Jeffrey M. Fish

Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties

Background—Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 &mgr;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 IKr (IC50=11.5 &mgr;mol/L), late INa, late ICa, peak ICa, and INa-Ca (IC50=5.9, 50, 296, and 91 &mgr;mol/L, respectively) and IKs (17% at 30 &mgr;mol/L), but caused little or no inhibition of Ito or IK1. 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). At [K+]o=4 mmol/L, 10 &mgr;mol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 &mgr;mol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective IKr blocker d-sotalol. Conclusions—Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced IKr, IKs, late INa, and ICa). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.

Ionic and Cellular Basis for the Predominance of the Brugada Syndrome Phenotype in Males

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 Ito-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 64.8±2.0% of that of phase 2 in males compared with 73.8±4.4% in females (P <0.05) at a cycle length of 2000 ms. Ito density was 26% smaller and time constant for inactivation 17% smaller at +40 mV in female versus male RV epicardial cells (P <0.05). The other functional characteristics of Ito, 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 &mgr;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 Ito in males versus females.

The Pathophysiological Mechanism Underlying Brugada Syndrome. Depolarization versus Repolarization

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.

Epicardial Activation of Left Ventricular Wall Prolongs QT Interval and Transmural Dispersion of Repolarization Implications for Biventricular Pacing

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 297.6±3.9 to 314.0±5.7 ms (n=12; P <0.001) and transmural dispersion of repolarization (TDR) increased from 35.5±5.2 to 70.3±6.2 ms (n=12; P <0.001) as pacing was shifted from endocardium to epicardium. Conduction time between M and epicardial cells increased from 12.1±1.2 to 24.2±1.5 ms (n=12; P <0.001). Amplification of TDR was further accentuated in the presence of rapidly activating delayed rectifier potassium current blockers (E-4031 and cisapride), increasing from 50.5±7.6 to 86.1±6.2 ms (n=8; P <0.01). 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. Conclusions—Reversal of the direction of activation of the LV wall, as occurs during biventricular pacing, leads to a prominent increase in QT and TDR as a result of earlier repolarization of epicardium and delayed activation and repolarization of the midmyocardial M cells. The increase in TDR creates the substrate for the development of torsade de pointes under long-QT conditions.

Distribution of M Cells in the Canine Ventricle

Distribution of M Cells. Introduction: M cells and transitional cells residing in the deep structures of the ventricular free walls are distinguished by the ability of their action potentials to prolong disproportionately to those of other ventricular cells at relatively slow rates. This feature of the M cell due, at least in part, to a smaller contribution of the slowly activating component of the delayed rectifier current (Iks) is thought to contribute to the unique pharmacologic responsiveness of M cells, making them the primary targets in ventricular myocardium lor agents that cause action potential prolongation and induce early and delayed afterdepolarizations and triggered activity. Previous studies dealt exclusively with the characteristics and distribution of M cells in the canine right and left ventricular free wall near the base of the ventricles. The present study uses standard microelectrode techniques to define their behavior and distribution in the apical region of the ventricular wall as well as in the endocardial structures of the ventricle, including the interventricular septum, papillary muscles, and trabeculae.

Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent.

Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 μM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks IKr (IC50 = 12 μM), late INa, late ICa, peak ICa, INa-Ca (IC50 = 5.9, 50, 296, and 91 μM, respectively) and IKs (17% at 30,uM), but causes little or no inhibition of Ito or IKl. In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block IKr and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early afterdepolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 μM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late INa, IKs, IKS, and ICa). Ranolazines actions to reduce TDR and suppress early afterdepolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.

Dimethyl Lithospermate B, an Extract of Danshen, Suppresses Arrhythmogenesis Associated With the Brugada Syndrome

Background— Dimethyl lithospermate B (dmLSB) is an extract of Danshen, a traditional Chinese herbal remedy, which slows inactivation of INa, leading to increased inward current during the early phases of the action potential (AP). We hypothesized that this action would be antiarrhythmic in the setting of Brugada syndrome. Methods and Results— The Brugada syndrome phenotype was created in canine arterially perfused right ventricular wedge preparations with the use of either terfenadine or verapamil to inhibit INa and ICa or pinacidil to activate IK-ATP. AP recordings were simultaneously recorded from epicardial and endocardial sites together with an ECG. Terfenadine, verapamil, and pinacidil each induced all-or-none repolarization at some epicardial sites but not others, leading to ST-segment elevation as well as an increase in both epicardial and transmural dispersions of repolarization (EDR and TDR, respectively) from 12.9±9.6 to 107.0±54.8 ms and from 22.4±8.1 to 82.2±37.4 ms, respectively (P<0.05; n=9). Under these conditions, phase 2 reentry developed as the epicardial AP dome propagated from sites where it was maintained to sites at which it was lost, generating closely coupled extrasystoles and ventricular tachycardia and fibrillation. Addition of dmLSB (10 &mgr;mol/L) to the coronary perfusate restored the epicardial AP dome, reduced EDR and TDR to 12.4±18.1 and 24.4±26.7 ms, respectively (P<0.05; n=9), and abolished phase 2 reentry-induced extrasystoles and ventricular tachycardia and fibrillation in 9 of 9 preparations. Conclusions— Our data suggest that dmLSB is effective in eliminating the arrhythmogenic substrate responsible for the Brugada syndrome and that it deserves further study as a pharmacological adjunct to implanted cardioverter/defibrillator usage.

Cellular Mechanism and Arrhythmogenic Potential of T‐Wave Alternans in the Brugada Syndrome

Introduction: T‐wave alternans (TWA) is characterized by beat to beat alteration in the amplitude, polarity and/or morphology of the electrocardiographic T wave. TWA has been reported in patients with the Brugada syndrome (BS) and is thought to be associated with an increased risk for development of VT/VF. The cellular mechanisms involved are not well‐defined and are the subject of this investigation.

Therapy for the Brugada Syndrome

The Brugada syndrome is a congenital syndrome of sudden cardiac death first described as a new clinical entity in 1992. Electrocardiographically characterized by a distinct coved-type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. The ECG manifestations of the Brugada syndrome are often dynamic or concealed and may be revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, and hypokalemia, as well as by alcohol and cocaine toxicity. An implantable cardioverter-defibrillator (ICD) is the most widely accepted approach to therapy. Pharmacological therapy aimed at rebalancing the currents active during phase 1 of the right ventricular action potential is used to abort electrical storms, as an adjunct to device therapy, and as an alternative to device therapy when use of an ICD is not possible. Isoproterenol and cilostazol boost calcium channel current, and drugs like quinidine inhibit the transient outward current, acting to diminish the action potential notch and thus suppress the substrate and trigger for ventricular tachycardia/fibrillation (VT/VF).

Contact Sensing Provides a Highly Accurate Means to Titrate Radiofrequency Ablation Lesion Depth

RF Ablation Lesion Depth Estimation Using Contact Sensing. Background: Transmural lesions are essential for efficacious ablation. There are, however, no accurate means to estimate lesion depth.