Mild metabolic acidosis impairs the beta-adrenergic response in isolated human failing myocardium

Abstract

Introduction: Pronounced extracellular acidosis reduces both cardiac contractility and the beta-adrenergic response. In the past, this was shown in some studies using animal models. However, few data exist regarding how the human end-stage failing myocardium, in which compensatory mechanisms are exhausted, reacts to acute mild metabolic acidosis. The aim of this study was to investigate the effect of mild metabolic acidosis on contractility and the beta-adrenergic response of isolated trabeculae from human end-stage failing hearts. Methods: Intact isometrically twitching trabeculae isolated from patients with end-stage heart failure were exposed to mild metabolic acidosis (pH 7.20). Trabeculae were stimulated at increasing frequencies and finally exposed to increasing concentrations of isoproterenol (0 to 1 x 10(-6) M). Results: A mild metabolic acidosis caused a depression in twitch-force amplitude of 26% (12.1 +/- 1.9 to 9.0 +/- 1.5 mN/mm(2); n = 12; P < 0.01) as compared with pH 7.40. Force-frequency relation measurements yielded no further significant differences of twitch force. At the maximal isoproterenol concentration, the force amplitude was comparable in each of the two groups (pH 7.40 versus pH 7.20). However, the half-maximal effective concentration (EC50) was significantly increased in the acidosis group, with an EC50 of 5.834 x 10(-8) M (confidence interval (CI), 3.48 x 10(-8) to 9.779 x 10(-8); n = 9), compared with the control group, which had an EC50 of 1.056 x 10(-8) M (CI, 2.626 x 10(-9) to 4.243 x 10(-8); n = 10; P < 0.05), indicating an impaired beta-adrenergic force response. Conclusions: Our data show that mild metabolic acidosis reduces cardiac contractility and significantly impairs the beta-adrenergic force response in human failing myocardium. Thus, our results could contribute to the still-controversial discussion about the therapy regimen of acidosis in patients with critical heart failure.