Cardiac cellular coupling and the spread of early instabilities in intracellular Ca2+.

Recent experimental and modeling studies demonstrate the fine spatial scale, complex nature, and independent contribution of Ca(2+) dynamics as a proarrhythmic factor in the heart. The mechanism of progression of cell-level Ca(2+) instabilities, known as alternans, to tissue-level arrhythmias is not well understood. Because gap junction coupling dictates cardiac syncytial properties, we set out to elucidate its role in the spatiotemporal evolution of Ca(2+) instabilities. We experimentally perturbed cellular coupling in cardiac syncytium in vitro. Coupling was quantified by fluorescence recovery after photobleaching, and related to function, including subtle fine-scale Ca(2+) alternans, captured by optical mapping. Conduction velocity and threshold for alternans monotonically increased with coupling. Lower coupling enhanced Ca(2+) alternans amplitude, but the spatial spread of early (<2 Hz) alternation was the greatest under intermediate (not low) coupling. This nonmonotonic relationship was closely matched by the percent of samples exhibiting large-scale alternans at higher pacing rates. Computer modeling corroborated these experimental findings for strong but not weak electromechanical (voltage-Ca(2+)) coupling, and offered mechanistic insight. In conclusion, using experimental and modeling approaches, we reveal a general mechanism for the spatial spread of subtle cellular Ca(2+) alternans that relies on a combination of gap-junctional and voltage-Ca(2+) coupling.