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Original Article Plasma Natriuretic Peptide Levels and the Risk of Cardiovascular Events and Death Thomas J. Wang, M.D., Martin G. Larson, Sc.D., Daniel Levy, M.D., Emelia J. Benjamin, M.D., Eric P. Leip, M.S., Torbjorn Omland, M.D., Philip A. Wolf, M.D., and Ramachandran S.
N Engl J Med 2004; 350:655-663 DOI: 10.1056/NEJMoa031994. Results During a mean follow-up of 5.2 years, 119 participants died and 79 had a first cardiovascular event. After adjustment for cardiovascular risk factors, each increment of 1 SD in log B-type natriuretic peptide levels was associated with a 27 percent increase in the risk of death (P=0.009), a 28 percent increase in the risk of a first cardiovascular event (P=0.03), a 77 percent increase in the risk of heart failure (P. Figure 1 Cumulative Incidence of Death (Panel A) and Heart Failure (Panel B), According to the Plasma B-Type Natriuretic Peptide Level at Base Line.
The lowest third, middle third, and highest third of plasma B-type natriuretic peptide levels were 4.0 pg per milliliter or less, 4.1 to 12.7 pg per milliliter, and 12.8 pg per milliliter or more, respectively, for men and 5.9 pg per milliliter or less, 6.0 to 15.7 pg per milliliter, and 15.8 pg per milliliter or more, respectively, for women. Follow-up results are truncated after six years. Atrial natriuretic peptide and B-type natriuretic peptide are secreted from cardiomyocytes in response to atrial or ventricular wall stretch.
The natriuretic peptides have a fundamental role in cardiovascular remodeling, volume homeostasis, and the response to ischemia. Clinical investigations of these peptides have focused on their diagnostic usefulness for heart failure and left ventricular dysfunction and their prognostic usefulness after acute coronary syndromes and heart failure. A few reports have suggested that elevated plasma natriuretic peptide levels in nonhospitalized persons are associated with an increased risk of death, but these studies have largely been restricted to very elderly persons.
We were interested in examining the relations of natriuretic peptides to the incidence of cardiovascular events, heart failure, and atrial fibrillation in an ambulatory cohort. We prospectively studied a large, community-based sample of persons in whom plasma natriuretic peptide levels were routinely measured and who were followed for the occurrence of major cardiovascular events and death. Study Sample The design and selection criteria of the Framingham Offspring Study have been described previously. The 3532 participants who attended the sixth examination cycle (1995 through 1998) were eligible for the present investigation. We excluded 186 attendees for the following reasons: heart failure in 40, a serum creatinine level of more than 2.0 mg per deciliter (177 μmol per liter) in 16, unavailability of natriuretic peptide levels in 78, missing covariate data in 49, and missing follow-up data in 3.
After exclusions, 3346 participants (95 percent) remained eligible. Participants underwent a clinical and laboratory evaluation and echocardiography, as described previously. Study protocols were approved by the institutional review board of Boston Medical Center. Written informed consent was obtained from all participants. Natriuretic Peptide Assays B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide were measured with the use of high-sensitivity, noncompetitive immunoradiometric assays (Shionogi).