The less familiar side of heart failure: Symptomatic diastolic dysfunction

Heart failure is a growing epidemic in the US, estimated to cause at least 20% of all hospitalizations in persons over 65 years of age. It is also the leading inpatient diagnosis among Medicare recipients with this age group.^1,2,3 More than 5 million people in the US have heart failure, with approximately 550,000 new cases diagnosed annually.

Growing epidemiologic evidence suggests that studies of heart failure have underrepresented a large patient population with a natural history different from that of left ventricular (LV) systolic dysfunction.^4-8One third to one half of patients with signs and symptoms of heart failure have preserved left ventricular function (LVF). They are said to have diastolic heart failure (DHF).

Identifying persons with this less-understood form of heart failure can be challenging. Skillful discernment is needed to avoid mistakenly attributing symptoms to other causes. DHF is particularly common among elderly women with hypertension; every patient with signs and symptoms of heart failure should undergo echocardiography to determine LV function.

Though the evidence base for DHF treatment is less well established than it is for systolic heart failure (SHF), data from recent trials have offered a promising direction.

New categorization of heart failure

The relative scopes of DHF and SHF will be better appreciated by understanding how recently developed guidelines have restructured the historical classification of heart failure.

Heart failure is defined by the American College of Cardiology (ACC) and the American Heart Association (AHA) as a complex syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricles to fill with or eject blood.⁹ The older terms, low-vs high-output failure, are now regarded as obsolete and have been abandoned in favor of distinguishing between abnormalities of systolic and diastolic function.^10-12

ACC/AHA heart failure staging system

Severity of heart failure symptoms has traditionally been gauged by the New York Heart Association (NYHA) classification system. A criticism of the NYHA scale, however, is that patients may fluctuate in and out of the varying functional classes. To correct this shortcoming of the NYHA scale, the ACC and the AHA devised a new staging system to describe the progression of heart failure.⁹ The premise of this new system is to provide permanence to each sequential progression through the stages of heart failure while complementing the existing NYHA scale.^9,13

New model. Patients with Stage A heart failure are at high risk of developing heart failure based on comorbidities and medical history.

Patients with Stage B heart failure have some component of structural heart disease but are asymptomatic.

Patients with Stage C heart failure have underlying structural abnormalities and have symptoms, or have had symptoms of heart failure in the past.

Patients with Stage D heart failure are refractory to conventional medical therapy and have end-stage symptoms.

TABLE 1 shows how the ACC/AHA Heart Failure Staging System correlates with the NYHA Classification scheme. Family practitioners can use the new heart failure staging system to identify and recognize risk factors for the development of heart failure and then seek to aggressively prevent or reverse them.

TABLE 1
Relationship of the ACC/AHA Heart Failure

Who is at risk for DHF?

Risk factors for the development of DHF include advanced age, female sex, hypertension, and coronary ischemia. Approximately 50% of those older than 70 years who have heart failure have preserved LV function.^14-16 In a large epidemiologic study of elderly patients with heart failure, women were twice as likely as men to have preserved LV function.¹⁷ In examining post-myocardial infarction (MI) patients with heart failure, women and those with smaller infarctions were also more likely to have preserved LV function (odds ratio=1.97; 95% confidence interval [CI], 1.27–3.07).¹⁸

Hypertension is a well known cause of left ventricular hypertrophy (LVH), which is a causal mechanism for DHF.^19,20 Levy et al, in a study of 5143 subjects from the original Framingham Heart Study participants and Framingham Offspring participants, found that hypertension predated the development of heart failure in 91% of cases among patients in this cohort.²¹ In this sample, hypertension also carried the greatest population-attributable risk for the development of heart failure of all risk factors considered (39% in men and 59% in women). Hypertension also had the highest prevalence of all risk factors in this study (60% in men and 62% in women). Untreated hypertension leads to an increasing incidence of LVH and associated diastolic dysfunction. Increased LV mass and stiffness cause noncompliance and abnormal relaxation of the ventricular wall leading to increased diastolic pressures.^4,19-21

Coronary ischemia can also cause diastolic dysfunction.²⁰ Data from the Framingham Heart Study indicate that the prevalence of MI was 10% in hypertensive men and 3% in hypertensive women.²¹ MI is a well known precursor of LV systolic dysfunction; however, the relationship to diastolic dysfunction is less clear. Although the prevalence of MI was associated with a 5- to 6-fold risk for heart failure in Framingham subjects, after adjustment for age and other risk factors, fewer than half of the patients who subsequently developed heart failure had a history of MI. This finding supports the role of untreated hypertension in the pathogenesis of DHF.²¹

Physical examination does not help distinguish between DHF and SHF. Signs and symptoms of both disorders are relatively the same.²² Therefore, the presence of one or more of these risk factors in the setting of heart failure and preserved LV function supports the diagnosis of DHF.^14-17TABLE 2 summarizes known clinical characteristics and features of SHF and DHF. All patients with systolic heart failure have some component of diastolic dysfunction as well.^10,12,23,24

TABLE 2
Characteristics of patients with systolic vs diastolic heart failure

Differentiating systolic and diastolic dysfunction
Etiology	Commonly associated with previous MI; exists concurrently with diastolic dysfunction	Pathogenesis is multifocal; associated more often with systemic hypertension, may exist alone without a component of systolic heart failure
Gender-specific differences	Both sexes affected	More common in women
Age-related differences	All ages affected	More common in elderly patients
Echocardiographic findings	Depressed LVEF <40%	Preserved LVEF >40%
Symptomatology	Identical—unable to differentiate with clinical examination	Identical—unable to differentiate with clinical examination
Long-term prognosis	15% annual mortality rate	5 to 8% annual mortality rate
MI, myocardial infarction; LVEF, left ventricular ejection fraction.

Diagnosis is made clinically

No consensus exists on standardized criteria for diagnosing diastolic heart failure. However, 3 diagnostic levels—possible, probable, and definite DHF—have been proposed by Vasan and Levy.¹¹

Possible DHF is defined as signs and symptoms of heart failure (TABLE 3) in patients with normal LV function, but lacking an assessment of ventricular function in proximity to the heart failure event.

Probable DHF is defined as (1) signs and symptoms of heart failure and (2) an ejection fraction >50% measured via echocardiography or radionuclide angio-graphy within 72 hours of the heart failure exacerbation.

Definite DHF is defined as (1) signs and symptoms of heart failure, (2) an ejection fraction >50% measured via the above methods within 72 hours of the patient’s presentation, and (3) increased left-ventricular end diastolic pressure (LVEDP) measured during cardiac catheterization.

TABLE 3
Modified Framingham criteria for diagnosing heart failure

Direct assessment of diastolic function unnecessary

Evidence of diastolic dysfunction as determined by echocardiography or cardiac catheterization has been debated as a necessary third diagnostic criterion.²⁴ The problem, though, is that there is no simple means of reliably diagnosing diastolic dysfunction with echocardiography (E:A ratios, deceleration or relaxation times), and that performing cardiac catheterization to measure LVEDP is impractical.²²

Furthermore, Zile et al have shown that, though cardiac catheterization helps to confirm diastolic dysfunction, it is not necessary to establish the diagnosis. In this study, 63 patients with clinically defined diastolic heart failure based on the Framingham criteria underwent diagnostic cardiac catheterization; 58 (92%) of these patients were also found to have an abnormal LVEDP, indicative of diastolic dysfunction.²⁵ Therefore, the diagnosis of DHF can be made in the setting of heart failure in a patient with a normal ejection fraction.

Order echocardiography within 72 hours of symptom onset

A major challenge for clinicians is to determine whether a patient’s dyspnea is a true symptom of heart failure. Signs and symptoms of heart failure must be defined using clinical indicators such as the Framingham heart failure criteria (FIGURE).²⁶ Diagnosis of heart failure is more easily made for a patient presenting to the emergency department with acute pulmonary edema than it is for an outpatient seen repeatedly for shortness of breath over months.

For a patient presenting with acute pulmonary edema, an echocardiogram should be performed within 72 hours of symptoms to document cardiac function in proximity to the heart failure exacerbation. The ejection fraction of patients with DHF can remain within normal range, even during acute decompensation.^27,28 Stroke volume and cardiac output may be decreased despite a normal ejection fraction.

Cardiogenic pulmonary edema in DHF patients results from the stiffened ventricle’s inability to compensate for increased venous return due to an expansion in central blood volume or sodium retention. Subsequently, diastolic pressures elevate and impede lung compliance, which increases the work of breathing and dyspnea.^20,29 A normal ejection fraction and symptom diminishment following diuresis in the setting of acute decompensation help confirm the diagnosis of DHF, especially when other disease states are complicating the clinical picture.³⁰

Elevated BNP levels may be helpful

An elevated level of b-type natriuretic peptide (BNP) can help confirm the clinical diagnosis of heart failure, and it has been shown in small studies to be a valid marker of DHF.^31,32 In a study of 294 patients referred for echocardiography to evaluate LV function, Lubien et al found that a BNP value of at least 62 pg/mL had a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% for heart failure in patients with a normal ejection fraction.³² All patients with systolic dysfunction defined by an ejection fraction <50% were excluded from this study. These results, though promising, must be confirmed by further studies evaluating the diagnostic utility of BNP to detect active heart failure symptoms in patients with diastolic dysfunction.

Treatment of symptomatic diastolic dysfunction

For SHF patients, multiple large outcome trials have clearly documented the benefit of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and aldosterone antagonists in reducing mortality.^33-36 The relative paucity of outcome data for DHF has resulted in medical therapy primarily centered on modifying physiologic factors to improve LV filling and relaxation. Specifically, treatment should focus on symptom reduction, balancing fluid status, controlling heart rate, decreasing any ischemia, and achieving blood pressure goals.^19,20,22,31 Though many of the medications used to treat SHF are also used for DHF, there are several important differences in appropriate initiation and subsequent titration of these drugs in the 2 settings.^20,31

While treatment of DHF is largely theoretical, a limited number of well-designed, randomized studies are available to help determine appropriate therapy.^37-39TABLE 4 provides a summary of the evidence base for evaluation and treatment of systolic vs diastolic heart failure.⁴⁰TABLE 5 gives a synopsis of these studies. A suggested diagnostic and treatment approach for patients with DHF is outlined in the FIGURE. After determining whether a patient has DHF— primarily through the ruling out of other conditions and confirmation with echocardiographic studies—consider the applicability of each treatment based on a patient’s medical history and present condition.

TABLE 4
Comparative evidence base for evaluation and treatment of systolic vs diastolic heart failure

TABLE 5
Diastolic heart failure outcome trials

Medications to control blood pressure

Hypertension is a major risk factor for DHF, and the ACC/AHA heart failure guidelines recommend a lower blood pressure goal for patients with diastolic heart failure than for those with uncomplicated hypertension (ie, <130/80 mm Hg).⁹ Angiotensin receptor blockers (ARBs), ACE inhibitors, beta-blockers, calcium channel blockers, and diuretics may all be employed to achieve this blood pressure goal.

Angiotensin II receptor blockers. The use of ARBs in the treatment of DHF was recently evaluated in the CHARM-Preserved Study. Candesartan, 32 mg once daily, when added to a background therapy of mostly diuretics and beta-blockers (initially excluding the use of ACE inhibitors but later permitted in appropriate patients following the release of the HOPE trial results), was found to have a modest impact in preventing recurrent admissions for heart failure exacerbations (number needed to treat [NNT]=42 over 3 years).³⁷ Candesartan also demonstrated a more favorable impact on the composite end-point of cardiovascular death, hospitalization for heart failure, MI, and stroke (NNT=36).

ACE inhibitors. For post-MI patients with DHF, ACE inhibitors have improved treadmill duration and NYHA functional class.⁴¹ Further studies are needed to determine whether an ACE inhibitor or an ARB is preferred or whether they may be used safely together in the management of DHF.

Beta-blockers. Propranolol, when added to an ACE inhibitor and diuretic, has been shown to significantly reduce mortality in a small prospective study of 158 post-MI patients with an average LVEF of 56% and NYHA Class II or III symptoms.³⁸ Seventy percent of the study patients were women (n=111) and the mean age was 81 years. The dose of pro-pranolol in this study was increased in 10-mg increments at 10-day intervals up to a total daily dose of 30 mg 3 times daily.

All 79 patients randomized to receive propranolol successfully reached the target dose; however, 14% (n=11) discontinued therapy due to worsening heart failure or hypotension. The absolute reduction in total mortality among patients receiving propranolol was 20%, compared with the study group receiving only standard heart failure therapy (NNT=5 for a median of 32 months of follow-up, P=.007). The positive effect of beta-blocker therapy in this small study merits another larger, complementary trial to confirm its benefits in a bigger patient population with the same characteristics.

Control of volume status

Diuretics. It has long been recognized that diuretics are a useful and necessary adjunct in the management of volume overload in patients with heart failure⁴²; however, no large, long-term studies are available to evaluate the effects of these medications on mortality.⁴³ Without concurrent ACE inhibitor/ARB and beta-blocker therapy, diuretics have been shown to cause rebound sympathetic activation.^44,45

For patients with either systolic or diastolic dysfunction, diuretics may be dosed aggressively to achieve euvolemia. But for patients with DHF who are partly dependent on volume coupled with increased heart rate to maintain cardiac output, excessive diuresis can cause a significant reduction in preload, which can worsen symptoms.^20,22,30 It is advocated that long-term diuretics should be used judiciously in the treatment of both SHF and DHF, with individualized, tailored therapy being preferred and daily weights used as a guide to determine optimum fluid status.⁹

Medications to control heart rate

Beta-blockers. In addition to their anti-hypertensive effects, beta-blockers may also be used as rate-lowering therapy in the treatment of DHF. Dosing and titration in this setting are handled differently than for SHF. Whereas titration of beta-blockers in SHF requires careful adjustment to avoid worsening of the patients’ symptoms and subsequent exacerbation,^46-48 dosing in DHF can be more aggressive, with a resting heart rate goal of 60 to 70 bpm.^20,49 Beta-blockers are used as negative chronotropes in this instance to improve left ventricular filling. Beta-blockers are also useful in the management of ischemia and angina associated with diastolic heart failure.^19,20

Calcium channel blockers. For patients with contraindications to beta-blocker therapy, non-dihydropyridine calcium channel blockers (verapamil, diltiazem) may be employed as rate-lowering therapy for DHF.¹⁹ Unlike the other drugs used in DHF, non-dihydropyridine calcium channel blockers have no role in the treatment of SHF except in the presence of tachyarrhythmias.²⁰

Dihyropyridine calcium channel blockers (ie, amlodipine, felodipine) should be reserved for heart failure patients in general with angina refractory to beta-blockers. Amlodipine and felodipine are probably the safest of the dihydropyridine calcium channel blockers to use for the treatment of angina as they have not been shown to worsen existing SHF.^50,51 Verapamil has been shown in a small study to increase exercise capacity and heart failure score in patients with DHF.⁵²

Digitalis. The use of digoxin in patients with DHF was evaluated in the Digitalis Investigation Group (DIG) ancillary trial, a parallel substudy of the overall DIG Trial that enrolled 988 patients with diastolic dysfunction.³⁹ DHF patients receiving digoxin were found to have fewer symptoms and hospitalizations, although this finding was not statistically significant. These findings should be weighed against recent data suggesting that digoxin predisposes women with depressed left ventricular systolic dysfunction to an increased risk of death.⁵³ The role of digoxin in DHF is unclear, and it is recommended that its use be restricted to patients with recurrent hospitalizations and refractory tachyarrhythmias despite optimized medical therapy.^9,20,30,54

Prognosis

The annual mortality of patients with DHF has been reported as 5% to 8%, whereas mortality associated with SHF approximates 10% to 15%. However, in patients aged >70 years, both SHF and DHF have a 5-year mortality of 50% and both have an estimated 50% annual hospital admission rate.⁵⁸

Looking forward

Greater recognition of the disorder and more enrollment of patients with DHF in outcome-based studies will hopefully improve our understanding and approach to treatment of this specific form of heart failure.^40,55

Ongoing studies that may provide more evidence-based data to guide therapy for DHF include the Irbesartan in Heart Failure with Preserved Systolic Function Trial (I-PRESERVE), Perindopril for Elderly People with Chronic Heart Failure Study (PEP-CHF) and Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS).^56-58

Acknowledgments

The authors wish to thank Thomas Hill and JoAnn Moates for their invaluable research assistance in preparation of this manuscript.

CORRESPONDING AUTHOR
Spencer A. Morris, PharmD, BCPS, Georgetown Hospital System, Georgetown Memorial Hospital, 606 Black River Road, Georgetown, SC 29440. E-mail: [email protected].

Heart failure is a growing epidemic in the US, estimated to cause at least 20% of all hospitalizations in persons over 65 years of age. It is also the leading inpatient diagnosis among Medicare recipients with this age group.^1,2,3 More than 5 million people in the US have heart failure, with approximately 550,000 new cases diagnosed annually.

Growing epidemiologic evidence suggests that studies of heart failure have underrepresented a large patient population with a natural history different from that of left ventricular (LV) systolic dysfunction.^4-8One third to one half of patients with signs and symptoms of heart failure have preserved left ventricular function (LVF). They are said to have diastolic heart failure (DHF).

Identifying persons with this less-understood form of heart failure can be challenging. Skillful discernment is needed to avoid mistakenly attributing symptoms to other causes. DHF is particularly common among elderly women with hypertension; every patient with signs and symptoms of heart failure should undergo echocardiography to determine LV function.

Though the evidence base for DHF treatment is less well established than it is for systolic heart failure (SHF), data from recent trials have offered a promising direction.

New categorization of heart failure

The relative scopes of DHF and SHF will be better appreciated by understanding how recently developed guidelines have restructured the historical classification of heart failure.

Heart failure is defined by the American College of Cardiology (ACC) and the American Heart Association (AHA) as a complex syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricles to fill with or eject blood.⁹ The older terms, low-vs high-output failure, are now regarded as obsolete and have been abandoned in favor of distinguishing between abnormalities of systolic and diastolic function.^10-12

ACC/AHA heart failure staging system

Severity of heart failure symptoms has traditionally been gauged by the New York Heart Association (NYHA) classification system. A criticism of the NYHA scale, however, is that patients may fluctuate in and out of the varying functional classes. To correct this shortcoming of the NYHA scale, the ACC and the AHA devised a new staging system to describe the progression of heart failure.⁹ The premise of this new system is to provide permanence to each sequential progression through the stages of heart failure while complementing the existing NYHA scale.^9,13

New model. Patients with Stage A heart failure are at high risk of developing heart failure based on comorbidities and medical history.

Patients with Stage B heart failure have some component of structural heart disease but are asymptomatic.

Patients with Stage C heart failure have underlying structural abnormalities and have symptoms, or have had symptoms of heart failure in the past.

Patients with Stage D heart failure are refractory to conventional medical therapy and have end-stage symptoms.

TABLE 1 shows how the ACC/AHA Heart Failure Staging System correlates with the NYHA Classification scheme. Family practitioners can use the new heart failure staging system to identify and recognize risk factors for the development of heart failure and then seek to aggressively prevent or reverse them.

TABLE 1
Relationship of the ACC/AHA Heart Failure

Who is at risk for DHF?

Risk factors for the development of DHF include advanced age, female sex, hypertension, and coronary ischemia. Approximately 50% of those older than 70 years who have heart failure have preserved LV function.^14-16 In a large epidemiologic study of elderly patients with heart failure, women were twice as likely as men to have preserved LV function.¹⁷ In examining post-myocardial infarction (MI) patients with heart failure, women and those with smaller infarctions were also more likely to have preserved LV function (odds ratio=1.97; 95% confidence interval [CI], 1.27–3.07).¹⁸

Hypertension is a well known cause of left ventricular hypertrophy (LVH), which is a causal mechanism for DHF.^19,20 Levy et al, in a study of 5143 subjects from the original Framingham Heart Study participants and Framingham Offspring participants, found that hypertension predated the development of heart failure in 91% of cases among patients in this cohort.²¹ In this sample, hypertension also carried the greatest population-attributable risk for the development of heart failure of all risk factors considered (39% in men and 59% in women). Hypertension also had the highest prevalence of all risk factors in this study (60% in men and 62% in women). Untreated hypertension leads to an increasing incidence of LVH and associated diastolic dysfunction. Increased LV mass and stiffness cause noncompliance and abnormal relaxation of the ventricular wall leading to increased diastolic pressures.^4,19-21

Coronary ischemia can also cause diastolic dysfunction.²⁰ Data from the Framingham Heart Study indicate that the prevalence of MI was 10% in hypertensive men and 3% in hypertensive women.²¹ MI is a well known precursor of LV systolic dysfunction; however, the relationship to diastolic dysfunction is less clear. Although the prevalence of MI was associated with a 5- to 6-fold risk for heart failure in Framingham subjects, after adjustment for age and other risk factors, fewer than half of the patients who subsequently developed heart failure had a history of MI. This finding supports the role of untreated hypertension in the pathogenesis of DHF.²¹

Physical examination does not help distinguish between DHF and SHF. Signs and symptoms of both disorders are relatively the same.²² Therefore, the presence of one or more of these risk factors in the setting of heart failure and preserved LV function supports the diagnosis of DHF.^14-17TABLE 2 summarizes known clinical characteristics and features of SHF and DHF. All patients with systolic heart failure have some component of diastolic dysfunction as well.^10,12,23,24

TABLE 2
Characteristics of patients with systolic vs diastolic heart failure

Differentiating systolic and diastolic dysfunction
Etiology	Commonly associated with previous MI; exists concurrently with diastolic dysfunction	Pathogenesis is multifocal; associated more often with systemic hypertension, may exist alone without a component of systolic heart failure
Gender-specific differences	Both sexes affected	More common in women
Age-related differences	All ages affected	More common in elderly patients
Echocardiographic findings	Depressed LVEF <40%	Preserved LVEF >40%
Symptomatology	Identical—unable to differentiate with clinical examination	Identical—unable to differentiate with clinical examination
Long-term prognosis	15% annual mortality rate	5 to 8% annual mortality rate
MI, myocardial infarction; LVEF, left ventricular ejection fraction.

Diagnosis is made clinically

No consensus exists on standardized criteria for diagnosing diastolic heart failure. However, 3 diagnostic levels—possible, probable, and definite DHF—have been proposed by Vasan and Levy.¹¹

Possible DHF is defined as signs and symptoms of heart failure (TABLE 3) in patients with normal LV function, but lacking an assessment of ventricular function in proximity to the heart failure event.

Probable DHF is defined as (1) signs and symptoms of heart failure and (2) an ejection fraction >50% measured via echocardiography or radionuclide angio-graphy within 72 hours of the heart failure exacerbation.

Definite DHF is defined as (1) signs and symptoms of heart failure, (2) an ejection fraction >50% measured via the above methods within 72 hours of the patient’s presentation, and (3) increased left-ventricular end diastolic pressure (LVEDP) measured during cardiac catheterization.

TABLE 3
Modified Framingham criteria for diagnosing heart failure

Direct assessment of diastolic function unnecessary

Evidence of diastolic dysfunction as determined by echocardiography or cardiac catheterization has been debated as a necessary third diagnostic criterion.²⁴ The problem, though, is that there is no simple means of reliably diagnosing diastolic dysfunction with echocardiography (E:A ratios, deceleration or relaxation times), and that performing cardiac catheterization to measure LVEDP is impractical.²²

Furthermore, Zile et al have shown that, though cardiac catheterization helps to confirm diastolic dysfunction, it is not necessary to establish the diagnosis. In this study, 63 patients with clinically defined diastolic heart failure based on the Framingham criteria underwent diagnostic cardiac catheterization; 58 (92%) of these patients were also found to have an abnormal LVEDP, indicative of diastolic dysfunction.²⁵ Therefore, the diagnosis of DHF can be made in the setting of heart failure in a patient with a normal ejection fraction.

Order echocardiography within 72 hours of symptom onset

A major challenge for clinicians is to determine whether a patient’s dyspnea is a true symptom of heart failure. Signs and symptoms of heart failure must be defined using clinical indicators such as the Framingham heart failure criteria (FIGURE).²⁶ Diagnosis of heart failure is more easily made for a patient presenting to the emergency department with acute pulmonary edema than it is for an outpatient seen repeatedly for shortness of breath over months.

For a patient presenting with acute pulmonary edema, an echocardiogram should be performed within 72 hours of symptoms to document cardiac function in proximity to the heart failure exacerbation. The ejection fraction of patients with DHF can remain within normal range, even during acute decompensation.^27,28 Stroke volume and cardiac output may be decreased despite a normal ejection fraction.

Cardiogenic pulmonary edema in DHF patients results from the stiffened ventricle’s inability to compensate for increased venous return due to an expansion in central blood volume or sodium retention. Subsequently, diastolic pressures elevate and impede lung compliance, which increases the work of breathing and dyspnea.^20,29 A normal ejection fraction and symptom diminishment following diuresis in the setting of acute decompensation help confirm the diagnosis of DHF, especially when other disease states are complicating the clinical picture.³⁰

Elevated BNP levels may be helpful

An elevated level of b-type natriuretic peptide (BNP) can help confirm the clinical diagnosis of heart failure, and it has been shown in small studies to be a valid marker of DHF.^31,32 In a study of 294 patients referred for echocardiography to evaluate LV function, Lubien et al found that a BNP value of at least 62 pg/mL had a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% for heart failure in patients with a normal ejection fraction.³² All patients with systolic dysfunction defined by an ejection fraction <50% were excluded from this study. These results, though promising, must be confirmed by further studies evaluating the diagnostic utility of BNP to detect active heart failure symptoms in patients with diastolic dysfunction.

Treatment of symptomatic diastolic dysfunction

For SHF patients, multiple large outcome trials have clearly documented the benefit of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and aldosterone antagonists in reducing mortality.^33-36 The relative paucity of outcome data for DHF has resulted in medical therapy primarily centered on modifying physiologic factors to improve LV filling and relaxation. Specifically, treatment should focus on symptom reduction, balancing fluid status, controlling heart rate, decreasing any ischemia, and achieving blood pressure goals.^19,20,22,31 Though many of the medications used to treat SHF are also used for DHF, there are several important differences in appropriate initiation and subsequent titration of these drugs in the 2 settings.^20,31

While treatment of DHF is largely theoretical, a limited number of well-designed, randomized studies are available to help determine appropriate therapy.^37-39TABLE 4 provides a summary of the evidence base for evaluation and treatment of systolic vs diastolic heart failure.⁴⁰TABLE 5 gives a synopsis of these studies. A suggested diagnostic and treatment approach for patients with DHF is outlined in the FIGURE. After determining whether a patient has DHF— primarily through the ruling out of other conditions and confirmation with echocardiographic studies—consider the applicability of each treatment based on a patient’s medical history and present condition.

TABLE 4
Comparative evidence base for evaluation and treatment of systolic vs diastolic heart failure

TABLE 5
Diastolic heart failure outcome trials

Medications to control blood pressure

Hypertension is a major risk factor for DHF, and the ACC/AHA heart failure guidelines recommend a lower blood pressure goal for patients with diastolic heart failure than for those with uncomplicated hypertension (ie, <130/80 mm Hg).⁹ Angiotensin receptor blockers (ARBs), ACE inhibitors, beta-blockers, calcium channel blockers, and diuretics may all be employed to achieve this blood pressure goal.

Angiotensin II receptor blockers. The use of ARBs in the treatment of DHF was recently evaluated in the CHARM-Preserved Study. Candesartan, 32 mg once daily, when added to a background therapy of mostly diuretics and beta-blockers (initially excluding the use of ACE inhibitors but later permitted in appropriate patients following the release of the HOPE trial results), was found to have a modest impact in preventing recurrent admissions for heart failure exacerbations (number needed to treat [NNT]=42 over 3 years).³⁷ Candesartan also demonstrated a more favorable impact on the composite end-point of cardiovascular death, hospitalization for heart failure, MI, and stroke (NNT=36).

ACE inhibitors. For post-MI patients with DHF, ACE inhibitors have improved treadmill duration and NYHA functional class.⁴¹ Further studies are needed to determine whether an ACE inhibitor or an ARB is preferred or whether they may be used safely together in the management of DHF.

Beta-blockers. Propranolol, when added to an ACE inhibitor and diuretic, has been shown to significantly reduce mortality in a small prospective study of 158 post-MI patients with an average LVEF of 56% and NYHA Class II or III symptoms.³⁸ Seventy percent of the study patients were women (n=111) and the mean age was 81 years. The dose of pro-pranolol in this study was increased in 10-mg increments at 10-day intervals up to a total daily dose of 30 mg 3 times daily.

All 79 patients randomized to receive propranolol successfully reached the target dose; however, 14% (n=11) discontinued therapy due to worsening heart failure or hypotension. The absolute reduction in total mortality among patients receiving propranolol was 20%, compared with the study group receiving only standard heart failure therapy (NNT=5 for a median of 32 months of follow-up, P=.007). The positive effect of beta-blocker therapy in this small study merits another larger, complementary trial to confirm its benefits in a bigger patient population with the same characteristics.

Control of volume status

Diuretics. It has long been recognized that diuretics are a useful and necessary adjunct in the management of volume overload in patients with heart failure⁴²; however, no large, long-term studies are available to evaluate the effects of these medications on mortality.⁴³ Without concurrent ACE inhibitor/ARB and beta-blocker therapy, diuretics have been shown to cause rebound sympathetic activation.^44,45

For patients with either systolic or diastolic dysfunction, diuretics may be dosed aggressively to achieve euvolemia. But for patients with DHF who are partly dependent on volume coupled with increased heart rate to maintain cardiac output, excessive diuresis can cause a significant reduction in preload, which can worsen symptoms.^20,22,30 It is advocated that long-term diuretics should be used judiciously in the treatment of both SHF and DHF, with individualized, tailored therapy being preferred and daily weights used as a guide to determine optimum fluid status.⁹

Medications to control heart rate

Beta-blockers. In addition to their anti-hypertensive effects, beta-blockers may also be used as rate-lowering therapy in the treatment of DHF. Dosing and titration in this setting are handled differently than for SHF. Whereas titration of beta-blockers in SHF requires careful adjustment to avoid worsening of the patients’ symptoms and subsequent exacerbation,^46-48 dosing in DHF can be more aggressive, with a resting heart rate goal of 60 to 70 bpm.^20,49 Beta-blockers are used as negative chronotropes in this instance to improve left ventricular filling. Beta-blockers are also useful in the management of ischemia and angina associated with diastolic heart failure.^19,20

Calcium channel blockers. For patients with contraindications to beta-blocker therapy, non-dihydropyridine calcium channel blockers (verapamil, diltiazem) may be employed as rate-lowering therapy for DHF.¹⁹ Unlike the other drugs used in DHF, non-dihydropyridine calcium channel blockers have no role in the treatment of SHF except in the presence of tachyarrhythmias.²⁰

Dihyropyridine calcium channel blockers (ie, amlodipine, felodipine) should be reserved for heart failure patients in general with angina refractory to beta-blockers. Amlodipine and felodipine are probably the safest of the dihydropyridine calcium channel blockers to use for the treatment of angina as they have not been shown to worsen existing SHF.^50,51 Verapamil has been shown in a small study to increase exercise capacity and heart failure score in patients with DHF.⁵²

Digitalis. The use of digoxin in patients with DHF was evaluated in the Digitalis Investigation Group (DIG) ancillary trial, a parallel substudy of the overall DIG Trial that enrolled 988 patients with diastolic dysfunction.³⁹ DHF patients receiving digoxin were found to have fewer symptoms and hospitalizations, although this finding was not statistically significant. These findings should be weighed against recent data suggesting that digoxin predisposes women with depressed left ventricular systolic dysfunction to an increased risk of death.⁵³ The role of digoxin in DHF is unclear, and it is recommended that its use be restricted to patients with recurrent hospitalizations and refractory tachyarrhythmias despite optimized medical therapy.^9,20,30,54

Prognosis

The annual mortality of patients with DHF has been reported as 5% to 8%, whereas mortality associated with SHF approximates 10% to 15%. However, in patients aged >70 years, both SHF and DHF have a 5-year mortality of 50% and both have an estimated 50% annual hospital admission rate.⁵⁸

Looking forward

Greater recognition of the disorder and more enrollment of patients with DHF in outcome-based studies will hopefully improve our understanding and approach to treatment of this specific form of heart failure.^40,55

Ongoing studies that may provide more evidence-based data to guide therapy for DHF include the Irbesartan in Heart Failure with Preserved Systolic Function Trial (I-PRESERVE), Perindopril for Elderly People with Chronic Heart Failure Study (PEP-CHF) and Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS).^56-58

Acknowledgments

The authors wish to thank Thomas Hill and JoAnn Moates for their invaluable research assistance in preparation of this manuscript.

CORRESPONDING AUTHOR
Spencer A. Morris, PharmD, BCPS, Georgetown Hospital System, Georgetown Memorial Hospital, 606 Black River Road, Georgetown, SC 29440. E-mail: [email protected].

Heart failure is a growing epidemic in the US, estimated to cause at least 20% of all hospitalizations in persons over 65 years of age. It is also the leading inpatient diagnosis among Medicare recipients with this age group.^1,2,3 More than 5 million people in the US have heart failure, with approximately 550,000 new cases diagnosed annually.

Growing epidemiologic evidence suggests that studies of heart failure have underrepresented a large patient population with a natural history different from that of left ventricular (LV) systolic dysfunction.^4-8One third to one half of patients with signs and symptoms of heart failure have preserved left ventricular function (LVF). They are said to have diastolic heart failure (DHF).

Identifying persons with this less-understood form of heart failure can be challenging. Skillful discernment is needed to avoid mistakenly attributing symptoms to other causes. DHF is particularly common among elderly women with hypertension; every patient with signs and symptoms of heart failure should undergo echocardiography to determine LV function.

Though the evidence base for DHF treatment is less well established than it is for systolic heart failure (SHF), data from recent trials have offered a promising direction.

New categorization of heart failure

The relative scopes of DHF and SHF will be better appreciated by understanding how recently developed guidelines have restructured the historical classification of heart failure.

Heart failure is defined by the American College of Cardiology (ACC) and the American Heart Association (AHA) as a complex syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricles to fill with or eject blood.⁹ The older terms, low-vs high-output failure, are now regarded as obsolete and have been abandoned in favor of distinguishing between abnormalities of systolic and diastolic function.^10-12

ACC/AHA heart failure staging system

Severity of heart failure symptoms has traditionally been gauged by the New York Heart Association (NYHA) classification system. A criticism of the NYHA scale, however, is that patients may fluctuate in and out of the varying functional classes. To correct this shortcoming of the NYHA scale, the ACC and the AHA devised a new staging system to describe the progression of heart failure.⁹ The premise of this new system is to provide permanence to each sequential progression through the stages of heart failure while complementing the existing NYHA scale.^9,13

New model. Patients with Stage A heart failure are at high risk of developing heart failure based on comorbidities and medical history.

Patients with Stage B heart failure have some component of structural heart disease but are asymptomatic.

Patients with Stage C heart failure have underlying structural abnormalities and have symptoms, or have had symptoms of heart failure in the past.

Patients with Stage D heart failure are refractory to conventional medical therapy and have end-stage symptoms.

TABLE 1 shows how the ACC/AHA Heart Failure Staging System correlates with the NYHA Classification scheme. Family practitioners can use the new heart failure staging system to identify and recognize risk factors for the development of heart failure and then seek to aggressively prevent or reverse them.

TABLE 1
Relationship of the ACC/AHA Heart Failure

Who is at risk for DHF?

Risk factors for the development of DHF include advanced age, female sex, hypertension, and coronary ischemia. Approximately 50% of those older than 70 years who have heart failure have preserved LV function.^14-16 In a large epidemiologic study of elderly patients with heart failure, women were twice as likely as men to have preserved LV function.¹⁷ In examining post-myocardial infarction (MI) patients with heart failure, women and those with smaller infarctions were also more likely to have preserved LV function (odds ratio=1.97; 95% confidence interval [CI], 1.27–3.07).¹⁸

Hypertension is a well known cause of left ventricular hypertrophy (LVH), which is a causal mechanism for DHF.^19,20 Levy et al, in a study of 5143 subjects from the original Framingham Heart Study participants and Framingham Offspring participants, found that hypertension predated the development of heart failure in 91% of cases among patients in this cohort.²¹ In this sample, hypertension also carried the greatest population-attributable risk for the development of heart failure of all risk factors considered (39% in men and 59% in women). Hypertension also had the highest prevalence of all risk factors in this study (60% in men and 62% in women). Untreated hypertension leads to an increasing incidence of LVH and associated diastolic dysfunction. Increased LV mass and stiffness cause noncompliance and abnormal relaxation of the ventricular wall leading to increased diastolic pressures.^4,19-21

Coronary ischemia can also cause diastolic dysfunction.²⁰ Data from the Framingham Heart Study indicate that the prevalence of MI was 10% in hypertensive men and 3% in hypertensive women.²¹ MI is a well known precursor of LV systolic dysfunction; however, the relationship to diastolic dysfunction is less clear. Although the prevalence of MI was associated with a 5- to 6-fold risk for heart failure in Framingham subjects, after adjustment for age and other risk factors, fewer than half of the patients who subsequently developed heart failure had a history of MI. This finding supports the role of untreated hypertension in the pathogenesis of DHF.²¹

Physical examination does not help distinguish between DHF and SHF. Signs and symptoms of both disorders are relatively the same.²² Therefore, the presence of one or more of these risk factors in the setting of heart failure and preserved LV function supports the diagnosis of DHF.^14-17TABLE 2 summarizes known clinical characteristics and features of SHF and DHF. All patients with systolic heart failure have some component of diastolic dysfunction as well.^10,12,23,24

TABLE 2
Characteristics of patients with systolic vs diastolic heart failure

Differentiating systolic and diastolic dysfunction
Etiology	Commonly associated with previous MI; exists concurrently with diastolic dysfunction	Pathogenesis is multifocal; associated more often with systemic hypertension, may exist alone without a component of systolic heart failure
Gender-specific differences	Both sexes affected	More common in women
Age-related differences	All ages affected	More common in elderly patients
Echocardiographic findings	Depressed LVEF <40%	Preserved LVEF >40%
Symptomatology	Identical—unable to differentiate with clinical examination	Identical—unable to differentiate with clinical examination
Long-term prognosis	15% annual mortality rate	5 to 8% annual mortality rate
MI, myocardial infarction; LVEF, left ventricular ejection fraction.

Diagnosis is made clinically

No consensus exists on standardized criteria for diagnosing diastolic heart failure. However, 3 diagnostic levels—possible, probable, and definite DHF—have been proposed by Vasan and Levy.¹¹

Possible DHF is defined as signs and symptoms of heart failure (TABLE 3) in patients with normal LV function, but lacking an assessment of ventricular function in proximity to the heart failure event.

Probable DHF is defined as (1) signs and symptoms of heart failure and (2) an ejection fraction >50% measured via echocardiography or radionuclide angio-graphy within 72 hours of the heart failure exacerbation.

Definite DHF is defined as (1) signs and symptoms of heart failure, (2) an ejection fraction >50% measured via the above methods within 72 hours of the patient’s presentation, and (3) increased left-ventricular end diastolic pressure (LVEDP) measured during cardiac catheterization.

TABLE 3
Modified Framingham criteria for diagnosing heart failure

Direct assessment of diastolic function unnecessary

Evidence of diastolic dysfunction as determined by echocardiography or cardiac catheterization has been debated as a necessary third diagnostic criterion.²⁴ The problem, though, is that there is no simple means of reliably diagnosing diastolic dysfunction with echocardiography (E:A ratios, deceleration or relaxation times), and that performing cardiac catheterization to measure LVEDP is impractical.²²

Furthermore, Zile et al have shown that, though cardiac catheterization helps to confirm diastolic dysfunction, it is not necessary to establish the diagnosis. In this study, 63 patients with clinically defined diastolic heart failure based on the Framingham criteria underwent diagnostic cardiac catheterization; 58 (92%) of these patients were also found to have an abnormal LVEDP, indicative of diastolic dysfunction.²⁵ Therefore, the diagnosis of DHF can be made in the setting of heart failure in a patient with a normal ejection fraction.

Order echocardiography within 72 hours of symptom onset

A major challenge for clinicians is to determine whether a patient’s dyspnea is a true symptom of heart failure. Signs and symptoms of heart failure must be defined using clinical indicators such as the Framingham heart failure criteria (FIGURE).²⁶ Diagnosis of heart failure is more easily made for a patient presenting to the emergency department with acute pulmonary edema than it is for an outpatient seen repeatedly for shortness of breath over months.

For a patient presenting with acute pulmonary edema, an echocardiogram should be performed within 72 hours of symptoms to document cardiac function in proximity to the heart failure exacerbation. The ejection fraction of patients with DHF can remain within normal range, even during acute decompensation.^27,28 Stroke volume and cardiac output may be decreased despite a normal ejection fraction.

Cardiogenic pulmonary edema in DHF patients results from the stiffened ventricle’s inability to compensate for increased venous return due to an expansion in central blood volume or sodium retention. Subsequently, diastolic pressures elevate and impede lung compliance, which increases the work of breathing and dyspnea.^20,29 A normal ejection fraction and symptom diminishment following diuresis in the setting of acute decompensation help confirm the diagnosis of DHF, especially when other disease states are complicating the clinical picture.³⁰

Elevated BNP levels may be helpful

An elevated level of b-type natriuretic peptide (BNP) can help confirm the clinical diagnosis of heart failure, and it has been shown in small studies to be a valid marker of DHF.^31,32 In a study of 294 patients referred for echocardiography to evaluate LV function, Lubien et al found that a BNP value of at least 62 pg/mL had a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% for heart failure in patients with a normal ejection fraction.³² All patients with systolic dysfunction defined by an ejection fraction <50% were excluded from this study. These results, though promising, must be confirmed by further studies evaluating the diagnostic utility of BNP to detect active heart failure symptoms in patients with diastolic dysfunction.

Treatment of symptomatic diastolic dysfunction

For SHF patients, multiple large outcome trials have clearly documented the benefit of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and aldosterone antagonists in reducing mortality.^33-36 The relative paucity of outcome data for DHF has resulted in medical therapy primarily centered on modifying physiologic factors to improve LV filling and relaxation. Specifically, treatment should focus on symptom reduction, balancing fluid status, controlling heart rate, decreasing any ischemia, and achieving blood pressure goals.^19,20,22,31 Though many of the medications used to treat SHF are also used for DHF, there are several important differences in appropriate initiation and subsequent titration of these drugs in the 2 settings.^20,31

While treatment of DHF is largely theoretical, a limited number of well-designed, randomized studies are available to help determine appropriate therapy.^37-39TABLE 4 provides a summary of the evidence base for evaluation and treatment of systolic vs diastolic heart failure.⁴⁰TABLE 5 gives a synopsis of these studies. A suggested diagnostic and treatment approach for patients with DHF is outlined in the FIGURE. After determining whether a patient has DHF— primarily through the ruling out of other conditions and confirmation with echocardiographic studies—consider the applicability of each treatment based on a patient’s medical history and present condition.

TABLE 4
Comparative evidence base for evaluation and treatment of systolic vs diastolic heart failure

TABLE 5
Diastolic heart failure outcome trials

Medications to control blood pressure

Hypertension is a major risk factor for DHF, and the ACC/AHA heart failure guidelines recommend a lower blood pressure goal for patients with diastolic heart failure than for those with uncomplicated hypertension (ie, <130/80 mm Hg).⁹ Angiotensin receptor blockers (ARBs), ACE inhibitors, beta-blockers, calcium channel blockers, and diuretics may all be employed to achieve this blood pressure goal.

Angiotensin II receptor blockers. The use of ARBs in the treatment of DHF was recently evaluated in the CHARM-Preserved Study. Candesartan, 32 mg once daily, when added to a background therapy of mostly diuretics and beta-blockers (initially excluding the use of ACE inhibitors but later permitted in appropriate patients following the release of the HOPE trial results), was found to have a modest impact in preventing recurrent admissions for heart failure exacerbations (number needed to treat [NNT]=42 over 3 years).³⁷ Candesartan also demonstrated a more favorable impact on the composite end-point of cardiovascular death, hospitalization for heart failure, MI, and stroke (NNT=36).

ACE inhibitors. For post-MI patients with DHF, ACE inhibitors have improved treadmill duration and NYHA functional class.⁴¹ Further studies are needed to determine whether an ACE inhibitor or an ARB is preferred or whether they may be used safely together in the management of DHF.

Beta-blockers. Propranolol, when added to an ACE inhibitor and diuretic, has been shown to significantly reduce mortality in a small prospective study of 158 post-MI patients with an average LVEF of 56% and NYHA Class II or III symptoms.³⁸ Seventy percent of the study patients were women (n=111) and the mean age was 81 years. The dose of pro-pranolol in this study was increased in 10-mg increments at 10-day intervals up to a total daily dose of 30 mg 3 times daily.

All 79 patients randomized to receive propranolol successfully reached the target dose; however, 14% (n=11) discontinued therapy due to worsening heart failure or hypotension. The absolute reduction in total mortality among patients receiving propranolol was 20%, compared with the study group receiving only standard heart failure therapy (NNT=5 for a median of 32 months of follow-up, P=.007). The positive effect of beta-blocker therapy in this small study merits another larger, complementary trial to confirm its benefits in a bigger patient population with the same characteristics.

Control of volume status

Diuretics. It has long been recognized that diuretics are a useful and necessary adjunct in the management of volume overload in patients with heart failure⁴²; however, no large, long-term studies are available to evaluate the effects of these medications on mortality.⁴³ Without concurrent ACE inhibitor/ARB and beta-blocker therapy, diuretics have been shown to cause rebound sympathetic activation.^44,45

For patients with either systolic or diastolic dysfunction, diuretics may be dosed aggressively to achieve euvolemia. But for patients with DHF who are partly dependent on volume coupled with increased heart rate to maintain cardiac output, excessive diuresis can cause a significant reduction in preload, which can worsen symptoms.^20,22,30 It is advocated that long-term diuretics should be used judiciously in the treatment of both SHF and DHF, with individualized, tailored therapy being preferred and daily weights used as a guide to determine optimum fluid status.⁹

Medications to control heart rate

Beta-blockers. In addition to their anti-hypertensive effects, beta-blockers may also be used as rate-lowering therapy in the treatment of DHF. Dosing and titration in this setting are handled differently than for SHF. Whereas titration of beta-blockers in SHF requires careful adjustment to avoid worsening of the patients’ symptoms and subsequent exacerbation,^46-48 dosing in DHF can be more aggressive, with a resting heart rate goal of 60 to 70 bpm.^20,49 Beta-blockers are used as negative chronotropes in this instance to improve left ventricular filling. Beta-blockers are also useful in the management of ischemia and angina associated with diastolic heart failure.^19,20

Calcium channel blockers. For patients with contraindications to beta-blocker therapy, non-dihydropyridine calcium channel blockers (verapamil, diltiazem) may be employed as rate-lowering therapy for DHF.¹⁹ Unlike the other drugs used in DHF, non-dihydropyridine calcium channel blockers have no role in the treatment of SHF except in the presence of tachyarrhythmias.²⁰

Dihyropyridine calcium channel blockers (ie, amlodipine, felodipine) should be reserved for heart failure patients in general with angina refractory to beta-blockers. Amlodipine and felodipine are probably the safest of the dihydropyridine calcium channel blockers to use for the treatment of angina as they have not been shown to worsen existing SHF.^50,51 Verapamil has been shown in a small study to increase exercise capacity and heart failure score in patients with DHF.⁵²

Digitalis. The use of digoxin in patients with DHF was evaluated in the Digitalis Investigation Group (DIG) ancillary trial, a parallel substudy of the overall DIG Trial that enrolled 988 patients with diastolic dysfunction.³⁹ DHF patients receiving digoxin were found to have fewer symptoms and hospitalizations, although this finding was not statistically significant. These findings should be weighed against recent data suggesting that digoxin predisposes women with depressed left ventricular systolic dysfunction to an increased risk of death.⁵³ The role of digoxin in DHF is unclear, and it is recommended that its use be restricted to patients with recurrent hospitalizations and refractory tachyarrhythmias despite optimized medical therapy.^9,20,30,54

Prognosis

The annual mortality of patients with DHF has been reported as 5% to 8%, whereas mortality associated with SHF approximates 10% to 15%. However, in patients aged >70 years, both SHF and DHF have a 5-year mortality of 50% and both have an estimated 50% annual hospital admission rate.⁵⁸

Looking forward

Greater recognition of the disorder and more enrollment of patients with DHF in outcome-based studies will hopefully improve our understanding and approach to treatment of this specific form of heart failure.^40,55

Ongoing studies that may provide more evidence-based data to guide therapy for DHF include the Irbesartan in Heart Failure with Preserved Systolic Function Trial (I-PRESERVE), Perindopril for Elderly People with Chronic Heart Failure Study (PEP-CHF) and Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS).^56-58

Acknowledgments

The authors wish to thank Thomas Hill and JoAnn Moates for their invaluable research assistance in preparation of this manuscript.

CORRESPONDING AUTHOR
Spencer A. Morris, PharmD, BCPS, Georgetown Hospital System, Georgetown Memorial Hospital, 606 Black River Road, Georgetown, SC 29440. E-mail: [email protected].