Barbara S. Fromm

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.

Age-Gender Influence on the Rate-Corrected QT Interval and the QT-Heart Rate Relation in Families With Genotypically Characterized Long QT Syndrome

OBJECTIVES We sought to analyze age-gender differences in the rate-corrected QT (QTc) interval in the presence of a QT-prolonging gene. BACKGROUND Compared with men, women exhibit a longer QTc interval and an increased propensity toward torsade de pointes. In normal subjects, the QTc gender difference reflects QTc interval shortening in men during adolescence. METHODS QTc intervals were analyzed according to age (< 16 or > or = 16 years) and gender in 460 genotyped blood relatives from families with long QT syndrome linked to chromosome 11p (KVLQT1; n = 199), 7q (HERG; n = 208) or 3p (SCN5A; n = 53). RESULTS The mean QTc interval in genotype-negative blood relatives (n = 240) was shortest in men, but similar among women, boys and girls. For genotype-positive blood relatives, men exhibited the shortest mean QTc interval in chromosome 7q- and 11p-linked blood relatives (n = 194), but not in the smaller 3p-linked group (n = 26). Among pooled 7q- and 11p-linked blood relatives, multiple regression analysis identified both genotype (p < 0.001) and age-gender group (men vs. women/children; p < 0.001) as significant predictors of the QTc interval; and heart rate (p < 0.001), genotype (p < 0.001) and age-gender group (p = 0.01) as significant predictors of the absolute QT interval. A shorter mean QT interval in men was most evident for heart rates < 60 beats/min. CONCLUSIONS In familial long QT syndrome linked to either chromosome 7q or 11p, men exhibit shorter mean QTc values than both women and children, for both genotype-positive and -negative blood relatives. Thus, adult gender differences in propensity toward torsade de pointes may reflect the relatively greater presence in men of a factor that blunts QT prolongation responses, especially at slow heart rates.

Probucol-associated tachyarrhythmic events and QT prolongation: Importance of gender

From published articles and adverse reactions reports filed with the FDA (available through the Freedom of Information Act), we analyzed occurrences of tachyarrhythmias and the magnitude of QTc prolongation associated with probucol therapy. Of 16 cases of tachyarrhythmic events reported in association with probucol, 15 (94%) occurred in women (p < 0.01 vs expected value of 58%). Tachyarrhythmias were specifically described as TdP in 11 (63%) cases, all women; additional potential contributory QT-prolonging factors (besides probucol) were not identifiable in 2 of the 11 cases. We also analyzed QTc responses in 359 probucol-treated patients, all having baseline QTc < or = 0.44 sec1/2. At doses of 500 to 1000 mg/day, probucol-associated prolongation of QTc to values > or = 0.45 sec1/2 was observed in 22% of women versus 7% of men (p < 0.001) and to values > or = 0.47 sec1/2 in 8% of women versus 2% of men (p < 0.03). Multivariate analysis identified baseline QTc (p < 0.0001) and female gender (p < 0.03), but neither age nor dose, as significant independent predictors of QTc prolongation to > or = 0.45 sec1/2 with probucol. These findings have relevance to the clinical use of probucol, provide further evidence that women have a relatively greater predisposition to development of acquired long QT syndrome, and carry implications for the design of trials involving QT-prolonging drugs.

Percutaneous coronary laser balloon angioplasty: Initial results of a multicenter experience

A multicenter clinical trial was initiated to test the potential safety and short-term efficacy of a percutaneous coronary application of laser balloon angioplasty, which has been shown experimentally to alleviate the common causes (dissection, recoil, thrombus) of suboptimal luminal results of conventional balloon angioplasty. Fifty-five patients, the majority (62%) of whom had relatively high risk lesions, were treated in 10 centers with a laser balloon that was identical in size (3 x 20 mm) to a balloon used for conventional balloon angioplasty performed on the same lesion immediately before laser balloon angioplasty. One or more neodymium:yttrium aluminum garnet (Nd:YAG) (1,060 nm) laser doses of 250 to 450 J were each delivered over a 20 s duration per exposure. Immediately and 1 day after laser balloon angioplasty no significant adverse effects on the arterial lumen were noted in any patient. By computerized image analysis of cineangiograms initial conventional balloon angioplasty failed to achieve a minimal luminal diameter greater than 1.5 mm in 14 patients (25%), including 3 patients with acute closure. However, after subsequent laser balloon angioplasty, minimal luminal diameter exceeded this value in all patients including this subgroup. Overall, minimal luminal diameter increased from 1.74 +/- 0.46 mm after conventional balloon angioplasty to 2.32 +/- 0.31 mm after laser balloon angioplasty (p less than 0.001) with no change found on 1 day and 1 month follow-up angiograms. Thus, laser balloon angioplasty is a safe, effective procedure for improving luminal dimensions after conventional balloon angioplasty.

Implantable cardioverter-defibrillator therapy in 300 patients with coronary artery disease presenting exclusively with ventricular fibrillation

To determine outcomes of implantable cardioverter-defibrillator (ICD) therapy in a uniform population of survivors of sudden cardiac death, we used epicardial defibrillation lead systems to study 300 patients with coronary artery disease (CAD) presenting exclusively with ventricular fibrillation (VF) unassociated with acute myocardial infarction. Operative (30-day) mortality, 2.7% overall, was lower (0.6%) in patients with ejection fractions (EF) > or = 0.30. Over a median follow-up of 1.9 years, cumulative actuarial shock incidence was similar in patients who underwent concomitant coronary artery bypass graft (CABG) surgery (38%) and in those who did not. The 2-year cumulative actuarial incidences of any or appropriate shocks were 65% and 38%, respectively. Sudden death survival at 2 years was 92.5% and 99.3% for patients with EFs < or = 0.30 and > 0.30, respectively. The total mortality rate was similar in shocked and in unshocked patients. Multivariate analysis identified EF and female gender as significant predictors of any and appropriate shock occurrence (all p values < or = 0.05) and EF as a significant predictor of sudden, cardiac, and total mortality (all p values < 0.03). We conclude that in CAD patients presenting exclusively with VF unassociated with acute myocardial infarction and treated with thoracotomy-requiring ICD therapy: (1) operative (30-day) mortality is minimal for patients with an EF > or = 0.30; (2) device use is high and sudden death rates low regardless of concomitant CABG; (3) low EF is a significant predictor of cumulative shock occurrence and mortality (sudden, cardiac, and total); (4) female gender may be a predictor of shock occurrence; and (5) similar mortalities and low sudden-death rates in shocked and nonshocked ICD patients imply that ICD therapy improves survival in shocked patients to a level observed in comparable patients in whom ventricular tachyarrhythmia does not recur.

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.

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.

Retrospective comparative study of primary intracoronary stenting versus balloon angioplasty for acute myocardial infarction

Balloon angioplasty has been shown to be an effective therapy for the treatment of acute myocardial infarction but is associated with a high restenosis rate, substantial early recoil, persistent thrombus and need for intracoronary thrombolysis, and a high rate of reclosure. Because many of the limitations of balloon angioplasty in the noninfarction setting are addressed by intracoronary stenting, we examined the results of primary stenting of 18 consecutive patients treated for acute myocardial infarction, and compared the results to those achieved with primary balloon angioplasty in 18 prior cases. Despite the presence of thrombus prior to angioplasty in 13 of the stented patients, no intracoronary thrombolytic therapy was required. Mean percent stenosis using quantitative coronary angiography was 17.7 +/- 10.2% after primary stenting compared with 43.7 +/- 20.3% after primary balloon angioplasty (P < .001). One stent patient who had all anticoagulant and antiplatelet therapy withdrawn early suffered subacute thrombosis. Patients were followed up to 3 yr. Complications were similar in two groups. We conclude that primary stenting for acute myocardial infarction results in superior angiographic appearance as well as resolution of thrombus without the need for routine thrombolysis, and is associated with a low complication rate and excellent short-term clinical patency.

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)

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.