Proarrhythmic effects of flecainide. Experimental evidence for increased susceptibility to reentrant arrhythmias

BACKGROUND. The goal of this study was to investigate the nature and electrophysiological mechanisms of the proarrhythmic effects of flecainide in Langendorff-perfused rabbit hearts. METHODS AND RESULTS. A thin layer of epicardium was obtained by an endocardial cryotechnique in 10 Langendorff-perfused rabbit hearts. Six other hearts were kept intact. Programmed electrical stimulation using up to three closely coupled premature stimuli and burst pacing was used to test the inducibility of arrhythmias both during control and administration of 1 micrograms/ml flecainide. During control, in the thin layer of epicardium, application of one to three premature stimuli induced nonsustained ventricular tachycardia in out of 10 hearts, and burst pacing induced nonsustained ventricular tachycardia in four hearts and sustained ventricular tachycardia in two hearts. During administration of 1 microgram/ml flecainide, application of one to three premature stimuli induced sustained ventricular tachycardia in five hearts, and burst pacing induced sustained ventricular tachycardia in nine hearts. All tachycardias were based on circus movement of the impulse around arcs of functional block. During administration of flecainide, different locations of the arc of block could be found in the same heart, leading to different reentrant circuits with different cycle lengths. In the control group of six intact hearts, application of up to three closely coupled premature stimuli in all cases induced ventricular fibrillation both during control and administration of flecainide. CONCLUSIONS. Flecainide alters propagation of the impulse in thin surviving layers of myocardium in a manner that facilitates the induction of functionally determined reentry.     

Increased susceptibility to ventricular arrhythmias in hypertensive paraplegic rats

Individuals with spinal cord injury (SCI) between thoracic vertebrae four (T4) and five (T5) have elevated levels of sympathetic activity to the heart. Notably, female spontaneously hypertensive rats (SHR) also have increased cardiac sympathetic nerve activity (SNA). Since elevated levels of cardiac SNA increase the risk for cardiac arrhythmias, we tested the hypothesis that hypertensive, paraplegic rats have an increased susceptibility to ventricular arrhythmias. To test this hypothesis, intact (n = 7) and paraplegic hypertensive rats (n = 6) were chronically instrumented with silver stimulating electrodes on the left ventricle, electrocardiogram (ECG) recording electrodes and an arterial catheter. After recovery, the effective refractory period, the electrical stimulation threshold to induce ventricular arrhythmias and cardiac sympathetic tonus (ST) were determined. Paraplegic rats had a lower effective refractory period (35%), lower electrical stimulation threshold to induce ventricular arrhythmias (62%), and higher cardiac ST (84%). These data document an increased susceptibility to ventricular arrhythmias in hypertensive, paraplegic rats.     

Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs

We calculated the wavelength of the atrial impulse in chronically instrumented conscious dogs by measuring both conduction velocity and refractory period: wavelength = refractory period X conduction velocity. Implantation of multiple stimulating and recording electrodes allowed wavelength determination at four different areas: the right and left parts of Bachmann's bundle and the free walls of the right and left atria. During programmed electrical stimulation, three types of arrhythmias were observed: rapid repetitive responses, atrial flutter, and atrial fibrillation. During normal rhythm, the wavelength of the atrial impulse varied between 14 and 18 cm. Premature beats had a shorter wavelength, depending on the degree of prematurity. Premature beats that evoked rapid repetitive responses showed a critical shortening of the wavelength below 12.3 cm. Episodes of atrial flutter were induced at a wavelength below 9.7 cm, while fibrillation occurred at wavelengths shorter than 7.8 cm. We correlated the induction of these arrhythmias with the values of refractory period, conduction velocity, and wavelength during control and during administration of several drugs. Intravenous administration of acetylcholine shortened the wavelength by 30-40%, mainly because of refractory period shortening. Both propafenone and lidocaine had strong but opposite effects on refractoriness and conduction and, consequently, little effect on the wavelength. Quinidine markedly prolonged the refractory period, but prolongation of wavelength was less because of a simultaneous decrease in conduction velocity. d-Sotalol also increased refractory period, but because it had no appreciable effect on conduction velocity, this drug was the most effective in prolongation of wavelength. Linear discriminant analysis of the data showed that the refractory period and the conduction velocity each were poor parameters to predict the occurrence of the different arrhythmias (predictive value 48% and 38%, respectively). The combination of both properties, however, as expressed in the wavelength, was a more reliable index that predicted the induction of the different arrhythmias correctly in 75% of the cases. We conclude that the wavelength is a useful parameter for evaluating antiarrhythmic drugs.     

The response of paediatric arrhythmias to intravenous and oral flecainide.

Flecainide acetate was administered intravenously and orally to 12 consecutive children, aged 1-15 years, presenting with arrhythmias that were life threatening or resistant to conventional medical treatment. Three children had arrhythmias related to Wolff-Parkinson-White syndrome, four had concealed accessory pathways, two had His bundle tachycardia, and three had ventricular tachycardia. Of seven patients who were given flecainide intravenously, four returned to sinus rhythm and in a fifth successful rate control of His bundle tachycardia was achieved. All 12 patients were given the drug orally: in nine it was successful in preventing recurrence of arrhythmia, in one satisfactory rate control was achieved, and in two it was withdrawn because it produced more frequent attacks of tachycardia. No other adverse effects occurred. The efficacy and low toxicity of treatment in this study suggests that flecainide acetate may have an important role in the management of selected paediatric arrhythmias.     

Conversion of supraventricular arrhythmias to sinus rhythm using flecainide

We evaluated the efficacy of flecainide acetate (given intravenouslyto a maximal dose of2 mg kg^–1 and then orally in a doseof 100 mg b.d. or 100 mg t.d.s.) in the conversion to sinusrhythm of 50 patients exhibiting supraventricular arrhythmias(39 with atrial fibrillation, 6 with atrial flutter, 4 withsupraventricu tachycardia and onewith supraventricular tachycardiain association with the Wolff—Parkinson—White syndrome).Conversion was achieved in 36 patients (72%) (29 cases withatrial fibrillation, 4 cases with supraventricular tachycardia,2 cases with atrial flutter and one case with Wolff—Parkinson–Whitesyndrome), over a mean period of 7.4 ± 9 h. The patientsin which conversion was achieved had arrhythmias which had beenin existence for a shorter time (5.3 ± 9.8 days) thanthose in which conversion was not achieved (16.7 ± 26.2days) (P<0.01). The mean dosage of flecainide used to achieveconversion was 2.5 ± 2.36 mg kg^–1. Flecainide appearsto be an effective agent for the conversion to sinus rhythmof atrial fibrillation and supraventricular tachycardias. Itsefficacy in cases of atrial flutter has not yet been demonstrated.     

Basic mechanisms of reentrant arrhythmias

The mechanisms responsible for active cardiac arrhythmias are generally divided into two major categories: (1) enhanced or abnormal impulse formation and (2) reentry. Reentry can be subdivided into three subcategories: (1) circus movement, (2) reflection, and (3) Phase 2 reentry. Reentry occurs when a propagating impulse fails to die out after normal activation of the heart and persists to re-excite the heart after expiration of the refractory period. Evidence implicating reentry as a mechanism of cardiac arrhythmias stems back to the turn of the century. Amplification of intrinsic electrical heterogeneities provides the substrate responsible for developing Phase 2 and circus movement reentry, which underlie ventricular tachycardia in the long QT and Brugada syndromes.     

Value of flecainide in supraventricular arrhythmias

Flecainide acetate (Flecaine) is a new antiarrhythmic which has recently become available; its efficacity in treatment of ventricular rhythm disorders has been amply demonstrated. In this study we have evaluated its efficacity per os in treatment of auricular rhythm disorders refractory to the usual therapies, and its effects on the accessory routes of atrioventricular conduction. The results are very promising and better than those obtained with amiodarone in auricular disorders. They show that flecainide is a drug of importance among therapeutic agents used in treatment of auricular arrhythmia, and its action on Kent's bundle makes it a drug of choice in management of Wolff-Parkinson-White syndrome, especially as it seems equally efficacious in its action on the accessory routes with a short refractory period. Most of our patients did not present organic cardiopathy and the side-effects were generally benign. A non-negligible number of cases of paroxysmal hypertension were noted, in disagreement with literature data, and this point needs to be clarified by further study.     

The response of paediatric arrhythmias to intravenous and oral flecainide

Flecainide acetate was administered intravenously and orally to 12 consecutive children, aged 1-15 years, presenting with arrhythmias that were life threatening or resistant to conventional medical treatment. Three children had arrhythmias related to Wolff-Parkinson-White syndrome, four had concealed accessory pathways, two had His bundle tachycardia, and three had ventricular tachycardia. Of seven patients who were given flecainide intravenously, four returned to sinus rhythm and in a fifth successful rate control of His bundle tachycardia was achieved. All 12 patients were given the drug orally: in nine it was successful in preventing recurrence of arrhythmia, in one satisfactory rate control was achieved, and in two it was withdrawn because it produced more frequent attacks of tachycardia. No other adverse effects occurred. The efficacy and low toxicity of treatment in this study suggests that flecainide acetate may have an important role in the management of selected paediatric arrhythmias.     

Treatment of paroxysmal reentrant supraventricular tachycardia with flecainide acetate

The electrophysiologic effects and therapeutic efficacy of intravenous and oral flecainide were studied in 15 patients with spontaneous and inducible sustained paroxysmal supraventricular tachycardia (SVT). Twelve patients had atrioventricular (AV) reentrance using an accessory pathway for retrograde conduction and 3 had AV nodal reentrance. Fourteen patients received intravenous flecainide (2 mg/kg body weight over 15 minutes) during an initial electrophysiologic study. Nine patients were restudied during oral flecainide administration (200 to 400 mg/day). After intravenous or oral flecainide therapy, reentrant SVT was noninducible in 6 patients with AV reentrance and in the 3 with AV nodal reentrance. In these 9 patients, intravenous flecainide prevented induction of reentrant SVT by depressing conduction over the retrograde limb of the reentry circuits. In the 6 patients with inducible sustained AV reentrant SVT before and after flecainide therapy, the cycle length of tachycardia increased significantly, mainly as the result of an increase in ventriculoatrial conduction time. There was concordance between the intravenous and the oral effects of flecainide on the mechanism of the SVT. Twelve patients continued oral flecainide treatment for a mean of 16 months (range 5 to 28). Tachycardia recurred in 3 of 4 patients whose arrhythmia remained inducible after flecainide therapy and in 1 of 8 patients whose SVT was suppressed. It is concluded that flecainide is an effective and convenient antiarrhythmic agent to treat patients who have AV nodal or AV reentrant SVT.     

Diabetes and susceptibility to reperfusion-induced ventricular arrhythmias.

Studies using chemically-induced models of diabetes have shown the diabetic myocardium to exhibit abnormalities in cellular ion transport, which may affect susceptibility to reperfusion-induced arrhythmias. We studied the incidence of reperfusion-induced ventricular tachycardia (VT) and fibrillation (VF) in isolated hearts from rats with streptozotocin-induced diabetes and from age-matched and weight-matched control rats (n = 12 per group). Following 5 min of regional ischaemia, reperfusion resulted in a similarly low incidence of arrhythmias in all three groups. Following 10 min of regional ischaemia, the incidence of VT was 92, 100 and 92%, and the incidence of VF was 75, 92 and 92% in diabetic, age-matched control and weight-matched control groups, respectively (NS). However, among those hearts which exhibited VF, the incidence of sustained (greater than or equal to 120 s) VF was 73 and 55% in age-matched and weight-matched control groups, respectively, and 0% in the diabetic group (P less than 0.05 vs both controls). The mean duration of VF in the diabetic group was reduced from 201 +/- 33 and 171 +/- 36 s in age-matched and weight-matched control groups, respectively, to 9 +/- 3 s (P less than 0.05). Thus, streptozotocin-induced diabetes in the rat does not result in an increased susceptibility to reperfusion-induced arrhythmias. To the contrary, hearts from diabetic rats are less susceptible to potentially lethal arrhythmias during reperfusion. Likely contributory factors to this phenomenon include (i) increased myocardial content of free radical scavenging enzymes, (ii) prolonged action potential duration, and (iii) reduced activity of sarcolemmal Na+/H+ and Na+/Ca2+ exchange processes, all of which have previously been reported in similar models of diabetes.     

Oral flecainide for suppression of ventricular arrhythmias

The efficacy and safety of oral flecainide for treatment of ventricular arrhythmias were assessed during a 3-day period in patients with various cardiac diseases. Of 11 patients who received a low dose of flecainide (median daily dose 240 mg), only 4 responded with 90% or greater reduction in premature ventricular complex frequency. Ventricular tachycardia could not be suppressed. During treatment no electrocardiographic changes occurred. 14 of the 19 patients who received a high dose of flecainide (median daily dose 480 mg), demonstrated a 90% or greater reduction in premature ventricular complexes, and ventricular tachycardia did not recur during treatment in 7 out of 9 patients. However, PQ, QRS, and QTc intervals were significantly increased. In general, flecainide was well tolerated and drug administration did not have to be discontinued because of side effects. Flecainide acetate treatment, with a median dose of 480 mg daily, appears to be highly effective for suppressing complex ventricular arrhythmias.     

Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide

Flecainide acetate is a new antiarrhythmic agent whose pharmacokinetics have suggested that effective therapy could be achieved with twice daily dosing. The antiarrhythmic and electrocardiographic effects of flecainide were evaluated in 11 patients with chronic ventricular ectopic beats. Nine patients had been resistant or intolerant to at least three antiarrhythmic agents and eight had recurrent nonsustained ventricular tachycardia. The antiarrhythmic efficacy of increasing doses of flecainide was determined by comparison with results during administration of a placebo 2 days before and 3 days after increasing doses of flecainide. All 11 patients had an antiarrhythmic response with a mean 97 percent (range 88 to 100) rate of suppression of ventricular ectopic beats and mean 100 percent rate of suppression of ventricular tachycardia with a mean daily dose of 410 mg (range 200 to 600) of flecainide. Effective therapy was accompanied by lengthening of the P-R (+ 29 percent), QRS (+ 27 percent) and Q-Tc (+ 11 percent) intervals. These changes were not associated with a deterioration in exercise tolerance or a reduction in ejection fraction (0.52 ± 0.08 with placebo, 0.53 ± 0.12 with flecainide) as assessed with two dimensional echocardiography. Increasing doses of flecainide were associated with progressive prolongation of the ventricular ectopic coupling interval before suppression of ventricular ectopic beats. During the placebo washout period after multiple oral doses, the terminal (postabsorptive) phase plasma half-life of flecainide was found to range from 13 to 27 hours (mean 20.3). The minimal effective plasma levels of flecainide (resulting in greater than 90 percent suppression of ventricular etopic beats) ranged from 245 to 980 ng/ml (mean 631). Adverse effects during the inpatient evaluation were limited to blurring of vision in three patients, which resolved with smaller but still effective doses.

Suppression of ventricular ectopic beats at a mean rate of 95 percent continued during outpatient therapy. During a mean of 12 months of outpatient follow-up in nine patients, regularly scheduled evaluation of ambulatory arrhythmia frequency continued to document suppression of arrhythmia. Outpatient follow-up occurred monthly for the first 6 months and every 2nd month thereafter. In three patients it was necessary to administer flecainide every 8 hours because blurring of vision occurred at the time of peak plasma levels when the drug was administered every 12 hours. Flecainide was highly effective in suppressing ventricular arrhythmias when administered twice daily.     

T-wave alternans and the susceptibility to ventricular arrhythmias.

T-wave alternans (TWA) reflects beat-to-beat fluctuations in the electrocardiographic T-wave, and is associated with dispersion of repolarization and the mechanisms for sudden cardiac arrest (SCA). This review examines the bench-to-bedside literature that, over decades, has linked alternans of repolarization in cellular, whole-heart, and human studies with spatial dispersion of repolarization, alternans of cellular action potential, and fluctuations in ionic currents that may lead to ventricular arrhythmias. Collectively, these studies provide a foundation for the clinical use of TWA to reflect susceptibility to ventricular arrhythmias in several disease states. This review then provides a contemporary evidence-based framework for the use of TWA to enhance risk stratification for SCA, identifying populations for whom TWA is best established, those for whom further studies are required, and areas for additional investigation.     

Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling

1. Download : Download high-res image (259KB)
2. Download : Download full-size image

     

电紧张扩布在折返性室性心律失常发生中的作用

目的探讨电紧张扩布在折返性心律失常发生中的作用。方法以冠状动脉灌注兔左室楔形组织块标本为研究对象,同步记录内、外膜侧心肌细胞动作电位和跨壁心电图。以1 000 ms的刺激周长(BCL)对标本施加基础刺激S1。根据期前刺激(S2)发放的位置,分为期前刺激内膜侧组和外膜侧组,每10次S1后施加S2。S1S2间期以1 ms的步长递增,诱发单向传导阻滞和室性心律失常,观察了S2刺激位置的改变对所诱发早搏QRS波极性的影响。同时用计算机仿真方法观察了动作电位过程中Na通道门控因子的特点。结果无论期前刺激S2在内膜侧,还是外膜侧,所诱发的第一个室性早搏的QRS波均为倒置的,提示不同位置S2刺激引发的室性早搏的兴奋均来自于外膜侧。由于内膜侧心肌细胞动作电位时程明显长于外膜侧,激活和失活门控因子逐步恢复至初始状态延迟。结论在此过程中缓慢的电紧张扩布起了重要作用,并参与了折返激动的产生。     

Short- and long-term efficacy and safety of flecainide acetate for supraventricular arrhythmias.

This report summarizes efficacy and safety data on the use of flecainide acetate for supraventricular arrhythmias. For this purpose, 60 original articles were identified by a literature search representing data from 1,835 treatment courses. In 18 trials, flecainide was administered intravenously; in 19, orally; and in 23, both forms of therapy were applied. There were 5 placebo-controlled and 12 comparative studies, whereas data from uncontrolled studies were represented in 43 articles. Short-term flecainide administration terminated atrial fibrillation in 65% of attempts and terminated atrial flutter in 28%. The drug was effective during long-term therapy for atrial fibrillation in 49% of patients, with similar efficacy rates in 11 comparative trials and in 16 uncontrolled studies. In randomized, placebo-controlled studies in patients with paroxysmal atrial fibrillation, flecainide was shown to reduce significantly the number of attacks, to prolong the time between attacks, and to improve quality of life. In patients with atrioventricular (AV) reciprocating tachycardias, acute drug administration was successful in 72%; 83% of patients with AV nodal reentrant tachycardias and 74% exhibiting arrhythmias associated with the Wolff-Parkinson-White syndrome responded acutely. During long-term therapy, efficacy rates were 70%, 78%, and 69%, respectively. Ectopic atrial tachycardia responded in 86% and 95% of patients treated with flecainide acutely or chronically. Data concerning drug-related side effects were available for 1,794 of 1,835 treatment courses (98%). Overall, 352 of 1,794 patients (20%) reported at least one non-cardiac or cardiac adverse experience.(ABSTRACT TRUNCATED AT 250 WORDS)