title: Sarcomere mechanics in uniform and non-uniform cardiac muscle: a link between pump function and arrhythmias.
abstract: Starling's Law and the well-known end-systolic pressure-volume relationship (ESPVR) of the left ventricle reflect the effect of sarcomere length (SL) on stress (sigma) development 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 skeletal sarcomeres and the existence of opposing forces in cardiac muscle shortened below slack length. The sigma-SL-[Ca2+]free relationships (sigma-SL-CaR) at submaximal [Ca2+] in intact and skinned trabeculae were similar, albeit that the sensitivity for Ca2+ of intact muscle was higher. We analyzed the mechanisms underlying the sigma-SL-CaR using a kinetic model where we assumed that the rates of Ca2+ binding by Troponin-C (Tn-C) and/or cross-bridge (XB) cycling are determined by SL, [Ca2+] or stress. We analyzed the correlation between the model results and steady state stress measurements at varied SL and [Ca2+] from skinned rat cardiac trabeculae to test the hypotheses that: (i) the dominant feedback mechanism is SL, stress or [Ca2+]-dependent; and (ii) the feedback mechanism regulates: Tn-C-Ca2+ affinity, XB kinetics or, unitary XB-force. The analysis strongly suggests that feedback of the number of strong XBs to cardiac Tn-C-Ca2+ affinity is the dominant mechanism that regulates XB recruitment. Application of this concept in a mathematical model of twitch-stress accurately reproduced the sigma-SL-CaR and the time course of twitch-stress as well as the time course of intracellular [Ca2+]i. Modeling of the response of the cardiac twitch to rapid stress changes using the above feedback model uniquely predicted the occurrence of [Ca2+]i transients as a result of accelerated Ca2+ dissociation from Tn-C. The above concept has important repercussions for the non-uniformly contracting heart in which arrhythmogenic Ca2+ waves arise from weakened areas in cardiac muscle. These Ca2+ waves can reversibly be induced in muscle with non-uniform 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 sarcomeres in the border zone during relaxation causes Ca2+ release from Tn-C and initiates Ca2+ waves propagated by the sarcoplasmic reticulum (SR). These observations suggest the unifying hypothesis that force feedback to Ca2+ binding by Tn-C is responsible for Starling's Law and the ESPVR in uniform myocardium and leads in non-uniform myocardium to a surge of Ca2+ released by the myofilaments during relaxation, which initiates arrhythmogenic propagating Ca2+ release by the SR.
authors.affiliation: Department Physiology, School of Medicine, University of Calgary, NW, Calgary, Alta., Canada. terkeurs@ucalgary.ca
authors.forename: Henk E D J
authors.initials: HE
authors.lastname: ter Keurs
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shinozaki
authors.forename: Ying Ming
authors.initials: YM
authors.lastname: Zhang
authors.forename: Mei Luo
authors.initials: ML
authors.lastname: Zhang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wakayama
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Sugai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kagaya
authors.forename: Masahito
authors.initials: M
authors.lastname: Miura
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
authors.forename: Bruno D M
authors.initials: BD
authors.lastname: Stuyvers
authors.forename: Amir
authors.initials: A
authors.lastname: Landesberg
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001696:Biomechanical Phenomena; D002118:Calcium / Q000502:physiology*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D012518:Sarcomeres / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D019209:Troponin C / Q000378:metabolism
chemical_list: D019209:Troponin C; D002118:Calcium