Abstract 15196: Dipeptidyl peptidase IV Inhibition Improves Cardiorenal Function in Pacing-Induced Heart Failure
Recent studies indicate that B-type natriuretic peptide (BNP1-32) may be truncated to BNP3-32 by the dipeptidylpeptidase IV (DPP4) and that BNP3-32 has reduced biological activities compared to BNP1-32. We hypothesized that chronic DPP4 inhibition potentiates the cardiorenal effects of endogenous and exogenous BNP. A hemodynamic and renal assessment was performed in 12 piglets at baseline, 4 weeks after pacing-induced heart failure and during BNP infusion. The piglets were randomized to placebo or DPP4 inhibitor (sitagliptin). At week 4, heart rate was reduced compared to baseline in the sitaglitpin group (60 ± 2 versus 95 ± 16 beats/min, p<0.01) and an increase in stroke volume was observed compared to the placebo group (+24% ± 6 versus −17% ± 7, p<0.01). Glomerular filtration rate declined at week 4 compared to baseline in the placebo group (1.3 ± 0.4 versus 2.3 ± 0.3 ml.kg−1.min−1, p<0.01) but remained preserved in the sitagliptin group (1.8 ± 0.2 versus 2.0 ± 0.3 ml.kg−1.min−1, p=NS). In the sitagliptin group, BNP infusion improved end-systolic elastance (Ees), ventricular-arterial coupling (Ees/Ea) and mechanical efficiency (Figure). In contrast, no hemodynamic changes were observed in the placebo group during BNP infusion. Compared to control piglets (n = 6), myocardial gene expressions of BNP, interleukin-6, Na-Ca exchanger and calmodulin were upregulated in the placebo group, but not in the sitagliptin group. In conclusion, in a large animal model of pacing-induced heart failure, DPP4 inhibition preserves renal function, modulates stroke volume and heart rate and potentiates the positive inotropic effect of exogenous BNP at no energy expense. This functional improvement is associated with normalization of myocardial gene expression of several calcium regulatory proteins, BNP and interleukin−6. Our findings provide insights into the role of DPP4 and warrant further studies to address its effects on prevention or treatment of the cardiorenal syndrome.
- © 2010 by American Heart Association, Inc.