Synchronous Systolic Subcellular Ca 2+ -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 2+ -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 2+ -transients from Langendorff rabbit hearts were measured at low (150×150 μm 2 /pixel) and high (1.5×1.5 μm 2 /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 2+ -elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca 2+- waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca 2+- elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca 2+ (40%–60% of peak-Ca 2+ -transients), appeared first in small islands (0.5×0.5 mm 2 ) that enlarged and spread throughout the epicardium. Synchronous systolic Ca 2+- elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca 2+ -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 2+ -dynamics (multiple chaotic Ca 2+ -waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca 2+ -elevations and arrhythmias. Conclusions— The results indicate that systolic and diastolic Ca 2+ -elevations emanate from sarcoplasmic reticulum Ca 2+ -release and systolic Ca 2+ -elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca 2+ , which overcomes source–sink mismatch to trigger arrhythmias in intact hearts.