Angiotensin Receptor Neprilysin Inhibitor Attenuates Myocardial Remodeling and Improves Infarct Perfusion in Experimental Heart Failure

Sci Rep. 2019 Apr 8;9(1):5791. doi: 10.1038/s41598-019-42113-0.

Abstract

Angiotensin receptor blocker-neprilysin inhibitor (ARNi) therapy improves the prognosis of heart failure patients. However, the mechanisms remain unclear. This study investigated the biological effects of ARNi with neprilysin inhibitor sacubitril and angiotensin receptor blocker valsartan on myocardial remodeling and cardiac perfusion in experimental heart failure (HF) after myocardial infarction (MI). Male Lewis rats (10-weeks old) with confirmed HF were randomized one-week post-MI to treatment with vehicle (water), sacubitril/valsartan or valsartan, as comparator group, for either 1 or 5 weeks. Sacubitril/valsartan for 1-week limited LV contractile dysfunction vs. vehicle and both sacubitril/valsartan and valsartan attenuated progressive LV dilation after 1 and 5 weeks treatment. After 5 weeks, both sacubitril/valsartan and valsartan reduced CTGF expression in the remote myocardium, although only sacubitril/valsartan prevented interstitial fibrosis. In the border zone, sacubitril/valsartan and valsartan reduced hypertrophic markers, but only sacubitril/valsartan reduced cardiomyocyte size and increased VEGFA expression. In the infarct, sacubitril/valsartan induced an early uptake of 99mTc-NC100692 (a radiotracer of angiogenesis) and improved perfusion, as determined by 201Tl microSPECT/CT imaging. In conclusion, ARNi improved global LV function, limited remodeling in the remote and border zones, and increased perfusion to the infarct. Sacubitril/valsartan had more consistent effects than valsartan on LV remodeling in experimental HF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates / administration & dosage
  • Aminobutyrates / pharmacology
  • Aminobutyrates / therapeutic use*
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin Receptor Antagonists / pharmacology
  • Angiotensin Receptor Antagonists / therapeutic use*
  • Animals
  • Drug Combinations
  • Heart / diagnostic imaging
  • Heart / drug effects
  • Heart Failure / drug therapy*
  • Male
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Neovascularization, Physiologic
  • Neprilysin / antagonists & inhibitors*
  • Organotechnetium Compounds / pharmacokinetics
  • Peptides, Cyclic / pharmacokinetics
  • Rats
  • Rats, Inbred Lew
  • Single Photon Emission Computed Tomography Computed Tomography
  • Tetrazoles / administration & dosage
  • Tetrazoles / pharmacology
  • Tetrazoles / therapeutic use*
  • Valsartan / administration & dosage
  • Valsartan / pharmacology
  • Valsartan / therapeutic use
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Ventricular Remodeling

Substances

  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Drug Combinations
  • Organotechnetium Compounds
  • Peptides, Cyclic
  • Tetrazoles
  • Vascular Endothelial Growth Factor A
  • Valsartan
  • Neprilysin
  • technetium 99m NC 100692
  • sacubitril and valsartan sodium hydrate drug combination