Objective. To study circulating pro-B-type natriuretic peptide (proBNP1-108) in the general community, evaluate its ability to detect left ventricular (LV) dysfunction, and determine its prognostic value for cardiovascular (CV) events.
Background. The current concept for cardiac endocrine function is that in response to cardiac stress the heart secretes B-type natriuretic peptide (BNP1-32) and amino-terminal proBNP (NT-proBNP1-76 ) after intracardiac cleavage of their molecular precursor, proBNP1-108. We hypothesized that proBNP1-108 circulates physiologically in normal human subjects and that it is a useful diagnostic and prognostic cardiac biomarker.
Methods. Our population-based study included a cohort of 1,939 adult (age ≥ 45 years) from Olmsted County, MN, with 672 participants defined as healthy normals. Subjects underwent in-depth clinical characterization, detailed echocardiography, and measurement of natriuretic peptide levels. Multivariable analysis, optimal cutpoints analysis and logistic regression were used to calculate independent factors associated with BNP-form levels and compare their diagnostic and prognostic utilities.
Results. ProBNP1-108 in normal humans was strongly influenced by gender, age, heart rate, and body mass index. The median concentration was 20 ng/L with a mean proBNP1-108/NT-proBNP 1-76 ratio of 0.366, which significantly decreased with increasing HF stage. ProBNP1-108 was a sensitive (78.8%) and specific (86.1%) biomarker for detecting LV systolic dysfunction, which was comparable to BNP 1-32, but less than NTproBNP1-76, in several subsets of the population. Subjects with proBNP1-108 levels in the top quintile (20%), compared to the bottom 80%, had significantly increased risk of CV events (OR=1.25, p=0.017) and mortality (OR=1.22, p<0.01) over a decade, adjusting for clinical and echocardiographic abnormalities.
Conclusion. We demonstrate for the first time that proBNP 1-108 circulates in the majority of normal humans in the general population and is a sensitive and specific biomarker for the detection of systolic dysfunction and identification of subjects of future adverse CV events and mortality. The proBNP1-108 /NT-proBNP1-76 ratio may provide insights into altered proBNP1-108 processing during HF progression. Thus, this highly specific assay for proBNP1-108 improves our understanding of the BNP system and its association with future cardiovascular risk. Application of this novel assay for prevention of HF and its associated comorbidites may reduce their tremendous economic and social burden.
