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1 Heart and Vascular Research Center, MetroHealth campus, Case Western Reserve University, Cleveland, Ohio, United States
2 Cleveland, Ohio, United States; Heart and Vascular Research Center, MetroHealth campus, Case Western Reserve University, Cleveland, Ohio, United States
3 Rammelkamp Center, MetroHealth Systems CWRU, Cleveland, Ohio, United States
* To whom correspondence should be addressed. E-mail: klaurita{at}metrohealth.org.
Arrhythmogenesis has been increasingly linked to cardiac Ryanodine receptor (RyR) dysfunction. However, the mechanistic relationship between abnormal RyR function and arrhythmogenesis in the heart is not clear. We hypothesize that under abnormal RyR conditions, triggered activity will be caused by spontaneous calcium release (SCR) events that depend on transmural heterogeneities of calcium handling. We performed high-resolution optical mapping of intracellular calcium and transmembrane potential imaging in the canine left ventricular wedge preparation (n=28). Rapid pacing was used to initiate triggered activity under normal and abnormal RyR conditions induced by FKBP12.6-dissociation and 
-adrenergic stimulation (Rapamycin, 20-150µM; Isoproterenol, 0.2µM). Under abnormal RyR conditions, almost all preparations experienced SCRs and triggered activity, in contrast to control, Rapamycin or Isoproterenol conditions alone. Furthermore, under abnormal RyR conditions, complex arrhythmias (monomorphic and polymorphic tachycardia) were commonly observed. Upon washout of Rapamycin and Isoproterenol, no triggered activity was observed. Surprisingly, triggered activity and SCRs occurred preferentially near the epicardium not the endocardium (p<0.01). Interestingly, the occurrence of triggered activity and SCR events could not be explained by cytoplasmic calcium levels, rather by fast calcium reuptake kinetics. These data suggest that under abnormal RyR conditions, triggered activity is caused by multiple SCR events that depend on the faster calcium reuptake kinetics near the epicardium. Furthermore, multiple regions of spontaneous calcium release may be a mechanism for multifocal arrhythmias associated with RyR dysfunction.
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