Role of Abnormal Intracellular Calcium Dynamics in the genesis of electrical alternans in the heart

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This study was designed to clarify the role of intracellular calcium dynamics in the electrical alternans; a clinically useful indicator for the development of fatal ventricular tachyarrhythmias. By applying a dual-view, rapid scanning confocal microscopy for simultaneous detection of both the intracellular calcium dynamics and the corresponding membrane potentials to Langendorff-perfused rat hearts, we conducted confocal imaging of the fluo4- and RH237-signals at cellular levels. With this novel approach, following results were obtained.1. We succeeded in detecting both the intracellular calcium dynamics and membrane potentials simultaneously in the perfused rat heart.2. Under atrio-ventricular conduction block, individual myocytes exhibited calcium waves sporadically with no discernible membrane depolarization.3. Under low K perfusion with isoproterenol, burst pacing of the heart resulted in genesis of triggered activity and subsequent calcium oscillation mediated by calcium waves that were accompanied by membrane oscillation.4. Such calcium wave-mediated oscillatory membrane potentials were attenuated by ryanodine and SEA0400, a blocker for Na-Ca exchange.5. Reduced calcium release from the sarcoplasmic reticulum, by ryanodine failed to evoke calcium alternans. However, high-frequency pacing of the heart at 4-5 Hz resulted in development of calcium alternans, whereas the individual myocytes showed no beat-to-beat alternans of action potential waveforms.In summary the present results indicate an essential role of calcium waves in the genesis of triggered activity. On the other hands, calcium alternans evoked presumably by depressed calcium release function were not accompanied by electrical alternans, suggesting that electrical alternans is not responsible for the cellular heterogeneity of calcium handings, but regional heterogeneity in the heart.