Spatial nonuniformity of contraction causes arrhythmogenic Ca2+ waves in rat cardiac muscle

Henk E.D.J. Ter Keurs, Yuji Wakayama, Masahito Miura, Bruno D. Stuyvers, Penelope A. Boyden, Amir Landesberg

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Landesberg and Sideman's four state model of the cardiac crossbridge (XB) hypothesizes a feedback of force development to Ca2+ binding by troponin C (TnC). We have further modeled this behavior and observed that the force (F)-Ca2+ relationship as well as the F-sarcomere length (SL) relationship and the time course of F and Ca2+ transients in cardiac muscle can be reproduced faithfully by a single effect of F on deformation of the TnC-Ca complex and, thereby, on the dissociation rate of Ca2+. Furthermore, this feedback predicts that rapid decline of F in the activated sarcomere causes release of Ca2+ from TnC-Ca2+, which is sufficient to initiate arrhythmogenic Ca2+ release from the sarcoplasmic reticulum (SR). This work investigated the initiation of Ca 2+ waves underlying triggered propagated contractions (TPCs) in rat cardiac trabeculae under conditions that simulate functional nonuniformity caused by mechanical or ischemic local damage of the myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small constant flow jet of solution that reduces excitation-contraction coupling in myocytes within that segment. Force was measured, and SL as well as [Ca 2+]i were measured regionally. When the jet contained caffeine, 2,3-butanedione monoxime or low-[Ca2+], muscle-twitch F decreased and the sarcomeres in the exposed segment were stretched by shortening the normal regions outside the jet. During relaxation, the sarcomeres in the exposed segment shortened rapidly. Short trains of stimulation at 2.5 Hz reproducibly caused Ca2+ waves to rise from the borders exposed to the jet. Ca2+ waves started during F relaxation of the last stimulated twitch and propagated into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were triggered when the amplitude of the Ca2+ wave increased by raising [Ca 2+]o. The arrhythmias disappeared when the muscle uniformity was restored by turning the jet off. These results show that nonuniform contraction can cause Ca2+ waves underlying TPCs, and suggest that Ca2+ dissociated from myofilaments plays an important role in the initiation of arrhythmogenic Ca2+ waves.

Original languageEnglish
Pages (from-to)345-365
Number of pages21
JournalAnnals of the New York Academy of Sciences
Volume1047
DOIs
Publication statusPublished - 2005

Keywords

  • Arrhythmias
  • Ca2+ waves
  • Nonuniformity
  • Rat trabeculae
  • Troponin C

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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