Dual calcium-voltage optical mapping of regional voltage and calcium signals in intact murine -R2474S hearts.

Unlabelled: Abnormal regional variations in electrical and calcium homeostasis properties have been implicated in catecholaminergic polymorphic ventricular tachycardias (CPVT) attributable to abnormal RyR2-mediated store Ca release, but their underlying mechanism have not been well explored in intact hearts.

Methods: We performed in vivo and ex vivo studies including high throughput mapping of Ca transients (CaT) and transmembrane voltage (V) in murine wild-type (WT) and heterozygous -R2474S/+ hearts, before and during isoprenaline (ISO) challenge.

Results: ISO-challenged -R2474S/+ showed increased incidence of arrhythmia accompanied by abnormal Ca transients compared to WT. CaT duration (CaTD) in the LV apex amongst regions studied both before and during ISO challenge in both WT and -R2474S/+ ventricles. -R2474S/+ ventricles showed prolonged CaTD, both before and during isoprenaline (ISO) challenge. Conversely, action potential durations (APD) were the same in WT and RyR2-R2474S/+ ventricles and identically reduced by ISO challenge. -R2474S/+ showed -CaT latencies at time to half decay, but not rise time to peak, which were significantly prolonged compared to WT in all ventricular regions examined with ISO challenge. Following burst pacing, ventricular localized concordant alternans in CaT and APD were readily observed in -R2474S/+ but not in WT mice. Such CaT and APD alternans occurred mostly semiannually in specific regions of the ventricular pre-occurrence of VT.

Conclusion: The pro-arrhythmic -R2474S/+ phenotype in intact hearts thus directly parallels delayed regional CaT recovery properties and alteration of -CaT latencies. Studies suggest that discordant localized calcium alternans are mechanistically responsible for action potential duration alternans and occurrence of VT in -R2474S/+ mice.