Benefits of long-term beta-blockade in experimental chronic aortic regurgitation

Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1888-95. doi: 10.1152/ajpheart.01286.2007. Epub 2008 Feb 22.

Abstract

The objective of this study was to assess the long-term effects of beta-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a beta-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg.kg(-1).day(-1)) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals (P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). beta-Adrenergic receptor ratio (beta(1)/beta(2)) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the beta-adrenergic receptor ratio.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists*
  • Adrenergic beta-2 Receptor Antagonists*
  • Adrenergic beta-Antagonists / pharmacology*
  • Adrenergic beta-Antagonists / therapeutic use
  • Animals
  • Aortic Valve Insufficiency / drug therapy*
  • Aortic Valve Insufficiency / metabolism
  • Aortic Valve Insufficiency / pathology
  • Aortic Valve Insufficiency / physiopathology
  • Chronic Disease
  • Disease Models, Animal
  • Echocardiography, Doppler
  • Fibrosis
  • Hemodynamics / drug effects
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypertrophy, Left Ventricular / prevention & control
  • Male
  • Metoprolol / pharmacology*
  • Metoprolol / therapeutic use
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, beta-1 / genetics
  • Receptors, Adrenergic, beta-1 / metabolism
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism
  • Severity of Illness Index
  • Stroke Volume / drug effects
  • Time Factors
  • Ventricular Function, Left / drug effects
  • Ventricular Remodeling / drug effects*

Substances

  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Antagonists
  • Adrenergic beta-Antagonists
  • RNA, Messenger
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Myosin Heavy Chains
  • Metoprolol