Brain natriuretic peptide: a marker for subclinical cardiovascular disease?

The natriuretic peptides constitute a family of closely related gene products, each of which possesses potent activity in the cardiovascular, endocrine, and renal systems (1). In humans, brain natriuretic peptide (BNP) is a 32–amino acid peptide that is derived from the carboxy-terminal portion of a 108 –amino acid precursor (proBNP). As its name implies, BNP was first isolated from porcine brain (2); however, in most organisms, including humans, it is produced predominantly in the ventricular myocardium. Although it is produced in modest levels in the adult ventricular myocyte under physiological conditions, like atrial natriuretic peptide (ANP), its expression is increased dramatically by experimental or clinical stimuli that promote hypertrophy or dilatation of the ventricular chamber (1). Increased expression results in increased secretion of natriuretic peptides into circulating plasma, and in advanced stages of heart failure, plasma levels increase to many times those found in normal healthy persons. This sensitivity to changes in structural or functional characteristics of the ventricular myocardium has engendered considerable interest in the use of natriuretic peptides in the diagnosis and management of cardiac disease. Plasma levels of natriuretic peptides have been used to assess prognosis in patients with established heart failure (3) as well as in those at risk of cardiac dysfunction (e.g., patients with acute ischemic syndromes or post–myocardial infarction) (4,5). They have also been used in the differential diagnosis of dyspnea in the acute care setting (i.e., assigning a cardiac vs. noncardiac etiology) (6,7), to assess response to therapy (8), and to guide treatment of underlying cardiac disease (9). In studies where direct comparisons have been made, measurements of BNP have been shown to be superior to ANP (10), perhaps reflecting the closer link between BNP production and the ventricular myocardium. Atrial natriuretic peptide, which is produced in both atrial and ventricular myocardium in the hypertrophied or failing heart, may be more sensitive to changes in central hemodynamics. The aminoterminal portion of the proBNP molecule, which is cleaved from BNP within the myocyte secretory granule, is thought to be nonfunctional; yet based on increased stability (vs. BNP), proBNP accrues to very high levels in the plasma of patients with heart failure. It appears to be at least as useful as, if not more useful than, conventional BNP measurements in assigning prognosis after myocardial infarction (11). Recent interest has focused on using plasma BNP levels to identify populations of asymptomatic or minimally symptomatic persons who are at risk of cardiovascular events or cardiac death. In a study of 2000 patients aged 25 to 74 years who were randomly selected from patient lists of family physicians in Glasgow, the United Kingdom (12), left ventricular systolic dysfunction was found to be closely related to elevations in plasma natriuretic peptide levels, particularly in patients aged 55 years or older. A more recent study by Vasan et al. (13) examined the utility of measuring plasma BNP levels, as well as aminoterminal ANP levels, as screening tools for left ventricular hypertrophy and left ventricular systolic dysfunction in 3177 patients from the Framingham Study who had undergone routine examination between 1995 and 1998. Only one third of participants with either finding were identified, suggesting that natriuretic peptide measurements may have limited utility as a mass screening tool. However, as noted in other studies (12,14), measurement of natriuretic peptide levels may be useful in detecting subclinical disease when confined to patient populations such as the elderly, who are at increased risk of cardiac dysfunction. Davis et al. (14) studied 331 frail, elderly subjects who were free of acute illness at the time of entry into the study and observed that in the 15% of the cohort who developed clinical heart failure within 1 year of follow-up, ANP levels at study entry were more than twofold higher than in those who did not develop heart failure. The only other variable that predicted development of heart failure was a history of heart failure in the previous year. A subsequent study by Wallen et al. (15) involving 541 patients aged 85 years or older showed a similar inverse relation between plasma BNP levels and survival during a 5-year follow-up, independent of coexisting clinical cardiovascular disease. In this issue of the Journal, Ueda et al. (16) expand on a similar theme. They followed a group of 111 patients, aged 80 years or older, who had no history of hospitalization for cardiovascular disease, a cardiothoracic ratio 55%, and a serum creatinine level 2.0 mg/mL. They found that BNP concentrations drawn at study entry were directly related to subsequent cardiovascular morbidity and overall mortality during the ensuing 24 months. Each increment of 50 pg/mL in plasma BNP level Am J Med. 2003;114:329 –330. From the Department of Medicine and Diabetes Center, University of California, San Francisco, San Francisco, California. Requests for reprints should be addressed to David G. Gardner, MD, Department of Medicine and Diabetes Center, University of California, San Francisco, 513 Parnassus, HSW-1119, Box 0540, San Francisco, California 94143-0540, or gardner@itsa.ucsf.edu. Manuscript submitted September 23, 2002.