Sarcomere mechanics in uniform and non-uniform cardiac muscle: A link between pump function and arrhythmias

• Published in: Progress in biophysics and molecular biology 2008-06, Vol.97 (2), p.312-331
• Main Authors: ter Keurs, Henk E.D.J., Shinozaki, Tsuyoshi, Zhang, Ying Ming, Zhang, Mei Luo, Wakayama, Yuji, Sugai, Yoshinao, Kagaya, Yutaka, Miura, Masahito, Boyden, Penelope A., Stuyvers, Bruno D.M., Landesberg, Amir
• Format: Article
• Language: English
• Subjects: Animals; Arrhythmias; Arrhythmias, Cardiac - physiopathology; Biomechanical Phenomena; Ca 2+ waves; Calcium - physiology; Models, Cardiovascular; Myocardial Contraction - physiology; Myocardium - metabolism; Rats; Sarcomeres - physiology; Sarcoplasmic Reticulum - physiology; Starling's Law; Troponin C - metabolism
• ISSN: 0079-6107; 1873-1732
• DOI: 10.1016/j.pbiomolbio.2008.02.013

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 ( σ) development and shortening by myocytes in the uniform ventricle. We show here that tetanic contractions of rat cardiac trabeculae exhibit a σ–SL relationship at saturating [Ca 2+] 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 σ–SL–[Ca 2+] free relationships ( σ–SL–CaR) at submaximal [Ca 2+] in intact and skinned trabeculae were similar, albeit that the sensitivity for Ca 2+ of intact muscle was higher. We analyzed the mechanisms underlying the σ–SL–CaR using a kinetic model where we assumed that the rates of Ca 2+ binding by Troponin-C (Tn-C) and/or cross-bridge (XB) cycling are determined by SL, [Ca 2+] or stress. We analyzed the correlation between the model results and steady state stress measurements at varied SL and [Ca 2+] from skinned rat cardiac trabeculae to test the hypotheses that: (i) the dominant feedback mechanism is SL, stress or [Ca 2+]-dependent; and (ii) the feedback mechanism regulates: Tn-C–Ca 2+ affinity, XB kinetics or, unitary XB–force. The analysis strongly suggests that feedback of the number of strong XBs to cardiac Tn-C–Ca 2+ affinity is the dominant mechanism that regulates XB recruitment. Application of this concept in a mathematical model of twitch-stress accurately reproduced the σ–SL–CaR and the time course of twitch-stress as well as the time course of intracellular [Ca 2+] i. Modeling of the response of the cardiac twitch to rapid stress changes using the above feedback model uniquely predicted the occurrence of [Ca 2+] i transients as a result of accelerated Ca 2+ dissociation from Tn-C. The above concept has important repercussions for the non-uniformly contracting heart in which arrhythmogenic Ca 2+ waves arise from weakened areas in cardiac muscle. These Ca 2+ 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 Ca 2+ waves and reversibly induced arrhythmias. We hypothesize that rapid force loss by sarcomeres in the border zone during relaxation causes Ca 2+ release from Tn-C and initiates Ca 2+ waves propagated by the sarcoplasmic reticulum (SR). These observations