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

BACKGROUND—Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca-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 Ca-transients from Langendorff rabbit hearts were measured at low (150×150 μm/pixel) and high (1.5×1.5 μm/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 Ca-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Cawaves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Caelevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca (40%–60% of peak-Ca-transients), appeared first in small islands (0.5×0.5 mm) that enlarged and spread throughout the epicardium. Synchronous systolic Caelevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca-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 Ca-dynamics (multiple chaotic Ca-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca-elevations and arrhythmias. CONCLUSIONS—The results indicate that systolic and diastolic Ca-elevations emanate from sarcoplasmic reticulum Ca-release and systolic Ca-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca, which overcomes source–sink mismatch to trigger arrhythmias in intact hearts.