Russell T. Steinman

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

OBJECTIVEnTo 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.nnnDATA SOURCESnA 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.nnnSTUDY SELECTIONnNinety-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).nnnDATA EXTRACTIONnClinical 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.nnnRESULTSnWomen 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.nnnCONCLUSIONSnThese 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.

Maximal Ascending and Descending Slopes of the T Wave in Men and Women

To investigate possible sex differences in the dynamics of T wave generation, the maximum instantaneous slope of the ascending and descending limbs of the T wave (max dV/dt and min dV/dt, respectively), were calculated. These rate of repolarization parameters, as well as more traditional repolarization duration parameters (QT, JT, Q to T wave peak [QTm] and J to T wave peak [JTm]), were measured by computer using digitized electrocardiograms (ECGs) from the V5 lead in 562 normal subjects (443 men and 119 women; mean age 37 years), whose heart rates (HRs) were confined to one of three narrow ranges, namely 60 +/- 1, 70 +/- 1, or 80 +/- 1 beats/min. In both men and women, for each HR range absolute values of min dV/dt exceeded those of max dV/dt (P < .0001). However, absolute values of both max dV/dt and min dV/dt were consistently greater in men than in women for each HR range (P < .0001 at HR 60 +/- 1; P < .02 at HR 70 +/- 1, or 80 +/- 1). By using correlation analysis, max dV/dt and min dV/dt were shown to be independent of the repolarization duration variables (r < .30). Thus, whereas in both men and women the descending limb of the T wave is steeper than the ascending limb, the maximum slope of each limb of the T wave is steeper in men than in women. These findings add to a growing body of data indicating fundamental sex differences in the physiology of cardiac repolarization and propensity to torsade de pointes.

Programmed electrical stimulation to determine the need for antiarrhythmic therapy in patients with complex ventricular ectopic activity

Patients with complex ventricular ectopy (greater than or equal to Lown grade III) and organic heart disease (OHD) are at increased risk for sudden cardiac death. Despite this fact, many such patients will remain free of symptomatic ventricular arrhythmia and thus are unnecessarily exposed to antiarrhythmic drug toxicity and arrhythmic potentiation. Programmed stimulation (PS) was used to direct therapy in 88 patients with asymptomatic ventricular ectopy complicating OHD. Thirty-three had inducible ventricular tachycardia (VT) and underwent treatment. The 55 patients without inducible VT (less than or equal to 6 repetitive ventricular responses) are the focus of this study. Three patients required treatment for persistent cardiac awareness. The remaining 52 have been followed for 22 months off antiarrhythmic drugs and all have remained free of subsequent major arrhythmic events. Therefore, in patients with complex ventricular ectopy, OHD, and absence of prior symptomatic ventricular arrhythmia, PS identifies patients at low risk for future disabling or life-threatening arrhythmic episodes and patients with absence of inducible VT can usually be managed without antiarrhythmic drugs.

Torsade de pointes as a complication of subarachnoid hemorrhage: A critical reappraisal

Subarachnoid hemorrhage is widely accepted as a potential cause of torsade de pointes (TdP), yet this putative etiologic relationship has never been systematically evaluated. We therefore undertook a MEDLINE search from 1966 through 1993, with relevant back referencing, and identified 20 cases of TdP in the setting of subarachnoid hemorrhage. It was impossible in any of these cases (usually because of insufficient data) to completely exclude one or more alternative explanations for TdP, including congenital long QT syndrome, hypokalemia, hypomagnesemia, or drug-induced QT prolongation. Furthermore, of a total of 1,139 patients in 16 prospective series of subarachnoid hemorrhage with electrographic analyses, there were only five reported cases of TdP, all in patients with hypokalemia. Thus, extremely limited scientific data exist to support the notion that subarachnoid hemorrhage can be a distinct cause of TdP. Until more definitive evidence is available, the development of TdP in patients with subarachnoid hemorrhage is probably better characterized as a multifactorial phenomenon occurring in an acute, typically intensive care, setting.

Long-term arrhythmic outcome in survivors of ventricular fibrillation with absence of inducible ventricular tachycardia

While programmed electrical stimulation of the heart is useful in directing therapy in cardiac arrest survivors who exhibit inducible ventricular tachycardia (VT), controversy exists as to the risk of recurrent ventricular fibrillation (VF) and need for antiarrhythmic therapy in patients without inducible VT during drug-free control programmed stimulation studies. In this study, the clinical features and arrhythmic outcome of 43 survivors of VF without inducible VT at control programmed stimulation were examined. In 38 patients, factors that may have played a potentiating role in the genesis of VF included ischemia in 15, proarrhythmia in 18, rapid rate response to atrial fibrillation in 3 and acute alcoholism in 2. Three patients required antiarrhythmic drugs for supraventricular tachyarrhythmia and 40 patients were discharged without antiarrhythmic therapy. At 32 +/- 21 months (range 1 to 82), 37 (92%) have remained free of arrhythmic recurrence while 3 have had sustained subsequent major arrhythmic events (syncope 1 patient, VF 1, sudden cardiac death 1). Thus, survivors of VF without inducible VT at drug-free control programmed stimulation are characterized by (1) potentiating factors--often identifiable and correctable--that may be important to the genesis of VF; (2) generally low risk of arrhythmic recurrence; and (3) effective long-term management often achieved without the use of additional antiarrhythmic drugs or antitachycardia/defibrillation devices.

Outcome with implantable cardioverter-defibrillator therapy for survivors of ventricular fibrillation secondary to idiopathic dilated cardiomyopathy or coronary artery disease without myocardial infarction

Patients with idiopathic dilated cardiomyopathy (IDC) constitute a minority among implantable cardioverter-defibrillator (ICD) recipients; how these patients fare versus those with coronary artery disease (CAD) is not well defined, nor is the mechanism of cardiac arrest recurrence, which may involve a more significant role of bradyarrhythmias. A retrospective multicenter study regarding outcome of ICD therapy was conducted in 224 patients with either IDC (n = 69; 31%) or CAD (n = 155; 69%) presenting exclusively with ventricular fibrillation (VF) unassociated with acute myocardial infarction. Patients with IDC were significantly younger (mean age 57 vs 61 years in patients with CAD, p < 0.04) and less male predominant (64 vs 79% in patients with CAD, p < 0.02). There was no significant difference in mean left ventricular ejection fraction (0.27 in IDC patients vs 0.29 in CAD patients), but sustained ventricular tachycardia was induced less often in patients with IDC (21 vs 58% in CAD patients, p < 0.001). Bradycardia pacing, either by an ICD with bradycardia pacing ability or a separate bradycardia pacemaker, was available in only 15% of ICD implantees. During a median follow-up duration of 1.7 years for patients with IDC and 1.9 years for patients with CAD, estimated cumulative event rates were similar for any type shock (2-year incidence of 74% in IDC patients, 69% in CAD patients) as well as for appropriate shock (2-year incidence of 46% in IDC patients, 40% in CAD patients).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Sudden Death Despite ICD Therapy: Why Does It Happen?

THE PRECISE role of ICD therapy in managing patients with sustained ventricular tachyarrhythmias remains controversial and is currently an area of active investigation.1 There is little debate, however, that ICD therapy can abort cardiac arrest due to sustained ventricular tachyarrhythmias.1,2 Although sudden death is strikingly reduced compared to the incidence observed in historical or certain other types of control populations (Chap. 22), fatal unexpected cardiac arrest may still occur in the ICD patient.

926-27 Probucol-associated Arrhythmic Events: Further Evidence for Increased Female Predisposition to Acquired Long QT Syndromes

Recent data suggest an increased female susceptibility to torsade de pointes (TdP) during exposure to cardiac drugs that prolong the QT interval. We investigated possible gender differences in the occurrence of arrhythmic events in pts taking Probucol (P), a lipid lowering agent that prolongs QTc. A MED- LINE search along with data obtained from the Food and Drug Administration, identified a total of 16 reported pts with arrhythmic events (TdP-10, VF-2, VT-2, cardiac arrest-2) during P therapy (median P dose 1000xa0mg/day, for median duration 1 yr). Of these 16 pts, 15 (94%) were female; yet, during approximately the same time period of these reports (from 1979–1991), nationwide P exposure, according to a large pharmacological database (IMS America), was only 60% female (pxa0lxa00.01). Among 10 of the reported pts having known QT interval data, 8 (80%) exhibited marked QTc prolongation (xa0gxa00.60xa0sec)on P. Nine of the 16 pts had additional potential causes of QT prolongation (Class IA agents-3, hypokalemia-2, prolonged baseline QTc-2, prolonged baseline QT/hypokalemia-1, Class IA agent/hypokalemia-1). In the 3 reported cases of TdP without concomitant causes of QT prolongation, all were female. From pooled studies, we also analyzed a total of 357 asymptomatic pts (64% female) with normal baseline QTc (xa0≤xa00.44xa0sec) in whom QTc intervals were obtained both prior to and during P therapy (median P dose 500xa0mg/day, for both men and women). On P, QTc wasxa0gxa00.45xa0sec in 16% of women (up to 0.51xa0sec) vs 3% men (up to 0.49xa0sec) [pxa0lxa00.001] and wasxa0≥xa00.47xa0sec in 8% of women vs 2% men [pxa0lxa00.03]; logistic regression revealed pre-P QTc (pxa0=xa00.0001) and female gender (pxa0=xa00.01) to be significant predictors of P-induced QTc prolongation (xa0gxa00.45xa0sec). Conclusions (1) Women appear to have increased susceptibility to Probucol-associated arrhythmic events (primarily TdP); (2) Probucol-associated arrhythmic events occur mainly, but not exclusively, in pts with additional conditions which may prolong QTc; (3) Even in the absence of Tdp, women are more likely to exhibit significant Probucol-induced QTc prolongation, suggesting a clinical continuum in the differential QT interval response of women to the drug.