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).

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Our study demonstrates important differences in the inactivation characteristics of atrial versus ventricular sodium channels and a striking atrial selectivity for the action of ranolazine to produce use-dependent block of sodium channels, leading to suppression of AF. Our results point to atrium-selective sodium channel block as a novel strategy for the management of AF.

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.

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.

Differences in the time course of repolarization of the three predominant myocardial cell types have been shown to contribute to the inscription of the T wave of the electrocardiogram (ECG). Voltage gradients developing as a result of the different time course of repolarization of phases 2 and 3 in the three cell types give rise to opposing voltage gradients on either side of the M region, which are in part responsible for the inscription of the T wave. 1 In the case of an upright T wave, the epicardial response is the earliest to repolarize and the M cell action potential is the latest. In the coronary-perfused wedge preparation, repolarization of the epicardial action potential coincides with the peak of the T wave and repolarization of the M cells is coincident with the end of the T wave, so that the interval from the peak to the end of the T wave provides a measure of transmural dispersion of repolarization (TDR).Based on these early studies, the Tpeak-Tend interval in precordial ECG leads was suggested to provide an index of transmural dispersion of repolarization. 2 More recent studies have also provided guidelines for the estimation of transmural dispersion of repolarization in the case of more complex T waves, including negative, biphasic and triphasic T waves. 3 In such cases, the interval from the nadir of the first component of the T wave to the end of the T wave was shown to provide an electrocardiographic approximation of TDR.While these relationships are relatively straight forward in the coronary-perfused wedge preparation, extrapolation to the surface ECG recorded in vivo must be approached with great caution and will require careful validation. The Tpeak-Tend interval is unlikely to provide an absolute measure of transmural dispersion in vivo, as elegantly demonstrated by Xia and coworkers 4 . However, changes in this parameter are thought to be capable of reflecting changes in spatial dispersion of repolarization, particularly TDR, and thus may be prognostic of arrhythmic risk under a variety of conditions. 5-10 Takenaka et al. recently demonstrated exercise-induced accentuation of the Tpeak-Tend interval in LQT1 patients, but not LQT2. 9

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...

Transmural heterogeneities of repolarizing currents underlie prominent differences in the electrophysiology and pharmacology of ventricular epicardial, endocardial, and M cells in a number of species. The degree to which heterogeneities exist between the right and left ventricles is not well appreciated. The present study uses standard microelectrode and whole cell patch-clamp techniques to contrast the electrophysiological characteristics and pharmacological responsiveness of tissues and myocytes isolated from right (RVE) and left canine ventricular epicardium (LVE). RVE and LVE studied under nearly identical conditions displayed major differences in the early repolarizing phases of the action potential. The magnitude of phase 1 in RVE was nearly threefold that in LVE: 28.7 +/- 6.2 vs. 10.6 +/- 4.1 mV (basic cycle length = 2,000 ms). Phase 1 in RVE was also more sensitive to alterations of the stimulation rate and to 4-aminopyridine (4-AP), suggesting a much greater contribution of the transient outward current (I(to) 1) in RVE than in LVE. The combination of 4-AP plus ryanodine, low chloride, or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (chloride channel blocker) completely eliminated the notch and all rate dependence of the early phases of the action potential, making RVE and LVE indistinguishable. At +70 mV, RVE myocytes displayed peak I(to) 1 densities between 28 and 37 pA/pF. LVE myocytes included cells with similar I(to) 1 densities (thought to represent subsurface cells) but also cells with much smaller current levels (thought to represent surface cells). Average peak I(to) 1 density was significantly smaller in LVE than in RVE at voltages more than or equal to +10 mV. Our data point to prominent differences in the magnitude of the I(to) 1-mediated action potential notch in cells at the surface of RVE compared with the LVE and suggest that important distinctions may exist in the response of these two tissues to pharmacological agents and pathophysiological states, as previously demonstrated for epicardium and endocardium. Our findings also suggest that a calcium-activated outward current contributes to the early repolarization phase in RVE and LVE and that the influence of this current, although small, is more important in the left ventricle.