Marc D. Meissner

Female Gender as a Risk Factor for Torsades de Pointes Associated With Cardiovascular Drugs

OBJECTIVE To test the hypothesis that female prevalence is greater than expected among reported cases of torsades de pointes associated with cardiovascular drugs that prolong cardiac repolarization. DATA SOURCES A MEDLINE search of the English-language literature for the period of 1980 through 1992, using the terms torsade de pointes, polymorphic ventricular tachycardia, atypical ventricular tachycardia, proarrhythmia, and drug-induced ventricular tachycardia, supplemented by pertinent references (dating back to 1964) from the reviewed articles and by personal communications with researchers involved in this field. STUDY SELECTION Ninety-three articles were identified describing at least one case of polymorphic ventricular tachycardia (with gender specified) associated with quinidine, procainamide hydrochloride, disopyramide, amiodarone, sotalol hydrochloride, bepridil hydrochloride, or prenylamine. A total of 332 patients were included in the analysis following application of prospectively defined criteria (eg, corrected QT [QTc] interval of 0.45 second or greater while receiving drug). DATA EXTRACTION Clinical and electrocardiographic descriptors were extracted for analysis. Expected female prevalence for torsades de pointes associated with quinidine, procainamide, disopyramide, and aminodarone was conservatively estimated from gender-specific data reported for antiarrhythmic drug prescriptions in 1986, as derived from the National Disease and Therapeutic Index, a large pharmaceutical database; expected female prevalence for torsades de pointes associated with sotalol, bepridil, and prenylamine was assumed to be 50% or less since these agents are prescribed for male-predominant cardiovascular conditions. RESULTS Women made up 70% (95% confidence interval, 64% to 75%) of the 332 reported cases of cardiovascular-drug-related torsades de pointes, and a female prevalence exceeding 50% was observed in 20 (83%) of 24 studies having at least four included cases. When analyzed according to various descriptors, women still constituted the majority (range, 51% to 94% of torsades de pointes cases), irrespective of the presence or absence of underlying coronary artery or rheumatic heart disease, left ventricular dysfunction, type of underlying arrhythmia, hypokalemia, hypomagnesemia, bradycardia, concomitant digoxin treatment, or level of QTc at baseline or while receiving drug. When cases of torsades de pointes were analyzed by individual drug, observed female prevalence was always greater than expected, representing a statistically significant difference (P < .05) for all agents except procainamide. CONCLUSIONS These findings strongly suggest that women are more prone than men to develop torsades de pointes during administration of cardiovascular drugs that prolong cardiac repolarization. The pathophysiological basis for, and therapeutic implications of, this gender disparity should be further investigated.

Preoperative Amiodarone as Prophylaxis against Atrial Fibrillation after Heart Surgery

Background Atrial fibrillation occurs commonly after open-heart surgery and may delay hospital discharge. The purpose of this study was to assess the use of preoperative amiodarone as prophylaxis against atrial fibrillation after cardiac surgery. Methods In this double-blind, randomized study, 124 patients were given either oral amiodarone (64 patients) or placebo (60 patients) for a minimum of seven days before elective cardiac surgery. Therapy consisted of 600 mg of amiodarone per day for seven days, then 200 mg per day until the day of discharge from the hospital. The mean (±SD) preoperative total dose of amiodarone was 4.8±0.96 g over a period of 13 ± 7 days. Results Postoperative atrial fibrillation occurred in 16 of the 64 patients in the amiodarone group (25 percent) and 32 of the 60 patients in the placebo group (53 percent) (P = 0.003). Patients in the amiodarone group were hospitalized for significantly fewer days than were patients in the placebo group (6.5 ± 2.6 vs. 7.9 ± 4.3 days, P = 0.04). ...

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.

Effect of Ibutilide, a New Class III Agent, On Sustained Atrial Fibrillation in a Canine Model of Acute Ischemia and Myocardial Dysfunction Induced By Microembolization

The effect of ibutiJide, a new Class III antiarrhythmic agent, upon acute onset atriai fibriJIation was investigated in a closed‐chest canine model of acute left ventricular fLVj dysfunction. Twenty‐four anesthetized mongrel dogs, mean weight 24.9 ± 4 kg were subjected to coronary artery microsphere emboiization and volume Joading, followed by attempted induction of atrial fihrillation (AF) by rapid atrial pacing. Acute ischemic LV dysfunction was successfully induced by emboiization in aii dogs, and caused significant (P < 0.02) decreases in LV systolic pressure, peak + dp/dt (and − dp/dtj, stroke volume, and RR interval; whereas LV end diastolic pressure and QTc significantiy increased. Sustained AF (≥ 30 min) was successfully induced in 15 of 24 dogs (62%) and unsustained AF (< 30 min) was induced in the remainder (38%). At 30 minutes after induction of sustained AF, 15 dogs were randomized to intravenous ibutiiide (0.15 mg/kg, given as a 0.075 mg/kg bolus, followed by 0.075 mg/kg infusion over 1 hour; n = 7) or placebo (saline; n = 8). There were no statistically significant differences between the ibutilide and the placebo groups with respect to mean LV systolic pressure, LV end diastoJic pressure, LV dp/dt, RR intervaJ, or QTc intervaJ during AF prior to infusion. All seven dogs receiving ibutiJide converted to sinus rhythm after a median of 3 minutes (range 0.5–26 min), whiJe onJy three of eight pJacebo dogs (P < 0.03J converted to sinus rhythm after a median duration of 30 minutes (range 15–60 min) (P < 0.04 for difference in time to conversionj. QTc prolonged by 27 ± 17%, 1 hour after ibutiJide, but was unaJtered after pJacebo (P ≥ 0.02). There were no significant hemodynamic changes after either ibutiJide or pJacebo. We concJude that: (1) sustained AF (> 30 min) can be readily induced in this closed‐chest animal model and used t o test antiarrhythmic agents acutely; and (2) intravenous ibutiJide is effective in rapidJy terminating acute onset AF; the drug prolongs the QTc intervaJ but does not exacerbate preexisting hemodynamic compromise in the acutely ischemic LV.

Differentiation of sinus tachycardia from ventricular tachycardia with 1: 1 ventriculoatrial conduction in dual chamber implantable cardioverter defibrillators: Feasibility of a criterion based on the atrioventricular interval

Tachycardia discrimination in future implantable cardioverter defibrillators (ICDs) is likely to be enhanced by the addition of an atrial sensing/pacing lead. However, differentiation of sinus tachycardia (ST) from ventricular tachycardia (VT) with 1:1 VA conduction will remain problematic. We assessed the use of the AV interval as a potential criterion for correctly differentiating ST from VT. Incremental V pacing at the right ventricular (HV) apex served as a “VT” model in each of 41 patients with 1:1 VA conduction to pacing cycle lengths ≤ 450 msec. High right atrial and RV apical electrograms during normal sinus rhythm (NSR) and during incremental V pacing were digitized (simulating ICD sensing). From these signals, AV interval versus pacing cycle length plots were computer generated to identify crossover cycle lengths, each defined as the cycle length at which the AV interval during V pacing equals the AV interval during NSR. At cycle lengths longer than the crossover value, the AV interval during “VT” exceeds the AV interval during NSR. In contrast, the AV interval during ST is physiologically shorter than the AV interval during NSR. Thus, ST can be readily differentiated from “VT” over a range of cycle lengths greater than the crossover value. The overall mean calculated crossover cycle length was 371 ± 52 msec. In 11 patients paced multiple times, each crossover cycle length was reproducible (mean coefficient of variation was 1.2%± 0.9% per patient). AV intervals measured at the RV apex were also analyzed with incremental V pacing during catecholamine stimulation (isoproterenol, n = 5) and during alternate site “VT” (RV outflow tract [n = 8] and left ventricle [n = 2]). In all these cases, the new “VT” plots of AV interval versus pacing cycle length coincided with or fell to the left of those obtained during control RV apical pacing and recording (i.e., these AV interval values crossed the NSR baseline at cycle lengths ≤ the crossover cycle length). Thus, the cycle length range for recognizable differentiation of ST from “VT” remained valid. The data suggest that the described AV interval criterion relying on the crossover cycle length: (1) is a promising approach to improve differentiation of ST from relatively slow VTs with 1:1 VA conduction, and (2) can readily be automated in future dual chamber ICDs, given its computational simplicity.

Ventriculoatrial conduction capability and prevalence of 1: 1 retrograde conduction during inducible sustained monomorphic ventricular tachycardia in 305 implantable cardioverter defibrillator recipients

Retrograde Conduction During Inducible Sustained Monomorphic Ventricular Tachycardia in 305 Implantable Cardioverter Defibrillator Recipients. Despite the advent of dual chamber ICDs, differentiation of VT (SMVT) with 1:1 VA conduction will remain a challenge. In this study, VA conduction capability and prevalence of inducible sustained monomorphic (SM) VT with 1:1 VA conduction was assessed in 305 ICD recipients. SMVT with a mean cycle length (CL) of 304 ± 61 ms was induced in 161 (53%) patients. Twenty‐six percent of the patients maintained 1:1 VA conduction to CL ≤ 400 ms during incremental ventricular pacing, regardless of presenting tachyarrhythmia or presence of inducible SMVT. Among ten patients who had inducible SMVT with possible 1:1 VA conduction (based on SMVT CL comparable to the shortest CL associated with 1:1 retrograde conduction during ventricular pacing), all seven with available intracardiac tracings had documented 1 :1 VA conduction during the induced SMVT—representing 4.4% of the patients with inducible SMVT (95% CI 1.2%‐7.6%), and 2.3% of the entire ICD cohort (95% CI 0.6%‐4.0%). We conclude that about one‐fifth of ICD recipients possess 1:1 VA conduction to CL ≤ 400 ms and that inducible SMVT with 1:1 VA conduction can be demonstrated in a small hut nonnegligible proportion of ICD recipients. These data are relevant to the design of tachyarrhythmia‐discrimination algorithms for dual chamber ICDs.

Quantitating AV nodal function: Has A1A2 outlived its usefulness?

Over five decades ago, Lewis’ observed that the PR interval could be considered a function of the prior RP, i.e., PR lengthened as P fell closer to the immediately preceding R. Once it was appreciated that the AV conduction time consisted of atrial, AV nodal, and His-Purkinje system components, the relationship described by Lewis was recast in terms of AH being a function of the HA “recovery i n t e r ~ a l ” . ~ The empiric graphic plots relating AH to HA (or, equivalently, AV to VA) have been fitted to exponential or hyperbolic functions that have been used with fairly good accuracy to predict beat-to-beat AV nodal conduction times during 1:1 conduction or Wenckebach b l o ~ k . ~ . ~ However, the AV interval can also be modeled as a function of AA, with good experimental agreement.6 Given the algebraic relationship AA = AV + VA, if one of these parameters is held constant, say, AA, any change in one of the remaining two parameters must be accompanied

Prominent ECG repolarization changes associated with intracoronary infusion of normal saline: Comparisons with alternate coronary catheter flush solutions

Normal saline (NS) is commonly used as a coronary catheter flush solution. We tested the hypothesis that intracoronary (i.c.) infusions of lactated Ringers solution (LR) and LR with 5% dextrose (D5LR), both of which contain potassium and calcium, would be associated with less prominent surface ECG changes compared with i.c. infusions of NS. In 34 patients, 10 mL each of NS, LR, and D5LR at 37°C were infused over 5 sec into the left main coronary artery. A 12‐lead ECG was recorded before, continuously during, and after each infusion. Blinded ECG analysis revealed T‐wave amplitude changes > 0.2 mV in 94%, 12%, and 3% of patients with the use of i.c. NS, D5LR, and LR, respectively (P < 0.0001, NS vs. D5LR or LR). QT prolongation > 40 msec occurred in 88%, 15%, and 18% of patients with i.c. NS, D5LR, and LR, respectively (P < 0.0001, NS vs. D5LR or LR). QT dispersion was increased by > 40 msec in 26% of patients during i.c. NS infusion compared to only 3% of patients with i.c. LR and D5LR infusions (P < 0.01). In conclusion, i.c. NS infusion is associated with more marked repolarization changes as compared with i.c. LR and D5LR infusions. Since such changes may lower arrhythmogenesis thresholds, the routine use of LR as a coronary catheter flush solution should be considered. Cathet. Cardiovasc. Intervent. 48:359–364, 1999.

Syncope: Mechanisms and Management: Blair P. Grubb, MD. 416 pp. Armonk, NY: Futura Publishing Company, Inc; 1997.

The challenge of tackling the problem of syncope is not for the faint of heart. So diverse are the mechanisms, and often so transient is the presentation and so elusive the specific cause, that patients and medical care providers alike are left frustrated. Syncope exacts an enormous personal and economic toll and has potentially serious medical-legal implications. Thus, it is rather remarkable that to date there has been no truly comprehensive book on the subject. Enter Grubb, Olshansky, and 22 other contributors, who have succeeded admirably in their aim “to bring together in one volume a comprehensive yet usable source on syncope.” The book reads easily, is well organized and referenced, and is liberally seasoned with useful tables, figures, and “real-life” cases …

89.00. ISBN 0-87993-6835.

BACKGROUND Atrial fibrillation occurs commonly after open-heart surgery and may delay hospital discharge. The purpose of this study was to assess the use of preoperative amiodarone as prophylaxis against atrial fibrillation after cardiac surgery. METHODS In this double-blind, randomized study, 124 patients were given either oral amiodarone (64 patients) or placebo (60 patients) for a minimum of seven days before elective cardiac surgery. Therapy consisted of 600 mg of amiodarone per day for seven days, then 200 mg per day until the day of discharge from the hospital. The mean (+/-SD) preoperative total dose of amiodarone was 4.8+/-0.96 g over a period of 13+/-7 days. RESULTS Postoperative atrial fibrillation occurred in 16 of the 64 patients in the amiodarone group (25 percent) and 32 of the 60 patients in the placebo group (53 percent) (P=0.003). Patients in the amiodarone group were hospitalized for significantly fewer days than were patients in the placebo group (6.5+/-2.6 vs. 7.9+/-4.3 days, P=0.04). Nonfatal postoperative complications occurred in eight amiodarone-treated patients (12 percent) and in six patients receiving placebo (10 percent, P=0.78). Fatal postoperative complications occurred in three patients who received amiodarone (5 percent) and in two who received placebo (3 percent, P= 1.00). Total hospitalization costs were significantly less for the amiodarone group than for the placebo group (