Related Experiment Videos
Mechanisms of carvedilol action in human congestive heart failure
D M Kaye1, L Johnston, G Vaddadi
1Department of Cardiovascular Medicine, Alfred Hospital and Baker Medical Research Institute, Melbourne, Australia. david.kaye@baker.edu.au
Insights
Carvedilol improved heart function in heart failure patients, but not by altering norepinephrine release or improving contractile efficiency. The drug
Area of Science:
- Cardiology
- Pharmacology
- Heart Failure Research
Background:
- The exact mechanisms behind beta-adrenoceptor blockers' benefits in heart failure are not fully understood.
- Proposed mechanisms include heart rate reduction, catecholamine release modulation, and direct myocardial effects.
Purpose of the Study:
- To investigate the effects of carvedilol on hemodynamics, norepinephrine levels, and myocardial metabolism in severe congestive heart failure.
- To determine if carvedilol's benefits are linked to changes in norepinephrine release or myocardial energetics.
Main Methods:
- A 3-month study involving 10 patients with severe congestive heart failure.
- Utilized isotope dilution to measure systemic and cardiac norepinephrine spillover.
- Assessed myocardial oxygen consumption and carbon dioxide release.
Main Results:
- Carvedilol significantly improved left ventricular ejection fraction and left ventricular stroke work.
- These functional improvements were not correlated with changes in norepinephrine spillover.
- Myocardial oxygen consumption increased slightly per beat, but contractile efficiency remained unchanged.
Conclusions:
- Carvedilol's positive effects on ventricular function in heart failure are not explained by alterations in norepinephrine release.
- Changes in myocardial contractile efficiency do not account for the observed benefits of carvedilol.
- Further research is needed to elucidate the precise mechanisms of carvedilol's efficacy in heart failure.
Abstract:
The precise mechanism by which beta-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, beta2-adrenoceptor-mediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. In the present study we evaluated the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and cardiac norepinephrine spillover (isotope dilution method), and myocardial metabolism (myocardial oxygen consumption and carbon dioxide release) in 10 patients with severe congestive heart failure. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction (17+/-1% to 28+/-3%; P<0.01) and left ventricular stroke work (87+/-13 to 119+/-21 g. m per beat; P<0.05), this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work was accompanied by a modest rise in myocardial oxygen consumption per beat (0.33+/-0.04 to 0.42+/-0.04; P=0.05), although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.