Background-Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 mol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations. Methods and Results-Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I Kr (IC 50 ϭ11.5 mol/L), late I Na , late I Ca , peak I Ca , and I Na-Ca (IC 50 ϭ5.9, 50, 296, and 91 mol/L, respectively) and I Ks (17% at 30 mol/L), but caused little or no inhibition of I to or I K1 . In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR).

Background-The Brugada syndrome displays an autosomal dominant mode of transmission with low penetrance. Despite equal genetic transmission of the disease, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this intriguing sex-related distinction is unknown. The present study tests the hypothesis that the disparity in expression of the Brugada phenotype is a result of a more prominent I to -mediated action potential notch in the right ventricular (RV) epicardium of males versus females. Methods and Results-We studied epicardial tissue slices, arterially perfused wedge preparations, and dissociated epicardial myocytes isolated from male and female canine hearts. RV epicardium action potential phase 1 amplitude was 64.8Ϯ2.0% of that of phase 2 in males compared with 73.8Ϯ4.4% in females (PϽ0.05) at a cycle length of 2000 ms. I to density was 26% smaller and time constant for inactivation 17% smaller at ϩ40 mV in female versus male RV epicardial cells (PϽ0.05). The other functional characteristics of I to , including the voltage dependence of inactivation and time course of reactivation, were no different between the sexes. Pinacidil caused loss of action potential dome in male, but not female, RV epicardial tissue slices. Terfenadine (5 mol/L) induced phase 2 reentry in 6 of 7 male but only 2 of 7 female arterially perfused wedge preparations. Two of 6 male and 1 of 2 female preparations developed polymorphic ventricular tachycardia/ventricular fibrillation. Conclusions-Our results suggest that the predominance of the Brugada phenotype in males is a result of the presence of a more prominent I to in males versus females.

Recent studies have established the presence of three distinct cell types in the ventricular myocardium: epicardial, M and endocardial cells. Epicardial and M cell action potentials differ from endocardial cells with respect to the morphology of phase 1. These cells possess a prominent transient outward current (I(to))-mediated notch responsible for the 'spike and dome' morphology of the epicardial and M cell response. M cells are distinguished from the other cell types in that they display a smaller slowly activating delayed rectifier current (I(Ks)), but a larger late sodium current (late I(Na)) and sodium-calcium exchange current (I(Na-Ca)). These ionic distinctions underlie the longer action potential duration (APD) and steeper APD-rate relationship of the M cell, which is more pronounced in the presence of antiarrhythmic agents with class III actions. The preferential prolongation of the M cell action potential results in the development of a transmural dispersion of repolarization (TDR), which can be estimated from the electrocardiogram (ECG) as the interval between the peak and the end of the T wave (QTpeak-QTend interval). Using the canine arterially perfused ventricular wedge model, transmembrane action potentials of the various cardiac cell types can be correlated to the waveforms of the ECG, providing insight into the cellular etiology of ECG abnormalities. Two congenital syndromes of sudden cardiac death that have been modeled using this technique are the long QT and Brugada syndromes. The long QT syndrome has been linked to 5 gene mutations on chromosomes 3, 7, 11, and 21. Mutations in the cardiac sodium channel SCN5A have been linked to families with a history of the Brugada syndrome. Although the etiologies of these two syndromes are different, lethal arrhythmias in both are thought to arise due to amplification of intrinsic electrical heterogeneities. Similar mechanisms are likely responsible for life-threatening arrhythmias in a variety of other cardiomyopathies ranging from heart failure and hypertrophy, which involve mechanisms similar to those operative in LQTS, to ischemia and infarction, which may involve mechanisms more closely resembling those responsible for the Brugada syndrome.

This Point/Counterpoint presents a scholarly debate of the mechanisms underlying the electrocardiographic and arrhythmic manifestations of Brugada syndrome (BrS), exploring in detail the available evidence in support of the repolarization vs. depolarization hypothesis.

Background-Epicardial pacing of the left ventricle (LV) has been shown to prolong the QT interval and predispose to the development of torsade de pointes arrhythmias. The present study examines the cellular basis for QT prolongation and arrhythmogenesis after reversal of the direction of activation of the LV wall. Methods and Results-A transmural ECG and transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial cells of arterially perfused canine LV wedge preparations. QT interval increased from 297.6Ϯ3.9 to 314.0Ϯ5.7 ms (nϭ12; PϽ0.001) and transmural dispersion of repolarization (TDR) increased from 35.5Ϯ5.2 to 70.3Ϯ6.2 ms (nϭ12; PϽ0.001) as pacing was shifted from endocardium to epicardium. Conduction time between M and epicardial cells increased from 12.1Ϯ1.2 to 24.2Ϯ1.5 ms (nϭ12; PϽ0.001).Amplification of TDR was further accentuated in the presence of rapidly activating delayed rectifier potassium current blockers (E-4031 and cisapride), increasing from 50.5Ϯ7.6 to 86.1Ϯ6.2 ms (nϭ8; PϽ0.01). Torsade de pointes arrhythmias could be induced during epicardial, but not endocardial, pacing of LV in the presence of rapidly activating delayed rectifier potassium current blockade. Key Words: electrocardiography Ⅲ torsade de pointes Ⅲ heart failure Ⅲ pacemakers Ⅲ electrophysiology R ecent studies have highlighted the benefits of resynchronization therapy involving biventricular pacing for patients with congestive heart failure, demonstrating enhanced cardiac output and New York Heart Association class improvement. [1][2][3][4] Despite improvements in hemodynamics and patient quality of life, the incidence of sudden death in patients treated with biventricular pacing remains high. 5,6 Recent reports document the development of R-on-T ventricular extrasystoles and ventricular tachyarrhythmias after the initiation of biventricular pacing. 7,8 Resynchronization therapy most commonly involves the placement of one stimulating catheter in the right ventricular (RV) apex and another in contact with the left ventricular (LV) epicardium via the coronary sinus. Although the mechanical benefits of resynchronization therapy have been studied extensively, little attention has been directed toward the consequences of reversing the electric activation of the LV free wall. Using a rabbit wedge preparation, Medina-Ravell et al 8 demonstrated the development of early afterdepolarizations and increased dispersion of epicardial and endocardial repolarization after reversal of the transmural sequence of activation, suggesting that these mechanisms may underlie the development of torsade de pointes in patients undergoing resynchronization therapy. Conclusions-ReversalOur laboratory first described the contribution of M cells to transmural dispersion of repolarization (TDR) in 1991 9 -11 and in more recent years has shown these cells to be the chief culprits in the development of torsade de pointes under a wide variety of conditions. 12 The present study tests the hypothesis that delayed activation and...