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 ...

Background-Specific ion channel mutations underlie the congenital long-QT syndrome (LQTS). However, the mechanisms by which dysfunction at the molecular level translates into functional electrical instability leading to torsade de pointes (TdP) in LQTS are poorly understood. Methods and Results-The cellular basis of TdP was investigated using a novel approach of transmural optical imaging in the canine wedge preparation (nϭ14). The spatial organization of repolarization and arrhythmogenesis were determined in a surrogate model of LQT2. Action potentials were recorded simultaneously from 128 sites spanning the transmural wall of the left ventricle. In LQT2, QT interval prolongation was paralleled by an abrupt rise in transmural dispersion of repolarization (DOR) from 2.7Ϯ0.9 ms/mm (controls) to 12.2Ϯ2.1 ms/mm (LQT2). Islands of midmyocardial (M) cells formed zones of increased refractoriness in LQT2, producing steep spatial gradients of repolarization that were directly responsible for conduction block and self-sustained intramural reentrant circuits underlying TdP. Conclusions-These data provide direct evidence supporting the functional expression of M cells in intact myocardium and a central role for M cells in the development of reentrant

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Several risk factors promote AF, among which diabetes mellitus has emerged as one of the most important. The growing recognition that obesity, diabetes and AF are closely intertwined disorders has spurred major interest in uncovering their mechanistic links. In this article we provide an update on the growing evidence linking oxidative stress and inflammation to adverse atrial structural and electrical remodeling that leads to the onset and maintenance of AF in the diabetic heart. We then discuss several therapeutic strategies to improve atrial excitability by targeting pathways that control oxidative stress and inflammation.

Abstract-Although expression of numerous ion channels is altered in heart failure (HF), mechanisms by which dysfunction at the ionic and molecular levels lead to ventricular tachyarrhythmias in HF are unknown. Previously, we found that transmural heterogeneities of repolarization play a critical role in the genesis of polymorphic ventricular tachycardia (PVT) when QT interval was prolonged in LQT2. Because QT interval is also prolonged in HF, we hypothesized that transmural heterogeneities are a mechanism of PVT in HF. Optical action potentials were measured simultaneously from cells spanning the entire transmural wall of arterially perfused canine wedge preparations. Wedges were isolated from dogs without (control, nϭ5) and with HF (nϭ8) produced by rapid ventricular pacing. In HF, action potential duration (APD) prolongation was markedly heterogeneous across the transmural wall, and was characterized by disproportionate APD prolongation of midmyocardial (M) cells. APD prolongation of M cells accounted for QT-interval prolongation, and caused significant increases (PϽ0.01) in spatial gradients of repolarization across the ventricular wall from 4.3Ϯ2.1 (control) to 12.4Ϯ3.5 ms/mm (HF). Enhanced gradients were directly responsible for development of functional conduction block, leading to PVT in 63% of HF wedges but in no controls (PϽ0.03). Moreover, intramural decremental conduction and block of the premature impulse, preceded each episode of PVT, and always occurred at the border between M-cell and subepicardial zones, where repolarization gradients were highest. Selective prolongation of APD within M cells underlies several key features of the HF phenotype, including QT-interval prolongation, transmural heterogeneity of repolarization, and susceptibility to conduction block and reentrant PVT. Key Words: heart failure Ⅲ long-QT syndrome Ⅲ repolarization Ⅲ action potentials Ⅲ arrhythmias V entricular arrhythmias leading to sudden cardiac death (SCD) account for Ϸ50% of deaths in patients with congestive heart failure (HF). 1 Recent investigations have markedly advanced our understanding of the molecular and ionic alterations that occur in response to HF in both humans 2 and animal models. 3,4 However, mechanisms by which HFinduced changes at the cellular and molecular levels form a substrate for life-threatening ventricular arrhythmias remain poorly understood.Although many discrepancies regarding the specific ionic and molecular processes in HF have been reported, a consistent finding is prolongation of cardiac repolarization. This may be attributed to functional downregulation of outward potassium currents 2,3 and/or upregulation of inward calcium 5,6 or late sodium currents 7 in hypertrophied and failing hearts. However, the relationship between alterations of repolarization and arrhythmia mechanisms in HF remains largely unknown. Previously, we found that transmural heterogeneities of cellular repolarization play a critical role in the genesis of the polymorphic ventricular tachycardia (PVT)Torsade de pointe...

Background-Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchronous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. Methods and Results-Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K ϩ current (I K1 ), delayed rectifier K ϩ current (I K ), and transient outward K ϩ current (I to ) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I K1 and I K but not I to , consistent with trends in the changes in steady state K ϩ channel mRNA and protein levels. DHF reduced the peak inward Ca 2ϩ current (I Ca ) density and slowed I Ca decay in lateral compared with anterior cells, whereas CRT restored peak I Ca amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca V 1.2 (␣1C) mRNA or protein expression, but reduced Ca V ␤2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca 2ϩ ATPase and increased Na ϩ -Ca 2ϩ exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca 2ϩ ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. Conclusions-CRT partially restores DHF-induced ion channel remodeling and abnormal Ca 2ϩ homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.