Synchronous Systolic Subcellular Ca2+-Elevations Underlie Ventricular Arrhythmia in Drug-Induced Long QT Type 2

Abstract

Background - Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca2+-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source-sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias. Methods and Results - Optical maps of action potentials and Ca2+-transients from Langendorff rabbit hearts were measured at low (150×150 μm2/pixel) and high (1.5×1.5 μm2/pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of IKr (the rapid component of rectifying K+ current), produced spontaneous Ca2+-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca2+-waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca2+-elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca2+ (40%-60% of peak-Ca2+-transients), appeared first in small islands (0.5×0.5 mm2) that enlarged and spread throughout the epicardium. Synchronous systolic Ca2+-elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca2+-transient-durations and action potential-durations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca2+-dynamics (multiple chaotic Ca2+-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca2+-elevations and arrhythmias. Conclusions - The results indicate that systolic and diastolic Ca2+-elevations emanate from sarcoplasmic reticulum Ca2+-release and systolic Ca2+-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca2+, which overcomes source-sink mismatch to trigger arrhythmias in intact hearts.