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Indian Journal of Medical Sciences
Medknow Publications on behalf of Indian Journal of Medical Sciences Trust
ISSN: 0019-5359 EISSN: 1998-3654
Vol. 64, Num. 12, 2010, pp. 564-576

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

1 Department of Internal Medicine, Divisions of General Medicine, University of Michigan Health System, Ann Arbor, MI, USA
2 Department of Cardiology, University of Michigan Health System, Ann Arbor, MI, USA

Correspondence Address:
Vineet Chopra
3119 Taubman Center, 1500 East Medical Center Drive SPC 5376, Ann Arbor, MI 48109

Code Number: ms10007

PMID: 21258154

DOI: 10.4103/0019-5359.75934


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


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.


1.Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: Part I: General considerations, the epidemiologic transition, risk factors and impact of urbanization. Circulation 2001;104:2746-53.  Back to cited text no. 1    
2.Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults: The Bogalusa Heart Study. N Engl J Med 1998;338:1650-6.  Back to cited text no. 2    
3.Raitakari OT, Juonala M, Kähönen M, Taittonen L, Laitinen T, Mäki-Torkko N, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: The Cardiovascular Risk in Young Finns Study. JAMA 2003;290:2277-83.  Back to cited text no. 3    
4.Kita Chun A, McGee SR. Bedside diagnosis of coronary artery disease: A systematic review. Am J Med 2004;117:334-43.  Back to cited text no. 4    
5.Swap CJ, Nagurney JT. Value and limitations of chest pain history in the evaluation of patients with suspected acute coronary syndromes. JAMA 2005;294:2623-9.  Back to cited text no. 5    
6.Root M, Cobb F. Traditional risk factors for coronary heart disease. JAMA 2004;291:299.  Back to cited text no. 6    
7.Apple FS, Wu AH, Mair J, Ravkilde J, Panteghini M, Tate J, et al. Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome. Clin Chem 2005;51:810-24.  Back to cited text no. 7    
8.Biomarker Definitions Working Group. Biomarkers and surrogate end-points: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89-95.  Back to cited text no. 8    
9.Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001;103:491-5.  Back to cited text no. 9    
10.Schonbeck U, Varo N, Libby P, Buring J, Ridker PM. Soluble CD40L and cardiovascular risk in women. Circulation 2001;103:491-5.  Back to cited text no. 10    
11.Cavusoglu E, Chopra V, Battala V, Ruwende C, Yanamadala S, Eng C, et al. Baseline plasma adiponectin levels as a predictor of left ventricular dysfunction in patients referred for coronary angiography. Am J Cardiol 2008;101:1073-8.  Back to cited text no. 11    
12.Fox N, Growdon JH. Biomarkers and surrogates. Neuro Rx 2004;1:181.  Back to cited text no. 12    
13.Giraldez RR, Giugliano RP, Mohanavelu S, Murphy SA, McCabe CH, Cannon CP, et al. Baseline low-density lipoprotein cholesterol is an important predictor of the benefit of intensive lipid lowering therapy: A PROVE-IT TIMI 22 analysis. J Am Coll Cardiol 2008;52:914-20.  Back to cited text no. 13    
14.Ehara S, Naruko T, Shirai N, Itoh A, Hai E, Sugama Y, et al. Small coronary calcium deposits and elevated plasma levels of oxidized low density lipoprotein are characteristic of acute myocardial infarction. J Atheroscler Thromb 2008;15:75-81.  Back to cited text no. 14    
15.Cohen JD, Cziraky MJ, Cai Q, Wallace A, Wasser T, Crouse JR, et al. 30-Year Trends in serum lipids among United States adults: Results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006. Am J Cardiol 2010;106:969-75.  Back to cited text no. 15    
16.Hatzitolios AI, Athyros VG, Karagiannis A, Savopoulos C, Charalambous C, Kyriakidis G, et al. Implementation of strategy for the management of overt dyslipidemia: The IMPROVE-dyslipidemia study. Int J Cardiol 2009;134:322-9.  Back to cited text no. 16    
17.Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, et al. Safety of Anacetrapib in patients with or at high risk for coronary artery disease. N Engl J Med 2010;363:2406-15.  Back to cited text no. 17    
18.Berglund L, Ramakrishnan R. Lipoprotein(a) an elusive cardiovascular risk factor Arterioscler Thromb Vasc Biol 2004;24:2219-26.  Back to cited text no. 18    
19.Tsimikas S, Mallat Z, Talmud PJ, Kastelein JJ, Wareham NJ, Sandhu MS, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events. J Am Coll Cardiol 2010;56:946-55.   Back to cited text no. 19    
20.Anuurad E, Boffa MB, Koschinsky ML, Berglund L. Lipoprotein(a): A unique risk factor for cardiovascular disease. Clin Lab Med 2006;26:751-72.  Back to cited text no. 20    
21.Lentz SR. Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost 2005;3:1646-54.  Back to cited text no. 21    
22.Finch JM, Joseph J. Homocysteine, cardiovascular inflammation, and myocardial remodeling. Cardiovasc Hematol Disord Drug Targets 2010;10:241-5.  Back to cited text no. 22    
23.Ntaios G, Savopoulous G, Grekas D, Hatzitolios AI. The controversial role of B Vitamins in cardiovascular risk: An update. Arch Cardiovasc Dis 2009;102:847-54.  Back to cited text no. 23    
24.Ntaios G, Savopoulos C, Karamitsos D, Economou I, Destanis E, Chryssogonidis I, et al. The effect of folic acid supplementation on carotid intima-media thickness in patients with cardiovascular risk: A randomized, placebo-controlled trial. Int J Cardiol 2010;143:16-9.  Back to cited text no. 24    
25.Wald DS, Wald NJ, Morris JK, Law M. Folic acid, homocysteine and cardiovascular disease: Judging causality in the face of inconclusive evidence. BMJ 2006;333:1114-7.  Back to cited text no. 25    
26.Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke MI, and death: The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.  Back to cited text no. 26    
27.Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578-88.  Back to cited text no. 27    
28.Ntaios G, Savopoulos C, Hatzitolios A, Chatzinikolaou A, Karamitsos D. Is there a beneficial effect of folic acid on carotid intima-media thickness? Int J Cardiol 2009;135:260-1.   Back to cited text no. 28    
29.Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2009;7:CD006612.  Back to cited text no. 29    
30.Ntaios G, Savopoulos C, Hatzitolios A. Lowering homocysteine with B vitamins in patients with coronary artery disease. JAMA 2008;300:2853-4.   Back to cited text no. 30    
31.Gotto AM. Role of C-Reactive Protein in Coronary Risk Reduction: Focus on Primary Prevention. Am J Cardiol 2007;99:718-25.  Back to cited text no. 31    
32.Ridker PM, Cook NR. Biomarkers for prediction of cardiovascular events. N Engl J Med 2007;356:1472-3.  Back to cited text no. 32    
33.Curb JD, Abbott RD, Rodriguez BL, Sakkinen P, Popper JS, Yano K, et al. C-reactive protein and the future risk of thromboembolic stroke in healthy men. Circulation 2003;107:2016-20.  Back to cited text no. 33    
34.Ridker PM, Stampfer MH, Rifai N. Novel risk factors for systemic atherosclerosis: A comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a) and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001;285:2481-5.  Back to cited text no. 34    
35.Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: The Reynolds Risk Score JAMA 2007;297:611-9.  Back to cited text no. 35    
36.Hein TW, Singh U, Vasquez-Vivar J, Devaraj S, Kuo L, Jialal I. Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo. Atherosclerosis 2009;206:61-8  Back to cited text no. 36    
37.Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.  Back to cited text no. 37    
38.Pasterkamp G, van Lammeren GW. Pleioptropic effects of statins in atherosclerotic disease. Expert Rev. Cardiovasc Ther 2010;8:1235-7.  Back to cited text no. 38    
39.Ridker PM, Macfadyen JG, Nordestgaard BG, Koenig W, Kastelein JJ, Genest J, et al. Rosuvastatin for primary prevention among individuals with elevated high-sensitivity C-reactive protein and 5% to 10% and 10% to 20% 10-year risk. Implications of the Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial for "intermediate risk". Circ Cardiovasc Qual Outcomes 2010;3:447-52.   Back to cited text no. 39    
40.Kuhlenbaeumer G, Huge A, Berger K, Kessler C, Voelze H, Funke H, et al. Genetic variants in the C-Reactive Protein gene are associated with microangiopathic ischemic stroke. Cerebrovasc Dis 2010;30:476-82  Back to cited text no. 40    
41.Beygui F, Silvain J, Pena A, Bellemain-Appaix A, Collet JP, Drexler H, et al. Usefulness of biomarker strategy to improve GRACE score's prediction performance in patients with non-ST-segment elevation acute coronary syndrome and low event rates. Am J Cardiol 2010;106:650-8.  Back to cited text no. 41    
42.Inokubo Y, Hanada H, Ishikaza H, Fukushi T, Kamada T. Plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 are increased in the coronary circulation in patients with acute coronary syndrome. Am Heart J 2001;141:211-7.  Back to cited text no. 42    
43.Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Kaski JC. High serum matrix metalloproteinase-9 level predict increased risk of in-hospital cardiac events in patients with type 2 diabetes and ST segment elevation myocardial infarction. Atherosclerosis 2008;196:365-71.  Back to cited text no. 43    
44.Death AK, Fisher EJ, McGrath KC, Yue DK. High glucose alters matrix metalloproteinase expression in two key vascular cells: Potential impact on atherosclerosis in diabetes. Atherosclerosis 2003;168:263-9.  Back to cited text no. 44    
45.Tayebee MH, Lim HS, Macfayden RJ, Lip GY. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 and -2 in type 2 diabetes: Effect of 1 year's cardiovascular risk reduction therapy. Diabetes Care 2004;27:2049-51.  Back to cited text no. 45    
46.Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349:1595-604.  Back to cited text no. 46    
47.Cavusoglu E, Ruwende C, Eng C, Chopra V, Yanamadala S, Clark LT, et al. Usefulness of baseline plasma myeloperoxidase levels as an independent predictor of myocardial infarction at two years in patients with acute coronary syndromes. Am J Cardiol 2007;99:1364-8.  Back to cited text no. 47    
48.Kubala L, Lu G, Baldus S, Bergland L, Eiserich JP. Plasma levels of myeloperoxidase are not elevated in patients with stable coronary artery disease. J Clin Chem Acta 2008;394:59-62.  Back to cited text no. 48    
49.Sinning C, Schnabel R, Peacock WF, Blankenberg S. Up and coming markers: Myeloperoxidase, a novel biomarker test for heart failure and acute coronary syndrome application? Congest Heart Fail 2008;14:46-8.  Back to cited text no. 49    
50.Chevion M, Jiang Y, Har-El R, Berenshtein E, Uretzky G, Kitrossky N. Copper and iron are mobilized following myocardial ischemia: Possible predictive criteria for tissue injury. Proc Natl Acad Sci USA 1993;90:1102-6.  Back to cited text no. 50    
51.Cobbe SM, Poole-Wilson PA. The time of onset and severity of acidosis in myocardial ischemia. J Mol Cell Cardiol 1980;12:745-60.  Back to cited text no. 51    
52.Kim JS, Hwang HJ, Ko YG, Kim JS, Choi D, Ha JW, et al. Ischemia-modified albumin: Is it a reliable diagnostic and prognostic marker for myocardial ischemia in real clinical practice? Cardiology 2010;116:123-9.  Back to cited text no. 52    
53.Van Belle E, Dallongeville J, Vicaut E, Degrandsart A, Baulac C, Montalescot G; OPERA Investigators. Ischemia-modified albumin levels predict long-term outcome in patients with acute myocardial infarction. The French Nationwide OPERA study. Am Heart J 2010;159:570-6.  Back to cited text no. 53    
54.Collinson PO, Gaze DC, Morris F, Morris B, Price A, Goodacre S. Comparison of biomarker strategies for rapid rule out of myocardial infarction in the emergency department using ACC/ESC diagnostic criteria. Ann Clin Biochem 2006;43:273-80.  Back to cited text no. 54    
55.Alpert JS, Thygesen K, Jaffe A, White HD. The universal definition of myocardial infarction: A consensus document: Ischemic heart disease. Heart 2008;10:1335-41.  Back to cited text no. 55    
56.Collinson PO, Boa FG, Gaze DC. Measurement of cardiac troponins. Ann Clin Biochem 2001;38:423-49.  Back to cited text no. 56    
57.Brancaccio P, Lippi G, Maffulli N. Biochemical markers of muscular damage. Clin Chem Lab Med 2010;48:757-67.  Back to cited text no. 57    
58.Fredericks S, Bainbridge K, Murray JF, Collinson PO, Carter ND, Holt DW. Measurement of cardiac troponin I in striated muscle using three experimental methods. Ann Clin Biochem 2003;40:244-8.  Back to cited text no. 58    
59.Tsutamoto T, Kawahara C, Yamaji M, Nishiyama K, Fujii M, Yamamoto T, et al. Relationship between renal function and serum cardiac troponin T in patients with chronic heart failure. Eur J Heart Fail 2009;11:653-8.   Back to cited text no. 59    
60.Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management. Lancet 1999;354:1757-62.  Back to cited text no. 60    
61.Morrow DA, Antman EM, Tanasijevic M, Rifai N, de Lemos JA, McCabe CH, et al. Cardiac troponin I for stratification of early outcomes and the efficacy of enoxaparin in unstable angina: A TIMI -11B substudy. J Am Coll Cardiol 2000;36:1812-7.  Back to cited text no. 61    
62.Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527-60.  Back to cited text no. 62    
63.Zaphiriou A, Robb S, Murray-Thomas T, Mendez G, Fox K, McDonagh T, et al. The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: Results of the UK natriuretic peptide study. Eur J Heart Fail 2005;7:537-41.  Back to cited text no. 63    
64.Groenning BA, Raymond I, Hildebrandt PR, Nilsson JC, Baumann M, Pedersen F. Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population. Heart 2004;90:297-303.  Back to cited text no. 64    
65.De Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014-21.  Back to cited text no. 65    
66.Lindahl B, Lindbäck J, Jernberg T, Johnston N, Stridsberg M, Venge P, et al. Serial analyses of N-terminal pro-B-type natriuretic peptide in patients with non-ST-segment elevation acute coronary syndromes: A Fragmin and fast Revascularisation during In Stability in Coronary artery disease (FRISC)-II substudy. J Am Coll Cardiol 2005;45:533-41.  Back to cited text no. 66    
67.Morrow DA, de Lemos JA, Blazing MA, Sabatine MS, Murphy SA, Jarolim P, et al. Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery disease. JAMA 2005;294:2866-71.   Back to cited text no. 67    
68.Galasko GI, Lahiri A, Barnes SC, Collinson P, Senior R. What is the normal range for N-terminal pro-brain natriuretic peptide? How well does this normal range screen for cardiovascular disease. Eur Heart J 2005;26:2269-76.  Back to cited text no. 68    
69.Berger R, Moertl D, Peter S, Ahmadi R, Huelsmann M, Yamuti S. N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3-arm, prospective, randomized pilot study. J Am Coll Cardiol 2010;55:645-53.  Back to cited text no. 69    
70.Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126-30.  Back to cited text no. 70    
71.Pfisterer M, Buser P, Rickli H, Gutmann M, Erne P, Rickenbacher P, et al. BNP-guided vs symptom-guided heart failure therapy: The trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009;28:383-92.  Back to cited text no. 71    
72.Porapakkham P, Zimmet H, Billah B, Krum H.B-type natriuretic peptide-guided heart failure therapy: A meta-analysis. Arch Intern Med. 2010;170:507-14.  Back to cited text no. 72    
73.Wylie JV, Murphy SA, Morrow DA, de Lemos JA, Antman EM, Cannon CP. Validated risk score predicts the development of congestive heart failure after presentation with unstable angina or non-ST-elevation myocardial infarction: Results from OPUS-TIMI 16 and TACTICS-TIMI 18. Am Heart J 2004;148:173-80.  Back to cited text no. 73    
74.Schnabel RB, Schulz A, Messow CM, Lubos E, Wild PS, Zeller T, et al. Multiple marker approach to risk stratification in patients with stable coronary artery disease. Eur Heart J 2010;31:3024-31.  Back to cited text no. 74    
75.Morrow DA, Sabatine MS, Brennan ML, de Lemos JA, Murphy SA, Ruff CT, et al. Concurrent evaluation of novel cardiac biomarkers in acute coronary syndrome: Myeloperoxidase and soluble CD40 ligand and the risk of recurrent ischaemic events in TACTICS-TIMI 18. Eur Heart J 2008;29:1096-102.  Back to cited text no. 75    
76.Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006;440:1217-21.  Back to cited text no. 76    
77.Swierkot J, Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol Rep 2006;58:473-92.  Back to cited text no. 77    
78.Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: A prospective study. Lancet 2002;359:1173-7.  Back to cited text no. 78    

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