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.

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.

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.

Comparison of dilated cardiomyopathy and coronary artery disease in patients with life-threatening ventricular arrhythmias: Differences in presentation and outcome in the AVID registry.

BACKGROUND: The etiology of structural heart disease in patients with life-threatening arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]) may define clinical characteristics at presentation, may require that different therapies be administered, and may cause different mortality outcomes. METHODS: In the Antiarrhythmics Versus Implantable Defibrillators (AVID) registry, baseline clinical characteristics, treatments instituted, and ultimate mortality outcomes from the National Death Index were obtained on 3117 patients seen at participating institutions with VT/VF, irrespective of participation in the randomized trial. By use of these data, 2268 patients with coronary artery disease (CAD) were compared with 334 patients with dilated nonischemic cardiomyopathy (DCM). RESULTS: The CAD group was 7 years older and had a higher percentage of males. DCM patients were more likely to be African American, have severely compromised left ventricular function (52% vs 39%), and have a history of congestive heart failure symptoms (62% vs 44%). Patients with CAD were more likely to be treated with b-blockers and calcium channel blockers and less likely to be treated with angiotensin-converting enzyme inhibitors. Patients with DCM were more likely to be treated with diuretics, warfarin, and an implantable cardioverter defibrillator for VT/VF (54% vs 48% for CAD); the use of other antiarrhythmic therapies did not differ between the 2 groups. Two-year survival was not significantly different between the groups (76.6% [95% CI 74.6%-78.7%] vs 78.2% [95% CI 73.6%-82.9%]). CONCLUSIONS: In AVID registry patients with VT/VF, demographic and clinical characteristics were different between patients with CAD and those with DCM. Despite these differences, overall survival was similar in these 2 groups.

Electrophysiology of beta blockers in supraventricular arrhythmias.

beta-adrenergic blocking agents are efficacious in the treatment of patients with a variety of supraventricular tachycardias, based directly on their capacity to counter the effects of beta-adrenergic stimulation on sinus and atrioventricular nodal tissue. Specifically, beta blockers depress sinus node automaticity and inhibit atrioventricular nodal function by prolonging refractoriness and slowing conduction. Supraventricular arrhythmias that depend on these structures either for perpetuation or for conduction to the ventricles are predictably sensitive to beta blockade. These arrhythmias include sinus tachycardia, sinoatrial reentrant, atrioventricular nodal reentrant (dual pathway) and atrioventricular reciprocating (concealed bypass tract) tachycardias, as well as atrial flutter and fibrillation. beta blockers may also be used, in selected patients, to inhibit catecholamine-facilitated accessory pathway function by prolonging refractoriness. beta blockers offer particular clinical advantages, including an acceptable side-effect profile, titratable effect, varied pharmacology and reasonable concordance between efficacy of parenteral and oral dosage forms. The key element in the most effective use of these drugs appears to be an accurate arrhythmia diagnosis that allows for the most appropriate application of a reliable treatment form.

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.

Effectiveness of propranolol added to a type I antiarrhythmic agent for sustained ventricular tachycardia secondary to coronary artery disease.

The effect of adding propranolol to procainamide, quinidine, propafenone or disopyramide was prospectively evaluated in 37 patients, all with prior infarction and inducible ventricular tachycardia (VT). After showing that VT remained inducible during therapy with a type I drug, 23 patients received intravenous propranolol. The ventricular effective refractory period, prolonged by the type I agent, was further increased by propranolol. The cycle length of the VT also increased after the type I drug and propranolol exaggerated this effect. Seven of the 23 patients were rendered noninducible after propranolol and another 10 manifested a greater than 100 ms increase in induced VT cycle length. In the other 14 patients, propranolol was infused immediately after the basal study. If VT remained inducible, testing was repeated after a type I drug was added. The ventricular effective refractory period, as well as the VT cycle length, increased after propranolol and was further prolonged after the addition of a type I agent. Seven of these 14 patients were rendered noninducible, 3 with propranolol alone and 4 others with the combination, and in 4, the VT cycle length was prolonged by greater than 100 ms. A total of 17 patients were discharged on either propranolol alone (3 patients) or on an effective combination (14 patients). During a mean follow-up of 20 months, 1 patient died suddenly, 2 had recurrence of well-tolerated VT and 9 remain on therapy. Thus, propranolol has a demonstrable antiarrhythmic effect in the invasive laboratory and may supplement the antiarrhythmic efficacy of conventional type I antiarrhythmic drugs.

Acute treatment of atrial fibrillation.

Atrial fibrillation (AFib) is a common clinical entity, responsible for significant morbidity and mortality, but it also accounts for a large percentage of healthcare dollar expenditures. Efforts to treat this arrhythmia in the past have focused on subacute antithrombotic therapy and eventually use of antiarrhythmic drugs for maintenance of sinus rhythm. However, there has been a growing interest in the concept of acute electrical and pharmacologic conversion. This treatment strategy has a number of benefits, including immediate alleviation of patient symptoms, avoidance of antithrombotic therapy, and prevention of electrophysiologic remodeling, which is thought to contribute to the perpetuation of the arrhythmia. There is also increasing evidence that this is a cost-effective strategy in that it may obviate admission to the hospital and the cost of long-term therapy. This article represents a summary of the treatments that may be used acutely to control the ventricular response to AFib, prevent thromboembolic events, and provide for acute conversion either pharmacologically or electrically. It includes information on modalities that are currently available and those that are under active development. We anticipate that an active, acute treatment approach to AFib and atrial flutter will become the therapeutic norm in the next few years, especially as the benefits of these interventions are demonstrated in clinical trials.

Intravenous antiarrhythmic therapy in the acute control of in-hospital destabilizing ventricular tachycardia and fibrillation.

Ventricular tachycardia, which causes hemodynamic instability, and ventricular fibrillation do not occur frequently in any hospital. However, they usually occur in patients who have severe underlying cardiovascular disease such as myocardial ischemia/infarction or congestive heart failure, and they are associated with high mortality. Most of those deaths are due to an intractable arrhythmia, not suppressible with even the most potent antiarrhythmic drugs. Fortunately, during the last few years, our ability to suppress highly lethal ventricular arrhythmia has been enhanced by the approval of intravenous amiodarone. When used in appropriate patient populations, intravenous amiodarone has been successful in suppressing the most malignant arrhythmia, thus permitting aggressive and successful treatment of severe underlying cardiac conditions. This article reviews data on the use of parenteral antiarrhythmic drugs for the control of ventricular arrhythmia in patients in hospital, and will attempt to provide some guidance as to how these antiarrhythmic drugs may be used in specific patient populations to maximize their efficacy and safety. We will also make recommendations on the sequence of therapy for specific arrhythmias to optimize the chances of patient survival.

Atrial fibrillation trials: will they teach us what we need to know?

Atrial fibrillation (AF) has captured the imagination of clinical investigators who have initiated trials to examine several aspects of this multifaceted arrhythmia. We will review the protocol designs of ongoing trials that are examining the relative value of rhythm versus rate control, new methods for pharmacologic restoration and maintenance of sinus rhythm (including prophylaxis after cardiac surgery), and nonpharmacologic interventions such as pacing and atrial defibrillation. We antic ipate that the results of these studies will have a major impact on the care of patients with AF in the new millennium.

Effectiveness of digitalis with or without acebutolol in preventing atrial arrhythmias after coronary artery surgery.

In this study, a beta-adrenergic blocker in combination with digoxin provided marginal protection against atrial fibrillation/flutter after coronary artery surgery. The economic comparison of patients who did and did not develop atrial fibrillation/flutter indicates that prevention of these arrhythmias can have a significant impact on length of hospital stay and cost of this common surgical procedure.

Safety and efficacy of amiodarone. The low-dose perspective.

Amiodarone has been reported to be a remarkably safe and effective drug in the European and South American experience but American investigators have published conflicting data. Since this disparity may be explained by a different dosing schedule, we prospectively evaluated the safety and efficacy of a low dose regimen in a group of 68 patients with cardiac arrhythmia resistant to conventional therapy, of whom 57 had manifested either ventricular tachycardia or fibrillation. All were loaded either intravenously (17) or orally, and maintained on an oral dose of 200 to 600 mg/day (mean daily dose 317 +/- 114 mg) and followed for 4 to 58 months (22 +/- 11). Results indicated that amiodarone was a safe and effective antiarrhythmic drug when used in lower doses.

Management of atrial fibrillation in patients with hypertension.

Atrial fibrillation (AF) is a common arrhythmia in patients with hypertensive heart disease. In addition, the presence of hypertension in patients with AF constitutes an important risk factor for the development of thromboembolic events and probably also selects out those individuals who may be resistant to drug therapy. AF in patients with hypertensive heart disease may lead to a number of serious clinical sequelae including stroke, left atrial myopathy, left ventricular dysfunction, and congestive heart failure. This needs to be treated aggressively since many patients may become quite symptomatic when AF develops in the setting of diastolic and systolic dysfunction, regular features of hypertensive heart disease. There are several treatment approaches that may be considered in such patients ranging from interventions to prevent thromboembolic events, drugs and procedures for control of the ventricular response, and drug and non-pharmacologic therapy specifically designed to prevent AF or to restore normal sinus rhythm. This review article will cover each of these components of therapy of AF and will attempt to focus on those therapies that might be best suited for patients with hypertensive heart disease.

Propafenone in the treatment of patients with malignant ventricular tachyarrhythmias.

This study was conducted to determine the value of propafenone in patients with resistant malignant ventricular arrhythmias. Forty patients with either sustained ventricular tachycardia (n = 34) or primary ventricular fibrillation (n = 6), who had failed an average of four previous drug trials, were studied prospectively. The mean age was 68 years. Thirty-five had had a previous infarction, and left ventricular ejection fractions ranged from 14 to 57% (mean 36%). Noninvasive evaluation, consisting of ambulatory monitoring and exercise testing, was used to guide therapy in 12 patients, and invasive electrophysiological study was employed in the other 28. The initial daily dose was 450 mg, and electrocardiographic intervals were used to titrate the dose upward to a maximum of 900 mg per day or to tolerance. Five of the 12 noninvasively studied patients had complete abolition of ventricular tachycardia salvos. Only five of the 28 patients were rendered noninducible, but another four had adequate rate slowing with good hemodynamic tolerance of their arrhythmias. In an additional six patients, the addition of a second antiarrhythmic drug produced supplemental rate slowing. Side effects occurred in 30 patients and necessitated drug withdrawal in 13. The most serious adverse effects were congestive heart failure (in eight patients, and three withdrawn) and proarrhythmia (in four patients, and all withdrawn). The 20 patients with an adequate response were discharged on propafenone. During a mean follow-up of 12 months, there have been three cardiac deaths, one of which was sudden, and three recurrences of sustained ventricular tachycardia. Efficacy and side effects did not correlate with dose or degree of increase in electrocardiographic intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis and treatment of cardiac rhythm disorders in the elderly.

The elderly patient is susceptible to a variety of cardiac rhythm disturbances that may or may not cause symptoms. It is incumbent on the physician who cares for geriatric patients to have a familiarity with the diagnostic criteria for each of these arrhythmias and with the drugs and devices that are used to treat them. This includes the potential adverse effects of therapy and methods to counter them. Even more important is a sense of when to intervene, which is based, in large measure, on a knowledge of "normal variation" in the aged.

Electropharmacologic effect of a standard dose of intravenous procainamide in patients with sustained ventricular tachycardia.

BACKGROUND: Patients with inducible sustained ventricular tachycardia (VT) sometimes receive intravenous procainamide during electrophysiologic testing. Unfortunately, the responses to intravenous and subsequent oral drug therapy are variable and may be discordant. HYPOTHESIS: It was the aim of this study to determine whether this variability might be explained by heterogeneity in the electropharmacologic response, even in a homogeneous population. METHODS: We studied 42 patients who had spontaneous malignant ventricular arrhythmia and were inducible to sustained monomorphous VT during electrophysiologic testing. Each received 15 mg/kg of intravenous procainamide followed by a 2 mg/min infusion. Serum levels were drawn immediately following programmed stimulation. The mean procainamide level was 6.7 +/- 1.4 mcg/ml with an N-acetyl procainamide level of 1.0 +/- 0.5 mcg/ml. The 14 procainamide responders (5 of whom were noninducible and 9 whose VT cycle length increased > 100 ms) and the 28 nonresponders had similar procainamide and NAPA levels (6.5 +/- 1.4 vs. 6.7 +/- 1.4 mcg/ml). RESULTS: There was no significant difference in baseline clinical parameters, His to ventricular electrogram (HV) interval, effective refractory period, or VT cycle length. Prolongation of the effective refractory period and infra His conduction time occurred to a similar extent in responders and nonresponders. CONCLUSION: We conclude that procainamide has a consistent dose-response relationship with respect to refractoriness and conduction in patients with malignant arrhythmias. However, acute antiarrhythmic efficacy of procainamide cannot be predicted by clinical factors, drug levels, or drug-induced changes in common electrophysiologic parameters.