Cardiac beta3-Adrenergic Receptor: A New Target for the Treatment of Exercise Intolerance in Heart Failure

Abstract

Background: The loss of cardiac β-adrenergic receptor (AR) responsiveness has been proposed to be responsible for exercise (Ex) intolerance in heart failure (HF). Recent observation indicates that up-regulation of cardiac β3-AR is the critical determinant to the dysfunctional cardiac β-AR regulation that occurs in HF. We have previously shown that both cardiac expression and function of β3-AR are increased in dogs with pacing-induced HF. At rest, stimulation of β3-AR by endogenous catecholamine depresses left ventricular (LV) contraction and relaxation. During Ex with HF, the adverse functional effects of β3-AR activation in HF may be accentuated due to increases in circulating and myocardial levels of catecholamine. Thus, a β3-AR antagonist (β3-ANT) may reverse the abnormal Ex response in HF. Methods: We assessed the effect of L-748,337 (50 μg/kg, iv), a selective β3-AR antagonist (β3-ANT), on LV systolic and diastolic functional performance, LV arterial coupling, and Ex duration in 8 instrumented dogs with pacing-induced HF. Results: After HF, Ex caused significant increases in LV end-systolic pressure (P) (PES, 124 vs 103 mmHg), minimum LV P (Pmin, 28.6 vs 18.9 mmHg), and the time constant of LV relaxation (τ, 42.5 vs 35.0 ms) (p<0.05) with an upward shift of early diastolic portion of LV P-volume (V) loop. Compared with HF at rest, during HF Ex, LV contractility (EES, 3.6 vs 4.4 mmHg/ml) decreased and arterial elastance (EA, 7.9 vs 7.2 mmHg/ml) increased. Thus, LV arterial coupling, quantified as EES/EA (0.47 vs 0.65) (p<0.05), was further impaired. Compared with Ex before β3-ANT, Ex after β3-ANT caused similar increases in heart rate (174 vs 176 bpm) and PES (123 vs 121 mmHg), but significantly decreased τ (32.2 vs 38.1ms), LV Pmin (20.1 vs 25.9 mmHg), and mean left atrial P (25.6 vs 29.9 mmHg) with a downward shift of the early diastolic portion of LV P-V loop. Moreover, with β3-ANT, LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, significantly improved from 0.47 to 0.69, which was close to the value reached during normal Ex. There were greater increases in EES (5.4 vs 3.6 mmHg/ml) and EES/EA (0.85 vs 0.54). The duration of Ex was also significantly increased (8.0 vs 5.2 minutes) (p<0.05). Conclusions: After HF, β3-AR blockade improves LV systolic and diastolic performance, increases LV arterial coupling and mechanical efficiency, and normalizes the response to Ex. Background: The loss of cardiac β-adrenergic receptor (AR) responsiveness has been proposed to be responsible for exercise (Ex) intolerance in heart failure (HF). Recent observation indicates that up-regulation of cardiac β3-AR is the critical determinant to the dysfunctional cardiac β-AR regulation that occurs in HF. We have previously shown that both cardiac expression and function of β3-AR are increased in dogs with pacing-induced HF. At rest, stimulation of β3-AR by endogenous catecholamine depresses left ventricular (LV) contraction and relaxation. During Ex with HF, the adverse functional effects of β3-AR activation in HF may be accentuated due to increases in circulating and myocardial levels of catecholamine. Thus, a β3-AR antagonist (β3-ANT) may reverse the abnormal Ex response in HF. Methods: We assessed the effect of L-748,337 (50 μg/kg, iv), a selective β3-AR antagonist (β3-ANT), on LV systolic and diastolic functional performance, LV arterial coupling, and Ex duration in 8 instrumented dogs with pacing-induced HF. Results: After HF, Ex caused significant increases in LV end-systolic pressure (P) (PES, 124 vs 103 mmHg), minimum LV P (Pmin, 28.6 vs 18.9 mmHg), and the time constant of LV relaxation (τ, 42.5 vs 35.0 ms) (p<0.05) with an upward shift of early diastolic portion of LV P-volume (V) loop. Compared with HF at rest, during HF Ex, LV contractility (EES, 3.6 vs 4.4 mmHg/ml) decreased and arterial elastance (EA, 7.9 vs 7.2 mmHg/ml) increased. Thus, LV arterial coupling, quantified as EES/EA (0.47 vs 0.65) (p<0.05), was further impaired. Compared with Ex before β3-ANT, Ex after β3-ANT caused similar increases in heart rate (174 vs 176 bpm) and PES (123 vs 121 mmHg), but significantly decreased τ (32.2 vs 38.1ms), LV Pmin (20.1 vs 25.9 mmHg), and mean left atrial P (25.6 vs 29.9 mmHg) with a downward shift of the early diastolic portion of LV P-V loop. Moreover, with β3-ANT, LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, significantly improved from 0.47 to 0.69, which was close to the value reached during normal Ex. There were greater increases in EES (5.4 vs 3.6 mmHg/ml) and EES/EA (0.85 vs 0.54). The duration of Ex was also significantly increased (8.0 vs 5.2 minutes) (p<0.05). Conclusions: After HF, β3-AR blockade improves LV systolic and diastolic performance, increases LV arterial coupling and mechanical efficiency, and normalizes the response to Ex.