BACKGROUND: It is clear that beta-blockers are effective for treatment of congestive heart failure, but their mechanism of action remains controversial. Hypothesized mechanisms include normalization of beta-receptor function and myocardial protection from the effects of catecholamines, possibly by the institution of bradycardia. We hypothesized that beta-blockade-induced bradycardia was an important mechanism by which these agents were effective for correction of LV dysfunction. METHODS AND RESULTS: In 2 groups of dogs with mitral regurgitation and LV dysfunction, beta-blockers were instituted. In 1 group that received beta-blockers and pacing (group beta+P), a pacemaker prevented the natural bradycardia that beta-blockers cause. In both groups, substantial LV dysfunction developed. Before beta-blockade, the end-systolic stiffness constant decreased from 3. 5+/-0.1 to 2.7+/-0.2 (P<0.01) at 3 months in group beta+P. A similar reduction occurred in the group that eventually received only beta-blockers (group betaB). In group betaB, end-systolic stiffness improved after 3 months of beta-blockade from 2.9+/-0.2 to 3.5+/-0.4 and was not different from baseline. However, in group beta+P, end-systolic stiffness failed to improve (2.7+/-0.2) after 3 months of mitral regurgitation, and was 2.9+/-0.2 at the end of the studies. The contractile function of cardiocytes isolated from the ventricles at the end of the studies confirmed these in vivo estimates of contractility. CONCLUSIONS: We conclude that institution of bradycardia is a major mechanism by which beta-blockers are effective for restoration of contractile function in a model of LV dysfunction.
BACKGROUND: It is clear that beta-blockers are effective for treatment of congestive heart failure, but their mechanism of action remains controversial. Hypothesized mechanisms include normalization of beta-receptor function and myocardial protection from the effects of catecholamines, possibly by the institution of bradycardia. We hypothesized that beta-blockade-induced bradycardia was an important mechanism by which these agents were effective for correction of LV dysfunction. METHODS AND RESULTS: In 2 groups of dogs with mitral regurgitation and LV dysfunction, beta-blockers were instituted. In 1 group that received beta-blockers and pacing (group beta+P), a pacemaker prevented the natural bradycardia that beta-blockers cause. In both groups, substantial LV dysfunction developed. Before beta-blockade, the end-systolic stiffness constant decreased from 3. 5+/-0.1 to 2.7+/-0.2 (P<0.01) at 3 months in group beta+P. A similar reduction occurred in the group that eventually received only beta-blockers (group betaB). In group betaB, end-systolic stiffness improved after 3 months of beta-blockade from 2.9+/-0.2 to 3.5+/-0.4 and was not different from baseline. However, in group beta+P, end-systolic stiffness failed to improve (2.7+/-0.2) after 3 months of mitral regurgitation, and was 2.9+/-0.2 at the end of the studies. The contractile function of cardiocytes isolated from the ventricles at the end of the studies confirmed these in vivo estimates of contractility. CONCLUSIONS: We conclude that institution of bradycardia is a major mechanism by which beta-blockers are effective for restoration of contractile function in a model of LV dysfunction.