John J. Baga

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.

Sudden death in implantable cardioverter-defibrillator recipients: clinical context, arrhythmic events and device responses

OBJECTIVES We sought to investigate the nature of terminal events and potential contributory clinical and nonclinical (e.g., device-related) factors associated with sudden death (SD) in recipients of an implantable cardioverter-defibrillator (ICD). BACKGROUND The ICD is very effective in terminating ventricular tachycardia (VT) or ventricular fibrillation (VF), but protection against SD is not absolute. Little is known about the nature and potential causes of SD in patients with ICDs. METHODS We analyzed 25 cases of out-of-hospital SD among patients enrolled in the clinical investigation of the Cadence Tiered-Therapy Defibrillator System. RESULTS All patients (24 men and 1 woman, mean age 62+/-10 years) received epicardial lead systems. The majority (92%) had coronary artery disease and a previous myocardial infarction (MI), with a mean left ventricular ejection fraction 0.25+/-0.07. At device implantation, the mean defibrillation threshold was 13+/-5 J. Sudden death occurred 13+/-11 months later. Twenty patients (80%) had received appropriate ICD therapies before death, and 18 (72%) were receiving > or = 1 antiarrhythmic drugs at the time of death. Sudden death was tachyarrhythmia-associated in 16 patients (64%), non-tachyarrhythmia-associated in 7 (28%) and indeterminate in 2 (8%). In the 16 patients with tachyarrhythmia-associated SD, the overall first therapy success rate in tachycardia and fibrillation zones was 60% and 67%, respectively. However, despite protracted therapies (> or = 2 shocks) in 7 (66%) of 12 patients who received fibrillation therapies, the final tachyarrhythmic episode was ultimately terminated by the ICD in 15 (94%) of the 16 patients, whereas 1 patient died after multiple (initially successful) internal and external shocks for intractable VT/VF during exercise. In 10 patients (40%) one or more, primarily clinical, factors potentially contributory to SD were identified: heart failure (n=8), angina (n=2), hypokalemia (n=1), adverse antiarrhythmic drug treatment (n=1) and acute MI (n=1). An additional 10 patients (40%) had experienced an increase in frequency of ICD shocks within 3 months of SD. Appropriate battery voltages and normal circuitry function were found in all devices interrogated and analyzed after death. CONCLUSIONS In this select group of patients receiving a third-generation ICD, SD was associated with VT or VF events in nearly two-thirds of patients, and death occurred despite ultimately successful, although often protracted, device therapies. These observations, along with evidence of recent worsening clinical status, suggest acute cardiac mechanical dysfunction as a frequent terminal factor. In recipients with ICDs, SD directly attributable to device failure seems to be rare.

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.

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.

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.

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.