Background: B-type natriuretic peptide (BNP) is produced as a biologically inactive prohormone (proBNP(1-108)), processed, and released as an inactive amino acid N-terminal fragment (proBNP(1-76)) and a biologically active carboxyl-terminal fragment (proBNP(77-108) or BNP32). We hypothesized that simultaneous assessment of proBNP(1-108) and active BNP32, as an index of natriuretic peptide processing efficiency, would improve risk stratification in patients with chronic systolic heart failure.
Methods and results: We quantified plasma proBNP(1-108) and BNP32 in 756 participants in the Penn Heart Failure Study, a prospective cohort of outpatients with predominantly systolic heart failure. Cox models were used to determine the association between biomarker level at the time of study entry and incident risk of adverse cardiovascular outcomes. A significant amount of unprocessed proBNP(1-108) circulates in patients with systolic heart failure (median, 271 pg/mL; interquartile range, 65 to 825). Higher levels of proBNP(1-108) were associated with an increased risk of all-cause death or cardiac transplantation (adjusted hazard ratio, 4.9; 95% CI, 2.5 to 9.7; P<0.001, comparing third versus first proBNP(1-108) tertile). ProBNP(1-108) provided additive information to BNP32 risk assessment, particularly in patients with BNP32 less than the median of 125 pg/mL (adjusted hazard ratio, 1.4; 95% CI, 1.2 to 1.8; P<0.001 per doubling of proBNP(1-108)).
Conclusions: Circulating proBNP(1-108) is independently associated with an increased risk of adverse cardiovascular outcomes in ambulatory patients with chronic systolic heart failure. The combined assessment of BNP32 and proBNP(1-108) provides additional information in determining risk of adverse clinical outcomes, particularly in patients with low BNP32 values that might otherwise be reassuring to the clinician.