QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization.

The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double-blind study in healthy individuals who received isavuconazole (after 2-day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post-hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L-type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein-bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose- and plasma concentration-related manner. There were no serious treatment-emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval.

Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall.

BACKGROUND: This study examined the role of phase 2 early afterdepolarization (EAD) in producing a trigger to initiate torsade de pointes (TdP) with QT prolongation induced by dl-sotalol and azimilide. The contribution of transmural dispersion of repolarization (TDR) to transmural propagation of EAD and the maintenance of TdP was also evaluated. METHODS AND RESULTS: Transmembrane action potentials from epicardium, midmyocardium, and endocardium were recorded simultaneously, together with a transmural ECG, in arterially perfused canine and rabbit left ventricular preparations. dl-Sotalol preferentially prolonged action potential duration (APD) in M cells dose-dependently (1 to 100 micromol/L), leading to QT prolongation and an increase in TDR. Azimilide, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 micromol/L but shortened them at 30 micromol/L. Unlike dl-sotalol, azimilide (>3 micromol/L) increased epicardial APD markedly, causing a diminished TDR. Although both dl-sotalol and azimilide rarely induced EADs in canine left ventricles, they produced frequent EADs in rabbits, in which more pronounced QT prolongation was seen. An increase in TDR by dl-sotalol facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left ventricles. Of note, although azimilide (3 to 10 micromol/L) increased APD more than dl-sotalol, its EADs often failed to propagate transmurally, probably because of a diminished TDR. CONCLUSIONS: This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under QT prolongation.

Left ventricular hypertrophy decreases slowly but not rapidly activating delayed rectifier potassium currents of epicardial and endocardial myocytes in rabbits.

BACKGROUND: Delayed rectifier K(+) currents are critical to action potential (AP) repolarization. The present study examines the effects of left ventricular hypertrophy (LVH) on delayed rectifier K(+) currents and their contribution to AP repolarization in both epicardial (Epi) and endocardial (Endo) myocytes. METHODS AND RESULTS: VH was induced in rabbits by a 1-kidney removal, 1-kidney vascular clamping method. Slowly (I(Ks)) and rapidly (I(Kr)) activating delayed rectifier K(+) currents were recorded by the whole-cell patch-clamp technique, and APs were recorded by the microelectrode technique. In normal rabbit left ventricular myocytes, I(Ks) densities were larger in Epi than in Endo (1.1+/-0.1 versus 0.43+/-0.07 pA/pF), whereas I(Kr) density was similar between Epi and Endo (0.31+/-0.05 versus 0.36+/-0.07 pA/pF) at 20 mV. LVH reduced I(Ks) density to a similar extent (approximately 40%) in both Epi and Endo but had no significant effect on I(Kr) in either Epi or Endo. Consequently, I(Kr) was expected to contribute more to AP repolarization in LVH than in control. This was confirmed by specific I(Kr) block with dofetilide, which prolonged AP significantly more in LVH than in control (31+/-3% versus 18+/-2% in Epi; 53+/-6% versus 32+/-4% in Endo at 2 Hz). In contrast, L-768,673 (a specific I(Ks) blocker) prolonged AP less in LVH than in control. The very small I(Ks) density in Endo with LVH is consistent with the greater incidence of early afterdepolarizations induced in this region by dofetilide. CONCLUSIONS: LVH induces a decrease in I(Ks) density and increases the propensity to develop early afterdepolarizations, especially in Endo.

Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery.

BACKGROUND: Atrial arrhythmias occur commonly after cardiac surgery and are a cause of significant morbidity and increased hospital costs, yet there is no well-studied treatment strategy to deal with them expeditiously. The purpose of this study was to determine the efficacy and safety of ibutilide fumarate, an approved drug for the rapid conversion of atrial fibrillation and flutter, in patients after cardiac surgery. METHODS AND RESULTS: Patients with atrial fibrillation or flutter occurring 1 to 7 days after surgery and lasting 1 hour to 3 days were randomized to receive two 10-minute blinded infusions of placebo or 0.25, 0.5, or 1.0 mg of ibutilide fumarate. Treatment was considered successful if sinus rhythm was restored for any period of time by hour 1.5. A total of 302 patients were randomized, 201 with fibrillation and 101 with flutter. Treatment with ibutilide resulted in significantly higher conversion rates than placebo, and efficacy was dose related (placebo 15%; ibutilide 0.25 mg 40%, 0.5 mg 47%, and 1.0 mg 57%). Conversion rates at all doses were higher for atrial flutter than for atrial fibrillation. Mean time to conversion decreased as the dose was increased. Polymorphic ventricular tachycardia was the most serious adverse effect and occurred in 1.8% of the ibutilide-treated patients compared with 1.2% of patients who received placebo. CONCLUSIONS: Ibutilide is a useful and safe treatment alternative for the atrial arrhythmias that occur after cardiac surgery.

Intravenous amiodarone.

Intravenous amiodarone was approved in 1995 for the treatment of malignant and resistant ventricular arrhythmia. Although it is an "old drug," much has been learned recently about this complex drug and its application in a variety of cardiac arrhythmias. The objectives of this review were to summarize what is known about intravenous amiodarone, including its pharmacologic and electrophysiologic effects, to review its efficacy for the treatment of patients with highly malignant ventricular arrhythmia and to provide specific information about its clinical use for this and other indications. The studies that were reviewed were selected on the basis of time published (from 1983 to 1995) and the completeness of information provided regarding patient clinical characteristics, drug dosing and methods of evaluation, efficacy analyses, long-term follow-up and complications. The full data from the three controlled trials that formed the basis of the drug's approval are contained in published reports that were also extensively reviewed. Intravenous amiodarone has demonstrable efficacy for the treatment of frequently recurrent destabilizing ventricular tachycardia and ventricular fibrillation, with suppression rates of 63% to 91% in uncontrolled trials. The three pivotal trials confirmed these findings and demonstrated a dose-response relation, with at least comparable efficacy to bretylium, a drug with a similar indication. The safety profile has also been well described; cardiovascular adverse effects are the most frequent, especially hypotension. Intravenous amiodarone is a useful addition to the drugs available for the treatment of patients with very severe ventricular arrhythmia. Its use in patients with other rhythm disorders appears promising, but final recommendations must await development of definitive data from ongoing clinical trials.

Late induction of tachycardia in patients with ventricular fibrillation associated with acute myocardial infarction.

A prospective study was made of 57 asymptomatic patients, 1 to 24 months after acute myocardial infarction, 17 with (Group I) and 40 without (Group II) ventricular fibrillation during the acute event. None of the 57 patients had symptomatic arrhythmias, uncontrolled heart failure or unstable angina. There was no significant difference between the two patient groups in time from acute myocardial infarction, medication used or left ventricular ejection fraction. Repetitive forms of arrhythmia (Lown grade 4) were more prevalent (29 versus 16%, not significant) during 24 hour ambulatory monitoring in patients in Group I (ventricular fibrillation group). Programmed extrastimulation was performed using 1 to 3 twice-threshold, 2 ms decremental extrastimuli delivered during right ventricular drive. Of the 17 patients in Group I, 8 had no induced arrhythmia (less than or equal to 4 extra responses), 4 had nonsustained ventricular tachycardia and 5 had sustained ventricular tachycardia (degenerating into ventricular fibrillation requiring electrical reversion in 4). None of the 40 patients in Group II had induced sustained ventricular tachycardia (p less than 0.005), although 9 had nonsustained ventricular tachycardia. Patients with ventricular fibrillation during acute myocardial infarction may have an increased risk for ventricular tachycardia or ventricular fibrillation that may be exposed by programmed electrical stimulation even when not yet clinically manifest.

Effect of calcium-binding additives on ventricular fibrillation and repolarization changes during coronary angiography.

Ventricular fibrillation during coronary angiography with Renografin-76 (meglumine sodium diatrizoate) has been attributed to the calcium-binding additives sodium citrate and sodium ethylenediaminetetraacetic acid (EDTA), which may produce repolarization changes manifested as prolongation of the QT interval. Angiovist-370 is a newer form of meglumine sodium diatrizoate that contains calcium EDTA as its additive and thus has a decreased calcium-binding effect. Eight hundred sixteen patients were prospectively randomized to receive either Renografin-76 or Angiovist-370. Ventricular fibrillation occurred in 10 of 410 patients receiving Renografin-76 and in 0 of 406 patients given Angiovist-370 (p less than 0.0005). Clinical data were analyzed without knowledge of other data in the 10 patients treated with Renografin-76 who had ventricular fibrillation (Group I), 103 randomly selected patients who also received Renografin-76 but had no ventricular fibrillation (Group II) and 108 randomly selected patients given Angiovist-370 (Group III). Of several variables examined, only the QT interval differentiated patients receiving Renografin-76 and Angiovist-370. The mean corrected QT interval (QTc interval) before coronary angiography was slightly but not significantly (p = 0.7) higher in Group I than in Groups II and III. Ten seconds after the first left coronary artery injection it was more prolonged in Groups I and II (0.552 and 0.561 second, respectively) than in Group III (0.448 second) (p less than 0.00005). Similarly, 10 seconds after the first right coronary artery injection it was significantly longer in Groups I and II (0.545 and 0.544 second) than in Group III (0.477 second) (p less than 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of oral propafenone on defibrillation and pacing thresholds in patients receiving implantable cardioverter-defibrillators. Propafenone Defibrillation Threshold Investigators.

OBJECTIVES: The effects of propafenone, a predominantly class IC antiarrhythmic drug, on defibrillation and pacing thresholds were evaluated in patients undergoing cardioverter-defibrillator implantation. BACKGROUND: Previous studies have shown that the class IC agents encainide and flecainide may increase the energy requirements for pacing and defibrillation. Animal studies with propafenone have shown inconsistent results regarding its effect on defibrillation energy requirements. This report investigated the effects of propafenone on defibrillation and pacing thresholds in humans. METHODS: After cardioverter-defibrillator implantation, 47 patients were enrolled in a double-blind, three-way parallel, randomized trial of 450 mg/day (Group 1) or 675 mg/day (Group 2) of oral propafenone or placebo (Group 3) for 3 to 7 days. Predischarge defibrillation and pacing thresholds after treatment were compared with baseline thresholds obtained at implantation. RESULTS: There was no statistically significant difference between implantation and predischarge defibrillation thresholds in the three groups (Group 1: [mean +/- SE] 11.0 +/- 1.3 vs. 12.1 +/- 1.5 J; Group 2: 11.5 +/- 1.1 vs. 13.6 +/- 1.3 J; Group 3: 12.5 +/- 1.2 vs. 13.3 +/- 1.6 J), and no significant difference between treatment groups was found with a 0.86 power to detect a 5-J difference between groups. Paired pulse width pacing thresholds at 2.8 V were compared in 14 patients. A small increase of 0.02 ms was noted at predischarge testing in patients treated with propafenone and placebo. CONCLUSIONS: Short-term oral propafenone (450 and 675 mg/day) does not significantly affect defibrillation or pacing thresholds. Concomitant use of propafenone in patients with implantable cardioverter-defibrillators with recurrent ventricular or atrial tachyarrhythmias should not interfere with proper device function.

Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation.

OBJECTIVES: This multicenter study compared the efficacy and safety of ibutilide versus procainamide for conversion of recent-onset atrial flutter or fibrillation. BACKGROUND: Ibutilide fumarate is an intravenous (IV) class III antiarrhythmic agent that has been shown to be significantly more effective than placebo in the pharmacologic conversion of atrial flutter and fibrillation to sinus rhythm. Procainamide is commonly used for conversion of recent-onset atrial fibrillation to normal sinus rhythm. METHODS: One hundred twenty-seven patients (age range 22 to 92 years) with atrial flutter or fibrillation of 3 h to 90 days' (mean 21 days) duration were randomized to receive either two 10-min IV infusions of 1 mg of ibutilide fumarate, separated by a 10-min infusion of 5% dextrose in sterile water, or three successive 10-min IV infusions of 400 mg of procainamide hydrochloride. RESULTS: Of the 127 patients, 120 were evaluated for efficacy: 35 (58.3%) of 60 in the ibutilide group compared with 11 (18.3%) of 60 in the procainamide group had successful termination within 1.5 h of treatment (p < 0.0001). Seven patients were found to have violated the protocol and were not included in the final evaluation. In the patients with atrial flutter, ibutilide had a significantly higher success rate than procainamide (76% [13 of 17] vs. 14% [3 of 22], p=0.001). Similarly, in the atrial fibrillation group, ibutilide had a significantly higher success rate than procainamide (51% [22 of 43] vs. 21% [8 of 38], p=0.005). One patient who received ibutilide, which was found to be a protocol violation, had sustained polymorphic ventricular tachycardia requiring direct current cardioversion. Seven patients who received procainamide became hypotensive. CONCLUSIONS: This study establishes the superior efficacy of ibutilide over procainamide when administered to patients to convert either atrial fibrillation or atrial flutter to sinus rhythm. Hypotension was the major adverse effect seen with procainamide. A low incidence of serious proarrhythmia was seen with the administration of ibutilide occurring at the end of infusion.

Pharmacological effects of antiarrhythmic drugs. Review and update.

Most antiarrhythmic drugs are potent compounds with a relatively narrow therapeutic index. When prescribed judiciously, they can have a key role in enhancing or prolonging the lives of patients with most common arrhythmias. But when misprescribed, through selection of an inappropriate drug or dosage regimen, the end result may range from inadequate control of the arrhythmia to a proarrhythmic effect. Ultimately, the optimal use of antiarrhythmic drug therapy depends in large part on understanding the pharmacodynamics and pharmacokinetics of each antiarrhythmic drug. Despite the common classification of antiarrhythmic drugs into class I, II, III, or IV, each drug has a unique pharmacological profile and must not be considered interchangeable with other members of its class. Likewise, each patient is unique with respect to the innumerable factors that can alter the pharmacokinetics of an antiarrhythmic drug, including coexisting diseases, concurrent drug therapies, and endogenous or age-related metabolic variations. This article provides an overview of the key pharmacodynamic and pharmacokinetic characteristics of the major antiarrhythmic drugs in use. It also offers specific examples that may be used to ensure that patients receive the most appropriate therapy.

Gender differences in device therapy for malignant ventricular arrhythmias.

BACKGROUND: Several recent reports have suggested a gender bias in the treatment of cardiovascular disease. It is not clear whether this is true in the treatment of malignant ventricular arrhythmias. OBJECTIVES: To perform a retrospective chart review of 130 patients evaluated for malignant ventricular arrhythmias between July 1990 and June 1992. To compare baseline cardiovascular and clinical parameters and treatment modalities, including cardioverter-defibrillator implantation rates, between women and men. RESULTS: There was no significant difference in the percentage of women and men who were advised to have cardioverter-defibrillator implantation (61% vs 53%) or who underwent cardioverter-defibrillator implantation (46% vs 52%). Women had a lower incidence of coronary artery disease than men (61% vs 85%, P < .01), a lower incidence of myocardial infarction (46% vs 75%, P < .01), and a higher mean left ventricular ejection fraction (38% vs 32%, P = .02). Of patients with indications for cardioverter-defibrillator implantation, significantly more women refused a device than men (19% vs 2%, P = .01), and significantly more women were considered medically ineligible for cardioverter-defibrillator implantation despite having less severe heart disease as a group (12% vs 0%, P = .04). This resulted in significantly fewer women receiving a defibrillator than men with similar indications (18 of 26 women vs 47 of 48 men, P < .01). Of patients who received defibrillators, significantly more women received investigational devices (50%) than men (21%) (P < .05) (35% of women and 19% of men with indication for cardioverter-defibrillator implantation). In-hospital mortality was low in both groups (women, 0%; men, 4%). The 30-month mortality in patients with indications for device intervention was similar in both groups (women, 21%; men, 19%). CONCLUSIONS: No evidence of difference was found between women and men in the rates of recommendation for, or implantation of, implantable cardioverter-defibrillators. Women refused device implantation more often than men, and they may be considered medically ineligible for device implantation more than men. This combination results in fewer women with medical indications for cardioverter-defibrillator implantation receiving defibrillators than men. This difference does not appear to be associated with increased short-term mortality.

New guidelines for potassium replacement in clinical practice: a contemporary review by the National Council on Potassium in Clinical Practice.

This article is the result of a meeting of the National Council on Potassium in Clinical Practice. The Council, a multidisciplinary group comprising specialists in cardiology, hypertension, epidemiology, pharmacy, and compliance, was formed to examine the critical role of potassium in clinical practice. The goal of the Council was to assess the role of potassium in terms of current medical practice and future clinical applications. The primary outcome of the meeting was the development of guidelines for potassium replacement therapy. These guidelines represent a consensus of the Council members and are intended to provide a general approach to the prevention and treatment of hypokalemia.

Decreased vulnerability to ventricular fibrillation by vasodilator-induced baroreceptor sensitisation.

Vulnerability to ventricular fibrillation (VF) is affected by changes in systemic arterial blood pressure which are mediated through the sympathetic nervous system. We determined that small doses of a vasodilator drug can abolish the enhanced ventricular vulnerability induced by norepinephrine infusion. Noradrenaline (0.5 micrograms X kg-1 X min-1) caused a fall in ventricular fibrillation threshold from 30 to 20 mA (P less than 0.001). Pretreatment with prostaglandin E1, I2 or nitroglycerin at doses which reduced mean arterial blood pressure by 0.7 to 1.3 kPa (5 to 10 mmHg) abolished the enhanced vulnerability produced by noradrenaline. Following baroreceptor denervation, these agents no longer afforded protection against the profibrillatory action of noradrenaline. We conclude that small doses of vasodilator agents can augment ventricular electrical stability. The mechanism for this protective action appears to be a decrease in cardiac sympathetic tone resulting from vasodilatation of baroreceptor areas.

Management and prevention of atrial fibrillation after cardiovascular surgery.

Atrial arrhythmias occur frequently after cardiac surgery. This article discusses the incidence of postoperative atrial arrhythmia as well as its prognosis, potential mechanisms of pathogenesis, and management. Prophylactic therapy for postoperative atrial arrhythmia is recommended because of the frequency of occurrence and the ease with which therapies can often be implemented. Treatments with pharmacologic and nonpharmacologic modalities are described. Management strategies for atrial arrhythmias that occur postoperatively, including pharmacologic and nonpharmacologic measures as well as anticoagulation recommendations, are discussed.

Generic antiarrhythmics are not therapeutically equivalent for the treatment of tachyarrhythmias.

The consequences of antiarrhythmic drug formulation substitution were assessed by survey of 130 experts on arrhythmias. Fifty-four arrhythmia recurrences, 7 proarrhythmic events, and 3 deaths resulting from generic substitution are reported, thus raising serious concerns about both antiarrhythmic drug substitution and the adequacy of the generic drug approval process.

Influence of intracoronary platelet aggregation on ventricular electrical properties during partial coronary artery stenosis.

Several clinical studies suggest that drugs which interfere with platelet function may protect persons at risk for sudden death. However, there is no direct evidence that intracoronary platelet aggregation produces cardiac arrhythmias. Induction of fixed partial coronary stenoses in dogs resulted in spontaneous cyclical reductions in coronary blood flow of 21 to 81% (p less than 0.01). These changes are known to be associated with the formation and distal embolization of platelet aggregates. These reductions in coronary blood flow were accompanied by significant decreases in the repetitive extrasystole (-40%) and ventricular fibrillation (-38%) thresholds. Prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet activation, in increasing doses of from 25 to 100 ng/kg/min caused a stepwise decrease in the frequency and magnitude of coronary blood flow fluctuations and restored the vulnerable period thresholds to control levels. Indomethacin (5 mg/kg), an inhibitor of cyclo-oxygenase activation and platelet thromboxane A2 production, produced similar results. The mechanism of coronary blood flow reduction appears to be mechanical blockade of the vessel lumen by platelet thrombi and production of myocardial ischemia. These results suggest that intracoronary platelet aggregation contributes to electrical destabilization of the myocardium and may predispose to ventricular fibrillation. A model is thus available for further investigating the role of platelets and antiplatelet drugs in modulating ventricular electrical stability.

Safety and risk/benefit analysis of ibutilide for acute conversion of atrial fibrillation/flutter.

Safety data were reviewed from several controlled clinical trials of ibutilide, a new class III antiarrhythmic drug recently approved for the acute interruption of atrial fibrillation and flutter. Noncardiovascular adverse effects of ibutilide were similar in frequency to those with placebo. Cardiovascular adverse effects occurred in 24.9% of 586 ibutilide-treated patients as compared with 22.2% of 108 sotalol-treated patients, and 7.1% of 127 patients who received placebo. Polymorphous ventricular tachycardia, diagnosed as torsades de pointes, was more common with ibutilide than with placebo or sotalol treatment. It occurred in 4.3% of patients, including 1.7% whose torsades de pointes was sustained and required cardioversion. In the ibutilide group, 4.9% of patients had nonsustained monomorphic ventricular tachycardia compared with 3.7% of patients who received sotalol and 0.8% of patients who received placebo. All of the sustained arrhythmias except 1 occurred within 1 hour of the end of ibutilide infusion, and all were successfully terminated without sequelae. In a multiple logistic regression analysis, bradycardia, low body weight, and history of congestive heart failure were predictive of the occurrence of torsades de pointes. Hypotension, conduction block, bradycardia, and all other cardiovascular adverse effects all occurred at similar rates in the ibutilide- and placebo-treated groups. For patients who failed to convert while receiving ibutilide, there was no decrease in the efficiency of cardioversion, nor was there an increase in the mean energy requirements for subsequent electrical cardioversion. Analysis of a 3-month follow-up study showed that patients receiving ibutilide had similar outcomes compared with patients receiving placebo. One placebo-treated patient died. Other than torsades de pointes, ibutilide has a very good safety profile. Under the proper clinical conditions, this complication of ibutilide therapy can be rapidly diagnosed and effectively treated.

Programmed electrical stimulation of the heart in coronary artery disease.

The induction of ventricular arrhythmia in patients with a history of malignant ventricular arrhythmia by programmed electrical stimulation (PES) is associated with a poor prognosis. However, the incidence and significance of inducible arrhythmia in patients with stable coronary artery disease (CAD) who do not have a history of serious arrhythmia are unknown. We studied 32 such patients (31 men, mean age 55 years) with PES at the time of cardiac catheterization. Fourteen patients (Group I) manifested greater than or equal to 3 extraventricular responses when challenged with 1 to 3 propagated right ventricular extrastimuli during ventricular pacing. Twelve (86%) of these 14 had evidence of left ventricular dysfunction (LVD), defined by a global ejection fraction of less than 50% or regional wall motion abnormalities. The remaining 18 patients (Group II) manifested less than or equal to 2 responses to extrastimulation. Only 4 (22%) of these 18 had LVD. Proximal 3-vessel CAD was more frequent in Group I patients (10 of 14, 71%) than in Group II (7 of 18, 39%). Only 5 patients (4 from Group I and 1 from Group II) demonstrated complex arrhythmia during exercise testing or ambulatory monitoring. The induction of extraventricular responses during PES may serve as an independent marker of electrical instability in the coronary population and is a much more common finding in those with LVD.

Value of electrophysiologic testing in patients with nonsustained ventricular tachycardia.

This study was undertaken to determine the value of electrophysiologic testing in 61 patients with nonsustained ventricular tachycardia (VT) (3 or more beats) on ambulatory monitoring and no history of sustained ventricular arrhythmia. The study group consisted of 38 patients with coronary artery disease (CAD), 9 with idiopathic dilated cardiomyopathy and 14 with a normal heart. Nonsustained VT (at least 3 but not more than 15 beats) was induced in 46%, sustained VT (more than 15 beats) in 15% and no VT in 39%. Sustained VT was induced more frequently in the presence of left ventricular dysfunction (p = 0.005) but was not related to the presence of CAD. Over a mean follow-up of 26 months, 10 patients died from cardiac causes (4 suddenly), including 1 patient with inducible sustained VT, 2 with nonsustained VT and 7 with no inducible VT. Inducibility was not related to survival, either as a single variable or when combined with CAD, left ventricular dysfunction or recent myocardial infarction. Left ventricular function alone was a good predictor of outcome. Of 46 patients with an ejection fraction of 35% more or in New York Heart Association functional class I or II, 3 (7%) died from cardiac causes, compared with 7 of 13 patients (54%) with an ejection fraction of less than 35% or in functional class III or IV (p = 0.0001). Thus, in patients with nonsustained VT, the incidence of sustained VT during electrophysiologic testing is low and is related to the degree of left ventricular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacologic and pharmacokinetic profile of class III antiarrhythmic drugs.

Cardiac arrhythmias frequently respond only to drugs that have as their predominant electrophysiologic effect the prolongation of repolarization and refractoriness. According to the Singh-Vaughan Williams classification, these drugs are known as class III agents. In the last few years, interest has increased in the development of class III antiarrhythmic drugs as alternatives to sodium channel blocking agents, which mainly affect cardiac conduction. Much of this interest results from a perceived danger of using drugs with sodium channel blocking properties, particularly in patients with ischemic heart disease, based on the results of the Cardiac Arrhythmia Suppression Trial (CAST) and several other trials. This article is a review of the pharmacology, including the pharmacokinetics and pharmacodynamics, of the most commonly used and investigated class III antiarrhythmic drugs. As will be seen from the discussion, each of these drugs has novel pharmacology that makes it applicable in specific clinical situations. Their putative effects on various arrhythmogenic mechanisms and their efficacy in treating specific target arrhythmias will be addressed.