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There are inconsistent observations on multiple biomarkers approaches in predicting cardiovascular events. Some Studies have showed only minimal improvement in the ability to classify cardiovascular risk by adding biomarkers to traditional risk factors (1-4). Some studies have suggested that adding several newer biomarkers can substantially improve risk classification (5-10).

1. Multiple biomarkers for the prediction of first major cardiovascular events and death. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, Jacques PF, Rifai N, Selhub J, Robins SJ, Benjamin EJ, D’Agostino RB, Vasan RS. N Engl J Med 2006; 355:2631–2639.
http://www.nejm.org/doi/pdf/10.1056/NEJMoa055373

For the incremental usefulness of multiple biomarkers from distinct pathophysiological pathways in relation to cardiovascular event, 10 biomarkers C-reactive protein, B-type natriuretic peptide, N-terminal pro–atrial natriuretic peptide, aldosterone, renin, fibrinogen,D-dimer, plasminogen-activator inhibitor type 1, and homocysteine; and the urinary albumin-to-creatinine have been evaluated for predicting the risk of cardiovascular events. It was observed that modest improvements in prediction with a multimarker panel compared with traditional risk factors alone.

2. Multimarker prediction of coronary heart disease risk: the women’s health initiative. Kim HC, Greenland P, Rossouw JE, Manson JE, Cochrane BB, Lasser NL, Limacher MC, Lloyd-Jones DM, Margolis KL, Robinson JG. J Am Coll Cardiol 2010; 55:2080–2091.
http://www.sciencedirect.com/science/article/pii/S0735109710009010

Purpose of the study was to find whether multiple biomarkers yield a better assessment of cardiovascular risk in post-menopausal women compared with a standard risk assessment incorporating major TRFs alone. The panel of biomarkers were assessed includes: lipoprotein(a), homocysteine, insulin, C-reactive protein (CRP), E-selectin, interleukin-6, matrix metalloproteinase-9, fibrin D-dimer, factor VIII, plasminogen activator inhibitor-1 antigen, prothrombin fragment 1.2, plasmin-antiplasmin complex, thrombinactivatable fibrinolysis inhibitor, von Willebrand factor, fibrinogen, hematocrit, and leukocyte and platelet counts. It has been reported that moderate improvement in CHD risk prediction was found when an 18-biomarker panel was added to predictive models using traditional risk factors in post-menopausal women. Among the 18 biomarkers measured, C-reactive protein level did not significantly improve CHD prediction either alone or in combination with other biomarkers.

3. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. Melander O, Newton-Cheh C, Almgren P, Hedblad B, Berglund G, Engstrom G,Persson M, Smith JG, Magnusson M, Christensson A, Struck J, Morgenthaler NG, Bergmann A, Pencina MJ, Wang TJ. JAMA 2009; 302:49–57.
http://jama.ama-assn.org/content/302/1/49.full.pdf+html

C-reactive protein (CRP), mid-regional-pro-atrial natriuretic peptide, N-terminal pro-B-type natriuretic peptide (N-BNP), mid-regional-pro-adrenomedullin (MRproADM), lipoprotein-associated phospholipase-2, and cystatin C have been evaluated for predicting cardiovascular risk. In this study it was demonstrated that selected biomarkers may be used to predict future cardiovascular events, but the gains over conventional risk factors are minimal. Risk classification improved in intermediate-risk individuals, mainly through the identification of those unlikely to develop events.

4. Comparative impact of multiple biomarkers and N-terminal pro-brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) study. Blankenberg S, McQueen MJ, Smieja M, Pogue J, Balion C, Lonn E, Rupprecht HJ, Bickel C, Tiret L, Cambien F, Gerstein H, Munzel T, Yusuf S.Circulation 2006; 114:201–208.
http://circ.ahajournals.org/content/114/3/201.full.pdf+html

The purpose of the study was to evaluate multimarker risk stratification approach in secondary prevention populations. Blankenberg et al studied eleven biomarkers include: nine inflammatory markers plus N-terminal pro-B-type natriuretic peptide (Nt-proBNP), and microalbuminuria in patients with a history of coronary heart disease, peripheral vascular disease, diabetes, or stroke and reported that although levels of various inflammatory biomarkers are significantly related to future cardiovascular risk, their incremental predictive value is modest. A model consisting of simple traditional risk factors and Nt-proBNP provided the best clinical prediction in the secondary-prevention population.

5. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. Zethelius B, Berglund L, Sundstrom J, Ingelsson E, Basu S, Larsson A, Venge P, Arnlov J.. N Engl J Med 2008; 358:2107–2116.
http://www.nejm.org/doi/pdf/10.1056/NEJMoa0707064

A combination of different pathophysiology biomarkers that reflect myocardial cell damage, left ventricular dysfunction, renal failure, and inflammation (troponin I, N-terminal pro–brain natriuretic peptide, cystatin C, and C-reactive protein, respectively) have been evaluated to investigate whether combination of biomarkers improved the risk stratification of an elder person beyond an assessment that was based on the established risk factors for cardiovascular disease. Data suggested that in elderly men with or without prevalent cardiovascular disease, the simultaneous addition of several biomarkers of cardiovascular and renal abnormalities substantially improves the risk stratification for death from cardiovascular causes beyond that of a model that is based only on established risk factors.

6. Contribution of 30 biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: the Monica, Risk, Genetics, Archiving, and Monograph (MORGAM) biomarker project. Blankenberg S, Zeller T, Saarela O, Havulinna AS, Kee F, Tunstall-Pedoe H, Kuulasmaa K, Yarnell J, Schnabel RB, Wild PS, Munzel TF, Lackner KJ, Tiret L, Evans A, Salomaa V. Circulation 2010;121:2388–2397.
http://circ.ahajournals.org/content/121/22/2388.full.pdf+html

MORGAM studies were also done using combination of different pathophysiology biomarkers, lipid related markers, marker of vascular function, renal function, inflammatory, metabolic, oxidative stress, coagulation, and necrosis makers. It has been reported that the addition of a biomarker score including N-terminal pro-brain natriuretic peptide, C-reactive protein, and sensitive troponin I to a conventional risk model improved 10-year risk estimation for cardiovascular events in 2 middle-aged European populations.

7. Multiple marker approach to risk stratification in patients with stable coronary artery disease. Schnabel RB, Schulz A, Messow CM, Lubos E, Wild PS, ZellerT, Sinning CR, Rupprecht HJ, Bickel C, Peetz D, Cambien F, Kempf T, Wollert KC, Benjamin EJ, Lackner KJ, Münzel TF, Tiret L, Vasan RS, and Blankenberg S. Eur Heart J. 2010 Dec; 31(24):3024-31. Epub 2010 Sep 18.
http://www.ncbi.nlm.nih.gov/pubmed/20852293

Comparative analysis of 12 biomarkers revealed Nt-proBNP, GDF-15, MR-proANP, cystatin C, and MR-proADM as the strongest predictors of cardiovascular outcome in stable angina. All five biomarkers taken separately offered incremental predictive ability over established risk factors. Combination of the single markers slightly improved model fit but did not enhance risk prediction from a clinical perspective.

8. Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo study. Daniels LB, Laughlin GA, Clopton P, Maisel AS, Barrett-Connor E. J Am Coll Cardiol 2008; 52:450–459.
http://www.sciencedirect.com/science/article/pii/S0735109708017853

In this study it has been reported that apparently healthy adults with detectable TnT or elevated NT-proBNP levels are at increased risk of death. Those with both TnT and NT-proBNP elevations are at even higher risk, and the increased risk persists for years.

9. Predictive modeling of health care costs: do cardiovascular risk markers improve prediction? Baumeister SE, Dörr M, Radke D, Nauck M, John U, Marschall P, Flea S, Schmidt CO, Alte D, Völzke H. Eur J Cardiovasc Prev Rehabil. 2010 Jun; 17(3):355-62.
http://www.ncbi.nlm.nih.gov/pubmed/19907337

Purpose of the study was to investigate the ability of multiple cardiovascular disease (CVD) markers to predict future health care costs. CVD markers included traditional risk factors (smoking status, body mass index, waist circumference, alcohol intake, diabetes, total : high-density lipoprotein cholesterol ratio, actual hypertension, physical activity) and newer markers (carotid intima-media thickness, hemoglobin A1c, apolipoprotein B : apolipoprotein A-1 ratio, lipoprotein (a), leukocyte count, high-sensitive C-reactive protein, plasma fibrinogen, estimated glomerular filtration rate, urinary albumin : creatinine ratio). Data suggest that for individuals without history of CVD, the simultaneous addition of several CVD risk markers improves predictive modeling of future health care costs beyond that of a model that is based on established health care predictors.

10. Inflammatory and non-invasive vascular markers: the multimarker approach for risk stratification in coronary artery disease. Ikonomidis I, Stamatelopoulos K, Lekakis J, Vamvakou GD, Kremastinos DT. Atherosclerosis. 2008; 199(1):3-11.
http://www.atherosclerosis-journal.com/article/S0021-9150%2808%2900124-X/abstract

The combination of an established inflammatory marker such as C-reactive protein or a vascular marker such as IMT with novel biochemical and vascular markers of cardiovascular disease may offer additive prognostic information for adverse outcome.

11. C-Reactive Protein, Fibrin D-Dimer, and Risk of Ischemic Heart Disease : The Caerphilly and Speedwell Studies. G.D.O. Lowe, P.M. Sweetnam, J.W.G. Yarnell, A. Rumley, C. Rumley, D. Bainton and Y. Ben-Shlomo. Arterioscler Thromb Vasc Biol 2004; 24:1957-1962.
http://atvb.ahajournals.org/content/24/10/1957.full.pdf+html

In this study, it has been reported that both inflammatory CRP and thrombogenic fibrin D-dimer markers are important (and potentially additive) predictors of coronary risk. However, authors suggested that further prospective epidemiological studies (and collaborative meta-analyses) of CRP and D-dimer and incident ischemic heart disease are required to clarify their relative (and additive) predictive values for IHD events.

12. Multimarker Approach to Risk Stratification in Non-ST Elevation Acute Coronary Syndromes: Simultaneous Assessment of Troponin I, C-Reactive Protein, and B-Type Natriuretic Peptide. Marc S. Sabatine, David A. Morrow, James A. de Lemos, C. Michael Gibson, Sabina A. Murphy, Nader Rifai, Carolyn McCabe, Elliott M. Antman, Christopher P. Cannon and Eugene Braunwald. Circulation 2002, 105:1760-1763.
http://circ.ahajournals.org/content/105/15/1760.full.pdf

Sabatine et al. have reported the utility of three bio makers of different pathophysiology, troponin, CRP, and BNP in combination and reported simultaneous assessment of troponin, CRP, and BNP in acute coronary syndromes provides unique prognostic information. Using a simple multimarker strategy in which patients are categorized based on the number of elevated biomarkers, clinicians can risk stratify patients over a broad range of short- and long-term major cardiac events.

13. Anti-cytomegalovirus antibodies and other atherosclerosis risk factors in patients with cardiovascular diseases. Jan Kazar, Elena Kovacova, Viera Mongiellova, Martin Gajdos, Jan Tomka, Roman Slysko, Viliam Fridrich. Journal of Geriatric Cardiology. 2007; 14(3):131-134.
http://www.jgc301.com/ch/reader/view_abstract.aspx?file_no=20070301&flag=1

Kazar et. al. has reported that the presence of anti-cytomegalovirus antibodies together with antibodies to anti-Chlamydia pneumoniae and markers of inflammation (CRP and IL-6) was associated with CVD, primarily in elderly patients who underwent reconstructive vascular surgery.