour ambulatory monitoring.34 Of these patients, 260 had normal HR turbulence, 152 had equivocal HR turbulence, and 86 had abnormal HR turbulence. The depressed patients were more likely than their nondepressed counterparts to have abnormal HR turbulence (risk factor–adjusted odds ratio [OR] = 1.8; 95% CI, 1.0 to 3.0; P = .03). The patients were followed for a median of 24 months. Consistent with earlier studies, depressed patients had worse survival (OR for death = 2.4; 95% CI, 1.2 to 4.6; P = .02) than the nondepressed patients. When HR turbulence was added to the statistical model, the adjusted hazard ratio for depression decreased to 1.9 (95% CI, 0.9 to 3.8; P = .08). When the LnVLF was added to this model, the adjusted hazard ratio decreased further, to 1.6 (95% CI, 0.8 to 3.4; P = .18). Thus, the combination of VLF and HR response to VPCs explained about half of the effect of depression on survival in these patients.

Causality not proven, but further study warranted

Obviously, these results do not prove that there is a causal relationship between depression, low HRV, and mortality. However, they are consistent with the interpretation that HRV, especially when combined with measures of HR response to VPCs, may account for a significant proportion of depression’s association with mortality following an MI. Future studies of these risk markers should explore their potential interrelationships to clarify how they may jointly contribute to the risk of death in patients with depression.

 

 

RELATIONSHIP AMONG HRV AND OTHER POSSIBLE BIOLOGICAL PATHWAYS

As discussed earlier, other biological pathways that may link depression to increased mortality have been reported. The two that have received the most support are proinflammatory and procoagulant processes. 18,19 Studies of medically healthy depressed psychiatric patients and of depressed CHD patients have found depression to be associated with higher levels of the inflammatory risk markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor–alpha (TNF-α) and with inflammatory-procoagulant markers such as fibrinogen,56–60 as well as with platelet activation. Low HRV and elevations in proinflammatory or procoagulant markers generally have been described as though they are independent pathways. However, both inflammatory and coagulant responses can be modulated by ANS activity,61,62 and a cholinergic anti-inflammatory pathway was recently proposed in which there is vagal efferent inhibition of proinflammatory cytokine release, thereby reducing systemic inflammation.62,63 Low HRV, reflecting reduced vagal activity, should therefore be associated with higher levels of both proinflammatory and procoagulant markers. Recent studies have found a relationship between HRV activity and increased markers of inflammation in other high-risk patients, including those with heart failure64,65 and with acute coronary syndrome.66

In a recent study of 44 patients with major depression, moderate negative correlations were found between fibrinogen and four measures of HRV.67 IL-6 was also negatively correlated with one measure of HRV (total power) and was marginally related to two others (VLF and LF power). On the other hand, neither CRP nor TNF-α was significantly related to any measure of HRV. The finding that fibrinogen and IL-6 are moderately related to HRV suggests a link between these factors in depressed CHD patients. Thus, these risk markers, which are commonly found in patients with depression, may be related and contribute to the increased mortality associated with depression. This possibility should be investigated in larger mechanistic studies of depression and cardiac morbidity and mortality.

SUMMARY AND FUTURE DIRECTIONS

Low HRV and other markers of cardiac ANS dysfunction in depressed patients are likely to contribute to the elevated risk associated with depression in patients with CHD. More work is needed to clarify the physiologic and behavioral mechanisms underlying depression’s role as a risk factor for mortality in patients with CHD. Work is also needed to identify treatments that improve both depression and HRV, and to determine whether such treatments might also improve survival in these patients.68

Depression is a common psychiatric disorder in patients with coronary heart disease (CHD). Whereas the lifetime prevalence of major depression in the United States is estimated to be about 16%,1 with an annual rate of about 7%, approximately 20% of patients with CHD have major depression at any point in time.2–5 About the same proportion have minor depression.3 During the 12 months following an acute coronary event, as many as 30% of patients may develop major depression;6 the prevalence of minor depression during this 12-month period has not been reported but is also estimated to be about 30%. Thus, up to 60% of patients with an acute coronary event experience symptoms of depression within the 12 months following the event.

In addition to being highly comorbid with CHD, depression is also a significant risk factor for cardiac morbidity and mortality in patients with CHD. This risk is present from the time of initial diagnosis of CHD by cardiac catheterization and angiography7,8 as well as after an acute myocardial infarction (MI),6,9–11 an episode of unstable angina,12 or coronary artery bypass graft surgery.13–15 A recent meta-analysis of more than 20 studies of depression following acute MI found that major depression more than doubles the risk of mortality in the months following the acute event.16 Another meta-analysis found that just having symptoms of depression at various times in the course of CHD doubles the risk of death, and that clinical depression is associated with an even higher risk.17

Depression has been associated with many behavioral and biological abnormalities that could help explain the increased mortality risk in depressed patients with cardiac disease, including reduced adherence to treatment regimens, increased prevalence of smoking and diabetes, platelet dysfunction and coagulant processes, inflammatory processes, and alterations in hypothalamic-pituitary-adrenal axis and autonomic nervous system (ANS) function.18,19 Any or all of these might contribute to the increased risk for cardiac morbidity and mortality in depressed patients. Of all these possibilities, however, ANS dysfunction probably has received the most attention.20 Excessive sympathetic or reduced parasympathetic nervous system activity in patients with CHD may promote myocardial ischemia, ventricular tachycardia, ventricular fibrillation, and even sudden cardiac death.21–23

Studies dating back to the 1960s have found plasma and urinary catecholamine levels and resting heart rate (HR) to be elevated in medically well psychiatric patients with major depression compared with nondepressed controls.24–30 Studies of patients with CHD have also found elevated resting and 24-hour HRs in depressed compared with nondepressed patients.31,32 Additional evidence of ANS dysfunction in depressed CHD patients includes increased HR response to orthostatic challenge;32 increased QT interval variability, reflecting abnormal ventricular repolarization;33 abnormal HR response to ventricular arrhythmias (turbulence);34 and an increased incidence of ventricular tachycardia.35 All of these factors have been related to ANS dysfunction, and all are predictors of mortality in cardiac patients.

Many, though not all, studies of medically well depressed psychiatric patients have also found reduced HR variability (HRV), reflecting abnormal ANS modulation of HR. Low HRV is an excellent predictor of cardiac-related mortality36–39 and thus may further help to explain the relationship of depression to increased risk of mortality.

MEASUREMENT OF HEART RATE VARIABILITY

Analysis of HRV is a widely used method for studying cardiac autonomic modulation of HR.36 Low HRV generally reflects excessive sympathetic and/or inadequate parasympathetic modulation of HR36 and is a strong predictor of mortality in patients with CHD.37–39

Three methods of deriving HRV

In large prognostic or epidemiologic studies, HRV is usually measured over a 24-hour period and is derived from electrocardiographic (ECG) data by one of three methods: time domain analysis, frequency domain analysis, and nonlinear statistical models.

Time domain indices are based on descriptive statistical analyses of the HR time series. These include the standard deviation of all normal-to-normal intervals (SDNN) and the root mean square of successive N-N differences (rMSSD).

Frequency domain indices. Fast Fourier transforms and spectral analyses of ECG data are used to characterize HRV in the frequency domain. Frequency domain indices are defined by specific frequency ranges:

  • Ultra low frequency (ULF;
  • Very low frequency (VLF; 0.0033 to 0.04 Hz)
  • Low frequency (LF; 0.04 to 0.15 Hz)
  • High frequency (HF; 0.15 to 0.4 Hz).

These indices are usually log-transformed to produce approximately normal distributions. Efferent vagal activity is largely responsible for the HF component, whereas LF power seems to reflect both sympathetic and parasympathetic activity.36 There is less certainly about the contributions to ULF.36 While not completely understood, VLF power is known to be unaffected by beta-blockade but nearly abolished by atropine, suggesting that the parasympathetic nervous system is the predominant determinant of VLF.40

Nonlinear statistical models. HRV has also been characterized by nonlinear mathematical models, such as those based on chaos theory and fractals. Nonlinear methods quantify the structure of the HR time series, including its regularity and self-similarity. These indices include the short-term fractal scaling exponent and approximate entropy.

 

 

HEART RATE VARIABILITY AND DEPRESSION IN CHD

Some studies have assessed HRV and depression following acute MI,41–45 whereas others have focused on HRV in medically stable patients with CHD. 46–49 Most of the studies have used frequency domain indices to calculate HRV.

HRV in post-MI patients with depression

In the largest study of depressed post-MI patients published to date,41 24-hour HRV levels were compared between 380 patients with a recent MI who had either major or minor depression and 425 post-MI patients who were not depressed. In univariate analyses, the four frequency domain indices of HRV (ULF, VLF, LF, and HF) were significantly lower in the depressed than in the nondepressed patients. After adjustment for possible confounders, all the indices except HF remained significantly lower in depressed patients than in nondepressed patients.

HRV in depressed patients with stable coronary disease

Most46–48 but not all49 studies have also found HRV to be lower in depressed than in nondepressed patients with stable CHD. The one exception was reported by Gehi et al,49 who assessed participants from the Heart and Soul Study cohort who had stable CHD at the time HRV was determined. Of the 873 outpatients with stable CHD who received 24-hour ambulatory ECG monitoring, 195 were found to have major depression. No differences between depressed and nondepressed patients were found on any time domain or frequency domain measure of HRV. This is the largest study to date of medically stable CHD patients assessed for depression and HRV, but its results differ from those of most smaller studies. The authors noted that although there was no difference in HRV between depressed and nondepressed patients, HRV in the nondepressed patients was similar to that in depressed patients in other samples.50 They speculated that the participants in their study, who were largely recruited from a Veterans Affairs hospital, may have been sicker than most participants in other studies and that this might have obscured depression-related differences in HRV.50

What is the clinical significance of HRV differences?

When evaluating differences in HRV between depressed and nondepressed patients, it is important to look past statistical comparisons and consider the clinical significance of these differences—ie, whether they are large enough to affect clinical outcomes or to be responsible for the depressed patients’ increased risk of death.

In the Cardiac Arrhythmia Pilot Study, HRV was assessed 1 year after acute MI in 331 patients.51 All measured indices of HRV were strong predictors of mortality. Patients with VLF power of less than 600 ms2 (natural logarithm of VLF power [LnVLF] 51 In a study of a similar group of medically stable (ie, eventfree for ≥6 months) patients with CHD,48 47% of those who were moderately to severely depressed, 29% of those who were mildly depressed, and 13% of those who were not depressed had VLF power below this cutpoint.

In the Multicenter Post-Infarction Program study, which evaluated patients in the immediate post–acute MI period, an LnVLF less than 5.2 was associated with a relative risk of 4.7 for cardiac mortality over the next 2.5 years.37 In our own study of post-MI patients, 7% of the nondepressed participants and 16% of the depressed participants had VLF power below this value, a difference that was significant even after adjusting for covariates (P = .006).41 Thus, mean 24-hour HRV is low enough in depressed patients with medically stable CHD and in those with recent acute MI to have prognostic significance.

How much of depression’s effect is due to low HRV?

In an attempt to determine whether low HRV accounts for at least part of the effect of depression on mortality, a statistical mediation model was applied to data collected in a follow-up study of the 311 depressed patients with recent acute MI described above,41 who were enrolled in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial,52 and 367 patients who met the ENRICHD medical inclusion criteria but were without depression.53 VLF was selected as the index of HRV for this study because of its prognostic importance in post-MI patients. As noted earlier, VLF was significantly lower in the depressed patients.41 During a median follow-up of 24 months, there were 47 deaths within the overall study population of 766 patients (6.1%).53 Consistent with earlier studies, the depressed patients were at higher risk for all-cause mortality, even after adjusting for potential confounders (hazard ratio = 2.8; 95% confidence interval [CI], 1.4 to 5.4; P P = .03), indicating that the LnVLF accounted for about one-quarter of the total mortality risk. Thus, the study results suggest that low HRV at least partially mediates the effect of depression on survival after acute MI.

A role for premature ventricular contractions

In one of the first prognostic studies of depression following acute MI, Frasure-Smith et al reported an interaction between depression and premature ventricular contractions (VPCs) on subsequent mortality.6 Specifically, they found that depressed patients who had 10 or more VPCs per hour after an MI were at considerably higher risk of death than were either depressed post-MI patients without VPCs or nondepressed post-MI patients with 10 or more VPCs per hour. One interpretation of these data is that depressed patients may be at greater risk for death due to an abnormal response to VPCs or other arrhythmias.

HR turbulence analysis is a method for quantifying HR response to VPCs. In most individuals, when a VPC occurs, HR first accelerates and then decelerates. HR responses that differ from this pattern have been found to be even better predictors of post-MI mortality than more traditional measures of HRV in these patients.54,55

A total of 498 patients from the study reported above53 were found to have VPCs during 24-hour ambulatory monitoring.34 Of these patients, 260 had normal HR turbulence, 152 had equivocal HR turbulence, and 86 had abnormal HR turbulence. The depressed patients were more likely than their nondepressed counterparts to have abnormal HR turbulence (risk factor–adjusted odds ratio [OR] = 1.8; 95% CI, 1.0 to 3.0; P = .03). The patients were followed for a median of 24 months. Consistent with earlier studies, depressed patients had worse survival (OR for death = 2.4; 95% CI, 1.2 to 4.6; P = .02) than the nondepressed patients. When HR turbulence was added to the statistical model, the adjusted hazard ratio for depression decreased to 1.9 (95% CI, 0.9 to 3.8; P = .08). When the LnVLF was added to this model, the adjusted hazard ratio decreased further, to 1.6 (95% CI, 0.8 to 3.4; P = .18). Thus, the combination of VLF and HR response to VPCs explained about half of the effect of depression on survival in these patients.

Causality not proven, but further study warranted

Obviously, these results do not prove that there is a causal relationship between depression, low HRV, and mortality. However, they are consistent with the interpretation that HRV, especially when combined with measures of HR response to VPCs, may account for a significant proportion of depression’s association with mortality following an MI. Future studies of these risk markers should explore their potential interrelationships to clarify how they may jointly contribute to the risk of death in patients with depression.

 

 

RELATIONSHIP AMONG HRV AND OTHER POSSIBLE BIOLOGICAL PATHWAYS

As discussed earlier, other biological pathways that may link depression to increased mortality have been reported. The two that have received the most support are proinflammatory and procoagulant processes. 18,19 Studies of medically healthy depressed psychiatric patients and of depressed CHD patients have found depression to be associated with higher levels of the inflammatory risk markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor–alpha (TNF-α) and with inflammatory-procoagulant markers such as fibrinogen,56–60 as well as with platelet activation. Low HRV and elevations in proinflammatory or procoagulant markers generally have been described as though they are independent pathways. However, both inflammatory and coagulant responses can be modulated by ANS activity,61,62 and a cholinergic anti-inflammatory pathway was recently proposed in which there is vagal efferent inhibition of proinflammatory cytokine release, thereby reducing systemic inflammation.62,63 Low HRV, reflecting reduced vagal activity, should therefore be associated with higher levels of both proinflammatory and procoagulant markers. Recent studies have found a relationship between HRV activity and increased markers of inflammation in other high-risk patients, including those with heart failure64,65 and with acute coronary syndrome.66

In a recent study of 44 patients with major depression, moderate negative correlations were found between fibrinogen and four measures of HRV.67 IL-6 was also negatively correlated with one measure of HRV (total power) and was marginally related to two others (VLF and LF power). On the other hand, neither CRP nor TNF-α was significantly related to any measure of HRV. The finding that fibrinogen and IL-6 are moderately related to HRV suggests a link between these factors in depressed CHD patients. Thus, these risk markers, which are commonly found in patients with depression, may be related and contribute to the increased mortality associated with depression. This possibility should be investigated in larger mechanistic studies of depression and cardiac morbidity and mortality.

SUMMARY AND FUTURE DIRECTIONS

Low HRV and other markers of cardiac ANS dysfunction in depressed patients are likely to contribute to the elevated risk associated with depression in patients with CHD. More work is needed to clarify the physiologic and behavioral mechanisms underlying depression’s role as a risk factor for mortality in patients with CHD. Work is also needed to identify treatments that improve both depression and HRV, and to determine whether such treatments might also improve survival in these patients.68

References
  1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289:3095–3105.
  2. Carney RM, Rich MW, teVelde A, et al. Major depressive disorder in coronary artery disease. Am J Cardiol 1987; 60:1273–1275.
  3. Hance M, Carney RM, Freedland KE, Skala J. Depression in patients with coronary heart disease: a 12-month follow-up. Gen Hosp Psychiatry 1996; 18:61–65.
  4. Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003; 54:227–240.
  5. Thombs BD, Bass EB, Ford DE, et al. Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 2006; 21:30–38.
  6. Frasure-Smith N, Lespérance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995; 91:999–1005.
  7. Carney RM, Rich MW, Freedland KE, et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Med 1988; 50:627–633.
  8. Herrmann C, Brand-Driehorst S, Buss U, Rüger U. Effects of anxiety and depression on 5-year mortality in 5,057 patients referred for exercise testing. J Psychosom Res 2000; 48:455–462.
  9. Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001; 88:337–341.
  10. Carney RM, Blumenthal JA, Catellier D, et al. Depression as a risk factor for mortality after acute myocardial infarction. Am J Cardiol 2003; 92:1277–1281.
  11. Ladwig KH, Kieser M, König J, Breithardt G, Borggrefe M. Affective disorders and survival after acute myocardial infarction: results from the post-infarction late potential study. Eur Heart J 1991; 12:959–964.
  12. Lespérance F, Frasure-Smith N, Juneau M, Théroux P. Depression and 1-year prognosis in unstable angina. Arch Intern Med 2000; 160:1354–1360.
  13. Blumenthal JA, Lett HS, Babyak MA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.
  14. Burg MM, Benedetto C, Rosenberg R, Soufer R. Depression prior to CABG predicts 6-month and 2-year morbidity and mortality. Psychosom Med 2001; 63:103. Abstract 1175.
  15. Connerney I, Shapiro PA, McLaughlin JS, Sloan RP. In-hospital depression after CABG surgery predicts 12-month outcome. Psychosom Med 2000; 62:106. Abstract 1195.
  16. van Melle JP, de Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 2004; 66:814–822.
  17. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a metaanalysis. Psychosom Med 2004; 66:802–813.
  18. Carney RM, Freedland KE, Miller GE, Jaffe AS. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res 2002; 53:897–902.
  19. Carney RM, Freedland KE. Depression, mortality, and medical morbidity in patients with coronary heart disease. Biol Psychiatry 2003; 54:241–247.
  20. Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med 2005; 67( suppl 1):S29–S33.
  21. Kliks BR, Burgess MJ, Abildskov JA. Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Am J Cardiol 1975; 36:45–49.
  22. Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation 1990; 82( 2 suppl):I103–I113.
  23. Schwartz PJ, Vanoli E. Cardiac arrhythmias elicited by interaction between acute myocardial ischemia and sympathetic hyperactivity: a new experimental model for the study of antiarrhythmic drugs. J Cardiovasc Pharmacol 1981; 3:1251–1259.
  24. Esler M, Turbott J, Schwarz R, et al. The peripheral kinetics of norepinephrine in depressive illness. Arch Gen Psychiatry 1982; 39:295–300.
  25. Lake CR, Pickar D, Ziegler MG, Lipper S, Slater S, Murphy DL. High plasma norepinephrine levels in patients with major affective disorder. Am J Psychiatry 1982; 139:1315–1318.
  26. Roy A, Pickar D, De Jong J, Karoum F, Linnoila M. Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression. Arch Gen Psychiatry 1988; 45:849–857.
  27. Veith RC, Lewis N, Linares OA, et al. Sympathetic nervous system activity in major depression: basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch Gen Psychiatry 1994; 51:411–422.
  28. Dawson ME, Schell AM, Catania JJ. Autonomic correlates of depression and clinical improvement following electroconvulsive shock therapy. Psychophysiology 1977; 14:569–578.
  29. Lahmeyer HW, Bellur SN. Cardiac regulation and depression. J Psychiatr Res 1987; 21:1–6.
  30. Wyatt RJ, Portnoy B, Kupfer DJ, Snyder F, Engelman K. Resting plasma catecholamine concentrations in patients with depression and anxiety. Arch Gen Psychiatry 1971; 24:65–70.
  31. Carney RM, Rich MW, teVelde A, et al. The relationship between heart rate, heart rate variability and depression in patients with coronary artery disease. J Psychosom Res 1988; 32:159–164.
  32. Carney RM, Freedland KE, Veith RC, et al. Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease. Biol Psychiatry 1999; 45:458–463.
  33. Carney RM, Freedland KE, Stein PK, et al. Effects of depression on QT interval variability after myocardial infarction. Psychosom Med 2003; 65:177–180.
  34. Carney RM, Howells WB, Blumenthal JA, et al. Heart rate turbulence, depression, and survival after acute myocardial infarction. Psychosom Med 2007; 69:4–9.
  35. Carney RM, Freedland KE, Rich MW, Smith LJ, Jaffe AS. Ventricular tachycardia and psychiatric depression in patients with coronary artery disease. Am J Med 1993; 95:23–28.
  36. Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996; 93:1043–1065.
  37. Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 1992; 85:164–171.
  38. Kleiger RE, Miller JP, Bigger JT, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987; 59:256–262.
  39. Vaishnav S, Stevenson R, Marchant B, Lagi K, Ranjadayalan K, Timmis AD. Relation between heart rate variability early after acute myocardial infarction and long-term mortality. Am J Cardiol 1994; 73:653–657.
  40. Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation 1998; 98:547–555.
  41. Carney RM, Blumenthal JA, Stein PK, et al. Depression, heart rate variability, and acute myocardial infarction. Circulation 2001; 104:2024–2028.
  42. Guinjoan SM, de Guevara MS, Correa C, et al. Cardiac parasympathetic dysfunction related to depression in older adults with acute coronary syndromes. J Psychosom Res 2004; 56:83–88.
  43. Pitzalis MV, Iacoviello M, Todarello O, et al. Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction. Am Heart J 2001; 141:765–771.
  44. van den Berg MP, Spijkerman TA, van Melle JP, et al. Depression as an independent determinant of decreased heart rate variability in patinets post myocardial infarction. Neth Heart J 2005; 13:1365–1369.
  45. Vigo DE, Nicola Siri L, Ladrón De Guevara MS, et al. Relation of depression to heart rate nonlinear dynamics in patients ≥60 years of age with recent unstable angina pectoris or acute myocardial infarction. Am J Cardiol 2004; 93:756–760.
  46. Carney RM, Saunders RD, Freedland KE, Stein P, Rich MW, Jaffe AS. Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol 1995; 76:562–564.
  47. Krittayaphong R, Cascio WE, Light KC, et al. Heart rate variability in patients with coronary artery disease: differences in patients with higher and lower depression scores. Psychosom Med 1997; 59:231–235.
  48. Stein PK, Carney RM, Freedland KE, et al. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J Psychosom Res 2000; 48:493–500.
  49. Gehi A, Mangano D, Pipkin S, Browner WS, Whooley MA. Depression and heart rate variability in patients with stable coronary heart disease: findings from the Heart and Soul Study. Arch Gen Psychiatry 2005; 62:661–666.
  50. Gehi A, Whooley M. Heart rate variability and depression [reply to letter]. Arch Gen Psychiatry 2006; 63:1052.
  51. Bigger JT, Fleiss JL, Rolnitzky LM, Steinman RC. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am Coll Cardiol 1993; 21:729–736.
  52. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 2003; 289:3106–3116.
  53. Carney RM, Blumenthal JA, Freedland KE, et al. Low heart rate variability and the effect of depression on post-myocardial infarction mortality. Arch Intern Med 2005; 165:1486–1491.
  54. Ghuran A, Reid F, La Rovere MT, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and Reflexes After Myocardial Infarction substudy). Am J Cardiol 2002; 89:184–190.
  55. Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 1999; 353:1390–1396.
  56. Dentino AN, Pieper CF, Rao MK, et al. Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc 1999; 47:6–11.
  57. Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 1995; 34:301–309.
  58. Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997; 9:853–858.
  59. Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 2002; 90:1279–1283.
  60. von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med 2001; 63:531–544.
  61. März P, Cheng JG, Gadient RA, et al. Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci USA 1998; 95:3251–3256.
  62. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853–859.
  63. Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun 2005; 19:493–499.
  64. Aronson D, Mittleman MA, Burger AJ. Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure. J Cardiovasc Electrophysiol 2001; 12:294–300.
  65. Malave HA, Taylor AA, Nattama J, Deswal A, Mann DL. Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure. Chest 2003; 123:716–724.
  66. Lanza GA, Sgueglia GA, Cianflone D, et al. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2006; 97:1702–1706.
  67. Carney RM, Freedland KE, Stein PK, et al. Heart rate variability and markers of inflammation and coagulation in depressed patients with coronary heart disease. J Psychosom Res 2007; 62:463–467.
  68. Carney RM, Freedland KE, Stein PK, et al. Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease. Psychosom Med 2000; 62:639–647.
References
  1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289:3095–3105.
  2. Carney RM, Rich MW, teVelde A, et al. Major depressive disorder in coronary artery disease. Am J Cardiol 1987; 60:1273–1275.
  3. Hance M, Carney RM, Freedland KE, Skala J. Depression in patients with coronary heart disease: a 12-month follow-up. Gen Hosp Psychiatry 1996; 18:61–65.
  4. Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003; 54:227–240.
  5. Thombs BD, Bass EB, Ford DE, et al. Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 2006; 21:30–38.
  6. Frasure-Smith N, Lespérance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995; 91:999–1005.
  7. Carney RM, Rich MW, Freedland KE, et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Med 1988; 50:627–633.
  8. Herrmann C, Brand-Driehorst S, Buss U, Rüger U. Effects of anxiety and depression on 5-year mortality in 5,057 patients referred for exercise testing. J Psychosom Res 2000; 48:455–462.
  9. Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001; 88:337–341.
  10. Carney RM, Blumenthal JA, Catellier D, et al. Depression as a risk factor for mortality after acute myocardial infarction. Am J Cardiol 2003; 92:1277–1281.
  11. Ladwig KH, Kieser M, König J, Breithardt G, Borggrefe M. Affective disorders and survival after acute myocardial infarction: results from the post-infarction late potential study. Eur Heart J 1991; 12:959–964.
  12. Lespérance F, Frasure-Smith N, Juneau M, Théroux P. Depression and 1-year prognosis in unstable angina. Arch Intern Med 2000; 160:1354–1360.
  13. Blumenthal JA, Lett HS, Babyak MA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.
  14. Burg MM, Benedetto C, Rosenberg R, Soufer R. Depression prior to CABG predicts 6-month and 2-year morbidity and mortality. Psychosom Med 2001; 63:103. Abstract 1175.
  15. Connerney I, Shapiro PA, McLaughlin JS, Sloan RP. In-hospital depression after CABG surgery predicts 12-month outcome. Psychosom Med 2000; 62:106. Abstract 1195.
  16. van Melle JP, de Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 2004; 66:814–822.
  17. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a metaanalysis. Psychosom Med 2004; 66:802–813.
  18. Carney RM, Freedland KE, Miller GE, Jaffe AS. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res 2002; 53:897–902.
  19. Carney RM, Freedland KE. Depression, mortality, and medical morbidity in patients with coronary heart disease. Biol Psychiatry 2003; 54:241–247.
  20. Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med 2005; 67( suppl 1):S29–S33.
  21. Kliks BR, Burgess MJ, Abildskov JA. Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Am J Cardiol 1975; 36:45–49.
  22. Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation 1990; 82( 2 suppl):I103–I113.
  23. Schwartz PJ, Vanoli E. Cardiac arrhythmias elicited by interaction between acute myocardial ischemia and sympathetic hyperactivity: a new experimental model for the study of antiarrhythmic drugs. J Cardiovasc Pharmacol 1981; 3:1251–1259.
  24. Esler M, Turbott J, Schwarz R, et al. The peripheral kinetics of norepinephrine in depressive illness. Arch Gen Psychiatry 1982; 39:295–300.
  25. Lake CR, Pickar D, Ziegler MG, Lipper S, Slater S, Murphy DL. High plasma norepinephrine levels in patients with major affective disorder. Am J Psychiatry 1982; 139:1315–1318.
  26. Roy A, Pickar D, De Jong J, Karoum F, Linnoila M. Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression. Arch Gen Psychiatry 1988; 45:849–857.
  27. Veith RC, Lewis N, Linares OA, et al. Sympathetic nervous system activity in major depression: basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch Gen Psychiatry 1994; 51:411–422.
  28. Dawson ME, Schell AM, Catania JJ. Autonomic correlates of depression and clinical improvement following electroconvulsive shock therapy. Psychophysiology 1977; 14:569–578.
  29. Lahmeyer HW, Bellur SN. Cardiac regulation and depression. J Psychiatr Res 1987; 21:1–6.
  30. Wyatt RJ, Portnoy B, Kupfer DJ, Snyder F, Engelman K. Resting plasma catecholamine concentrations in patients with depression and anxiety. Arch Gen Psychiatry 1971; 24:65–70.
  31. Carney RM, Rich MW, teVelde A, et al. The relationship between heart rate, heart rate variability and depression in patients with coronary artery disease. J Psychosom Res 1988; 32:159–164.
  32. Carney RM, Freedland KE, Veith RC, et al. Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease. Biol Psychiatry 1999; 45:458–463.
  33. Carney RM, Freedland KE, Stein PK, et al. Effects of depression on QT interval variability after myocardial infarction. Psychosom Med 2003; 65:177–180.
  34. Carney RM, Howells WB, Blumenthal JA, et al. Heart rate turbulence, depression, and survival after acute myocardial infarction. Psychosom Med 2007; 69:4–9.
  35. Carney RM, Freedland KE, Rich MW, Smith LJ, Jaffe AS. Ventricular tachycardia and psychiatric depression in patients with coronary artery disease. Am J Med 1993; 95:23–28.
  36. Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996; 93:1043–1065.
  37. Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 1992; 85:164–171.
  38. Kleiger RE, Miller JP, Bigger JT, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987; 59:256–262.
  39. Vaishnav S, Stevenson R, Marchant B, Lagi K, Ranjadayalan K, Timmis AD. Relation between heart rate variability early after acute myocardial infarction and long-term mortality. Am J Cardiol 1994; 73:653–657.
  40. Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation 1998; 98:547–555.
  41. Carney RM, Blumenthal JA, Stein PK, et al. Depression, heart rate variability, and acute myocardial infarction. Circulation 2001; 104:2024–2028.
  42. Guinjoan SM, de Guevara MS, Correa C, et al. Cardiac parasympathetic dysfunction related to depression in older adults with acute coronary syndromes. J Psychosom Res 2004; 56:83–88.
  43. Pitzalis MV, Iacoviello M, Todarello O, et al. Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction. Am Heart J 2001; 141:765–771.
  44. van den Berg MP, Spijkerman TA, van Melle JP, et al. Depression as an independent determinant of decreased heart rate variability in patinets post myocardial infarction. Neth Heart J 2005; 13:1365–1369.
  45. Vigo DE, Nicola Siri L, Ladrón De Guevara MS, et al. Relation of depression to heart rate nonlinear dynamics in patients ≥60 years of age with recent unstable angina pectoris or acute myocardial infarction. Am J Cardiol 2004; 93:756–760.
  46. Carney RM, Saunders RD, Freedland KE, Stein P, Rich MW, Jaffe AS. Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol 1995; 76:562–564.
  47. Krittayaphong R, Cascio WE, Light KC, et al. Heart rate variability in patients with coronary artery disease: differences in patients with higher and lower depression scores. Psychosom Med 1997; 59:231–235.
  48. Stein PK, Carney RM, Freedland KE, et al. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J Psychosom Res 2000; 48:493–500.
  49. Gehi A, Mangano D, Pipkin S, Browner WS, Whooley MA. Depression and heart rate variability in patients with stable coronary heart disease: findings from the Heart and Soul Study. Arch Gen Psychiatry 2005; 62:661–666.
  50. Gehi A, Whooley M. Heart rate variability and depression [reply to letter]. Arch Gen Psychiatry 2006; 63:1052.
  51. Bigger JT, Fleiss JL, Rolnitzky LM, Steinman RC. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am Coll Cardiol 1993; 21:729–736.
  52. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 2003; 289:3106–3116.
  53. Carney RM, Blumenthal JA, Freedland KE, et al. Low heart rate variability and the effect of depression on post-myocardial infarction mortality. Arch Intern Med 2005; 165:1486–1491.
  54. Ghuran A, Reid F, La Rovere MT, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and Reflexes After Myocardial Infarction substudy). Am J Cardiol 2002; 89:184–190.
  55. Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 1999; 353:1390–1396.
  56. Dentino AN, Pieper CF, Rao MK, et al. Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc 1999; 47:6–11.
  57. Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 1995; 34:301–309.
  58. Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997; 9:853–858.
  59. Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 2002; 90:1279–1283.
  60. von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med 2001; 63:531–544.
  61. März P, Cheng JG, Gadient RA, et al. Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci USA 1998; 95:3251–3256.
  62. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853–859.
  63. Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun 2005; 19:493–499.
  64. Aronson D, Mittleman MA, Burger AJ. Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure. J Cardiovasc Electrophysiol 2001; 12:294–300.
  65. Malave HA, Taylor AA, Nattama J, Deswal A, Mann DL. Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure. Chest 2003; 123:716–724.
  66. Lanza GA, Sgueglia GA, Cianflone D, et al. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2006; 97:1702–1706.
  67. Carney RM, Freedland KE, Stein PK, et al. Heart rate variability and markers of inflammation and coagulation in depressed patients with coronary heart disease. J Psychosom Res 2007; 62:463–467.
  68. Carney RM, Freedland KE, Stein PK, et al. Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease. Psychosom Med 2000; 62:639–647.
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Depression and heart rate variability in patients with coronary heart disease
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Autonomic function and prognosis

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Autonomic function and prognosis
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Michael S. Lauer, MD

First-year medical students are well aware that the autonomic nervous system regulates heart rate and blood pressure along with respiratory and digestive functions. The past 10 to 20 years have seen increased appreciation of the medical relevance of the the autonomic nervous system beyond first-year physiology examinations; even mild disturbances of autonomic nervous system function predict materially worse prognosis.1–3 Researchers have focused on the use of readily available measures, such as heart rate,4 heart rate variability,5 and heart rate recovery,6 to link autonomic nervous system dysfunction with mortality and morbidity.1 In addition, epidemiologists have exploited these tools to identify correlates of autonomic nervous system dysfunction at patient and environmental levels.7 Although it is not yet known how best to incorporate autonomic nervous system measures into routine clinical care, there is increasing excitement about the insights that this work has revealed.

MEASURES OF AUTONOMIC NERVOUS SYSTEM FUNCTION

Although many measures of autonomic nervous system function have been described, three relatively straightforward approaches are based on heart rate.1

Resting heart rate is the simplest to obtain, as it does not require any special technology. People with high levels of parasympathetic nervous system tone have lower resting heart rates, as is typically seen in world-class athletes. Conversely, conditions characterized by increased levels of sympathetic tone manifest as sinus tachycardia; classic examples include congestive heart failure, anemia, and hypovolemia.

Reprinted, with permission, from Annals of Internal Medicine (van Ravenswaaij-Arts et al. Heart rate variability. Ann Intern Med 1993; 118:436–447).
Figure 1. Example of time-domain measures of heart rate variability (STV = short-term variability; LTV = long-term variability). The top plot shows heart rate as a function of time. In the bottom plot, Fourier transform yields power values of very-low-frequency (VLF), low-frequency (LF), and high-frequency (HF) domains. The high-frequency domain is thought to reflect parasympathetic tone, where-as the very-low-frequency and low-frequency domains are thought to reflect a mixture of parasympathetic and sympathetic tone.
Heart rate variability. Even before the advent of the electrocardiogram, it was known that heart rate normally varies with respiration.8 Physiologic sinus arrhythmia can be easily demonstrated by plotting heart rate over time in resting supine subjects, typically yielding a tracing characterized by high-frequency, low-amplitude waves. When a normal subject assumes an upright position, the resting heart rate increases and there is an increased absolute amount of variability, but the frequency of the variability wave decreases. Using Fourier transform techniques, one can translate the amplitude and frequency of the waves shown in the top plot of Figure 1 into power domain functions, as shown in the bottom plot of Figure 1.8 Heart rate variability functions can be divided into high-frequency, low-frequency, and very-low-frequency domains.8,9 The high-frequency peak, which is reflective of the very fine variability seen with respiration at rest, is thought to reflect parasympathetic nervous system tone. The low-frequency and very-low-frequency peaks are thought to reflect mixed effects of parasympathetic tone and sympathetic tone.

Heart rate recovery. Heart rate variability measures require continuous Holter monitoring as well as sophisticated software. The numerous types of heart rate variability measures are not intuitive for most clinicians. Exercise heart rate recovery is an arguably more straightforward method of assessing parasympathetic tone.1 During a graded exercise test, heart rate increases as a result of withdrawal of parasympathetic tone and increased sympathetic tone. During the first 30 seconds after exercise, heart rate decreases quickly, mainly because of rapid reactivation of the parasympathetic nervous system.10

Figure 2. Demonstration of the association between parasympathetic tone and heart rate recovery. (A) Absolute heart rates (after logarithmic transformation) are shown during the first 2 minutes after exercise in three groups of subjects. Among athletes and normal subjects, there is a biexponential relationship. (B) Postexercise absolute heart rates are shown again, this time after administration of atropine, in which case the initial steep slope disappears.  Figure is based on data from Imai et al.10
The association between early heart rate recovery and parasympathetic nervous system function was demonstrated elegantly by Imai and colleagues in a study of three groups of subjects—athletes, normal subjects, and patients with heart failure.10 Among athletes and normal subjects there was a biexponential pattern of heart rate during early recovery, with a steep log-linear decrease during the first 30 seconds followed by a more shallow decline (Figure 2A). When the same subjects were given atropine and exercise testing was repeated, the initial steep decrease in heart rate observed among athletes and normal subjects disappeared (Figure 2B). The authors concluded that early heart rate recovery is primarily a manifestation of parasympathetic reactivation.

AUTONOMIC NERVOUS SYSTEM FUNCTION AND MORTALITY

Resting heart rate

There is a remarkably strong association between heart rate and survival, an association that transcends species.4 Small mammals that have rapid heart rates have short life expectancies. Larger mammals that have slower heart rates have correspondingly higher life expectancies. Among nearly all mammals, life expectancy is close to 1 billion heartbeats.

Investigators have been able to increase survival in animal models by deliberate slowing of heart rate. An experiment performed in mice more than 30 years ago showed that life expectancy increases with low-dose digoxin, a parasympathomimetic agent.11 More recently, a mouse model has been used to show that ivabradine, a sinus node ion channel blocking agent that specifically reduces heart rate without affecting vascular tone, inhibits development of atherosclerosis in genetically susceptible knockout mice.12

There is an extensive epidemiological literature linking heart rate to mortality in large human populations. 4,13 As heart rate increases to 75 to 80 beats per minute, there are marked increases in total mortality and mortality due to coronary heart disease. As is well known, administration of beta-blockers reduces mortality in survivors of myocardial infarction. What is particularly remarkable is that the magnitude of reduction in mortality with beta-blocker therapy is directly proportional to the magnitude of heart rate decrease.14 In a recent analysis of hypertensive patients enrolled in a large-scale randomized trial, a strong association was noted between mortality and increasing heart rate at the time of randomization as well as after treatment with either verapamil or a beta-blocker.15

Heart rate variability

Figure 3. Association between measures of heart rate variability and cardiac events in the Framingham Heart Study. Each measure is divided into tertiles from lowest to highest (SDNN = standard deviation of R-R intervals of normal beats; LF = low-frequency power; HF = high-frequency power; LF/HF = ratio of LF power to HF power). Figure is based on data from Tsuji et al.16
Just as with resting heart rate, there is a robust literature linking decreased heart rate variability to cardiac events and mortality. Among healthy elderly subjects enrolled in the Framingham Heart Study, decreased heart rate variability was associated with a substantially increased likelihood of major cardiac events (Figure 3).16 The Framingham investigators measured the standard deviation of R-R intervals that do not include ventricular ectopic beats (SDNN) as well as time-domain measures. Lower values of the ratio of low-frequency power to high-frequency power, which would correspond to lower levels of parasympathetic tone, were also associated with increased mortality. Similarly, among survivors of myocardial infarction, especially those with low ejection fractions, decreased heart rate variability predicted substantially higher mortality rates.5,17,18

 

 

Heart rate recovery

In 1999, Cole and colleagues reported on the association between heart rate recovery during the first minute after exercise and all-cause mortality in approximately 2,400 patients who were candidates for first-time coronary angiography.6 An abnormal heart rate recovery was defined as a reduction from the peak heart rate of 12 beats per minute or less, which corresponded to the lowest quartile. Thus, a patient achieving a peak heart rate of 160 beats per minute would be considered to have an abnormal heart rate recovery if 1 minute later the heart rate was 148 beats per minute or higher. Patients who had an abnormal heart rate recovery had a nearly fourfold increased risk of all-cause death; even after adjusting for numerous confounders, including exercise capacity, there was still a twofold independent increased risk of death. This initial observation has since been confirmed in other cohorts.19,20 The link between heart rate recovery, mortality, and cardiovascular prognosis appears to be independent of symptom status,21 type of recovery protocol,22 left ventricular ejection fraction,22 and angiographic severity of coronary artery disease.23

The mechanism by which an abnormal heart rate recovery predicts increased mortality is unclear. Given that heart rate recovery is thought to reflect parasympathetic nervous system function, and given that increased parasympathetic tone is believed to have antiarrhythmic effects, one might hypothesize that lower heart rate recovery would predict sudden cardiac death. In 2005, investigators from the Paris Civil Service Study reported on the association of exercise heart rate recovery and type of mortality; low heart rate recovery was strongly predictive of sudden cardiac death but not of non-sudden cardiac myocardial infarction death.20 A separate study from the Cleveland Clinic showed that among more than 29,000 patients, frequent ventricular ectopy during early recovery was strongly predictive of death, whereas frequent ventricular ectopy during exercise was not.24 These two studies together suggest that the link between heart rate recovery and mortality may be a reflection of the antiarrhythmic properties of the parasympathetic nervous system.

It is well known that there is an exceptionally powerful link between functional capacity and cardiovascular risk.25,26 People who are in excellent physical shape have high levels of parasympathetic tone. Among patients with suspected coronary artery disease, there is a strong dose-response relationship between heart rate recovery and physical fitness.6 While the link between functional capacity and prognosis is complex, it is conceivable that parasympathetic protection against arrhythmias and shear-induced plaque rupture may play a role.

Figure 4. User interface of an externally validated mortality prediction model for primary prevention patients with normal electrocardiograms undergoing exercise testing.27 This prediction model includes easily obtained cardiovascular risk factors as well as measures of autonomic function.
Both heart rate recovery and functional capacity are easy to measure using standard exercise test equipment. Recently, investigators from the Cleveland Clinic and Kaiser Permanente derived and externally validated a simple multivariable instrument by which all-cause mortality can be predicted in subjects with a normal electrocardiogram and no history of coronary disease.27 This instrument includes measures of functional capacity, heart rate recovery, and frequent ventricular ectopy during recovery. An example of the user interface is shown in Figure 4.

DETERMINANTS OF AUTONOMIC NERVOUS SYSTEM FUNCTION

There is an extensive literature documenting a number of determinants of autonomic tone.3,7 On a patient level, decreased levels of parasympathetic tone or increased levels of sympathetic tone have been linked to obesity, insulin resistance, diabetes, hypertension, hypercholesterolemia, depression, anxiety, heart failure, and peripheral vascular disease.3

Copyright © 2002 American Diabetes Association. From Diabetes®, Vol. 51, 2002; 803–807. Adapted with permission from The American Diabetes Association.
Figure 5. Association of fasting plasma glucose with abnormal heart rate recovery among healthy subjects enrolled in the Lipid Research Clinics observational cohort study.
The association between diabetes and autonomic nervous system dysfunction is well known to clinicians caring for patients with clinically manifest autonomic neuropathy. What is less appreciated is that even minor degrees of glucose intolerance are associated with abnormalities of autonomic balance. For example, among patients enrolled in a population-based cohort, the likelihood of an abnormal heart rate recovery increased in a steady fashion as fasting plasma glucose increased from 70 to 80 to 90 mg/dL and above (Figure 5).28 Even at levels of plasma glucose that would be considered normal, the likelihood of an abnormal heart rate recovery increased as plasma glucose increased.28

Perturbations of autonomic nervous system function have also been associated with environmental exposures. People who have lower levels of education,29 live in neighborhoods characterized by lower socio-economic status,30 or are exposed to small-particulate air pollution31 have been shown to manifest abnormal heart rate recovery or decreased heart rate variability.

CONCLUSIONS

Autonomic nervous system function can be measured in the clinic by recording resting heart rate, heart rate variability, or exercise heart rate recovery.1 All three of these measures are strong predictors of cardiovascular risk and all-cause mortality in both primary and secondary prevention settings. A number of determinants of autonomic nervous system function have been identified, including patient-level factors like obesity, diabetes, and heart failure as well as environmental correlates like smoking, social stress, and air pollution. It is not yet known, however, how best to take advantage of the associations between abnormal autonomic nervous system function and poor prognosis to improve patient outcomes. Future research will be needed to identify strategies of favorably modulating autonomic function that improve outcomes in the clinic and among large populations.

References
  1. Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol 2008; 51:1725–1733.
  2. Katz A, Liberty IF, Porath A, Ovsyshcher I, Prystowsky EN. A simple bedside test of 1-minute heart rate variability during deep breathing as a prognostic index after myocardial infarction. Am Heart J 1999; 138(1 Pt 1):32–38.
  3. Curtis BM, O’Keefe JH. Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight. Mayo Clin Proc 2002; 77:45–54.
  4. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol 1997; 30:1104–1106.
  5. Huikuri HV, Makikallio T, Airaksinen KE, Mitrani R, Castellanos A, Myerburg RJ. Measurement of heart rate variability: a clinical tool or a research toy? J Am Coll Cardiol 1999; 34:1878–1883.
  6. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999; 341:1351–1357.
  7. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 2007; 74:224–242.
  8. van Ravenswaaij-Arts CM, Kollee LA, Hopman JC, Stoelinga GB, van Geijn HP. Heart rate variability. Ann Intern Med 1993; 118:436–447.
  9. Pumprla J, Howorka K, Groves D, Chester M, Nolan J. Functional assessment of heart rate variability: physiological basis and practical applications. Int J Cardiol 2002; 84:1–14.
  10. Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994; 24:1529–1535.
  11. Coburn AF, Grey RM, Rivera SM. Observations on the relation of heart rate, life span, weight and mineralization in the digoxintreated A-J mouse. Johns Hopkins Med J 1971; 128:169–193.
  12. Custodis F, Baumhakel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008; 117:2377–2387.
  13. Wilhelmsen L, Berglund G, Elmfeldt D, et al. The multifactor primary prevention trial in GÖteborg, Sweden. Eur Heart J 1986; 7:279–288.
  14. Reil JC, Bohm M. The role of heart rate in the development of cardiovascular disease. Clin Res Cardiol 2007; 96:585–592.
  15. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J 2008; 29:1327–1334.
  16. Tsuji H, Larson MG, Venditti FJ, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996; 94:2850–2855.
  17. Makikallio TH, Hoiber S, Kober L, et al. Fractal analysis of heart rate dynamics as a predictor of mortality in patients with depressed left ventricular function after acute myocardial infarction. TRACE Investigators. TRAndolapril Cardiac Evaluation. Am J Cardiol 1999; 83:836–839.
  18. La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351:478–484.
  19. Shetler K, Marcus R, Froelicher VF, et al. Heart rate recovery: validation and methodologic issues. J Am Coll Cardiol 2001; 38:1980–1987.
  20. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetiere P. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med 2005; 352:1951–1958.
  21. Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. Ann Intern Med 2000; 132:552–555.
  22. Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation 2001; 104:1911–1916.
  23. Vivekananthan DP, Blackstone EH, Pothier CE, Lauer MS. Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary disease. J Am Coll Cardiol 2003; 42:831–838.
  24. Frolkis JP, Pothier CE, Blackstone EH, Lauer MS. Frequent ventricular ectopy after exercise as a predictor of death. N Engl J Med 2003; 348:781–790.
  25. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346:793–801.
  26. Gulati M, Black HR, Shaw LJ, et al. The prognostic value of a nomogram for exercise capacity in women. N Engl J Med 2005; 353:468–475.
  27. Lauer MS, Pothier CE, Magid DJ, Smith SS, Kattan MW. An externally validated model for predicting long-term survival after exercise treadmill testing in patients with suspected coronary artery disease and a normal electrocardiogram. Ann Intern Med 2007; 147:821–828.
  28. Panzer C, Lauer MS, Brieke A, Blackstone E, Hoogwerf B. Association of fasting plasma glucose with heart rate recovery in healthy adults: a population-based study. Diabetes 2002; 51:803–807.
  29. Shishehbor MH, Baker DW, Blackstone EH, Lauer MS. Association of educational status with heart rate recovery: a population-based propensity analysis. Am J Med 2002; 113:643–649.
  30. Shishehbor MH, Litaker D, Pothier CE, Lauer MS. Association of socioeconomic status with functional capacity, heart rate recovery, and all-cause mortality. JAMA 2006; 295:784–792.
  31. Magari SR, Hauser R, Schwartz J, Williams PL, Smith TJ, Christiani DC. Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation 2001; 104:986–991.
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First-year medical students are well aware that the autonomic nervous system regulates heart rate and blood pressure along with respiratory and digestive functions. The past 10 to 20 years have seen increased appreciation of the medical relevance of the the autonomic nervous system beyond first-year physiology examinations; even mild disturbances of autonomic nervous system function predict materially worse prognosis.1–3 Researchers have focused on the use of readily available measures, such as heart rate,4 heart rate variability,5 and heart rate recovery,6 to link autonomic nervous system dysfunction with mortality and morbidity.1 In addition, epidemiologists have exploited these tools to identify correlates of autonomic nervous system dysfunction at patient and environmental levels.7 Although it is not yet known how best to incorporate autonomic nervous system measures into routine clinical care, there is increasing excitement about the insights that this work has revealed.

MEASURES OF AUTONOMIC NERVOUS SYSTEM FUNCTION

Although many measures of autonomic nervous system function have been described, three relatively straightforward approaches are based on heart rate.1

Resting heart rate is the simplest to obtain, as it does not require any special technology. People with high levels of parasympathetic nervous system tone have lower resting heart rates, as is typically seen in world-class athletes. Conversely, conditions characterized by increased levels of sympathetic tone manifest as sinus tachycardia; classic examples include congestive heart failure, anemia, and hypovolemia.

Reprinted, with permission, from Annals of Internal Medicine (van Ravenswaaij-Arts et al. Heart rate variability. Ann Intern Med 1993; 118:436–447).
Figure 1. Example of time-domain measures of heart rate variability (STV = short-term variability; LTV = long-term variability). The top plot shows heart rate as a function of time. In the bottom plot, Fourier transform yields power values of very-low-frequency (VLF), low-frequency (LF), and high-frequency (HF) domains. The high-frequency domain is thought to reflect parasympathetic tone, where-as the very-low-frequency and low-frequency domains are thought to reflect a mixture of parasympathetic and sympathetic tone.
Heart rate variability. Even before the advent of the electrocardiogram, it was known that heart rate normally varies with respiration.8 Physiologic sinus arrhythmia can be easily demonstrated by plotting heart rate over time in resting supine subjects, typically yielding a tracing characterized by high-frequency, low-amplitude waves. When a normal subject assumes an upright position, the resting heart rate increases and there is an increased absolute amount of variability, but the frequency of the variability wave decreases. Using Fourier transform techniques, one can translate the amplitude and frequency of the waves shown in the top plot of Figure 1 into power domain functions, as shown in the bottom plot of Figure 1.8 Heart rate variability functions can be divided into high-frequency, low-frequency, and very-low-frequency domains.8,9 The high-frequency peak, which is reflective of the very fine variability seen with respiration at rest, is thought to reflect parasympathetic nervous system tone. The low-frequency and very-low-frequency peaks are thought to reflect mixed effects of parasympathetic tone and sympathetic tone.

Heart rate recovery. Heart rate variability measures require continuous Holter monitoring as well as sophisticated software. The numerous types of heart rate variability measures are not intuitive for most clinicians. Exercise heart rate recovery is an arguably more straightforward method of assessing parasympathetic tone.1 During a graded exercise test, heart rate increases as a result of withdrawal of parasympathetic tone and increased sympathetic tone. During the first 30 seconds after exercise, heart rate decreases quickly, mainly because of rapid reactivation of the parasympathetic nervous system.10

Figure 2. Demonstration of the association between parasympathetic tone and heart rate recovery. (A) Absolute heart rates (after logarithmic transformation) are shown during the first 2 minutes after exercise in three groups of subjects. Among athletes and normal subjects, there is a biexponential relationship. (B) Postexercise absolute heart rates are shown again, this time after administration of atropine, in which case the initial steep slope disappears.  Figure is based on data from Imai et al.10
The association between early heart rate recovery and parasympathetic nervous system function was demonstrated elegantly by Imai and colleagues in a study of three groups of subjects—athletes, normal subjects, and patients with heart failure.10 Among athletes and normal subjects there was a biexponential pattern of heart rate during early recovery, with a steep log-linear decrease during the first 30 seconds followed by a more shallow decline (Figure 2A). When the same subjects were given atropine and exercise testing was repeated, the initial steep decrease in heart rate observed among athletes and normal subjects disappeared (Figure 2B). The authors concluded that early heart rate recovery is primarily a manifestation of parasympathetic reactivation.

AUTONOMIC NERVOUS SYSTEM FUNCTION AND MORTALITY

Resting heart rate

There is a remarkably strong association between heart rate and survival, an association that transcends species.4 Small mammals that have rapid heart rates have short life expectancies. Larger mammals that have slower heart rates have correspondingly higher life expectancies. Among nearly all mammals, life expectancy is close to 1 billion heartbeats.

Investigators have been able to increase survival in animal models by deliberate slowing of heart rate. An experiment performed in mice more than 30 years ago showed that life expectancy increases with low-dose digoxin, a parasympathomimetic agent.11 More recently, a mouse model has been used to show that ivabradine, a sinus node ion channel blocking agent that specifically reduces heart rate without affecting vascular tone, inhibits development of atherosclerosis in genetically susceptible knockout mice.12

There is an extensive epidemiological literature linking heart rate to mortality in large human populations. 4,13 As heart rate increases to 75 to 80 beats per minute, there are marked increases in total mortality and mortality due to coronary heart disease. As is well known, administration of beta-blockers reduces mortality in survivors of myocardial infarction. What is particularly remarkable is that the magnitude of reduction in mortality with beta-blocker therapy is directly proportional to the magnitude of heart rate decrease.14 In a recent analysis of hypertensive patients enrolled in a large-scale randomized trial, a strong association was noted between mortality and increasing heart rate at the time of randomization as well as after treatment with either verapamil or a beta-blocker.15

Heart rate variability

Figure 3. Association between measures of heart rate variability and cardiac events in the Framingham Heart Study. Each measure is divided into tertiles from lowest to highest (SDNN = standard deviation of R-R intervals of normal beats; LF = low-frequency power; HF = high-frequency power; LF/HF = ratio of LF power to HF power). Figure is based on data from Tsuji et al.16
Just as with resting heart rate, there is a robust literature linking decreased heart rate variability to cardiac events and mortality. Among healthy elderly subjects enrolled in the Framingham Heart Study, decreased heart rate variability was associated with a substantially increased likelihood of major cardiac events (Figure 3).16 The Framingham investigators measured the standard deviation of R-R intervals that do not include ventricular ectopic beats (SDNN) as well as time-domain measures. Lower values of the ratio of low-frequency power to high-frequency power, which would correspond to lower levels of parasympathetic tone, were also associated with increased mortality. Similarly, among survivors of myocardial infarction, especially those with low ejection fractions, decreased heart rate variability predicted substantially higher mortality rates.5,17,18

 

 

Heart rate recovery

In 1999, Cole and colleagues reported on the association between heart rate recovery during the first minute after exercise and all-cause mortality in approximately 2,400 patients who were candidates for first-time coronary angiography.6 An abnormal heart rate recovery was defined as a reduction from the peak heart rate of 12 beats per minute or less, which corresponded to the lowest quartile. Thus, a patient achieving a peak heart rate of 160 beats per minute would be considered to have an abnormal heart rate recovery if 1 minute later the heart rate was 148 beats per minute or higher. Patients who had an abnormal heart rate recovery had a nearly fourfold increased risk of all-cause death; even after adjusting for numerous confounders, including exercise capacity, there was still a twofold independent increased risk of death. This initial observation has since been confirmed in other cohorts.19,20 The link between heart rate recovery, mortality, and cardiovascular prognosis appears to be independent of symptom status,21 type of recovery protocol,22 left ventricular ejection fraction,22 and angiographic severity of coronary artery disease.23

The mechanism by which an abnormal heart rate recovery predicts increased mortality is unclear. Given that heart rate recovery is thought to reflect parasympathetic nervous system function, and given that increased parasympathetic tone is believed to have antiarrhythmic effects, one might hypothesize that lower heart rate recovery would predict sudden cardiac death. In 2005, investigators from the Paris Civil Service Study reported on the association of exercise heart rate recovery and type of mortality; low heart rate recovery was strongly predictive of sudden cardiac death but not of non-sudden cardiac myocardial infarction death.20 A separate study from the Cleveland Clinic showed that among more than 29,000 patients, frequent ventricular ectopy during early recovery was strongly predictive of death, whereas frequent ventricular ectopy during exercise was not.24 These two studies together suggest that the link between heart rate recovery and mortality may be a reflection of the antiarrhythmic properties of the parasympathetic nervous system.

It is well known that there is an exceptionally powerful link between functional capacity and cardiovascular risk.25,26 People who are in excellent physical shape have high levels of parasympathetic tone. Among patients with suspected coronary artery disease, there is a strong dose-response relationship between heart rate recovery and physical fitness.6 While the link between functional capacity and prognosis is complex, it is conceivable that parasympathetic protection against arrhythmias and shear-induced plaque rupture may play a role.

Figure 4. User interface of an externally validated mortality prediction model for primary prevention patients with normal electrocardiograms undergoing exercise testing.27 This prediction model includes easily obtained cardiovascular risk factors as well as measures of autonomic function.
Both heart rate recovery and functional capacity are easy to measure using standard exercise test equipment. Recently, investigators from the Cleveland Clinic and Kaiser Permanente derived and externally validated a simple multivariable instrument by which all-cause mortality can be predicted in subjects with a normal electrocardiogram and no history of coronary disease.27 This instrument includes measures of functional capacity, heart rate recovery, and frequent ventricular ectopy during recovery. An example of the user interface is shown in Figure 4.

DETERMINANTS OF AUTONOMIC NERVOUS SYSTEM FUNCTION

There is an extensive literature documenting a number of determinants of autonomic tone.3,7 On a patient level, decreased levels of parasympathetic tone or increased levels of sympathetic tone have been linked to obesity, insulin resistance, diabetes, hypertension, hypercholesterolemia, depression, anxiety, heart failure, and peripheral vascular disease.3

Copyright © 2002 American Diabetes Association. From Diabetes®, Vol. 51, 2002; 803–807. Adapted with permission from The American Diabetes Association.
Figure 5. Association of fasting plasma glucose with abnormal heart rate recovery among healthy subjects enrolled in the Lipid Research Clinics observational cohort study.
The association between diabetes and autonomic nervous system dysfunction is well known to clinicians caring for patients with clinically manifest autonomic neuropathy. What is less appreciated is that even minor degrees of glucose intolerance are associated with abnormalities of autonomic balance. For example, among patients enrolled in a population-based cohort, the likelihood of an abnormal heart rate recovery increased in a steady fashion as fasting plasma glucose increased from 70 to 80 to 90 mg/dL and above (Figure 5).28 Even at levels of plasma glucose that would be considered normal, the likelihood of an abnormal heart rate recovery increased as plasma glucose increased.28

Perturbations of autonomic nervous system function have also been associated with environmental exposures. People who have lower levels of education,29 live in neighborhoods characterized by lower socio-economic status,30 or are exposed to small-particulate air pollution31 have been shown to manifest abnormal heart rate recovery or decreased heart rate variability.

CONCLUSIONS

Autonomic nervous system function can be measured in the clinic by recording resting heart rate, heart rate variability, or exercise heart rate recovery.1 All three of these measures are strong predictors of cardiovascular risk and all-cause mortality in both primary and secondary prevention settings. A number of determinants of autonomic nervous system function have been identified, including patient-level factors like obesity, diabetes, and heart failure as well as environmental correlates like smoking, social stress, and air pollution. It is not yet known, however, how best to take advantage of the associations between abnormal autonomic nervous system function and poor prognosis to improve patient outcomes. Future research will be needed to identify strategies of favorably modulating autonomic function that improve outcomes in the clinic and among large populations.

First-year medical students are well aware that the autonomic nervous system regulates heart rate and blood pressure along with respiratory and digestive functions. The past 10 to 20 years have seen increased appreciation of the medical relevance of the the autonomic nervous system beyond first-year physiology examinations; even mild disturbances of autonomic nervous system function predict materially worse prognosis.1–3 Researchers have focused on the use of readily available measures, such as heart rate,4 heart rate variability,5 and heart rate recovery,6 to link autonomic nervous system dysfunction with mortality and morbidity.1 In addition, epidemiologists have exploited these tools to identify correlates of autonomic nervous system dysfunction at patient and environmental levels.7 Although it is not yet known how best to incorporate autonomic nervous system measures into routine clinical care, there is increasing excitement about the insights that this work has revealed.

MEASURES OF AUTONOMIC NERVOUS SYSTEM FUNCTION

Although many measures of autonomic nervous system function have been described, three relatively straightforward approaches are based on heart rate.1

Resting heart rate is the simplest to obtain, as it does not require any special technology. People with high levels of parasympathetic nervous system tone have lower resting heart rates, as is typically seen in world-class athletes. Conversely, conditions characterized by increased levels of sympathetic tone manifest as sinus tachycardia; classic examples include congestive heart failure, anemia, and hypovolemia.

Reprinted, with permission, from Annals of Internal Medicine (van Ravenswaaij-Arts et al. Heart rate variability. Ann Intern Med 1993; 118:436–447).
Figure 1. Example of time-domain measures of heart rate variability (STV = short-term variability; LTV = long-term variability). The top plot shows heart rate as a function of time. In the bottom plot, Fourier transform yields power values of very-low-frequency (VLF), low-frequency (LF), and high-frequency (HF) domains. The high-frequency domain is thought to reflect parasympathetic tone, where-as the very-low-frequency and low-frequency domains are thought to reflect a mixture of parasympathetic and sympathetic tone.
Heart rate variability. Even before the advent of the electrocardiogram, it was known that heart rate normally varies with respiration.8 Physiologic sinus arrhythmia can be easily demonstrated by plotting heart rate over time in resting supine subjects, typically yielding a tracing characterized by high-frequency, low-amplitude waves. When a normal subject assumes an upright position, the resting heart rate increases and there is an increased absolute amount of variability, but the frequency of the variability wave decreases. Using Fourier transform techniques, one can translate the amplitude and frequency of the waves shown in the top plot of Figure 1 into power domain functions, as shown in the bottom plot of Figure 1.8 Heart rate variability functions can be divided into high-frequency, low-frequency, and very-low-frequency domains.8,9 The high-frequency peak, which is reflective of the very fine variability seen with respiration at rest, is thought to reflect parasympathetic nervous system tone. The low-frequency and very-low-frequency peaks are thought to reflect mixed effects of parasympathetic tone and sympathetic tone.

Heart rate recovery. Heart rate variability measures require continuous Holter monitoring as well as sophisticated software. The numerous types of heart rate variability measures are not intuitive for most clinicians. Exercise heart rate recovery is an arguably more straightforward method of assessing parasympathetic tone.1 During a graded exercise test, heart rate increases as a result of withdrawal of parasympathetic tone and increased sympathetic tone. During the first 30 seconds after exercise, heart rate decreases quickly, mainly because of rapid reactivation of the parasympathetic nervous system.10

Figure 2. Demonstration of the association between parasympathetic tone and heart rate recovery. (A) Absolute heart rates (after logarithmic transformation) are shown during the first 2 minutes after exercise in three groups of subjects. Among athletes and normal subjects, there is a biexponential relationship. (B) Postexercise absolute heart rates are shown again, this time after administration of atropine, in which case the initial steep slope disappears.  Figure is based on data from Imai et al.10
The association between early heart rate recovery and parasympathetic nervous system function was demonstrated elegantly by Imai and colleagues in a study of three groups of subjects—athletes, normal subjects, and patients with heart failure.10 Among athletes and normal subjects there was a biexponential pattern of heart rate during early recovery, with a steep log-linear decrease during the first 30 seconds followed by a more shallow decline (Figure 2A). When the same subjects were given atropine and exercise testing was repeated, the initial steep decrease in heart rate observed among athletes and normal subjects disappeared (Figure 2B). The authors concluded that early heart rate recovery is primarily a manifestation of parasympathetic reactivation.

AUTONOMIC NERVOUS SYSTEM FUNCTION AND MORTALITY

Resting heart rate

There is a remarkably strong association between heart rate and survival, an association that transcends species.4 Small mammals that have rapid heart rates have short life expectancies. Larger mammals that have slower heart rates have correspondingly higher life expectancies. Among nearly all mammals, life expectancy is close to 1 billion heartbeats.

Investigators have been able to increase survival in animal models by deliberate slowing of heart rate. An experiment performed in mice more than 30 years ago showed that life expectancy increases with low-dose digoxin, a parasympathomimetic agent.11 More recently, a mouse model has been used to show that ivabradine, a sinus node ion channel blocking agent that specifically reduces heart rate without affecting vascular tone, inhibits development of atherosclerosis in genetically susceptible knockout mice.12

There is an extensive epidemiological literature linking heart rate to mortality in large human populations. 4,13 As heart rate increases to 75 to 80 beats per minute, there are marked increases in total mortality and mortality due to coronary heart disease. As is well known, administration of beta-blockers reduces mortality in survivors of myocardial infarction. What is particularly remarkable is that the magnitude of reduction in mortality with beta-blocker therapy is directly proportional to the magnitude of heart rate decrease.14 In a recent analysis of hypertensive patients enrolled in a large-scale randomized trial, a strong association was noted between mortality and increasing heart rate at the time of randomization as well as after treatment with either verapamil or a beta-blocker.15

Heart rate variability

Figure 3. Association between measures of heart rate variability and cardiac events in the Framingham Heart Study. Each measure is divided into tertiles from lowest to highest (SDNN = standard deviation of R-R intervals of normal beats; LF = low-frequency power; HF = high-frequency power; LF/HF = ratio of LF power to HF power). Figure is based on data from Tsuji et al.16
Just as with resting heart rate, there is a robust literature linking decreased heart rate variability to cardiac events and mortality. Among healthy elderly subjects enrolled in the Framingham Heart Study, decreased heart rate variability was associated with a substantially increased likelihood of major cardiac events (Figure 3).16 The Framingham investigators measured the standard deviation of R-R intervals that do not include ventricular ectopic beats (SDNN) as well as time-domain measures. Lower values of the ratio of low-frequency power to high-frequency power, which would correspond to lower levels of parasympathetic tone, were also associated with increased mortality. Similarly, among survivors of myocardial infarction, especially those with low ejection fractions, decreased heart rate variability predicted substantially higher mortality rates.5,17,18

 

 

Heart rate recovery

In 1999, Cole and colleagues reported on the association between heart rate recovery during the first minute after exercise and all-cause mortality in approximately 2,400 patients who were candidates for first-time coronary angiography.6 An abnormal heart rate recovery was defined as a reduction from the peak heart rate of 12 beats per minute or less, which corresponded to the lowest quartile. Thus, a patient achieving a peak heart rate of 160 beats per minute would be considered to have an abnormal heart rate recovery if 1 minute later the heart rate was 148 beats per minute or higher. Patients who had an abnormal heart rate recovery had a nearly fourfold increased risk of all-cause death; even after adjusting for numerous confounders, including exercise capacity, there was still a twofold independent increased risk of death. This initial observation has since been confirmed in other cohorts.19,20 The link between heart rate recovery, mortality, and cardiovascular prognosis appears to be independent of symptom status,21 type of recovery protocol,22 left ventricular ejection fraction,22 and angiographic severity of coronary artery disease.23

The mechanism by which an abnormal heart rate recovery predicts increased mortality is unclear. Given that heart rate recovery is thought to reflect parasympathetic nervous system function, and given that increased parasympathetic tone is believed to have antiarrhythmic effects, one might hypothesize that lower heart rate recovery would predict sudden cardiac death. In 2005, investigators from the Paris Civil Service Study reported on the association of exercise heart rate recovery and type of mortality; low heart rate recovery was strongly predictive of sudden cardiac death but not of non-sudden cardiac myocardial infarction death.20 A separate study from the Cleveland Clinic showed that among more than 29,000 patients, frequent ventricular ectopy during early recovery was strongly predictive of death, whereas frequent ventricular ectopy during exercise was not.24 These two studies together suggest that the link between heart rate recovery and mortality may be a reflection of the antiarrhythmic properties of the parasympathetic nervous system.

It is well known that there is an exceptionally powerful link between functional capacity and cardiovascular risk.25,26 People who are in excellent physical shape have high levels of parasympathetic tone. Among patients with suspected coronary artery disease, there is a strong dose-response relationship between heart rate recovery and physical fitness.6 While the link between functional capacity and prognosis is complex, it is conceivable that parasympathetic protection against arrhythmias and shear-induced plaque rupture may play a role.

Figure 4. User interface of an externally validated mortality prediction model for primary prevention patients with normal electrocardiograms undergoing exercise testing.27 This prediction model includes easily obtained cardiovascular risk factors as well as measures of autonomic function.
Both heart rate recovery and functional capacity are easy to measure using standard exercise test equipment. Recently, investigators from the Cleveland Clinic and Kaiser Permanente derived and externally validated a simple multivariable instrument by which all-cause mortality can be predicted in subjects with a normal electrocardiogram and no history of coronary disease.27 This instrument includes measures of functional capacity, heart rate recovery, and frequent ventricular ectopy during recovery. An example of the user interface is shown in Figure 4.

DETERMINANTS OF AUTONOMIC NERVOUS SYSTEM FUNCTION

There is an extensive literature documenting a number of determinants of autonomic tone.3,7 On a patient level, decreased levels of parasympathetic tone or increased levels of sympathetic tone have been linked to obesity, insulin resistance, diabetes, hypertension, hypercholesterolemia, depression, anxiety, heart failure, and peripheral vascular disease.3

Copyright © 2002 American Diabetes Association. From Diabetes®, Vol. 51, 2002; 803–807. Adapted with permission from The American Diabetes Association.
Figure 5. Association of fasting plasma glucose with abnormal heart rate recovery among healthy subjects enrolled in the Lipid Research Clinics observational cohort study.
The association between diabetes and autonomic nervous system dysfunction is well known to clinicians caring for patients with clinically manifest autonomic neuropathy. What is less appreciated is that even minor degrees of glucose intolerance are associated with abnormalities of autonomic balance. For example, among patients enrolled in a population-based cohort, the likelihood of an abnormal heart rate recovery increased in a steady fashion as fasting plasma glucose increased from 70 to 80 to 90 mg/dL and above (Figure 5).28 Even at levels of plasma glucose that would be considered normal, the likelihood of an abnormal heart rate recovery increased as plasma glucose increased.28

Perturbations of autonomic nervous system function have also been associated with environmental exposures. People who have lower levels of education,29 live in neighborhoods characterized by lower socio-economic status,30 or are exposed to small-particulate air pollution31 have been shown to manifest abnormal heart rate recovery or decreased heart rate variability.

CONCLUSIONS

Autonomic nervous system function can be measured in the clinic by recording resting heart rate, heart rate variability, or exercise heart rate recovery.1 All three of these measures are strong predictors of cardiovascular risk and all-cause mortality in both primary and secondary prevention settings. A number of determinants of autonomic nervous system function have been identified, including patient-level factors like obesity, diabetes, and heart failure as well as environmental correlates like smoking, social stress, and air pollution. It is not yet known, however, how best to take advantage of the associations between abnormal autonomic nervous system function and poor prognosis to improve patient outcomes. Future research will be needed to identify strategies of favorably modulating autonomic function that improve outcomes in the clinic and among large populations.

References
  1. Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol 2008; 51:1725–1733.
  2. Katz A, Liberty IF, Porath A, Ovsyshcher I, Prystowsky EN. A simple bedside test of 1-minute heart rate variability during deep breathing as a prognostic index after myocardial infarction. Am Heart J 1999; 138(1 Pt 1):32–38.
  3. Curtis BM, O’Keefe JH. Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight. Mayo Clin Proc 2002; 77:45–54.
  4. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol 1997; 30:1104–1106.
  5. Huikuri HV, Makikallio T, Airaksinen KE, Mitrani R, Castellanos A, Myerburg RJ. Measurement of heart rate variability: a clinical tool or a research toy? J Am Coll Cardiol 1999; 34:1878–1883.
  6. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999; 341:1351–1357.
  7. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 2007; 74:224–242.
  8. van Ravenswaaij-Arts CM, Kollee LA, Hopman JC, Stoelinga GB, van Geijn HP. Heart rate variability. Ann Intern Med 1993; 118:436–447.
  9. Pumprla J, Howorka K, Groves D, Chester M, Nolan J. Functional assessment of heart rate variability: physiological basis and practical applications. Int J Cardiol 2002; 84:1–14.
  10. Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994; 24:1529–1535.
  11. Coburn AF, Grey RM, Rivera SM. Observations on the relation of heart rate, life span, weight and mineralization in the digoxintreated A-J mouse. Johns Hopkins Med J 1971; 128:169–193.
  12. Custodis F, Baumhakel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008; 117:2377–2387.
  13. Wilhelmsen L, Berglund G, Elmfeldt D, et al. The multifactor primary prevention trial in GÖteborg, Sweden. Eur Heart J 1986; 7:279–288.
  14. Reil JC, Bohm M. The role of heart rate in the development of cardiovascular disease. Clin Res Cardiol 2007; 96:585–592.
  15. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J 2008; 29:1327–1334.
  16. Tsuji H, Larson MG, Venditti FJ, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996; 94:2850–2855.
  17. Makikallio TH, Hoiber S, Kober L, et al. Fractal analysis of heart rate dynamics as a predictor of mortality in patients with depressed left ventricular function after acute myocardial infarction. TRACE Investigators. TRAndolapril Cardiac Evaluation. Am J Cardiol 1999; 83:836–839.
  18. La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351:478–484.
  19. Shetler K, Marcus R, Froelicher VF, et al. Heart rate recovery: validation and methodologic issues. J Am Coll Cardiol 2001; 38:1980–1987.
  20. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetiere P. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med 2005; 352:1951–1958.
  21. Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. Ann Intern Med 2000; 132:552–555.
  22. Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation 2001; 104:1911–1916.
  23. Vivekananthan DP, Blackstone EH, Pothier CE, Lauer MS. Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary disease. J Am Coll Cardiol 2003; 42:831–838.
  24. Frolkis JP, Pothier CE, Blackstone EH, Lauer MS. Frequent ventricular ectopy after exercise as a predictor of death. N Engl J Med 2003; 348:781–790.
  25. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346:793–801.
  26. Gulati M, Black HR, Shaw LJ, et al. The prognostic value of a nomogram for exercise capacity in women. N Engl J Med 2005; 353:468–475.
  27. Lauer MS, Pothier CE, Magid DJ, Smith SS, Kattan MW. An externally validated model for predicting long-term survival after exercise treadmill testing in patients with suspected coronary artery disease and a normal electrocardiogram. Ann Intern Med 2007; 147:821–828.
  28. Panzer C, Lauer MS, Brieke A, Blackstone E, Hoogwerf B. Association of fasting plasma glucose with heart rate recovery in healthy adults: a population-based study. Diabetes 2002; 51:803–807.
  29. Shishehbor MH, Baker DW, Blackstone EH, Lauer MS. Association of educational status with heart rate recovery: a population-based propensity analysis. Am J Med 2002; 113:643–649.
  30. Shishehbor MH, Litaker D, Pothier CE, Lauer MS. Association of socioeconomic status with functional capacity, heart rate recovery, and all-cause mortality. JAMA 2006; 295:784–792.
  31. Magari SR, Hauser R, Schwartz J, Williams PL, Smith TJ, Christiani DC. Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation 2001; 104:986–991.
References
  1. Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol 2008; 51:1725–1733.
  2. Katz A, Liberty IF, Porath A, Ovsyshcher I, Prystowsky EN. A simple bedside test of 1-minute heart rate variability during deep breathing as a prognostic index after myocardial infarction. Am Heart J 1999; 138(1 Pt 1):32–38.
  3. Curtis BM, O’Keefe JH. Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight. Mayo Clin Proc 2002; 77:45–54.
  4. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol 1997; 30:1104–1106.
  5. Huikuri HV, Makikallio T, Airaksinen KE, Mitrani R, Castellanos A, Myerburg RJ. Measurement of heart rate variability: a clinical tool or a research toy? J Am Coll Cardiol 1999; 34:1878–1883.
  6. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999; 341:1351–1357.
  7. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 2007; 74:224–242.
  8. van Ravenswaaij-Arts CM, Kollee LA, Hopman JC, Stoelinga GB, van Geijn HP. Heart rate variability. Ann Intern Med 1993; 118:436–447.
  9. Pumprla J, Howorka K, Groves D, Chester M, Nolan J. Functional assessment of heart rate variability: physiological basis and practical applications. Int J Cardiol 2002; 84:1–14.
  10. Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994; 24:1529–1535.
  11. Coburn AF, Grey RM, Rivera SM. Observations on the relation of heart rate, life span, weight and mineralization in the digoxintreated A-J mouse. Johns Hopkins Med J 1971; 128:169–193.
  12. Custodis F, Baumhakel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008; 117:2377–2387.
  13. Wilhelmsen L, Berglund G, Elmfeldt D, et al. The multifactor primary prevention trial in GÖteborg, Sweden. Eur Heart J 1986; 7:279–288.
  14. Reil JC, Bohm M. The role of heart rate in the development of cardiovascular disease. Clin Res Cardiol 2007; 96:585–592.
  15. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J 2008; 29:1327–1334.
  16. Tsuji H, Larson MG, Venditti FJ, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996; 94:2850–2855.
  17. Makikallio TH, Hoiber S, Kober L, et al. Fractal analysis of heart rate dynamics as a predictor of mortality in patients with depressed left ventricular function after acute myocardial infarction. TRACE Investigators. TRAndolapril Cardiac Evaluation. Am J Cardiol 1999; 83:836–839.
  18. La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351:478–484.
  19. Shetler K, Marcus R, Froelicher VF, et al. Heart rate recovery: validation and methodologic issues. J Am Coll Cardiol 2001; 38:1980–1987.
  20. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetiere P. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med 2005; 352:1951–1958.
  21. Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. Ann Intern Med 2000; 132:552–555.
  22. Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation 2001; 104:1911–1916.
  23. Vivekananthan DP, Blackstone EH, Pothier CE, Lauer MS. Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary disease. J Am Coll Cardiol 2003; 42:831–838.
  24. Frolkis JP, Pothier CE, Blackstone EH, Lauer MS. Frequent ventricular ectopy after exercise as a predictor of death. N Engl J Med 2003; 348:781–790.
  25. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346:793–801.
  26. Gulati M, Black HR, Shaw LJ, et al. The prognostic value of a nomogram for exercise capacity in women. N Engl J Med 2005; 353:468–475.
  27. Lauer MS, Pothier CE, Magid DJ, Smith SS, Kattan MW. An externally validated model for predicting long-term survival after exercise treadmill testing in patients with suspected coronary artery disease and a normal electrocardiogram. Ann Intern Med 2007; 147:821–828.
  28. Panzer C, Lauer MS, Brieke A, Blackstone E, Hoogwerf B. Association of fasting plasma glucose with heart rate recovery in healthy adults: a population-based study. Diabetes 2002; 51:803–807.
  29. Shishehbor MH, Baker DW, Blackstone EH, Lauer MS. Association of educational status with heart rate recovery: a population-based propensity analysis. Am J Med 2002; 113:643–649.
  30. Shishehbor MH, Litaker D, Pothier CE, Lauer MS. Association of socioeconomic status with functional capacity, heart rate recovery, and all-cause mortality. JAMA 2006; 295:784–792.
  31. Magari SR, Hauser R, Schwartz J, Williams PL, Smith TJ, Christiani DC. Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation 2001; 104:986–991.
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Vagal tone and the inflammatory reflex

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The neurovisceral integration model of cardiac vagal tone integrates autonomic, attentional, and affective systems into a functional and structural network. This neural network can be indexed by heart rate variability (HRV). High HRV is associated with greater prefrontal inhibitory tone. A lack of inhibition leads to undifferentiated threat responses to environmental challenges.

THE CENTRAL AUTONOMIC NETWORK

Adapted, with permission, from Mayo Clinic Proceedings (Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc 1993; 10:988–1001).
Figure 1. Locations of structures in the central autonomic network.1
Some of the structures involved in this model, called the central autonomic network, are illustrated in Figure 1.1 Communication is bidirectional between these neural structures, which include the medial prefrontal cortex, insular cortex, central nucleus of the amygdala, periaqueductal gray region, and parabrachial region. At the medullary level are the autonomic output regions, including the nucleus ambiguus and the nucleus tractus solitarius. The primary outputs for this set of neural structures are from the stellate ganglia and the vagus nerve to the sinoatrial node of the heart.

Activity of the heart permits us to infer activity in this set of neural structures. Excitatory and inhibitory pathways form the connections between the prefrontal cortex and the autonomic output regions in the medullary area, with further connections to heart rate (HR) and HRV.

Central, respiratory, cardiopulmonary, and arterial baroreflex influences on the brainstem signal the sinoatrial node of the heart. Autonomic inputs at the heart have a differential influence. The sympathetic inputs to the sinoatrial node of the heart are relatively slow, such that a burst of sympathetic outflow from the brain produces an effect on the heart several seconds later. In contrast, inputs to the cholinergic or vagal pathway are relatively fast, on the order of milliseconds. The interplay of sympathetic and vagal neural control of the heart produces a complex variability in heart rhythm that characterizes a healthy system.

PARASYMPATHETIC CONTROL AND THE RIGHT VAGUS NERVE

Pharmacologic blockade of prefrontal cortex

The effect of pharmacologic blockade of the prefrontal cortex on HR and HRV was investigated in patients undergoing preoperative evaluation for epilepsy surgery.2 The hypothesis was that inactivation of the prefrontal cortex (using an injection of intracarotid sodium amobarbital) would be associated with an increase in HR and a decrease in vagally mediated HRV.

During 10 minutes of inactivation, an increase in HR was observed in both the left and right hemispheres. HR peaked 3 to 4 minutes postinjection and decreased gradually, returning to preinjection baseline at about 10 minutes. The increase was larger in the right hemisphere, a finding that is consistent with the known neuroanatomy in which the right-sided neural inputs selectively signal the sinoatrial node, and the left-sided inputs signal the atrioventricular node. The pronounced effect on HR in the right hemisphere was related specifically to the vagally mediated (high-frequency) component of HRV. This experiment strongly suggests that cerebral structures tonically inhibit sympathoexcitatory circuits, and that the inhibition is mediated via vagal mechanisms.

Further analysis, in which the subjects were divided into tertiles based on age, revealed disinhibition of brainstem sympathoexcitatory circuits, resulting in an increase in HR of approximately 9 beats per minute in the youngest individuals (mean age, 20 years), but an absence of a laterality effect, which suggests that the prefrontal cortex is not fully developed in this young age group. Disinhibition of sympathoexcitatory circuits as indicated by a HR increase of 11 beats per minute and a right-sided laterality effect occurred in subjects in the second tertile (mean age, 33 years). In the oldest age group (mean age, 45 years), the disinhibition effect on HR was only 3 beats per minute, consistent with the known changes in prefrontal inhibitory tone and prefrontal activity that occur with age.3

Confirmation from neuroimaging studies

Neuroimaging studies support the predominant role of the right hemisphere in the regulation of vagal tone during emotion. Twelve healthy females underwent measurements of cerebral blood flow and the high-frequency component of HRV during two stimulus modalities (film, recall) and six stimulus conditions (happiness, sadness, disgust, and three neutral conditions), for a total of 12 conditions.4 Significant covariation (increased activity associated with increased HRV) was found for four brain areas: the right superior prefrontal cortex, the right dorsal lateral prefrontal cortex, the right parietal cortex, and the left anterior cingulate.

 

 

THE INFLAMMATORY REFLEX

The cholinergic anti-inflammatory pathway

Acetylcholine and parasympathetic tone inhibit proinflammatory cytokines such as interleukin (IL)-6. These proinflammatory cytokines are under tonic inhibitory control via the vagus nerve, and this function may have important implications for health and disease.5

The cholinergic anti-inflammatory pathway is associated with efferent activity in the vagus nerve, leading to acetylcholine release in the reticuloendothelial system that includes the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with the alpha-7 nicotinic receptor on tissue macrophages to inhibit the release of proinflammatory cytokines, but not anti-inflammatory cytokines such as IL-10.

Approximately 80% of the fibers of the vagus nerve are sensory; ie, they sense the presence of proinflammatory cytokines and convey the signal to the brain. Efferent vagus nerve activity leads to the release of acetylcholine, which inhibits tumor necrosis factor (TNF)-alpha on the macrophages. Cytokine regulation also involves the sympathetic nervous system and the endocrine system (the hypothalamic-pituitary axis).

The sympathetic system has both pro- and anti-inflammatory influences. The inflammatory response is a cascade of cytokines, such that it may begin with the release of TNF-alpha, leading to the production of IL-1 and IL-6. IL-6 has both pro- and anti-inflammatory properties and represents a negative feedback mechanism. Expression of IL-6 in the liver promotes the production of the acute-phase reactant C-reactive protein (CRP). Therefore, activation of the cholinergic receptor to induce acetylcholine release may be an early intervention to short-circuit this inflammatory cascade, a potential therapeutic strategy to blunt inflammatory-mediated disease.

Inverse relationship between HRV and CRP

In a study of 613 airplane factory workers in southern Germany, vagally mediated HRV was inversely related to high-sensitivity CRP in men and premenopausal women, even after controlling for urinary norepinephrine as an index of sympathetic activity.6 Most previous studies in which the relationship between HRV and CRP (or other inflammatory markers) was assessed failed to control for sympathetic nervous system activity. In the total sample and in men, the parasympathetic effect on CRP was comparable with that of smoking; in women, the effect was 4 times larger and comparable with that of high body mass index. A negative association was again found between vagally mediated HRV and white blood cell count.

Inverse relationship between HRV and fibrinogen

In a related report from the same study, vagal modulation of fibrinogen was investigated.7 Fibrinogen is a large glycoprotein that is synthesized by the liver. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis. Meta-analyses have shown a prospective association between elevated plasma fibrinogen levels even in the normal range and an increased risk of coronary artery disease in different populations. We investigated the relationship between nighttime HRV, assessed by root mean square of successive R-R interval differences (RMSSD), and fibrinogen in 559 mostly male workers from southern Germany. Among all workers, there was a mean ± SEM increase of 0.41 ± 0.13 mg/dL fibrinogen for each ms decrease in nighttime RMSSD, even after controlling for established cardiovascular risk factors. The increase in men was 0.28 ± 0.13 mg/dL and, in women, 1.16 ± 0.41 mg/dL for each ms decrease in nighttime RMSSD. Such an autonomic mechanism might contribute to the atherosclerotic process and its thrombotic complications.

Vagal regulation of allostatic systems

Whereas the role of the autonomic nervous system, and the vagus nerve in particular, in the regulation of the cardiovascular system seems clear, the role of the vagus nerve in the regulation of other systems associated with allostasis is less evident. In addition to the regulation of inflammatory markers as discussed thus far, decreased vagal function and HRV have been associated with increased fasting glucose and glycated hemoglobin (HbA1c) levels, and with increased overnight urinary cortisol.8 These factors have been associated with increased allostatic load and poor health. Thus, vagal activity seems to have an inhibitory function in the regulation of allostatic systems. The prefrontal cortex and the amygdala are important central nervous system structures linked to the regulation of these allostatic systems, including inflammation via the vagus nerve. The next section describes evidence for the prefrontal regulation of inflammation.

Prefrontal cortical activity and immune indices

Ohira et al used neuroimaging to explore the association between the brain and immune function.9 Their study examined the neural basis of the top-down modulation accompanying cognitive appraisal during a controllable or uncontrollable acute stressor. HR and blood pressure increased significantly during a mental arithmetic task and returned to baseline soon after termination of the task. HR increased to a greater extent in the controllable versus the uncontrollable condition; blood pressure was unaffected by controllability. Endocrine and immune indices were also affected by the acute stress task: the proportions of natural killer cells increased and helper T cells decreased acutely during the stressor.

Importantly, cerebral blood flow measurements demonstrated that the areas of the prefrontal cortex that we have found to be associated with HRV, including the medial prefrontal cortex and the insula, were also associated with immune indices (medial and lateral orbitofrontal cortices and insula), suggesting prefrontal or frontal modulation of immune responses possibly via the same vagal pathways.

VAGAL ACTIVITY AND CARDIOVASCULAR RISK FACTORS

The regulation of physiologic systems that are important for health and disease has been linked to vagal function and HRV. We have recently reviewed the literature on the relationship between vagal function and the risk for cardiovascular disease and stroke. The National Heart, Lung, and Blood Institute lists eight risk factors for heart disease and stroke.10 Six are considered modifiable. Of the six modifiable factors, three are associated with what could be called biologic factors: high blood pressure (hypertension), diabetes, and abnormal cholesterol; the other three could be considered lifestyle factors: tobacco use (smoking), physical inactivity (exercise), and overweight (obesity). Two factors, age and family history of early heart disease or stroke, are considered nonmodifiable. At least some data suggest that each of these risk factors is associated with decreased vagal function as indexed by HRV.11

Interventions to modify HRV include exercise, ingestion of omega-3 fatty acids, stress reduction (eg, mediation), pharmacologic manipulations, and vagus nerve stimulation, suggesting that methods that increase vagus nerve activity might favorably modify an individual’s risk profile.

CONCLUSION

The brain and the heart are intimately connected. Both epidemiologic and experimental data suggest an association between HRV and inflammation, including similar neural mechanisms. Evidence of an association between HRV and inflammation supports the concept of a cholinergic anti-inflammatory pathway.

References
  1. Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc 1993; 68:988–1001.
  2. Ahern GL, Sollers JJ, Lane RD, et al. Heart rate and heart rate variability changes in the intracarotid sodium amobarbital test. Epilepsia 2001; 42:912–921.
  3. Thayer JF, Sollers JJ, Labiner DM, et al Age-related differences in prefrontal control of heart rate in humans: a pharmacological blockade study [published online ahead of print September 19, 2008] Int J Psychophysioldoi: 10.1016/j.ijpsycho.2008.04.007.
  4. Lane RD, McRae K, Reiman EM, Chen K, Ahern GL, Thayer JF. Neural correlates of heart rate variability during emotion. Neuroimage 2009; 44:213–222.
  5. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853–859.
  6. Thayer JF, Fischer JE Heart rate variability, overnight urinary norepinephrine, and C-reactive protein: evidence for the cholinergic anti-inflammatory pathway in healthy human adults [published online ahead of print November 15, 2008] J Intern Meddoi: 10.1111/j.1365-2796.2008.02023.x.
  7. von Kanel R, Thayer JF, Fischer JE Night-time vagal cardiac control and plasma fibrinogen levels in a population of working men and women Ann Noninvasive Electrocardiol In press
  8. Thayer JF, Sternberg EM. Beyond heart rate variability: vagal regulation of allostatic systems. Ann N Y Acad Sci 2006; 1088:361–372.
  9. Ohira H, Isowa T, Nomura M, et al. Imaging brain and immune association accompanying cognitive appraisal of an acute stressor. Neuroimage 2008; 39:500–514.
  10. Your guide to lowering blood pressure: risk factors. National Heart, Lung, and Blood Institute Web site. http://www.nhlbi.nih.gov/hbp/hbp/hdrf.htm. Accessed January 13, 2009.
  11. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 2007; 74:224–242.
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Correspondence: Julian F. Thayer, PhD, Department of Psychology, 133 Psychology Building, 1835 Neil Ave., Columbus, OH 43210; [email protected]

Dr. Thayer reported that he has no financial interests or relationships that pose a potential conflict of interest with this article.

This article was developed from an audio transcript of Dr. Thayer’s presentation at the 3rd Heart-Brain Summit. The transcript was formatted and edited by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Thayer.

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Correspondence: Julian F. Thayer, PhD, Department of Psychology, 133 Psychology Building, 1835 Neil Ave., Columbus, OH 43210; [email protected]

Dr. Thayer reported that he has no financial interests or relationships that pose a potential conflict of interest with this article.

This article was developed from an audio transcript of Dr. Thayer’s presentation at the 3rd Heart-Brain Summit. The transcript was formatted and edited by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Thayer.

Author and Disclosure Information

Julian F. Thayer, PhD
Professor, Department of Psychology, The Ohio State University, Columbus, OH

Correspondence: Julian F. Thayer, PhD, Department of Psychology, 133 Psychology Building, 1835 Neil Ave., Columbus, OH 43210; [email protected]

Dr. Thayer reported that he has no financial interests or relationships that pose a potential conflict of interest with this article.

This article was developed from an audio transcript of Dr. Thayer’s presentation at the 3rd Heart-Brain Summit. The transcript was formatted and edited by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Thayer.

Article PDF
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The neurovisceral integration model of cardiac vagal tone integrates autonomic, attentional, and affective systems into a functional and structural network. This neural network can be indexed by heart rate variability (HRV). High HRV is associated with greater prefrontal inhibitory tone. A lack of inhibition leads to undifferentiated threat responses to environmental challenges.

THE CENTRAL AUTONOMIC NETWORK

Adapted, with permission, from Mayo Clinic Proceedings (Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc 1993; 10:988–1001).
Figure 1. Locations of structures in the central autonomic network.1
Some of the structures involved in this model, called the central autonomic network, are illustrated in Figure 1.1 Communication is bidirectional between these neural structures, which include the medial prefrontal cortex, insular cortex, central nucleus of the amygdala, periaqueductal gray region, and parabrachial region. At the medullary level are the autonomic output regions, including the nucleus ambiguus and the nucleus tractus solitarius. The primary outputs for this set of neural structures are from the stellate ganglia and the vagus nerve to the sinoatrial node of the heart.

Activity of the heart permits us to infer activity in this set of neural structures. Excitatory and inhibitory pathways form the connections between the prefrontal cortex and the autonomic output regions in the medullary area, with further connections to heart rate (HR) and HRV.

Central, respiratory, cardiopulmonary, and arterial baroreflex influences on the brainstem signal the sinoatrial node of the heart. Autonomic inputs at the heart have a differential influence. The sympathetic inputs to the sinoatrial node of the heart are relatively slow, such that a burst of sympathetic outflow from the brain produces an effect on the heart several seconds later. In contrast, inputs to the cholinergic or vagal pathway are relatively fast, on the order of milliseconds. The interplay of sympathetic and vagal neural control of the heart produces a complex variability in heart rhythm that characterizes a healthy system.

PARASYMPATHETIC CONTROL AND THE RIGHT VAGUS NERVE

Pharmacologic blockade of prefrontal cortex

The effect of pharmacologic blockade of the prefrontal cortex on HR and HRV was investigated in patients undergoing preoperative evaluation for epilepsy surgery.2 The hypothesis was that inactivation of the prefrontal cortex (using an injection of intracarotid sodium amobarbital) would be associated with an increase in HR and a decrease in vagally mediated HRV.

During 10 minutes of inactivation, an increase in HR was observed in both the left and right hemispheres. HR peaked 3 to 4 minutes postinjection and decreased gradually, returning to preinjection baseline at about 10 minutes. The increase was larger in the right hemisphere, a finding that is consistent with the known neuroanatomy in which the right-sided neural inputs selectively signal the sinoatrial node, and the left-sided inputs signal the atrioventricular node. The pronounced effect on HR in the right hemisphere was related specifically to the vagally mediated (high-frequency) component of HRV. This experiment strongly suggests that cerebral structures tonically inhibit sympathoexcitatory circuits, and that the inhibition is mediated via vagal mechanisms.

Further analysis, in which the subjects were divided into tertiles based on age, revealed disinhibition of brainstem sympathoexcitatory circuits, resulting in an increase in HR of approximately 9 beats per minute in the youngest individuals (mean age, 20 years), but an absence of a laterality effect, which suggests that the prefrontal cortex is not fully developed in this young age group. Disinhibition of sympathoexcitatory circuits as indicated by a HR increase of 11 beats per minute and a right-sided laterality effect occurred in subjects in the second tertile (mean age, 33 years). In the oldest age group (mean age, 45 years), the disinhibition effect on HR was only 3 beats per minute, consistent with the known changes in prefrontal inhibitory tone and prefrontal activity that occur with age.3

Confirmation from neuroimaging studies

Neuroimaging studies support the predominant role of the right hemisphere in the regulation of vagal tone during emotion. Twelve healthy females underwent measurements of cerebral blood flow and the high-frequency component of HRV during two stimulus modalities (film, recall) and six stimulus conditions (happiness, sadness, disgust, and three neutral conditions), for a total of 12 conditions.4 Significant covariation (increased activity associated with increased HRV) was found for four brain areas: the right superior prefrontal cortex, the right dorsal lateral prefrontal cortex, the right parietal cortex, and the left anterior cingulate.

 

 

THE INFLAMMATORY REFLEX

The cholinergic anti-inflammatory pathway

Acetylcholine and parasympathetic tone inhibit proinflammatory cytokines such as interleukin (IL)-6. These proinflammatory cytokines are under tonic inhibitory control via the vagus nerve, and this function may have important implications for health and disease.5

The cholinergic anti-inflammatory pathway is associated with efferent activity in the vagus nerve, leading to acetylcholine release in the reticuloendothelial system that includes the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with the alpha-7 nicotinic receptor on tissue macrophages to inhibit the release of proinflammatory cytokines, but not anti-inflammatory cytokines such as IL-10.

Approximately 80% of the fibers of the vagus nerve are sensory; ie, they sense the presence of proinflammatory cytokines and convey the signal to the brain. Efferent vagus nerve activity leads to the release of acetylcholine, which inhibits tumor necrosis factor (TNF)-alpha on the macrophages. Cytokine regulation also involves the sympathetic nervous system and the endocrine system (the hypothalamic-pituitary axis).

The sympathetic system has both pro- and anti-inflammatory influences. The inflammatory response is a cascade of cytokines, such that it may begin with the release of TNF-alpha, leading to the production of IL-1 and IL-6. IL-6 has both pro- and anti-inflammatory properties and represents a negative feedback mechanism. Expression of IL-6 in the liver promotes the production of the acute-phase reactant C-reactive protein (CRP). Therefore, activation of the cholinergic receptor to induce acetylcholine release may be an early intervention to short-circuit this inflammatory cascade, a potential therapeutic strategy to blunt inflammatory-mediated disease.

Inverse relationship between HRV and CRP

In a study of 613 airplane factory workers in southern Germany, vagally mediated HRV was inversely related to high-sensitivity CRP in men and premenopausal women, even after controlling for urinary norepinephrine as an index of sympathetic activity.6 Most previous studies in which the relationship between HRV and CRP (or other inflammatory markers) was assessed failed to control for sympathetic nervous system activity. In the total sample and in men, the parasympathetic effect on CRP was comparable with that of smoking; in women, the effect was 4 times larger and comparable with that of high body mass index. A negative association was again found between vagally mediated HRV and white blood cell count.

Inverse relationship between HRV and fibrinogen

In a related report from the same study, vagal modulation of fibrinogen was investigated.7 Fibrinogen is a large glycoprotein that is synthesized by the liver. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis. Meta-analyses have shown a prospective association between elevated plasma fibrinogen levels even in the normal range and an increased risk of coronary artery disease in different populations. We investigated the relationship between nighttime HRV, assessed by root mean square of successive R-R interval differences (RMSSD), and fibrinogen in 559 mostly male workers from southern Germany. Among all workers, there was a mean ± SEM increase of 0.41 ± 0.13 mg/dL fibrinogen for each ms decrease in nighttime RMSSD, even after controlling for established cardiovascular risk factors. The increase in men was 0.28 ± 0.13 mg/dL and, in women, 1.16 ± 0.41 mg/dL for each ms decrease in nighttime RMSSD. Such an autonomic mechanism might contribute to the atherosclerotic process and its thrombotic complications.

Vagal regulation of allostatic systems

Whereas the role of the autonomic nervous system, and the vagus nerve in particular, in the regulation of the cardiovascular system seems clear, the role of the vagus nerve in the regulation of other systems associated with allostasis is less evident. In addition to the regulation of inflammatory markers as discussed thus far, decreased vagal function and HRV have been associated with increased fasting glucose and glycated hemoglobin (HbA1c) levels, and with increased overnight urinary cortisol.8 These factors have been associated with increased allostatic load and poor health. Thus, vagal activity seems to have an inhibitory function in the regulation of allostatic systems. The prefrontal cortex and the amygdala are important central nervous system structures linked to the regulation of these allostatic systems, including inflammation via the vagus nerve. The next section describes evidence for the prefrontal regulation of inflammation.

Prefrontal cortical activity and immune indices

Ohira et al used neuroimaging to explore the association between the brain and immune function.9 Their study examined the neural basis of the top-down modulation accompanying cognitive appraisal during a controllable or uncontrollable acute stressor. HR and blood pressure increased significantly during a mental arithmetic task and returned to baseline soon after termination of the task. HR increased to a greater extent in the controllable versus the uncontrollable condition; blood pressure was unaffected by controllability. Endocrine and immune indices were also affected by the acute stress task: the proportions of natural killer cells increased and helper T cells decreased acutely during the stressor.

Importantly, cerebral blood flow measurements demonstrated that the areas of the prefrontal cortex that we have found to be associated with HRV, including the medial prefrontal cortex and the insula, were also associated with immune indices (medial and lateral orbitofrontal cortices and insula), suggesting prefrontal or frontal modulation of immune responses possibly via the same vagal pathways.

VAGAL ACTIVITY AND CARDIOVASCULAR RISK FACTORS

The regulation of physiologic systems that are important for health and disease has been linked to vagal function and HRV. We have recently reviewed the literature on the relationship between vagal function and the risk for cardiovascular disease and stroke. The National Heart, Lung, and Blood Institute lists eight risk factors for heart disease and stroke.10 Six are considered modifiable. Of the six modifiable factors, three are associated with what could be called biologic factors: high blood pressure (hypertension), diabetes, and abnormal cholesterol; the other three could be considered lifestyle factors: tobacco use (smoking), physical inactivity (exercise), and overweight (obesity). Two factors, age and family history of early heart disease or stroke, are considered nonmodifiable. At least some data suggest that each of these risk factors is associated with decreased vagal function as indexed by HRV.11

Interventions to modify HRV include exercise, ingestion of omega-3 fatty acids, stress reduction (eg, mediation), pharmacologic manipulations, and vagus nerve stimulation, suggesting that methods that increase vagus nerve activity might favorably modify an individual’s risk profile.

CONCLUSION

The brain and the heart are intimately connected. Both epidemiologic and experimental data suggest an association between HRV and inflammation, including similar neural mechanisms. Evidence of an association between HRV and inflammation supports the concept of a cholinergic anti-inflammatory pathway.

The neurovisceral integration model of cardiac vagal tone integrates autonomic, attentional, and affective systems into a functional and structural network. This neural network can be indexed by heart rate variability (HRV). High HRV is associated with greater prefrontal inhibitory tone. A lack of inhibition leads to undifferentiated threat responses to environmental challenges.

THE CENTRAL AUTONOMIC NETWORK

Adapted, with permission, from Mayo Clinic Proceedings (Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc 1993; 10:988–1001).
Figure 1. Locations of structures in the central autonomic network.1
Some of the structures involved in this model, called the central autonomic network, are illustrated in Figure 1.1 Communication is bidirectional between these neural structures, which include the medial prefrontal cortex, insular cortex, central nucleus of the amygdala, periaqueductal gray region, and parabrachial region. At the medullary level are the autonomic output regions, including the nucleus ambiguus and the nucleus tractus solitarius. The primary outputs for this set of neural structures are from the stellate ganglia and the vagus nerve to the sinoatrial node of the heart.

Activity of the heart permits us to infer activity in this set of neural structures. Excitatory and inhibitory pathways form the connections between the prefrontal cortex and the autonomic output regions in the medullary area, with further connections to heart rate (HR) and HRV.

Central, respiratory, cardiopulmonary, and arterial baroreflex influences on the brainstem signal the sinoatrial node of the heart. Autonomic inputs at the heart have a differential influence. The sympathetic inputs to the sinoatrial node of the heart are relatively slow, such that a burst of sympathetic outflow from the brain produces an effect on the heart several seconds later. In contrast, inputs to the cholinergic or vagal pathway are relatively fast, on the order of milliseconds. The interplay of sympathetic and vagal neural control of the heart produces a complex variability in heart rhythm that characterizes a healthy system.

PARASYMPATHETIC CONTROL AND THE RIGHT VAGUS NERVE

Pharmacologic blockade of prefrontal cortex

The effect of pharmacologic blockade of the prefrontal cortex on HR and HRV was investigated in patients undergoing preoperative evaluation for epilepsy surgery.2 The hypothesis was that inactivation of the prefrontal cortex (using an injection of intracarotid sodium amobarbital) would be associated with an increase in HR and a decrease in vagally mediated HRV.

During 10 minutes of inactivation, an increase in HR was observed in both the left and right hemispheres. HR peaked 3 to 4 minutes postinjection and decreased gradually, returning to preinjection baseline at about 10 minutes. The increase was larger in the right hemisphere, a finding that is consistent with the known neuroanatomy in which the right-sided neural inputs selectively signal the sinoatrial node, and the left-sided inputs signal the atrioventricular node. The pronounced effect on HR in the right hemisphere was related specifically to the vagally mediated (high-frequency) component of HRV. This experiment strongly suggests that cerebral structures tonically inhibit sympathoexcitatory circuits, and that the inhibition is mediated via vagal mechanisms.

Further analysis, in which the subjects were divided into tertiles based on age, revealed disinhibition of brainstem sympathoexcitatory circuits, resulting in an increase in HR of approximately 9 beats per minute in the youngest individuals (mean age, 20 years), but an absence of a laterality effect, which suggests that the prefrontal cortex is not fully developed in this young age group. Disinhibition of sympathoexcitatory circuits as indicated by a HR increase of 11 beats per minute and a right-sided laterality effect occurred in subjects in the second tertile (mean age, 33 years). In the oldest age group (mean age, 45 years), the disinhibition effect on HR was only 3 beats per minute, consistent with the known changes in prefrontal inhibitory tone and prefrontal activity that occur with age.3

Confirmation from neuroimaging studies

Neuroimaging studies support the predominant role of the right hemisphere in the regulation of vagal tone during emotion. Twelve healthy females underwent measurements of cerebral blood flow and the high-frequency component of HRV during two stimulus modalities (film, recall) and six stimulus conditions (happiness, sadness, disgust, and three neutral conditions), for a total of 12 conditions.4 Significant covariation (increased activity associated with increased HRV) was found for four brain areas: the right superior prefrontal cortex, the right dorsal lateral prefrontal cortex, the right parietal cortex, and the left anterior cingulate.

 

 

THE INFLAMMATORY REFLEX

The cholinergic anti-inflammatory pathway

Acetylcholine and parasympathetic tone inhibit proinflammatory cytokines such as interleukin (IL)-6. These proinflammatory cytokines are under tonic inhibitory control via the vagus nerve, and this function may have important implications for health and disease.5

The cholinergic anti-inflammatory pathway is associated with efferent activity in the vagus nerve, leading to acetylcholine release in the reticuloendothelial system that includes the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with the alpha-7 nicotinic receptor on tissue macrophages to inhibit the release of proinflammatory cytokines, but not anti-inflammatory cytokines such as IL-10.

Approximately 80% of the fibers of the vagus nerve are sensory; ie, they sense the presence of proinflammatory cytokines and convey the signal to the brain. Efferent vagus nerve activity leads to the release of acetylcholine, which inhibits tumor necrosis factor (TNF)-alpha on the macrophages. Cytokine regulation also involves the sympathetic nervous system and the endocrine system (the hypothalamic-pituitary axis).

The sympathetic system has both pro- and anti-inflammatory influences. The inflammatory response is a cascade of cytokines, such that it may begin with the release of TNF-alpha, leading to the production of IL-1 and IL-6. IL-6 has both pro- and anti-inflammatory properties and represents a negative feedback mechanism. Expression of IL-6 in the liver promotes the production of the acute-phase reactant C-reactive protein (CRP). Therefore, activation of the cholinergic receptor to induce acetylcholine release may be an early intervention to short-circuit this inflammatory cascade, a potential therapeutic strategy to blunt inflammatory-mediated disease.

Inverse relationship between HRV and CRP

In a study of 613 airplane factory workers in southern Germany, vagally mediated HRV was inversely related to high-sensitivity CRP in men and premenopausal women, even after controlling for urinary norepinephrine as an index of sympathetic activity.6 Most previous studies in which the relationship between HRV and CRP (or other inflammatory markers) was assessed failed to control for sympathetic nervous system activity. In the total sample and in men, the parasympathetic effect on CRP was comparable with that of smoking; in women, the effect was 4 times larger and comparable with that of high body mass index. A negative association was again found between vagally mediated HRV and white blood cell count.

Inverse relationship between HRV and fibrinogen

In a related report from the same study, vagal modulation of fibrinogen was investigated.7 Fibrinogen is a large glycoprotein that is synthesized by the liver. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis. Meta-analyses have shown a prospective association between elevated plasma fibrinogen levels even in the normal range and an increased risk of coronary artery disease in different populations. We investigated the relationship between nighttime HRV, assessed by root mean square of successive R-R interval differences (RMSSD), and fibrinogen in 559 mostly male workers from southern Germany. Among all workers, there was a mean ± SEM increase of 0.41 ± 0.13 mg/dL fibrinogen for each ms decrease in nighttime RMSSD, even after controlling for established cardiovascular risk factors. The increase in men was 0.28 ± 0.13 mg/dL and, in women, 1.16 ± 0.41 mg/dL for each ms decrease in nighttime RMSSD. Such an autonomic mechanism might contribute to the atherosclerotic process and its thrombotic complications.

Vagal regulation of allostatic systems

Whereas the role of the autonomic nervous system, and the vagus nerve in particular, in the regulation of the cardiovascular system seems clear, the role of the vagus nerve in the regulation of other systems associated with allostasis is less evident. In addition to the regulation of inflammatory markers as discussed thus far, decreased vagal function and HRV have been associated with increased fasting glucose and glycated hemoglobin (HbA1c) levels, and with increased overnight urinary cortisol.8 These factors have been associated with increased allostatic load and poor health. Thus, vagal activity seems to have an inhibitory function in the regulation of allostatic systems. The prefrontal cortex and the amygdala are important central nervous system structures linked to the regulation of these allostatic systems, including inflammation via the vagus nerve. The next section describes evidence for the prefrontal regulation of inflammation.

Prefrontal cortical activity and immune indices

Ohira et al used neuroimaging to explore the association between the brain and immune function.9 Their study examined the neural basis of the top-down modulation accompanying cognitive appraisal during a controllable or uncontrollable acute stressor. HR and blood pressure increased significantly during a mental arithmetic task and returned to baseline soon after termination of the task. HR increased to a greater extent in the controllable versus the uncontrollable condition; blood pressure was unaffected by controllability. Endocrine and immune indices were also affected by the acute stress task: the proportions of natural killer cells increased and helper T cells decreased acutely during the stressor.

Importantly, cerebral blood flow measurements demonstrated that the areas of the prefrontal cortex that we have found to be associated with HRV, including the medial prefrontal cortex and the insula, were also associated with immune indices (medial and lateral orbitofrontal cortices and insula), suggesting prefrontal or frontal modulation of immune responses possibly via the same vagal pathways.

VAGAL ACTIVITY AND CARDIOVASCULAR RISK FACTORS

The regulation of physiologic systems that are important for health and disease has been linked to vagal function and HRV. We have recently reviewed the literature on the relationship between vagal function and the risk for cardiovascular disease and stroke. The National Heart, Lung, and Blood Institute lists eight risk factors for heart disease and stroke.10 Six are considered modifiable. Of the six modifiable factors, three are associated with what could be called biologic factors: high blood pressure (hypertension), diabetes, and abnormal cholesterol; the other three could be considered lifestyle factors: tobacco use (smoking), physical inactivity (exercise), and overweight (obesity). Two factors, age and family history of early heart disease or stroke, are considered nonmodifiable. At least some data suggest that each of these risk factors is associated with decreased vagal function as indexed by HRV.11

Interventions to modify HRV include exercise, ingestion of omega-3 fatty acids, stress reduction (eg, mediation), pharmacologic manipulations, and vagus nerve stimulation, suggesting that methods that increase vagus nerve activity might favorably modify an individual’s risk profile.

CONCLUSION

The brain and the heart are intimately connected. Both epidemiologic and experimental data suggest an association between HRV and inflammation, including similar neural mechanisms. Evidence of an association between HRV and inflammation supports the concept of a cholinergic anti-inflammatory pathway.

References
  1. Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc 1993; 68:988–1001.
  2. Ahern GL, Sollers JJ, Lane RD, et al. Heart rate and heart rate variability changes in the intracarotid sodium amobarbital test. Epilepsia 2001; 42:912–921.
  3. Thayer JF, Sollers JJ, Labiner DM, et al Age-related differences in prefrontal control of heart rate in humans: a pharmacological blockade study [published online ahead of print September 19, 2008] Int J Psychophysioldoi: 10.1016/j.ijpsycho.2008.04.007.
  4. Lane RD, McRae K, Reiman EM, Chen K, Ahern GL, Thayer JF. Neural correlates of heart rate variability during emotion. Neuroimage 2009; 44:213–222.
  5. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853–859.
  6. Thayer JF, Fischer JE Heart rate variability, overnight urinary norepinephrine, and C-reactive protein: evidence for the cholinergic anti-inflammatory pathway in healthy human adults [published online ahead of print November 15, 2008] J Intern Meddoi: 10.1111/j.1365-2796.2008.02023.x.
  7. von Kanel R, Thayer JF, Fischer JE Night-time vagal cardiac control and plasma fibrinogen levels in a population of working men and women Ann Noninvasive Electrocardiol In press
  8. Thayer JF, Sternberg EM. Beyond heart rate variability: vagal regulation of allostatic systems. Ann N Y Acad Sci 2006; 1088:361–372.
  9. Ohira H, Isowa T, Nomura M, et al. Imaging brain and immune association accompanying cognitive appraisal of an acute stressor. Neuroimage 2008; 39:500–514.
  10. Your guide to lowering blood pressure: risk factors. National Heart, Lung, and Blood Institute Web site. http://www.nhlbi.nih.gov/hbp/hbp/hdrf.htm. Accessed January 13, 2009.
  11. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 2007; 74:224–242.
References
  1. Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc 1993; 68:988–1001.
  2. Ahern GL, Sollers JJ, Lane RD, et al. Heart rate and heart rate variability changes in the intracarotid sodium amobarbital test. Epilepsia 2001; 42:912–921.
  3. Thayer JF, Sollers JJ, Labiner DM, et al Age-related differences in prefrontal control of heart rate in humans: a pharmacological blockade study [published online ahead of print September 19, 2008] Int J Psychophysioldoi: 10.1016/j.ijpsycho.2008.04.007.
  4. Lane RD, McRae K, Reiman EM, Chen K, Ahern GL, Thayer JF. Neural correlates of heart rate variability during emotion. Neuroimage 2009; 44:213–222.
  5. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853–859.
  6. Thayer JF, Fischer JE Heart rate variability, overnight urinary norepinephrine, and C-reactive protein: evidence for the cholinergic anti-inflammatory pathway in healthy human adults [published online ahead of print November 15, 2008] J Intern Meddoi: 10.1111/j.1365-2796.2008.02023.x.
  7. von Kanel R, Thayer JF, Fischer JE Night-time vagal cardiac control and plasma fibrinogen levels in a population of working men and women Ann Noninvasive Electrocardiol In press
  8. Thayer JF, Sternberg EM. Beyond heart rate variability: vagal regulation of allostatic systems. Ann N Y Acad Sci 2006; 1088:361–372.
  9. Ohira H, Isowa T, Nomura M, et al. Imaging brain and immune association accompanying cognitive appraisal of an acute stressor. Neuroimage 2008; 39:500–514.
  10. Your guide to lowering blood pressure: risk factors. National Heart, Lung, and Blood Institute Web site. http://www.nhlbi.nih.gov/hbp/hbp/hdrf.htm. Accessed January 13, 2009.
  11. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 2007; 74:224–242.
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