Increase In Transmural Dispersion Research Articles

Effect of Percentage Reduction in Action Potential Duration of M-cells on Re-entry in Short QT Syndrome.

Increase in transmural dispersion of repolarisation along with a diminished QT interval have been known to aid in the development of arrhythmia during KCNQ1-linked short QT syndrome type 2 (SQTS2). However, the percentage by which action potential duration (APD) shortens in the different cell types that make up the ventricular wall are not fully understood. In this study, the percentage of APD shortening of M-cells was varied to determine the conditions under which re-entry occurs during SQTS2. A 2D transmural section of the heart with anisotropic properties is considered. Slight modifications to the TP06 equations are used to simulate the electrophysiology of the endocardial (endo), midmyocardial (M) and epicardial (epi) cells. A discrete network of 250×100 cells are interconnected using gap junction conductances and from this, a pseudo ECG is generated. On pacing the tissue with premature beats in the midst of normal pacing pulses and on including SQTS, it is observed that re-entry is sustained for a longer duration when the APD shortening in M-cells is more compared to the epi or endo cells while the percentage reduction in APD of M-cells is about 5% to 7% lesser than that in epi and endo cells. Further, when the percentage reduction in APD of M-cells is similar to epi or endo cells, no re-entry is generated. This analysis highlights the key role of percentage reduction in APD of M-cells compared to epi and endo cells in maintaining the re-entrant waves.

QT interval shortening in spontaneous reports submitted to the FDA: the need for consensus

QT interval shortening in spontaneous reports submitted to the FDA: the need for consensus

U-waves and T-wave peak to T-wave end intervals in patients with catecholaminergic polymorphic ventricular tachycardia, effects of beta-blockers

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by risk of polymorphic ventricular tachycardia (pVT) and sudden death during stress. Experimental CPVT models show that delayed afterdepolarization (DAD)-induced triggered activity is the initiating mechanism of pVT, whereas an increase in transmural dispersion of repolarization (TDR) controls degeneration of pVT to ventricular fibrillation. U-wave and T-wave peak to T-wave end interval (TPE) are regarded as electrocardiographic counterparts of DAD and TDR, respectively. We tested hypotheses that patients with CPVT might show abnormal U-waves and TPE intervals and that beta-blockers could suppress appearance of these repolarization abnormalities. We reviewed Holter recordings from 19 CPVT patients with a RyR2 mutation (P2328S or V4653F) and from 19 healthy unaffected subjects to record U-waves and TPE intervals as well as to measure beta-blockers' effects on ventricular repolarization by use of an automated computerized program. The maximal U-wave to T-wave amplitude ratio was 0.8 +/- 0.6 in CPVT patients and 0.4 +/- 0.3 in unaffected subjects (P = .009). Patients with most ventricular extrasystoles had a higher U-wave to T-wave amplitude ratio than those with fewest extrasystoles. Treatment with beta-blockers decreased U-wave amplitude at high heart rates. CPVT patients had longer TPE intervals than unaffected subjects at high heart rates, and beta-blocker treatment shortened their TPE intervals. Present data support the hypothesis that U-waves associate with the DAD-triggered extrasystolic activity in CPVT patients. Patients with a RyR2 mutation show increased TPE at high heart rates. Beta-blocker treatment suppresses observed repolarization abnormalities in CPVT patients.

Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes

Torsade de pointes (TdP) is a life-threatening arrhythmia that develops as a consequence of a reduction in the repolarization reserve of cardiac cells leading to amplification of electrical heterogeneities in the ventricular myocardium as well as to the development of early after depolarization-induced triggered activity. Electrical heterogeneities within the ventricles are due to differences in the time course of repolarization of the three predominant cell types that make up the ventricular myocardium, giving rise to transmural voltage gradients and a dispersion of repolarization that contributes to the inscription of the electrocardiographic T wave. A number of non-antiarrhythmic drugs and antiarrhythmic agents with class III actions and/or the various mutations and cardiomyopathies associated with the long QT syndrome reduce net repolarizing current and amplify spatial dispersion of repolarization, thus creating the substrate for re-entry. This results in a prolongation of the QT interval, abnormal T waves, and development of TdP. Agents that prolong the QT interval but do not cause an increase in transmural dispersion of repolarization (TDR) do not induce TdP, suggesting that QT prolongation is not the sole or optimal determinant for arrhythmogenesis. This article reviews recent advances in our understanding of these mechanisms, particularly the role of TDR in the genesis of drug-induced TdP, and examines how these may guide us towards development of safer drugs.

Cellular basis for the electrocardiographic and arrhythmic manifestations of Timothy syndrome: Effects of ranolazine

Timothy syndrome is a multisystem disorder associated with QT interval prolongation and ventricular cardiac arrhythmias. The syndrome has been linked to mutations in Ca(V)1.2 resulting in gain of function of the L-type calcium current (I(Ca,L)). Ranolazine is an antianginal agent shown to exert an antiarrhythmic effect in experimental models of long QT syndrome. The purpose of this study was to develop and characterize an experimental model of Timothy syndrome by using BayK8644 to mimic the gain of function of I(Ca,L) and to examine the effects of ranolazine. Action potentials from epicardial and M regions and a pseudo-electrocardiogram (ECG) were simultaneously recorded from coronary-perfused left ventricular wedge preparations, before and after addition of BayK8644 (1 microM). BayK8644 preferentially prolonged action potential duration of the M cell, leading to prolongation of the QT interval and an increase in transmural dispersion of repolarization (from 44.3 +/- 7 ms to 86.5 +/- 25 ms). Stimulation at cycle lengths of 250-500 ms led to ST-T wave alternans due to alternation of the plateau voltage of the M cell action potential as well as development of delayed afterdepolarizations in epicardial and M cell action potentials. Ventricular extrasystoles and tachycardia (monomorphic, bidirectional, or torsades de pointes) developed spontaneously or after rapid pacing. Peak and late I(Na) were unaffected by BayK8644. Clinically relevant concentrations of ranolazine (10 microM) suppressed all actions of BayK8644. A left ventricular wedge model of long QT syndrome created by augmentation of I(Ca,L) recapitulates the ECG and arrhythmic manifestations of Timothy syndrome, which can be suppressed by ranolazine.

Desflurane??s Effect on QTc Interval: Electrophysiological Mechanisms Need to Be Explored

In Response: The letter from Dr. Venkatesan (1) correctly notes that several months before publishing our article (2) in Anesthesia & Analgesia, Yildirim et al. (3) had published an article regarding the influence of desflurane on some variables of cardiac ventricular repolarization. Yildirim et al.'s paper was published after our manuscript had been submitted to Anesthesia & Analgesia, and we had no knowledge of their work at the time our work was submitted. However, in our opinion the patients in the Yildirim et al. study may not have received the equivalent of 1 MAC of anesthesia. Patients in that study ranged from 16 to 50 yr of age. Rampil et al. (4) determined 1 MAC of desflurane in 100% oxygen as 7.25 ± 0.0 vol% in the 18–30-yr age range and 6.0 ± 0.29 vol% in the 31–65-yr age group. This suggests that some patients in the Yildirim et al. study received <1 MAC of desflurane. Dr. Venkatesan suggested two mechanisms connected with use of volatile anesthetics that may prolong the QTc interval and induce arrhythmia: reduction of IK current for sevoflurane and an increase in transmural dispersion of repolarization for halothane. The first mechanism was also described for isoflurane and halothane (5). There was no increase in transmural dispersion of repolarization for sevoflurane in children (6). We are not familiar with any data on the mechanism of QTc prolongation with desflurane. It seems probable that the prolongation might be caused by the influence of desflurane on IK current, similar to that induced by sevoflurane and isoflurane. Moreover, transient increases in sympathetic activity from desflurane might further prolong the QTc interval. As suggested by Yildirim et al., potential arrhythmogenic effects of desflurane may be caused by increased dispersion of the QTc interval. Further research is required to fully understand the mechanisms of QTc prolongation with inhaled anesthetics. Radoslaw Owczuk, MD, PhD Magdalena A. Wujtewicz, MD Wioletta Sawicka, MD Department of Anaesthesiology and Intensive Therapy [email protected] Jerzy Lasek, MD, PhD Department of Trauma Surgery Maria Wujtewicz, MD, PhD Department of Anaesthesiology and Intensive Therapy Medical University of Gdansk Gdansk, Poland

AB40-4: Increased global dispersion of ventricular repolarization during left ventricular epicardial pacing: In vivo evaluation by monophasic action potential mapping in swine

Recent studies have highlighted the benefits of biventricular pacing therapy for patients with congestive heart failure, but latest in vitro studies suggested that epicardial pacing might lead to a prominent increase in transmural dispersion, which may be linked to the reported malignant ventricular arrhythmias in patients with biventricular pacing. However, the dispersion of global repolarization under epicardial pacing has never been in vivo evaluated.

Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7)

Andersen-Tawil syndrome, a skeletal muscle syndrome associated with periodic paralysis and long QT intervals on the ECG, has been linked to defects in KCNJ2, the gene encoding for the inward rectifier potassium channel (I(K1).) The purpose of this study was to examine the cellular mechanisms underlying the ECG and arrhythmic manifestations of Andersen-Tawil syndrome. To investigate the effects of KCNJ2 loss-of-function mutations responsible for Andersen-Tawil syndrome, we used barium chloride (BaCl(2)) to inhibit I(K1) in arterially perfused wedge preparation. Transmembrane action potentials (APs) were simultaneously recorded from endocardial, midmyocardial, and epicardial cells, together with a transmural ECG. BaCl(2) (1 to 30 microM) produced a concentration-dependent prolongation of the QT interval, secondary to a homogeneous prolongation of AP duration of the three cell types. QT interval was prolonged without an increase in transmural dispersion of repolarization (TDR). Low extracellular potassium (2.0 mM), isoproterenol (20-50 nM), and an abrupt increase in temperature (36 degrees C-39 degrees C) in the presence of 10 microM BaCl(2) did not significantly increase TDR but increased ectopic extrasystolic activity. Early afterdepolarizations were not observed under any condition. Spontaneous torsades de pointes arrhythmias were never observed, nor could they be induced with programmed electrical stimulation under any of the conditions studied. Our results provide an understanding of why QT prolongation associated with Andersen-Tawil syndrome is relatively benign in the clinic and provide further support for the hypothesis that the increase in TDR, rather than QT interval, is responsible for development of torsades de pointes.

Modulation of Transmural Repolarization

Ventricular myocardium in larger mammals has been shown to be comprised of three distinct cell types: epicardial, M, and endocardial. Epicardial and M cell action potentials differ from endocardial cells with respect to the morphology of phase 1. These cells possess a prominent 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 I(Ks), but a larger late I(Na) and I(Na-Ca). These ionic distinctions underlie the longer action potential duration (APD) and steeper APD-rate relationship of the M cell. Difference in the time course of repolarization of phase 1 and phase 3 are responsible for the inscription of the electrocardiographic J wave and T wave, respectively. These repolarization gradients are sensitively modulated by electrotonic communication among the three cells types, [K(1)](o), and the presence of drugs that either reduce or augment net repolarizing current. A reduction in net repolarizing current generally leads to a preferential prolongation of the M cell action potential, responsible for a prolongation of the QT interval and an increase in transmural dispersion of repolarization (TDR), which underlies the development of torsade de pointes arrhythmias. An increase in net repolarizing current can lead to a preferential abbreviation of the action potential of epicardium in the right ventricle (RV), and endocardium in the left ventricle (LV). These actions also lead to a TDR that manifests as the Brugada syndrome in RV and the short QT syndrome in LV.

Refractory patterns and susceptibility to drug-induced polymorphic ventricular tachycardias in dogs with chronic atrioventricular block: relation to the type of anesthesia.

Controversy exists as to the homogeneity of repolarization throughout the canine ventricular wall in vivo. The type of anesthesia has been shown to affect regional differences in monophasic action potential duration and the inducibility of polymorphic ventricular tachycardias (PVTs) in normal canine hearts. This study was conducted to determine refractory patterns and arrhythmia susceptibility in relation to halothane or pentobarbital anesthesia in dogs with chronic atrioventricular block and biventricular hypertrophy. In 12 dogs with chronic atrioventricular block, 60 needle electrodes (12 mm long, four bipolar electrodes, interelectrode distance of 2 mm) were inserted into the left and right ventricle. Six dogs were anesthetized with pentobarbital and six with halothane. Effective refractory periods (ERPs) were determined along 14 randomly selected needles at baseline and after application of almokalant (0.34 mmol/kg) (basic cycle length 1,000 ms, extrastimulus technique). At baseline and on almokalant, ERPs were uniform, independent of the type of anesthesia. With halothane anesthesia, ERPs were significantly longer under both conditions. Almokalant induced not only a prolongation of ERP in both groups but also a significant increase in transmural dispersion of ERP and in maximum dispersion of ERP. However, local refractory gradients were not specific to any muscle layer and did not seem to be related to the occurrence of PVTs. Almokalant did not induce arrhythmias in any dog in the pentobarbital group, but in four of six animals in the halothane group, apparently due to the more marked prolongation in ERP. Independent of the type of anesthesia, hypertrophied hearts of dogs with chronic atrioventricular block exhibit uniform refractory patterns. Longer ERPs with a comparable degree of dispersion on halothane are associated with a high incidence of drug-induced PVTs, whereas shorter ERPs on pentobarbital seem to prevent arrhythmia induction.

Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol.

The present study was designed to examine the effects of chronic amiodarone on the different ventricular cell subtypes in situ and to evaluate its interactions with sotalol. Three groups of dogs were studied. Group I (n = 8) received no treatment. Group II (n = 7) and group III (n = 8) received, respectively, 100 and 200 mg amiodarone orally twice a day for 6 weeks to 8 months. In vivo studies were performed under halothane anesthesia 14 h after the last administration of amiodarone. Three leads ECG, femoral blood pressure and left ventricular intramural monophasic action potentials (MAP) were continuously recorded. Bradycardia was obtained by clamping the sinus node and beta-blockade and the heart was driven by atrial pacing. Three weeks before the in vivo experiments, the cellular electrophysiologic properties of right ventricular tissues obtained by cardiac biopsy in six treated and six control dogs were studied with standard microelectrodes. Amiodarone produced a dose-dependent decrease in plasma levels of triiodothyronine (T3; 5.9 +/- 0.4 pM in control dogs, 3.1 +/- 0.2 pM in group III, P < 0.001) without affecting thyroxine (T4). Under anesthesia, the QT interval was 14% larger in group III compared to group I at a paced cycle length (PCL) of 1500 ms (P < 0.05). This is consistent with the 10% increase in endocardial MAP duration in group III at the same PCL (P < 0.05). There was no significant increase in transmural dispersion of MAP duration. In group I, sotalol induced a significant reverse use-dependent increase in MAP duration. This effect was reduced in group II and completely suppressed in group III. Amiodarone prevented the sotalol-induced increase in transmural dispersion of ventricular repolarization which was 69 +/- 12 ms in untreated dogs, 41 +/- 8 ms in group II (P < 0.05) and 34 +/- 8 ms (P < 0.05) in group III at PCL = 1500 ms. Amiodarone also prevented the sotalol-induced ventricular tachyarrhythmias. In vitro, the action potential duration was longer in amiodarone-treated dogs that in control ones (208 +/- 5 ms versus 188 +/- 9 ms at PCL = 1000 ms, P < 0.05). The sotalol-induced prolongation of repolarization was reduced in amiodarone-treated dogs. Chronic treatment of dogs with amiodarone induced a moderate prolongation of the QT interval and MAP duration without affecting transmural dispersion of repolarization and inhibited the effects of acute sotalol, including the prolongation of repolarization, the increase in transmural dispersion of repolarization and the induction of arrhythmias.

Electrophysiological effects of cetirizine, astemizole and D-sotalol in a canine model of long QT syndrome.

Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to D-sotalol and to astemizole in a model of acquired long QT syndrome. Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with beta-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400-1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for D-sotalol). Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by D-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 +/- 8 msec (mean +/- SE) at baseline to 343 +/- 10, 379 +/- 13 and 468 +/- 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 +/- 6 msec to 377 +/- 7, 444 +/- 15 and 485 +/- 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 +/- 8 msec at baseline Vs 330 +/- 8, 324 +/- 9 and 323 +/- 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 +/- 19 msec after astemizole, +59 +/- 21 msec after D-sotalol and only +7 +/- 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and D-sotalol (4/7 dogs) but never during cetirizine. In the present model, astemizole and D-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.

Use of the 12-lead ECG for non-invasive prediction of the culprit artery in acute inferior myocardial infarction

Genetic studies have identified four forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes located on chromosomes 3 (LQT3), 7 (LQT2), 11 (LQT1), and 21 (LQT5). Preliminary clinical studies have reported different phenotypic electrocardiographic patterns and different sensitivity to pacing or pharmacological therapy for each genotype. A transmural electrocardiogram and transmembrane action potentials from epicardial, M, and endocardial cells were simultaneously recorded from an arterially perfused wedge of canine left ventricle. Isoproterenol (100 nmol/L) in the presence of chromanol 293B (30 μmol/L), an IKs blocker (LQT1 model), produced a preferential prolongation of M-cell action potential duration (APD), resulting in an increase in transmural dispersion of repolarization (TDR) and a broad-based T wave, as commonly seen in LQT1 patients. D-Sotalol (100 μmol/L), an IKr blocker (LQT2 model), and ATX-II (20 nmol/L), an agent that augments late INa (LQT3 model), also produced a preferential prolongation of M-cell APD, an increase in TDR, and low-amplitude T wave with a bifurcated appearance (LQT2), and late-appearing T wave (LQT3), respectively. APD-, QT-, and TDR-rate relations were much steeper in the LQT3 model than in either the LQT1 or LQT2 model, whereas the rate relations in the LQT1 and LQT2 models were both steeper than those under control conditions. Spontaneous and programmed electrical stimulation-induced torsade de pointes (TdP) were observed in all 3 models. Propranolol (1 μmol/L), a beta blocker, completely prevented the effect of isoproterenol to persistently or transiently increase TDR and to induce TdP in the LQT1 and LQT2 models, but facilitated TdP in the LQT3 model. Mexiletine, a class IB Na+ channel blocker, dose-dependently (2–20 μmol/L) abbreviated the QT and APD more in the LQT3 model, but decreased TDR and suppressed TdP in the 3 models.

Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome

Genetic studies have identified four forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes located on chromosomes 3 (LQT3), 7 (LQT2), 11 (LQT1), and 21 (LQT5). Preliminary clinical studies have reported different phenotypic electrocardiographic patterns and different sensitivity to pacing or pharmacological therapy for each genotype. A transmural electrocardiogram and transmembrane action potentials from epicardial, M, and endocardial cells were simultaneously recorded from an arterially perfused wedge of canine left ventricle. Isoproterenol (100 nmol/L) in the presence of chromanol 293B (30 μmol/L), an I Ks blocker (LQT1 model), produced a preferential prolongation of M-cell action potential duration (APD), resulting in an increase in transmural dispersion of repolarization (TDR) and a broad-based T wave, as commonly seen in LQT1 patients. D-Sotalol (100 μmol/L), an I Kr blocker (LQT2 model), and ATX-II (20 nmol/L), an agent that augments late I Na (LQT3 model), also produced a preferential prolongation of M-cell APD, an increase in TDR, and low-amplitude T wave with a bifurcated appearance (LQT2), and late-appearing T wave (LQT3), respectively. APD-, QT-, and TDR-rate relations were much steeper in the LQT3 model than in either the LQT1 or LQT2 model, whereas the rate relations in the LQT1 and LQT2 models were both steeper than those under control conditions. Spontaneous and programmed electrical stimulation-induced torsade de pointes (TdP) were observed in all 3 models. Propranolol (1 μmol/L), a beta blocker, completely prevented the effect of isoproterenol to persistently or transiently increase TDR and to induce TdP in the LQT1 and LQT2 models, but facilitated TdP in the LQT3 model. Mexiletine, a class IB Na + channel blocker, dose-dependently (2–20 μmol/L) abbreviated the QT and APD more in the LQT3 model, but decreased TDR and suppressed TdP in the 3 models.

Effects of Sodium Channel Block with Mexiletine to Reverse Action Potential Prolongation in In Vitro Models of the Long QT Syndrome

Recent clinical studies have reported a greater effectiveness of sodium channel block with mexiletine to abbreviate the QT interval in patients with the chromosome 3 variant (SCN5A, LQT3) of the long QT syndrome (LQTS) than those with the chromosome 7 form of the disease (HERG, LQT2), suggesting the possibility of gene-specific therapy for the two distinct forms of the congenital LQTS. Experimental studies using the arterially perfused left ventricular wedge preparation have confirmed these clinical observations on the QT interval but have gone on to further demonstrate a potent effect of mexiletine to reduce dispersion of repolarization and prevent torsades de pointes (TdP) in both LQT2 and LQT3 models. A differential action of sodium channel block on the three ventricular cell types is thought to mediate these actions of mexiletine. This study provides a test of this hypothesis by examining the effects of mexiletine in isolated canine ventricular epicardial, endocardial, and M region tissues under conditions that mimic the SCN5A and HERG gene defects. We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle. d-Sotalol, an IKr blocker, was used to mimic the HERG defect (LQT2), and ATX-II, which increases late Na channel current, was used to mimic the SCN5A defect (LQT3). d-Sotalol (100 microM) preferentially prolonged the action potential of the mid-myocardial M cell (APD90 increased from 340 +/- 65 to 623 +/- 203 msec) as did ATX-II (10 to 20 nM; APD90 increased from 325 +/- 51 to 580 +/- 178 msec; basic cycle length = 2000 msec), thus causing a marked increase in transmural dispersion of repolarization (TDR). Mexiletine (2 to 20 microM) dose-dependently reversed the ATX-II-induced prolongation of APD90 in all three cell types. Mexiletine also reversed the d-sotalol-induced prolongation of the M cell action potential duration (APD), but had little effect on the action potential of epicardium and endocardium. Due to its preferential effect to abbreviate the action potential of M cells, mexiletine reduced the dispersion of repolarization in both models. Low concentrations of mexiletine (5 to 10 microM) totally suppressed early afterdepolarization (EAD) and EAD-induced triggered activity in both models. Our results indicate that the actions of mexiletine are both cell and model specific, but that sodium channel block with mexiletine is effective in reducing transmural differences in APD and in abolishing triggered activity induced by d-sotalol and ATX-II. The data suggest that mexiletine's actions to reduce TDR and prevent the induction of spontaneous and programmed stimulation-induced TdP in these models are due to a preferential effect of the drug to abbreviate the APD of the M cell and to suppress the development of EADs. The data provide further support for the hypothesis that block of the late sodium current may be of value in the treatment of LQT2 as well as LQT3 and perhaps other congenital and acquired (drug-induced) forms of LQTS.

D-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Empirical or Endocardial Cells of the Canine Ventricle.

BACKGROUND: Despite its class III antiarrhythmic actions, experimental and clinical studies have shown that d-sotalol can also be proarrhythmic; a recent clinical trial that evaluated d-sotalol in postmyocardial patients (SWORD) had to be prematurely interrupted because of the excess mortality in the treated group. Previous studies have demonstrated the existence of a marked heterogeneity across the ventricular wall; epicardial, endocardial, and M cells have been shown to display distinct electrophysiologic characteristics and pharmacologic behavior. The present study was designed to test the hypothesis that M cells are the primary target for the class III actions of d-sotalol in canine ventricular myocardium and may contribute to its proarrhythmic effects. METHODS AND RESULTS: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, midmyocardial, and transmural strips, isolated from the canine left ventricle. d-Sotalol (100 µM, 60 minutes of exposure, [K(+)]o = 4 mM) prolongs the action potential in the three cell types, but more so in M than epicardial or endocardial cells, especially at the slower rates. At a basic cycle length of 2000 ms, action potential duration after 90% repolarization increases from 199 +/- 20 to 247.5 +/- 28 ms in epicardium (n = 10), from 212 +/- 26 to 274 +/- 27 ms in endocardium (n = 11), and from 309 +/- 65 to 533 +/- 207 ms in M cells (n = 13). d-Sotalol produces a marked steepening of action potential duration-rate relationships of M cells and an upward shift of restitution of action potential duration curves, more accentuated in M cells. Early afterdepolarizations were observed at slow rates (basic cycle lengths > 1000 ms) in 7 of 13 M cell preparation s(54%) but not in endocardial or epicardial preparations. A sudden acceleration of the rate could also induce a transient prolongation of the action potential and early afterdepolarization activity. CONCLUSION: In canine ventricular tissues, d-sotalol manifests its class III effects preferentially in the M cells, leading to the development of early afterdepolarizations and a marked increase in transmural dispersion of repolarization. The data suggest an important role of M cells in the proarrhythmic effects of the drug.