Effects Of Flecainide Research Articles

Effect of flecainide on suppression of ventricular fibrillation in a patient with early repolarization syndrome

Effect of flecainide on suppression of ventricular fibrillation in a patient with early repolarization syndrome

Effect of Flecainide Derivatives on Sarcoplasmic Reticulum Ca2+ Release Confirms a Lack of Direct Action on the Cardiac Ryanodine Receptor

Flecainide is a use-dependent blocker of the cardiac Na+ channel. It has been shown to be effective in the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), however, its mechanism of action is contentious. The mechanisms involved in block have been elucidated by using fully charged (QX-FL) and neutral (NU-FL) derivatives of flecainide, establishing that Na+ channel block requires entry of the cationic form of the molecule into the cytosolic vestibule of the open channel. We investigated how flecainide derivatives influence RyR2-mediated Ca2+-release from the sarcoplasmic reticulum and whether this correlates with their effectiveness as blockers of Na+ channels and/or RyR2. We compared the effects of flecainide, QX-FL and NU-FL applied extracellulary or via intra-pipette, on the properties of Ca2+ sparks in intact adult rat cardiac myocytes with their ability to block recombinant human RyR2. Intracellular flecainide or QX-FL reduced Ca2+ spark frequency whereas NU-FL did not. Both QX-FL and NU-FL were partial blockers of the non-physiological cytosolic to luminal flux of cations through RyR2 (resulting in different residual currents) but were significantly less effective than flecainide. None of the compounds influenced luminal to cytosol cation flux through RyR2. Given QX-FL inability to block physiologically-relevant cation flux through RyR2, and its comparative lack of efficacy in blocking the cytosolic-to-luminal current through the channel, the effect of QX-FL on Ca2+ sparks is likely, by analogy with flecainide, to result from Na+ channel block. Our data reveal important differences in the nature of molecular interaction of flecainide with sites in the cytosolic vestibules of Na+ and RyR2 channels. Research supported by the British Heart Foundation.

Inhibition of RYR2 Activity by Intracellular Flecainide Effectively Suppresses Arrhythmogenic Ca Waves in Intact Ventricular Myocytes from Casq2 -/- Mice

We reported previously that flecainide suppresses Ca waves in MEMBRANE-PERMEABILIZED ventricular myocytes from Casq2-/- mice and that flecainide is more potent (i.e., lower IC50) in Casq2-/-compared to WT myocytes. Other groups reported that in INTACT myocytes flecainide acts only by blocking Na+ channels and has no effect on RyR2. Here we test the effect of flecainide on INTACT ventricular myocytes from Casq2-/- and WT littermates using voltage-clamp. To eliminate any contribution of Na channels, all solutions contained 30 µM TTX. Complete block INa was confirmed for each cell tested. Spontaneous Ca waves were elicited by a pacing train followed by a holding potential of −70mV for 45 s. 6 µM flecainide or vehicle (H2O) was added to both external and pipette solutions. Under such conditions, flecainide had no significant effect on the average number of spontaneous Ca waves in WT myocytes (Vehicle: 3.1±0.6, n=24, Flecainide: 3.0±0.8, n=20, p=NS). In Casq2-/- myocytes, however, flecainide significantly reduced Ca waves (Vehicle: 6.6±1.2, n=23; Flecainide: 2.1±0.4, n=19, p 0.5 vs. Casq2-/- vehicle), suggesting that intracellular dialysis by the patch pipette removed flecainide from the cytosol. We conclude that intracellular concentrations of 6 µM flecainide effectively inhibit arrhythmogenic Ca waves in Casq2-/- but not in WT myocytes, indicating that flecainide action is dependent on the state of RyR2. Our results further demonstrate that flecainide suppression of Ca waves is independent from its Na channel block.

Abstract 18111: Flecainide Exerts its Antiarrhythmic Action in CPVT Through Blockade of Neuronal Na+ channel-mediated Arrhythmogenic Diastolic Ca2+ Release

Background: Flecaininde is an effective antiarrhythmic in management of CPVT. Its antiarrhythmic action has been attributed to direct effect on RyR2 and reduced cellular excitability through the inhibition of cardiac-type Na + channels. Recently we demonstrated that neuronal Na + channels (nNa v s) colocalize with the ryanodine receptors (RyR2) Ca 2+ release channels on the sarcoplasmic reticulum. Here we explore a novel mechanism that may contribute to the antiarrhythmic effect of flecainide, mainly uncoupling of aberrant Na + /Ca 2+ signaling through nNa v inhibition. Methods: To study the effects of flecainide on Ca 2+ signaling we used a murine model of cardiac calsequestrin-associated CPVT. We performed confocal microscopy in intact isolated ventricular myocytes to assess Ca 2+ handling and recorded late Na + current (I Na ) during various pharmacological interventions. Surface electrocardiograms were performed during catecholamine challenge to monitor arrhythmic activity in vivo . Results: During catecholamine stimulation with isoproterenol (Iso; 100 nM) disruption of the cross-talk between nNa v s and RyR2 by nNa v blockade with 100nM tetrodotoxin (TTX) and riluzole (10μM) as well as flecainide (2.5μM) reduced Iso-promoted late I Na and DCR in isolated intact CPVT cardiomyocytes. To further examine the role of nNa v -mediated late I Na in genesis of DCR we augmented nNa v channel activity with β-Pompilidotoxin (β-PMTX, 40μM). Effects of β-PMTX in CPVT cardiomyocytes were reversed by nNa v blockade with TTX and riluzole as well as flecainide. This reduction in late I Na and DCR frequency with riluzole and flecainide in the presence of β-PMTX on cellular level translated to decreased ventricular arrhythmias in CPVT mice. Conclusion: These data suggest that disruption of nNa v -mediated late I Na can prevent arrhythmogenic DCR in CPVT. Importantly, the antiarrhythmic effects of flecainide can be attributed, at least in part, to its nNa v blocking properties.

Flecainide attenuates rate adaptation of ventricular repolarization in guinea-pig heart

Objectives: Flecainide is class Ic antiarrhythmic agent that was found to increase the risk of sudden cardiac death. Arrhythmic responses to flecainide could be precipitated by exercise, suggesting a role played by inappropriate rate adaptation of ventricular repolarization. This study therefore examined flecainide effect on adaptation of the QT interval and ventricular action potential duration (APD) to abrupt reductions of the cardiac cycle length. Design: ECG and ventricular epicardial and endocardial monophasic APD were recorded in isolated, perfused guinea-pig heart preparations upon a sustained cardiac acceleration (rapid pacing for 30 s), and following a single perturbation of the cycle length evoked by extrasystolic stimulation. Results: Sustained increase in heart rate was associated with progressive bi-exponential shortening of the QT interval and APD. Flecainide prolonged ventricular repolarization, delayed its rate adaptation, and decreased the amplitude of QT interval and APD shortening upon rapid cardiac pacing. During extrasystolic stimulation, flecainide attenuated APD shortening in premature ventricular beats, with effect being greater upon using a longer basic drive cycle length (S1-S1=550 ms versus S1-S1=300 ms). Conclusions: Flecainide-induced arrhythmia may be partly accounted for by attenuated adaptation of ventricular repolarization to sudden changes in cardiac cycle length provoked by transient tachycardia or ectopic beats.

Antiarrhythmic Action of Flecainide in Polymorphic Ventricular Arrhythmias Caused by a Gain-of-Function Mutation in the Nav 1.5 Sodium Channel.

The cardiac sodium channel Nav 1.5, encoded by the gene SCN5A, is associated with a wide spectrum of hereditary arrhythmias. The gain-of-function mutation p.I141V in SCN5A was identified in a large multigenerational family with exercise-induced polymorphic ventricular arrhythmias. The purpose of this study was to evaluate the molecular and clinical effects of flecainide administration on patients with this syndrome. Eleven p.I141V carriers who exhibited frequent multiformic premature ventricular complexes (PVCs) during exercise were subjected to exercise stress tests, both before and after intravenous infusion of 2 mg/kg flecainide. The in vitro effects of flecainide were evaluated using the patch-clamp technique with HEK293 cells expressing the Nav 1.5 channel. The flecainide treatment significantly reduced the frequency of PVCs during and after exercise. Next, the sensitivity of the p.I141V mutant channel to flecainide was compared to that of the wild type channel. Perfusion of flecainide inhibited the peak and window currents in both groups. The clinical investigations of the affected patients, as well as the molecular and pharmacological characterization of the SCN5A p.I141V mutation, provide new evidence supporting the association of this mutation with exercise-induced polymorphic ventricular arrhythmias. These data also demonstrate that flecainide may serve as an effective treatment for the defect in Nav 1.5 that leads to an increased sodium window current.

Flecainide-induced prolongation of ventricular repolarization contributes to the proarrhythmic profile of action

Flecainide is class Ic Na + channel blocker that is used to restore sinus rhythm and to prevent the arrhythmia recurrence in patients with atrial fibrillation. Antiarrhythmic effect of flecainide is attribut- ed to prolonged atrial effective refractory period and depressed car- diac action potential upstroke. Nevertheless, flecainide has been reported to produce arrhythmogenic responses in ventricular myo- cardium. In this regard, the Cardiac Arrhythmia Suppression Trial (CAST) has shown that flecainide therapy is associated with marked- ly increased risk of sudden arrhythmic death in patients with healed myocardial infarction, an effect possibly accounted for by the drug- induced anisotropic conduction slowing in the peri-infarct zone. Based on these findings, indications for flecainide therapy are cur- rently limited to the atrial fibrillation control in patients with no structural heart disease. Although flecainide-induced conduction abnormalities are unlikely to occur in the absence of myocardial ischemia or fibrosis, there is in- creasing evidence to suggest that flecainide may promote arrhythmo- genic responses in patients with structurally normal hearts. Flecainide administration has been reported to induce torsade de pointes, a poten- tially life-threatening polymorphic ventricular tachycardia, in patients with no coronary artery disease or severe heart failure (1,2). This kind of arrhythmia is thought to be attributed to the prolonged QT interval and increased spatial dispersion of ventricular repolarization. However, the contribution of these factors to flecainide-induced proarrhythmia is often overlooked, because flecainide (along with other class Ic Na + channel blockers) is generally regarded asanagentproducingonly little or no effect on ventricular repolarization.

169 PITX2C deficiency augments the anti-arrhythmic properties of flecainide: results in a mouse model and validation in a human atrium simulation study

Background and objectives Polymorphisms close to the PITX2 gene on chromosome 4q25 are associated with incident and recurrent atrial fibrillation (AF). Carriers of variant rs10033464 respond relatively well to antiarrhythmic drug therapy with sodium channel blockers. To test whether altered atrial PITX2 mRNA expression alters the electrophysiological effect of sodium channel blockers, we studied the effect of flecainide (Flec) in hearts of mice with heterozygous Pitx2c gene deletion, a model for reduced Pitx2 mRNA expression and AF susceptibility. Methods We assessed the effect of 1µM Flec on left atrial (LA) monophasic, transmembrane and optical action potentials in Pitx2c +/– mice and their wild type (WT) littermates. We measured conduction velocity (CV), action potential duration (APD), AP amplitude (APA), maximum upstroke velocity (dV/dt max ) and resting membrane potential (RMP) during atrial pacing at 80–120 ms fixed-rate cycle lengths (CL); and effective refractory periods (ERP) with arrhythmia inducibility during programmed (S2) stimulation. Post-repolarisation refractoriness (PRR) was defined as the difference between ERP and APD90. We assessed whether the electrophysiological changes associated with reduced Pitx2c mRNA expression alters the response to sodium current (I Na ) block using the Courtemanche et al . human atrial model. Taqman low density array analysis was also used to measure changes in 20 ion channel, and related, genes of interest. Results Flec abolished arrhythmias in Pitx2c +/– (6/18 base vs 0/15 Flec, p +/– atria compared with WT (Pitx2c +/– 14 ± 2 ms, n = 13 vs WT 7 ± 2 ms, n = 10; p +/– 21 ± 3 ms, n = 6 vs WT 6 ± 4 ms, n = 6, p +/– atria had a slightly more positive resting membrane potential (WT –70 ± 0.7 mV, n = 30 cells vs PITX2c +/– –68 ± 0.7 mV, n = 32 cells, p +/– 73 ± 1.3 mV, n = 32). Flec had no effect on the RMP but reduced CV, APA and dV/dt max in both genotypes to a similar extent. Hearts with PRR were not susceptible to arrhythmias (0/17). As with the isolated hearts, I Na block prolonged PRR in the Pitx2c deficiency simulation (500 ms CL: reference model 30ms; Pitx2c deficiency model 42 ms) and had no differential effects of I Na on RMP, CV, APD, or dV/dt max . The human atrial model thus qualitatively reproduced the experimental findings. mRNA expression of Kcnk5 and Kcna6 was altered in Pitx2c +/– left atria. Conclusion Flecainide suppresses atrial arrhythmias in mice with reduced Pitx2 mRNA expression. We propose that this genotype-specific antiarrhythmic effect can be explained by a more positive resting membrane potential and higher post-repolarisation refractoriness. These data suggest that flecainide may be effective for rhythm control in carriers of genetic variants on chromosome 4q25.

Effect of flecainide on the extension and localization of complex fractionated electrogram during atrial fibrillation

Aims. Complex fractionated electrogram (CFE) ablation in addition to pulmonary vein isolation is an accepted strategy for the treatment of non-paroxysmal atrial fibrillation (AF). We sought to determine the effect of flecainide on the distribution and extension of CFE areas. Methods. Twenty-three non-paroxysmal AF patients were enrolled in this prospective study. A first CFE map was obtained under baseline conditions by sampling 5 s of continuous recording from the distal electrodes of the ablation catheter. Intravenous flecainide (1 mg/kg) was administered over 10 min and followed by 30-min observation time. A second CFE map was obtained with the same modalities. CFE-mean values, CFE areas, and atrial electrogram amplitude were retrieved from the electro-anatomical mapping system (Ensite NavX). Results. After flecainide administration, CFE-mean values increased (111.5 ± 55.3 vs. 132.3 ± 65.0 ms, p < 0.001) with a decrease of CFE area (32.9%) in all patients. Atrial electrogram amplitude decreased significantly (0.30 ± 0.31 vs. 0.25 ± 0.20 mV, p < 0.001). We observed 80.9% preservation of CFE areas. A CFE mean of 78 ms was the best cutoff for predicting stable CFE areas. Conclusions. Flecainide reduces the extension of CFE areas while preserving their spatial localization. A CFE-mean value <80 ms may be crucial to define and locate stable CFE areas.

Acute atrial wall stretch and the efficacy of flecainide-induced conversion of atrial fibrillation

Acute atrial wall stretch and the efficacy of flecainide-induced conversion of atrial fibrillation

The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2.

Flecainide, a class 1c antiarrhythmic, has emerged as an effective therapy in preventing arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) refractory to β-adrenergic receptor blockade. It has been proposed that the clinical efficacy of flecainide in CPVT is because of the combined actions of direct blockade of ryanodine receptors (RyR2) and Na(+) channel inhibition. However, there is presently no direct evidence to support the notion that flecainide blocks RyR2 Ca(2+) flux in the physiologically relevant (luminal-to-cytoplasmic) direction. The mechanism of flecainide action remains controversial. To examine, in detail, the effect of flecainide on the human RyR2 channel and to establish whether the direct blockade of physiologically relevant RyR2 ion flow by the drug contributes to its therapeutic efficacy in the clinical management of CPVT. Using single-channel analysis, we show that, even at supraphysiological concentrations, flecainide did not inhibit the physiologically relevant, luminal-to-cytosolic flux of cations through the channel. Moreover, flecainide did not alter RyR2 channel gating and had negligible effect on the mechanisms responsible for the sarcoplasmic reticulum charge-compensating counter current. Using permeabilized cardiac myocytes to eliminate any contribution of plasmalemmal Na(+) channels to the observed actions of the drug at the cellular level, flecainide did not inhibit RyR2-dependent sarcoplasmic reticulum Ca(2+) release. The principal action of flecainide in CPVT is not via a direct interaction with RyR2. Our data support a model of flecainide action in which Na(+)-dependent modulation of intracellular Ca(2+) handling attenuates RyR2 dysfunction in CPVT.

199 Pitx2c Deficiency May Increase the Antiarrhythmic Properties of Flecainide

Background and ObjectivesSingle nucleotide polymorphisms (SNPs) close to the PITX2 gene (paired-like homeodomain transcription factor 2) are associated with atrial fibrillation, including recurrent AF with therapy: Carriers of the minor...

Arrhythmogenic effects by local left ventricular stretch: effects of flecainide and streptomycin.

Mechanical stretch has been shown to provoke arrhythmia. We wanted to analyze ventricular arrhythmia induced by local left ventricular stretch in order to find out, where arrhythmias originate and whether they can be prevented pharmacologically. Isolated rabbit hearts (Langendorff technique) were submitted to increased left ventricular stretch at the left wall by insertion of an additional intraventricular balloon and adjusting the end-diastolic pressure (EDP) to 25 mmHg for 10 min followed by 20 min recovery at normal EDP of 5-8 mmHg. Activation and repolarization processes were investigated by ventricular 256 electrode epicardial mapping. The hearts were treated during the whole procedure either with vehicle, 0.5 μM flecainide (sodium channel blocker) or 100 μM streptomycin (here used as stretch-activated ion-channel blocker). In addition, we performed a series of experiments, in which we enhanced EDP to 30 mmHg (global stretch instead of local stretch) by inflating the left ventricular pressure balloon (strain, 0.148 ± 0.034). Each series was performed with n = 6. Stretch resulted in local strain of 25% at the left wall together with a local slowing of the activation process at the left wall, in a change in the activation pattern, and in ventricular arrhythmia. Coronary flow was not affected. Ventricular arrhythmias originated from the border between the stretched area and the non-stretched region. Flecainide and streptomycin reduced the prolongation of the activation process at the stretched left wall and mitigated the difference in total activation time between left and front wall but only partially prevented arrhythmia. In the additional global stretch experiments relative coronary flow and the other parameters remained unchanged, in particular TAT. Thus, in contrast to the local stretch series, there was no difference in the change in TAT between left and front wall. Only rare single ventricular extrasystoles (<1/min; originating from LV (front and left wall) i.e. from within the stretched region) were seen during stretch (but not at the beginning) and during recovery. Local left ventricular stretch can elicit ventricular arrhythmias. Local slowing of electrical activation seems involved so that the difference in total activation time of the stretched free left wall and the non-stretched increased.

Effects of Flecainide and Ranolazine on Intracellular Calcium Handling and Sarcolemmal Sodium Current

Flecainide has received considerable interest due to its antiarrhythmic efficacy. However, more detailed analyses of calcium (Ca2+)-dependent processes are required to demonstrate a conclusive mechanism of action. We characterise flecainide's ability to suppress arrhythmogenic Ca2+-waves and examine the involvement of ryanodine receptors in flecainide's antiarrhythmic efficacy, Further, we evaluate the native cardiac sodium channel contribution to flecainide¯s pharmacological profile and compare its actions with a late sodium current inhibitor, ranolazine. Extracellular drug effects on Ca2+-sparks and Ca2+-waves were measured in field-stimulated Fluo-4AM loaded human and rat ventricular cardiomyocytes. Whole-cell sodium currents (INa) were measured before and after a series of high-frequency depolarizing pulses, establishing acute- and use-dependent inhibition, respectively. A therapeutic dose of flecainide (5μM) significantly decreased spark-mediated Ca2+ leak, primarily as a result of reduced Ca2+-spark amplitude (P < 0.001). Following flecainide perfusion spontaneous wave frequency was significantly reduced (P < 0.001), whilst wave-free survival and inter-wave interval were significantly increased (P < 0.01 and P < 0.05, respectively). The late INa blocker ranolazine (10-50μM) was evaluated against flecainide for its potential to inhibit sarcolemmal INa and Ca2+-waves. Under acute application, 5μM flecainide reduced peak INa to 49 ± 7% of control compared to 75 ± 9% and 66 ± 10% with 10μM and 50μM ranolazine respectively. Flecainide showed increased use-dependency, causing 35 ± 5% peak INa inhibition compared to control, while 10μM and 50μM ranolazine resulted in 73 ± 7% and 60 ± 7% reduction, respectively. Furthermore, flecainide's effect on Ca2+-wave frequency show correspondingly higher efficacy (P < 0.001) versus increasing concentrations of ranolazine (P < 0.01). Our results suggest that flecainide normalizes arrythmogenic Ca2+-waves by selectively reducing spark mass and a corresponding wave initiation. Additionally, we draw parallel between the ability of flecainide and ranolazine to suppress arrhythmogenic Ca2+-waves, and establish correlation with membrane sodium influx.

Triple mode of action of flecainide in catecholaminergic polymorphic ventricular tachycardia: reply

We thank Steele et al . for their interest and comments regarding our recent study focusing on the effects of INa reduction on spontaneous sarcoplasmic reticulum (SR) Ca2+ release.1 In the context of the authors' previous publications regarding the mechanism of action of flecainide at the cardiac ryanodine receptor (RyR2),2–4 it appears they have interpreted our study as an attempt to infer that flecainide has no effect on RyR2. We would like to clarify this misinterpretation. Our work demonstrates that a reduction in Na+ influx into the cardiomyocyte can, via the enhancement of Ca2+ efflux through the Na+/Ca2+ exchanger, reduce [Ca2+]i in the vicinity of the RyR2 and thus reduce the frequency of spontaneous SR Ca2+ release events. We demonstrate that this is a class effect of INa blockers, and that flecainide causes no reduction in SR Ca2+ leak when INa is eliminated by altering the holding potential via voltage clamp. This mechanism also appears to be relevant in whole-heart models of arrhythmia induced by increased SR Ca2+ release as evidenced by recent data from Radwanski et al .5 Our data should not be taken as a dismissal of the effects of flecainide at RyR2. We merely conclude that, under our experimental conditions, INa blockade confers a greater reduction in spontaneous SR Ca2+ release than effects at the RyR2. Flecainide has been …

Flecainide reduces ventricular arrhythmias via a mechanism that differs from that of β-blockers in catecholaminergic polymorphic ventricular tachycardia

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by episodic ventricular tachycardia induced by adrenergic stress. Although β-blockers are used as first-line therapy, their therapeutic effects are largely incomplete. Flecainide has recently been shown to modify the molecular defects in CPVT. The aim of this study was to investigate the effects of flecainide as an add-on to conventional therapy on exercise-induced ventricular arrhythmia and compare them with those of conventional therapy alone. MethodsThe study included 5 CPVT patients with a mutation in RYR2. They experienced episodic arrhythmic events despite conventional β-blocker therapy and were therefore given flecainide in addition. The effects of the addition of flecainide therapy on ventricular arrhythmia during exercise testing were compared with those of conventional therapy alone. ResultsBoth β-blockers alone and with additional flecainide increased the maximal workload attained at the onset of ventricular arrhythmia; however, only flecainide increased the sinus rate at the onset of ventricular arrhythmias. Furthermore, flecainide increased the exercise capacity by preventing exercise-induced arrhythmias. During a follow-up period of 17±2 months, 1 patient experienced recurrent arrhythmic episodes that were associated with noncompliance. All patients reported improvements in their ability to perform the activities of daily living. ConclusionFlecainide effectively reduced ventricular arrhythmias via a mechanism that differs from that of β-blockers in genotype-positive patients with CPVT. The specific effects of flecainide may be critical in the improvement noted in the patients' ability to perform daily activities.

Comparison of the Intrinsic Vasorelaxant and Inotropic Effects of the Antiarrhythmic Agents Vernakalant and Flecainide in Human Isolated Vascular and Cardiac Tissues

This study explored the intrinsic vasorelaxant and inotropic effects of the mixed potassium and sodium channel blocker atrial antiarrhythmic vernakalant and the class IC antiarrhythmic agent flecainide in human isolated subcutaneous resistance artery and in ventricular trabecular muscle preparations. At test concentrations encompassing free plasma concentrations associated with clinical efficacy for conversion of atrial fibrillation, vernakalant (1-10 μM) displayed no significant direct effects on human resistance artery tone or ventricular contractility. In contrast, tested at equimolar concentrations, flecainide significantly reduced peak isometric contractile force (10 μM) and maximal rates of force development and decline (3 and 10 μM) in the human ventricular muscle preparation while displaying no significant effect on human resistance artery tone. The lack of effects of vernakalant on human resistance artery tone and ventricular muscle contractile function suggests that direct vasorelaxant and inotropic effects do not underlie the rare hypotensive events observed clinically with vernakalant, raising the possibility that secondary (eg, reflex) effects may mediate these events. The demonstration of negative inotropic effects with flecainide in the human ventricular muscle preparations in the absence of an effect on resistance artery tone suggests that the hemodynamic effects of flecainide observed clinically result primarily from direct negative inotropic effects.

Effects of flecainide on exercise-induced ventricular arrhythmias and recurrences in genotype-negative patients with catecholaminergic polymorphic ventricular tachycardia

Conventional therapy with beta-blockers is incompletely effective in preventing arrhythmic events in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). We have previously discovered that flecainide in addition to conventional drug therapy prevents ventricular arrhythmias in patients with genotype-positive CPVT. To study the efficacy of flecainide in patients with genotype-negative CPVT. We studied the efficacy of flecainide for reducing ventricular arrhythmias during exercise testing and preventing arrhythmia events during long-term follow-up. Twelve patients with genotype-negative CPVT were treated with flecainide. Conventional therapy failed to control ventricular arrhythmias in all patients. Flecainide was initiated because of significant ventricular arrhythmias (n = 8), syncope (n = 3), or cardiac arrest (n = 1). At the baseline exercise test before flecainide, 6 patients had ventricular tachycardia and 5 patients had bigeminal or frequent ventricular premature beats. Flecainide reduced ventricular arrhythmias at the exercise test in 8 patients compared to conventional therapy, similar to that in patients with genotype-positive CPVT in our previous report. Notably, flecainide completely prevented ventricular arrhythmias in 7 patients. Flecainide was continued in all patients except for one who had ventricular tachycardia at the exercise test on flecainide. During a follow-up of 48±94 months, arrhythmia events (sudden cardiac death and aborted cardiac arrest) associated with noncompliance occurred in 2 patients. Flecainide was not discontinued owing to side effects in any of the patients. Flecainide was effective in patients with genotype-negative CPVT, suggesting that spontaneous Ca(2+) release from ryanodine channels plays a role in arrhythmia susceptibility, similar to that in patients with genotype-positive CPVT.

Flecainide reduces Ca2+ spark and wave frequency via inhibition of the sarcolemmal sodium current

AimsCa2+ waves are thought to be important in the aetiology of ventricular tachyarrhythmias. There have been conflicting results regarding whether flecainide reduces Ca2+ waves in isolated cardiomyocytes. We sought to confirm whether flecainide inhibits waves in the intact cardiomyocyte and to elucidate the mechanism.Methods and resultsWe imaged spontaneous sarcoplasmic reticulum (SR) Ca2+ release events in healthy adult rat cardiomyocytes. Variation in stimulation frequency was used to produce Ca2+ sparks or waves. Spark frequency, wave frequency, and wave velocity were reduced by flecainide in the absence of a reduction of SR Ca2+ content. Inhibition of INa via alternative pharmacological agents (tetrodotoxin, propafenone, or lidocaine) produced similar changes. To assess the contribution of INa to spark and wave production, voltage clamping was used to activate contraction from holding potentials of −80 or −40 mV. This confirmed that reducing Na+ influx during myocyte stimulation is sufficient to reduce waves and that flecainide only causes Ca2+ wave reduction when INa is active. It was found that Na+/Ca2+-exchanger (NCX)-mediated Ca2+ efflux was significantly enhanced by flecainide and that the effects of flecainide on wave frequency could be reversed by reducing [Na+]o, suggesting an important downstream role for NCX function.ConclusionFlecainide reduces spark and wave frequency in the intact rat cardiomyocyte at therapeutically relevant concentrations but the mechanism involves INa reduction rather than direct ryanodine receptor (RyR2) inhibition. Reduced INa results in increased Ca2+ efflux via NCX across the sarcolemma, reducing Ca2+ concentration in the vicinity of the RyR2.

Effects of flecainide and dronedarone on atrial and ventricular effective refractory period in the dog with pacing induced atrial remodeling

Effects of flecainide and dronedarone on atrial and ventricular effective refractory period in the dog with pacing induced atrial remodeling