title: Sarcomere mechanics in uniform and nonuniform cardiac muscle: a link between pump function and arrhythmias.
abstract: Starling's law and the end-systolic pressure-volume relationship (ESPVR) reflect the effect of sarcomere length (SL) on the development of stress (sigma) and shortening by myocytes in the uniform ventricle. We show here that tetanic contractions of rat cardiac trabeculae exhibit a sigma-SL relationship at saturating [Ca2+] that depends on sarcomere geometry in a manner similar to that of skeletal sarcomeres and the existence of opposing forces in cardiac muscle shortened below slack length. The sigma-SL -[Ca2+](free) relationships (sigma-SL-Ca relationships) at submaximal [Ca2+] in intact and skinned trabeculae were similar, although the sensitivity for Ca2+ of intact muscle was higher. We analyzed the mechanisms underlying the sigma-SL-Ca relationship by using a kinetic model assuming that the rates of Tn-C Ca2+ binding and/or cross-bridge (XB) cycling are determined by either the SL, [Ca2+], or sigma. We analyzed the correlation between the model results and steady-state sigma measurements at varied SL at [Ca2+] from skinned rat cardiac trabeculae to test the hypotheses that the dominant feedback mechanism is SL-, sigma-, or [Ca2+]-dependent, and that the feedback mechanism regulates Tn-C Ca2+ affinity, XB kinetics, or the unitary XB force. The analysis strongly suggests that the feedback of the number of strong XBs to cardiac Tn-C Ca2+ affinity is the dominant mechanism regulating XB recruitment. Using this concept in a model of twitch-sigma accurately reproduced the sigma-SL-Ca relationship and the time courses of twitch sigma and the intracellular [Ca2+]i. The foregoing concept has equally important repercussions for the nonuniformly contracting heart, in which arrhythmogenic Ca2+ waves arise from weakened areas in the cardiac muscle. These Ca2+ waves can reversibly be induced with nonuniform excitation-contraction coupling (ECC) by the cycle of stretch and release in the border zone between the damaged and intact regions. Stimulus trains induced propagating Ca2+ waves and reversibly induced arrhythmias. We hypothesize that rapid force loss by the sarcomeres in the border zone during relaxation causes Ca2+ release from Tn-C and initiates Ca2+ waves propagated by the sarcoplasmic reticulum (SR). Modeling of the response of the cardiac twitch to rapid force changes using the feedback concept uniquely predicts the occurrence of [Ca2+]i transients as a result of accelerated Ca2+ dissociation from Tn-C. These results are consistent with the hypothesis that a force feedback to Ca2+ binding by Tn-C is responsible for Starling's law and the ESPVR in the uniform myocardium and leads to a surge of Ca2+ released by the myofilaments during relaxation in the nonuniform myocardium, which initiates arrhythmogenic propagating Ca2+ release by the SR.
authors: Department of Physiology, School of Medicine, University of Calgary, 3330 Hospital Dr., N.W., Calgary, Alberta T2N 4N1, Canada. terkeurs@ucalgary.ca
authors: Henk E D J
authors: HE
authors: Ter Keurs
authors: Tsuyoshi
authors: T
authors: Shinozaki
authors: Ying Ming
authors: YM
authors: Zhang
authors: Yuji
authors: Y
authors: Wakayama
authors: Yoshinao
authors: Y
authors: Sugai
authors: Yutaka
authors: Y
authors: Kagaya
authors: Masahito
authors: M
authors: Miura
authors: Penelope A
authors: PA
authors: Boyden
authors: Bruno D M
authors: BD
authors: Stuyvers
authors: Amir
authors: A
authors: Landesberg
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology; D006321:Heart / Q000502:physiology*; D007700:Kinetics; D008954:Models, Biological; D009200:Myocardial Contraction / Q000502:physiology*; D051381:Rats; D012518:Sarcomeres / Q000502:physiology* / Q000648:ultrastructure; D013314:Stress, Mechanical
chemical_list: D002118:Calcium