Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome

Background-Both phase 2 and phase 3 early afterdepolarizations (EADs) occur in long-QT syndromes, but their respective roles in generating arrhythmias in intact cardiac tissue are incompletely understood. Methods and Results-Intracellular Ca (Ca_i) and membrane voltage (V_m) were optically mapped in a quasi 2-dimensional model of cryoablated Langendorff-perfused rabbit ventricles (n=16). E-4031 (an I_Kr blocker) combined with reduced extracellular K ([K⁺]o) and Mg ([Mg²⁺]o) prolonged action potential duration heterogeneously and induced phase 2 and phase 3 EADs. Whereas phase 2 EADs were Cai-dependent, phase 3 EADs were not. The origins of 47 triggered activity episodes were attributed to phase 2 EADs in 12 episodes (26%) and phase 3 EADs in 35 episodes (74%). When phase 2 EADs accompanied phase 3 EADs, they accentuated action potential duration heterogeneity, creating a large Vm gradient across the boundary between long and short action potential duration regions from which triggered activity emerged. The amplitude of phase 3 EADs correlated with the Vm gradient (r=0.898, P<0.001). Computer simulation studies showed that coupling of cells with heterogeneous repolarization could extrinsically generate phase 3 EADs via electrotonic current flow. Alternatively, reduced I_K1 caused by low [K⁺]o could generate intrinsic phase 3 EADs capable of inducing triggered activity at the boundary zone. Conclusions-Phase 3 EADs can be extrinsic as the result of electrotonic current across steep repolarization gradients or intrinsic as the result of low I_K1 and do not require spontaneous sarcoplasmic reticulum Ca release. Reduction of I_K1 by low [K⁺]o strongly promotes ventricular arrhythmias mediated by phase 3 EADs in acquired long-QT syndrome caused by I_Kr blockade.