Background-Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear. Methods and Results-T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209Ϯ46 bpm) that was significantly lower (by 57Ϯ36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation. Conclusions-Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG.Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death. (Circulation. 1999;99:1385-1394.)

Recovery of the mitochondrial inner membrane potential (∆Ψ m ) is a key determinant of postischemic functional recovery of the heart. Mitochondrial ROS-induced ROS release causes the collapse of ∆Ψ m and the destabilization of the action potential (AP) through a mechanism involving a mitochondrial inner membrane anion channel (IMAC) modulated by the mitochondrial benzodiazepine receptor (mBzR). Here, we test the hypothesis that this mechanism contributes to spatiotemporal heterogeneity of ∆Ψ m during ischemia-reperfusion (IR), thereby promoting abnormal electrical activation and arrhythmias in the whole heart. High-resolution optical AP mapping was performed in perfused guinea pig hearts subjected to 30 minutes of global ischemia followed by reperfusion. Typical electrophysiological responses, including progressive AP shortening followed by membrane inexcitablity in ischemia and ventricular fibrillation upon reperfusion, were observed in control hearts. These responses were reduced or eliminated by treatment with the mBzR antagonist 4′-chlorodiazepam (4′-Cl-DZP), which blocks depolarization of ∆Ψ m . When applied throughout the IR protocol, 4′-Cl-DZP blunted AP shortening and prevented reperfusion arrhythmias. Inhibition of ventricular fibrillation was also achieved by bolus infusion of 4′-Cl-DZP just before reperfusion. Conversely, treatment with an agonist of the mBzR that promotes ∆Ψ m depolarization exacerbated IR-induced electrophysiological changes and failed to prevent arrhythmias. The effects of these compounds were consistent with their actions on IMAC and ∆Ψ m . These findings directly link instability of ∆Ψ m to the heterogeneous electrophysiological substrate of the postischemic heart and highlight the mitochondrial membrane as a new therapeutic target for arrhythmia prevention in ischemic heart disease.

We conclude that electrically active, hESC-derived CMs are capable of actively pacing quiescent, recipient, ventricular CMs in vitro and ventricular myocardium in vivo. Our results may lead to an alternative or a supplemental method for correcting defects in cardiac impulse generation, such as cell-based pacemakers.

Abstract-Heart Failure (HF) is associated with an increased risk of sudden death caused by ventricular tachyarrhythmias.Recent studies have implicated repolarization abnormalities and, in particular, exaggerated heterogeneity of transmural repolarization in the genesis of polymorphic ventricular tachycardia in a canine model of nonischemic dilated cardiomyopathy. The presence and degree to which conduction abnormalities play a role in arrhythmogenesis in this model are uncertain. HF was produced in dogs by rapid RV-pacing for 3 to 4 weeks. High-resolution optical action potentials were recorded from epicardial and endocardial surfaces of arterially perfused canine wedge preparations isolated from LV and RV of normal and failing dogs. Cellular and molecular determinants of conduction were investigated using patch-clamp recordings, Western blot analysis, and immunocytochemistry. HF was associated with marked prolongation (by 33%) of the QRS duration of the volume conducted electrocardiogram and significant (Ͼ20%) slowing of epicardial and endocardial conduction velocities (CV) in both LV and RV. Cx43 expression was reduced by Ͼ40% in epicardial and endocardial layers of the LV, but was unchanged in the RV of failing hearts. Despite greater epicardial than endocardial Cx43 expression, epicardial CV was consistently slower (PϽ0.01). Immunocytochemical analysis revealed predominant colocalization of Cx43 with N-cadherin in normal versus failing samples, because Cx43 was redistributed from the intercalated disk to lateral cell borders in failing tissue. Moreover, a significant (PϽ0.05) increase in hypophosphorylated Cx43 was detected in the LV and RV of failing hearts. Action potential upstroke velocities in isolated ventricular myocytes from normal and failing hearts were not different (Pϭ0.8, not significant), and Masson trichrome staining revealed no significant change in fibrosis content in HF. Nonischemic dilated cardiomyopathy is associated with significant slowing of CV that was not directly related to reduced Cx43 expression. Changes in phosphorylation and localization of Cx43 may contribute to gap-junction dysfunction, CV slowing, and arrhythmias in HF. Key Words: heart failure Ⅲ arrhythmias Ⅲ optical mapping Ⅲ connexin Ⅲ gap junctions S udden cardiac death (SCD), presumably because of ventricular tachyarrhythmias, accounts for Ϸ50% of the mortality in patients with congestive heart failure (HF). 1,2 Recent studies have highlighted the importance of repolarization abnormalities, including nonuniform prolongation of action potential durations (APD) across the ventricular wall in a canine model of nonischemic dilated cardiomyopathy. 3 Such repolarization changes may lead to the development of reentrant arrhythmias in HF. 3 When considering the prerequisites for reentry, however, two conditions must be met: (1) the excitation wavefront must undergo unidirectional conduction block; and (2) the path of the reentrant circuit must be sufficiently long or conduction of the wavefront sufficiently slow, such that ...