Prognostic value of multiple emerging biomarkers in cardiovascular risk prediction in patients with stable cardiovascular disease

  • Namanjeet Ahluwalia
    UMR U557 Inserm, U1125 Inra, Cnam, UFR SMBH, Université Paris 13, CRNH IdF, 74 rue Marcel Cachin, F-93017 Bobigny, France
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  • Jacques Blacher
    UMR U557 Inserm, U1125 Inra, Cnam, UFR SMBH, Université Paris 13, CRNH IdF, 74 rue Marcel Cachin, F-93017 Bobigny, France

    Université Paris-Descartes, Faculté de Médecine, AP-HP, Hôtel-Dieu, Centre de Diagnostic et Thérapeutique, Paris, France
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  • Fabien Szabo de Edelenyi
    Corresponding author. Tel.: +33 1 48 38 89 51; fax: +33 1 48 38 89 31.
    UMR U557 Inserm, U1125 Inra, Cnam, UFR SMBH, Université Paris 13, CRNH IdF, 74 rue Marcel Cachin, F-93017 Bobigny, France
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  • Patrice Faure
    Département de Biochimie, Toxicologie et Pharmacologie, UJF et CHU de Grenoble, Grenoble, France

    Laboratoire d'étude de la physiopathologie de l'hypoxie (HP2), Inserm U 1042, Grenoble, France
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  • Chantal Julia
    UMR U557 Inserm, U1125 Inra, Cnam, UFR SMBH, Université Paris 13, CRNH IdF, 74 rue Marcel Cachin, F-93017 Bobigny, France

    Département de Santé Publique, Hôpital Avicenne, Bobigny, France
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  • Serge Hercberg
    UMR U557 Inserm, U1125 Inra, Cnam, UFR SMBH, Université Paris 13, CRNH IdF, 74 rue Marcel Cachin, F-93017 Bobigny, France

    Département de Santé Publique, Hôpital Avicenne, Bobigny, France
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  • Pilar Galan
    UMR U557 Inserm, U1125 Inra, Cnam, UFR SMBH, Université Paris 13, CRNH IdF, 74 rue Marcel Cachin, F-93017 Bobigny, France
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      • We found two natriuretic peptides with a significant prognostic value for CVD.
      • Homocysteine and CRP did not offer additional value for risk prediction.
      • NT-proBNP and MR-ANP, may offer additional tools for CVD risk stratification.



      Few studies have examined simultaneously the prognostic value of traditional and emerging biomarkers including atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP), for major cardiovascular disease (CVD) outcomes in patients with stable CVD, and results are equivocal.


      and Methods: Mid-regional pro-ANP (MR-proANP) and N-Terminal pro-BNP (NT-proBNP), CRP and homocysteine were measured in stable CVD patients (n = 1456; age: 61.8 y) at inclusion in the SU.FOL.OM3 cohort. Prospective association of biomarkers with risk of heart failure, major cardiovascular (non-fatal myocardial infarction, ischemic stroke or death from CVD) or overall cardiovascular event were examined with Cox proportional-hazards analyses. Increase in prediction risk upon addition of biomarker(s) to the traditional risk model was examined by change in C-statistic, NRI and IDI.


      During follow-up (median: 4.7 y), 40 heart failure, 145 major cardiovascular and 493 overall cardiovascular events were diagnosed. In models adjusted for age, sex, smoking, diabetes, serum creatinine and CVD inclusion criteria, NT-proBNP and CRP associated significantly with heart failure. Both natriuretic peptides predicted the risk of major cardiovascular events in adjusted models; Hazard ratio (HR) and 95% CI for each SD increase in MR-proANP and NT-proBNP were 1.24 (1.04–1.47), and 1.31 (1.09–1.57), respectively. The addition of NT-proBNP to a traditional risk model increased significantly the area-under-curve for heart failure and overall cardiovascular events (by 6 and 12%, respectively); addition of MR-proANP or homocysteine yielded modest (2%) but statistically significant increase for major cardiovascular events.


      NT-proBNP consistently predicted CVD outcomes and may be useful singly or in combination with MR-proANP for risk-stratification in high-risk patients.


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        • Levin E.R.
        • Gardner D.G.
        • Samson W.K.
        Natriuretic peptides.
        N Engl J Med. 1998; 339: 321-328
        • de Lemos J.A.
        • McGuire D.K.
        • Drazner M.H.
        B-type natriuretic peptide in cardiovascular disease.
        Lancet. 2003; 362: 316-322
        • Richards A.M.
        • McDonald D.
        • Fitzpatrick M.A.
        • et al.
        Atrial natriuretic hormone has biological effects in man at physiological plasma concentrations.
        J Clin Endocrinol Metab. 1988; 67: 1134-1139
        • Ruskoaho H.
        Cardiac hormones as diagnostic tools in heart failure.
        Endocr Rev. 2003; 24: 341-356
        • Wannamethee S.G.
        • Welsh P.
        • Lowe G.D.
        • et al.
        N-terminal pro-brain natriuretic Peptide is a more useful predictor of cardiovascular disease risk than C-reactive protein in older men with and without pre-existing cardiovascular disease.
        J Am Coll Cardiol. 2011; 58: 56-64
        • Katan M.
        • Fluri F.
        • Schuetz P.
        • et al.
        Midregional pro-atrial natriuretic peptide and outcome in patients with acute ischemic stroke.
        J Am Coll Cardiol. 2010; 56: 1045-1053
        • Di A.E.
        • Chowdhury R.
        • Sarwar N.
        • et al.
        B-type natriuretic peptides and cardiovascular risk: systematic review and meta-analysis of 40 prospective studies.
        Circulation. 2009; 120: 2177-2187
        • Richards M.
        • Nicholls M.G.
        • Espiner E.A.
        • et al.
        Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease.
        J Am Coll Cardiol. 2006; 47: 52-60
        • Moertl D.
        • Berger R.
        • Struck J.
        • et al.
        Comparison of midregional pro-atrial and B-type natriuretic peptides in chronic heart failure: influencing factors, detection of left ventricular systolic dysfunction, and prediction of death.
        J Am Coll Cardiol. 2009; 53: 1783-1790
        • Squire I.B.
        • Orn S.
        • Ng L.L.
        • et al.
        Plasma natriuretic peptides up to 2 years after acute myocardial infarction and relation to prognosis: an OPTIMAAL substudy.
        J Card Fail. 2005; 11: 492-497
        • Morgenthaler N.G.
        • Struck J.
        • Thomas B.
        • Bergmann A.
        Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma.
        Clin Chem. 2004; 50: 234-236
        • Pepys M.B.
        • Hirschfield G.M.
        C-reactive protein: a critical update.
        J Clin Invest. 2003; 111: 1805-1812
        • Wald D.S.
        • Morris J.K.
        • Wald N.J.
        Reconciling the evidence on serum homocysteine and ischaemic heart disease: a meta-analysis.
        PLoS One. 2011; 6: e16473
        • Humphrey L.L.
        • Fu R.
        • Rogers K.
        • Freeman M.
        • Helfand M.
        Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis.
        Mayo Clin Proc. 2008; 83: 1203-1212
        • Veeranna V.
        • Zalawadiya S.K.
        • Niraj A.
        • et al.
        Homocysteine and reclassification of cardiovascular disease risk.
        J Am Coll Cardiol. 2011; 58: 1025-1033
        • Sabatine M.S.
        • Morrow D.A.
        • de Lemos J.A.
        • et al.
        Evaluation of multiple biomarkers of cardiovascular stress for risk prediction and guiding medical therapy in patients with stable coronary disease.
        Circulation. 2012; 125: 233-240
        • Galan P.
        • Kesse-Guyot E.
        • Czernichow S.
        • Briancon S.
        • Blacher J.
        • Hercberg S.
        Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
        BMJ. 2010; 341: c6273
        • Pencina M.J.
        • D'Agostino R.B.
        Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation.
        Stat Med. 2004; 23: 2109-2123
        • Pencina M.J.
        • D'Agostino Sr., R.B.
        • D'Agostino Jr., R.B.
        • Vasan R.S.
        Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.
        Stat Med. 2008; 27: 157-172
        • Antolini L.
        • Nam B.H.
        • D'Agostino Sr R.B.
        Inference on correlated discrimination measures in survival analysis: nonparametric approach.
        Commun Stat Theory Methods. 2004; 33: 2117-2135
        • Harrell Jr., F.E.
        • Lee K.L.
        • Mark D.B.
        Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors.
        Stat Med. 1996; 15: 361-387
        • Zethelius B.
        • Berglund L.
        • Sundstrom J.
        • et al.
        Use of multiple biomarkers to improve the prediction of death from cardiovascular causes.
        N Engl J Med. 2008; 358: 2107-2116
        • Kablak-Ziembicka A.
        • Przewlocki T.
        • Sokolowski A.
        • Tracz W.
        • Podolec P.
        Carotid intima-media thickness, hs-CRP and TNF-alpha are independently associated with cardiovascular event risk in patients with atherosclerotic occlusive disease.
        Atherosclerosis. 2011; 214: 185-190
        • Blankenberg S.
        • McQueen M.J.
        • Smieja M.
        • et al.
        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.
        Circulation. 2006; 114: 201-208
        • Bibbins-Domingo K.
        • Gupta R.
        • Na B.
        • Wu A.H.
        • Schiller N.B.
        • Whooley M.A.
        N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP), cardiovascular events, and mortality in patients with stable coronary heart disease.
        JAMA. 2007; 297: 169-176
        • Hlatky M.A.
        • Greenland P.
        • Arnett D.K.
        • et al.
        Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association.
        Circulation. 2009; 119: 2408-2416
        • Rothenbacher D.
        • Koenig W.
        • Brenner H.
        Comparison of N-terminal pro-B-natriuretic peptide, C-reactive protein, and creatinine clearance for prognosis in patients with known coronary heart disease.
        Arch Intern Med. 2006; 166: 2455-2460
        • Omland T.
        • Richards A.M.
        • Wergeland R.
        • Vik-Mo H.
        B-type natriuretic peptide and long-term survival in patients with stable coronary artery disease.
        Am J Cardiol. 2005; 95: 24-28
        • Maeder M.T.
        • Mueller C.
        • Pfisterer M.E.
        • Buser P.T.
        • Brunner-La Rocca H.P.
        Use of B-type natriuretic peptide outside of the emergency department.
        Int J Cardiol. 2008; 127: 5-16
        • Kragelund C.
        • Gronning B.
        • Kober L.
        • Hildebrandt P.
        • Steffensen R.
        N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease.
        N Engl J Med. 2005; 352: 666-675
        • Kaski J.C.
        • Fernandez-Berges D.J.
        • Consuegra-Sanchez L.
        • et al.
        A comparative study of biomarkers for risk prediction in acute coronary syndrome-Results of the SIESTA (Systemic Inflammation Evaluation in non-ST-elevation Acute coronary syndrome) study.
        Atherosclerosis. 2010; 212: 636-643
        • Mangoni A.A.
        • Woodman R.J.
        Homocysteine and cardiovascular risk an old foe creeps back.
        J Am Coll Cardiol. 2011; 58: 1034-1035
        • Wallen T.
        • Landahl S.
        • Hedner T.
        • Hall C.
        • Saito Y.
        • Nakao K.
        Atrial natriuretic peptides predict mortality in the elderly.
        J Intern Med. 1997; 241: 269-275
        • Wang T.J.
        • Larson M.G.
        • Levy D.
        • et al.
        Plasma natriuretic peptide levels and the risk of cardiovascular events and death.
        N Engl J Med. 2004; 350: 655-663
        • Sacco R.L.
        • Anand K.
        • Lee H.S.
        • et al.
        Homocysteine and the risk of ischemic stroke in a triethnic cohort: the NOrthern MAnhattan study.
        Stroke. 2004; 35: 2263-2269
        • Schnabel R.
        • Lackner K.J.
        • Rupprecht H.J.
        • et al.
        Glutathione peroxidase-1 and homocysteine for cardiovascular risk prediction: results from the AtheroGene study.
        J Am Coll Cardiol. 2005; 45: 1631-1637