Editorial

When is QT prolongation antiarrhythmic and when is it proarrhythmic?☆

We studied ten women (age: 40±12 years) with primary hypothyroidism. Baseline and after T4 treatment (euthyroid stage), all patients’ resting ECGs were recorded. After T4 treatment, QTd (P=0.036), QTad (P=0.016), JTd (P=0.0001), JTad (P=0.005), Ted (P=0.036), QRS (P=0.046), QTcd (P=0.036), QTacd (P=0.028), JTcd (P=0.006), JTacd (P=0.016), Tecd (P=0.036) values shortened in patients with hypothyroidism. We found that regional inhomogeneity of ventricular repolarization in patients with hypothyroidism improves after T4 treatment.

Background This study was designed to assess the efficacy and safety of intravenous dofetilide in acute termination of atrial fibrillation (AF) and flutter (AFL). Dofetilide, an investigational class III antiarrhythmic agent, selectively inhibits the rapid component of the delayed rectifier potassium current, thus prolonging the effective refractory period and duration of the action potential. Dofetilide can be administered intravenously and has a rapid onset of electrophysiologic action. Methods and Results Ninety-six patients with AF (n = 79) or AFL (n = 17) with a median arrhythmia duration of 62 days (range 1 to 180) were randomized to placebo (n = 30) or 8 μg/kg IV dofetilide (n = 66) over 30 minutes. Conversion was defined as termination of the atrial arrhythmia within 3 hours from the start of infusion. The conversion rate was 30.3% after dofetilide and 3.3% after placebo (P < .006). Conversion rate was higher in AFL than in AF: 64% versus 24% (P = .012). In nonconverters, there was no statistically significant difference between the change in heart rate among the dofetilide-treated compared with the placebo-treated patients (P = .42). Torsade de pointes ventricular tachycardia developed in 2 patients (3%). In both patients, drug infusion was discontinued before the event because of prolongation of the QT interval. Conclusions Intravenous dofetilide is effective in acute termination of AF and AFL of medium duration, with a particularly high efficacy rate in AFL. A small but serious risk of proarrhythmia must be anticipated. (Am Heart J 1999;137:1062-9.)

The inadequacy of the QT interval to shorten following heart rate increase is a feature of the inherited long QT syndrome and may have a role in the genesis of the typical arrhythmias associated with this syndrome (torsade des pointes). The aim of our study was to evaluate whether drugs that prolong the QT interval, such as amiodarone andd-sotalol, may also impair the ability of the QT interval to adapt to sudden heart rate changes. Experiments were carried out on isolated perfused guinea pig hearts (Langendorff preparation). Driving frequency was changed, in steps, every two minutes (Hz: 2·5–3–2·5–3·75–2·5–5–2·5), while epicardial ECG was continuously recorded on magnetic tape. QT interval was automatically measured by means of a beat-by-beat analysis program.d-sotalol was added to the perfusion medium at a concentration of 4 μg ml⁻¹, while amiodarone was administered, before in vitro evaluation, for seven days (50 mg kg⁻¹per day, intraperitoneally). In control experiments two phases of QT adaptation were identified: an abrupt QT shortening at the first beat after frequency change (QT₁), followed by a gradual, exponential QT shortening that reached a new steady state in about 1 min (half life: 13 sec). The electrical restitution curve (the relation between QT₁and the corresponding diastolic interval) had a rate constant of 57±8 ms. Neither drug changed the slow component of QT adaptation. However, both drugs increased the ability of QT to shorten upon premature stimulation:d-sotalol by increasing the rate constant of the restitution curve and amiodarone by decreasing the y-intercept. Our results indicate thatd-sotalol and amiodarone do not impair QT shortening during tachycardia but, on the contrary, they may favour QT adaptation, thus reducing the likelihood of the potentially lethal ‘R on T phenomenon’. This may be an additional mechanism by which these drugs can exert their antifibrillatory action.

Objectives. This study sought to determine the safety and efficacy of a single bolus of intravenous dofetilide, a pure class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter.

Background. Dofetilide is a highly selective blocker of the rapid component of the delayed rectifier current causing action potential prolongation. These effects, and preliminary clinical data, suggest that it may be effective in the treatment of atrial fibrillation and flutter.

Methods. Ninety-one patients with sustained atrial fibrillation (75 patients) or flutter (16 patients) were entered into a double-blind, randomized multicenter study of one of two doses of dofetilide (4 or 8 μg/kg body weight) or placebo.

Results. Dofetilide effectively terminated the arrhythmia in 31% of patients receiving 8 μg/kg, a statistically significant difference from those receiving 4 μg/kg (conversion rate 12.5%, p < 0.05) or placebo (no conversion, p < 0.01). Patients with atrial flutter had a greater response to dofetilide (54% conversion rate) than those with atrial fibrillation (14.5% conversion rate, p < 0.001).

Conclusions. Intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm. However, its efficacy is greater in flutter—a response that contrasts with the poorer response seen with class I agents. This finding potentially represents an important advance in the pharmacologic termination of atrial flutter.

(J Am Coll Cardiol 1997;29:385–90)