Journal
EUROPEAN JOURNAL OF HEART FAILURE
Volume 14, Issue 1, Pages 14-21Publisher
WILEY
DOI: 10.1093/eurjhf/hfr146
Keywords
Chronic heart failure; DPP4 inhibitor; Sitagliptin; Contractility; Cardiorenal syndrome
Categories
Funding
- Biosite Incorporated, San Diego, USA
- Foundation for Cardiac Surgery, Brussels, Belgium
- Research Foundation - Flanders, Brussels, Belgium (FWO Vlaanderen) [G016209]
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Aims Recent studies indicate that brain natriuretic peptide (BNP1-32) may be truncated into BNP3-32 by dipeptidyl peptidase IV (DPP4) and that BNP3-32 has reduced biological activities compared with BNP1-32. We investigated if DPP4 contributes to the cardiorenal alterations and to the attenuated response to BNP seen in heart failure. Methods and results Haemodynamic and renal assessment was performed in 12 pigs at baseline, 4 weeks after pacing-induced heart failure, and during BNP infusion. They were randomized to either placebo or treatment with a DPP4 inhibitor, sitagliptin. After 4 weeks of pacing, heart rate was reduced compared with baseline in the sitagliptin group (60 +/- 2 vs. 95 +/- 16 b.p.m., P < 0.01), and an increase in stroke volume was observed in the sitagliptin group compared with placebo (+24 +/- 6% vs. -17 +/- 7%, P < 0.01). Glomerular filtration rate declined at week 4 compared with baseline in the placebo group (1.3 +/- 0.4 vs. 2.3 +/- 0.3 mL/kg/min, P < 0.01) but remained preserved in the sitagliptin group [1.8 +/- 0.2 vs. 2.0 +/- 0.3 mL/kg/min, P = NS (non-significant)]. In the sitagliptin group, BNP infusion improved end-systolic elastance (68 +/- 5 vs. 31 +/- 4 mmHg/kg/mL, P < 0.05), ventricular-arterial coupling, and mechanical efficiency. Compared with controls (n = 6), myocardial gene expression of BNP, interleukin-6, Na+-Ca2+ exchanger, and calmodulin was up-regulated in the placebo group, but not in the sitagliptin group. Conclusion In pacing-induced heart failure, DPP4 inhibition preserves the glomerular filtration rate, modulates stroke volume and heart rate, and potentiates the positive inotropic effect of exogenous BNP at no energy expense.
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