Simultaneous Assessment of Unprocessed ProBNP1-108 in Addition to Processed BNP32 Improves Identification of High-Risk Ambulatory Patients With Heart Failure

Background—B-type natriuretic peptide (BNP) is produced as a biologically inactive prohormone (proBNP1-108), processed, and released as an inactive amino acid N-terminal fragment (proBNP1-76) and a biologically active carboxyl-terminal fragment (proBNP77-108 or BNP32). We hypothesized that simultaneous assessment of proBNP1-108 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 proBNP1-108 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 proBNP1-108 circulates in patients with systolic heart failure (median, 271 pg/mL; interquartile range, 65 to 825). Higher levels of proBNP1-108 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; P0.001, comparing third versus first proBNP1-108 tertile). ProBNP1-108 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; P0.001 per doubling of proBNP1-108). Conclusions—Circulating proBNP1-108 is independently associated with an increased risk of adverse cardiovascular outcomes in ambulatory patients with chronic systolic heart failure. The combined assessment of BNP32 an