This study was designed to determine whether alternate pro-B-type natriuretic peptide (proBNP) and BNP forms circulate in the general population.Bioactive BNP(1-32) and NT-proBNP(1-76) are derived from a precursor molecule, proBNP(1-108). Recent data suggest that aminodipeptidase-processed forms of BNP(1-32) (BNP(3-32)) and of proBNP(1-108) itself (proBNP(3-108)) may circulate and have additional diagnostic potential.Residents (age > or =45 years) of Olmsted County, Minnesota, underwent medical review, echocardiography, and phlebotomy for 2 novel assays specific for proBNP(3-108) and BNP(3-32) and 2 commercial assays (Triage BNP and Roche NT-proBNP). Groups included normal subjects (n = 613), cardiovascular disease with normal ventricular function (n = 1,043), preclinical ventricular dysfunction (ALVD, n = 130), and chronic heart failure (HF, n = 52).ProBNP(3-108) levels were above assay detection limits in 68% of normal subjects (50th; 25th to 75th percentiles: 7.85; 3.00 to 22.45 pmol/l) and correlated with age, gender, body size, and renal function and with results of commercial assays. ProBNP(3-108) levels were higher in ALVD (17.88; 6.07 to 42.76 pmol/l) or HF (42.75; 20.51 to 65.73 pmol/l), where they correlated more strongly with commercial assays. BNP(3-32) was above assay detection limits in 22% of normal subjects; levels were not correlated with age, body size, or renal function but were higher in HF. Neither novel assay was superior to commercial assays for the detection of ALVD or HF.The presence of alternate circulating proBNP and BNP forms provides evidence for diverse proBNP and BNP processing in the general population. The physiologic consequences of these observations, both in terms of assay performance and endogenous BNP bioactivity, deserve further study.