title: Spatial nonuniformity of excitation-contraction coupling causes arrhythmogenic Ca2+ waves in rat cardiac muscle.
abstract: Ca2+ waves underlying triggered propagated contractions (TPCs) are initiated in damaged regions in cardiac muscle and cause arrhythmias. We studied Ca2+ waves underlying TPCs in rat cardiac trabeculae under experimental conditions that simulate the functional nonuniformity caused by local mechanical or ischemic local damage of myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small jet of solution with a composition that reduces excitation-contraction coupling (ECC) in myocytes within that segment. The jet solution contained either caffeine (5 mmol/L), 2,3-butanedione monoxime (BDM; 20 mmol/L), or low Ca2+ concentration ([Ca2+]; 0.2 mmol/L). Force was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques in 15 trabeculae. Simultaneously, [Ca2+]i was measured locally using epifluorescence of Fura-2. The jet of solution was applied perpendicularly to a small muscle region (200 to 300 microm) at constant flow. When the jet contained caffeine, BDM, or low [Ca2+], during the stimulated twitch, muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening normal regions outside the jet. Typical protocols for TPC induction (7.5 s-2.5 Hz stimulus trains at 23 degrees C; [Ca2+]o=2.0 mmol/L) reproducibly generated Ca2+ waves that arose from the border between shortening and stretched regions. Such Ca2+ waves started during force-relaxation of the last stimulated twitch of the train and propagated (0.2 to 2.8 mm/sec) into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were induced when the amplitude of the Ca2+-wave was increased by raising [Ca2+]o. Arrhythmias disappeared rapidly when uniformity of ECC throughout the muscle was restored by turning the jet off. These results show, for the first time, that nonuniform ECC can cause Ca2+ waves underlying TPCs and suggest that Ca2+ dissociated from myofilaments plays an important role in the initiation of Ca2+ waves.
authors.affiliation: First Department of Internal Medicine, Tohoku University School of Medicine, Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wakayama
authors.forename: Masahito
authors.initials: M
authors.lastname: Miura
authors.forename: Bruno D
authors.initials: BD
authors.lastname: Stuyvers
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
authors.forename: Henk E D J
authors.initials: HE
authors.lastname: ter Keurs
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D012518:Sarcomeres / Q000187:drug effects; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: C004717:diacetylmonoxime; D002110:Caffeine; D003931:Diacetyl; D002118:Calcium