Abstract 11253: Inhibition of Dipeptidyl Peptidase IV Improves Left Ventricular Compliance in Obese Diabetic Mice
INTRODUCTION: Diabetes cardiomyopathy (DCMP) is a leading cause of cardiac morbidity and mortality. DCMP is characterized by left ventricular (LV) hypertrophy and fibrosis, and by LV diastolic dysfunction, the latter which has been linked to increased cardiomyocyte stiffness. Inhibitors of dipeptidyl peptidase-IV (DPP-IV) are novel drugs for the treatment of patients with type 2 diabetes, shown to improve myocardial metabolism. This study investigates the effects of sitagliptin (SITA), an orally active inhibitor of DPP-IV, on LV structure and function in diabetic mice.
RESULTS: Obese male type 2 diabetic mice (Leprdb/db, n=24) were treated with SITA (300 mg/kg/day in drinking water) or vehicle during 8 weeks. SITA inhibited more than 85% of serum DPP-IV activity but had no effect on fasting glucose levels. SITA reduced cardiomyocyte size (p<0.05) and minimally affected LV collagen fraction. Invasive pressure-volume recordings in anesthetized mice at varying preloads showed that SITA increased LV stroke volume (p<0.005), cardiac output (p<0.005), LV stroke work (p<0.001) and LV compliance (p<0.05), whereas LV end-systolic elastance and preload-recruitable stroke work remained unchanged. Furthermore, in isolated cardiomyocytes, SITA reduced cardiomyocyte resting tension (Fpassive) and increased total titin phosphorylation (p<0.001).
CONCLUSION: In obese diabetic mice, in absence of hypoglycaemic effects, DPP-IV inhibition by SITA improves overall LV performance and LV compliance. These effects seem at least partially mediated by effects of SITA on the phosphorylation status of total titin and on the cardiomyocyte stiffness modulus.
- © 2012 by American Heart Association, Inc.