Mechanism of lethal proarrhythmia observed in the Cardiac Arrhythmia Suppression Trial: role of adrenergic modulation of drug binding.

A variety of recent in vivo studies have sought to clarify the mechanism underlying the proarrhythmic response of flecainide in the Cardiac Arrhythmia Suppression Trial (CAST). Increased inducibility of relatively stable ventricular arrhythmias in subacute and chronic postinfarction models has been universally observed. The arrhythmogenesis has been explained in part by drug induced modulation of anisotropic conduction in persistently ischemic tissue, increased durations of vulnerable windows, enhanced generation of unidirectional block with the introduction of extrastimuli, variability of repolarization within the ventricular wall, and the creation of stable reentrant circuits with narrow central zones of propagation. While these data explain arrhythmogenesis in general, malignant ventricular arrhythmia capable of producing the excess sudden or arrhythmic death mortality in the CAST trial have not been universally observed, nor have the proported beneficial effects of beta-blockade seen in the CAST trial and other studies been explained. Additional studies examining the adrenergic modulation of flecainide binding have shown reversal of flecainide effects in normal tissue, but paradoxical amplification of flecainide induced conduction slowing in depolarized tissue. This variable effect in normal versus abnormal tissue produces significant dispersions of conduction with an expected increased propensity for conduction failure in response to ectopy, increased liminal length for impulse propagation, enhanced vulnerability to premature extrastimuli, and completed reentrant circuits in regions of depressed membrane potentials. This, along with the decrease in action potential duration and accompanying refractoriness in the setting of adrenergic modulation may favor more malignant double wavelet or unstable ventricular arrhythmias.

Flecainide blocks the stimulatory effect of veratridine on slowly adapting pulmonary stretch receptors in anaesthetized rabbits without changing lung mechanics.

We examined the responses of slowly adapting pulmonary stretch receptors (PSRs), total lung resistance (RL) and dynamic lung compliance (Cdyn) to administered veratridine before and after pretreatment with atropine or flecainide in anaesthetized, artificially ventilated rabbits with bilateral vagotomy. Administration of veratridine (10 and 30 micrograms kg-1) caused vigorous stimulation of PSRs, resulting in a tonic discharge of receptors during both inflation and deflation, but did not significantly alter either RL or Cdyn. The veratridine-induced PSR stimulation became more prominent, as the dose of this alkaloid was increased. Pretreatment with atropine (1 or 2 mg kg-1) had no significant effect on the excitatory response of PSRs to veratridine. The veratridine-induced PSR stimulation was inhibited by treatment with flecainide (1, 2 and 3 mg kg-1), a sodium channel blocker, and this inhibition was dose-dependent. These results suggest that activation of PSRs following veratridine administration probably related to the increased influx of sodium ions into the receptive terminals but does not depend upon bronchoconstriction.

Comparative study on the proarrhythmic effects of some antiarrhythmic agents.

BACKGROUND: A main side effect of antiarrhythmic drug therapy is the tendency of these drugs to promote arrhythmia within the therapeutic concentration range, i.e., the proarrhythmic activity of these drugs. However, a model for in vitro assessment, quantification, and comparison of proarrhythmic drug activities was still lacking, and only sparse data were available. METHODS AND RESULTS: To analyze the arrhythmogenic risk of common antiarrhythmic drugs in a quantitative and comparative manner, isolated perfused rabbit hearts were treated with increasing concentrations of antiarrhythmic drugs corresponding to low, medium, and high therapeutic concentrations. For analysis of the epicardial activation process, an epicardial mapping (256 unipolar leads) was performed. For each electrode, the activation time was determined. From these data, the origins of epicardial activation ("breakthrough points" [BTP]) were determined. At each electrode, an activation vector (VEC) was calculated giving direction and velocity of the local excitation wave. The beat similarity of various heartbeats (under treatment) compared with control was evaluated by determination of the percentage of identical BTPs (deviation < or = 1 mm) and of similar VECs (deviation < or = 5 degrees). BTP and VEC were reduced by all antiarrhythmic agents tested (propafenone = flecainide > quinidine > ajmaline > procainamide > disopyramide > mexiletine = lidocaine > sotalol), indicating a more or less pronounced disturbance of the epicardial activation process. Treatment with propafenone, quinidine, and disopyramide and to a lesser extent sotalol prolonged the activation-recovery interval (ARI). ARI dispersion was greatly enhanced by flecainide and was reduced by sotalol. In addition, it could be shown that propranolol is able to reduce the proarrhythmic action of flecainide. This effect seemed to be due to a reduction of the flecainide-induced increase in ARI dispersion. CONCLUSIONS: From the results of our study, we propose the following rank order of the arrhythmogenic risk: flecainide > propafenone > quinidine > ajmaline > disopyramide > procainamide > mexiletine, lidocaine > sotalol. Moreover, we conclude that propranolol given additionally may be helpful in reducing the proarrhythmic risk of flecainide.

Safety and efficacy of oral flecainide therapy in patients with atrioventricular re-entrant tachycardia.

OBJECTIVE: To assess the short- and long-term safety and efficacy of oral flecainide therapy in patients with symptomatic tachycardia and an extranodal accessory pathway. DESIGN: Open-label, uncontrolled trial with a mean follow-up of 24 months. SETTING: Referral-based, teaching medical center. PATIENTS: Sixty-three patients with symptomatic tachycardia and an extranodal accessory pathway. INTERVENTIONS: Patients had electrophysiologic testing before and after the initiation of oral flecainide therapy and were followed long-term for the presence of symptoms, new physical limitations, and adverse effects of therapy. MEASUREMENTS AND MAIN RESULTS: Flecainide therapy prevented or slowed (324 +/- 59 ms to 398 +/- 55 ms; P less than 0.001) inducible sustained atrioventricular reciprocating tachycardia in 44 of 63 patients (70%). Of the 44 patients discharged from the hospital, 33 (75%) have continued to receive flecainide therapy and have shown no adverse effects (mean follow-up, 24 +/- 10 months). Adverse cardiac reactions (proarrhythmia or sinus node suppression) attributable to flecainide occurred in 11 of 63 patients (17%); in 9 (82%) of these 11 patients, events were detected during either in-hospital monitoring or the electrophysiologic study done before discharge. Structural heart disease was detected by two-dimensional echocardiography in 8 of 11 patients who had adverse cardiac events and in 6 of 52 patients who did not have such events (P less than 0.001). Isoproterenol reversed the effects of flecainide therapy in 11 of 21 patients; 7 of the 11 patients had spontaneous clinical recurrences of tachycardia or palpitations during the follow-up period, but these symptoms occurred in only 1 of 10 patients who did not show isoproterenol-induced reversal (P = 0.02). CONCLUSIONS: Oral flecainide therapy was effective in 33 of 63 patients who had tachycardia and an extranodal accessory connection. Hospital monitoring during initial therapy is recommended, and flecainide should be used with caution, if at all, in patients with structural heart disease. An isoproterenol challenge appears to be helpful in predicting late recurrence of tachycardia.

Electrophysiologic effects of isoproterenol in patients with atrioventricular reentrant tachycardia treated with flecainide.

UNLABELLED: The electrophysiologic effects of isoproterenol in patients treated with flecainide for atrioventricular (AV) reentrant tachycardia were studied to evaluate the mechanism of tachycardia inducibility after isoproterenol and the value of isoproterenol challenge as a predictor of spontaneous arrhythmia recurrence. Seventeen patients underwent electrophysiologic study before and after oral flecainide administration and after the addition of isoproterenol to flecainide. No patient had inducible sustained supraventricular tachycardia after flecainide alone. Two patients had inducible sustained and six had inducible nonsustained tachycardia after isoproterenol was added to flecainide. The patients were then followed up on the same flecainide dose they received at the time of the electrophysiologic study. FINDINGS: 1) Flecainide treatment prolonged HV and VA intervals, and the addition of isoproterenol did not affect these variables. 2) Isoproterenol shortened anterograde and retrograde block cycle length and the refractory period of the accessory pathway and the AV node. It also decreased the tachycardia cycle length, an effect that was due solely to shortening of AV node conduction time. 3) Flecainide treatment prevented tachycardia induction by affecting retrograde conduction over the accessory pathway. Isoproterenol allowed for tachycardia induction and for more sustained episodes of tachycardia by reversing the effect of flecainide on retrograde accessory pathway conduction. 4) Tachycardia recurred during follow-up in all three patients in whom tachycardia of greater than or equal to 10 s duration was induced after isoproterenol but in no patient who had no or shorter episodes of induced tachycardia (and who did not have a change in medical regimen). CONCLUSIONS: 1) Isoproterenol reverses flecainide-induced prolongation of block cycle length and refractory periods of the accessory pathway and AV node. 2) Isoproterenol reverses flecainide-induced prevention of tachycardia induction through reversal of the effects of flecainide on the retrograde accessory pathway. 3) The addition of isoproterenol during flecainide restudy is valuable in predicting long-term drug efficacy.

Lack of effect of hypertonic sodium bicarbonate on QRS duration in patients taking therapeutic doses of class IC antiarrhythmic drugs.

Hypertonic sodium bicarbonate (HSB) has been reported to reduce the toxicity of Class IC antiarrhythmic agents in rats and, anecdotally, in patients. A pilot study was conducted of the safety and efficacy of HSB for reversing the electrocardiographic effects of therapeutic doses of encainide or flecainide in ten patients taking these drugs for chronic ventricular arrhythmias. Patients had a mean drug-induced QRS prolongation before treatment of 27.6 +/- 8.8%. Each patient received a single dose of HSB 100 mEq or normal saline IV over 5 minutes on two separate occasions. The administration of treatments was blinded and balanced. There were no important side effects of HSB. Venous blood pH, CO2 content and sodium concentration were all significantly increased by HSB in comparison to saline. No differences were found during the 2-hour observation period in the primary endpoint, QRS duration, the PR or QT intervals, or the frequency of premature ventricular beats. It was concluded that HSB 100 mEq does not reduce QRS duration in patients taking therapeutic doses of flecainide or encainide. Because HSB was well tolerated, investigation of its use in higher doses or in patients with overt toxicity due to Class IC drugs is feasible.

Reversal of electrophysiologic effects of flecainide on the accessory pathway by isoproterenol in the Wolff-Parkinson-White syndrome.

To determine the reversibility of the effects of flecainide on accessory pathways, electrophysiologic studies were performed in the drug-free control state, after flecainide loading and with isoproterenol infusion during flecainide treatment in 12 patients with symptomatic preexcitation syndrome. After the baseline drug-free evaluation, oral flecainide was given in dosages of 50 to 200 mg twice daily (mean daily dose 282 +/- 75) for at least 4 days before the repeat electrophysiologic study. Isoproterenol infusion was given in dosages of 1 to 4 micrograms/min to increase the heart rate at rest by 50%. Anterograde block in the accessory pathway was observed in 3 patients with flecainide therapy, whereas in the other patients the anterograde refractory period increased from 243 +/- 20 to 315 +/- 23 ms (p less than 0.05). The shortest preexcited RR interval during atrial fibrillation lengthened from 234 +/- 27 ms before flecainide to 313 +/- 38 ms (p less than 0.05). Retrograde block occurred in 2 patients after flecainide, whereas the retrograde refractory period of the accessory pathway increased from 247 +/- 26 to 337 +/- 45 ms in the other patients. Orthodromic atrioventricular reciprocating tachycardia, inducible in 10 patients before therapy, became noninducible in 3 patients. Its rate was significantly slowed in the other 7 patients (from 346 +/- 50 to 471 +/- 81 ms). In 2 patients the tachycardia was nonsustained during flecainide treatment. Atrial fibrillation, inducible in all patients at baseline, was rendered nonsustained and more difficult to induce in 7 patients with flecainide. When isoproterenol was infused during flecainide treatment, complete anterograde (3 patients) or retrograde block (2 patients) persisted in the accessory pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertonic sodium bicarbonate partially reverses QRS prolongation due to flecainide in rats.

Hypertonic (1M) sodium bicarbonate can partially reverse the cardiac toxicity of some Class IA antiarrhythmic agents, presumably by antagonizing sodium channel inhibition. We studied the effects of 1M sodium bicarbonate on toxicity due to the Class IC drug flecainide. Anesthetized rats received i.v. loading and maintenance doses of flecainide to produce QRS prolongation of 76% that was stable over the 60 min study period. 20 min after the start of the maintenance infusion, groups of 8 rats received an i.v. infusion of 1M sodium bicarbonate (6 meq/kg) or an equal volume of 0.9% saline. QRS prolongation was reduced by 1M sodium bicarbonate but not only 0.9% saline (% change -12.2 +/- 10.0 v. +3.0 +/- 2.7, p = 0.001). Expressed as a percent of the flecainide-induced QRS prolongation, bicarbonate reduced this prolongation by 26.5%. The improvement in QRS duration persisted until sacrifice 30 min later. Compared to controls, the bicarbonate group had a significantly higher blood pH (7.55 +/- 0.06 v. 7.44 +/- 0.05) and serum sodium concentration (149 +/- 5 v. 137 +/- 2 meq/l). Serum flecainide concentrations were similar. These data suggest that 1M sodium bicarbonate can partially reverse flecainide-induced conduction delay in rats. This effect may be due to changes in the extracellular pH and sodium concentration. 1M sodium bicarbonate may be useful in assessing the role of sodium channel inhibition in mediating the toxicity of flecainide or other Class IC drugs.