Effect of Chronic Heart Rate Reduction by I(f) Current Inhibitor Ivabradine on Left Ventricular Remodeling and Systolic Performance in Middle-Aged Rats With Postmyocardial Infarction Heart Failure

J Cardiovasc Pharmacol Ther. 2015 May;20(3):299-312. doi: 10.1177/1074248414553231. Epub 2014 Oct 5.

Abstract

Background: A large myocardial infarction (MI) initiates progressive cardiac remodeling that leads to systolic heart failure (HF). Long-term heart rate reduction (HRR) induced by the I f current inhibitor ivabradine (IVA) ameliorates left ventricular (LV) remodeling and improves systolic performance in young post-MI rats. However, the beneficial effects of chronic IVA treatment in middle-aged rats remain to be determined.

Methods: A large MI was induced in 12-month-old rats by left coronary artery ligation. Rats were treated with IVA via osmotic pumps intraperitoneal in a dose of 10.5 mg/kg/d (MI + IVA) and compared with MI and sham-operated animals 12 weeks after MI.

Results: Heart rate in MI + IVA rats was on average 29% lower than that of rats in the MI group. Left ventricular remodeling was comparable between post-MI groups, although MI + IVA rats did not show the compensatory thickening of the noninfarcted myocardium. Chronic HRR had no effect on transverse cardiac myocyte size and capillary growth, but it reduced the collagen content in noninfarcted myocardium. Left ventricular systolic performance remained similarly impaired in MI and MI + IVA rats. Moreover, abrupt IVA withdrawal led to worsening HF and reduction of coronary reserve.

Conclusion: Our data reveal that chronic IVA-induced HRR does not provide sustainable benefits for LV systolic performance in middle-aged rats with post-MI HF.

Keywords: cardiac remodeling; heart failure; heart rate reduction; ivabradine; myocardial infarction.

Publication types

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

MeSH terms

  • Aging
  • Animals
  • Benzazepines / therapeutic use*
  • Collagen / analysis
  • Coronary Vessels / drug effects
  • Cyclic Nucleotide-Gated Cation Channels / antagonists & inhibitors*
  • Heart Failure / drug therapy*
  • Heart Failure / pathology
  • Heart Failure / physiopathology
  • Heart Rate / drug effects*
  • Ivabradine
  • Male
  • Myocardial Infarction / complications*
  • Rats
  • Rats, Sprague-Dawley
  • Systole / drug effects*
  • Ventricular Function, Left
  • Ventricular Remodeling / drug effects*

Substances

  • Benzazepines
  • Cyclic Nucleotide-Gated Cation Channels
  • Ivabradine
  • Collagen