Published Online
on February 13, 2006

A more recent version of this article appeared on February 21, 2006

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Submitted on August 1, 2005
Revised on November 20, 2005
Accepted on December 1, 2005

Cross-Sectional Relations of Multiple Biomarkers From Distinct Biological Pathways to Brachial Artery Endothelial Function

Sekar Kathiresan MD, Philimon Gona PhD, Martin G. Larson ScD, Joseph A. Vita MD, Gary F. Mitchell MD, Geoffrey H. Tofler MD, Daniel Levy MD, Christopher Newton-Cheh MD, MPH, Thomas J. Wang MD, Emelia J. Benjamin MD, ScM, and Ramachandran S. Vasan MD^*

From National Heart, Lung, and Blood Institute’s Framingham Heart Study (S.K., P.G., M.G.L., D.L., C.N.-C., T.J.W., E.J.B., R.S.V.), Framingham, Mass; Department of Mathematics and Statistics (P.G., M.G.L.), Evans Department of Medicine (J.A.V., E.J.B., R.S.V.), and Whitaker Cardiovascular Institute (J.A.V., R.S.V., E.J.B.), Boston University, Boston, Mass; Cardiovascular Engineering, Inc. (G.F.M.), Holliston, Mass; Royal North Shore Hospital (G.H.T.), Sydney, Australia; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University (S.K., C.N.-C.), Cambridge, Mass; and Cardiology Division (S.K., C.N-.C., T.J.W.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: vasan{at}bu.edu.

Background--Endothelial dysfunction is a critical intermediate phenotype in the pathogenesis of cardiovascular disease. We evaluated the relative contributions of distinct biological pathways to interindividual variation in endothelial function by relating prototype biomarkers (representing these pathways) to brachial artery vasodilator function.

Methods and Results--We investigated the cross-sectional relations of a panel of 7 biomarkers measured at a routine examination to brachial artery vasodilator function (flow-mediated dilation [FMD] and reactive hyperemia) assessed at a subsequent examination (mean interval, 2.9 years) in 2113 Framingham Heart Study participants (mean age, 61 years; 54% women). We selected biomarkers from 4 biological domains: neurohormonal (N-terminal pro-atrial natriuretic peptide [N-ANP], B-type natriuretic peptide [BNP], renin, aldosterone), hemostatic factors (plasminogen activator inhibitor-1 [PAI-1]), inflammation (C-reactive protein [CRP]), and target organ damage (urine albumin-creatinine ratio). In age- and sex-adjusted models, several biomarkers were related to baseline brachial artery diameter (PAI-1, CRP, urine albumin-creatinine ratio), baseline mean flow (N-ANP, BNP, PAI-1, CRP, aldosterone), FMD (N-ANP, PAI-1, CRP, renin), and reactive hyperemia (BNP, PAI-1, CRP, renin, urine albumin-creatinine ratio). In multivariable analyses relating the 7 biomarkers conjointly to each vascular function measure (adjusting for known risk factors), N-ANP and renin were positively related to FMD (P=0.001 and P=0.04, respectively), and N-ANP was inversely related to baseline mean flow velocity (P=0.01). None of the other biomarkers was significantly related to the vascular function measures studied.

Conclusions--In our large community-based sample, a conservative strategy relating several biomarkers to vascular endothelial function identified plasma N-ANP as a key correlate of mean flow under basal conditions and of FMD in response to forearm cuff occlusion.

Key words: atrial natriuretic factor • endothelium • inflammation • natriuretic peptides • renin

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