Clinical outcomes after ablation and pacing therapy for atrial fibrillation : a meta-analysis.

BACKGROUND: Radiofrequency ablation of the atrioventricular node and permanent pacing are used for symptomatic relief in patients with medically refractory atrial fibrillation. In this study, meta-analysis was used to clarify clinical outcomes and survival after ablation and pacing therapy using data from the published literature. METHODS AND RESULTS: We used 21 studies with a total of 1181 patients in the meta-analysis. All patients had medically refractory atrial tachyarrhythmias, primarily atrial fibrillation (97%). Nineteen measures of clinical outcome, encompassing quality of life, ventricular function, exercise duration, and healthcare use, were derived from the studies. The meta-analysis demonstrated significant improvement after ablation and pacing therapy in all outcome measures except fractional shortening, which demonstrated a trend toward improvement (P=0.08). Ejection fraction did show significant improvement (P<0.001). The calculated 1-year total and sudden death mortality rates after ablation and pacing therapy were 6.3% and 2.0%, respectively. CONCLUSIONS: Ablation and pacing therapy improves a broad range of clinical outcomes for patients with medically refractory atrial fibrillation. The calculated 1-year mortality rates after this therapy are low and comparable with medical therapy.

Pharmacologic alterations in human type I atrial flutter cycle length and monophasic action potential duration. Evidence of a fully excitable gap in the reentrant circuit.

OBJECTIVES: This study compared the effect of changes in action potential duration versus conduction velocity on atrial flutter cycle length to determine whether there is a fully or partially excitable gap in atrial flutter. BACKGROUND: In an excitable gap reentrant circuit, cycle length is proportional to conduction velocity. Action potential duration is not a direct determinant of cycle length when the gap is fully excitable. METHODS: Right atrial monophasic action potentials were recorded from 41 patients during type I atrial flutter before and during pharmacologic interventions. RESULTS: Adenosine (17 +/- 3 mg [mean +/- SD]) shortened (p < 0.001) action potential duration but did not change cycle length. Edrophonium (10 mg) had no significant effect on action potential duration or cycle length. Isoproterenol (0.03 microgram/kg body weight per min) shortened (p < 0.05) and procainamide (15 mg/kg, then 2 mg/min) prolonged (p < 0.001) action potential duration and cycle length. Alterations in cycle length were not correlated with changes in action potential duration. Procainamide's prolongation of action potential duration was reversed by adenosine without affecting cycle length. Procainamide's prolongation of action potential duration and cycle length was partially reversed by isoproterenol. Adenosine's and isoproterenol's shortening of action potential duration and isoproterenol's shortening of cycle length were enhanced by procainamide. CONCLUSIONS: Atrial flutter cycle length is determined primarily by conduction velocity and does not depend directly on action potential duration. Atrial flutter has a fully excitable gap, and procainamide does not convert the gap from full to partial excitability. Adenosine and isoproterenol interact with procainamide such that their effects are enhanced and procainamide's effects are diminished.

Conversion of atrial flutter by ibutilide is associated with increased atrial cycle length variability.

OBJECTIVES: This study was designed to test the hypothesis that conversion of atrial flutter in humans by ibutilide, a new class III antiarrhythmic agent, is characterized by an increase in atrial cycle length variability. BACKGROUND: Conversion of tachyarrhythmias has been associated with increased oscillations of cycle length. METHODS: Electrograms and monophasic action potentials from the right atrium in 35 patients with spontaneous, sustained atrial flutter were recorded before, during and after intravenous ibutilide (0.005 to 0.025 mg/kg body weight, n = 25) or placebo (n = 10). Atrial cycle length, cycle length variability (coefficient of variation), diastolic interval and diastolic interval variability were measured from 10 consecutive cycles at baseline and 3 min before, 1 min before, 30 s before and immediately before conversion. Similar measurements were made in patients who received ibutilide or placebo but did not convert. RESULTS: Ibutilide converted atrial flutter in 14 of 25 patients 25 +/- 16 min (mean +/- SD) after initiation of the infusion, whereas placebo converted no patients. Atrial cycle length was prolonged to the same extent in ibutilide converters and nonconverters (36 +/- 19 vs. 38 +/- 21 ms, p = NS) and was not affected by placebo. Beat-to-beat variability in atrial cycle length (baseline 1.2 +/- 0.7 vs. preconversion 7.3 +/- 4.9, p < 0.01) and diastolic interval (baseline 11 +/- 8 vs. preconversion 33 +/- 23, p < 0.05) increased significantly just before atrial flutter conversion and remained unchanged in ibutilide nonconverters and placebo group patients. CONCLUSIONS: Ibutilide prolongs atrial cycle length, but conversion of atrial flutter by ibutilide is characterized by increased variability in atrial cycle length and diastolic interval.

Sympathetic neural responses to induced ventricular tachycardia.

Although sympathetic mechanisms play a major role in buffering abrupt arterial pressure reductions, including those that occur during tachyarrhythmias, human sympathetic nervous system responses to ventricular tachycardia have not been measured. Muscle sympathetic nerve activity was recorded directly from the peroneal nerve in 16 patients during diagnostic induction of 19 episodes of sustained monomorphic ventricular tachycardia (average rate 189 beats/min, range 130 to 250). Average systolic and diastolic pressures decreased from 149/78 to 61/49 mm Hg by 10 s and increased toward baseline levels to 88/64 mm Hg by 1 min of ventricular tachycardia. Average sympathetic nerve activity increased by 92% at 10 s in direct proportion to arterial pressure reductions and in inverse proportion to ventricular rate and remained 83% above baseline levels at 1 min. The late recovery of arterial pressure during ventricular tachycardia was related significantly to the magnitude of early sympathetic responses. Sympathetic activity tended to lose its discrete bursting pattern during ventricular tachycardia, and power spectral analysis showed that the large sympathetic peaks at the heart rate frequency present during sinus rhythm are absent during ventricular tachycardia. This study is the first to delineate human sympathetic nervous system responses to ventricular tachycardia. The results suggest that in the patients studied, large early sympathetic surges differed from those that occur during sinus rhythm and contributed to hemodynamic stability during ventricular tachycardia.

Higher sympathetic nerve activity during ventricular (VVI) than during dual-chamber (DDD) pacing.

OBJECTIVES: We determined the short-term effects of single-chamber ventricular pacing and dual-chamber atrioventricular (AV) pacing on directly measured sympathetic nerve activity. BACKGROUND: Dual-chamber AV cardiac pacing results in greater cardiac output and lower systemic vascular resistance than does single-chamber ventricular pacing. However, it is unclear whether these hemodynamic advantages result in less sympathetic nervous system outflow. METHODS: In 13 patients with a dual-chamber pacemaker, we recorded the electrocardiogram, noninvasive arterial pressure (Finapres), respiration and muscle sympathetic nerve activity (microneurography) during 3 min of underlying basal heart rate and 3 min of ventricular and AV pacing at rates of 60 and 100 beats/min. RESULTS: Arterial pressure was lowest and muscle sympathetic nerve activity was highest at the underlying basal heart rate. Arterial pressure increased with cardiac pacing and was greater with AV than with ventricular pacing (change in mean blood pressure +/- SE: 10 +/- 3 vs. 2 +/- 2 mm Hg at 60 beats/min; 21 +/- 5 vs. 14 +/- 2 mm Hg at 100 beats/min; p < 0.05). Sympathetic nerve activity decreased with cardiac pacing and the decline was greater with AV than with ventricular pacing (60 beats/min -40 +/- 11% vs. -17 +/- 7%; 100 beats/min -60 +/- 9% vs. -48 +/- 10%; p < 0.05). Although most patients showed a strong inverse relation between arterial pressure and muscle sympathetic nerve activity, three patients with severe left ventricular dysfunction (ejection fraction < or = 30%) showed no relation between arterial pressure and sympathetic activity. CONCLUSIONS: Short-term AV pacing results in lower sympathetic nerve activity and higher arterial pressure than does ventricular pacing, indicating that cardiac pacing mode may influence sympathetic outflow simply through arterial baroreflex mechanisms. We speculate that the greater incidence of adverse outcomes in patients treated with single-chamber ventricular rather than dual-chamber pacing may be due in part to increased sympathetic nervous outflow.

A placebo-controlled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atrial fibrillation and atrial flutter: a multicenter study.

The safety and efficacy of a 10- to 15-mg/h continuous infusion of intravenous diltiazem were evaluated in 47 patients with atrial fibrillation or flutter who first responded to 20 mg or 20 mg followed by one or more 25-mg bolus doses of open label intravenous diltiazem. Of the 47 patients, 44 responded to the bolus injection and were randomized under double-blind conditions to receive either a continuous infusion of intravenous diltiazem (10 to 15 mg/h) (23 patients) or placebo (21 patients) for up to 24 h. Seventeen (74%) of the 23 patients receiving diltiazem infusion and none of the 21 with placebo infusion maintained a therapeutic response for 24 h (p less than 0.001). Over 24 h, patients receiving diltiazem infusion lost response significantly more slowly than did those receiving placebo infusion (p less than 0.001). Nonresponders to the double-blind infusion were given an additional bolus injection of open label intravenous diltiazem and administered an open label 24-h intravenous diltiazem infusion. The overall proportion of patients maintaining a response to a 24-h infusion of intravenous diltiazem under double-blind or open label conditions combined was 83% (34 of 41). Efficacy of the 24-h infusion of intravenous diltiazem was similar in elderly versus young patients, those who did versus those who did not receive digoxin and those weighing less than 84 versus greater than or equal to 84 kg. However, intravenous diltiazem appeared to be more effective in atrial fibrillation than in atrial flutter. No significant untoward effects were noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Subnormal heart period variability in heart failure: effect of cardiac transplantation.

Heart period variability and arterial baroreceptor-cardiac reflex function were studied in cardiac transplant patients to determine if correction of heart failure restores parasympathetic control mechanisms toward normal. Heart period variability (standard deviation [SD] of 120 consecutive RR or PP intervals) was measured at supine rest in 34 patients with congestive heart failure (23 patients receiving diuretics, digoxin or vasodilators and 11 patients weaned from all medications), 30 cardiac transplant patients (both innervated recipient and denervated donor atrial rates) and 16 age-matched healthy control subjects. Arterial baroreflex gain was evaluated with intravenous bolus injections of phenylephrine in 22 transplant patients. Mean heart period variability (+/- SEM) was significantly lower (p less than 0.05) in the heart failure groups (22 +/- 3 ms for medicated and 17 +/- 3 ms for nonmedicated) than in the transplant patients (41 +/- 5 ms) or control subjects (58 +/- 5 ms). Heart period variability of the transplant patients was less than that of the control patients (p less than 0.05). A stepwise regression model revealed that heart period variability was inversely related to systolic arterial pressure and directly related to time after transplantation (R2 = 0.39; p = 0.03) in the transplant patients. Baroreflex gain of normotensive transplant patients was normal (11.7 +/- 1.0 ms/mm Hg) and correlated directly with heart period variability (r = 0.62; p less than 0.001). These data suggest that subnormal levels of cardiac parasympathetic activity at rest associated with congestive heart failure can be restored progressively toward normal by correction of congestive heart failure after cardiac transplantation. Post-transplant hypertension opposes this correction of baseline parasympathetic activity.

Lessons learned from data logging in a multicenter clinical trial using a late-generation implantable cardioverter-defibrillator. The Guardian ATP 4210 Multicenter Investigators Group.

OBJECTIVES: This study examined patterns of implantable cardioverter-defibrillator use as documented by data logging. BACKGROUND: Implantable cardioverter-defibrillators are accepted therapy for malignant ventricular tachyarrhythmias; however, relatively little is known about their patterns of use. Incorporation of data-storage capacities into these devices provides insight into long-term defibrillator function. METHODS: Stored data-logging information was retrieved from 401 implanted cardioverter-defibrillators in 393 patients over an average of 303 days of follow-up. RESULTS: A total of 91,443 detections were recorded in 299 patients. One hundred-six patients (26%) had detections due to supraventricular tachycardias, electrical noise or other causes, resulting in inappropriate therapy delivery to 92 patients (23%). Two hundred eighty-one patients recorded 66,276 episodes of ventricular tachycardia or ventricular fibrillation. Of these, 74.4% episodes terminated spontaneously without any delivered therapy, 22.1% terminated after antitachycardia pacing, and 1.7% terminated after shock therapy. Antitachycardia pacing was activated without formal testing in 47% of all patients receiving this therapy and was successful in 96% of all episodes receiving this therapy. Acceleration of tachycardia to shock therapy occurred in 1.3% of all episodes and in 30.5% of patients receiving antitachycardia pacing. Thirty-four patients (8.7%) died during follow-up. Mortality was associated with patient age, heart failure functional class at implantation and frequency of shocks received during follow-up (all p < or = 0.05). CONCLUSIONS: Most ventricular tachyarrhythmia detections by this noncommitted implantable cardioverter-defibrillator resolve spontaneously, whereas the majority receiving therapy can be treated with antitachycardia pacing. Mortality after implantable cardioverter-defibrillator implantation is associated with age, heart failure class and frequency of shocks received during follow-up. Data-logging capabilities provide valuable insights into the patterns of defibrillator use.

Diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in patients with unexplained syncope.

OBJECTIVES: The purpose of the present study was to systematically evaluate the diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in a consecutive series of patients with recurrent unexplained syncope. BACKGROUND: Carotid sinus hypersensitivity (CSH) is an infrequently recognized cause of recurrent unexplained syncope usually diagnosed by carotid sinus massage (CSM) in the supine position. The diagnostic utility of systematic assessment of mechanical, pharmacological and orthostatic stimulation of the carotid sinus has not been clearly established. METHODS: Eighty consecutive patients (63 +/- 12 years) with a history of recurrent unexplained syncope (mean episodes: 6 +/- 3); 30 age-matched controls (65 +/- 14 years) and 16 patients (59 +/- 12 years) with syncope not related to CSH were studied. Pharmacological stimulation of the carotid sinus was achieved by randomly administering bolus injections of nitroprusside and phenylephrine. Mechanical stimulation of the carotid sinus was performed by CSM applied for 5 s in the supine position and after 2 min at 60 degrees. A 60 degree low-dose isoproterenol head-up tilt test (HUTT) was also performed for a total duration of 30 min. RESULTS: Carotid sinus hypersensitivity was elicited by CSM in the supine position in seven (8.7%) patients, two (6.6%) controls and one (6.3%) patient with syncope unrelated to CSH, compared with 48 (60%) patients, two (6.6%) controls and one (6.3%) syncope unrelated to CSH patient after 60 degree HUTT, increasing the diagnostic yield by 51%. Baroreceptor gain was significantly reduced in the CSH group. Head-up tilt test was positive in 12 (25%) patients with CSH, two (6.6%) controls and two (12%) with documented syncope but not positive in any of the patients in which syncope remained unexplained. Diagnostic accuracy was enhanced by 38% (31% supine vs. 69% upright) when CSM was performed at 60 degrees. CONCLUSIONS: CSH was documented in 68% of patients, 8.7% in the supine position and 60% in the upright position. Sensitivity was increased by 51%, and diagnostic accuracy was enhanced by 38% by performing CSM in the upright position. Decreased baroreceptor gain was documented and may play a role in the pathophysiology of CSH.

Circadian pattern of ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators.

OBJECTIVES: This study examined the temporal patterns of ventricular tachycardia detections by implantable cardioverter-defibrillators for circadian variability. BACKGROUND: Previous studies of circadian arrhythmia patterns have been methodologically limited by very brief observational periods. Late-generation implantable cardioverter-defibrillators accurately record the times of arrhythmia detections during unlimited follow-up. METHODS: Forty-three patients with late-generation implantable cardioverter-defibrillators were followed up for 226 +/- 179 days (mean +/- SD). The times of all recorded episodes of ventricular tachyarrhythmias were retrieved from the data log of each device during follow-up. RESULTS: The weighted distribution of 830 ventricular tachyarrhythmia episodes from the 43 patients fit a single harmonic sine curve model with a peak between 2 and 3 P.M. (95% confidence interval 1:13 to 4:13 P.M., R = 0.75, p < 0.05). The distributions of spontaneously terminating episodes, episodes receiving device therapy, episodes receiving shocks and episodes in the absence of antiarrhythmic therapy also fit the sine curve model (all R = 0.53 and 0.73, all p < 0.05), all with peak frequencies between 2:08 and 3:09 P.M. and 95% confidence intervals for peak frequencies between 11:38 A.M. and 5:07 P.M. Episodes recorded during continuous antiarrhythmic drug therapy did not fit the model (p > 0.05). CONCLUSIONS: The distribution of ventricular tachyarrhythmias detected by late-generation implantable cardioverter-defibrillators follows a circadian pattern, with a peak tachycardia frequency between noon and 5 P.M. This pattern was not observed in patients receiving antiarrhythmic drug therapy. Knowledge of circadian periodicity for these events has implications for patient management.

Characterization of retrograde conduction by direct endocardial recording from an accessory atrioventricular pathway.

Accessory pathway electrograms are rarely recorded in patients with Wolff-Parkinson-White syndrome. In one patient, during electrophysiologic study, simultaneous local ventricular (V) accessory pathway (AP) and atrial (A) deflections were recorded during bipolar catheter endocardial mapping over the pathway. Analysis of changes in electrographic intervals during performance of the ventricular extrastimulus technique allowed characterization of the retrograde conduction properties of the pathway. As coupling intervals were decreased, an initial increase was seen in the AP2A2 interval with subsequent ventriculoatrial block between the accessory pathway and atrium. When coupling intervals were further decreased, the V2AP2 interval lengthened with ultimate block between the ventricle and accessory pathway. These findings support the concept of impedance mismatch as the cause of conduction block in accessory pathways with the distal junction of the accessory pathway being the most vulnerable.

Hemodynamic effects of intravenous sematilide in patients with congestive heart failure: a class III antiarrhythmic agent without cardiodepressant effects.

OBJECTIVES: This study sought to evaluate the hemodynamic effects of intravenous sematilide hydrochloride, a selective class III antiarrhythmic agent, in patients with heart failure and left ventricular systolic dysfunction. BACKGROUND: Class I antiarrhythmic agents, which primarily slow conduction, can depress ventricular function, particularly in patients with heart failure. In contrast, pure class III agents, which selectively prolong repolarization, do not adversely affect hemodynamic variables in animal models, but there are no data evaluating their hemodynamic effects in humans. METHODS: In 39 patients with congestive heart failure and a left ventricular ejection fraction < 40%, hemodynamic and electrocardiographic measurements were obtained at baseline, after a loading dose and during a maintenance infusion of intravenous sematilide using either a low (0.75 then 0.3 mg/min) or high dose (1.5 then 0.6 mg/min) regimen. The study had an 80% power to detect clinically meaningful differences in hemodynamic variables. RESULTS: Both low (n = 20) and high (n = 19) dose sematilide infusions produced dose-dependent increases in QT interval (5 +/- 8% [mean +/- SD] and 18 +/- 10%, respectively) and corrected QT interval (4 +/- 8% and 14 +/- 10%), and high dose sematilide decreased heart rate by 7 +/- 10% (all p < 0.025 vs. baseline). Neither dose regimen had a statistically significant effect on any other hemodynamic variable, including mean arterial, right atrial, pulmonary artery and pulmonary capillary wedge pressures; cardiac index, stroke volume, systemic and pulmonary vascular resistances; and left ventricular stroke work index. Sematilide showed no adverse hemodynamic effects in patients with left ventricular ejection fraction < or = 25% or > 25% and in patients with cardiac index < 2 or > or = 2 liters/min per m2. Sustained polymorphic ventricular tachycardia (n = 1) and excessive QT prolongation (n = 4) were seen during the high dose. CONCLUSIONS: Sematilide, in the doses administered, prolonged repolarization but did not alter hemodynamic variables in patients with heart failure. These data suggest that class III antiarrhythmic agents, which selectively prolong repolarization, are not cardiodepressant but may be proarrhythmic in humans, especially at high doses.

Sensing/pacing lead complications with a newer generation implantable cardioverter-defibrillator: worldwide experience from the Guardian ATP 4210 clinical trial.

OBJECTIVES: This report describes the sensing/pacing lead complications that developed during a worldwide clinical trial of a new implantable cardioverter-defibrillator. BACKGROUND: The reliability of the leads used for sensing and pacing with the implantable cardioverter-defibrillator has not been adequately studied. METHODS: The Guardian ATP 4210 was implanted in 302 patients. The sensing/pacing leads consisted of either two unipolar epicardial electrodes or a bipolar endocardial electrode from a variety of manufacturers. RESULTS: During a mean follow-up period of 380 days, 39 patients (12.9%) required reoperation because their device developed sensing/pacing lead system complications. The most common clinical presentation was device oversensing (multiple tachycardia or noise detections or inappropriate shocks), which was observed in 27 patients, whereas elevated pacing thresholds were seen in 10 patients. Forty-one (11.8%) of 347 implanted lead systems required revision. The mean time to revision was 156 +/- 145 days. Actuarial lead survival rate at 1 and 3 years was 89% and 79%, respectively. Epicardial lead systems required significantly (p < 0.05) more revision than did endocardial systems, but when adapter problems were excluded, the revision rates of epicardial and endocardial leads were similar. Causes of lead system failures included adapter connection problems, lead dislodgement and insulation disruption. Predictors of lead revision were use of an epicardial lead system or an adapter. CONCLUSIONS: A high rate of sensing/pacing lead complications was found with this newer generation implantable cardioverter-defibrillator. The enhanced diagnostic and data storage capabilities of this implantable cardioverter-defibrillator facilitated the recognition and troubleshooting of these complications. These findings emphasize the need for careful surveillance and testing of implantable cardioverter-defibrillator sensing/pacing leads during follow-up.

Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies.

The increasing prevalence of congestive heart failure has focused importance on the search for potentially reversible etiologies of cardiomyopathy. The concept that incessant or chronic tachycardias can lead to ventricular dysfunction that is reversible is supported by both animal models of chronic rapid pacing as well as human studies documenting improvement in ventricular function with tachycardia rate or rhythm control. Sustained rapid pacing in experimental animal models can produce severe biventricular systolic dysfunction. Hemodynamic changes occur as soon as 24 h after rapid pacing, with continued deterioration in ventricular function for up to 3 to 5 weeks, resulting in end-stage heart failure. The recovery from pacing-induced cardiomyopathy demonstrates that the myopathic process associated with rapid heart rates is largely reversible. Within 48 h after termination of pacing, hemodynamic variables approach control levels, and left ventricular ejection fraction shows significant recovery with subsequent normalization after 1 to 2 weeks. In humans, descriptions of reversal of cardiomyopathy with rate or rhythm control of incessant or chronic tachycardias have been reported with atrial tachycardias, accessory pathway reciprocating tachycardias, atrioventricular (AV) node reentry and atrial fibrillation (AF) with rapid ventricular responses. Control of AF rapid ventricular responses has been demonstrated to improve ventricular dysfunction with cardioversion to sinus rhythm, pharmacologic ventricular rate control and AV junction ablation and permanent ventricular pacing. The investigation of potential tachycardia-induced cardiomyopathy in patients with heart failure requires further prospective confirmation in larger numbers of patients, with study of mechanisms, patient groups affected and optimal therapies.

Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study.

OBJECTIVES: Currently available antiarrhythmic drugs have limited efficacy for short-term, rapid termination of atrial fibrillation and atrial flutter. BACKGROUND: Ibutilide fumarate is an investigational class III antiarrhythmic agent that prolongs repolarization by increasing the slow inward sodium current and by blocking the delayed rectifier current. It can be administered intravenously and has a rapid onset of electrophysiologic effects. METHODS: The efficacy and safety of ibutilide were studied in 200 patients with atrial flutter > 3 h in duration or atrial fibrillation 3 h to 90 days in duration. Patients were randomized to receive a single intravenous dose of placebo or an infusion of ibutilide fumarate at 0.005, 0.010, 0.015 or 0.025 mg/kg body weight over 10 min. Conversion was defined as termination of the atrial arrhythmia during or within 60 min after infusion. Forty-one patients received placebo and 159 received ibutilide (0.005 mg/kg [n = 41], 0.010 mg/kg [n = 40], 0.015 mg/kg [n = 38] or 0.025 mg/kg [n = 40]). RESULTS: The arrhythmia terminated in 34% of drug-treated patients. The rates of successful arrhythmia termination were 3% for placebo and 12%, 33%, 45% and 46%, respectively, for 0.005-, 0.010-, 0.015- and 0.025-mg/kg ibutilide. The placebo and 0.005-mg/kg ibutilide groups had lower success rates than all other dose groups (p < 0.05). The mean time to termination of the arrhythmia was 19 min (range 3 to 70) from the start of infusion. Successful arrhythmia termination was not affected by enlarged left atrial diameter, decreased ejection fraction, presence of valvular heart disease or the use of concomitant medications (beta-adrenergic blocking agents, calcium channel blocking agents or digoxin). Arrhythmia termination was not predicted by the magnitude of corrected QT interval prolongation but was associated with a shorter duration of atrial arrhythmia. The most frequent adverse events in ibutilide-treated patients were sustained and nonsustained polymorphic ventricular tachycardia (3.6%). All patients with sustained polymorphic ventricular tachycardia were successfully treated with direct current cardioversion and had no recurrence. The occurrence of proarrhythmia did not correlate with ibutilide plasma concentration. CONCLUSIONS: These data demonstrate that ibutilide is able to rapidly terminate atrial fibrillation and atrial flutter.

Effects of bolus injection of esmolol in healthy, exercising subjects.

Esmolol is an investigational ultra-short-acting beta-adrenergic blocker that has potential application in many clinical cardiology settings. The purpose of this study was to investigate the effect of a bolus dose of esmolol on heart rate, blood pressure, and PR interval in healthy, exercising male subjects. We gave a single esmolol bolus over 30 seconds to 13 men who exercised to a predetermined target heart rate. Each subject performed the exercise protocol twice, receiving a different dose between 10 and 300 mg each time. An additional eight subjects received two esmolol boluses 5 minutes apart while performing the same exercise protocol. Esmolol doses of 180 mg or greater caused a 13% to 18% decrease in heart rate, an 11% to 18% decrease in blood pressure, and a 13% to 22% prolongation of the PR interval. The median time to peak esmolol effect was 1 minute for heart rate, 2 minutes for blood pressure, and 4 minutes for PR interval. The median time required to recover 50%, 75%, and 90% of the decrement in heart rate was 8, 10, and 13 minutes, respectively. The rapid onset and disappearance of esmolol effects may make it an appealing drug in acute care settings.

Pharmacodynamics and pharmacokinetics of oral pirmenol.

The efficacy, pharmacokinetics, and pharmacodynamics of pirmenol, a class Ia antiarrhythmic agent, were studied in patients with frequent symptomatic premature ventricular complexes (PVCs). Pirmenol was given every 12 hours to eight patients in a dose-ranging protocol, and median PVC suppression of 94% (range 72% to 100%) was achieved. The median effective pirmenol dose was 300 mg/day (range 200 to 500 mg/day), and mean (+/- SD) trough plasma pirmenol concentration at the effective dose was 0.98 +/- 0.29 micrograms/ml. The mean half-life of elimination was 10.5 +/- 2 hours. There was considerable overlap among patients with respect to plasma pirmenol concentration and times at which PVC frequency returned to 25%, 50%, and 75% of baseline during drug washout trials. Altering pirmenol's dose interval (while maintaining a constant daily dose) from 12 to 6 hours did not improve drug efficacy. Pirmenol was given to seven patients for long-term therapy (24 to 44 months). Median PVC suppression at 24 months was 70%. Pirmenol is safe and well tolerated, and it can be administered twice daily for PVC suppression.

The management of atrial fibrillation.

Atrial fibrillation affects approximately one million persons in the United States, making it the most common cardiac arrhythmia seen in clinical practice. Its prevalence increases with age, and occurs in up to 10% of the population in the eighth decade of life. Unlike coronary heart disease, atrial fibrillation affects men and women approximately equally and, in an increasingly elderly population, will become an increasing burden to the health care system. The management of atrial fibrillation has undergone significant change in recent years. Large randomized controlled trials have shown that anticoagulation markedly reduces the risk of stroke, and a number of new antiarrhythmic agents are available for the restoration and maintenance of sinus rhythm. Furthermore, physicians have become more aware of the potential proarrhythmic side effects of all antiarrhythmic drugs. Finally, new procedures such as radiofrequency ablation of the atrioventricular junction and permanent pacing are playing increasing roles in the management of this arrhythmia. In this review, the identification of underlying causes and/or precipitating factors of atrial fibrillation, methods to control the ventricular response with atrioventricular nodal blocking drugs, the questions of whether restoration of sinus rhythm is a possible or desirable goal and how best to maintain sinus rhythm, should sinus rhythm be restored, and the importance of long-term anticoagulation with warfarin or antiplatelet therapy with aspirin are discussed.

Role of calcium antagonists for heart rate control in atrial fibrillation.

Atrial fibrillation is one of the most common symptomatic sustained arrhythmias seen in clinical practice. Many patients with atrial fibrillation and a ventricular response greater than 120 beats/min will experience cardiac symptoms. In the past, control of heart rate in these patients consisted of administration of intravenous digoxin, but this often proved to be ineffective or limited by toxicity. Recently, intravenous beta blockers such as esmolol have been used to slow the ventricular rate during atrial arrhythmias, but in some studies their use has been limited by hypotension. Alternatively, a bolus of an intravenous calcium antagonist, e.g., diltiazem or verapamil, may be administered to achieve acute slowing of the ventricular response. An intravenous bolus of diltiazem or verapamil may be effective, but use of either may be limited by its short duration of action and the inability to administer repeated boluses to tightly control or "fine tune" the heart rate. However, a new bolus plus maintenance infusion technique with diltiazem has shown promise in initial studies. It appears that in the future, continuous infusion techniques with intravenous calcium antagonists will be available that provide safe and effective sustained control of the ventricular response during atrial arrhythmias.

Effects of cardiac denervation on atrioventricular nodal accommodation and hysteresis.

Conduction through the atrioventricular (AV) node is significantly altered by changes in autonomic tone. AV nodal accommodation (time-dependent changes in AV nodal conduction after a sudden change in atrial cycle length) and AV nodal hysteresis (asymmetry of AV nodal accommodation after directionally opposite atrial pacing cycle length changes) have been characterized in humans. Studies in dogs after cardiac transplantation suggest that the rapid phase of AV nodal accommodation is altered following ablation of neural input to the AV node. To determine if cardiac denervation alters AV nodal accommodation and hysteresis in humans, 13 patients after orthotopic cardiac transplantation and 12 control patients with normal AV nodal function were studied. Atrial pacing was performed for 1 minute at different pacing cycle lengths and AH or AV intervals were measured after cycle length changes. The rapid phase of accommodation is defined as the time required for the AV interval to reach 75% of the final AV interval. During abrupt changes from long to short pacing cycle lengths, the rapid phase of accommodation took 3.2 +/- 1.0 and 4.3 +/- 1.0 beats in control subjects and transplant patients, respectively (p = not significant [NS]). When going from short to long pacing cycle lengths, the rapid phase of accommodation took 1.7 +/- 1.2 and 2.1 +/- 1.8 beats in control subjects and transplant patients, respectively (p = NS). Hysteresis of 1.5 +/- 1.3 and 2.1 +/- 1.4 beats was noted in the control and transplant groups, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)