Sarcomere Mechanics in Uniform andNonuniform Cardiac Muscle A Link between Pump Function and Arrhythmias

摘要

Starling's law and the end-systolic pressure-volume relationship (ESPVR) reflect the effect of sar-comere length (SL) on the development of stress (σ) and shortening by myocytes in the uniform ventricle. We show here that tetanic contractions of rat cardiac trabeculae exhibit a a-SL rela-tionship at saturating [Ca~(2+)] that depends on sarcomere geometry in a manner similar to thatof skeletal sarcomeres and the existence of opposing forces in cardiac muscle shortened belowslack length. The σ -SL - [Ca~(2+)]_(free)relationships (σ-SL-Ca relationships) at submaximal [Ca~(2+)]in intact and skinned trabeculae were similar, although the sensitivity for Ca~(2+) of intact musclewas higher. We analyzed the mechanisms underlying the σ-SL-Ca relationship by using a kineticmodel assuming that the rates of Tn-C Ca~(2+) binding and/or cross-bridge (XB) cycling are deter-mined by either the SL, [Ca~(2+)], or σ. We analyzed the correlation between the model results andsteady-state a measurements at varied SL at [Ca~(2+)]from skinned rat cardiac trabeculae to test thehypotheses that the dominant feedback mechanism is SL-, σ-, or [Ca~(2+)]-dependent, and that thefeedback mechanism regulates Tn-C Ca~(2+) affinity, XB kinetics, or the unitary XB force. The anal-ysis strongly suggests that the feedback of the number of strong XBs to cardiac Tn-C Ca~(2+) affinityis the dominant mechanism regulating XB recruitment. Using this concept in a model of twitch-aaccurately reproduced the σ-SL-Ca relationship and the time courses of twitch a and the intra-cellular [Ca~(2+)]_i. The foregoing concept has equally important repercussions for the nonuniformlycontracting heart, in which arrhythmogenic Ca~(2+) waves arise from weakened areas in the cardiacmuscle. These Ca~(2+)waves can reversibly be induced with nonuniform excitation-contraction cou-pling (ECC) by the cycle of stretch and release in the border zone between the damaged and intactregions. Stimulus trains induced propagating Ca~(2+) waves and reversibly induced arrhythmias. Wehypothesize that rapid force loss by the sarcomeres in the border zone during relaxation causesCa~(2+)release from Tn-C and initiates Ca~(2+) waves propagated by the sarcoplasmic reticulum (SR).Modeling of the response of the cardiac twitch to rapid force changes using the feedback conceptuniquely predicts the occurrence of [Ca~(2+)]_itransients as a result of accelerated Ca~(2+)dissociationfrom Tn-C. These results are consistent with the hypothesis that a force feedback to Ca~(2+) bindingby Tn-C is responsible for Starling's law and the ESPVR in the uniform myocardium and leads toa surge of Ca~(2+) released by the myofilaments during relaxation in the nonuniform myocardium,which initiates arrhythmogenic propagating Ca~(2+) release by the SR.