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Indian Journal of Medical Sciences, Vol. 64, No. 12, December, 2010, pp. 564-576 Practitioner Section Cardiac biomarkers in the diagnosis, prognosis and management of coronary artery disease: A primer for internists Vineet Chopra1, Kim A Eagle2 1 Department of Internal Medicine, Divisions of General Medicine, University of Michigan Health System, Ann Arbor, MI, USA Correspondence Address: Code Number: ms10007 PMID: 21258154 DOI: 10.4103/0019-5359.75934 Abstract Initially coined in 1989, biomarkers have become a cornerstone of modern cardiovascular medicine. The past decade has borne witness to the rapid transition of cardiac biomarkers from bench to bedside in the management of patients with coronary artery disease. The implementation of cardiac biomarkers has transformed the internists' approach to cardiovascular patients. This article reviews several cardiac biomarkers in the context of diagnosis, prognosis, risk-assessment and management of patients at risk of adverse cardiovascular outcomes. Biomarkers are presented according to their relevant role in the atherosclerotic cascade, a pathologic classification of particular value for internists, as it defines the role of these agents in the pathogenesis of heart disease. Where pertinent, limitations of cardiac biomarkers are discussed, thus allowing the discerning practitioner to remain cognizant of situations that may lead to spurious marker elevation or suppression. The review concludes with highlights on novel avenues of biomarker research that promise an exciting future for these entities.Keywords: Biomarker, brain natiuretic peptide, coronary artery disease, C-reactive protein, homocysteine Introduction Coronary artery disease (CAD) is the leading cause of mortality among developed nations. [1] The traditional theory for causation of CAD centers on a complex interplay between genetic and environmental, modifiable and non-modifiable risk factors setting into motion an inflammatory cascade of monocyte migration, lipid oxidation and atheromatous plaque formation. [2],[3] Therefore, the clinical management of the at-risk patient is conventionally directed toward the identification and attenuation of these provocative risk factors. Though clinical assessment and risk factor identification remain cornerstones in estimating the burden of coronary disease, they fail to both adequately predict CAD risk and risk of recurrent events. [4],[5] In fact, conventional risk factors explain <50% of the variability in quantitative measures of atherosclerosis and form an imperfect too1 for identifying coronary disease. [6] Clinicians have thus turned to biomarkers to help better elucidate the presence, propagation and mitigation of coronary disease. [7] The term biomarker is an abbreviation for "biological-marker," a phrase first introduced in 1989. In 2001, the definition of biomarker was refined as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes or pharmacologic responses to a therapeutic intervention". [8] As biomarkers reflect atherosclerosis, they perform a myriad of clinical functions. For example, cardiac troponin (cTn) distinguishes unstable angina from myocardial infarction (MI), radically changing subsequent management. In a study involving >28,000 asymptomatic women, elevated levels of P-selectin and soluble CD40 ligand were predictive of cardiovascular events. [9],[10] A single baseline measure of the biomarker, adiponectin, has been associated with left ventricular dysfunction. [11] Through informing the practitioner on various aspects of cardiac disease, biomarkers offer the potential to optimize and enhance patient management. A suitable cardiac biomarker must possess several properties to serve this formidable clinical task [Table - 1]. Biomarkers of Atherosclerotic Heart Disease Due to their multifaceted roles, cardiac biomarkers can be categorized in numerous ways. [12] A clinically relevant classification is based according to their putative role in the process of atherosclerosis. To that end, cardiac biomarkers may be classified as those that relate to (a) plaque formation, (b) plaque inflammation, instability and ischemia, (c) myocardial necrosis, and lastly (d) cardiac dysfunction [Table - 2]. Biomarkers of Plaque Formation Several molecules initiate the formation of the fatty streak, the first stage of atherosclerosis. These biomarkers form important targets for preventing the initiation of cardiovascular disease. Important among these markers are total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) as well as the novel markers, lipoprotein (a) [Lp(a)] and homocysteine. The role of total cholesterol, LDL and HDL has been well described in the initiation and propagation of atherosclerosis Epidemiologic data link diets high in saturated fat to the development of dyslipidemia and CAD. Conversely, therapy with statins simultaneously reduces both plasma LDL and cardiac event rates. [13] Unlike other risk factors for heart disease, LDL is found both within atherosclerotic plaque and in plasma as oxidized LDL, a form which stimulates macrophages and initiates inflammatory events within the vessel intima. [14] Current NCEP guidelines recommend the therapeutic manipulation of LDL to levels below 100 mg/dL and preferentially to levels of 70 mg/dL in patients at high risk of cardiac events. It is important to note that a recent study confirmed that pure reduction of LDL is insufficient for the amelioration of CAD; rather, obesity and hypertriglyceridemia must also be adequately and concurrently treated to prevent cardiac events. [15] Similarly, lifestyle changes regarding diet and exercise are important cornerstones for the control of LDL. [16] HDL is the smallest and densest of the lipoprotein particles, containing the greatest concentration of protein. Unlike LDL, HDL is protective and transformative in atherosclerosis as it scavenges cholesterol from the vasculature and delivers it for excretion via bile in the liver. Reduced levels of plasma HDL are associated with physical inactivity and are an important and independent risk factor in the development of atherosclerosis. The elevation of plasma HDL in an effort to improve outcomes among those with CAD has long been a goal of research in this area. A recent study has reported early success in the pharmacologic elevation of HDL levels. [17] Lp(a) and homocysteine are novel biomarkers of plaque initiation. Lp(a) is a circulating lipoprotein similar to LDL in composition, but differs by it′s disulfide linkage of apoB-100 to aplolipoprotein B-100. Lp(a) is considered atherogenic and several prospective studies have found elevated Lp(a) levels to be independently associated with future coronary events. [18] For example, a recent study found that individuals in the top tertile of Lp(a) were at significantly higher risk for a cardiovascular events (odds ratio 1.4; P < 0.001) after adjustment for traditional risk factors such as diabetes, smoking, etc. [19] A prospective study found elevated Lp(a) to be the only independent risk factor for recurrent coronary events out of a set of 17 thrombogenic, inflammatory and metabolic blood markers in obese, post-infarction patients. [20] Elevated Lp(a) levels may thus identify patient subsets that stand to benefit from earlier, more aggressive treatment. Homocysteine is a toxic, sulfur containing amino acid that is associated with severe, premature atherosclerotic disease. It is produced during protein catabolism, i.e., when methionine is converted to cysteine and is metabolized by trans-sulfuration and re-methylation dependent on vitamins B6, B12, and folate. [21] Several different mechanisms have been proposed to explain the association between homocysteine levels and atherosclerotic vascular disease, including endothelial cell dysfunction or injury, promotion of the proliferation of smooth muscle cells into the intima, enhanced platelet aggregation, increased binding of lipoprotein(a) to fibrin, generation of free radicals, stimulation of oxidation of LDL, and procoagulant effects. [22] Despite these proposed mechanisms, it is unclear if homocysteine is causative or simply a marker of accelerated atherosclerosis. To explore this hypothesis, the lowering of plasma homocysteine has been attempted by several investigators as a means to reduce cardiovascular risk in both healthy subjects and in those with CAD. [23],[24],[25],[26],[27],[28] Despite there being a large number of studies, a recent systematic review and meta-analysis summarizing the pooled effect of these outcomes failed to conclude that lowering of homocysteine was associated with improved cardiac outcomes. [29] As many of these studies were performed in patients with normal homocysteine levels and for short durations, it is unclear whether trial design may have influenced the ability to detect an effect of homocysteine lowering on cardiac risk. [30] Further study of homocysteine remains of interest as It may reveal unrecognized pathogenic mechanisms of atherosclerosis. Biomarkers of Plaque Instability and Ischemia The use of biomarkers as a tool for the diagnosis of plaque rupture has generated great interest in clinicians due to their promise to either "rule-in" or "rule-out" acute coronary syndromes (ACS). We review the best studied of these molecules: C-reactive protein measured (CRP/hsCRP), matrix metalloproteinase-9 (MMP-9), myeloperoxidase (MPO) and ischemia modified albumin (IMA). CRP is a sensitive but nonspecific acute-phase reactant that (when elevated to ≥3 mg/L) is a predictor of cardiovascular events in otherwise asymptomatic individuals. [31] Importantly, CRP elevation is not directly related to plaque burden but rather to plaque inflammation and instability. Though CRP can be elevated in other conditions [Table - 3] , it possesses several traits that make it an attractive biomarker: (a) it is highly stable in plasma with a limited coefficient of variation, (b) it has been demonstrated to have predictive capacity in multiple ethnic groups, (c) it predicts both short- and long-term outcomes, and (d) it provides independent predictive value in asymptomatic individuals, high-risk patients and also in disease states such as stroke, peripheral arterial disease and sudden death. [32] There is controversy as to whether CRP plays an active role in plaque destabilization (and is therefore causative) or is simply a surrogate marker of plaque rupture. [33],[34] However, it is known that CRP exerts a direct effect on endothelial cells, including up-regulation of adhesion molecules, release of pro-inflammatory mediators and impairment of nitric oxide mediated vasodilatation. [35],[36] Ad hoc data from a recent study revealed that individuals who achieved CRP lowering to ≤2 mg/L with statin therapy had lower event rates than those with higher values, irrespective of LDL level. [37] The benefit of statins may be mediated by non-lipid lowering or pleiotropic effects such as attenuation of inflammation, plaque stabilization and decreases in vascular reactivity through CRP attenuation. [38] The JUPITER study was designed to test whether lowering CRP via statins was beneficial in patients with coronary artery disease with normal lipid profiles. JUPITER found that reduction of CRP irrespective of LDL was associated with a statistically significant reduction of cardiac events in the treatment group (hazard ratio 0.53; 95% CI 0.40-0.69; P < 0.00001). Thus, directed therapy with statins to lower inflammation, CRP and LDL cholesterol may represent an important treatment paradigm for primary prevention of CAD in high-risk cohorts. [39] Recently, in a large German cohort study, variants of the CRP gene were associated with microangiopathic stroke. [40] It is unclear if similar variation in the genetic structure of CRP may exist and/or influence cardiac disease. The matrix metalloproteinases (MMP) are an enzyme system responsible for the remodeling and degradation of extracellular collagen. MMP-9 is chiefly expressed in inflammatory cells, including neutrophils and macrophages. MMP-9 is of unique interest as its levels elevate in patients with acute myocardial infarction (AMI). [41],[42] In addition, MMP-9 provides prognostic information on mortality in patients with AMI. [43] Among type-2 diabetics presenting with ST-elevation MI, a baseline elevation of MMP-9 was associated with in-hospital mortality and cardiogenic shock. [44],[45] MMP-9 may be an important inflammatory precursor of plaque rupture and is thus a marker of great promise for both detection and prognostication of ACS. MPO is a redox-active hemoprotein released by activated neutrophils. Elevated levels of MPO reflect acute inflammatory changes within plaque in the clinical setting of ACS. A single baseline measurement of MPO has been shown to predict the early risk of AMI in patients presenting with chest pain. [46] Elevated baseline MPO levels in patients presenting with ACS independently predict risk of AMI at 2-year follow-up, confirming that a heightened inflammatory state at the time of AMI impacts risk of future events. [47] Kubala et al, demonstrated that plasma levels of MPO do not rise in patients with stable CAD, reinforcing association of this enzyme with acute destabilization of plaque. [48] MPO may be of particular value as part of a multimarker strategy in ACS. [49] IMA is a novel biomarker that is formed by the interaction between oxygen radicals, generated in myocardial ischemia, and transition metals that bind to albumin . [50],[51] The primary advantage of IMA over other biomarkers is its rapid rise (minutes) and return to baseline (2 hours) from the onset of symptoms in ACS. [52] IMA also has prognostic value; in the OPERA study, IMA measured within 24 hours was a strong and independent predictor of cardiac outcome at 1 year and reliably for those requiring more aggressive medical management. [53] Importantly, in another study of 538 patients admitted with chest pain, the combination of IMA and cTn impressively yielded 100% sensitivity for MI. [54] In conjunction with creatine kinase and troponin, IMA may have an important role in the early detection of ACS. Biomarkers of Myocardial Necrosis The peripheral presence of markers of myocardial necrosis represents an irreversible outcome of cardiovascular disease. cTn has recently become the biomarker of choice for detecting myocardial injury. In fact, the definition of AMI has recently been changed based on the presence of this biomarker. [55] The cTns are a complex of three main proteins: cTnC, cTnT and cTnI. [56] cTnT and cTnI are of primary interest as cardiac biomarkers as cTnC is found in both skeletal and cardiac muscle. Thus, assays that also measure cTnC may report elevated levels of cTn in the presence of skeletal muscle injury. [57],[58] Assay imprecision is frequently the reason why troponin levels are spuriously elevated in patients with significant skeletal muscle injury. cTnT and cTnI leak into the circulation following myocardial injury from a preformed cytosolic pool, peaking 12-24 hours after release. Troponin is unique in that the magnitude and duration of its release is directly related to the extent of underlying myocardial damage in the presence of normal renal function. The marker remains elevated in a plateau phase for several days returning to normal 7-14 days post infarction. It is important for clinicians to remember that troponin kinetics are altered in patients with renal failure, making the diagnosis of MI challenging in this population. [59] Troponin is also predictive of outcomes: the PRISM trial showed that cTnI elevation in 2222 patients with CAD and chest pain predicted 30-day event rates (13% for cTnI positive vs. 4.9% for cTnI negative). [60] Similarly, in the TIMI-11B study, cTnI elevations predicted risk of death and/or MI in 359 patients with non-ST-segment elevation ACS. Elevated cTnI also correlated with a higher rate of recurrent ischemia requiring urgent revascularization at 48 hours and at 14 days. [61] Biomarkers of Myocardial Dysfunction Heart failure is a clinicopathologic syndrome characterized by tissue hypoperfusion due to cardiac dysfunction. The diagnosis of heart failure is occasionally elusive since it is often well compensated in patients. [62] Measurement of the natriuretic peptides serves as a quantitative indicator of the presence and severity of heart failure. Brain natiuretic peptide (BNP) release occurs in response to left or right ventricular wall stretch in the form of proBNP. proBNP is cleaved to the biologically active BNP and the inactive terminal fragment, NT-proBNP. The half-life of NT-proBNP is considerably longer than that of BNP (120 minutes vs. 20 minutes, respectively), making the assay of NT-proBNP clinically more meaningful. BNP alleviates cardiac dysfunction by producing myocardial relaxation, decreasing peripheral vascular resistance, and antagonizing the anti-diuretic effects of the renin-angiotensin-aldosterone system. As a biomarker, BNP has the greatest utility in the diagnosis of suspected heart failure, with a negative predictive value ranging from 95 to 100% for this diagnosis. [63],[64] BNP values are best interpreted as a continuous variable; thus, the higher the value of BNP, the more likely dyspnea is attributable to heart failure. It is important that the discerning internist remain aware of other conditions that may also cause a rise in serum BNP and these should be considered in the absence of clinical stigmata of heart failure [Table - 4]. BNP and NT-proBNP also predictcardiovascular outcomes. In the OPUS-TIMI 16 trial, a single measurement of BNP taken within 72 hours of symptom onset predicted increased risk of death in the entire study cohort and in specific subgroups such as STEMI, non-STEMI and unstable angina. [65] Similarly, in a retrospective analysis of the FRISC-II trial, NT-proBNP values predicted 2-year mortality at time intervals of 48 hours, 6 weeks, 3 months and 6 months. [66] In a follow-up study of the A-to-Z trial cohort, serial determinations of BNP levels during outpatient follow-up after ACS predicted the risk of death or new congestive heart failure (CHF). Changes in BNP levels over time are associated with long-term clinical outcomes and may provide a basis for enhanced clinical decision making in patients after the onset of ACS. [67] BNP measurement has also been applied as a screening test in a primary care setting and in emergency departments, where negative values reliably excluded systolic and diastolic dysfunction. [68] A recent clinical study reported that the addition of N-terminal pro-B-type natriuretic peptide-guided intensive patient management improved outcomes in patients following hospitalization due to heart failure. [69] Serial BNP measurement has therefore been proposed as a means to direct therapy in CHF. Troughton et al, randomized 69 patients with an left ventricular ejection fraction (LVEF) of <40% to determine whether pharmacotherapy guided by serial BNP estimation led to superior outcomes than clinical judgment. [70] The authors found that treatment guided by BNP values led to fewer cardiovascular events at 6-month follow-up. A recent, large, randomized controlled study in elderly patients found that BNP-guided therapy improved neither the clinical outcomes nor the quality of life when compared to symptom-guided therapy. [71] A large meta-analysis of the topic noted that BNP-guided treatment reduced all-cause mortality in patients with CHF (especially among those <75 years of age) but had no observable effect on hospitalization. [72] Future Directions and Conclusion Cardiac biomarkers have emerged as indispensable tools in the early detection, management and prognostication of patients throughout the spectrum of CAD. They have added new dimensions to the existing clinical parameters, helping to identify patients who may benefit from earlier intervention or more intensive therapies. [73] It is important that biomarkers extend the utility of existing clinical strategies. The recently introduced Reynolds Risk Score, for example, added CRP to the clinical Framingham Risk Score and showed greater accuracy in correctly reclassifying those at "intermediate risk" to either low- or high-risk subsets. [35] While a single biomarker assay can provide valuable information, the development of algorithms that utilize multiple biomarkers (multimarker strategy) is of great interest. A recent study reported that combining Nt-proBNP, GDF-15, MR-proANP, cystatin C, and MR-proADM strongly predicted cardiovascular outcomes in patients with stable angina. [74] Similarly, combining a number of select biomarkers in patients with ACS was associated with near-doubling of the predicted mortality risk in another study. [75] The combination of biomarkers seems to offer incremental predictive ability over established risk factors in both stable and unstable settings. Could preventing biomarker rise abrogate cardiovascular risk? In an experimental study, treatment with the CRP inhibitor [1,6-bis(phosphocholine)-hexane] decreased both infarct size and cardiac dysfunction in a rodent model. [76] Among human data, the recent JUPITER study lends credence to the strategy of targeting CRP via potent statin therapy to prevent cardiovascular events. [39] Similarly, methotrexate also reduces CRP levels and was separately reported to reduce CV death by 70% in a non-randomized, observational cohort study. [77],[78] Along these lines, several novel interleukin-6 (IL-6) and tumor necrosis factor (TNF) inhibitors are under study. The next generation of biomarkers promises better risk identification, improved therapeutic decision making and new therapeutic targets, ultimately leading to improved cardiovascular outcomes. Biomarkers have helped guide treatment decisions and provide novel insight into cardiovascular disease. Future populations will benefit from the continued application of cardiac biomarkers to routine health care. References
Copyright 2010 - Indian Journal of Medical Sciences The following images related to this document are available:Photo images[ms10007t1.jpg] [ms10007t4.jpg] [ms10007t2.jpg] [ms10007t3.jpg] |
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