Alteration of contractile function and excitation-contraction coupling in dilated cardiomyopathy.

Abstract

Myocardial failure in dilated cardiomyopathy may result from subcellular alterations in contractile protein function, excitation-contraction coupling processes, or recovery metabolism. We used isometric force and heat measurements to quantitatively investigate these subcellular systems in intact left ventricular muscle strips from nonfailing human hearts (n=14) and from hearts with end-stage failing dilated cardiomyopathy (n = 13). In the failing myocardium, peak isometric twitch tension, maximum rate of tension rise, and maximum rate of relaxation were reduced by 46%o (p =0.013), 51% (p =0.003), and 46% (p=0.018), respectively (37°C, 60 beats per minute). Tension-dependent heat, reflecting the number of crossbridge interactions during the isometric twitch, was reduced by 61% in the failing myocardium (p=0.006). In terms of the individual crossbridge cycle, the average crossbridge force-time integral was increased by 33% (p=0.04) in the failing myocardium. In the nonfailing myocardium, the crossbridge force-time integral was positively correlated with the patient's age (r=0.86, p<0.02), whereas there was no significant correlation with age in the failing group. The amount and rate of excitation-contraction coupling-related heat evolution (tension-independent heat) were reduced by 69%1 (p=0.024) and 71% (p=0.028), respectively, in the failing myocardium, reflecting a considerable decrease in the amount of calcium released and in the rate of calcium removal. The efficiency of the metabolic recovery process, as assessed by the ratio of initial heat to total activity-related heat, was similar in failing and nonfailing myocardium (0.54±0.03 versus 0.50±0.02, p =0.23). Thus, in failing dilated cardiomyopathy, contractile protein function is altered with an increased force-time integral of the individual crossbridge cycle. However, this alteration does not explain failure since the same changes are present in nonfailing myocardium from older patients. The findings suggest that reduced tension generation in failing dilated cardiomyopathy primarily results from disturbed excitation-contraction coupling processes with a reduced amount of calcium released and a reduced rate of calcium removal. (Circulation Research 1992;70:1225-1232 The recent development of a method for dissecting thin viable muscle strips from larger pieces of human myocardium13 makes it possible to investigate these subcellular systems in the intact muscle by means of a myothermal method14 under physiological conditions (37°C, 60 beats per minute). Heat evolution represents the entire metabolic energy turnover during the isometric twitch. Total activity-related heat can be partitioned into the heat evolution of the contractile proteins, the excitation-contraction coupling system, and the recovery system. These measurements in conjunction with the mechanical performance provide quantitative information on the extent and rate of the reactions involved

Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation.

“…Because cardiomyopathic preparations were obtained from older and predominately male patients, while donor hearts were obtained from younger and predominately female patients, we cannot exclude an effect of age or sex on our results. In fact, a relationship between age and cross-bridge force-time integral has been previously demonstrated in studies of normal human myocardium (46). In our study, we did not observe a significant correlation between age and calcium sensitivity of isometric tension (using age as a covariate, with the presence or absence of heart failure, in the multiple regression analysis of linearized tension-calcium relations).…”

Mechanical Unloading Restores β-Adrenergic Responsiveness and Reverses Receptor Downregulation in the Failing Human Heart

“…The absolute DT of our muscles was similar in magnitude to that reported previously by us 24,25 and by others. 26 Early studies of failing human muscles reported decreased DT 27 or prolonged TPT and THR. 23 More recently, studies performed at physiological temperatures and stimulation rates showed no change in DT 28 or a decrease only at elevated stimulation frequencies.…”

Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. Functional evidence for alterations in intracellular Ca2+ handling.

“…Gwathmey et al (7) and Morgan et al (8) were the first to demonstrate prolonged intracellular Ca 2 ϩ transients and isometric twitches in hypertrophic and failing human myocardium. Disturbed excitation-contraction coupling and intracellular Ca 2 ϩ handling has been suggested from myothermal measurements, showing reduced Ca 2 ϩ cycling in association with reduced force generation in failing dilated cardiomyopathy (9). Accordingly, FURA-2 measurements showed reduced systolic Ca 2 ϩ transients in isolated myocytes from failing human hearts (10).…”