Class IA Antiarrhythmic Agents Research Articles

Inhibitory effects of class I antiarrhythmic agents on Na+ and Ca2+ currents of human iPS cell-derived cardiomyocytes.

IntroductionHuman induced pluripotent stem cells (hiPSCs) harboring cardiac myosin heavy chain 6 promoter can differentiate into functional cardiomyocytes called “iCell cardiomyocytes” under blasticidin treatment condition. While iCell cardiomyocytes are expected to be used for predicting cardiotoxicity of drugs, their responses to antiarrhythmic agents remain to be elucidated. We first examined electrophysiological properties of iCell cardiomyocytes and mRNA levels of ion channels and Ca handling proteins, and then evaluated effects of class I antiarrhythmic agents on their Na+ and Ca2+ currents.MethodsiCell cardiomyocytes were cultured for 8–14 days (38–44 days after inducing their differentiation), according to the manufacturer's protocol. We determined their action potentials (APs) and sarcolemmal ionic currents using whole-cell patch clamp techniques, and also mRNA levels of ion channels and Ca handling proteins by RT-PCR. Effects of three class I antiarrhythmic agents, pirmenol, pilsicainide and mexiletine, on Na+ channel current (INa) and L-type Ca2+ channel current (ICaL) were evaluated by the whole-cell patch clamp.ResultsiCell cardiomyocytes revealed sinoatrial node-type (18%), atrial-type (18%) and ventricular-type (64%) spontaneous APs. The maximum peak amplitudes of INa, ICaL, and rapidly-activating delayed-rectifier K+ channel current were −62.7 ± 13.7, −8.1 ± 0.7, and 3.0 ± 1.0 pA/pF, respectively. The hyperpolarization-activated cation channel and inward-rectifier K+ channel currents were observed, whereas the T-type Ca2+ channel or slowly-activating delayed-rectifier K+ channel current was not detectable. mRNAs of Nav1.5, Cav1.2, Kir2.1, HCN4, KvLQT1, hERG and SERCA2 were detected, while that of HCN1, minK or MiRP was not. The class Ia antiarrhythmic agent pirmenol and class Ic agent pilsicainide blocked INa in a concentration-dependent manner with IC50 of 0.87 ± 0.37 and 0.88 ± 0.16 μM, respectively; the class Ib agent mexiletine revealed weak INa block with a higher IC50 of 30.0 ± 3.0 μM. Pirmenol, pilsicainide and mexiletine blocked ICaL with IC50 of 2.00 ± 0.39, 7.7 ± 2.5 and 5.0 ± 0.1 μM, respectively.ConclusionsIn iCell cardiomyocytes, INa was blocked by the class Ia and Ic antiarrhythmic agents and ICaL was blocked by all the class I agents within the ranges of clinical concentrations, suggesting their cardiotoxicity.

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles.

The short QT syndrome (SQTS) is a rare cardiac disorder associated with arrhythmias and sudden death. Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, IKr, underlie SQTS variant 1 (SQT1), in which treatment with Na+ and K+ channel blocking class Ia anti-arrhythmic agents has demonstrated some efficacy. This study used computational modeling to gain mechanistic insights into the actions of two such drugs, disopyramide and quinidine, in the setting of SQT1. The O'Hara-Rudy (ORd) human ventricle model was modified to incorporate a Markov chain formulation of IKr describing wild type (WT) and SQT1 mutant conditions. Effects of multi-channel block by disopyramide and quinidine, including binding kinetics and altered potency of IKr/hERG channel block in SQT1 and state-dependent block of sodium channels, were simulated on action potential and multicellular tissue models. A one-dimensional (1D) transmural ventricular strand model was used to assess prolongation of the QT interval, effective refractory period (ERP), and re-entry wavelength (WL) by both drugs. Dynamics of re-entrant excitation waves were investigated using a 3D human left ventricular wedge model. In the setting of SQT1, disopyramide, and quinidine both produced a dose-dependent prolongation in (i) the QT interval, which was primarily due to IKr block, and (ii) the ERP, which was mediated by a synergistic combination of IKr and INa block. Over the same range of concentrations quinidine was more effective in restoring the QT interval, due to more potent block of IKr. Both drugs demonstrated an anti-arrhythmic increase in the WL of re-entrant circuits. In the 3D wedge, disopyramide and quinidine at clinically-relevant concentrations decreased the dominant frequency of re-entrant excitations and exhibited anti-fibrillatory effects; preventing formation of multiple, chaotic wavelets which developed in SQT1, and could terminate arrhythmias. This computational modeling study provides novel insights into the clinical efficacy of disopyramide and quinidine in the setting of SQT1; it also dissects ionic mechanisms underlying QT and ERP prolongation. Our findings show that both drugs demonstrate efficacy in reversing the SQT1 phenotype, and indicate that disopyramide warrants further investigation as an alternative to quinidine in the treatment of SQT1.

Platitudes and Attitudes.

Platitudes and Attitudes.

Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis

Objectives: The role of sotalol is well established for the maintenance of sinus rhythm after successful conversion of atrial fibrillation (AF). However, its role in pharmacologic conversion of AF is poorly defined. The purpose of this study is to compare the efficacy of sotalol to that of other antiarrhythmic agents for AF conversion. Methods: Standard methods of meta-analysis were employed. Full-text publications of clinical trials in English that compared the efficacy of sotalol to that of other antiarrhythmics or placebo/no treatment were eligible for inclusion. Results: A systematic review revealed 10 eligible publications. Sotalol was superior to placebo and/or no antiarrhythmic therapy in AF conversion, with a relative success of 24 (95% CI 4.7-119, p < 0.001). Sotalol was not significantly different from class IA antiarrhythmic drugs. Similarly, sotalol was not different from class IC antiarrhythmic drugs or amiodarone in terms of conversion efficacy. In one study, sotalol was less effective than high-dose ibutilide (2 mg), with a relative success of 0.248 (95% CI 0.128-0.481, p < 0.001). Ibutilide caused more proarrhythmia. Conclusions: Sotalol is as effective as class IA and class IC antiarrhythmic agents, and it is also as effective as amiodarone for pharmacologic conversion of AF. Only ibutilide at a high dose showed a greater conversion rate of AF.

Antiarrhythmic properties of some 1,4-disubstituted piperazine derivatives with α1-adrenoceptor affinities

A series of 1,4-disubstituted piperazine derivatives with α1-adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity in vitro and in vivo. Most of them displayed strong antiarrhythmic activity in the adrenaline induced model of arrhythmia and in the rat coronary artery ligation-reperfusion model. Their antiarrhythmic effect is mainly related to α1-adrenolytic properties. Among them one compound showed characteristics similar to quinidine in different arrhythmia models as well as electrocardiogram (ECG) studies which suggests that it possesses not only α1-adrenoceptor blocking properties but also affinity for cardiac Na+ and K+ channels, similar to class IA antiarrhythmic agents. Two other compounds revealed some antioxidant effects. Another compound (MH-79) is particularly promising since it displayed a strong antiarrhythmic effect without the influence on ECG record.

Cardiovascular Drugs Inducing QT Prolongation: Facts and Evidence

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

Clinical Efficacy of Bepridil for Class I Antiarrhythmic Drug-Induced Atrial Flutter in Patients with Paroxysmal Atrial Fibrillation

Background: Class I antiarrhythmic drugs can promote the organization of atrial fibrillation (AF) and sometimes converts AF into atrial flutter (AFL) concomitant with difficulty of rate control. We studied the usefulness of Bepridil, which exhibits a class III‐like effect, for class I drug‐induced AFL in patients with paroxysmal AF.Methods: The study population consisted of 17 consecutive patients (15 men, mean age 65 ± 8 years) with AFL converted from paroxysmal AF following oral treatment of class IA or IC antiarrhythmic agents including pilsicainide (n = 8), cibenzoline (n = 5), flecainide (n = 2), aprindine (n = 1), and propafenone with cibenzoline (n = 1). After the occurrence of AFL, class I drug was replaced by bepridil with a dose of 100–200 mg per day in all patients.Results: After the treatment with bepridil, 15 (88%) out of the 17 patients restored sinus rhythm after 1 to 68 days (average of 21 days). In 12 (80%) of the 15 patients, sinus rhythm was maintained for an average of 23.6 months (range of 1 to 62 months) follow‐up period. Although torsade de pointes was not recognized, a marked QT prolongation (0.60 sec) was observed in one patient during the administration of bepridil at a daily dose of 200 mg. In this patient, QT interval was normalized (0.45 sec) after reduction of bepridil to 150 mg daily.Conclusion: Bepridil treatment may be safe and effective for class I drug‐induced AFL in patients with paroxysmal AF to restore and maintain sinus rhythm as an alternative therapy for catheter ablation. However, the QT interval must be carefully monitored during this medication.

Clinical Efficacy of Bepridil for Class I Antiarrhythmic Drug-Induced Atrial Flutter in Patients with Paroxysmal Atrial Fibrillation

Background: Class I antiarrhythmic drugs can promote the organization of atrial fibrillation (AF) and sometimes converts AF into atrial flutter (AFL) concomitant with difficulty of rate control. We studied the usefulness of Bepridil, which exhibits a class III-like effect, for class I drug-induced AFL in patients with paroxysmal AF. Methods: The study population consisted of 17 consecutive patients (15 men, mean age 65 ± 8 years) with AFL converted from paroxysmal AF following oral treatment of class IA or IC antiarrhythmic agents including pilsicainide (n = 8), cibenzoline (n = 5), flecainide (n = 2), aprindine (n = 1), and propafenone with cibenzoline (n = 1). After the occurrence of AFL, class I drug was replaced by bepridil with a dose of 100–200 mg per day in all patients. Results: After the treatment with bepridil, 15 (88%) out of the 17 patients restored sinus rhythm after 1 to 68 days (average of 21 days). In 12 (80%) of the 15 patients, sinus rhythm was maintained for an average of 23.6 months (range of 1 to 62 months) follow-up period. Although torsade de pointes was not recognized, a marked QT prolongation (0.60 sec) was observed in one patient during the administration of bepridil at a daily dose of 200 mg. In this patient, QT interval was normalized (0.45 sec) after reduction of bepridil to 150 mg daily. Conclusion: Bepridil treatment may be safe and effective for class I drug-induced AFL in patients with paroxysmal AF to restore and maintain sinus rhythm as an alternative therapy for catheter ablation. However, the QT interval must be carefully monitored during this medication.

Brugada Pattern Electrocardiogram Associated with Supratherapeutic Phenytoin Levels and the Risk of Sudden Death

The emergence of Brugada pattern on electrocardiogram in response to class IA or IC antiarrhythmic agents is widely utilized to diagnose concealed Brugada syndrome and recognized as a risk factor for sudden death. Phenytoin, a class IB antiarrhythmic agent, has not been reported to induce Brugada pattern. We report a patient who presented with Brugada electrocardiogram at supratherapeutic phenytoin level. Considering that patients with syncope may falsely be labeled to have seizures and some epilepsy patients are at increased risk of sudden death, all patients with supratherapeutic phenytoin level should be evaluated with an electrocardiogram for emergence of Brugada pattern.

Mode-dependent inhibition by quinidine of Na+-Ca2+ exchanger current from guinea-pig isolated ventricular myocytes

1. The aim of the present study was to determine whether or not the class Ia anti-arrhythmic agent quinidine modulates ionic current (INaCa) generated by the sarcolemmal Na+-Ca2+ exchanger of adult ventricular cardiac myocytes. 2. Selective whole-cell voltage-clamp recordings of INaCa were made from guinea-pig ventricular myocytes, with major interfering currents blocked. The INaCa was measured as the ionic current sensitive to 10 mmol/L external Ni2+ during a descending voltage ramp protocol. 3. The effects of quinidine concentrations in the range 10-100 micromol/L were studied. Quinidine produced a concentration-dependent partial blockade of outward INaCa, generated by reverse-mode exchange. At +60 mV, 100 micromol/L quinidine blocked INaCa by 33.0 +/- 4.1% (mean+/-SEM; n = 4). This was the maximal concentration that we were able to test, because concentrations of quinidine higher than 100 micromol/L were found to be toxic to cells under our conditions. The drug did not produce any significant inhibition of inward INaCa (generated by forward-mode exchange). 4. The Ni2+-insensitive residual current was not significantly altered by quinidine at any membrane potential, confirming that the inhibitory effects of quinidine we observed could be attributed to an action on the Na+-Ca2+ exchanger. 5. For the purpose of comparison, quinidine was tested against L-type Ca current (ICa,L). It blocked peak ICa,L at 0 mV, with an IC50 of 14.9 +/- 1.5 micromol/L. Thus, quinidine was less potent against the exchanger than against ICa,L. 6. Our data suggest that quinidine preferentially inhibits the Naout/Cain mode of exchanger function. We conclude that this drug is a weak inhibitor of ventricular INaCa and that the inhibitory effect is mode dependent.

Involvement of K + channel in procainamide-induced relaxation of bovine tracheal smooth muscle

The relaxant effect of procainamide, a class Ia antiarrhythmic agent, was examined in bovine tracheal smooth muscle. Procainamide produced concentration-dependent decreases in tension and full relaxation in the preparations contracted with methacholine (0.3 μM). By comparison, in preparations contracted with 40 mM K +, procainamide had only slight relaxant effects. The relaxant effects of cromakalim and salbutamol on 40 mM K +-contracted preparations were significantly ( P<0.01) smaller than those on 0.3 μM methacholine-contracted ones. On the other hand, the concentration–response relationships for quinidine, lidocaine, mexiletine and propafenone were not so dramatically different between 0.3 μM methacholine- and 40 mM K +-contracted preparations. Tetraethylammonium (300 μM), iberiotoxin (30 nM) and Ba 2+ (1 mM) significantly ( P<0.05) attenuated the relaxant effects of procainamide on methacholine-induced contractions, whereas apamin (100 nM), 4-aminopyridine (300 μM), and glibenclamide (10 μM) did not affect them. The inhibitory effect of a combination of iberiotoxin and Ba 2+ was greater than that of iberiotoxin or Ba 2+ alone ( P<0.01). These results suggest that the activation of at least two types of K + (maxi-K + and inward rectifier K +) channels contributes to the procainamide-induced relaxation of bovine tracheal smooth muscle.

Disopyramide block of K ATP channels is mediated by the pore-forming subunit

The class Ia antiarrhythmic agent disopyramide blocks native ATP-sensitive K + (K ATP) channels at micromolar concentrations. The K ATP channel is a complex of a pore-forming inwardly rectifying K + channel (Kir6.2) and a sulfonylurea receptor (SUR). The aim of the present study was to further localize the site of action of disopyramide. We have used a C-terminal truncated form of Kir6.2 (Kir6.2Δ26), which — in contrast to Kir6.2 — expresses independently of SUR. Kir6.2Δ26 channels were expressed in African green monkey kidney COS-7 cells, and enhanced green fluorescent protein (EGFP) cDNA was used as a reporter gene. EGFP fluorescence was visualized by a laser scanning confocal microscope. Disopyramide applied to the cytoplasmic membrane surface of inside-out patches inhibited Kir6.2Δ26 channels half-maximally at 7.1 μM (at pH 7.15). Lowering the intracellular pH to 6.5 potentiated the inhibition of Kir6.2Δ26 channels by disopyramide. These observations suggest that disopyramide directly blocks the pore-forming Kir6.2 subunit, in particular at reduced intracellular pH values that occur under cardiac ischaemia.

ASSESSMENT OF BIOAVAILABILITY FROM PHARMACOLOGICAL RESPONSES

A novel method of assessing the extent of bioavailability (EBA) of drugs from pharmacological data was presented. Disopyramide, a class Ia antiarrhythmic agent, arginine-vasopressin (AVP), a nona-peptide hormone, and human insulin were used as the model drugs. The prolongation of QT interval, the anti-diuretic response and the hypoglycemic response were used as the pharmacological indexes of disopyramide, AVP and human insulin, respectively. After intra-vascular administration (I.V. bolus, short-term infusion or long-term infusion) of drugs to the rats, the relationship between blood (plasma or serum) concentrations and their pharmacological responses were described on the basis of an integrated pharmacokinetic-pharmacodynamic (PK-PD) model. A sigmoid Emax model or a linear model was applied to describe the drugreceptor interaction. Pharmacological responses after intra-vascular administration of these 3 drugs were reasonably described by the PK-PD model. Since PK-PD relationship after oral administration was assumed to be identical with that after intra-vascular administration, the PK-PD model obtained under I.V. bolus study was used to assess the extent of oral bioavailability (EBAp.o.). The EBAp.o. values, estimated from pharmacological effects after oral administration of disopyramide (25 mg/kg to 100 mg/kg) was 96.6% and this value were almost identical with the actual EBAp.o. values (57.6 to 99.4%). However, the EBAp.o. values, estimated from pharmacological effects after oral administration of AVP were significantly underestimated the actual EBAp.o. values. While, the EBA values, estimated from pharmacological effects after subcutaneous administration of human insulin using an osmotic mini-pump were significantly overestimated the actual EBA values. These results indicated that PK-PD relationship was significantly influenced by intra-vascular input rate of drugs, especially the peptide drugs. Then we re-estimated the EBA values using the PK-PD model constructed under the long-term infusion study, and obtained reasonable results. From these results, we concluded that the EBA was reasonably predicted by a PK-PD model, provided that appropriate pharmacological effects and appropriate intra-vascular dosing rate as a reference formulation are available. The method may be the alternative to methods based on plasma concentrations, when drug concentration cannot be measured and when appropriate pharmacological data are available.

Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic β-cells

The effect of metabolic inhibition on the blocking of beta-cell ATP-sensitive K+ channels (KATP channels) by glibenclamide was investigated using a patch-clamp technique. Inhibition of KATP channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1 microM) of ATP applied in the inside-out mode, KATP channel activity was not fully abolished, even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete KATP channel inhibition under 10 microM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits KATP channel activity in a dose-dependent manner and completely blocks it, even under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, KATP channel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic beta-cells, probably because of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.

Clinical Evaluation of Celiprolol in the Treatment of Atrial Tachyarrhythmias

The results of the Cardiac Arrhythmia Suppression Trial warn against the use of class Ia and Ic antiarrhythmic agents as first-line therapy for arrhythmia. The objective of the present study was to evaluate the efficacy of celiprolol, a β-blocker, in patients with supraventricular arrhythmia. Celiprolol (200 mg/day) was administered for a mean duration of 90 days (range: 32 to 128 days) to 30 patients with supraventricular arrhythmia, including 7 with chronic atrial fibrillation associated with bradycardia, 18 with paroxysmal atrial fibrillation, and 5 with premature atrial contraction (PAC). The antiarrhythmic effect of celiprolol was assessed based on changes in symptoms and heart rate determined by Holter ECG. After celiprolol therapy, arrhythmic symptoms improved in 60% of the patients. The post-treatment Holter ECG showed a decrease in the daily maximum, but not minimum, heart rate, a good control of heart rate in patients with atrial fibrillation, and a decrease of PACs. Importantly, bradycardia improved even in patients with chronic atrial fibrillation who concomitantly received digitalis. Celiprolol exerted an adequate antihypertensive effect in hypertensive patients but did not affect normal blood pressure. In conclusion, celiprolol may be used as first-line therapy for the treatment of patients with supraventricular arrhythmia.

Electrophysiologic Mechanisms of Antiarrhythmic Efficacy of a Sotalol and Class Ia Drug Combination: Elimination of Reverse Use Dependence

Objectives. We sought to determine the electrophysiologic mechanisms explaining the efficacy of combination therapy with dl-sotalol and a type Ia drug in the treatment of ventricular tachycardia (VT).Background. Combination antiarrhythmic drug therapy with low dose dl-sotalol plus a type Ia antiarrhythmic agent has been shown to prevent spontaneous and induced VT. The mechanisms underlying the efficacy of this drug combination have not been fully elucidated.Methods. We studied 32 patients with spontaneous sustained VT by using programmed electrical stimulation in the drug-free condition and after treatment with dl-sotalol (average dose [mean ± SE] 151 ± 8 mg/day) and a class Ia agent (quinidine, 1,337 ± 59 mg/day, or procainamide, 2,083 ± 327 mg/day). Sustained VT was induced in all patients at baseline study, and induction was reattempted during drug therapy. Monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (ERP) were recorded with use of a contact electrode.Results. Ventricular ERP increased from 258 ± 4 ms at baseline to 310 ± 6 ms at a 600-ms drive cycle length (DCL600) with treatment (p < 0.001). APD90increased from 288 ± 6 ms by +10.1% at DCL600 and from 267 ± 7 ms by +13.3% at a 400-ms drive cycle length (DCL400) (p < 0.001). Paced QRS duration increased from 141 ± 3 to 158 ± 6 ms at DCL400 (p < 0.05).At baseline, the shortest achieved coupling interval between successive propagated extrastimuli decreased progressively with respect to the first extrastimulus, following double and triple extrastimuli, at both DCL600 (−14.0% and −20.0%, respectively) and at DCL400 (−16.4% and −22.4%, respectively). This “peeling back” of refractoriness was attenuated on therapy with sotalol plus a class Ia antiarrhythmic agent to −6.7% and −10.5% (DCL600, p < 0.05), and −8.1%, −9.5% (DCL400, p < 0.05), for double and triple extrastimuli, respectively. The absolute prolongation of functional refractory periods by the drug combination increased with successive extrastimuli, from 55 ± 6 ms for the V1V2interval to 75 ± 6 ms for V2V3and 67 ± 6 ms for V3V4at DCL600, and from 51 ± 5 ms for V1V2to 69 ± 6 ms for V2V3and 74 ± 7 ms for V3V4at DCL400 (p < 0.001).Conclusions. The combination of low dose sotalol and a class Ia agent greatly prolongs refractoriness. The magnitude of the effect increases at shorter coupling intervals.(J Am Coll Cardiol 1997;29:100–5)>

Comparative efficacy of intravenous ibutilide versus procainamide for enhancing termination of atrial flutter by atrial overdrive pacing

This study compares the influence of intravenous ibutilide, a class III antiarrhythmic agent, with procainamide, a class IA antiarrhythmic agent, and with placebo on its ability to terminate atrial flutter using rapid atrial pacing. Fifty-nine episodes of atrial flutter in 54 patients who failed to terminate with an intravenous infusion of ibutilide, procainamide, or placebo alone underwent attempts at pacing termination using a standard protocol of burst atrial overdrive pacing. Atrial flutter cycle length and atrial monophasic action potential duration recorded from the right atrium during atrial flutter were measured at baseline and following infusion of ibutilide, procainamide, or placebo. Both ibutilide and procainamide significantly enhanced (p < 0.001) pacing-induced termination of atrial flutter compared with placebo. Pacing converted 2 of 11 patients (18%) who received placebo, 13 of 15 patients (87%) who received ibutilide, and 29 of 33 patients (88%) who received procainamide to sinus rhythm. Ibutilide and procainamide compared with placebo markedly reduced (p < 0.001) the incidence of pacing-induced atrial fibrillation. The atrial flutter cycle length was prolonged significantly less (p < 0.001), and the atrial monophasic action potential duration was increased significantly more (p < 0.001) by ibutilide than by procainamide. Although the electrophysiologic changes induced by these antiarrhythmic agents contributed to facilitating pacing-induced termination, neither tachycardia cycle length nor action potential duration were useful predictors of the ability of pacing to terminate atrial flutter. In conclusion, despite differing electrophysiologic effects, the use of intravenous ibutilide or procainamide enhances the termination of atrial flutter by atrial overdrive pacing.

Usefulness of QTc dispersion in interpreting exercise electrocardiograms

The ECG QT interval is a measure of the duration ofventricular repolarization and is sensitive to myocardial ischemia. The interlead variation in the 12-lead ECG is referred ~to as QT dispersion. The QT or QTc dispersion is a noninvasive measure of regional variation in ventricular recovery time. Increased dispersion ofventricular recovery time has been associated with increased risk of serious arrhythmias, 1-3 particularly in conditions in which QT is prolonged, including congenital long QT syndrome, 4 drug toxicity, hypertrophic cardiomyopathy, 5 and post-myocardial infarction arrhythmias. 6 Class Ia antiarrhythmic agents are associated with increased nonhomogeneous, regional QT-interva ! prolongation, giving rise to widened QT dispersion, and that this widened dispersion is associated with increased risk of torsades de pointes. On the other hand, class III drugs such as amiodarone and sotalol have a homogeneous prolongation of QT and are not associated with torsades de pointes. 7 The QT dispersion is also increased in patients with myocardial infarction compared with dispersion in control subjects and may be reduced by the class III antiarrhythmic agent. This pattern may account for the salutary effects of class III antiarrhythmic agents on ventricular arrhythmias after myocardial infarction. An increase in interlead QT variability or dispersion on the surface of 12-lead ECG has been associated with regional ischemia and wall motion abnormality, s Some data support the theory that successful thrombolysis is associated with less QT dispersion in post-acute myocardial infarction patients. 9 We hypothesized that exercise-induced myocardial ischemia could change QT interval regionally in the area of ischemia, giving rise to an increased QT dispersion in the 12-lead electrocardiogram, which may be helpful in the interpretation of exercise stress tests. Methods. We studied 56 unselected patients (55 men and 1 woman) who had undergone symptom-limited treadmill exercise tests for clinical indications and were not taking antiarrhythmic agents. On the basis of the results of the stress test and the results of coronary angiograms in patients with positive test results, patients were divided into three groups: (1) The normal (NL) group consisted of 23 patients with a mean age of 51 -+ 11 years who had nor-

Role of intracellular calcium in the antiarrhythmic effect of procainamide during ventricular fibrillation in rat hearts

Increased intracellular calcium (calcium overload) is considered one of the factors that can initiate ventricular fibrillation. In addition, ventricular fibrillation itself can cause and possibly maintain calcium overload. The goal of this study was to determine whether the class IA antiarrhythmic agent procainamide can reduce calcium overload during ventricular fibrillation and, if so, whether this reduction could be responsible for the recovery of the left ventricular function after defibrillation. For this purpose, the effects of 0.1 mmol/L of procainamide perfusion on left ventricular developed pressure, cardiac rate, and intracellular calcium during pacing-induced ventricular fibrillation were measured in isolated perfused rat hearts. Intracellular calcium was assessed by surface fluorometry after indo 1 loading. The concentration of procainamide was selected such that approximately half of the hearts would functionally recover from fibrillation. Cardiac rate and intracellular calcium were compared among four groups, depending on both the perfusate used and the recovery of left ventricular developed pressure at the end of the experiment. We found that procainamide reduced intracellular calcium to steady-state levels in hearts in which left ventricular function completely recovered (developed pressure >67% of the steady-state value). However, intracellular calcium remained elevated in partially recovered hearts (33% ≤ pressure ≤ 67%) and in nonrecovered hearts (pressure <33%). Thus procainamide can reduce calcium overload during ventricular fibrillation, and this reduction could be responsible for the recovery of left ventricular function after defibrillation. This reduction was use dependent, that is, dependent on high cardiac rates during fibrillation rather than on the decrease of cardiac rates before or during defibrillation.

The routine use of class IA antiarrhythmic agents to prevent recurrent atrial fibrillation should be abandoned

The routine use of class IA antiarrhythmic agents to prevent recurrent atrial fibrillation should be abandoned