Elsevier

Atherosclerosis

Volume 228, Issue 2, June 2013, Pages 478-484
Atherosclerosis

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

https://doi.org/10.1016/j.atherosclerosis.2013.03.017Get rights and content

Highlights

  • 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.

Abstract

Background

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.

Design

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.

Results

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.

Conclusion

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

Introduction

New avenues for prevention of cardiovascular disease (CVD) including better diagnosis and risk evaluation are of increasing interest in high-risk groups. In this regard, novel biomarkers such as natriuretic peptides namely atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP) as well as C-reactive protein (CRP) and homocysteine are of interest.

ANP and BNP are vasoactive cardiac peptide hormones with natriuretic, diuretic, and vasodilator activity [1], that could be important diagnostic and prognostic tools for CVD and related mortality in general population and coronary heart disease (CHD) patients [2], [3], [4], [5], [6], [7], [8]. Few studies have simultaneously evaluated the prognostic value of both natriuretic peptides (proANP and proBNP) over and above conventional cardiovascular risk factors, beyond the period of hospitalization after an acute CVD event (MI, left ventricular systolic dysfunction and chronic heart failure) [9], [10]. In addition, newer assays targeting more stable epitopes of ANP, such as mid-regional pro-ANP (MR-proANP) have become available that could offer more refined risk assessment [11]. In clinical practice established tests such as CRP and homocysteine are often considered in CVD risk assessment. CRP is commonly determined using routinely available assays as a systemic inflammatory marker [12]. Although the evidence linking elevated homocysteine and CVD risk is inconsistent [13], [14], recent promising findings from NHANES III and Multi-Ethnic Study of Atherosclerosis (MESA) studies showing significant improvement in risk prediction for future CVD and CHD events in intermediate-risk patients upon addition of homocysteine to the Framingham risk model [15], has re-sparked interest in this marker for CVD risk assessment. The current study, thus, evaluated the comparative prognostic value of four biomarkers (natriuretic peptides MR-proANP and NT-proBNP, CRP and homocysteine) alone and in combination, in addition to conventional risk factors, in patients with stable CVD, in whom information on predictive risk has not been extensively evaluated using emerging biomarkers [9], [16].

Section snippets

Study design

The SU.FOL.OM3 trial is a multicenter, double-blind randomized controlled trial (RCT) that evaluated the separate and combined effects of daily supplementation with B-vitamins, and/or n-3 polyunsaturated fatty acid for prevention of CVD [17]. Participants (45–80 y) were recruited via a nationwide network of 417 cardiologists, neurologists or other physicians. Those meeting the CVD inclusion criteria of a history of ischemic stroke or other coronary event i.e. acute coronary syndrome with or

Results

The study involved 1456 subjects who were diagnosed with either acute coronary syndrome (31%), or acute MI (49.2%) or stroke (19.5%) at 1–12 months (mean: 4 mo) prior to inclusion in the study. Briefly, subjects were randomly assigned to receive either a placebo (23%) or a supplement (omega-3 fatty acids alone (25%), B-vitamins folic acid and B-12 alone (27%) or with omega-3 fatty acids (25%) [17]. The supplementation had no effect on the occurrence of CVD outcomes [17] nor on specific CVD

Discussion

The comparative prognostic value of a panel of emerging biomarkers namely MR-proANP, NT-proBNP, CRP, and homocysteine for predicting cardiovascular risk was evaluated in this relatively large prospective study of stable CVD patients, who had a major CVD event on average 4 months prior to baseline assessment. Although studies have examined the improvement in CVD risk prediction using novel and classic biomarkers [5], [10], [22], [23], [24], [25], most focused on individuals in early stages of

Funding

The SU.FOL.OM3 trial was supported by the French Ministry of Research [R02010JJ]; Ministry of Health (DGS); Sodexo; Candia; Unilever; Danone; Roche Laboratory; Merck EPROVA GS; and Pierre Fabre Laboratory. The funding agencies were not involved in study design, analysis, and interpretation.

Declaration of conflicting interests

The Authors declare that there is no conflict of interest.

References (36)

  • M.T. Maeder et al.

    Use of B-type natriuretic peptide outside of the emergency department

    Int J Cardiol

    (2008)
  • J.C. Kaski 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)
  • A.A. Mangoni et al.

    Homocysteine and cardiovascular risk an old foe creeps back

    J Am Coll Cardiol

    (2011)
  • R. Schnabel et al.

    Glutathione peroxidase-1 and homocysteine for cardiovascular risk prediction: results from the AtheroGene study

    J Am Coll Cardiol

    (2005)
  • E.R. Levin et al.

    Natriuretic peptides

    N Engl J Med

    (1998)
  • A.M. Richards et al.

    Atrial natriuretic hormone has biological effects in man at physiological plasma concentrations

    J Clin Endocrinol Metab

    (1988)
  • H. Ruskoaho

    Cardiac hormones as diagnostic tools in heart failure

    Endocr Rev

    (2003)
  • A.E. Di et al.

    B-type natriuretic peptides and cardiovascular risk: systematic review and meta-analysis of 40 prospective studies

    Circulation

    (2009)
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