A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats

J Mol Cell Cardiol. 2019 Apr;129:257-265. doi: 10.1016/j.yjmcc.2019.03.009. Epub 2019 Mar 14.

Abstract

To date, there is no established treatment for heart failure with preserved ejection fraction (HFpEF). Dipeptidyl peptidase-IV (DPP-IV) inhibitors reportedly have improved not only diabetes mellitus but also heart failure with systolic dysfunction in experimental models. We investigated the effects of a DPP-IV inhibitor on HFpEF in rats. Dahl salt-sensitive rats were fed either high-salt (high-salt diet (HSD): 8% NaCl) or low-salt diets (0.3% NaCl) from 6.5 weeks of age. They were then treated with or without a DPP-IV inhibitor, vildagliptin (10 mg/kg/day, orally), from 11 weeks of age for 9 weeks and analyzed at the age of 20 weeks. HSD rats mimicked the pathophysiology of HFpEF. There were no differences in heart rate, blood pressure, left ventricular (LV) systolic function, or the extent of LV hypertrophy between HSD rats with or without vildagliptin. However, vildagliptin decreased LV end-diastolic pressure, the most reliable hemodynamic parameter of HFpEF in HSD rats. Vildagliptin also decreased the LV distensibility index, a sensitive marker of LV diastolic function in HSD rats. Vildagliptin decreased the expression of collagen genes in HSD hearts and attenuated LV interstitial fibrosis (HSD with vehicle and vildagliptin, 2.9% vs. 1.9%; P < 0.05). Furthermore, vildagliptin administration reduced both plasma renin activity and aldosterone concentrations in HSD rats. A DPP-IV inhibitor, vildagliptin, improved the severity of LV fibrosis, and thus, diastolic dysfunction of HFpEF in Dahl salt-sensitive hypertensive rats. DPP-IV inhibitors are promising medicines for treatment of HFpEF in patients with diabetes mellitus.

Keywords: Cardiac fibrosis; Left ventricular diastolic dysfunction; Left ventricular diastolic pressure–volume relationship; Renal dysfunction; Renin–angiotensin–aldosterone system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Collagen / genetics
  • Collagen / metabolism
  • Diastole / drug effects*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Fibrosis
  • Gene Expression Regulation / drug effects
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Glucose / metabolism
  • Heart Failure / diagnostic imaging
  • Heart Failure / genetics
  • Heart Failure / physiopathology
  • Heart Function Tests / drug effects
  • Heart Ventricles / drug effects
  • Heart Ventricles / physiopathology
  • Hypertension / genetics
  • Hypertension / physiopathology
  • Inflammation / pathology
  • Kidney Function Tests
  • Male
  • Myocardium / pathology
  • Rats, Inbred Dahl
  • Renin-Angiotensin System / drug effects
  • Stroke Volume / drug effects
  • Vildagliptin / pharmacology

Substances

  • Biomarkers
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glucagon-Like Peptide-1 Receptor
  • Collagen
  • Vildagliptin
  • Glucose