Direct effects of chronic beta-adrenergic receptor blockade on left ventricular and myocyte function in a model of tachycardia-induced congestive heart failure.

BACKGROUND

Chronic beta-receptor blockade (beta-blockade) has been reported to improve symptoms and increase survival in patients with congestive heart failure (CHF); however, whether the mechanisms for the effects of beta-blockade in CHF are due to modulating chronotropy, inotropy, or both remains unknown. To address this issue, left ventricular function and isolated myocyte function were examined with chronic beta-blockade in a rapid pacing model of CHF, thereby eliminating potential chronotropic effects of beta-blockade.

METHODS AND RESULTS

Pigs were randomly assigned to three groups of six pigs each: supraventricular tachycardia (SVT): 3 weeks of atrial pacing at 240 beats/min; SVT/beta-blockade: 3 weeks of rapid pacing and beta-blockade (25 mg atenolol twice daily on days 14-21 of pacing); control group, sham control animals. This dosage schedule for beta-blockade was chosen because catecholamines are persistently elevated by day 14 in this model of CHF. Left ventricular fractional shortening and end-diastolic dimension were measured by echocardiography in the conscious state with a resting ambient heart rate. Isolated left ventricular myocyte function was examined using high-speed videomicroscopy. Supraventricular tachycardia caused left ventricular dilation (5.4 +/- 0.1 vs 3.5 +/- 0.1 cm) and reduced fractional shortening (12 +/- 1% vs 35 +/- 1%) compared with control animals (P < .05). The SVT/beta-blockade group showed no significant effects on left ventricular size or function compared with the SVT group, but their ambient resting heart rate was reduced by 20% relative to the SVT group (P < .05). Myocyte shortening was reduced in the SVT group (2.2 +/- 0.1% vs 4.5 +/- 0.1%, P < .05) compared with the control group and increased from SVT-only values with beta-blockade (2.7 +/- 0.1%, P < .05). Similarly, myocyte shortening velocity was similarly reduced in the SVT and SVT/beta-blockade groups (31 +/- 1 and 32 +/- 1 microns/s) compared with the control group (51 +/- 1 microns/s, P < .05). With SVT/beta-blockade myocyte contraction duration was prolonged (525 +/- 5 ms) compared with SVT-only or control values (469 +/- 9 and 473 +/- 4 ms, P < .05). Thus, institution of beta-1-selective blockade during the development of SVT-induced CHF altered the temporal characteristics of the myocyte contraction process, which resulted in improved myocyte shortening.

CONCLUSIONS

In a model of CHF due to the maintenance of a chronically elevated heart rate, institution of beta-1-selective blockade during the progression of the CHF process minimally affected left ventricular size and function. At the level of the myocyte, chronic beta-1-receptor blockade prolonged the contraction interval and thereby increased myocyte shortening. These unique results suggest that a contributory mechanism for the effects of beta-blockade in the setting of CHF is chronotropic modulation.