Published Online
on January 22, 2007

A more recent version of this article appeared on March 1, 2007

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Submitted on October 12, 2006
Revised on October 24, 2006

Multiple Biomarkers and the Risk of Incident Hypertension

Thomas J. Wang^*; Philimon Gona; Martin G. Larson; Daniel Levy; Emelia J. Benjamin; Geoffrey H. Tofler; Paul F. Jacques; James B. Meigs; Nader Rifai; Jacob Selhub; Sander J. Robins; Christopher Newton-Cheh; and Ramachandran S. Vasan

From the Framingham Heart Study (T.J.W., P.G., M.G.L., D.L., E.J.B., S.J.R., C.N.C., R.S.V.), Framingham, Mass; the Divisions of Cardiology (T.J.W., C.N.C.) and General Medicine (J.B.M.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston; the Department of Mathematics and Statistics (P.G., M.G.L.), Boston University, Boston; the National Heart, Lung, and Blood Institute (D.L.), Bethesda, Md; Royal North Shore Hospital (G.H.T.), Sydney, Australia; Jean Mayer Department of Agriculture Human Nutrition Research Center on Aging (P.F.J., J.S.), Tufts University, Boston, Mass; the Department of Laboratory Medicine (N.R.), Children’s Hospital, Harvard Medical School, Boston, Mass; and the Preventive Medicine and Cardiology Sections (D.L., E.J.B., R.S.V.), Division of Endocrinology, Nutrition, and Diabetes (S.J.R.), Boston Medical Center, Boston University School of Medicine, Mass.

^* To whom correspondence should be addressed. E-mail: tjwang{at}partners.org.

Abstract--An understanding of mechanisms underlying the development of essential hypertension is critical for designing prevention and treatment strategies. Selected biomarkers may be elevated before the onset of hypertension, but previous studies are limited by cross-sectional designs or a focus on single biomarkers. We prospectively studied 1456 nonhypertensive individuals who had baseline measurement of 9 biomarkers: C-reactive protein (inflammation); fibrinogen (inflammation and thrombosis); plasminogen activator inhibitor-1 (fibrinolytic potential); aldosterone, renin, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide (neurohormonal activity); homocysteine (renal function and oxidant stress); and urinary albumin/creatinine ratio (glomerular endothelial function). Incident hypertension, defined as blood pressure 140/90 mm Hg or antihypertensive therapy, developed in 232 participants over a mean follow-up of 3 years. After adjustment for clinical risk factors, the biomarker panel was significantly associated with incident hypertension (P=0.002). Three (of 9) biomarkers were significantly related to incident hypertension on backward elimination (multivariable-adjusted odds ratios, per SD increment in biomarker): C-reactive protein (1.26; 95% CI: 1.05 to 1.51), plasminogen activator inhibitor-1 (1.28; 95% CI: 1.05 to 1.57), and urinary albumin/creatinine ratio (1.21; 95% CI: 1.02 to 1.43). The incidence of hypertension was 4.5, 6.4, and 9.9 per 100 person years for participants with 0, 1, and 2 elevated biomarkers, respectively (elevation defined as 1 SD above the mean). The threshold of 2 elevated biomarkers for predicting hypertension was associated with high specificity (0.92) but low sensitivity (0.15). Biomarkers of inflammation, reduced fibrinolytic potential, and low-grade albuminuria are jointly associated with the incidence of hypertension. These data support the premise that abnormalities in multiple biological pathways antedate the onset of overt hypertension.

Key words: epidemiology • hypertension • C-reactive protein • plasminogen activator inhibitor-1 • aldosterone • albuminuria

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