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

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 μm) 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°C; [Ca²⁺]_o = 2.0 mmol/L) reproducibly generated Ca ²⁺ 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.