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.

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.

Atrial fibrillation, anticoagulation, and stroke.

There is a demonstrated statistical association between atrial fibrillation, rheumatic valvular disease, and embolic stroke. This article assesses the results of 6 major clinical trials (AFASAK, BAATAF, SPINAF, SPAF [parts I and II], CAFA and EAFTA--see text for trial names). Multivariate analysis revealed 4 independent clinical features that identified patients with atrial fibrillation at an increased risk for stroke: hypertension, increasing age, previous transient ischemic attack, and diabetes mellitus. Without anticoagulation therapy, patients with any of these risk factors had a 4% annual risk of stroke. Patients with cardiac disorders such as congestive heart failure and coronary artery disease have a stroke rate 3 times higher than patients without any risk factors; patients with atrial fibrillation but no concomitant risk factors or structural heart disease seemed to have little concomitant risk for stroke. Meta-analysis revealed a 64% reduction of risk for stroke in patients treated with warfarin, as compared with placebo. The value of warfarin therapy in patients > 75 years old is less clear because of a high risk of hemorrhagic complications.

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.

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.

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.

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.

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.

Effects of atropine on the cardiac arrest induced by propranolol and digitoxin in dogs.

The present study examines the hypothesis that vagal activity can accelerate the onset of cardiac arrest produced by administering a beta-adrenergic blocking dose of propranolol to digitoxin-intoxicated dogs. In 11 experiments, intravenous injection of 0.75 mg/kg propranolol into digitoxin intoxicated dogs induced a sustained ventricular asystole (early-phase cardiac arrest). In six of these eleven experiments, intermittent pacing of the ventricles for as long as 150 min to maintain blood pressure after the onset of asystole, led to the resumption of spontaneous heart beats in only one dog. In five other experiments, injection of atropine (1 mg/kg) three min after the onset of early-phase cardiac arrest elicited sustained spontaneous junctional rhythms. In another four experiments the injection of atropine prior to or simultaneously with propranolol prevented the occurrence of asystole and caused the emergence of a junctional pacemaker. In eight experiments in which the cardiac arrest was reversed or prevented, injection of maintenance doses of atropine and propranolol caused eventual failure of the junctional pacemaker (late-phase cardiac arrest). This failure could not be prevented or reversed by atropine. The results suggest that early-phase cardiac arrest is due to vagal suppression of cardiac pacemakers and therefore supports the above hypothesis.

Arrhythmias 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 part on a knowledge of "normal variation" in the aged.

Electrophysiologic testing in patients who respond acutely to intravenous amiodarone for incessant ventricular tachyarrhythmias.

The outcome of patients who receive intravenous amiodarone for suppression of incessant ventricular tachyarrhythmia has not been studied conclusively. We conducted a prospective study in which all patients who responded acutely to intravenous amiodarone and went on to receive a subsequent oral loading dose were subjected to electrophysiologic testing before hospital discharge to determine whether additional or alternative therapy would be required. Among 18 patients (17 with ischemic heart disease) who entered the protocol, 16 had a clinical response to intravenous amiodarone alone (12 patients) or in combination with another antiarrhythmic drug (4 patients) and survived to study. Of these, 10 had monomorphic ventricular tachycardia (VT) when first seen, five had polymorphous VT or ventricular fibrillation (VF), and three had both. In seven patients sustained monomorphic VT was inducible (group 1), and in nine it was not (group 2). The only clinical factor that distinguished group 1 from group 2 was age (group 1 > group 2). Five patients in group 1 and one in group 2 received an implantable cardioverter defibrillator; one patient in group 1 had a successful endocardial resection. During a mean follow-up period of 11 months, four patients in group 1 have had appropriate implantable cardioverter defibrillator discharges, whereas only one patient in group 2 has had a clinical event (sudden death). We conclude that intravenous amiodarone is a highly effective drug used alone or in combination to suppress spontaneous incessant VT/VF. Predischarge electrophysiologic testing, even in patients who have polymorphous VT, has predictive value over and above the observed clinical response. These preliminary results favor predischarge testing and aggressive device treatment in this cohort.

Does programmed stimulation really help in the evaluation of patients with nonsustained ventricular tachycardia? Results of a meta-analysis.

There has been considerable debate regarding the value of programmed electrical stimulation in patients who present with asymptomatic, or minimally symptomatic, nonsustained VT. Unfortunately, there has never been a sufficiently large study of an untreated group of patients to make any sense of the issue. We culled the literature for reports published between 1986 and 1990 that met certain minimum requirements, the most important of which were adequate patient profiling and outcome data. The survey identified 12 studies of 926 patients, mean age 61 years, with a 5:1 male preponderance. Underlying heart disease was coronary in 818 patients, including 665 who had experienced previous but not recent myocardial infarctions. Of these, 302 (33%) had inducible sustained ventricular arrhythmias (monomorphic VTs in 264). Eighty-three percent of these patients were treated with antiarrhythmic drugs compared to only 13% of the noninducible group (p less than 0.0001). Sudden death or a sustained arrhythmic event occurred in 54 (18%) of the 302 patients in the inducible group compared with 46 (7%) of the 624 in the noninducible group (p less than 0.001). The sensitivity, specificity, and positive and negative predictive accuracies of the test were 54%, 70%, 18%, and 93%, respectively. Thus a patient with an inducible sustained arrhythmia who manifests nonsustained VT is two and a half times as likely to have a major arrhythmic event, but a negative result bodes well for the patient. However, widespread application of the technique cannot be recommended until these results are confirmed in a large, prospective study in which antiarrhythmic therapy is controlled.

Parenteral antiarrhythmics for life-threatening ventricular arrhythmias.

The acute management of life-threatening ventricular tachyarrhythmias often includes the use of parenteral antiarrhythmics. There are a number of agents currently available for this purpose. They are used to suppress inducible monomorphic ventricular tachycardia during programmed electrical stimulation, they terminate spontaneous sustained ventricular tachycardia, and prevent ventricular fibrillation in the setting of an acute myocardial infarction. Serious adverse reactions include proarrhythmia, hypotension, severe bradyarrhythmias, and precipitation of congestive heart failure. A comparative evaluation of intravenous antiarrhythmics is difficult due to inherent differences in the choice of agents for study, protocol design, patient population, defined endpoint, and serum drug levels. Likewise, the reported adverse reaction rates vary from 0.4% to 75%. To understand the difficulties in clinical decision-making in this problem area, particularly drug selection, we present here a review of pertinent clinical trials evaluating parenteral drug efficacy and adverse effects.

Classification and pharmacology of antiarrhythmic drugs.

Despite the emergence of several forms of nonpharmacologic therapy for cardiac arrhythmias, antiarrhythmic drugs continue to play an important role in the management of patients with this common clinical problem. The key to the proper use of antiarrhythmic drugs is a thorough knowledge of their mode of action and pharmacology. The pharmacology of antiarrhythmic drugs is particularly important because patients with cardiac arrhythmias frequently have multiorgan disease, which may influence the metabolism and elimination of antiarrhythmic drugs. The accumulation of toxic amounts of these agents can lead to dire effects including, but not limited to, ventricular proarrhythmia and malignant bradycardia. The goals of pharmacologic therapy of cardiac arrhythmia are to provide the maximum benefit in terms of arrhythmia suppression while maintaining patient safety. To accomplish these goals, a knowledge of the pharmacology of several antiarrhythmic drugs is mandatory.

The top ten fallacies of nonsustained ventricular tachycardia.

Nonsustained ventricular tachycardia (NSVT) continues to remain a subject of controversy. This is true despite a wealth of epidemiologic and basic/clinical laboratory findings that have accumulated during the past 2 decades. However, these data not only generate the impetus to conduct further research, but also provide compelling arguments against continued adherence to time honored precepts about NSVT that evolved since the inception of the "PVC Hypothesis," although never substantiated by rigorous scientific inquiry. This paper discusses the "top ten" fallacies of NSVT and details the data that support abandonment of them.

The properties of the inward rectifier potassium currents in rabbit coronary arterial smooth muscle cells.

In freshly-isolated, single, smooth muscle cells of rabbit coronary arteries, an inward rectifier K+ current [IK(IR)] was identified using the whole-cell voltage-clamp technique. The current/voltage (I/V) relationship of IK(IR) showed strong inward rectification with a very small outward current when the smooth muscle cells were dialyzed with a pipette solution containing Mg2+. However, dialyzing the cells with a nominally Mg2+-free pipette solution revealed a significant outward current hump in the I/V relation of IK(IR), suggesting that the strong inward rectification of IK(IR) is partly due to the inhibitory effects of internal Mg2+. IK(IR) was unaffected by tetraethylammonium (1 mM), 4-aminopyridine (1 mM), or glibenclamide (1 microM), but was inhibited by extracellular Ba2+ with a concentration of 0.87 microM eliciting half-maximal inhibition at -120 mV. IK(IR) induced in rabbit coronary smooth muscle cells declined during very negative hyperpolarizing steps, due largely to a block by external Na+. IK(IR) was inhibited by alpha1-adrenergic stimuli. Methoxamine, an alpha1-adrenergic agonist, concentration dependently inhibited IK(IR) in the presence of the beta-adrenergic antagonist propranolol. The methoxamine concentration required for half-maximal inhibition was 205 microM. We conclude that inward rectifier K+ current is present in rabbit coronary smooth muscle cells and that it shares many properties with the inward rectifier K+ current described for other cell types.