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Introduction: Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia that are encountered in the clinical practice. Recent data suggests that high PVC burden may lead to the development of PVC‐induced cardiomyopathy (PVC‐CM) even in patients without structural heart disease. Treatment for effective suppression of PVCs, can reverse PVC‐CM. Both antiarrhythmic drugs (AADs) and catheter ablation (CA) are recognized treatment modalities for any cardiac arrhythmias. However, with increasing preference of CA, the role of AADs needs further defining regarding their efficacy, safety, indications and patient selection to treat PVC‐CM. Methods: To ascertain the role of AADs to treat PVC‐CM; whether they are indicated to treat PVC‐CM, and if so, when, we interrogated PubMed and other search engines for English language publications with key words premature ventricular complexes (PVCs), cardiomyopathy, anti‐arrhythmic drugs, catheter ablation, and pharmacological agents. All publications were carefully reviewed and scrutinized by the authors for their inclusion in the review paper. For illustration of cases, ethical standard was observed as per the 1975 Declaration of Helsinki, and the patient was treated as per the prevailing standard of care. Informed consent was obtained from the patient for conducting the ablation procedure. Results: Our literature search specifically the pharmacological treatment of PVC‐CM with AADs revealed significant paradigm shift in treatment approach for PVCs and PVC‐induced cardiomyopathy. No major large, randomized control trials of AADs versus CA for PVC‐CM were found. We found that beta‐blockers and calcium channel blockers are particularly effective in the treatment of PVCs originating from right ventricular outflow tract. For Class Ic AADs ‐ flecainide and propafenone, small clinical studies showed Class Ic AADs to be effective in PVC suppression, but their usage was not recommended in patients with significant coronary artery disease. Mexiletine was found to have modest effect on PVC suppression. Studies showed sotalol to significantly reduce PVCs frequency in patients receiving both low and high doses. Studies also showed amiodarone to have higher successful PVC suppression, but not recommended as a first‐line treatment for patients with idiopathic PVCs in the absence of symptoms and left ventricular dysfunction. For dronedarone, no major clinical data were available. Conclusions: Based on the available data in the literature, we conclude that AADs play important role in the treatment of PVC‐induced cardiomyopathy. However, appropriate patient selection criteria are vitally important, and in general terms AADs are indicated or polymorphic PVCs, epicardial PVCs; and when CA procedure is contraindicated, or not feasible or failed. [ABSTRACT FROM AUTHOR]

Introduction: The use of flecainide and propafenone for medical cardioversion of atrial fibrillation (AF) and atrial flutter/intra‐atrial reentrant tachycardia (IART) is well‐described in adults without congenital heart disease (CHD). Data are sparse regarding their use for the same purpose in adults with CHD and in adolescent patients with anatomically normal hearts and we sought to describe the use of class IC drugs in this population and identify factors associated with decreased likelihood of success. Methods: Single center retrospective cohort study of patients who received oral flecainide or propafenone for medical cardioversion of AF or IART from 2000 to 2022. The unit of analysis was each episode of AF/IART. We performed a time‐to‐sinus rhythm analysis using a Cox proportional hazards model clustering on the patient to identify factors associated with increased likelihood of success. Results: We identified 45 episodes involving 41 patients. As only episodes of AF were successfully cardioverted with medical therapy, episodes of IART were excluded from our analyses. Use of flecainide was the only factor associated with increased likelihood of success. There was a statistically insignificant trend toward decreased likelihood of success in patients with CHD. Conclusions: Flecainide was more effective than propafenone. We did not detect a difference in rate of conversion to sinus rhythm between patients with and without CHD and were likely underpowered to do so, however, there was a trend toward decreased likelihood of success in patients with CHD. That said, medical therapy was effective in >50% of patients with CHD with AF. [ABSTRACT FROM AUTHOR]

Introduction: We describe a unique case of TECRL‐CPVT presented with cardiac arrest. Methods: Post resuscitation, the patient developed regular ventricular tachycardia featuring a left purkinje system morphology. Results: There was clear suppression of arrhythmia with the addition of flecainide and isolated ventricular ectopy causing secondary T‐wave changes. Conclusion: A high index of suspicion was required to eventually make the diagnosis through whole exome sequencing. [ABSTRACT FROM AUTHOR]

Pharmacological cardioversion using intravenous antiarrhythmic agents is commonly indicated in symptomatic patients with recent‐onset atrial fibrillation (AF). Except in hemodynamically unstable patients who require emergency direct current electrical cardioversion, for the majority of hemodynamically stable patients, pharmacological cardioversion represents a valid option and requires the clinician to be familiar with the properties and use of antiarrhythmic agents. The main characteristics of selected intravenous antiarrhythmic agents for conversion of recent‐onset AF, the reported success rates, and possible adverse events are discussed. Among intravenous antiarrhythmics, flecainide, propafenone, amiodarone, sotalol, dofetilide, ibutilide, and vernakalant are commonly used. Antazoline, an old antihistaminic agent with antiarrhythmic properties was also reported to give encouraging results in Poland. Intravenous flecainide and propafenone are the only Class I agents still recommended by recent guidelines. Intravenous new Class III agents as dofetilide and ibutilide have high and rapid efficacy in converting AF to sinus rhythm but require strict surveillance with electrocardiogram (ECG) monitoring during and after intravenous administration because of the potential risk of QT prolongation and Torsades de Pointes, which can be prevented and properly managed. Vernakalant, a partial atrial selective was shown to have a high success rate and to be safe in real‐life use. [ABSTRACT FROM AUTHOR]

Background: β‐Blockers are first‐line therapy in patients with long QT syndrome (LQTS). However, β‐blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add‐on therapy for LQT3 patients. However, the pooled effect of sodium channel blockers in all LQTS patients remains unknown. Methods: We conducted a systematic electronic search of PubMed, Embase, and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc ≥ 500 ms and QTc ≤ 460 ms in LQTS patients. Results: Pooled analysis of 14 studies with 213 LQTS (9 LQT1 + 63 LQT2 + 135 LQT3 + 6 others) patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (mean difference [MD], −49.43; 95% confidence interval [CI], −57.80 to −41.05, p <.001), reduced the incidence of CEs (risk ratio [RR], 0.23; 95% CI, 0.11–0.47; p <.001) and the proportion of QTc ≥ 500 ms (RR, 0.33; 95% CI, 0.24–0.47; p <.001), and increased the proportion of QTc ≤ 460 ms (RR, 10.33; 95% CI, 4.62–23.09; p <.001). Sodium channel blockers significantly shortened QTc both in LQT3 and LQT2 patients, while the QTc shortening effect in LQT3 was superior to that in LQT2 (57.39 vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 vs. 49.08 vs. 50.10 ms). Conclusions: Sodium channel blockers can be useful both in LQT3 and LQT2 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best. [ABSTRACT FROM AUTHOR]

Introduction: Sotalol and flecainide are used as second line agents in children for the treatment of supraventricular arrhythmias (SA) refractory to anti‐beta adrenergic antiarrhythmics or digoxin. Efficacy and adverse events in this cohort have not been well described. Here, we report our institutional experience of second line treatment initiation for SA in children. Methods and Results: Utilizing an institutional database, 247 patients initiated on sotalol and 81 patients initiated on flecainide were identified. Congenital heart disease (CHD) was present in 40% of patients. Arrhythmia‐free discharge on single or dual agent therapy (in combination with other antiarrhythmics) was 87% for sotalol and 91% for flecainide. Neither age, sex, dosing, presence of CHD nor arrhythmia subtype were associated with alterations in in‐hospital efficacy. Compared to baseline, QTc intervals in sotalol patients (436 [416–452 ms] vs. 415 [400–431 ms], p <.01) and QRS intervals in flecainide patients (75 [68–88 ms] vs. 62 [56–71 ms], p <.01) were prolonged. Dose reduction or discontinuation due to QRS prolongation occurred in 9% of patients on flecainide. QTc prolongation resulting in dose reduction/discontinuation of sotalol was encountered in 9 patients (4%) and death with documented torsade de pointes in 2 patients (1%), with 9 of 11 patients having underlying CHD. Conclusion: In children requiring second line agents for treatment of SA, both sotalol and flecainide appear to be highly efficacious. Although predominantly safe in otherwise healthy patients, electrocardiogram changes can occur and children with underlying cardiac disease may have an increased risk of adverse events and rhythm‐related side effects during initiation. [ABSTRACT FROM AUTHOR]

Introduction: Flecainide is a class 1C antiarrhythmic primarily usedfor the management of supraventricular arrhythmias. Adverse effects in patientswith pacemakers are poorly described in the current literature. We report acase of worsening intracardiac conduction in a patient with baseline atriallatency. Case: A patient with paroxysmalatrial fibrillation and recently implanted dual chamber pacemaker withresultant atrial latency underwent flecainide treatment resulting in worseningatrial latency, progressive dyspnea, and pacemaker syndrome physiology. The patientexperienced symptomatic improvement with pacemaker reprogramming to AAI andreduced flecainide dosages. Conclusion: Prudence should be exercised when initiating flecainide therapy, particularly in pacemaker‐dependentpatients, who may be at risk for increasedthresholds, inconsistent capture, and latency. In the setting of apparentcapture latency, changing to AAI mode may both confirm the diagnosis andprovide a symptomatic benefit. [ABSTRACT FROM AUTHOR]

Introduction: Antiarrhythmic drugs (AADs) are commonly used for the treatment of newly diagnosed symptomatic atrial fibrillation (AF), however initial AAD choice, duration of therapy, rates of discontinuation, and factors associated with a durable response to therapy are poorly understood. This study assesses the initial choice and duration of antiarrhythmic drug therapy in the first 2 years after diagnosis of AF in a younger, commercially insured population. Methods: A large nationally representative sample of patients age 20–64 was studied using the IBM MarketScan Database. Patients who started an AAD within 90 days of AF diagnosis with continuous enrollment for 1‐year pre‐index diagnosis and 2 years post‐index were included. A Cox proportional hazards model was used to determine factors associated with AAD discontinuation. Results: Flecainide was used most frequently (26.8%), followed by amiodarone (22.5%), dronedarone (18.3%), sotalol (15.8%), and propafenone (14.0%), with other AADs used less frequently. Twenty‐two percent of patients who started on an AAD underwent ablation within 2 years, with 79% discontinuing the AAD after ablation. Ablation was the strongest predictor of AAD discontinuation (hazard ratio [HR], 1.70; 95% confidence interval [CI]: 1.61–1.80), followed by the male gender (HR, 1.10; CI: 1.02–1.19). Older patients (HR, 0.76; CI: 0.72–0.80; reference age 18–49) and those with comorbidities, including cardiomyopathy (HR, 075; CI: 0.61–0.91), diabetes (HR, 0.83; CI: 0.75–0.91), and hypertension (HR, 0.87; CI: 0.81–0.94) were less likely to discontinue AADs. Conclusion: Only 31% of patients remained on the initial AAD at 2 years, with a mean duration of initial therapy 7.6 months before discontinuation. [ABSTRACT FROM AUTHOR]

Introduction: A drug provocation test (DPT) is important for the diagnosis of Brugada syndrome (BrS). The link, however, between dynamic changes of electrocardiography (ECG) features after DPT and unstable ventricular arrhythmia (VA) in BrS remains unknown. Methods: Between 2014 and 2019, we assessed 27 patients with BrS (median age: 37.0 [interquartile range, IQR: 22.0–51.0] years; 25 men), including 9 (33.3%) with a history of unstable VA and 18 (66.7%) without. All patients in the study presented with Brugada‐like ECG features before DPT. The ECG parameters and dynamic changes (∆) in 12‐lead ECGs recorded from the second, third, and fourth intercostal spaces (ICS) before and at 1, 6, 12, 18, and 24 h after DPT (oral flecainide 400 mg) were analyzed. Results: The total amplitude of V1 at the third ICS 18 and 24 h after DPT was significantly lower in patients with a history of unstable VA than in those without. Patients with BrS and unstable VAs had a significantly larger ∆ amplitude of V1 at the second ICS 12 h after DPT than in those without unstable VAs (0.28 [0.18–0.41] mV vs. 0.08 [0.01–0.15] mV, p =.01). A multivariate analysis revealed that the amplitude of V1 at the third ICS 18 and 24 h after DPT and the ∆ amplitude of V1 at the second ICS 12 h after DPT were associated with a history of unstable VA. Conclusion: Nonuniform changes and spatiotemporal differences in precordial ECG features after DPT were observed in patients with BrS and these may be surrogate markers for risk stratification. [ABSTRACT FROM AUTHOR]

The aticle presents a case study of a 17‐year‐old young lady, without any history of cardiovascular disease, has admitted to hospital because of recurrent crisis of palpitations to undergo an electrophysiological study. Topics include the Holter monitoring revealed several blocked sinus P waves interspersed with junctional ectopic beats; and lower panel showing the intracardiac tracings the sinus P wave does not conduct to the ventricles.

Objectives: To describe a single institutional experience managing fetuses with supraventricular tachycardia (SVT) and to identify associations between patient characteristics and fetal and postnatal outcomes. Background: Sustained fetal SVT is associated with significant morbidity and mortality if untreated, yet the optimal management strategy remains unclear. Methods: Retrospective cohort study including fetuses diagnosed with sustained SVT (>50% of the diagnostic echocardiogram) between 1985 and 2018. Fetuses with congenital heart disease were excluded. Results: Sustained SVT was diagnosed in 65 fetuses at a median gestational age of 30 weeks (range, 14‐37). Atrioventricular re‐entrant tachycardia and atrial flutter were the most common diagnoses, seen in 41 and 16 cases, respectively. Moderate/severe ventricular dysfunction was present in 20 fetuses, and hydrops fetalis was present in 13. Of the 57 fetuses initiated on transplacental drug therapy, 47 received digoxin first‐line, yet 39 of 57 (68%) required advanced therapy with sotalol, flecainide, or amiodarone. Rate or rhythm control was achieved in 47 of 57 treated fetuses. There were no cases of intrauterine fetal demise. Later gestational age at fetal diagnosis (odds ratio [OR], 1.1, 95% confidence interval [CI], 1.01‐1.2, P =.02) and moderate/severe fetal ventricular dysfunction (OR, 6.1, 95% CI, 1.7‐21.6, P =.005) were associated with postnatal SVT. Two postnatal deaths occurred. Conclusions: Fetuses with structurally normal hearts and sustained SVT can be effectively managed with transplacental drug therapy with minimal risk of intrauterine fetal demise. Treatment requires multiple antiarrhythmic agents in over half of cases. Later gestational age at fetal diagnosis and the presence of depressed fetal ventricular function, but not hydrops, predict postnatal arrhythmia burden. [ABSTRACT FROM AUTHOR]

Introduction: Inhaled flecainide significantly alters atrial electrical properties with the potential to terminate atrial fibrillation (AF) efficiently by optimizing dose and drug formulation. Methods: Seventeen Yorkshire pigs were studied. Intrapericardial acetylcholine and burst pacing were used to induce AF. Effects of a novel cyclodextrin formulation (hydroxypropyl‐ß‐cyclodextrin [HPßCD]) of flecainide (75 mg/mL, 0.5 or 1.0 mg/kg, bolus) instilled intratracheally at 2 minutes after AF initiation were studied. Concentration time‐area analyses of flecainide HPßCD were compared to the traditional acetate formulation. Results: Intratracheal instillation of flecainide HPßCD accelerated the conversion of AF to sinus rhythm in a dose‐proportional manner, shortening AF duration by 47% (P =.014) and 79% (P =.002) at the lower and higher doses, respectively, compared to intratracheal sterile water placebo. AF dominant frequency was reduced by 11% (P =.04) and 29% (P =.004) respective to dose. At 2 minutes after intratracheal flecainide HPßCD, atrial depolarization (Pa) duration increased by 12% (P =.02) and 17% (P =.009) at the lower and higher doses, respectively. At this time, the PR interval was prolonged by 9% (P =.04 for the higher dose) and AV node conduction was slowed, decreasing the ventricular rate during AF by 16% (P =.002) and 28% (P =.007) for the lower and higher doses. Flecainide HPßCD achieved the more efficient conversion of AF than the acetate formulation, reflected in a markedly reduced area under the curve (P =.04). Conclusion: Intratracheal instillation of the new flecainide HPßCD formulation effectively terminates AF through efficient multimodal actions including slowing of atrial conduction velocity and decreasing AF dominant frequency, allowing reduced net drug delivery and inhalation time. [ABSTRACT FROM AUTHOR]

Background: Pulmonary delivery of flecainide results in the rapid conversion of atrial fibrillation (AF) to normal sinus rhythm in large‐animal models and is safe and well‐tolerated by normal human volunteers. Objective: We investigated the effects of pulmonary delivery of flecainide on atrial and ventricular depolarization and repolarization duration. Methods: Intratracheal instillation (1.5 mg/kg, rapid push) of flecainide or sterile water (placebo) was performed in 12 closed‐chest, anesthetized Yorkshire pigs with a catheter positioned at the bifurcation of the main bronchi. High‐resolution electrograms obtained from catheters fluoroscopically positioned in the right atrium and left ventricle circumvented measurement errors due to the fusion of P and T waves in surface leads when rapid heart rates shortened the TP interval. Pacing was achieved using electrical stimuli delivered via right atrial catheter electrodes. Results: During sinus rhythm (98 ± 4.7 beats/min), intratracheal flecainide caused comparable (P = 0.56) increases in atrial depolarization (P a) duration by 22% (39.8 ± 3.2 to 48.7 ± 3.3  milliseconds) and left ventricular (LV) QRS complex duration by 20% (47.9 ± 1.6 to 57.3 ± 1.8  milliseconds) at peak effect at 2 minutes post‐dosing. During right atrial pacing at 180 beats/min, Pa duration increased by 55% (37.0 ± 2.0 to 57.2 ± 1.6  milliseconds; P < 0.0001). The atrial response was greater (p = 0.001) than the 30% increase in LV QRS complex duration (46.6 ± 1.7 to 60.6 ± 2.5  milliseconds; P = 0.005). Pa duration and QRS complex duration were unchanged by placebo independent of pacing (P ≥ 0.4 for both). Atrial repolarization duration (PTa; P = 0.46) and QTc interval (P = 0.49) remained unchanged. Conclusion: Intratracheal flecainide exerts a rate‐dependent, predominant effect on atrial compared with ventricular depolarization duration. Pulmonary delivery of flecainide could facilitate AF conversion to sinus rhythm with reduced ventricular proarrhythmia risk. [ABSTRACT FROM AUTHOR]

The article offers information on the automatic verification of capture and output management which lead to increased patient safety and pacemaker (PM) longevity with greater benefit at high pacing thresholds and also highlights the algorithms that available in pacemaker (PM) and cardiac resynchronization therapy (CRT) devices .

Background: The diagnostic work-up for cardiac arrest from ventricular tachyarrhythmias occurring in younger adults and structurally normal hearts is variable and often incomplete., Methods: We reviewed records for all recipients of a secondary prevention implantable cardiac defibrillator (ICD) younger than 60 years at a single quaternary referral hospital from 2010 to 2021. Patients with unexplained ventricular arrhythmias (UVA) were identified as those with no structural heart disease on echocardiogram, no obstructive coronary disease, and no clear diagnostic features on ECG. We specifically evaluated the adoption rate of five modalities of "second-line" cardiac investigations: cardiac magnetic resonance imaging (CMR), exercise ECG, flecainide challenge, electrophysiology study (EPS), and genetic testing. We also evaluated patterns of antiarrhythmic drug therapy and device-detected arrhythmias and compared them with secondary prevention ICD recipients with a clear etiology found on initial assessment., Results: One hundred and two recipients of a secondary prevention ICD under the age of 60 were analyzed. Thirty-nine patients (38.2%) were identified with UVA and were compared with the remaining 63 patients with VA of clear etiology (61.8%). UVA patients were younger (35.6 ± 13.0 vs. 46.0 ± 8.6 years, p < .001) and were more often female (48.7% vs. 28.6%, p = .04). CMR was performed in 32 patients with UVA (82.1%), whereas flecainide challenge, stress ECG, genetic testing, and EPS were only performed in a minority of patients. Overall, the use of a second-line investigation suggested an etiology in 17 patients with UVA (43.5%). Compared to patients with VA of clear etiology, UVA patients had lower rates of antiarrhythmic drug prescription (64.1% vs. 88.9%, p = .003) and had a higher rate of device-delivered tachy-therapies (30.8% vs. 14.3%, p = .045)., Conclusion: In this real-world analysis of patients with UVA, the diagnostic work-up is often incomplete. While CMR was increasingly utilized at our institution, investigations for channelopathies and genetic causes appear to be underutilized. Implementation of a systematic protocol for work-up of these patients requires further study., (© 2023 Wiley Periodicals LLC.)

Ivabradine in Atrial Tachycardia Ivabradine is indicated in cardiac failure and ischemia to reduce sinus rate by inhibition of the pacemaker I(f) current in sinoatrial node. We report a case of an 18-year-old woman with left atrial tachyarrhythmia resistant to several antiarrhythmic drugs and to electric cardioversion who responded only to ivabradine, which significantly reduced heart rate without abolishing the arrhythmia itself. An ectopic focus in the ostium of left pulmonary veins was found and the patient was successfully ablated. We suggest that ivabradine might be therefore useful in the treatment of supraventricular tachyarrhythmias due to an enhanced automaticity. [ABSTRACT FROM AUTHOR]

Acidosis and hERG K+ Channel Pharmacology. Introduction: Human Ether-à-go-go related gene (hERG) is responsible for channels that mediate the rapid delayed rectifier K+ channel current (IKr), which participates in repolarization of the ventricles and is a target for some antiarrhythmic drugs. Acidosis occurs in the heart in some pathological situations and can modify the function and responses to drugs of ion channels. The aim of this study was to determine the effects of extracellular and intracellular acidosis on the potency of hERG channel current (IhERG) inhibition by the antiarrhythmic agents dofetilide, flecainide, and amiodarone at 37 °C. Methods and Results: Whole-cell patch-clamp recordings of IhERG were made at 37 °C from hERG-expressing Human Embryonic Kidney (HEK293) cells. Half-maximal inhibitory concentration (IC50) values for IhERG tail inhibition at −40 mV following depolarizing commands to +20 mV were significantly higher at external pH 6.3 than at pH 7.4 for both flecainide and dofetilide, but not for amiodarone. Lowering pipette pH from 7.2 to 6.3 altered neither IhERG kinetics nor the extent of observed IhERG blockade by any of these drugs. Conclusion: Conditions leading to localized extracellular acidosis may facilitate heterogeneity of action of dofetilide and flecainide, but not amiodarone via modification of hERG channel blockade. Such effects depend on the external pH change rather than intracellular acidification. (J Cardiovasc Electrophysiol, Vol. 22, pp. 1163-1170, October 2011) [ABSTRACT FROM AUTHOR]

. Radiofrequency ablation is the treatment of choice to cure symptomatic patients with atrioventricular accessory pathways (APs). Septal APs are challenging because of the proximity of the normal conduction system. In some patients, despite aggressive lesion creation on the right anteroseptal region pathway, ablation is unsuccessful. We report 3 cases where the successful ablation site was in the noncoronary cusp of the aortic valve and discuss possible defining features of this variant of septal APs and an approach for successful ablation. (J Cardiovasc Electrophysiol, Vol. 22, pp. 203-209, February 2011) [ABSTRACT FROM AUTHOR]

Repolarization Gradients in Brugada Syndrome. Introduction: Brugada syndrome (BrS) is associated with loss of Na+ channel function and increased risks of a ventricular tachycardia exacerbated by flecainide but reduced by quinidine. Previous studies in nongenetic models have implicated both altered conduction times and repolarization gradients in this arrhythmogenicity. We compared activation latencies and spatial differences in action potential recovery between different ventricular regions in a murine Scn5a+/− BrS model, and investigated the effect of flecainide and quinidine upon these. Methods and Results: Langendorff-perfused wild-type and Scn5a+/− hearts were subjected to regular pacing and a combination of programmed electrical stimulation techniques. Monophasic action potentials were recorded from the right (RV) and left ventricular (LV) epicardium and endocardium before and following flecainide (10 μM) or quinidine (5 μM) treatment, and activation latencies measured. Transmural repolarization gradients were then calculated from the difference between neighboring endocardial and epicardial action potential durations (APDs). Scn5a+/− hearts showed decreased RV epicardial APDs, accentuating RV, but not LV, transmural gradients. This correlated with increased arrhythmic tendencies compared with wild-type. Flecainide increased RV transmural gradients, while quinidine decreased them, in line with their respective pro- and antiarrhythmic effects. In contrast, Scna5+/− hearts showed slowed conduction times in both RV and LV, exacerbated not only by flecainide but also by quinidine, in contrast to their differing effects on arrhythmogenesis. Conclusion: We use a murine genetic model of BrS to systematically analyze LV and RV action potential kinetics for the first time. This establishes a key role for accentuated transmural gradients, specifically in the RV, in its arrhythmogenicity. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1153-1159) [ABSTRACT FROM AUTHOR]

Activation of IKr Impairs Conduction. Introduction: The hERG (Kv11.1) potassium channel underlies cardiac IKr and is important for cardiac repolarization. Recently, hERG agonists have emerged as potential antiarrhythmic drugs. As modulation of outward potassium currents has been suggested to modulate cardiac conduction, we tested the hypothesis that pharmacological activation of IKr results in impaired cardiac conduction. Methods and Results: Cardiac conduction was assessed in Langendorff-perfused guinea pig hearts. Application of the hERG agonist NS3623 (10 μM) prolonged the QRS rate dependently. A significant prolongation (16 ± 6%) was observed at short basic cycle length (BCL 90 ms) but not at longer cycle lengths (BCL 250 ms). The effect could be reversed by the IKr blocker E4031 (1 μM). While partial INa inhibition with flecainide (1 μM) alone prolonged the QRS (34 ± 3%, BCL 250 ms), the QRS was further prolonged by 19 ± 2% when NS3623 was added in the presence of flecainide. These data suggest that the effect of NS3623 was dependent on sodium channel availability. Surprisingly, in the presence of the voltage sensitive dye di-4-ANEPPS a similar potentiation of the effect of NS3623 was observed. With di-4-ANEPPS, NS3623 prolonged the QRS significantly (26 ± 4%, BCL 250 ms) compared to control with a corresponding decrease in conduction velocity. Conclusion: Pharmacological activation of IKr by the hERG agonist NS3623 impairs cardiac conduction. The effect is dependent on sodium channel availability. These findings suggest a role for IKr in modulating cardiac conduction and may have implications for the use of hERG agonists as antiarrhythmic drugs. (J Cardiovasc Electrophysiol, Vol. 21, pp. 923-929, August 2010) [ABSTRACT FROM AUTHOR]

Introduction: Intrapericardial (IPC) delivery of antiarrhythmic agents is an appealing idea to increase the therapeutic width and reduce side effects of drugs, particularly in the thin atria. The aim of this study was to determine the effects of IPC versus intravenous (IV) d,l-sotalol and flecainide infusion on transmural atrial electrophysiology and sustained atrial fibrillation (AF) in the goat. Methods and Results: Effects of IPC and IV sotalol and flecainide infusion on epi- and endocardial atrial electrophysiology, ECG, and tissue drug concentrations were studied in goats without and with persistent AF (>24 hours). Epicardial atrial refractory period (AERP, bcl 400 ms) increased after 120 minutes of 1 mg/kg/hour IPC sotalol with 61 ± 8 ms (P = 0.02), whereas the endocardial AERP was not affected. One mg/kg/hour IPC flecainide increased the epicardial pacing threshold and the epicardial AERP with 4 ± 0.5 mA (P = 0.003) and 33 ± 11 ms (P = 0.05), respectively. Endocardial values were unchanged. Marked ST-elevations in the precordial ECG leads were observed after IPC flecainide. In the AF group, IPC drugs did not prolong AF cycle length to a greater extent than IV delivery. The number of cardioversions was not different between the two delivery routes. A steep transmural drug concentration gradient after IPC sotalol and flecainide was observed in all heart chambers. Conclusion: IPC sotalol and flecainide infusion in goats markedly affects epicardial atrial electrophysiology. IPC delivery, however, does not prolong AFCL or terminate AF to a greater extent than IV infusion. This suggests that the perpetuation of AF is not dominated by the epicardial and sub epicardial atrial layers. [ABSTRACT FROM AUTHOR]

Background: The atrial fibrillation cycle length (AFCL) is a critical parameter for the perpetuation and termination of AF. In the present study, we evaluated a new method to measure the AFCL based on transthoracic tissue Doppler imaging (TDI) of the right atrium (RA) and left atrium (LA). Methods: Twenty patients with AF (6 acute AF, 14 persistent or permanent AF) were studied. A quadripolar catheter was positioned at RA or LA to measure AFCL (AFCLEGM, gold standard). Transthoracic echocardiography (apical 4-chamber view) was used to perform pulsed wave TDI at the free wall of RA or LA. AFCLTDI was defined as the time interval between two consecutive positive to negative crossings of the baseline of the atrial time velocity curves. AFCLEGM and AFCLTDI were measured at baseline and during a 10-minute infusion of flecainide (1.5 mg/kg). Results: Measurement of AFCLTDI was feasible in all but one patient. At baseline, AFCLEGM was 170 ± 22 ms, AFCLTDI 172 ± 22 ms (difference 2 ± 5 ms). AFCLTDI correlated significantly with AFCLEGM (R = 0.91, P < 0.0001). Bland-Altman analysis showed a bias of −2 ms with a 95% limit of agreement between −26 ms and +22 ms. During flecainide, the AFCLTDI method yielded an AFCL prolongation from 176 ± 23 ms at baseline to 279 ± 68 ms (P < 0.01) after 10 minutes of infusion (57 ± 26%). Conclusions: (1) Tissue Doppler imaging of the atria during transthoracic echocardiography can be used to reliably determine the AFCL during both acute and persistent or permanent AF. (2) Continuous measurement of AFCL with TDI can be used to monitor the effect of antiarrhythmic drugs on atrial rate during AF. (3) This novel method is attractive because of the ease of acquiring the data and its noninvasive character. [ABSTRACT FROM AUTHOR]

Introduction: Provocation tests with sodium channel blockers are often required to unmask ECG abnormalities in Brugada syndrome (BrS). However, their diagnostic value is only partially established, while life-threatening ventricular arrhythmias during these tests were reported. We aimed to establish sensitivity, specificity, and safety of flecainide testing, and to predict a positive test outcome from the baseline ECG. Methods and Results: We performed 160 tests with flecainide in subjects determined to be at risk for BrS. P wave width, PQ duration, QRS width, S wave amplitude and duration in leads II-III, in addition to ST morphology and J point elevation in V1-V3 were measured before and after flecainide administration. Moreover, leads were positioned over the third intercostal space (V1IC3-V2IC3). Flecainide tests were considered positive if criteria from the First Consensus Report on BrS were fulfilled. In 64 cases, the test was positive, while 95 were negative (1 test was prematurely interrupted). The sensitivity and specificity, calculated in SCN5A-positive probands and their family members, were 77% and 80%, respectively. Baseline ECGs exhibited significant group differences in P, PQ, and QRS duration, J point elevation (leads V1-V2 and V1IC3-V2IC3), and S duration in II, but an attempt to predict the outcome of flecainide testing from these baseline ECG parameters failed. No malignant arrhythmias were observed. Conclusion: Flecainide testing is a valid and safe tool to identify SCN5A-related BrS patients. Baseline ECGs do not predict test outcomes, but point to conduction slowing as a core mechanism in BrS. [ABSTRACT FROM AUTHOR]

Synergism Between Atrial Dilation and Flecainide. Introduction:The aim of this study was to investigate the interaction of atrial dilation and blockade of the rapid sodium channel on atrial conduction and degree of anisotropy.Methods and Results:The right atrium was acutely dilated by increasing intra-atrial pressure from 2 to 9 cm H2O in 14 isolated rabbit hearts. A rectangular mapping array of 240 electrodes (spatial resolution 0.5 mm) was positioned on the free wall of the right atrium during pacing from four different directions at intervals of 240 and 140 msec. In nondilated atria, 0.5 and 1.0 mg/L of the use-dependent INa blocker flecainide prolonged the total conduction time under the mapping electrode by 15% to 75%. In dilated atria, flecainide depressed conduction by 24% to 89% (P<0.05). The incidence of intra-atrial conduction block increased from 0.6%–0.8% to 3.3%–7.2% in nondilated atria and from 3.9%–4.6% to 13%–21% in dilated atria (P<0.05). The direction of activation relative to the crista terminalis and major pectinate muscles was of major importance for occurrence of conduction block. During rapid pacing, the degree of anisotropy in conduction increased by the combination of atrial dilation and flecainide (1.0 mg/L) from 1.7± 0.1 to 2.2± 0.4 (P<0.05). The effects of dilation and flecainide on conduction were clearly synergistic. The effect of flecainide on the atrial refractory period also was enhanced by atrial dilation.Conclusion:In dilated atria, blockade of the rapid sodium channels caused a higher degree of local conduction delay and intra-atrial conduction block than in nondilated atria.(J Cardiovasc Electrophysiol, Vol. 15, pp. 1453-1461, December 2004) [ABSTRACT FROM AUTHOR]

Extracellular Acidosis Decreases Drug Block of Kv4.3. Introduction: As a molecular model of the effect of ischemia on drug block of the transient outward potassium current, the effect of acidosis on the blocking properties of flecainide and quinidine on Kv4.3 currents was studied. Methods and Results: Kv4.3 channels were stably expressed in Chinese hamster ovary cells. Whole-cell, voltage clamp techniques were used to measure the effect of flecainide and quinidine on Kv4.3 currents in solutions of pH 7.4 and 6.0. Extracellular acidosis attenuated flecainide block of Kv4.3 currents, with the IC[sub 50] for flecainide (based on current-time integrals) increasing from 7.8 ± 1.1 μM at pH 7.4 to 125.1 ± 1.1 μM at pH 6.0. Similar effects were observed for quinidine ( IC[sub 50] 5.2 ± 1.1 μM at pH 7.4 and 22.1 ± 1.3 μM at pH 6.0). Following block by either drug, Kv4.3 channels showed a hyperpolarizing shift in the voltage sensitivity of inactivation and a slowing in the time to recover from inactivation/block that was unaffected by acidosis. In contrast, acidosis attenuated the effects on the time course of inactivation and the degree of tonic- and frequency-dependent block for both drugs. Conclusion: Extracellular acidosis significantly decreases the potency of blockade of Kv4.3 by both flecainide and quinidine. This change in potency may be due to allosteric changes in the channel, changes in the proportion of uncharged drug, and/or changes in the kinetics of drug binding or unbinding. These findings are in contrast to the effects of extracellular acidosis on block of the fast sodium channel by these agents and provide a molecular mechanism for divergent modulation of drug block potentially leading to ischemia-associated proarrhythmia.(J Cardiovasc Electrophysiol, Vol. 14, pp. 641-650, June 2003). [ABSTRACT FROM AUTHOR]

Introduction: The mechanisms by which Class IC drugs slow the rate of functional reentrant arrhythmias are not completely understood. We hypothesized that flecainide widens the excitable gap beyond the pivot point of premature turning wavefronts. Methods and Results: In eight perfused subepicardial layers of rahbit left ventricle, a linear lesion was made by radiofrequency (RF) ablation parallel to the fiber orientation. One end of the RF lesion was extended by a short incision. Pacing next to the lesion induced a wavefront propagating with a sharp U-turn around the end of the lesion in either the clockwise or counterclockwise direction. A high-density mapping electrode (240 electrodes, 350-μm resolution) was used to record unipolar electrograms at the pivot point During control, the shortest V1-V2 interval proximal to the pivot point was 162 ± 12 msec compared with 173 ± 13 msec distal to the pivot point difference 11 ± 8 msec; P < 0.01). After infusion of flecainide 2 mg/L, the shortest V1-V2 interval proximal and distal to the pivot point were 217 ± 29 msec and 244 ± 36 msec (difference 27 ± 16 msec; P < 0.01). Due to the increase in V1-V2 interval at the pivot point, flecainide widened the temporal excitable gap in the returning limb of the turning wavefront from 30 ± 11 msec to 55 ± 22 msec (P < 0.01). High-density mapping at the pivot point revealed that this widening of the excitable gap was due to both macroscopic discoutinuous conduction and functional conduction block at the pivot point. Conclusion: Flecainide widens the excitable gap in the returning limb of premature U-turning wavefronts by causing macroscopic discontinuous conduction and functional conduction block at the pivot point. [ABSTRACT FROM AUTHOR]

Transient ST segment elevation in right precordial leads with use of psychotropic drugs is reported in two cases of overdose and one case of therapeutic administration. Flecainide did not reproduce ST segment elevation. The relationship of these abnormalities to the Brugada syndrome and the electrophysiologic hypothesis are discussed. [ABSTRACT FROM AUTHOR]

Introduction: Brugada syndrome is characterized by an ST segment elevation in leads V1-V3 and a high Incidence of ventricular fibrillation (VF). A mutation in a cardiac Na+ channel gene, SCN5A, has been linked to Brugada syndrome, and sodium channel blockers have been shown to be effective in unmasking the syndrome when concealed. The aim of this study was to examine the effects of NC channel blockers on ST segment elevation, QRS corrected QT (QTc) interval, and ventricular arrhythmias in patients with Brugada syndrome. Methods and Results: We examined the effects of three different NC channel blockers (flecainide, disopyramide, and mexiletine) on the amplitude of the ST segment 20 msec after the end of QRS (ST2O), QRS duration, QTc interval measured from 12-lead ECG, and ventricular arrhythmias in 12 Brugada and 10 control patients. Maximum ST20 observed in the V2 or V3 leads under baseline conditions was greater in the Brugada patients than In control patients, whereas QRS duration and maximum QTc interval were no different between the two groups. Flecainide and disopyramide. but not mexiletine, significantly increased maximum ST20 and QRS duration in both groups, although these effects were much more pronounced in the Brugada patients. The increases in ST20 and QRS duration with flecainide were significantly larger than those with disopyramide. An increase of 0.15 mV in ST20 with flecainide separated the two groups without overlap. Ventricular premature complexes developed only with flecainide in Brugada patients (3/12) displaying a marked ST elevation but not widening of QRS. conclusion: Our findings suggest that NC channel blockers amplify existing INa and possibly other ion channel defects, with a potency inversely proportional to the rate of dissociation of the drug from the Nat channel, thus causing a prominent elevation of the ST segment and, in some cases, prolongation of QRS duration in patients with Brugada syndrome. [ABSTRACT FROM AUTHOR]

Preferential Depression of Conduction at Pivot Points. Introduction: During reentrant arrhythmias, the circulating wavefront often makes a sharp turn around a functional or anatomic harrier. We tested the hypothesis that lowering the safety factor for conduction by high K+ or flecainide preferentially depresses conduction of sharply turning wavefronts. [ABSTRACT FROM AUTHOR]

We evaluated two patients without previous episodes of syncope who showed characteristic ECG changes similar to Brugada syndrome following administration of Class IC drugs, flecainide and pilsicainide, but not following Class IA drugs. Patient I had frequent episodes of paroxysmal atrial fibrillation resistant to Class IA drugs. After treatment with flecainide, the ECG showed a marked ST elevation in leads V2 and V3, and the coved-type configuration of ST segment in lead V2. A signal-averaged ECU showed late potentials that became more prominent after flecainide. Pilsicainide, a Class IC drugs induced the same ST segment elevation as tiecainide, but procainamide did not. Patient 2 also had frequent episodes of paroxysmal atrial fibrillation. Pilsicainide changed atrial fibrillation to atrial flutter with 2:1 ventricular response, and the ECG showed right bundle branch block and a marked coved-type ST elevation in leads V1 and V2. After termination of atrial flutter, ST segment elevation in leads V1 and V2 continued. In this patient, procainamide and quinidine did not induce this type of ECG change. In conclusion, strong Na channel blocking drugs induce ST segment elevation similar to Brugada syndrome even in patients without any history of syncope or ventricular fibrillation. [ABSTRACT FROM AUTHOR]

Introduction: Recently, we reported that repetitive induction of atrial fibrillation (AF) in the goat causes electrical remodeling of the atria leading to the development of sustained AK The aim of the present study was to compare Class IA, IC, and III drugs In their ability to cardiovert chronic AF in remodeled atria. Methods and Results: In 16 goats with sustained AF, hydroquinidine (HQ), clbenzoline (Ci), flecainide (Fl), and d-sotalol (dS) were infused. HQ, Ci, Fl, and dS restored sinus rhythm (SR) in 83%, 91%, 67%, and 92% of the cases, while adverse drug effects occurred in 17%, 36%, 56%, and 8%. Prior to restoration of SR, AF cycle Length prolonged by 68%, 103%, 53%, and 20%, respectively. The QRS width increased by 14%, 64%, and 58% (HQ, Ci, and Fl), and remained unchanged by administration of dS. RR intervals were slightly prolonged by HQ, Ci, and Fl, and markedly prolonged by dS (48%). The QT Interval was moderately prolonged by HQ, Ci, and Fl, and considerably by dS (34 %). QTc was only slightly prolonged by each of the drugs. Directly after cardioversion of AF, the atrial refractory period was 87 ± 29 (HQ), 119 ± 32 (Cl), 66 ± 10 (Fl), and 73 ± 18 msec (dS) (control: 146 ± 18 msec). Atrial conduction velocity was 85 ± 6, 71 ± 11,86 ± 12, and 110 ± 11 cm/sec compared with a control value of 116 ± 10 cm/sec. Because directly after cardioversion the atrial wavelength was still very short (5.7 to 8.4 cm), the vulnerability for AF was still very high, and a single premature beat reinduced AF in 71 % (Ci) to 100% (HQ, Fl, and dS) of the cases. conclusion: In a goat model of sustained AF, Class IA, IC, and III drugs restored sinus rhythm in 67% to 92% of the cases. However, after cardioversion, the atrial wavelength was still abnormally short, and AF was readily inducible In 71% to 100% of the cases. [ABSTRACT FROM AUTHOR]

Sodium Block-Induced ST Segment Elevation. Three patients in whom Class IC sodium channel blockers induced ST segment elevation In leads V1 through V3 are described. The underlying electrophysiologic mechanism, implications for drug-induced proarrhythmia, and the relationship of the finding to the Brugada syndrome type of idiopathic ventricular fibrillation are discussed. [ABSTRACT FROM AUTHOR]

ST Elevation with Flecainide and Pilsicainide. Flecainide and pilsicainide, Class IC antiarrhythmic drugs with slow kinetics, were administered to a 64-year-old man experiencing ventricular tachycardia. Both drugs suppressed the arrhythmia, but caused ST segment elevation in leads II, III, and aVF. No evidence of ischemic heart disease was detected. Withdrawal of the drugs eliminated the ST change. Because these drugs frequently are used to treat tachyarrhythmias in patients who may present with chest pain, this rare ECG manifestation of Class IC drugs should be recognized to avoid misdiagnosis of acute inferior myocardial infarction. [ABSTRACT FROM AUTHOR]

Introduction: The interaction between acute ventricular dilatation (AYE)) as one aspect of ventricular dysfunction and Class I and Ill antiarrhythmic drugs is uncertain. We therefore investigated the effects of AVI) on the electrophyslologic properties of d,l-sotalol and flecainide. Methods and Results: The isolated rabbit heart was used as a model of AVD. The ventricular size and, therefore, the diastolic pressure were modified by sudden volume changes of a fluid- filled balloon placed in the left ventricle. Pacing was performed alternately using epic and endocardial monophasic action potential (MAP)-pacing catheters at cycle lengths from 1,000 to 300 msec. d,I-Sotalol (10 μM) resulted in a significant (P < 0.05) lengthening of refractoriness (+13.5% ±3.1%), MAP duration (+14.9% ± 3.2%), and QT interval (+15.5% ± 4.1%) (mean ± SEM at 1000 msec). These effects had a reverse rate-dependence. ASP to a diastolic pressure of 30 mmHg reduced refractoriness and left ventricular MAP duration, in comparison with the control group with the same extent of AVD, d,l-sotalol still led to a significant prolongation of repolarization for all cycle lengths except 300 msec, so that its effects were not absolutely but relatively preserved. In contrast, flecalnide (2 μM) had no significant effects on refractoriness or MAP duration. It led to a significant, rate-dependent increase of pacing thresholds (+47.6% ± 8.2%), prolongation of QRS (+48.8% ± 5.6%), and conduction time (+78.6% ± 8.6%) (mean ± SEM at 300 msec). In the flecainide group, AVD significantly increased the normal rate-dependent prolongation of QRS (+16.7% ±5.5%) and conduction time (+17.1% ±4.3%). Conclusion: Our data demonstrate that, during AVD, the Class III effect of d,l-sotalol is preserved, whereas flecainide's effect of slowing conduction is exaggerated. This may cone tribute to flecainide-related proarrhythmia in certain clinical situations. [ABSTRACT FROM AUTHOR]

Introduction: Anisotropic conduction characteristics, expressed as the ratio of conduction velocities in the longitudinal (V1) and transverse (Vt) fiber directions, may play a role in the mechanism of some ventricular tachycardias and is influenced by pharmacologic interventions. Discrepancies exist among the reported orientation-dependent effects of available Class I antiarrhythmic drugs. The aim of this study was to assess the respective effects of quinidine (Class IA), flecainide (Class IC), and cibenzoline (not subclassified) on the anisotropic conduction of porcine hearts, in corroboration of their effects on ventricular action potentials. Methods and Results: We studied the actions of 3 and 10 μM quinidine, 1 and 3 μM flecainide, and 0.3 and 1 μM cibenzoline on V1 and Vt determined from 128 electrograms recorded with a plaque electrode on the anterior left ventricle of isolated perfused hearts (spacing 2.5 mm). V1 and Vt were computed from isochronal maps displaying ellipsoid activation during stimulation from the center of the plaque. The effects on the maximal rate of depolarization (Vmax) of action potentials were obtained from ventricular muscle exposed to the same drugs. Flecainide [1 μM] and cibenzoline [0.3 μM] did not alter V1 and Vt significantly. Quinidine [3 μM] predominantly depressed V1 at rapid pacing rates, but the V1/Vt ratio was not significantly altered. Quinidine [10 μM] and flecainide [3 μM] reduced V1 and Vt in a frequency-dependent fashion. Conversely, cibenzoline [1 μM] mostly decreased Vt and thus decreased the V1/Vt ratio and increased the V1/Vt at all pacing rates. This different effect was not related to a greater depressant effect on &Vdot;max. Conclusion: Quinidine and flecainide act similarly on the anisotropic pattern of conduction (both drugs increase the &Vdot;1/Vt ratio), whereas cibenzoline exerts opposite effects. Orientation-dependent effects are different among Class I antiarrhythmic drugs and may be of importance in their therapeutic efficacy or proarrhythmic potential. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) remains a challenge to medical therapy. Over the past several years, a variety of experimental models of AF have been developed. These have provided insights into mechanisms underlying AF and antiarrhythmic drug action against the arrhythmia. A variety of drugs effective against clinical AF, including flecainide, propafenone, procainamide, and sotalol, have been found to terminate experimental AF. All of these agents appear to act by prolonging the wavelength for atrial reentry at rapid rates, thereby increasing the size and decreasing the number of functional circuits maintaining the arrhythmia. While the ability to terminate AF is determined by refractoriness prolongation at rapid rates, refractoriness prolongation at slow rates (e.g., sinus rhythm) can prevent AF induction by premature beats. Thus, drugs with strong reverse use-dependence (like sotalol) may be much more effective in preventing than in terminating AK. Spacial heterogeneity in refractoriness is an important contributor to AF occurrence in some models, particularly vagal AF, and is reduced by some (but not all) drugs that terminate AF. New insights are being gained into mechanisms of electrical remodeling, which promotes AF maintenance when rapid atrial rates are maintained, such as during AF. This electrical remodeling may be an interesting novel target for therapy of AF. Insights into AF mechanisms obtained in experimental models of AF should help in the development of new and improved therapeutic approaches. [ABSTRACT FROM AUTHOR]

Flecainide and Excitability. Flecainide was associated with excess mortality distributed virtually equally throughout the period of the Cardiac Arrhythmia Suppression Trial, suggesting the intersection of two events, drug effect and perhaps ischemia. Flecainide's effect on active properties has been studied extensively, but nothing is known of its effects on passive properties or on the balance among active and passive cellular properties that determines cardiac excitability. The multiple microelectrode method of intracellular current application and transmembrane voltage recording was used in sheep Purkinje fibers to determine strength-and charge-duration as well as constant current-voltage relationships and to estimate active properties, liminal length, and cable properties at a normal [K+]0, and in a setting of hyperkalemia analogous to that of ischemia. A computer tracked in time the alterations in the active and passive properties relevant to excitability. Flecainide slightly decreased excitability at a normal [K+]0 primarily by depressing the sodium system with some contributory effect of passive properties. At high [K+]0, flecainide caused a frequency-dependent decrease in excitability and conduction, the latter best interpreted as a failure of the fiber to attain the liminal length requirements to produce a local action potential due primarily to an effect on sodium conductance. Together, the observations suggest that the action potential is the local phenomenon and that the propagated event is the sequential fulfillment of liminal length requirements. The data were interpreted in terms of the electrophysiologic matrix first proposed in detail in this Journal, which indicated that the electrophysiologic universe moved as a system in response to the drug and a change in [K+]0 the presumed antiarrhythmic and proarrhythmic electrophysiologic matrices for flecainide were quite similar, and the matrical configuration shared characteristics with the matrices of other drugs with known proarrhythmic potential. [ABSTRACT FROM AUTHOR]

Antiarrhythmics and Placental Vessels, introduction: Antiarrhythmic medications are commonly used during pregnancy for treatment of maternal or fetal arrhythmias, but little is known about their effect on human placental vascular tone and, consequently, placental blood flow. The objective of this study was to evaluate the tone responses caused by antiarrhythmic medications in human placental vessels from normal term pregnancies in vitro. Methods and Results: Isolated human placental arteries and veins from uncomplicated term pregnancies incubated in Krehs'--bicarbonate under 5% oxygen/5% carbon dioxide/balance nitrogen (PO2 35 to 38 torr) were exposed to cumulative doses of quinidine, procainamide, lidocaine, flecainide, propranolol, amiodarone, verapamil, digoxin, and adenosine after submaximal contraction with 5-hydroxytryptamine. The study was conducted both in the presence and absence of endothelium. The addition of the tested medications caused a significant, dose-dependent relaxation of human placental arteries and veins except for adenosine, which induced a sustained, dose-dependent contraction of human placental vessels regardless of the presence or absence of tone. Removal of the endothelium did not alter these responses. Conclusions: Based on these results, the medications tested should have no decremental effect on placental blood flow, with the possible exception of adenosine, which causes significant, dose-dependent contraction of human placental vessels in vitro. Should similar contraction be present in vivo, it may have an adverse effect on the fetus when administering adenosine to pregnant women at term or during labor. [ABSTRACT FROM AUTHOR]

Flecainide is a Class IC antiarrhythmic agent whose primary electrophysiologic effect is a slowing of conduction in a wide range of cardiac tissues. It is well absorbed and effective in suppressing isolated premature ventricular contractions (PVCs) or nonsustained ventricular arrhythmia hut has only a modest efficacy when electrophysiologic testing is used as an endpoint. Its adverse effect on mortality in the CAST trial suggested a propensity to proarrhythmia--a phenomenon to which the Class IC agents appear particularly prone. Despite the applicability of the CAST study only to patients with a prior myocardial infarction, there has been a shift away from flecainide in ventricular arrhythmia, hut the low noncardiac side effect profile of the agent allows for its continued use in a wide variety of supraventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Introduction: We investigated a method of defibrillation in which two shocks were delivered to the same electrodes with a separation based on the cycle length of the fibrillation event (FCL). Methods and Results: In pentobarbital anesthetized dogs, a computerized system determined the FCL from the fibrillation event, computed the desired double-pulse (DP) shock separation, and immediately delivered the DP shocks. In group 1, energy for 50% success at defibrillation (E50) was measured using separations from 55% to 95% of the FCL and remeasured after administration of flecainide, clofilium, or vehicle to change the FCL. Both drugs increased FCL by = 25%. Plots of E50 versus %FCL aligned before and after drug showed that the optimum pulse separation followed the FCL. In group 2, E50s were measured for 55% to 185% FCL separations in clofilium or vehicle-treated animals. The optimum DP F50 was at 85% FCL and was not significantly different from the single-shock F50. In group 3, no differences were found when comparing the probability of success versus total energy relationships for single and optimum DP shocks. Group 4 compared E50s for single and DP shocks using a single-catheter configuration and three-electrode configurations (catheter-subdermal patch). F50s for single and DP shocks were equal using the single-catheter configuration but DP shocks required = 20% more energy in the three-electrode configurations. Conclusion: In single-pathway lead configurations, two shocks with 85% FCL separation can be reliably combined to defibrillate using the same total energy as a larger single shock. Since the energy is unchanged but the total duration is doubled, DP shock currents are reduced by 20% to 30%. [ABSTRACT FROM AUTHOR]

The use of multiple His bundle-right bundle branch recordings in electrophysiologic studies has facilitated definition of the mechanism and elucidation of the direction of impulse propagation in bundle branch reentrant tachycardia, "Mahaim" fiber reciprocating tachycardia, and retrograde His depolarization in fascicular or ventricular tachycardias. This report details the electrophysiologic evaluation of pleomorphic ventricular tachycardia in a patient with advanced coronary heart disease. The ventricular tachycardia at baseline revealed variation in the QRS duration without alteration of the electrocardiographic (ECG) morphology. Following flecainide administration, a ventricular tachycardia with close resemblance of the ECG morphology to sinus rhythm was induced. Proximal and distal His-bundle recordings revealed early antegrade His-bundle activation during this tachycardia. Programmed stimulation converted this tachycardia back to the clinical ventricular tachycardia with intermittent narrowing of the QRS complexes. Early His activation was evident only during the narrower complexes but not in the tachycardia beats with wide complex. Penetration of the His bundle by ventricular tachycardia, with resultant fusion from intramyocardial ventricular activation and His-Purkinje activation, could have accounted for the near normalization of the QRS morphology during the ventricular tachycardia. [ABSTRACT FROM AUTHOR]

Introduction: Toxic levels of flecainide can cause life-threatening electrophysiologic and hemodynamic changes. Isoproterenol is known to reverse therapeutic drug effects in patients with ventricular and supraventricular tachycardias. In a single cell preparation it appears that isoproterenol Increases inward Na current and it is conceivable that isoproterenol may also be capable of decreasing the electrophysiologic effects of flecainide toxicity. This study was aimed at detailed characterization of the electrophysiologic changes induced by toxic levels of flecainide, the extent that isoproterenol may reverse these changes, and the effect of beta blockade on these changes. Methods and Results: In this experimental model, using the strength-interval stimulation method, conduction time, and epicardial activation times, we defined the changes in conduction, refractoriness, and excitability caused by toxic levels of flecainide (> 3µg/mL), during infusions of flecainide and isoproterenol, and lastly, these infusions and propranolol. In nine dogs, using atrial and ventricular stimulation at pacing rates of 120 and 210 beats/min, atrioventricular conduction, right ventricular refractoriness, and conduction changes were evaluated at baseline and following isoproterenol infusion (0.09µg/kg/min), flecainide infusion (4 mg/kg followed by 5 mg/kg/hr), flecainide combined with isoproterenol infusion, and lastly, flecainide, isoproterenol, and propranolol (0.2 mg/kg). Compared to baseline, toxic levels of flecainide (3.71-3.86 µg/mL) produced a 64% and 93% increase in the atrial-His interval at pacing rates of 120 and 210 beats/minute, respectively. Isoproterenol reversed 15% and 55% of this prolongation. The His-ventricular conduction was prolonged by 82% and 124% after flecainide at 120 and 210 beats/min, respectively. These changes were reversed by 29% and 53% with isoproterenol. With flecainide, the relative and effective refractory periods of the ventricular myocardium (during right ventricular pacing) were lengthened by 16% and 19%, respectively, and reversed to baseline values following isoproterenol. None of the ventricular electrophysiologic parameters altered by flecainide were significantly affected with increasing pacing rate. The QRS complex duration increased by 59% with flecainide, and isoprotereno) reversed 30% of this increase. Left ventricular (LV) activation time during right ventricular (RV) pacing increased by 88% with flecainide, 59% of which was reversed by isoproterenol. Propranolol resulted in complete elimination of the isoproterenol-produced partial reversal of flecainide toxicity. RV diastolic pacing threshold was raised by 61% with flecainide, but this effect was not reversed with isoproterenol. Conclusion: It is concluded that at least 30% of the toxic effects of flecainide can be reversed by isoproterenol. Such reversal may be useful in treating flecainide toxicity. Pacing threshold, however, does not improve with isoproterenol, and all the isoproterenol effects are abolished by propranolol. The electrophysiologic effects of toxic levels of flecainide were further aggravated with the addition of propranolol. [ABSTRACT FROM AUTHOR]

To better understand the manner in which Class I antiarrhythmic drugs suppress ventricular tachycardia in the Harris dog model of ventricular arrhythmia, we used a preparation in which vagal fibers to the sinus node could be stimulated through a chronically implanted electrode. Twenty-four hours after two-stage ligation of the LAD, animals were studied in the conscious state under control conditions and after IV injection of flecainide (5 mg/kg), encainide <5 mg/kg), and moricizine (3 mg/kg). Records of atrial and ventricular electrograms and the ECG were obtained during spontaneous rhythm, during atrial overdrive pacing, and during vagal stimulation sufficient to arrest or markedly slow the sinus rhythm. We found that when each of the antiarrhythmic drugs had restored sinus rhythm, sinus slowing by vagal stimulation demonstrated the persistence of the ventricular tachycardia. In some instances, the rate of the ventricular focus had been slowed minimally, and restoration of sinus rhythm resulted primarily from a slight increase in sinus rate. The degree to which the drugs slowed the ectopic tachycardia was greater with flecainide and encainide than with moricizine but in no case was the ectopic pacemaker arrested. Overdrive suppression of the ectopic pacemaker was minimal under control conditions and increased by drugs; this effect was most prominent with flecainide and clearly contributed to the overall antiarrhythmic effect. [ABSTRACT FROM AUTHOR]

Ventricular tachycardia/fibrillation and sudden cardiac death occur frequently following myocardial ischemia or infarction. The recent Cardiac Arrhythmia Suppression Trial (CAST Study) found that patients treated with the Na-channel antagonists encainide and flecainide suffered increased mortality over placebo. This unexpected result has dampened enthusiasm for treatment of asymptomatic ventricular arrhythmias and more subtly suggests a need for review of current strategies for analysis and treatment of cardiac arrhythmias. This article focuses on two nonsarcolemmal ion channels that may be involved in certain types of ventricular arrhythmias: the gap junction channel and the Ca2+-release channel of sarcoplasmic reticulum (SR). Gap junctions enable conduction of the cardiac impulse from cell-to-cell and may be involved in reentrant arrhythmias. SR Ca2+-release channels regulate the level of cytosolic Ca2+ during initiation of contraction and seem to be the basis for triggered activity. Gap junction and SR Ca2+-release channels, though structurally dissimilar molecules, share certain functional and gating characteristics. In different ways, both channels couple the electrical response to the mechanical response. Furthermore, dysfunction of gap junction channels and/or SR Ca2+-release channels may underlie the development of arrhythmias in postischemic cells. Classification of arrhythmias on the basis of which channel(s) is principally involved might expedite the development of new drugs targeted at functional regions of the channel(s). Ultimately, pharmacotherapy of arrhythmias directed at the molecules responsible for the electrical dysfunction may replace the empirical approach that dominates current cardiology practice. [ABSTRACT FROM AUTHOR]