Natriuretic Peptides and Cardiovascular Events
Authors: Marvin A. Konstam
Journal: JAMA (2007)

IN PATIENTS WITH KNOWN OR SUSPECTED CARDIOVASCUlar disease, biomarkers are increasingly being explored as indicators of disease presence, severity, or activity; prognosis; and therapeutic efficacy. A biomarker may be a by-product of the disease state and may also directly participate in its pathogenesis or modulation. The cardiac natriuretic peptides (secreted in response to myocardial stretch) promote vasodilation and natriuresis and are believed to mitigate adverse cardiovascular remodeling. Circulating levels of these peptides have proved useful in gauging the severity of heart failure and in assessing the differential diagnosis of acute dyspnea. N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) is an inactive cleavage product with much slower clearance than the biologically active BNP. Its plasma concentration, therefore, principally reflects myocardial secretion over a prolonged time. Prior investigations have identified plasma BNP and NT-proBNP levels as independent predictors of mortality or cardiovascular events in populations with chronic heart failure, acute coronary syndromes, prior myocardial infarction, established vascular disease or elevated coronary risk, and in community-based samples. In this issue of JAMA, the study by Bibbins-Domingo and colleagues extends these observations within a population of patients with stable coronary artery disease (CAD) and further clarifies the utility of NT-proBNP level as a predictor of a variety of subsequent cardiovascular events. The authors observe that plasma NT-proBNP concentration remains an independent predictor of all-cause mortality, CAD mortality, stroke, and events related to heart failure, even after sequentially adjusting for known measures of cardiac risk, left ventricular remodeling and function, inducible ischemia, functional capacity, inflammation, myocyte necrosis, and symptoms. Furthermore, plasma NT-proBNP concentration approaches significance as an independent predictor of myocardial infarction. These findings challenge the conventional view of the natriuretic peptide levels as mere hemodynamic markers of worsening heart failure or left ventricular dysfunction. Furthermore, these findings provoke reconsideration of the value of these markers as diagnostic tools and potentially as triggers for therapeutic intervention. How can a marker of myocardial stretch, measured at a single time point within a stable population, predict such a wide variety of cardiovascular events? Levels of NTproBNP may reflect a variety of adverse factors, all potentially resulting in increased hormonal release from stretched myocardium. However, to the extent that levels denote myocardial stretch, it seems likely that their value in predicting cardiovascular events would diminish after accounting for numerous known biochemical, echocardiographic, and functional markers of myocardial injury, ventricular remodeling, and active or inducible ischemia. The value of NTproBNP in predicting stroke, also observed for BNP in an analysis of the Framingham cohort, could be linked to its role as a marker of cardiac dilation with a predisposition to atrial fibrillation. However, the preserved predictive value for stroke after correction for multiple covariates, including echocardiographic measures of left ventricular function, supports consideration of alternative mechanisms responsible for the linkage between NT-proBNP levels and vascular events, including stroke. Along with myocardial stretch, a variety of other factors have been found to stimulate or enhance secretion of BNP in vitro, including myocardial ischemia and paracrine or endocrine agents such as endothelin A, angiotensin II, and tumor necrosis factor . Cardiac fibroblasts, as well as cardiac myocytes, secrete BNP, and its secretion modulates fibrosis through induction of matrix metalloproteinases. These observations suggest that the predictive value of plasma NT-proBNP concentration, particularly in a stable population without clinical heart failure, results not merely from its relationship with acute myocardial stretch but to