Clinical Review

We, and our patients, are fortunate to have a robust armamentarium of osteoporosis preventives and treatments in the 21st century. Still, we have much to learn about the preservation and restoration of bone. Fine-tuning of individual therapies, and clarification of their attendant risks, are ongoing concerns.

In this article, I highlight several recent studies:

• an assessment of the periodontium in a group of postmenopausal women who were long-term users of bisphosphonates, versus nonusers, to determine the effects of these agents on periodontal health
• guidance from the American Society for Bone and Mineral Research on the risk of atypical femoral fracture in long-term users of bisphosphonates
• 2-year data on a new, delayed-release, weekly formulation of risedronate that can be taken with food
• two meta-analyses exploring the risk of fracture with use of a proton-pump inhibitor (PPI), as well as a recent summary of evidence
• a randomized trial of 2% nitroglycerin ointment to prevent fracture.

Bisphosphonates may reduce the risk of postmenopausal periodontal disease

Palomo L, Buencamino-Francisco MC, Carey JJ, Sivanandy M, Thacker H. Is long-term bisphosphonate therapy associated with benefits to the periodontium in postmenopausal women? Menopause. 2011;18(2):164–170.

The risk of periodontal disease increases in menopause. Inflammation can erode structures (i.e., periodontal ligament and alveolar bone) that attach the teeth into the jaw, leading, eventually, to loss of teeth (FIGURE).

Anatomy of healthy periodontium
In periodontal disease, inflammation can erode structures, such as the periodontal ligament and alveolar bone, that attach the teeth into the jaw.In periodontal inflammation, a bacterial biofilm on tooth surfaces triggers a response by neutrophils and macrophages. In this respect, osteoporosis and periodontitis are mediated by common cytokines. Local production of cytokines seems to enhance osteoclast-mediated loss of skeletal and alveolar bone in estrogen-deficient women. In addition, generalized bone loss in postmenopausal osteoporosis renders the jaw susceptible to accelerated alveolar bone resorption and loss of periodontal attachment. For these reasons, physicians who care for postmenopausal women are advised to monitor their periodontal health; be vigilant for dental problems; and encourage them to practice good oral hygiene as a preventive measure against periodontitis and to seek regular dental care.

There has been tremendous publicity about the rare but very serious occurrence of osteonecrosis of the jaw in women who use bisphosphonates. In contrast, this study by Palomo and colleagues from the Case Western Reserve School of Dental Medicine seems to offer some preliminary good news about bisphosphonates and dental health: Long-term use appears to have some beneficial effects on the periodontium of postmenopausal women.

Details of the study

The aim of the study was to compare the periodontium in two groups of postmenopausal women known to have low bone mineral density (BMD): those who were long-term users (>2 years) of bisphosphonate therapy (n=28) and those who were not (n=28). The average age of participants in the study was 63 years, and the average T-score was –2.5. All women underwent cone-beam computed tomography of the jaw and a complete periodontal examination to determine the plaque score, periodontal probing depth, clinical attachment loss, bleeding on probing, and alveolar bone height.

Findings: Bisphosphonate users had a higher plaque score, a lower probing depth, and less loss of clinical attachment than did women in the control group. These differences were determined to be statistically significant. Bisphosphonate users also had less bleeding on probing and a higher alveolar bone height, but these differences were not significant. After adjustment for the plaque score, bisphosphonate use was a significant factor for probing depth but not for the other parameters.

Atypical femoral fracture is a real risk—but a rarity—with long-term use of antiresorptive drugs

Shane E, Burr D, Ebeling PR, et al; American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25(11):2267–2294.

As ObGyns, we are often the first-line providers of diagnostic services and treatment for postmenopausal women at risk of osteoporotic fracture. Oral and, more recently, parenteral bisphosphonates have been a mainstay of such treatment. Isolated reports of atypical femoral fracture in long-term users of bisphosphonates first surfaced around 2005.¹ Since then, several case series have appeared, some with as many as 102 cases.² In fact, atypical femoral fracture in bisphosphonate users has drawn so much attention that patients have begun to ask about these agents and express reservations about using them.

The issue has drawn the focus of the American Society for Bone and Mineral Research (ASBMR), which appointed a task force to address it. A multidisciplinary expert group reviewed pertinent published reports of atypical femoral fracture, as well as preclinical studies, that could provide insight into its pathogenesis.

What we know about this type of fracture

Preclinical data lend biologic plausibility to a potential association between long-term bisphosphonate use and atypical femoral fracture. These data highlight the effects of bisphosphonates on:

• collagen cross-linking and maturation
• accumulation of microdamage and advanced glycation end products
• heightened mineralization, remodeling, vascularity, and angiogenesis.

The task force concluded that bisphosphonates are highly effective at reducing the risk of spinal and nonspinal fractures, including typical and common femoral neck and intertrochanteric fractures. However, there is evidence of a relationship between long-term bisphosphonate use and a specific type of subtrochanteric and femoral shaft fracture. This type of fracture is characterized by unique radiographic features:

• transverse or short oblique orientation
• absence of comminution
• cortical thickening
• stress fracture or stress reaction on the symptomatic and/or contralateral side
• delayed healing.

This type of fracture also has unique clinical features—namely, prodromal pain and bilaterality.

The apparent increase in the risk of atypical femoral fracture in patients using glucocorticoids is a concern because bisphosphonates are the mainstay of prevention of glucocorticoid-induced osteoporotic fracture.

Bone biopsies from the iliac crest or fracture site, or both, generally show reduced bone formation consistent with bisphosphonate action. Paradoxically, some patients show biopsy evidence of enhanced bone resorption. Biochemical bone-turnover markers are often normal but may be increased.

Atypical femoral fracture can occur in patients who have not been treated with bisphosphonates, and its true incidence in treated and untreated patients is unknown. However, it appears to be more common in patients who have been exposed to long-term bisphosphonates—usually for longer than 3 years (median treatment: 7 years).

It must be emphasized that this type of fracture is rare, particularly considering the millions of patients who have used bisphosphonates and the much higher incidence of typical and common femoral neck and intertrochanteric fractures in untreated patients.

Bisphosphonates are important drugs for the prevention of common osteoporotic fractures. However, atypical femoral fracture is a concern, and more information is needed to help us identify patients at risk and to guide decision-making about the optimal duration of bisphosphonate therapy.

New delayed-release bisphosphonate can be taken with food

Benhamou CL, Zanchetta JR, Kaufman JM, et al. A novel delayed-release risedronate 35 mg once-a-week formulation taken with or without breakfast: 2 year BMD data. Osteoporosis Int. 2011;22:S337-S338.

Oral bisphosphonates are poorly absorbed from the gastrointestinal (GI) tract, with bioavailability of less than 1%. Absorption is further reduced when a bisphosphonate is taken with food, beverages other than plain water, medications, or supplements. Because of this limited absorption, oral bisphosphonates must be taken at least 30 to 60 minutes before the first food, drink, or other medication of the day. Noncompliance leads to reduced bioavailability and, potentially, decreased efficacy.

A new delayed-release formulation of risedronate (Atelvia) was approved by the FDA in late 2010 and made available for prescribing earlier this year. It is designed to improve absorption of risedronate in the presence of food, allowing for administration immediately after breakfast.

Two innovations were utilized in the manufacture of this tablet. First, it has an enteric coating to deliver risedronate beyond the stomach in the small intestine, with active drug released at a pH level above 5.5. Second, it contains a chelating agent—edetate disodium (EDTA)—which binds free divalent cations, such as calcium, magnesium, and iron.

Details of the study

Benhamou and colleagues compared three regimens of risedronate:

• 35 mg weekly of the delayed-release formulation, taken at least 30 minutes before breakfast
• 35 mg weekly of the delayed-release formulation, taken 30 minutes after breakfast
• 5 mg daily of the immediate-release risedronate formulation, taken 30 minutes before breakfast.

This phase 3, randomized, double-blind, active-controlled study involved 43 centers across North America, Europe, and South America. Characteristics of women in the study included:

• age of 50 years or older
• at least 5 years since the last menstrual period
• lumbar spine or total hip BMD corresponding to a T-score of –2.5 or worse, or a T-score of –2.0 or worse with at least one prevalent vertebral fracture.

The primary efficacy endpoint was the mean percentage of change in BMD at the lumbar spine.

Findings: At 2 years, the mean change for both delayed-release arms was significantly greater than for the 5-mg immediate-release dose. The authors concluded that the 35-mg weekly delayed-release regimen—whether taken at least 30 minutes before or after breakfast—is as effective and safe as the 5-mg daily immediate-release regimen.

Do proton-pump inhibitors increase the risk of fracture?

Targownik LE, Leslie WD. The relationship among proton pump inhibitors, bone disease and fracture [published online ahead of print May 20, 2011]. Expert Opin Drug Saf. doi: 10.1517/14740338.2011.586628.

Yu EW, Bauer SR, Bain PA, Bauer DC. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011;124(6):519–526.

Ye X, Liu H, Wu C, et al. Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2011;23:794–800.

In May 2010, the FDA revised prescription and over-the-counter (OTC) labels for proton-pump inhibitors to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with use of these medications.

Proton pump inhibitors are so named because they prevent hydrogen ion (proton) secretion into the gastric lumen, thereby reducing acid in the stomach. Esomeprazole magnesium (Nexium), dexlansoprazole (Dexilant), omeprazole (Prilosec), omeprazole with sodium bicarbonate (Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), rabeprazole (Aciphex), and naproxen with esomeprazole magnesium (Vimovo) are available by prescription to treat conditions such as gastroesophageal reflux disease (GERD), ulcers of the stomach and small intestine, and inflammation of the esophagus. Delayed-release omeprazole magnesium (Prilosec OTC, Zegerid OTC) and delayed-release lansoprazole (Prevacid 24HR) are sold OTC for treatment of frequent heartburn.

The new safety information was based on an FDA review of several epidemiologic studies reporting an increased risk of fractures of the hip, wrist, and spine with PPI use. Some studies found that those at greatest risk of fracture received high doses of PPIs or used them for 1 year or longer. Most of the studies involved individuals 50 years and older; the increased risk of fracture was observed primarily in this age group.

Although the greatest risk of fracture involved people who had been taking a prescription PPI for at least 1 year or who had been taking a high dose of a prescription PPI, the FDA took the precaution of altering the “Drug facts” label on OTC agents as well. (Over-the-counter PPIs are indicated for 14 days of continuous use.) However, in March 2011, the FDA reversed its decision and retracted the wording on the label of OTC formulations. Following a thorough review of safety data, the agency concluded that the risk of fracture with short-term, low-dose use of PPIs is unlikely. Nevertheless, the FDA acknowledged that consumers sometimes use a PPI longer than the directions advise. Therefore, the agency recommends that health-care professionals be aware of the risk of fracture if the patient uses an OTC PPI at a higher dose or longer time than the label advises.

Two meta-analyses find a modestly increased risk of fracture

Yu and colleagues analyzed 11 observational case-control or cohort studies that involved mostly older adults. They found a modestly increased risk of hip fracture among individuals taking a PPI, compared with nonusers (relative risk [RR], 1.30; 95% CI, 1.19–1.43). They also found an increase in spinal (RR, 1.56; 95% CI, 1.31–1.85) and any-site fractures (RR, 1.16; 95% CI, 1.04–1.30) among PPI users. They acknowledged that residual confounding could not be excluded.

A separate meta-analysis by Ye and colleagues included seven studies. They found a statistically significant increase in the risk of hip fracture, compared with nonusers (odds ratio [OR], 1.24; 95% CI, 1.15–1.34). However, because of different effects of PPIs at different durations of therapy, Ye and colleagues concluded that evidence was insufficient to support a causal relationship between PPI use and hip fracture. Further investigation is warranted.

What we know about PPIs and bone

Because PPIs are widely used, it is of paramount importance to understand the precise effects through which use of a PPI may affect bone mineral metabolism and influence fracture risk.

Targownik and Leslie discuss the evidence supporting an association between PPIs and fragility fracture, the association between PPIs and calcium malabsorption, and the underlying condition that predisposes patients who have osteoporosis to fracture. They also explore the possible mechanisms by which PPIs may increase the risk of fracture. After conducting a PubMed search and review of the literature, they found limited evidence supporting the FDA’s assertion that PPIs may increase the risk of fracture. Other findings:

• Multiple analyses have demonstrated a modest association between chronic PPI use and an increased risk of fracture
• No studies have convincingly demonstrated that PPIs cause fracture
• Overall, PPI use does not interfere with calcium absorption in most instances; therefore, it is unlikely that PPIs influence the risk of fracture by interfering with the absorption of dietary calcium
• Dual-energy x-ray absorptiometry (DEXA) testing demonstrates no consistent effect of PPIs on BMD
• Preliminary evidence suggests that PPIs may interfere with normal osteoclastic function, although it is unclear whether such interference influences the risk of fracture.

Will nitroglycerin be the next treatment for osteoporosis?

Jamal SA, Hamilton CJ, Eastell R, Cummings SR. Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial. JAMA. 2011;305(8):800–807.

Khosla S. Is nitroglycerin a novel and inexpensive treatment for osteoporosis? JAMA. 2011;305(8):826–827.

Data suggesting that nitrates may protect against fracture date back to 2006, when Rejnmark and colleagues explored the use of these agents in 124,655 individuals who sustained a fracture and 373,963 age- and sex-matched controls.³ After adjustment for possible confounders, use of nitrates was associated with an 11% reduction in the risk of any fracture (OR, 0.89; 95% CI, 0.86–0.92) and a 15% reduction in the risk of hip fracture (OR, 0.85; 95% CI, 0.79–0.92).³

However, in 2009, Wimalawansa and colleagues found no benefit of transdermal nitroglycerin in preventing bone loss in early postmenopausal women.⁴ In their 3-year, randomized, double-blind, placebo-controlled trial, 186 postmenopausal women (mean age, 56 years) were randomized to receive nitroglycerin ointment (22.5 mg/d) or placebo. After 36 months of therapy, changes in BMD at multiple sites were comparable between groups. Due to the significant incidence of headache related to nitroglycerin treatment, adherence was suboptimal (estimated at approximately 70%), perhaps contributing to the negative findings.⁴

Enter this study by Jamal and associates, who performed a double-blind, randomized, placebo-controlled trial 24 months in duration. Participants were 243 women with a mean age of 62 years and a lumbar spine T-score between 0 and –2.0. They were randomized to 15 mg daily of 2% nitroglycerin ointment (applied to the upper outer arm at bedtime) or placebo.

At 2 years, women in the nitroglycerin group had a significant increase in BMD at the:

• lumbar spine, from 1.05 to 1.14 g/cm², for a percentage change of 6.7% (P<0.001) (placebo group change: 1.06 to 1.08 g/cm²)
• total hip, from 0.92 to 0.97 g/cm², for a percentage change of 6.2% (P<0.001) (placebo group change: 0.93 to 0.92 g/cm²)
• femoral neck, from 0.88 to 0.93 g/cm², for a percentage change of 7% (P<0.001) (placebo group change: 0.87 to 0.86 g/cm²).

Nitroglycerin also increased bone-specific alkaline phosphatase by 34.8% and decreased urine N-telopeptide by 54% (P<0.001). Incidence of serious adverse events did not differ between nitroglycerin and placebo groups (5 [42.5%]).

Among women who continued treatment for 24 months, headaches were reported by 40 (35%) nitroglycerin users versus six (5.4%) nonusers during the first month, decreasing substantially after 12 months.

We want to hear from you! Tell us what you think.

We, and our patients, are fortunate to have a robust armamentarium of osteoporosis preventives and treatments in the 21st century. Still, we have much to learn about the preservation and restoration of bone. Fine-tuning of individual therapies, and clarification of their attendant risks, are ongoing concerns.

In this article, I highlight several recent studies:

• an assessment of the periodontium in a group of postmenopausal women who were long-term users of bisphosphonates, versus nonusers, to determine the effects of these agents on periodontal health
• guidance from the American Society for Bone and Mineral Research on the risk of atypical femoral fracture in long-term users of bisphosphonates
• 2-year data on a new, delayed-release, weekly formulation of risedronate that can be taken with food
• two meta-analyses exploring the risk of fracture with use of a proton-pump inhibitor (PPI), as well as a recent summary of evidence
• a randomized trial of 2% nitroglycerin ointment to prevent fracture.

Bisphosphonates may reduce the risk of postmenopausal periodontal disease

Palomo L, Buencamino-Francisco MC, Carey JJ, Sivanandy M, Thacker H. Is long-term bisphosphonate therapy associated with benefits to the periodontium in postmenopausal women? Menopause. 2011;18(2):164–170.

The risk of periodontal disease increases in menopause. Inflammation can erode structures (i.e., periodontal ligament and alveolar bone) that attach the teeth into the jaw, leading, eventually, to loss of teeth (FIGURE).

Anatomy of healthy periodontium
In periodontal disease, inflammation can erode structures, such as the periodontal ligament and alveolar bone, that attach the teeth into the jaw.In periodontal inflammation, a bacterial biofilm on tooth surfaces triggers a response by neutrophils and macrophages. In this respect, osteoporosis and periodontitis are mediated by common cytokines. Local production of cytokines seems to enhance osteoclast-mediated loss of skeletal and alveolar bone in estrogen-deficient women. In addition, generalized bone loss in postmenopausal osteoporosis renders the jaw susceptible to accelerated alveolar bone resorption and loss of periodontal attachment. For these reasons, physicians who care for postmenopausal women are advised to monitor their periodontal health; be vigilant for dental problems; and encourage them to practice good oral hygiene as a preventive measure against periodontitis and to seek regular dental care.

There has been tremendous publicity about the rare but very serious occurrence of osteonecrosis of the jaw in women who use bisphosphonates. In contrast, this study by Palomo and colleagues from the Case Western Reserve School of Dental Medicine seems to offer some preliminary good news about bisphosphonates and dental health: Long-term use appears to have some beneficial effects on the periodontium of postmenopausal women.

Details of the study

The aim of the study was to compare the periodontium in two groups of postmenopausal women known to have low bone mineral density (BMD): those who were long-term users (>2 years) of bisphosphonate therapy (n=28) and those who were not (n=28). The average age of participants in the study was 63 years, and the average T-score was –2.5. All women underwent cone-beam computed tomography of the jaw and a complete periodontal examination to determine the plaque score, periodontal probing depth, clinical attachment loss, bleeding on probing, and alveolar bone height.

Findings: Bisphosphonate users had a higher plaque score, a lower probing depth, and less loss of clinical attachment than did women in the control group. These differences were determined to be statistically significant. Bisphosphonate users also had less bleeding on probing and a higher alveolar bone height, but these differences were not significant. After adjustment for the plaque score, bisphosphonate use was a significant factor for probing depth but not for the other parameters.

Atypical femoral fracture is a real risk—but a rarity—with long-term use of antiresorptive drugs

Shane E, Burr D, Ebeling PR, et al; American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25(11):2267–2294.

As ObGyns, we are often the first-line providers of diagnostic services and treatment for postmenopausal women at risk of osteoporotic fracture. Oral and, more recently, parenteral bisphosphonates have been a mainstay of such treatment. Isolated reports of atypical femoral fracture in long-term users of bisphosphonates first surfaced around 2005.¹ Since then, several case series have appeared, some with as many as 102 cases.² In fact, atypical femoral fracture in bisphosphonate users has drawn so much attention that patients have begun to ask about these agents and express reservations about using them.

The issue has drawn the focus of the American Society for Bone and Mineral Research (ASBMR), which appointed a task force to address it. A multidisciplinary expert group reviewed pertinent published reports of atypical femoral fracture, as well as preclinical studies, that could provide insight into its pathogenesis.

What we know about this type of fracture

Preclinical data lend biologic plausibility to a potential association between long-term bisphosphonate use and atypical femoral fracture. These data highlight the effects of bisphosphonates on:

• collagen cross-linking and maturation
• accumulation of microdamage and advanced glycation end products
• heightened mineralization, remodeling, vascularity, and angiogenesis.

The task force concluded that bisphosphonates are highly effective at reducing the risk of spinal and nonspinal fractures, including typical and common femoral neck and intertrochanteric fractures. However, there is evidence of a relationship between long-term bisphosphonate use and a specific type of subtrochanteric and femoral shaft fracture. This type of fracture is characterized by unique radiographic features:

• transverse or short oblique orientation
• absence of comminution
• cortical thickening
• stress fracture or stress reaction on the symptomatic and/or contralateral side
• delayed healing.

This type of fracture also has unique clinical features—namely, prodromal pain and bilaterality.

The apparent increase in the risk of atypical femoral fracture in patients using glucocorticoids is a concern because bisphosphonates are the mainstay of prevention of glucocorticoid-induced osteoporotic fracture.

Bone biopsies from the iliac crest or fracture site, or both, generally show reduced bone formation consistent with bisphosphonate action. Paradoxically, some patients show biopsy evidence of enhanced bone resorption. Biochemical bone-turnover markers are often normal but may be increased.

Atypical femoral fracture can occur in patients who have not been treated with bisphosphonates, and its true incidence in treated and untreated patients is unknown. However, it appears to be more common in patients who have been exposed to long-term bisphosphonates—usually for longer than 3 years (median treatment: 7 years).

It must be emphasized that this type of fracture is rare, particularly considering the millions of patients who have used bisphosphonates and the much higher incidence of typical and common femoral neck and intertrochanteric fractures in untreated patients.

Bisphosphonates are important drugs for the prevention of common osteoporotic fractures. However, atypical femoral fracture is a concern, and more information is needed to help us identify patients at risk and to guide decision-making about the optimal duration of bisphosphonate therapy.

New delayed-release bisphosphonate can be taken with food

Benhamou CL, Zanchetta JR, Kaufman JM, et al. A novel delayed-release risedronate 35 mg once-a-week formulation taken with or without breakfast: 2 year BMD data. Osteoporosis Int. 2011;22:S337-S338.

Oral bisphosphonates are poorly absorbed from the gastrointestinal (GI) tract, with bioavailability of less than 1%. Absorption is further reduced when a bisphosphonate is taken with food, beverages other than plain water, medications, or supplements. Because of this limited absorption, oral bisphosphonates must be taken at least 30 to 60 minutes before the first food, drink, or other medication of the day. Noncompliance leads to reduced bioavailability and, potentially, decreased efficacy.

A new delayed-release formulation of risedronate (Atelvia) was approved by the FDA in late 2010 and made available for prescribing earlier this year. It is designed to improve absorption of risedronate in the presence of food, allowing for administration immediately after breakfast.

Two innovations were utilized in the manufacture of this tablet. First, it has an enteric coating to deliver risedronate beyond the stomach in the small intestine, with active drug released at a pH level above 5.5. Second, it contains a chelating agent—edetate disodium (EDTA)—which binds free divalent cations, such as calcium, magnesium, and iron.

Details of the study

Benhamou and colleagues compared three regimens of risedronate:

• 35 mg weekly of the delayed-release formulation, taken at least 30 minutes before breakfast
• 35 mg weekly of the delayed-release formulation, taken 30 minutes after breakfast
• 5 mg daily of the immediate-release risedronate formulation, taken 30 minutes before breakfast.

This phase 3, randomized, double-blind, active-controlled study involved 43 centers across North America, Europe, and South America. Characteristics of women in the study included:

• age of 50 years or older
• at least 5 years since the last menstrual period
• lumbar spine or total hip BMD corresponding to a T-score of –2.5 or worse, or a T-score of –2.0 or worse with at least one prevalent vertebral fracture.

The primary efficacy endpoint was the mean percentage of change in BMD at the lumbar spine.

Findings: At 2 years, the mean change for both delayed-release arms was significantly greater than for the 5-mg immediate-release dose. The authors concluded that the 35-mg weekly delayed-release regimen—whether taken at least 30 minutes before or after breakfast—is as effective and safe as the 5-mg daily immediate-release regimen.

Do proton-pump inhibitors increase the risk of fracture?

Targownik LE, Leslie WD. The relationship among proton pump inhibitors, bone disease and fracture [published online ahead of print May 20, 2011]. Expert Opin Drug Saf. doi: 10.1517/14740338.2011.586628.

Yu EW, Bauer SR, Bain PA, Bauer DC. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011;124(6):519–526.

Ye X, Liu H, Wu C, et al. Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2011;23:794–800.

In May 2010, the FDA revised prescription and over-the-counter (OTC) labels for proton-pump inhibitors to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with use of these medications.

Proton pump inhibitors are so named because they prevent hydrogen ion (proton) secretion into the gastric lumen, thereby reducing acid in the stomach. Esomeprazole magnesium (Nexium), dexlansoprazole (Dexilant), omeprazole (Prilosec), omeprazole with sodium bicarbonate (Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), rabeprazole (Aciphex), and naproxen with esomeprazole magnesium (Vimovo) are available by prescription to treat conditions such as gastroesophageal reflux disease (GERD), ulcers of the stomach and small intestine, and inflammation of the esophagus. Delayed-release omeprazole magnesium (Prilosec OTC, Zegerid OTC) and delayed-release lansoprazole (Prevacid 24HR) are sold OTC for treatment of frequent heartburn.

The new safety information was based on an FDA review of several epidemiologic studies reporting an increased risk of fractures of the hip, wrist, and spine with PPI use. Some studies found that those at greatest risk of fracture received high doses of PPIs or used them for 1 year or longer. Most of the studies involved individuals 50 years and older; the increased risk of fracture was observed primarily in this age group.

Although the greatest risk of fracture involved people who had been taking a prescription PPI for at least 1 year or who had been taking a high dose of a prescription PPI, the FDA took the precaution of altering the “Drug facts” label on OTC agents as well. (Over-the-counter PPIs are indicated for 14 days of continuous use.) However, in March 2011, the FDA reversed its decision and retracted the wording on the label of OTC formulations. Following a thorough review of safety data, the agency concluded that the risk of fracture with short-term, low-dose use of PPIs is unlikely. Nevertheless, the FDA acknowledged that consumers sometimes use a PPI longer than the directions advise. Therefore, the agency recommends that health-care professionals be aware of the risk of fracture if the patient uses an OTC PPI at a higher dose or longer time than the label advises.

Two meta-analyses find a modestly increased risk of fracture

Yu and colleagues analyzed 11 observational case-control or cohort studies that involved mostly older adults. They found a modestly increased risk of hip fracture among individuals taking a PPI, compared with nonusers (relative risk [RR], 1.30; 95% CI, 1.19–1.43). They also found an increase in spinal (RR, 1.56; 95% CI, 1.31–1.85) and any-site fractures (RR, 1.16; 95% CI, 1.04–1.30) among PPI users. They acknowledged that residual confounding could not be excluded.

A separate meta-analysis by Ye and colleagues included seven studies. They found a statistically significant increase in the risk of hip fracture, compared with nonusers (odds ratio [OR], 1.24; 95% CI, 1.15–1.34). However, because of different effects of PPIs at different durations of therapy, Ye and colleagues concluded that evidence was insufficient to support a causal relationship between PPI use and hip fracture. Further investigation is warranted.

What we know about PPIs and bone

Because PPIs are widely used, it is of paramount importance to understand the precise effects through which use of a PPI may affect bone mineral metabolism and influence fracture risk.

Targownik and Leslie discuss the evidence supporting an association between PPIs and fragility fracture, the association between PPIs and calcium malabsorption, and the underlying condition that predisposes patients who have osteoporosis to fracture. They also explore the possible mechanisms by which PPIs may increase the risk of fracture. After conducting a PubMed search and review of the literature, they found limited evidence supporting the FDA’s assertion that PPIs may increase the risk of fracture. Other findings:

• Multiple analyses have demonstrated a modest association between chronic PPI use and an increased risk of fracture
• No studies have convincingly demonstrated that PPIs cause fracture
• Overall, PPI use does not interfere with calcium absorption in most instances; therefore, it is unlikely that PPIs influence the risk of fracture by interfering with the absorption of dietary calcium
• Dual-energy x-ray absorptiometry (DEXA) testing demonstrates no consistent effect of PPIs on BMD
• Preliminary evidence suggests that PPIs may interfere with normal osteoclastic function, although it is unclear whether such interference influences the risk of fracture.

Will nitroglycerin be the next treatment for osteoporosis?

Jamal SA, Hamilton CJ, Eastell R, Cummings SR. Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial. JAMA. 2011;305(8):800–807.

Khosla S. Is nitroglycerin a novel and inexpensive treatment for osteoporosis? JAMA. 2011;305(8):826–827.

Data suggesting that nitrates may protect against fracture date back to 2006, when Rejnmark and colleagues explored the use of these agents in 124,655 individuals who sustained a fracture and 373,963 age- and sex-matched controls.³ After adjustment for possible confounders, use of nitrates was associated with an 11% reduction in the risk of any fracture (OR, 0.89; 95% CI, 0.86–0.92) and a 15% reduction in the risk of hip fracture (OR, 0.85; 95% CI, 0.79–0.92).³

However, in 2009, Wimalawansa and colleagues found no benefit of transdermal nitroglycerin in preventing bone loss in early postmenopausal women.⁴ In their 3-year, randomized, double-blind, placebo-controlled trial, 186 postmenopausal women (mean age, 56 years) were randomized to receive nitroglycerin ointment (22.5 mg/d) or placebo. After 36 months of therapy, changes in BMD at multiple sites were comparable between groups. Due to the significant incidence of headache related to nitroglycerin treatment, adherence was suboptimal (estimated at approximately 70%), perhaps contributing to the negative findings.⁴

Enter this study by Jamal and associates, who performed a double-blind, randomized, placebo-controlled trial 24 months in duration. Participants were 243 women with a mean age of 62 years and a lumbar spine T-score between 0 and –2.0. They were randomized to 15 mg daily of 2% nitroglycerin ointment (applied to the upper outer arm at bedtime) or placebo.

At 2 years, women in the nitroglycerin group had a significant increase in BMD at the:

• lumbar spine, from 1.05 to 1.14 g/cm², for a percentage change of 6.7% (P<0.001) (placebo group change: 1.06 to 1.08 g/cm²)
• total hip, from 0.92 to 0.97 g/cm², for a percentage change of 6.2% (P<0.001) (placebo group change: 0.93 to 0.92 g/cm²)
• femoral neck, from 0.88 to 0.93 g/cm², for a percentage change of 7% (P<0.001) (placebo group change: 0.87 to 0.86 g/cm²).

Nitroglycerin also increased bone-specific alkaline phosphatase by 34.8% and decreased urine N-telopeptide by 54% (P<0.001). Incidence of serious adverse events did not differ between nitroglycerin and placebo groups (5 [42.5%]).

Among women who continued treatment for 24 months, headaches were reported by 40 (35%) nitroglycerin users versus six (5.4%) nonusers during the first month, decreasing substantially after 12 months.

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We, and our patients, are fortunate to have a robust armamentarium of osteoporosis preventives and treatments in the 21st century. Still, we have much to learn about the preservation and restoration of bone. Fine-tuning of individual therapies, and clarification of their attendant risks, are ongoing concerns.

In this article, I highlight several recent studies:

• an assessment of the periodontium in a group of postmenopausal women who were long-term users of bisphosphonates, versus nonusers, to determine the effects of these agents on periodontal health
• guidance from the American Society for Bone and Mineral Research on the risk of atypical femoral fracture in long-term users of bisphosphonates
• 2-year data on a new, delayed-release, weekly formulation of risedronate that can be taken with food
• two meta-analyses exploring the risk of fracture with use of a proton-pump inhibitor (PPI), as well as a recent summary of evidence
• a randomized trial of 2% nitroglycerin ointment to prevent fracture.

Bisphosphonates may reduce the risk of postmenopausal periodontal disease

Palomo L, Buencamino-Francisco MC, Carey JJ, Sivanandy M, Thacker H. Is long-term bisphosphonate therapy associated with benefits to the periodontium in postmenopausal women? Menopause. 2011;18(2):164–170.

The risk of periodontal disease increases in menopause. Inflammation can erode structures (i.e., periodontal ligament and alveolar bone) that attach the teeth into the jaw, leading, eventually, to loss of teeth (FIGURE).

Anatomy of healthy periodontium
In periodontal disease, inflammation can erode structures, such as the periodontal ligament and alveolar bone, that attach the teeth into the jaw.In periodontal inflammation, a bacterial biofilm on tooth surfaces triggers a response by neutrophils and macrophages. In this respect, osteoporosis and periodontitis are mediated by common cytokines. Local production of cytokines seems to enhance osteoclast-mediated loss of skeletal and alveolar bone in estrogen-deficient women. In addition, generalized bone loss in postmenopausal osteoporosis renders the jaw susceptible to accelerated alveolar bone resorption and loss of periodontal attachment. For these reasons, physicians who care for postmenopausal women are advised to monitor their periodontal health; be vigilant for dental problems; and encourage them to practice good oral hygiene as a preventive measure against periodontitis and to seek regular dental care.

There has been tremendous publicity about the rare but very serious occurrence of osteonecrosis of the jaw in women who use bisphosphonates. In contrast, this study by Palomo and colleagues from the Case Western Reserve School of Dental Medicine seems to offer some preliminary good news about bisphosphonates and dental health: Long-term use appears to have some beneficial effects on the periodontium of postmenopausal women.

Details of the study

The aim of the study was to compare the periodontium in two groups of postmenopausal women known to have low bone mineral density (BMD): those who were long-term users (>2 years) of bisphosphonate therapy (n=28) and those who were not (n=28). The average age of participants in the study was 63 years, and the average T-score was –2.5. All women underwent cone-beam computed tomography of the jaw and a complete periodontal examination to determine the plaque score, periodontal probing depth, clinical attachment loss, bleeding on probing, and alveolar bone height.

Findings: Bisphosphonate users had a higher plaque score, a lower probing depth, and less loss of clinical attachment than did women in the control group. These differences were determined to be statistically significant. Bisphosphonate users also had less bleeding on probing and a higher alveolar bone height, but these differences were not significant. After adjustment for the plaque score, bisphosphonate use was a significant factor for probing depth but not for the other parameters.

Atypical femoral fracture is a real risk—but a rarity—with long-term use of antiresorptive drugs

Shane E, Burr D, Ebeling PR, et al; American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25(11):2267–2294.

As ObGyns, we are often the first-line providers of diagnostic services and treatment for postmenopausal women at risk of osteoporotic fracture. Oral and, more recently, parenteral bisphosphonates have been a mainstay of such treatment. Isolated reports of atypical femoral fracture in long-term users of bisphosphonates first surfaced around 2005.¹ Since then, several case series have appeared, some with as many as 102 cases.² In fact, atypical femoral fracture in bisphosphonate users has drawn so much attention that patients have begun to ask about these agents and express reservations about using them.

The issue has drawn the focus of the American Society for Bone and Mineral Research (ASBMR), which appointed a task force to address it. A multidisciplinary expert group reviewed pertinent published reports of atypical femoral fracture, as well as preclinical studies, that could provide insight into its pathogenesis.

What we know about this type of fracture

Preclinical data lend biologic plausibility to a potential association between long-term bisphosphonate use and atypical femoral fracture. These data highlight the effects of bisphosphonates on:

• collagen cross-linking and maturation
• accumulation of microdamage and advanced glycation end products
• heightened mineralization, remodeling, vascularity, and angiogenesis.

The task force concluded that bisphosphonates are highly effective at reducing the risk of spinal and nonspinal fractures, including typical and common femoral neck and intertrochanteric fractures. However, there is evidence of a relationship between long-term bisphosphonate use and a specific type of subtrochanteric and femoral shaft fracture. This type of fracture is characterized by unique radiographic features:

• transverse or short oblique orientation
• absence of comminution
• cortical thickening
• stress fracture or stress reaction on the symptomatic and/or contralateral side
• delayed healing.

This type of fracture also has unique clinical features—namely, prodromal pain and bilaterality.

The apparent increase in the risk of atypical femoral fracture in patients using glucocorticoids is a concern because bisphosphonates are the mainstay of prevention of glucocorticoid-induced osteoporotic fracture.

Bone biopsies from the iliac crest or fracture site, or both, generally show reduced bone formation consistent with bisphosphonate action. Paradoxically, some patients show biopsy evidence of enhanced bone resorption. Biochemical bone-turnover markers are often normal but may be increased.

Atypical femoral fracture can occur in patients who have not been treated with bisphosphonates, and its true incidence in treated and untreated patients is unknown. However, it appears to be more common in patients who have been exposed to long-term bisphosphonates—usually for longer than 3 years (median treatment: 7 years).

It must be emphasized that this type of fracture is rare, particularly considering the millions of patients who have used bisphosphonates and the much higher incidence of typical and common femoral neck and intertrochanteric fractures in untreated patients.

Bisphosphonates are important drugs for the prevention of common osteoporotic fractures. However, atypical femoral fracture is a concern, and more information is needed to help us identify patients at risk and to guide decision-making about the optimal duration of bisphosphonate therapy.

New delayed-release bisphosphonate can be taken with food

Benhamou CL, Zanchetta JR, Kaufman JM, et al. A novel delayed-release risedronate 35 mg once-a-week formulation taken with or without breakfast: 2 year BMD data. Osteoporosis Int. 2011;22:S337-S338.

Oral bisphosphonates are poorly absorbed from the gastrointestinal (GI) tract, with bioavailability of less than 1%. Absorption is further reduced when a bisphosphonate is taken with food, beverages other than plain water, medications, or supplements. Because of this limited absorption, oral bisphosphonates must be taken at least 30 to 60 minutes before the first food, drink, or other medication of the day. Noncompliance leads to reduced bioavailability and, potentially, decreased efficacy.

A new delayed-release formulation of risedronate (Atelvia) was approved by the FDA in late 2010 and made available for prescribing earlier this year. It is designed to improve absorption of risedronate in the presence of food, allowing for administration immediately after breakfast.

Two innovations were utilized in the manufacture of this tablet. First, it has an enteric coating to deliver risedronate beyond the stomach in the small intestine, with active drug released at a pH level above 5.5. Second, it contains a chelating agent—edetate disodium (EDTA)—which binds free divalent cations, such as calcium, magnesium, and iron.

Details of the study

Benhamou and colleagues compared three regimens of risedronate:

• 35 mg weekly of the delayed-release formulation, taken at least 30 minutes before breakfast
• 35 mg weekly of the delayed-release formulation, taken 30 minutes after breakfast
• 5 mg daily of the immediate-release risedronate formulation, taken 30 minutes before breakfast.

This phase 3, randomized, double-blind, active-controlled study involved 43 centers across North America, Europe, and South America. Characteristics of women in the study included:

• age of 50 years or older
• at least 5 years since the last menstrual period
• lumbar spine or total hip BMD corresponding to a T-score of –2.5 or worse, or a T-score of –2.0 or worse with at least one prevalent vertebral fracture.

The primary efficacy endpoint was the mean percentage of change in BMD at the lumbar spine.

Findings: At 2 years, the mean change for both delayed-release arms was significantly greater than for the 5-mg immediate-release dose. The authors concluded that the 35-mg weekly delayed-release regimen—whether taken at least 30 minutes before or after breakfast—is as effective and safe as the 5-mg daily immediate-release regimen.

Do proton-pump inhibitors increase the risk of fracture?

Targownik LE, Leslie WD. The relationship among proton pump inhibitors, bone disease and fracture [published online ahead of print May 20, 2011]. Expert Opin Drug Saf. doi: 10.1517/14740338.2011.586628.

Yu EW, Bauer SR, Bain PA, Bauer DC. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011;124(6):519–526.

Ye X, Liu H, Wu C, et al. Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2011;23:794–800.

In May 2010, the FDA revised prescription and over-the-counter (OTC) labels for proton-pump inhibitors to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with use of these medications.

Proton pump inhibitors are so named because they prevent hydrogen ion (proton) secretion into the gastric lumen, thereby reducing acid in the stomach. Esomeprazole magnesium (Nexium), dexlansoprazole (Dexilant), omeprazole (Prilosec), omeprazole with sodium bicarbonate (Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), rabeprazole (Aciphex), and naproxen with esomeprazole magnesium (Vimovo) are available by prescription to treat conditions such as gastroesophageal reflux disease (GERD), ulcers of the stomach and small intestine, and inflammation of the esophagus. Delayed-release omeprazole magnesium (Prilosec OTC, Zegerid OTC) and delayed-release lansoprazole (Prevacid 24HR) are sold OTC for treatment of frequent heartburn.

The new safety information was based on an FDA review of several epidemiologic studies reporting an increased risk of fractures of the hip, wrist, and spine with PPI use. Some studies found that those at greatest risk of fracture received high doses of PPIs or used them for 1 year or longer. Most of the studies involved individuals 50 years and older; the increased risk of fracture was observed primarily in this age group.

Although the greatest risk of fracture involved people who had been taking a prescription PPI for at least 1 year or who had been taking a high dose of a prescription PPI, the FDA took the precaution of altering the “Drug facts” label on OTC agents as well. (Over-the-counter PPIs are indicated for 14 days of continuous use.) However, in March 2011, the FDA reversed its decision and retracted the wording on the label of OTC formulations. Following a thorough review of safety data, the agency concluded that the risk of fracture with short-term, low-dose use of PPIs is unlikely. Nevertheless, the FDA acknowledged that consumers sometimes use a PPI longer than the directions advise. Therefore, the agency recommends that health-care professionals be aware of the risk of fracture if the patient uses an OTC PPI at a higher dose or longer time than the label advises.

Two meta-analyses find a modestly increased risk of fracture

Yu and colleagues analyzed 11 observational case-control or cohort studies that involved mostly older adults. They found a modestly increased risk of hip fracture among individuals taking a PPI, compared with nonusers (relative risk [RR], 1.30; 95% CI, 1.19–1.43). They also found an increase in spinal (RR, 1.56; 95% CI, 1.31–1.85) and any-site fractures (RR, 1.16; 95% CI, 1.04–1.30) among PPI users. They acknowledged that residual confounding could not be excluded.

A separate meta-analysis by Ye and colleagues included seven studies. They found a statistically significant increase in the risk of hip fracture, compared with nonusers (odds ratio [OR], 1.24; 95% CI, 1.15–1.34). However, because of different effects of PPIs at different durations of therapy, Ye and colleagues concluded that evidence was insufficient to support a causal relationship between PPI use and hip fracture. Further investigation is warranted.

What we know about PPIs and bone

Because PPIs are widely used, it is of paramount importance to understand the precise effects through which use of a PPI may affect bone mineral metabolism and influence fracture risk.

Targownik and Leslie discuss the evidence supporting an association between PPIs and fragility fracture, the association between PPIs and calcium malabsorption, and the underlying condition that predisposes patients who have osteoporosis to fracture. They also explore the possible mechanisms by which PPIs may increase the risk of fracture. After conducting a PubMed search and review of the literature, they found limited evidence supporting the FDA’s assertion that PPIs may increase the risk of fracture. Other findings:

• Multiple analyses have demonstrated a modest association between chronic PPI use and an increased risk of fracture
• No studies have convincingly demonstrated that PPIs cause fracture
• Overall, PPI use does not interfere with calcium absorption in most instances; therefore, it is unlikely that PPIs influence the risk of fracture by interfering with the absorption of dietary calcium
• Dual-energy x-ray absorptiometry (DEXA) testing demonstrates no consistent effect of PPIs on BMD
• Preliminary evidence suggests that PPIs may interfere with normal osteoclastic function, although it is unclear whether such interference influences the risk of fracture.

Will nitroglycerin be the next treatment for osteoporosis?

Jamal SA, Hamilton CJ, Eastell R, Cummings SR. Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial. JAMA. 2011;305(8):800–807.

Khosla S. Is nitroglycerin a novel and inexpensive treatment for osteoporosis? JAMA. 2011;305(8):826–827.

Data suggesting that nitrates may protect against fracture date back to 2006, when Rejnmark and colleagues explored the use of these agents in 124,655 individuals who sustained a fracture and 373,963 age- and sex-matched controls.³ After adjustment for possible confounders, use of nitrates was associated with an 11% reduction in the risk of any fracture (OR, 0.89; 95% CI, 0.86–0.92) and a 15% reduction in the risk of hip fracture (OR, 0.85; 95% CI, 0.79–0.92).³

However, in 2009, Wimalawansa and colleagues found no benefit of transdermal nitroglycerin in preventing bone loss in early postmenopausal women.⁴ In their 3-year, randomized, double-blind, placebo-controlled trial, 186 postmenopausal women (mean age, 56 years) were randomized to receive nitroglycerin ointment (22.5 mg/d) or placebo. After 36 months of therapy, changes in BMD at multiple sites were comparable between groups. Due to the significant incidence of headache related to nitroglycerin treatment, adherence was suboptimal (estimated at approximately 70%), perhaps contributing to the negative findings.⁴

Enter this study by Jamal and associates, who performed a double-blind, randomized, placebo-controlled trial 24 months in duration. Participants were 243 women with a mean age of 62 years and a lumbar spine T-score between 0 and –2.0. They were randomized to 15 mg daily of 2% nitroglycerin ointment (applied to the upper outer arm at bedtime) or placebo.

At 2 years, women in the nitroglycerin group had a significant increase in BMD at the:

• lumbar spine, from 1.05 to 1.14 g/cm², for a percentage change of 6.7% (P<0.001) (placebo group change: 1.06 to 1.08 g/cm²)
• total hip, from 0.92 to 0.97 g/cm², for a percentage change of 6.2% (P<0.001) (placebo group change: 0.93 to 0.92 g/cm²)
• femoral neck, from 0.88 to 0.93 g/cm², for a percentage change of 7% (P<0.001) (placebo group change: 0.87 to 0.86 g/cm²).

Nitroglycerin also increased bone-specific alkaline phosphatase by 34.8% and decreased urine N-telopeptide by 54% (P<0.001). Incidence of serious adverse events did not differ between nitroglycerin and placebo groups (5 [42.5%]).

Among women who continued treatment for 24 months, headaches were reported by 40 (35%) nitroglycerin users versus six (5.4%) nonusers during the first month, decreasing substantially after 12 months.

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Since the 1950s, researchers and clinicians have sought a simple chemical biomarker that would aid in the diagnosis and treatment of cardiovascular disease (CVD). An initial discovery was that proteins normally found within cardiac myocytes are released into the circulation when the myocardial cell membrane loses its integrity as a result of hypoxic injury.¹ Over the past 60 years, major advances have been made to distinguish which proteins are highly cardiac specific, and which are suggestive of other pathologic cardiovascular processes.

In the past 15 to 20 years, significant data have emerged that support the role of cardiac-specific troponins in the cardiac disease process, making their measurement an important consideration in diagnosis and clinical decision-making for patients with various forms of CVD.^2-7 With the exception of 1918, CVD has accounted for more deaths in the United States than any other illness in every year since 1900.⁸ It has been suggested that nearly 2,300 Americans die of CVD each day—an average of one death every 38 seconds. The direct and indirect costs of CVD for 2010 were projected at $503.2 billion—including $155 billion for total hospital costs alone.⁹ By comparison, a 2010 projection from the National Cancer Institute was $124.57 billion for the direct costs of cancer care.¹⁰

It is imperative for practitioners in all areas of medicine to have a working knowledge of the role of cardiac biomarkers and their potential impact on patients’ overall health. Primary care clinicians in particular should be familiar with the release kinetics of certain cardiac biomarkers to aid in the diagnosis and treatment of the cardiac patient. This article is intended as an overview of the cardiac biomarkers that are being used in practice today, and to review the novel biomarkers that may have an impact on the way clinicians practice in the near future.

BIOMARKERS CURRENTLY IN USE

Cardiac Troponins

The cardiac-specific troponins (cTn) are an integral component of the myosin-actin binding complex found in striated muscle tissue. The troponin complex includes three regulatory proteins: troponin C, troponin I, and troponin T. The genes that code for troponin C are identical in skeletal and cardiac tissue; for this reason, troponin C becomes much less cardiospecific.

However, cardiac troponin T (cTnT) and cardiac troponin I (cTnI) have differing amino acid sequences, making it possible to develop highly sensitive immunoassays to detect circulating antibody-troponin complexes after myocardial cell injury, as seen in acute coronary syndrome (ACS).12-14 No cross-reactivity occurs between skeletal and cardiac sources, indicating the unique cardiospecificity of the cTn proteins.11

Of note, there are numerous patient populations in which elevated cTn may be found; the associated conditions are outlined in Table 1.^11,15,16 In particular, elevations in cTn (more specifically cTnT) are commonly observed in patients with end-stage renal disease (ESRD).^11,17 The pathogenesis of elevated cTnT is not completely understood but has been proposed as a promising prognostic tool for use in patients with ESRD. Elevated levels of cTnT identify patients whose chance of survival is poor, with an increased risk for cardiac death.⁷ It should be noted that a significant proportion of patients with chronic renal failure succumb to cardiovascular death.¹⁷

Recently, deFilippi and colleagues¹⁸ reported a correlation between trace amounts of circulating cTnT in older patients not known to have CVD and an increased risk for future heart failure or even cardiovascular-related death. This novel finding may add valuable information to the screening and risk stratification of relatively healthy but sedentary individuals older than 65.

Elevations in cTn can be seen as early as two to four hours after myocardial injury.¹¹ A small portion of cTnT and cTnI is found within the myocardial cells’ cytosol and is not bound to the troponin complex, which begins to degrade after cell injury.^1,14 This cytosolic pool allows for earlier recognition of cardiac injury. As increasingly sensitive assays are developed, rises in cTn levels can be detected earlier after symptom onset, thus making the use of less specific early biomarkers, such as myoglobin and creatine kinase–MB, obsolete.

Because of the continuous release of structural proteins from the degrading myocardial tissue, elevations of cTnI may persist for seven to 10 days, while cTnT elevations can continue for 10 to 14 days postinfarction.¹¹ This prolonged period allows for detection of even very slight cardiac damage and provides an advantage for identification and treatment of high-risk patients. When measured 72 hours after infarction, cTnI can also provide prognostic information, such as the potential size of the affected myocardial area.^5,6 This, too, facilitates risk stratification. Timing of the release of key biomarkers can be seen in Table 2.^11,19-21

Natriuretic Peptides

The natriuretic peptides are cardiac neurohormones that are released in response to myocardial wall stress.¹¹ B-type natriuretic peptide (BNP; previously known as brain natriuretic peptide) is synthesized and released from the ventricular myocardium in times of volume expansion and increased pressure burden. Initially, the prohormone proBNP is released and is enzymatically cleaved to N-terminal proBNP (NT-proBNP) and then to “mature” BNP.¹¹

Today, BNP is used widely as a biomarker for congestive heart failure.²² In the Breathing Not Properly (BNP) study,²³ BNP was able to accurately distinguish dyspnea caused by heart failure from that with a pulmonary etiology; it was found to be the strongest predictor for the diagnosis of heart failure. In the evaluation of serum BNP, a level below 100 ng/L makes heart failure unlikely (negative predictive value, 90%). If the value rises above 500 ng/L, heart failure is highly likely (positive predictive value, 90%).²³

As for NT-proBNP, levels exceeding 450 ng/L in patients younger than 50 and exceeding 900 ng/L in patients 50 or older have been found highly sensitive and specific for heart failure–related dyspnea.²⁴ Current studies suggest that NT-proBNP may have greater sensitivity and specificity than standard BNP when these age-related cut-off limits are applied.²⁵

Researchers for the International Collaborative of NT-proBNP Study reported that when NT-proBNP was measured in the emergency department (ED) in patients with dyspnea, patients were less likely to require hospitalization for heart failure.²⁶ Instead, patients were presenting with exacerbations of chronic obstructive pulmonary disease, which would best be managed on an outpatient basis. Those who were admitted experienced shorter lengths of stay with subsequent reductions in health care costs, and had no significant difference in readmission or mortality rates.

Use of BNP as a cardiac biomarker does not come without its limitations. In addition to right-sided heart failure, ACS, and MI, elevations in BNP have been associated with septic shock, sepsis, renal dysfunction, and acute pulmonary embolus.²⁷ Correlations have been made between the degree of BNP elevation and the extent of myocardial ischemia; increased levels of both BNP and cTnI were associated with higher mortality rates.²⁸

C-Reactive Protein

Inflammation is known to play a key role in the development of atherosclerotic plaques. Measuring byproducts of the atherosclerotic process, from the initial development of fatty streaks to plaque rupture, can help determine whether a patient is at an increased risk for a cardiovascular event.²⁹ Primary proinflammatory markers from the local site of intravascular inflammation signal messenger cytokines that are altered in the liver via an acute-phase reaction.

One of the major acute-phase reactants, C-reactive protein (CRP) is simply a byproduct of inflammation—yet it has become a major indicator of atherosclerotic plaque stability.³⁰ A high-sensitivity CRP assay (hsCRP) can be a significantly effective predictor for MI, stroke, and peripheral vascular disease, even in patients who appear to be healthy.³¹ Studies have suggested that hsCRP is a better indicator of unstable plaque, and a better predictor of adverse cardiovascular events, than is low-density lipoprotein cholesterol (LDL-C), when these markers are used independently.³² When detected together, however, hsCRP and LDL-C elevations have been shown to be an even better predictor of adverse events in patients with no overt cardiovascular risk factors.³¹

As a risk factor, elevated hsCRP has been called as important as smoking or hypertension—highlighting the role of inflammation in formation of atherosclerosis at every level.³³

In the evaluation of serum hsCRP, it is important to know that levels tend to be stable over long periods of time, have no circadian rhythms, and are not affected by various prandial states. Levels can be measured conveniently during the standard annual cholesterol screening. Relative cardiovascular risk is deemed low, medium, and high, in patients with an hsCRP measurement of less than 1 mg/L, 1 to 3 mg/L, and greater than 3 mg/L, respectively.² Values exceeding 8.0 mg/L may be consistent with an acute infectious or inflammatory process, thus exposing the nonspecific nature of this popular biomarker.³⁴ However, when used in conjunction with cTn, BNP, and patient history, hsCRP still proves to be an important clinical tool, offering prognostic information to facilitate clinical decision making.

Chronically elevated hsCRP signifies a very high risk for future cardiovascular events and should prompt the clinician to target the patient’s modifiable risk factors, including consideration of statin therapy as a part of the treatment regimen.³⁵ According to results from the PROVE IT–TIMI 22 trial,³⁵ statin use appears particularly cardioprotective in patients whose hsCRP levels are lower than 2 mg/L and who maintain LDL-C below 70 mg/dL. Researchers for this study group recommend monitoring hsCRP along with serum lipids for a more comprehensive cardiovascular risk profile.

Creatine Kinase

Three isoenzymes of creatine kinase (CK) exist: MM (skeletal muscle type), BB (brain type), and MB (myocardial band). The CK-MB isoenzyme was the diagnostic marker of choice for ACS until the introduction of cardiac-specific troponins in the early 1990s.^36,37

CK-MB is an intracellular carrier protein for high-energy phosphates, found in higher concentrations in the myocardium than are the other CK isoenzymes.¹¹ CK-MB accounts for about 15% of total CK, but it also exists in skeletal muscle and to a lesser extent in the small intestine, diaphragm, uterus, and prostate.²¹ As with most cardiac biomarkers, cardiospecificity of CK-MB is not 100%, and false-positive elevations can occur in a multitude of clinical settings, including significant musculoskeletal injury, heavy exertion, and myopathies.¹¹

CK-MB is detectable three to four hours after myocardial injury, peaks at 24 hours, and returns to normal in 48 to 72 hours. CK-MB may be used to evaluate for ACS if cardiac troponin assays are not accessible,²¹ but its usefulness is limited during the early hours of ACS onset and after 72 hours.

The relative index of CK-MB to total CK (CK-MB/CK) can help the clinician assess whether the rise in CK-MB is attributable to a skeletal muscle source (CK-MB/CK < 3) or a cardiac source (CK-MB/CK > 5, indicating myocardial release of CK-MB). A relative index that falls between 3 and 5 warrants further investigation with serial analyses.³⁶ It may also be helpful to know that a CK-MB elevation associated with skeletal muscle release tends to persist and plateau over a period of several days—as opposed to CK-MB elevation with a myocardial source, which follows the time course stated above.²¹

In a 2006 study that included nearly 30,000 patients, it was found that 28% of those with ACS had conflicting results between troponin levels and CK-MB.³⁸ Patients with no elevations in cardiac troponins but elevations in CK-MB had no significant increased risk for in-hospital mortality, compared with patients with negative results for both markers. Thus, an isolated elevation in CK-MB has limited prognostic value in patients with negative troponin levels.

By contrast, however, Lim et al³⁹ recently found that elevations in CK-MB were closely associated with perioperative necrosis and MI after percutaneous coronary intervention (PCI) as a result of currently oversensitive thresholds for cTnI. Thus, CK-MB use may play a role as an independent marker of necrosis in certain situations.

Myoglobin

Because of its small molecular size, myoglobin has timely release kinetics, with elevations appreciable before those of CK-MB or cTn.^11,21 Myoglobin typically rises one to four hours after myocardial injury, peaks at six to 12 hours, and returns to normal within 24 hours. For this reason, it has held special interest as an early marker of cardiac injury.

With its early release/degradation kinetics, myoglobin may serve as a marker for reinfarction.²¹ It can also be used to assess further damage to the myocardium, as seen with distal thrombus embolization or coronary artery manipulation. However, troponin values provide similar information on reinfarction status.⁴

An established shortcoming of myoglobin as an early marker of necrosis is its lack of cardiac specificity, as it is found extensively in skeletal muscle.²¹ Patients who present with inflammation, trauma, or significant skeletal muscle injury can have extremely high levels of serum myoglobin without myocardial involvement. Since 2000, when cTn was designated the myocardial biomarker of choice (according to the revised definition of MI, as presented that year by the European Society of Cardiology and American College of Cardiology), the use of myoglobin to identify ACS has been considered obsolete.¹⁴

NOVEL BIOMARKERS OF CARDIOVASCULAR DISEASE

Heart-Type Fatty Acid–Binding Protein

A low–molecular-weight protein, heart-type fatty acid–binding protein (H-FABP) is involved in the intracellular uptake and buffering of myocardial free fatty acids. Because its molecular size is similar to that of troponin, it is rapidly released from the cytosol and has been proposed as an early sensitive marker of acute MI.⁴⁰ In a 2010 study, H-FABP was shown to be of additional prognostic value when used in conjunction with cTnI in patients at low to moderate risk for suspected ACS.⁴¹ According to the known release kinetics of H-FABP after myocardial ischemia or infarct, a rise is detectable as early as 1.5 hours after symptom onset. The marker peaks after four to six hours and, because of rapid renal clearance, returns to baseline within 20 hours.²⁰

Interpreting results may be hindered in the patient with impaired renal function—with not only higher levels, but sustained levels of H-FABP.²⁰ Early assays used antibodies to detect circulating H-FABP levels, but cross-reactivity occurring between other fatty acid–binding protein types have limited the clinical applications of H-FABP testing.²⁰ As more highly specific assays are produced, more practical protocols can be implemented to confirm the presence of ACS in patients presenting early to the ED with apparent ACS.

Ischemia-Modified Albumin

A biomarker that could detect ischemia alone would help identify patients at highest risk for infarction; immediate intervention could then prevent the progression of ACS, as evidenced by rising markers of necrosis. Ischemia-modified albumin (IMA), which is produced rapidly when circulating albumin comes into contact with ischemic myocardial tissue, has been touted as such a biomarker.⁴²

Several changes occur in the human albumin molecule in the presence of ischemia, including its ability to bind transition metals—especially cobalt. This discovery led to the creation of an albumin-cobalt–binding assay, approved by the FDA for rapid detection of myocardial ischemia.¹⁹ When artificial ischemia is produced by ­balloon inflation during percutaneous coronary angioplasty, IMA levels can be detected, using the assay, within minutes of coronary artery occlusion. Levels tend to peak within six hours and can be elevated for as long as 12 hours.¹⁹

When IMA is used in conjunction with ECG findings and cTnT levels, a sensitivity of 97% for detecting ACS can be achieved. This could reduce the number of patients being discharged from the ED with occult ACS,⁴³ giving IMA a potentially important precautionary and supplemental role. As with most cardiac biomarkers, IMA alone is not 100% specific for ACS since it is also present in other ischemic conditions, thus hindering its usefulness in clinical practice. Elevations had been reported in patients with liver cirrhosis, uncontrolled type 2 diabetes mellitus, obstetric conditions associated with placental ischemia, carbon monoxide poisoning, and cerebrovascular ischemia.^44-47

Recent suggestions to use IMA to rule out rather than diagnose ACS show promise, since the absence of this acute-phase reactant should exclude the presence of myocardial ischemia.⁴⁸ Further studies are needed to determine the exact physiology of IMA production in order to identify its cardiac specificity for clinical use.⁴⁹

Homocysteine

As a marker of increased cardiovascular risk, homocysteine is thought to have multiple effects on the cardiovascular system. These include endothelial dysfunction, decreased arteriole vasodilation (ie, reduced release of nitric oxide), increased platelet activation, increased production of free radicals, and increased LDL oxidation with arteriole lipid accumulation.⁵⁰

In patients with severe hyperhomocysteinemia (ie, homocysteine serum levels > 100 mol/L), risk for premature atherothrombosis and venous thromboembolism is increased. In the general public, mildly elevated homocysteine levels (> 15 mol/L) have been attributed to insufficient dietary intake of folic acid. Folate in its natural form has been known to decrease serum homocysteine levels by 25%, if supplemented appropriately with vitamins B₆ and B₁₂.⁵⁰

In recent years, folate deficiency has declined due to enrichment of certain foods with this crucial nutrient, initially mandated to decrease the incidence of neural tube defects in developing embryos. From a cardiovascular standpoint, researchers have been unable to determine whether elevated homocysteine increases CVD risk or is simply a marker of existing disease burden.⁵⁰ In clinical trials in which subjects took B-vitamins supplemented with folate, homocysteine levels were reduced; yet in one study, stroke risk was not reduced in patients with a history of stroke⁵¹; in a second, in-stent restenosis was more common in patients who took the supplement after undergoing angioplasty⁵²; and in a third, patients following the vitamin regimen after a recent acute MI proved to be at higher cardiovascular risk.⁵³

As a result of this conflicting evidence, no recommendations have been made for routine homocysteine screening except in patients with a history of markedly premature atherosclerosis or a family history of early-onset acute MI or stroke.⁵⁰ Monitoring may be advisable in patients who take a folate antagonist (eg, methotrexate, carbamazepine), considering the risk for folate deficiency and subsequent hyperhomocysteinemia.

ACUTE INFLAMMATORY MARKERS OF PLAQUE RUPTURE OR VULNERABILITY

Myeloperoxidase

Many researchers have taken a particular interest in the acute substances formed as a result of atherothrombotic plaque inflammation or rupture. One such biomarker is myeloperoxidase (MPO), which is thought to be expressed from the degranulation of activated leukocytes found in atherosclerotic plaques. This acute-phase enzyme may convert LDL into a high-uptake form for macrophages, leading to foam cell formation and depletion of nitric oxide, contributing to additional ischemia by way of vasoconstriction.⁵⁴

Recently, a high systemic MPO level was found to be a more significant marker of plaque at risk for rupture, compared with already-ruptured plaque.⁵⁵ Although MPO elevations may also occur in a number of inflammatory, infectious, or infiltrative conditions, the association between MPO, inflammation, and oxidative stress supports its use as a marker for plaque that is vulnerable to rupture.^56,57

Serum levels of MPO have been shown to predict increased risk for subsequent death or MI in patients who present to the ED with ACS, independent of other cardiac risk factors or cardiac biomarkers. In a 2001 study, Zhang et al⁵⁴ established an association between elevated MPO levels and angiographically proven coronary atherosclerosis, with a 20-fold higher risk for coronary artery disease; earlier this year, Oemrawsingh et al⁵⁸ reported an independent association between MPO and long-term adverse outcomes in patients who presented with non–ST-segment elevation ACS. Thus, MPO may be a significant indicator of vascular inflammation.⁵⁷

Soluble CD40 Ligand

In the 1980s, postmortem studies confirmed that erosions or ruptures in atherosclerotic fibrous caps lead to platelet activation—the main pathophysiologic contributor in ACS.⁵⁹ This fundamental actuality suggests that biomarkers of platelet activation may provide supplemental information in patients who present with chest pain of cardiac origin. Another acute inflammatory marker, soluble CD40 ligand, is a marker of active platelet stimulation.⁶⁰ Increased serum levels of soluble CD40 ligand have been correlated to increased risk for cardiovascular events in apparently healthy women.⁶¹

Soluble CD40 ligand, expressed within seconds of platelet activation, is also commonly found on various leukocytes, endothelial cells, and smooth-­muscle cells.⁶⁰ This may provide insight into cardiovascular disease progression and plaque deterioration that precedes the events of ACS.

Therapeutic antiplatelet medications are now the mainstay in the treatment and prevention of cardiovascular complications associated with ischemic thrombus formation.¹¹ Platelet biomarkers are likely to play an essential supplemental role in the diagnosis of ACS.

Pregnancy-Associated Plasma Protein A

Additional risk-stratifying biomarkers include those that may determine whether a patient has plaques that are acutely vulnerable to rupture. Pregnancy-associated plasma protein A (PAPP-A), first detected in the 1970s in the circulation of pregnant women, is now widely used in first-trimester screening for fetal trisomy.⁶²

Since then, it has been found that PAPP-A, which is theorized to be produced by vascular smooth-muscle cells, is extensively expressed in unstable coronary artery plaques, while minimally expressed in stable plaques.⁶³ Since a significant proportion of patients who present with symptoms of ACS have normal cTn levels, PAPP-A may help identify patients who are at increased risk for subsequent short-term cardiovascular complications resulting from occult disease.⁶⁴ This relatively new marker may also prove useful for screening in the office setting, identifying outpatients who are at high cardiovascular risk. Further studies are needed to define the release kinetics of PAPP-A, guiding clinicians in its implementation and clinical use.

CONCLUSION

When used in conjunction with the history and physical exam, cardiac biomarkers can provide a simple, noninvasive means to further the clinician’s exploration into a suspected underlying cardiovascular process. As advances continue in the understanding of the pathogenesis of heart disease, new interpretations of existing markers and discovery of novel markers may allow for specific therapeutic interventions to improve patient outcomes.

It is important to note that the list of biomarkers described here is by no means complete, and there is continued interest in finding more specific and sensitive markers of heart disease. Numerous cardiovascular organizations are now suggesting a shift toward a multi-marker strategy to determine the best etiology in the patient who presents with decompensating cardiovascular disease. A change in cardiac enzyme panels may be inevitable in the near future. Practicing PAs and NPs, particularly those who care for patients at risk for CVD, should remain up-to-date and proficient in interpreting those results to help determine the best course of action for each patient.

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39. Lim CC, van Gaal WJ, Testa L, et al. With the “universal definition,” measurement of creatine kinase–myocardial band rather than troponin allows more accurate diagnosis of periprocedural necrosis and infarction after coronary intervention. J Am Coll Cardiol. 2011;57(6):653-661.

40. Kilcullen N, Viswanathan K, Das R, et al; EMMACE-2 Investigators. Heart-type fatty acid–binding protein predicts long-term mortality after acute coronary syndrome and identifies high-risk patients across the range of troponin values. J Am Coll Cardiol. 2007;50(21):2061-2067.

41. Viswanathan K, Kilcullen N, Morrell C, et al. Heart-type fatty acid–binding protein predicts long-term mortality and re-infarction in consecutive patients with suspected acute coronary syndrome who are troponin-negative. J Am Coll Cardiol. 2010; 55(23): 2590-2598.

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44. Piwowar A, Knapik-Kordecka M, Warwas M. Ischemia-modified albumin level in type 2 diabetes mellitus: preliminary report. Dis Markers. 2008; 24(6):311-317.

45. Prefumo F, Gaze DC, Papageorghiou AT, et al. First trimester maternal serum ischaemia-modified albumin: a marker of hypoxia-ischaemia-driven early trophoblast development. Hum Reprod. 2007; 22(7):2029-2032.

46. Gunduz A, Turedi S, Mentese A, et al. Ischemia-modified albumin levels in cerebrovascular accidents. Am J Emerg Med. 2008;26(8):874-878.

47. Turedi S, Cinar O, Kaldirim U, et al. Ischemia-modified albumin levels in carbon monoxide poisoning. Am J Emerg Med. 2011;29(6):675-681.

48. Sbarouni E, Georgiadou P, Voudris V. Ischemia modified albumin changes: review and clinical implications. Clin Chem Lab Med. 2011;49(2):177-184.

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Since the 1950s, researchers and clinicians have sought a simple chemical biomarker that would aid in the diagnosis and treatment of cardiovascular disease (CVD). An initial discovery was that proteins normally found within cardiac myocytes are released into the circulation when the myocardial cell membrane loses its integrity as a result of hypoxic injury.¹ Over the past 60 years, major advances have been made to distinguish which proteins are highly cardiac specific, and which are suggestive of other pathologic cardiovascular processes.

In the past 15 to 20 years, significant data have emerged that support the role of cardiac-specific troponins in the cardiac disease process, making their measurement an important consideration in diagnosis and clinical decision-making for patients with various forms of CVD.^2-7 With the exception of 1918, CVD has accounted for more deaths in the United States than any other illness in every year since 1900.⁸ It has been suggested that nearly 2,300 Americans die of CVD each day—an average of one death every 38 seconds. The direct and indirect costs of CVD for 2010 were projected at $503.2 billion—including $155 billion for total hospital costs alone.⁹ By comparison, a 2010 projection from the National Cancer Institute was $124.57 billion for the direct costs of cancer care.¹⁰

It is imperative for practitioners in all areas of medicine to have a working knowledge of the role of cardiac biomarkers and their potential impact on patients’ overall health. Primary care clinicians in particular should be familiar with the release kinetics of certain cardiac biomarkers to aid in the diagnosis and treatment of the cardiac patient. This article is intended as an overview of the cardiac biomarkers that are being used in practice today, and to review the novel biomarkers that may have an impact on the way clinicians practice in the near future.

BIOMARKERS CURRENTLY IN USE

Cardiac Troponins

The cardiac-specific troponins (cTn) are an integral component of the myosin-actin binding complex found in striated muscle tissue. The troponin complex includes three regulatory proteins: troponin C, troponin I, and troponin T. The genes that code for troponin C are identical in skeletal and cardiac tissue; for this reason, troponin C becomes much less cardiospecific.

However, cardiac troponin T (cTnT) and cardiac troponin I (cTnI) have differing amino acid sequences, making it possible to develop highly sensitive immunoassays to detect circulating antibody-troponin complexes after myocardial cell injury, as seen in acute coronary syndrome (ACS).12-14 No cross-reactivity occurs between skeletal and cardiac sources, indicating the unique cardiospecificity of the cTn proteins.11

Of note, there are numerous patient populations in which elevated cTn may be found; the associated conditions are outlined in Table 1.^11,15,16 In particular, elevations in cTn (more specifically cTnT) are commonly observed in patients with end-stage renal disease (ESRD).^11,17 The pathogenesis of elevated cTnT is not completely understood but has been proposed as a promising prognostic tool for use in patients with ESRD. Elevated levels of cTnT identify patients whose chance of survival is poor, with an increased risk for cardiac death.⁷ It should be noted that a significant proportion of patients with chronic renal failure succumb to cardiovascular death.¹⁷

Recently, deFilippi and colleagues¹⁸ reported a correlation between trace amounts of circulating cTnT in older patients not known to have CVD and an increased risk for future heart failure or even cardiovascular-related death. This novel finding may add valuable information to the screening and risk stratification of relatively healthy but sedentary individuals older than 65.

Elevations in cTn can be seen as early as two to four hours after myocardial injury.¹¹ A small portion of cTnT and cTnI is found within the myocardial cells’ cytosol and is not bound to the troponin complex, which begins to degrade after cell injury.^1,14 This cytosolic pool allows for earlier recognition of cardiac injury. As increasingly sensitive assays are developed, rises in cTn levels can be detected earlier after symptom onset, thus making the use of less specific early biomarkers, such as myoglobin and creatine kinase–MB, obsolete.

Because of the continuous release of structural proteins from the degrading myocardial tissue, elevations of cTnI may persist for seven to 10 days, while cTnT elevations can continue for 10 to 14 days postinfarction.¹¹ This prolonged period allows for detection of even very slight cardiac damage and provides an advantage for identification and treatment of high-risk patients. When measured 72 hours after infarction, cTnI can also provide prognostic information, such as the potential size of the affected myocardial area.^5,6 This, too, facilitates risk stratification. Timing of the release of key biomarkers can be seen in Table 2.^11,19-21

Natriuretic Peptides

The natriuretic peptides are cardiac neurohormones that are released in response to myocardial wall stress.¹¹ B-type natriuretic peptide (BNP; previously known as brain natriuretic peptide) is synthesized and released from the ventricular myocardium in times of volume expansion and increased pressure burden. Initially, the prohormone proBNP is released and is enzymatically cleaved to N-terminal proBNP (NT-proBNP) and then to “mature” BNP.¹¹

Today, BNP is used widely as a biomarker for congestive heart failure.²² In the Breathing Not Properly (BNP) study,²³ BNP was able to accurately distinguish dyspnea caused by heart failure from that with a pulmonary etiology; it was found to be the strongest predictor for the diagnosis of heart failure. In the evaluation of serum BNP, a level below 100 ng/L makes heart failure unlikely (negative predictive value, 90%). If the value rises above 500 ng/L, heart failure is highly likely (positive predictive value, 90%).²³

As for NT-proBNP, levels exceeding 450 ng/L in patients younger than 50 and exceeding 900 ng/L in patients 50 or older have been found highly sensitive and specific for heart failure–related dyspnea.²⁴ Current studies suggest that NT-proBNP may have greater sensitivity and specificity than standard BNP when these age-related cut-off limits are applied.²⁵

Researchers for the International Collaborative of NT-proBNP Study reported that when NT-proBNP was measured in the emergency department (ED) in patients with dyspnea, patients were less likely to require hospitalization for heart failure.²⁶ Instead, patients were presenting with exacerbations of chronic obstructive pulmonary disease, which would best be managed on an outpatient basis. Those who were admitted experienced shorter lengths of stay with subsequent reductions in health care costs, and had no significant difference in readmission or mortality rates.

Use of BNP as a cardiac biomarker does not come without its limitations. In addition to right-sided heart failure, ACS, and MI, elevations in BNP have been associated with septic shock, sepsis, renal dysfunction, and acute pulmonary embolus.²⁷ Correlations have been made between the degree of BNP elevation and the extent of myocardial ischemia; increased levels of both BNP and cTnI were associated with higher mortality rates.²⁸

C-Reactive Protein

Inflammation is known to play a key role in the development of atherosclerotic plaques. Measuring byproducts of the atherosclerotic process, from the initial development of fatty streaks to plaque rupture, can help determine whether a patient is at an increased risk for a cardiovascular event.²⁹ Primary proinflammatory markers from the local site of intravascular inflammation signal messenger cytokines that are altered in the liver via an acute-phase reaction.

One of the major acute-phase reactants, C-reactive protein (CRP) is simply a byproduct of inflammation—yet it has become a major indicator of atherosclerotic plaque stability.³⁰ A high-sensitivity CRP assay (hsCRP) can be a significantly effective predictor for MI, stroke, and peripheral vascular disease, even in patients who appear to be healthy.³¹ Studies have suggested that hsCRP is a better indicator of unstable plaque, and a better predictor of adverse cardiovascular events, than is low-density lipoprotein cholesterol (LDL-C), when these markers are used independently.³² When detected together, however, hsCRP and LDL-C elevations have been shown to be an even better predictor of adverse events in patients with no overt cardiovascular risk factors.³¹

As a risk factor, elevated hsCRP has been called as important as smoking or hypertension—highlighting the role of inflammation in formation of atherosclerosis at every level.³³

In the evaluation of serum hsCRP, it is important to know that levels tend to be stable over long periods of time, have no circadian rhythms, and are not affected by various prandial states. Levels can be measured conveniently during the standard annual cholesterol screening. Relative cardiovascular risk is deemed low, medium, and high, in patients with an hsCRP measurement of less than 1 mg/L, 1 to 3 mg/L, and greater than 3 mg/L, respectively.² Values exceeding 8.0 mg/L may be consistent with an acute infectious or inflammatory process, thus exposing the nonspecific nature of this popular biomarker.³⁴ However, when used in conjunction with cTn, BNP, and patient history, hsCRP still proves to be an important clinical tool, offering prognostic information to facilitate clinical decision making.

Chronically elevated hsCRP signifies a very high risk for future cardiovascular events and should prompt the clinician to target the patient’s modifiable risk factors, including consideration of statin therapy as a part of the treatment regimen.³⁵ According to results from the PROVE IT–TIMI 22 trial,³⁵ statin use appears particularly cardioprotective in patients whose hsCRP levels are lower than 2 mg/L and who maintain LDL-C below 70 mg/dL. Researchers for this study group recommend monitoring hsCRP along with serum lipids for a more comprehensive cardiovascular risk profile.

Creatine Kinase

Three isoenzymes of creatine kinase (CK) exist: MM (skeletal muscle type), BB (brain type), and MB (myocardial band). The CK-MB isoenzyme was the diagnostic marker of choice for ACS until the introduction of cardiac-specific troponins in the early 1990s.^36,37

CK-MB is an intracellular carrier protein for high-energy phosphates, found in higher concentrations in the myocardium than are the other CK isoenzymes.¹¹ CK-MB accounts for about 15% of total CK, but it also exists in skeletal muscle and to a lesser extent in the small intestine, diaphragm, uterus, and prostate.²¹ As with most cardiac biomarkers, cardiospecificity of CK-MB is not 100%, and false-positive elevations can occur in a multitude of clinical settings, including significant musculoskeletal injury, heavy exertion, and myopathies.¹¹

CK-MB is detectable three to four hours after myocardial injury, peaks at 24 hours, and returns to normal in 48 to 72 hours. CK-MB may be used to evaluate for ACS if cardiac troponin assays are not accessible,²¹ but its usefulness is limited during the early hours of ACS onset and after 72 hours.

The relative index of CK-MB to total CK (CK-MB/CK) can help the clinician assess whether the rise in CK-MB is attributable to a skeletal muscle source (CK-MB/CK < 3) or a cardiac source (CK-MB/CK > 5, indicating myocardial release of CK-MB). A relative index that falls between 3 and 5 warrants further investigation with serial analyses.³⁶ It may also be helpful to know that a CK-MB elevation associated with skeletal muscle release tends to persist and plateau over a period of several days—as opposed to CK-MB elevation with a myocardial source, which follows the time course stated above.²¹

In a 2006 study that included nearly 30,000 patients, it was found that 28% of those with ACS had conflicting results between troponin levels and CK-MB.³⁸ Patients with no elevations in cardiac troponins but elevations in CK-MB had no significant increased risk for in-hospital mortality, compared with patients with negative results for both markers. Thus, an isolated elevation in CK-MB has limited prognostic value in patients with negative troponin levels.

By contrast, however, Lim et al³⁹ recently found that elevations in CK-MB were closely associated with perioperative necrosis and MI after percutaneous coronary intervention (PCI) as a result of currently oversensitive thresholds for cTnI. Thus, CK-MB use may play a role as an independent marker of necrosis in certain situations.

Myoglobin

Because of its small molecular size, myoglobin has timely release kinetics, with elevations appreciable before those of CK-MB or cTn.^11,21 Myoglobin typically rises one to four hours after myocardial injury, peaks at six to 12 hours, and returns to normal within 24 hours. For this reason, it has held special interest as an early marker of cardiac injury.

With its early release/degradation kinetics, myoglobin may serve as a marker for reinfarction.²¹ It can also be used to assess further damage to the myocardium, as seen with distal thrombus embolization or coronary artery manipulation. However, troponin values provide similar information on reinfarction status.⁴

An established shortcoming of myoglobin as an early marker of necrosis is its lack of cardiac specificity, as it is found extensively in skeletal muscle.²¹ Patients who present with inflammation, trauma, or significant skeletal muscle injury can have extremely high levels of serum myoglobin without myocardial involvement. Since 2000, when cTn was designated the myocardial biomarker of choice (according to the revised definition of MI, as presented that year by the European Society of Cardiology and American College of Cardiology), the use of myoglobin to identify ACS has been considered obsolete.¹⁴

NOVEL BIOMARKERS OF CARDIOVASCULAR DISEASE

Heart-Type Fatty Acid–Binding Protein

A low–molecular-weight protein, heart-type fatty acid–binding protein (H-FABP) is involved in the intracellular uptake and buffering of myocardial free fatty acids. Because its molecular size is similar to that of troponin, it is rapidly released from the cytosol and has been proposed as an early sensitive marker of acute MI.⁴⁰ In a 2010 study, H-FABP was shown to be of additional prognostic value when used in conjunction with cTnI in patients at low to moderate risk for suspected ACS.⁴¹ According to the known release kinetics of H-FABP after myocardial ischemia or infarct, a rise is detectable as early as 1.5 hours after symptom onset. The marker peaks after four to six hours and, because of rapid renal clearance, returns to baseline within 20 hours.²⁰

Interpreting results may be hindered in the patient with impaired renal function—with not only higher levels, but sustained levels of H-FABP.²⁰ Early assays used antibodies to detect circulating H-FABP levels, but cross-reactivity occurring between other fatty acid–binding protein types have limited the clinical applications of H-FABP testing.²⁰ As more highly specific assays are produced, more practical protocols can be implemented to confirm the presence of ACS in patients presenting early to the ED with apparent ACS.

Ischemia-Modified Albumin

A biomarker that could detect ischemia alone would help identify patients at highest risk for infarction; immediate intervention could then prevent the progression of ACS, as evidenced by rising markers of necrosis. Ischemia-modified albumin (IMA), which is produced rapidly when circulating albumin comes into contact with ischemic myocardial tissue, has been touted as such a biomarker.⁴²

Several changes occur in the human albumin molecule in the presence of ischemia, including its ability to bind transition metals—especially cobalt. This discovery led to the creation of an albumin-cobalt–binding assay, approved by the FDA for rapid detection of myocardial ischemia.¹⁹ When artificial ischemia is produced by ­balloon inflation during percutaneous coronary angioplasty, IMA levels can be detected, using the assay, within minutes of coronary artery occlusion. Levels tend to peak within six hours and can be elevated for as long as 12 hours.¹⁹

When IMA is used in conjunction with ECG findings and cTnT levels, a sensitivity of 97% for detecting ACS can be achieved. This could reduce the number of patients being discharged from the ED with occult ACS,⁴³ giving IMA a potentially important precautionary and supplemental role. As with most cardiac biomarkers, IMA alone is not 100% specific for ACS since it is also present in other ischemic conditions, thus hindering its usefulness in clinical practice. Elevations had been reported in patients with liver cirrhosis, uncontrolled type 2 diabetes mellitus, obstetric conditions associated with placental ischemia, carbon monoxide poisoning, and cerebrovascular ischemia.^44-47

Recent suggestions to use IMA to rule out rather than diagnose ACS show promise, since the absence of this acute-phase reactant should exclude the presence of myocardial ischemia.⁴⁸ Further studies are needed to determine the exact physiology of IMA production in order to identify its cardiac specificity for clinical use.⁴⁹

Homocysteine

As a marker of increased cardiovascular risk, homocysteine is thought to have multiple effects on the cardiovascular system. These include endothelial dysfunction, decreased arteriole vasodilation (ie, reduced release of nitric oxide), increased platelet activation, increased production of free radicals, and increased LDL oxidation with arteriole lipid accumulation.⁵⁰

In patients with severe hyperhomocysteinemia (ie, homocysteine serum levels > 100 mol/L), risk for premature atherothrombosis and venous thromboembolism is increased. In the general public, mildly elevated homocysteine levels (> 15 mol/L) have been attributed to insufficient dietary intake of folic acid. Folate in its natural form has been known to decrease serum homocysteine levels by 25%, if supplemented appropriately with vitamins B₆ and B₁₂.⁵⁰

In recent years, folate deficiency has declined due to enrichment of certain foods with this crucial nutrient, initially mandated to decrease the incidence of neural tube defects in developing embryos. From a cardiovascular standpoint, researchers have been unable to determine whether elevated homocysteine increases CVD risk or is simply a marker of existing disease burden.⁵⁰ In clinical trials in which subjects took B-vitamins supplemented with folate, homocysteine levels were reduced; yet in one study, stroke risk was not reduced in patients with a history of stroke⁵¹; in a second, in-stent restenosis was more common in patients who took the supplement after undergoing angioplasty⁵²; and in a third, patients following the vitamin regimen after a recent acute MI proved to be at higher cardiovascular risk.⁵³

As a result of this conflicting evidence, no recommendations have been made for routine homocysteine screening except in patients with a history of markedly premature atherosclerosis or a family history of early-onset acute MI or stroke.⁵⁰ Monitoring may be advisable in patients who take a folate antagonist (eg, methotrexate, carbamazepine), considering the risk for folate deficiency and subsequent hyperhomocysteinemia.

ACUTE INFLAMMATORY MARKERS OF PLAQUE RUPTURE OR VULNERABILITY

Myeloperoxidase

Many researchers have taken a particular interest in the acute substances formed as a result of atherothrombotic plaque inflammation or rupture. One such biomarker is myeloperoxidase (MPO), which is thought to be expressed from the degranulation of activated leukocytes found in atherosclerotic plaques. This acute-phase enzyme may convert LDL into a high-uptake form for macrophages, leading to foam cell formation and depletion of nitric oxide, contributing to additional ischemia by way of vasoconstriction.⁵⁴

Recently, a high systemic MPO level was found to be a more significant marker of plaque at risk for rupture, compared with already-ruptured plaque.⁵⁵ Although MPO elevations may also occur in a number of inflammatory, infectious, or infiltrative conditions, the association between MPO, inflammation, and oxidative stress supports its use as a marker for plaque that is vulnerable to rupture.^56,57

Serum levels of MPO have been shown to predict increased risk for subsequent death or MI in patients who present to the ED with ACS, independent of other cardiac risk factors or cardiac biomarkers. In a 2001 study, Zhang et al⁵⁴ established an association between elevated MPO levels and angiographically proven coronary atherosclerosis, with a 20-fold higher risk for coronary artery disease; earlier this year, Oemrawsingh et al⁵⁸ reported an independent association between MPO and long-term adverse outcomes in patients who presented with non–ST-segment elevation ACS. Thus, MPO may be a significant indicator of vascular inflammation.⁵⁷

Soluble CD40 Ligand

In the 1980s, postmortem studies confirmed that erosions or ruptures in atherosclerotic fibrous caps lead to platelet activation—the main pathophysiologic contributor in ACS.⁵⁹ This fundamental actuality suggests that biomarkers of platelet activation may provide supplemental information in patients who present with chest pain of cardiac origin. Another acute inflammatory marker, soluble CD40 ligand, is a marker of active platelet stimulation.⁶⁰ Increased serum levels of soluble CD40 ligand have been correlated to increased risk for cardiovascular events in apparently healthy women.⁶¹

Soluble CD40 ligand, expressed within seconds of platelet activation, is also commonly found on various leukocytes, endothelial cells, and smooth-­muscle cells.⁶⁰ This may provide insight into cardiovascular disease progression and plaque deterioration that precedes the events of ACS.

Therapeutic antiplatelet medications are now the mainstay in the treatment and prevention of cardiovascular complications associated with ischemic thrombus formation.¹¹ Platelet biomarkers are likely to play an essential supplemental role in the diagnosis of ACS.

Pregnancy-Associated Plasma Protein A

Additional risk-stratifying biomarkers include those that may determine whether a patient has plaques that are acutely vulnerable to rupture. Pregnancy-associated plasma protein A (PAPP-A), first detected in the 1970s in the circulation of pregnant women, is now widely used in first-trimester screening for fetal trisomy.⁶²

Since then, it has been found that PAPP-A, which is theorized to be produced by vascular smooth-muscle cells, is extensively expressed in unstable coronary artery plaques, while minimally expressed in stable plaques.⁶³ Since a significant proportion of patients who present with symptoms of ACS have normal cTn levels, PAPP-A may help identify patients who are at increased risk for subsequent short-term cardiovascular complications resulting from occult disease.⁶⁴ This relatively new marker may also prove useful for screening in the office setting, identifying outpatients who are at high cardiovascular risk. Further studies are needed to define the release kinetics of PAPP-A, guiding clinicians in its implementation and clinical use.

CONCLUSION

When used in conjunction with the history and physical exam, cardiac biomarkers can provide a simple, noninvasive means to further the clinician’s exploration into a suspected underlying cardiovascular process. As advances continue in the understanding of the pathogenesis of heart disease, new interpretations of existing markers and discovery of novel markers may allow for specific therapeutic interventions to improve patient outcomes.

It is important to note that the list of biomarkers described here is by no means complete, and there is continued interest in finding more specific and sensitive markers of heart disease. Numerous cardiovascular organizations are now suggesting a shift toward a multi-marker strategy to determine the best etiology in the patient who presents with decompensating cardiovascular disease. A change in cardiac enzyme panels may be inevitable in the near future. Practicing PAs and NPs, particularly those who care for patients at risk for CVD, should remain up-to-date and proficient in interpreting those results to help determine the best course of action for each patient.

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Since the 1950s, researchers and clinicians have sought a simple chemical biomarker that would aid in the diagnosis and treatment of cardiovascular disease (CVD). An initial discovery was that proteins normally found within cardiac myocytes are released into the circulation when the myocardial cell membrane loses its integrity as a result of hypoxic injury.¹ Over the past 60 years, major advances have been made to distinguish which proteins are highly cardiac specific, and which are suggestive of other pathologic cardiovascular processes.

In the past 15 to 20 years, significant data have emerged that support the role of cardiac-specific troponins in the cardiac disease process, making their measurement an important consideration in diagnosis and clinical decision-making for patients with various forms of CVD.^2-7 With the exception of 1918, CVD has accounted for more deaths in the United States than any other illness in every year since 1900.⁸ It has been suggested that nearly 2,300 Americans die of CVD each day—an average of one death every 38 seconds. The direct and indirect costs of CVD for 2010 were projected at $503.2 billion—including $155 billion for total hospital costs alone.⁹ By comparison, a 2010 projection from the National Cancer Institute was $124.57 billion for the direct costs of cancer care.¹⁰

It is imperative for practitioners in all areas of medicine to have a working knowledge of the role of cardiac biomarkers and their potential impact on patients’ overall health. Primary care clinicians in particular should be familiar with the release kinetics of certain cardiac biomarkers to aid in the diagnosis and treatment of the cardiac patient. This article is intended as an overview of the cardiac biomarkers that are being used in practice today, and to review the novel biomarkers that may have an impact on the way clinicians practice in the near future.

BIOMARKERS CURRENTLY IN USE

Cardiac Troponins

The cardiac-specific troponins (cTn) are an integral component of the myosin-actin binding complex found in striated muscle tissue. The troponin complex includes three regulatory proteins: troponin C, troponin I, and troponin T. The genes that code for troponin C are identical in skeletal and cardiac tissue; for this reason, troponin C becomes much less cardiospecific.

However, cardiac troponin T (cTnT) and cardiac troponin I (cTnI) have differing amino acid sequences, making it possible to develop highly sensitive immunoassays to detect circulating antibody-troponin complexes after myocardial cell injury, as seen in acute coronary syndrome (ACS).12-14 No cross-reactivity occurs between skeletal and cardiac sources, indicating the unique cardiospecificity of the cTn proteins.11

Of note, there are numerous patient populations in which elevated cTn may be found; the associated conditions are outlined in Table 1.^11,15,16 In particular, elevations in cTn (more specifically cTnT) are commonly observed in patients with end-stage renal disease (ESRD).^11,17 The pathogenesis of elevated cTnT is not completely understood but has been proposed as a promising prognostic tool for use in patients with ESRD. Elevated levels of cTnT identify patients whose chance of survival is poor, with an increased risk for cardiac death.⁷ It should be noted that a significant proportion of patients with chronic renal failure succumb to cardiovascular death.¹⁷

Recently, deFilippi and colleagues¹⁸ reported a correlation between trace amounts of circulating cTnT in older patients not known to have CVD and an increased risk for future heart failure or even cardiovascular-related death. This novel finding may add valuable information to the screening and risk stratification of relatively healthy but sedentary individuals older than 65.

Elevations in cTn can be seen as early as two to four hours after myocardial injury.¹¹ A small portion of cTnT and cTnI is found within the myocardial cells’ cytosol and is not bound to the troponin complex, which begins to degrade after cell injury.^1,14 This cytosolic pool allows for earlier recognition of cardiac injury. As increasingly sensitive assays are developed, rises in cTn levels can be detected earlier after symptom onset, thus making the use of less specific early biomarkers, such as myoglobin and creatine kinase–MB, obsolete.

Because of the continuous release of structural proteins from the degrading myocardial tissue, elevations of cTnI may persist for seven to 10 days, while cTnT elevations can continue for 10 to 14 days postinfarction.¹¹ This prolonged period allows for detection of even very slight cardiac damage and provides an advantage for identification and treatment of high-risk patients. When measured 72 hours after infarction, cTnI can also provide prognostic information, such as the potential size of the affected myocardial area.^5,6 This, too, facilitates risk stratification. Timing of the release of key biomarkers can be seen in Table 2.^11,19-21

Natriuretic Peptides

The natriuretic peptides are cardiac neurohormones that are released in response to myocardial wall stress.¹¹ B-type natriuretic peptide (BNP; previously known as brain natriuretic peptide) is synthesized and released from the ventricular myocardium in times of volume expansion and increased pressure burden. Initially, the prohormone proBNP is released and is enzymatically cleaved to N-terminal proBNP (NT-proBNP) and then to “mature” BNP.¹¹

Today, BNP is used widely as a biomarker for congestive heart failure.²² In the Breathing Not Properly (BNP) study,²³ BNP was able to accurately distinguish dyspnea caused by heart failure from that with a pulmonary etiology; it was found to be the strongest predictor for the diagnosis of heart failure. In the evaluation of serum BNP, a level below 100 ng/L makes heart failure unlikely (negative predictive value, 90%). If the value rises above 500 ng/L, heart failure is highly likely (positive predictive value, 90%).²³

As for NT-proBNP, levels exceeding 450 ng/L in patients younger than 50 and exceeding 900 ng/L in patients 50 or older have been found highly sensitive and specific for heart failure–related dyspnea.²⁴ Current studies suggest that NT-proBNP may have greater sensitivity and specificity than standard BNP when these age-related cut-off limits are applied.²⁵

Researchers for the International Collaborative of NT-proBNP Study reported that when NT-proBNP was measured in the emergency department (ED) in patients with dyspnea, patients were less likely to require hospitalization for heart failure.²⁶ Instead, patients were presenting with exacerbations of chronic obstructive pulmonary disease, which would best be managed on an outpatient basis. Those who were admitted experienced shorter lengths of stay with subsequent reductions in health care costs, and had no significant difference in readmission or mortality rates.

Use of BNP as a cardiac biomarker does not come without its limitations. In addition to right-sided heart failure, ACS, and MI, elevations in BNP have been associated with septic shock, sepsis, renal dysfunction, and acute pulmonary embolus.²⁷ Correlations have been made between the degree of BNP elevation and the extent of myocardial ischemia; increased levels of both BNP and cTnI were associated with higher mortality rates.²⁸

C-Reactive Protein

Inflammation is known to play a key role in the development of atherosclerotic plaques. Measuring byproducts of the atherosclerotic process, from the initial development of fatty streaks to plaque rupture, can help determine whether a patient is at an increased risk for a cardiovascular event.²⁹ Primary proinflammatory markers from the local site of intravascular inflammation signal messenger cytokines that are altered in the liver via an acute-phase reaction.

One of the major acute-phase reactants, C-reactive protein (CRP) is simply a byproduct of inflammation—yet it has become a major indicator of atherosclerotic plaque stability.³⁰ A high-sensitivity CRP assay (hsCRP) can be a significantly effective predictor for MI, stroke, and peripheral vascular disease, even in patients who appear to be healthy.³¹ Studies have suggested that hsCRP is a better indicator of unstable plaque, and a better predictor of adverse cardiovascular events, than is low-density lipoprotein cholesterol (LDL-C), when these markers are used independently.³² When detected together, however, hsCRP and LDL-C elevations have been shown to be an even better predictor of adverse events in patients with no overt cardiovascular risk factors.³¹

As a risk factor, elevated hsCRP has been called as important as smoking or hypertension—highlighting the role of inflammation in formation of atherosclerosis at every level.³³

In the evaluation of serum hsCRP, it is important to know that levels tend to be stable over long periods of time, have no circadian rhythms, and are not affected by various prandial states. Levels can be measured conveniently during the standard annual cholesterol screening. Relative cardiovascular risk is deemed low, medium, and high, in patients with an hsCRP measurement of less than 1 mg/L, 1 to 3 mg/L, and greater than 3 mg/L, respectively.² Values exceeding 8.0 mg/L may be consistent with an acute infectious or inflammatory process, thus exposing the nonspecific nature of this popular biomarker.³⁴ However, when used in conjunction with cTn, BNP, and patient history, hsCRP still proves to be an important clinical tool, offering prognostic information to facilitate clinical decision making.

Chronically elevated hsCRP signifies a very high risk for future cardiovascular events and should prompt the clinician to target the patient’s modifiable risk factors, including consideration of statin therapy as a part of the treatment regimen.³⁵ According to results from the PROVE IT–TIMI 22 trial,³⁵ statin use appears particularly cardioprotective in patients whose hsCRP levels are lower than 2 mg/L and who maintain LDL-C below 70 mg/dL. Researchers for this study group recommend monitoring hsCRP along with serum lipids for a more comprehensive cardiovascular risk profile.

Creatine Kinase

Three isoenzymes of creatine kinase (CK) exist: MM (skeletal muscle type), BB (brain type), and MB (myocardial band). The CK-MB isoenzyme was the diagnostic marker of choice for ACS until the introduction of cardiac-specific troponins in the early 1990s.^36,37

CK-MB is an intracellular carrier protein for high-energy phosphates, found in higher concentrations in the myocardium than are the other CK isoenzymes.¹¹ CK-MB accounts for about 15% of total CK, but it also exists in skeletal muscle and to a lesser extent in the small intestine, diaphragm, uterus, and prostate.²¹ As with most cardiac biomarkers, cardiospecificity of CK-MB is not 100%, and false-positive elevations can occur in a multitude of clinical settings, including significant musculoskeletal injury, heavy exertion, and myopathies.¹¹

CK-MB is detectable three to four hours after myocardial injury, peaks at 24 hours, and returns to normal in 48 to 72 hours. CK-MB may be used to evaluate for ACS if cardiac troponin assays are not accessible,²¹ but its usefulness is limited during the early hours of ACS onset and after 72 hours.

The relative index of CK-MB to total CK (CK-MB/CK) can help the clinician assess whether the rise in CK-MB is attributable to a skeletal muscle source (CK-MB/CK < 3) or a cardiac source (CK-MB/CK > 5, indicating myocardial release of CK-MB). A relative index that falls between 3 and 5 warrants further investigation with serial analyses.³⁶ It may also be helpful to know that a CK-MB elevation associated with skeletal muscle release tends to persist and plateau over a period of several days—as opposed to CK-MB elevation with a myocardial source, which follows the time course stated above.²¹

In a 2006 study that included nearly 30,000 patients, it was found that 28% of those with ACS had conflicting results between troponin levels and CK-MB.³⁸ Patients with no elevations in cardiac troponins but elevations in CK-MB had no significant increased risk for in-hospital mortality, compared with patients with negative results for both markers. Thus, an isolated elevation in CK-MB has limited prognostic value in patients with negative troponin levels.

By contrast, however, Lim et al³⁹ recently found that elevations in CK-MB were closely associated with perioperative necrosis and MI after percutaneous coronary intervention (PCI) as a result of currently oversensitive thresholds for cTnI. Thus, CK-MB use may play a role as an independent marker of necrosis in certain situations.

Myoglobin

Because of its small molecular size, myoglobin has timely release kinetics, with elevations appreciable before those of CK-MB or cTn.^11,21 Myoglobin typically rises one to four hours after myocardial injury, peaks at six to 12 hours, and returns to normal within 24 hours. For this reason, it has held special interest as an early marker of cardiac injury.

With its early release/degradation kinetics, myoglobin may serve as a marker for reinfarction.²¹ It can also be used to assess further damage to the myocardium, as seen with distal thrombus embolization or coronary artery manipulation. However, troponin values provide similar information on reinfarction status.⁴

An established shortcoming of myoglobin as an early marker of necrosis is its lack of cardiac specificity, as it is found extensively in skeletal muscle.²¹ Patients who present with inflammation, trauma, or significant skeletal muscle injury can have extremely high levels of serum myoglobin without myocardial involvement. Since 2000, when cTn was designated the myocardial biomarker of choice (according to the revised definition of MI, as presented that year by the European Society of Cardiology and American College of Cardiology), the use of myoglobin to identify ACS has been considered obsolete.¹⁴

NOVEL BIOMARKERS OF CARDIOVASCULAR DISEASE

Heart-Type Fatty Acid–Binding Protein

A low–molecular-weight protein, heart-type fatty acid–binding protein (H-FABP) is involved in the intracellular uptake and buffering of myocardial free fatty acids. Because its molecular size is similar to that of troponin, it is rapidly released from the cytosol and has been proposed as an early sensitive marker of acute MI.⁴⁰ In a 2010 study, H-FABP was shown to be of additional prognostic value when used in conjunction with cTnI in patients at low to moderate risk for suspected ACS.⁴¹ According to the known release kinetics of H-FABP after myocardial ischemia or infarct, a rise is detectable as early as 1.5 hours after symptom onset. The marker peaks after four to six hours and, because of rapid renal clearance, returns to baseline within 20 hours.²⁰

Interpreting results may be hindered in the patient with impaired renal function—with not only higher levels, but sustained levels of H-FABP.²⁰ Early assays used antibodies to detect circulating H-FABP levels, but cross-reactivity occurring between other fatty acid–binding protein types have limited the clinical applications of H-FABP testing.²⁰ As more highly specific assays are produced, more practical protocols can be implemented to confirm the presence of ACS in patients presenting early to the ED with apparent ACS.

Ischemia-Modified Albumin

A biomarker that could detect ischemia alone would help identify patients at highest risk for infarction; immediate intervention could then prevent the progression of ACS, as evidenced by rising markers of necrosis. Ischemia-modified albumin (IMA), which is produced rapidly when circulating albumin comes into contact with ischemic myocardial tissue, has been touted as such a biomarker.⁴²

Several changes occur in the human albumin molecule in the presence of ischemia, including its ability to bind transition metals—especially cobalt. This discovery led to the creation of an albumin-cobalt–binding assay, approved by the FDA for rapid detection of myocardial ischemia.¹⁹ When artificial ischemia is produced by ­balloon inflation during percutaneous coronary angioplasty, IMA levels can be detected, using the assay, within minutes of coronary artery occlusion. Levels tend to peak within six hours and can be elevated for as long as 12 hours.¹⁹

When IMA is used in conjunction with ECG findings and cTnT levels, a sensitivity of 97% for detecting ACS can be achieved. This could reduce the number of patients being discharged from the ED with occult ACS,⁴³ giving IMA a potentially important precautionary and supplemental role. As with most cardiac biomarkers, IMA alone is not 100% specific for ACS since it is also present in other ischemic conditions, thus hindering its usefulness in clinical practice. Elevations had been reported in patients with liver cirrhosis, uncontrolled type 2 diabetes mellitus, obstetric conditions associated with placental ischemia, carbon monoxide poisoning, and cerebrovascular ischemia.^44-47

Recent suggestions to use IMA to rule out rather than diagnose ACS show promise, since the absence of this acute-phase reactant should exclude the presence of myocardial ischemia.⁴⁸ Further studies are needed to determine the exact physiology of IMA production in order to identify its cardiac specificity for clinical use.⁴⁹

Homocysteine

As a marker of increased cardiovascular risk, homocysteine is thought to have multiple effects on the cardiovascular system. These include endothelial dysfunction, decreased arteriole vasodilation (ie, reduced release of nitric oxide), increased platelet activation, increased production of free radicals, and increased LDL oxidation with arteriole lipid accumulation.⁵⁰

In patients with severe hyperhomocysteinemia (ie, homocysteine serum levels > 100 mol/L), risk for premature atherothrombosis and venous thromboembolism is increased. In the general public, mildly elevated homocysteine levels (> 15 mol/L) have been attributed to insufficient dietary intake of folic acid. Folate in its natural form has been known to decrease serum homocysteine levels by 25%, if supplemented appropriately with vitamins B₆ and B₁₂.⁵⁰

In recent years, folate deficiency has declined due to enrichment of certain foods with this crucial nutrient, initially mandated to decrease the incidence of neural tube defects in developing embryos. From a cardiovascular standpoint, researchers have been unable to determine whether elevated homocysteine increases CVD risk or is simply a marker of existing disease burden.⁵⁰ In clinical trials in which subjects took B-vitamins supplemented with folate, homocysteine levels were reduced; yet in one study, stroke risk was not reduced in patients with a history of stroke⁵¹; in a second, in-stent restenosis was more common in patients who took the supplement after undergoing angioplasty⁵²; and in a third, patients following the vitamin regimen after a recent acute MI proved to be at higher cardiovascular risk.⁵³

As a result of this conflicting evidence, no recommendations have been made for routine homocysteine screening except in patients with a history of markedly premature atherosclerosis or a family history of early-onset acute MI or stroke.⁵⁰ Monitoring may be advisable in patients who take a folate antagonist (eg, methotrexate, carbamazepine), considering the risk for folate deficiency and subsequent hyperhomocysteinemia.

ACUTE INFLAMMATORY MARKERS OF PLAQUE RUPTURE OR VULNERABILITY

Myeloperoxidase

Many researchers have taken a particular interest in the acute substances formed as a result of atherothrombotic plaque inflammation or rupture. One such biomarker is myeloperoxidase (MPO), which is thought to be expressed from the degranulation of activated leukocytes found in atherosclerotic plaques. This acute-phase enzyme may convert LDL into a high-uptake form for macrophages, leading to foam cell formation and depletion of nitric oxide, contributing to additional ischemia by way of vasoconstriction.⁵⁴

Recently, a high systemic MPO level was found to be a more significant marker of plaque at risk for rupture, compared with already-ruptured plaque.⁵⁵ Although MPO elevations may also occur in a number of inflammatory, infectious, or infiltrative conditions, the association between MPO, inflammation, and oxidative stress supports its use as a marker for plaque that is vulnerable to rupture.^56,57

Serum levels of MPO have been shown to predict increased risk for subsequent death or MI in patients who present to the ED with ACS, independent of other cardiac risk factors or cardiac biomarkers. In a 2001 study, Zhang et al⁵⁴ established an association between elevated MPO levels and angiographically proven coronary atherosclerosis, with a 20-fold higher risk for coronary artery disease; earlier this year, Oemrawsingh et al⁵⁸ reported an independent association between MPO and long-term adverse outcomes in patients who presented with non–ST-segment elevation ACS. Thus, MPO may be a significant indicator of vascular inflammation.⁵⁷

Soluble CD40 Ligand

In the 1980s, postmortem studies confirmed that erosions or ruptures in atherosclerotic fibrous caps lead to platelet activation—the main pathophysiologic contributor in ACS.⁵⁹ This fundamental actuality suggests that biomarkers of platelet activation may provide supplemental information in patients who present with chest pain of cardiac origin. Another acute inflammatory marker, soluble CD40 ligand, is a marker of active platelet stimulation.⁶⁰ Increased serum levels of soluble CD40 ligand have been correlated to increased risk for cardiovascular events in apparently healthy women.⁶¹

Soluble CD40 ligand, expressed within seconds of platelet activation, is also commonly found on various leukocytes, endothelial cells, and smooth-­muscle cells.⁶⁰ This may provide insight into cardiovascular disease progression and plaque deterioration that precedes the events of ACS.

Therapeutic antiplatelet medications are now the mainstay in the treatment and prevention of cardiovascular complications associated with ischemic thrombus formation.¹¹ Platelet biomarkers are likely to play an essential supplemental role in the diagnosis of ACS.

Pregnancy-Associated Plasma Protein A

Additional risk-stratifying biomarkers include those that may determine whether a patient has plaques that are acutely vulnerable to rupture. Pregnancy-associated plasma protein A (PAPP-A), first detected in the 1970s in the circulation of pregnant women, is now widely used in first-trimester screening for fetal trisomy.⁶²

Since then, it has been found that PAPP-A, which is theorized to be produced by vascular smooth-muscle cells, is extensively expressed in unstable coronary artery plaques, while minimally expressed in stable plaques.⁶³ Since a significant proportion of patients who present with symptoms of ACS have normal cTn levels, PAPP-A may help identify patients who are at increased risk for subsequent short-term cardiovascular complications resulting from occult disease.⁶⁴ This relatively new marker may also prove useful for screening in the office setting, identifying outpatients who are at high cardiovascular risk. Further studies are needed to define the release kinetics of PAPP-A, guiding clinicians in its implementation and clinical use.

CONCLUSION

When used in conjunction with the history and physical exam, cardiac biomarkers can provide a simple, noninvasive means to further the clinician’s exploration into a suspected underlying cardiovascular process. As advances continue in the understanding of the pathogenesis of heart disease, new interpretations of existing markers and discovery of novel markers may allow for specific therapeutic interventions to improve patient outcomes.

It is important to note that the list of biomarkers described here is by no means complete, and there is continued interest in finding more specific and sensitive markers of heart disease. Numerous cardiovascular organizations are now suggesting a shift toward a multi-marker strategy to determine the best etiology in the patient who presents with decompensating cardiovascular disease. A change in cardiac enzyme panels may be inevitable in the near future. Practicing PAs and NPs, particularly those who care for patients at risk for CVD, should remain up-to-date and proficient in interpreting those results to help determine the best course of action for each patient.

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