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Background: Intravenous (IV) flecainide is recommended for the pharmacological cardioversion of recent-onset atrial fibrillation (AF). The aim of this study was to study the efficacy and safety of IV flecainide, co-administered with oral b-blockers, for the cardioversion of paroxysmal AF. Methods: Single-center registry, initiated in the "Skylitseion" General Hospital of Chios in January 2020. The main inclusion criterion was IV flecainide administration plus oral b-blocker for recent-onset AF (≤48 h). The primary outcome was conversion to sinus rhythm at 2 h. Results: A total of 121 (73 males and 48 females, with mean age 61.4 years) consecutive, unselected patients who complied with the study protocol were included. A successful conversion to sinus rhythm at 2 h was achieved in 99 patients (success rate: 81.8%). The median conversion time was 11.7 min (varied from 3 to 23 min). Duration of hospitalization was significantly shorter in patients who were successfully cardioverted with IV flecainide (10.9 vs. 30.7 h, p < 0.001). No serious adverse events were recorded. Conclusion: This is one of the largest registries worldwide, evaluating the effectiveness and safety of IV flecainide co-administered with a b-blocker in the acute management of recent-onset AF. The successful conversion rate at 2 h is very high and quick with no serious adverse events. [ABSTRACT FROM AUTHOR]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe hereditary arrhythmia syndrome predominantly affecting children and young adults. It manifests through bidirectional or polymorphic ventricular arrhythmia, often culminating in syncope triggered by physical exertion or emotional stress which can lead to sudden cardiac death. Most cases stem from mutations in the gene responsible for encoding the cardiac ryanodine receptor (RyR2), or in the Calsequestrin 2 gene (CASQ2), disrupting the handling of calcium ions within the cardiac myocyte sarcoplasmic reticulum. Diagnosing CPVT typically involves unmasking the arrhythmia through exercise stress testing. This diagnosis emerges in the absence of structural heart disease by cardiac imaging and with a normal baseline electrocardiogram. Traditional first-line treatment primarily involves β-blocker therapy, significantly reducing CPVT-associated mortality. Adjunctive therapies such as moderate exercise training, flecainide, left cardiac sympathetic denervation and implantable cardioverter-defibrillators have been utilized with reasonable success. However, the spectrum of options for managing CPVT has expanded over time, demonstrating decreased rates of arrhythmic events. Furthermore, ongoing research into potential new therapies including gene therapies has the potential to further enhance treatment paradigms. This review aims to succinctly encapsulate the contemporary understanding of the clinical characteristics, diagnostic approach, established therapeutic interventions and the promising future directions in managing CPVT. [ABSTRACT FROM AUTHOR]

Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder that may lead patients to sudden cell death through the occurrence of ventricular arrhythmias. ACM is characterised by the progressive substitution of cardiomyocytes with fibrofatty scar tissue that predisposes the heart to life-threatening arrhythmic events. Cardiac mesenchymal stromal cells (C-MSCs) contribute to the ACM by differentiating into fibroblasts and adipocytes, thereby supporting aberrant remodelling of the cardiac structure. Flecainide is an Ic antiarrhythmic drug that can be administered in combination with β-adrenergic blockers to treat ACM due to its ability to target both Nav1.5 and type 2 ryanodine receptors (RyR2). However, a recent study showed that flecainide may also prevent fibro-adipogenic differentiation by inhibiting store-operated Ca2+ entry (SOCE) and thereby suppressing spontaneous Ca2+ oscillations in C-MSCs isolated from human ACM patients (ACM C-hMSCs). Herein, we briefly survey ACM pathogenesis and therapies and then recapitulate the main molecular mechanisms targeted by flecainide to mitigate arrhythmic events, including Nav1.5 and RyR2. Subsequently, we describe the role of spontaneous Ca2+ oscillations in determining MSC fate. Next, we discuss recent work showing that spontaneous Ca2+ oscillations in ACM C-hMSCs are accelerated to stimulate their fibro-adipogenic differentiation. Finally, we describe the evidence that flecainide suppresses spontaneous Ca2+ oscillations and fibro-adipogenic differentiation in ACM C-hMSCs by inhibiting constitutive SOCE. [ABSTRACT FROM AUTHOR]

Pharmacologic cardioversion is a well-established alternative to electric cardioversion for hemodynamically stable patients, as it skips the risks associated with anesthesia. A recent network meta-analysis identifies the most effective antiarrhythmics for pharmacologic cardioversion with flecainide exhibiting a more efficacious and safer profile towards faster cardioversion. Moreover, the meta-analysis of class Ic antiarrhythmics revealed an absence of adverse events when used for pharmacologic cardioversion of AF in the ED, including patients with structural heart disease. The primary goals of this clinical trial are to prove the superiority of flecainide over amiodarone in the successful cardioversion of paroxysmal atrial fibrillation in the Emergency Department and to prove that the safety of flecainide is non-inferior to amiodarone in patients with coronary artery disease without residual ischemia, and an ejection fraction over 35%. The secondary goals of this study are to prove the superiority of flecainide over amiodarone in the reduction in hospitalizations from the Emergency Department due to atrial fibrillation in the time taken to achieve cardioversion, and in the reduction in the need to conduct electrical cardioversion. [ABSTRACT FROM AUTHOR]

Fetal arrhythmias complicate 1% of pregnancies. Although most of them have a benign and intermittent course, sustained fetal tachyarrhythmias constitute an emerging situation, which is associated with high fetal morbidity and mortality. However, one of the major milestones in fetal therapy is the pharmacologic management of fetal arrhythmias by crossing the placental barrier. To date, there is no consensus on the first-line antiarrhythmic treatment for fetal tachyarrhythmias. The role of sotalol in therapeutic management, the use of flecainide versus digoxin as first line of treatment, the need for fetal intramuscular treatment administration, or the best treatment in case of fetal hydrops are situations whose application or management are controversial. The current paper is a scoping review of observational and experimental evidence, addressing the types of best management strategies for each type of tachyarrhythmia and the optimal pharmacological dose, considering precautions and safety elements. Finally, we will highlight new therapeutic perspectives and future diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

The mechanism of premature ventricular complexes (PVC) occurring in the ventricular outflow tract (OT) is related to an intracellular calcium overload and delayed afterdepolarizations that lead to triggered activity. The guidelines recommend using beta-blockers and flecainide for idiopathic PVCs, but they also acknowledge the limited evidence supporting this recommendation. We conducted a multicenter, randomized, open-label pilot study comparing the effect of carvedilol and flecainide on OT PVC, which are widely used to treat this arrhythmia. Patients with a 24 h Holter recording a PVC burden ≥ 5%, which showed positive R waves in leads II, III, and aVF, and without structural heart disease were enrolled. They were randomly assigned to the carvedilol or flecainide group, and the maximum tolerated dose was administered for 12 weeks. A total of 103 participants completed the protocol: 51 with carvedilol and 52 with flecainide. After 12 weeks of treatment, the mean PVC burden significantly decreased in both groups: 20.3 ± 11.5 to 14.6 ± 10.8% with carvedilol (p < 0.0001) and 17.1 ± 9.9 to 6.6 ± 9.9% with flecainide (p < 0.0001). Both carvedilol and flecainide effectively suppressed OT PVCs in patients without structural heart disease, with flecainide showing a superior efficacy compared to carvedilol. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable progressive myocardial disorder that predisposes patients to ventricular arrhythmias and sudden cardiac death. Antiarrhythmic medications have an important role in reducing the frequency of ventricular arrhythmias and the morbidity associated with recurrent implantable cardioverter-defibrillator (ICD) shocks. Although several studies have examined the use of antiarrhythmic drugs in ARVC, these have been mostly retrospective in nature and inconsistent in their methodology, patient population and endpoints. Thus, current prescribing practices are largely based on expert opinion and extrapolation from other diseases. Herein, we discuss the major studies of the use of antiarrhythmics in ARVC, present the current approach employed at the Johns Hopkins Hospital and identify areas where further research is needed. Most notably, there is a great need for high-quality studies with consistent methodology and randomized controlled trial data into the use of antiarrhythmic drugs in ARVC. This would improve management of the condition and ensure antiarrhythmic prescribing is based on robust evidence. [ABSTRACT FROM AUTHOR]

The negative chronotropic effects of eight Vaughan Williams Class I antiarrhythmic drugs were examined in guinea pig right atrial tissue preparations. The drugs decreased the spontaneous beating rate at concentrations overlapping with their therapeutic blood levels. Cibenzoline, aprindine, flecainide, and propafenone showed stronger effects; 10 µM of each drug decreased the beating rate to about 75% of initial values. Disopyramide, mexiletine, pilsicainide, and ranolazine showed weaker effects; 10 µM of each drug decreased the beating rate to about 90% of initial values. The potency of drugs correlated with the reported IC50 values to block the L-type Ca2+ channel current rather than the Na+ and K+ channel currents. The reported IC50 values for the blockade of the hyperpolarization-activated inward current (If) and the Na+-Ca2+ exchanger current were much higher than those for the blockade of the L-type Ca2+ channel current. These results indicate that the negative chronotropic effects of Class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca2+ channel. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent ESC Atrial Fibrillation guidelines introduced some changes in the options for rate control, such as the possibility to combine beta-blockers and non-dihydropyridine calcium channel blockers to address the need for a personalised pharmacologic rate control treatment for AF. However, there are limited data on this topic. This real-world prospective observational study aims to explore the prognostic impact of a patient-specific therapy for rate control in atrial fibrillation, including the use of non-dihydropyridine calcium channel blockers in patients with heart failure or in combination with beta-blockers, compared to standard rate control therapy, as defined by previous ESC guidelines. We performed an analysis of 1112 patients on exclusive rate control treatment referred to our University Hospital. Our results showed no difference in the one-year overall survival in the patient-specific therapy group compared to the standard treatment group. The use of non-dihydropyridine calcium channel blockers for rate control in patients with atrial fibrillation, either alone or in combination with beta-blockers, showed clinical benefit in selected patients, including a group of subjects with heart failure. Future controlled studies are needed to confirm our findings and identify subjects who will obtain greater benefit from such patient-specific rate-control strategies. Atrial fibrillation (AF) is a multifaceted disease requiring personalised treatment. The aim of our study was to explore the prognostic impact of a patient-specific therapy (PT) for rate control, including the use of non-dihydropyridine calcium channel blockers (NDDC) in patients with heart failure (HF) or in combination with beta-blockers (BB), compared to standard rate control therapy (ST), as defined by previous ESC guidelines. This is a single-centre prospective observational registry on AF patients who were followed by our University Hospital. We included 1112 patients on an exclusive rate control treatment. The PT group consisted of 125 (11.2%) patients, 93/125 (74.4%) of whom were prescribed BB + NDCC (±digoxin), while 85/125 (68.0%) were HF patients who were prescribed NDCC, which was diltiazem in all cases. The patients treated with a PT showed no difference in one-year overall survival compared to those with an ST. Notably, the patients with HF in ST had a worse prognosis (p < 0.001). To better define this finding, we performed three sensitivity analyses by matching each patient in the PT subgroups with three subjects from the ST cohort, showing an improved one-year survival of the HF patients treated with PT (p = 0.039). Our results suggest a potential outcome benefit of NDCC for rate control in AF patients, either alone or in combination with BB and in selected patients with HF. [ABSTRACT FROM AUTHOR]

Several studies have suggested the potential role of Magnesium Sulfate (MgSO4) for the treatment of Atrial Fibrillation (AF) but, in clinical practice, the use of magnesium is not standardized although it is largely used for the treatment of supraventricular arrhythmias. Objectives. We evaluated the role of MgSO4 infusion in association with flecainide in cardioversion of patients presenting in ED with symptomatic AF started less than 48 h before. We retrospectively searched for all patients presented in ED from 1 January 2019 to 31 December 2019 requiring pharmacological cardioversion with flecainide 2 mg/kg. Ninety-seven patients met these criteria, 46 received the administration of intravenous MgSO4 2 gr (Group A), and 51 did not (Group B). Among the 97 patients, the overall cardioversion rate was 85.6%, 91.3% in Group A and 80.4% in Group B. In 27 patients out of 97, the Flecainide was not administered because of spontaneous restoration of sinus rhythm of 9 pts (Group B) and 18 pts (Group A). We also found a statistical significance in the HR at the time of cardioversion between Group A (77.8 ± 19.1 bpm) and Group B (87 ± 21.7 bpm). No complications emerged. The association between MgSO4 and Flecainide has not yielded statistically significant results. However, in consideration of its high safety profile, MgSO4 administration may play a role in ED cardioversion of acute onset AF, reducing the need for antiarrhythmic medications and electrical cardioversion procedures, relieving symptoms reducing heart rate, and reducing the length of stay in the ED. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blockade of Nav1.5 (and its current, INa) and Kv1.5 (and its current, IKur) ion channels yield a synergistic anti-arrhythmic effect without alterations in ventricles. We focused on Kv1.5 and Nav1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD) as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We present a computational workflow for a flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of the flecainide-Nav1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the central cavity and consists of a hydrophobic patch and a polar region, involving residues from the S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment. [ABSTRACT FROM AUTHOR]

Introduction: Supraventricular tachycardia (SVT) is one of the arrhythmias that can occur in newborns. Most SVT incidents in the neonatal period are spontaneously resolved around the first year of life, but since tachycardia can frequently occur before complete resolution, appropriate medication use is required. However, no clear guidelines or consensus on the treatment of neonatal SVT have been established yet. Methods: From January 2011 to December 2021, demographic data and antiarrhythmic medications used were retrospectively analyzed for 18 newborns diagnosed with SVT at a single center. Results: A total of four medications (propranolol, amiodarone, flecainide, and atenolol) were used as maintenance therapy to prevent tachycardia recurrence, and propranolol was the most used, followed by amiodarone. Thirty-nine percent of the patients were controlled with monotherapy, but the remainder required two or more medications. The median period from medication initiation after diagnosis to the last tachycardia event was 15.5 days, and the median total duration of medication use was 362 days. None of the patients experienced any side effects of antiarrhythmic medications. The total duration of medication use was statistically significant according to the mechanism of SVT, and the usage time of the increased automaticity group was shorter than that of the re-entry group. Conclusion: Since most neonatal SVT resolves within 1 year, it is significant to provide prophylactic medication to prevent tachycardia recurrence at least until 1 year of age, and depending on the patient, the appropriate combination of medications should be identified. [ABSTRACT FROM AUTHOR]

Cardiac diseases are the leading causes of death, with a growing number of cases worldwide, posing a challenge for both healthcare and research. Therefore, the most relevant aim of cardiac research is to unravel the molecular pathomechanisms and identify new therapeutic targets. Cardiac ryanodine receptor (RyR2), the Ca2+ release channel of the sarcoplasmic reticulum, is believed to be a good therapeutic target in a group of certain heart diseases, collectively called cardiac ryanopathies. Ryanopathies are associated with the impaired function of the RyR, leading to heart diseases such as congestive heart failure (CHF), catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and calcium release deficiency syndrome (CRDS). The aim of the current review is to provide a short insight into the pathological mechanisms of ryanopathies and discuss the pharmacological approaches targeting RyR2. [ABSTRACT FROM AUTHOR]

Supraventricular tachyarrhythmia (SVT) is the most common type of arrhythmia in childhood. Management can be challenging with an associated risk of mortality. A female neonate was diagnosed with episodes of SVT, controlled antenatally with digoxin. Flecainide was commenced prophylactically at birth. Despite treatment, the infant developed a narrow complex tachycardia at 5 days of age. The electrocardiogram features were suggestive of either re-entry tachycardia or of automatic atrial tachycardia (AAT). Following several unsuccessful treatments, a wide complex tachycardia developed. A transesophageal electrophysiological study led to a diagnosis of AAT. Stable sinus rhythm was finally achieved through increasing daily administrations of flecainide up to six times a day, in association with nadolol. The shortening of intervals to this extent has never been reported before and supports the evidence of a personal, age-specific variability in pharmacokinetics of flecainide. Larger studies are needed to better define the appropriate dose and timing of administration. [ABSTRACT FROM AUTHOR]

A diagnosis of Brugada syndrome (BrS) is based on the presence of a type 1 electrocardiogram (ECG) pattern, either spontaneously or after a Sodium Channel Blocker Provocation Test (SCBPT). Several ECG criteria have been evaluated as predictors of a positive SCBPT, such as the β-angle, the α-angle, the duration of the base of the triangle at 5 mm from the r'-wave (DBT- 5 mm), the duration of the base of the triangle at the isoelectric line (DBT- iso), and the triangle base/height ratio. The aim of our study was to test all previously proposed ECG criteria in a large cohort study and to evaluate an r'-wave algorithm for predicting a BrS diagnosis after an SCBPT. We enrolled all patients who consecutively underwent SCBPT using flecainide from January 2010 to December 2015 in the test cohort and from January 2016 to December 2021 in the validation cohort. We included the ECG criteria with the best diagnostic accuracy in relation to the test cohort in the development of the r'-wave algorithm (β-angle, α-angle, DBT- 5 mm, and DBT- iso.) Of the total of 395 patients enrolled, 72.4% were male and the average age was 44.7 ± 13.5 years. Following the SCBPTs, 24.1% of patients (n = 95) were positive and 75.9% (n = 300) were negative. ROC analysis of the validation cohort showed that the AUC of the r'-wave algorithm (AUC: 0.92; CI 0.85-0.99) was significantly better than the AUC of the β-angle (AUC: 0.82; 95% CI 0.71-0.92), the α-angle (AUC: 0.77; 95% CI 0.66-0.90), the DBT- 5 mm (AUC: 0.75; 95% CI 0.64-0.87), the DBT- iso (AUC: 0.79; 95% CI 0.67-0.91), and the triangle base/height (AUC: 0.61; 95% CI 0.48-0.75) ( p < 0.001), making it the best predictor of a BrS diagnosis after an SCBPT. The r'-wave algorithm with a cut-off value of ≥2 showed a sensitivity of 90% and a specificity of 83%. In our study, the r'-wave algorithm was proved to have the best diagnostic accuracy, compared with single electrocardiographic criteria, in predicting the diagnosis of BrS after provocative testing with flecainide.

Background and Objectives: In this study, we attempted to determine the effects of acupuncture on cardiac remodeling and atrial fibrillation (AF) recurrence rates in patients with AF after electrical cardioversion (EC). Materials and Methods: We randomly assigned 44 patients with persistent AF to an acupuncture group or a sham acupuncture group. An electroacupuncture treatment session was administered once weekly for 12 weeks at four acupuncture points (left PC5, PC6, ST36, and ST37). Results: Among the 44 recruited participants, 16 (treatment group) and 15 (control group) completed the trial. The three-month AF recurrence rate (primary outcome) was not significantly different between the two groups. Following the completion of treatment, patients who had been treated with acupuncture had a significant reduction in left atrial volume index (42.2 ± 13.9 to 36.1 ± 9.7 mL/m2; p = 0.028), whereas no change in atrial size was observed in the sham acupuncture group. No serious adverse events were observed. The AF recurrence rate and cardiac function did not differ significantly between the two groups. At three months, the acupuncture treatment group showed more favorable atrial structural remodeling compared to the sham acupuncture group. Conclusion: In future research on acupuncture in AF management, it is recommended that the inclusion criteria be amended to include only symptomatic AF, that an appropriate control group is designed, and that the acupuncture treatment frequency is increased to several times per week. [ABSTRACT FROM AUTHOR]

The availability of liquid oral preparations compounded by pharmacists is essential to meet paediatric needs which remain unanswered by the pharmaceutical industry. Unfortunately, compendial monographs are often not available and, in many cases, pre-formulation studies (e.g., compatibility with other excipients and solubility evaluations) are not performed in-depth, leading, in some rare cases, to the inadvertent administration of a toxic dose. In this study, the preparation of an oral liquid formulation for paediatric use, containing flecainide acetate at different strengths, was considered, taking into account the possible effects of conventionally used excipients. First, the optimal vehicle was selected based on a solubility study, evidencing some unexpected formations of precipitates. As a matter of fact, the buffers commonly used for oral solutions significantly reduced flecainide solubility, and the concomitant presence of citrate buffer and methylparaben even caused the formation of non-resuspendable crystals. Then, chemical, physical, and microbiological stability were assessed. Solutions at strengths of 10 and 20 mg/mL flecainide acetate were stable up to 8 weeks when compounded by using a 40% sucrose solution as a vehicle. Microbiological data showed that the use of methylparaben was not necessary over this time period. [ABSTRACT FROM AUTHOR]

Background and Objectives: In this study, we attempted to determine the effects of acupuncture on cardiac remodeling and atrial fibrillation (AF) recurrence rates in patients with AF after electrical cardioversion (EC). Materials and Methods: We randomly assigned 44 patients with persistent AF to an acupuncture group or a sham acupuncture group. An electroacupuncture treatment session was administered once weekly for 12 weeks at four acupuncture points (left PC5, PC6, ST36, and ST37). Results: Among the 44 recruited participants, 16 (treatment group) and 15 (control group) completed the trial. The three-month AF recurrence rate (primary outcome) was not significantly different between the two groups. Following the completion of treatment, patients who had been treated with acupuncture had a significant reduction in left atrial volume index (42.2 ± 13.9 to 36.1 ± 9.7 mL/m 2 ; p = 0.028), whereas no change in atrial size was observed in the sham acupuncture group. No serious adverse events were observed. The AF recurrence rate and cardiac function did not differ significantly between the two groups. At three months, the acupuncture treatment group showed more favorable atrial structural remodeling compared to the sham acupuncture group. Conclusion: In future research on acupuncture in AF management, it is recommended that the inclusion criteria be amended to include only symptomatic AF, that an appropriate control group is designed, and that the acupuncture treatment frequency is increased to several times per week.

Flecainide is an IC antiarrhythmic drug (AAD) that received in 1984 Food and Drug Administration approval for the treatment of sustained ventricular tachycardia (VT) and subsequently for rhythm control of atrial fibrillation (AF). Currently, flecainide is mainly employed for sinus rhythm maintenance in AF and the treatment of idiopathic ventricular arrhythmias (IVA) in absence of ischaemic and structural heart disease on the basis of CAST data. Recent studies enrolling patients with different structural heart diseases demonstrated good effectiveness and safety profile of flecainide. The purpose of this review is to assess current evidence for appropriate and safe use of flecainide, 30 years after CAST data, in the light of new diagnostic and therapeutic tools in the field of ischaemic and non-ischaemic heart disease. [ABSTRACT FROM AUTHOR]

Cardiac ryanodine receptor (RyR2) mutations are implicated in the potentially fatal catecholaminergic polymorphic ventricular tachycardia (CPVT) and in atrial fibrillation. CPVT has been successfully treated with flecainide monotherapy, with occasional notable exceptions. Reported actions of flecainide on cardiac sodium currents from mice carrying the pro-arrhythmic homozygotic RyR2-P2328S mutation prompted our explorations of the effects of flecainide on their RyR2 channels. Lipid bilayer electrophysiology techniques demonstrated a novel, paradoxical increase in RyR2 activity. Preceding flecainide exposure, channels were mildly activated by 1 mM luminal Ca2+ and 1 µM cytoplasmic Ca2+, with open probabilities (Po) of 0.03 ± 0.01 (wild type, WT) or 0.096 ± 0.024 (P2328S). Open probability (Po) increased within 0.5 to 3 min of exposure to 0.5 to 5.0 µM cytoplasmic flecainide, then declined with higher concentrations of flecainide. There were no such increases in a subset of high Po channels with Po ≥ 0.08, although Po then declined with ≥5 µM (WT) or ≥50 µM flecainide (P2328S). On average, channels with Po < 0.08 were significantly activated by 0.5 to 10 µM of flecainide (WT) or 0.5 to 50 µM of flecainide (P2328S). These results suggest that flecainide can bind to separate activation and inhibition sites on RyR2, with activation dominating in lower activity channels and inhibition dominating in more active channels. [ABSTRACT FROM AUTHOR]

Acute antiarrhythmics poisoning represents a challenge in the Emergency Department (ED). These patients often develop malignant arrhythmias in need of exceptional therapeutic measures in the ICU. We report a 47-year-old patient admitted to the ED 5 h after the ingestion of a large dose of amiodarone and flecainide in a suicide attempt. During their ED stay, the patient developed signs of cardiotoxicity evidenced by electrocardiogram and ventricular arrhythmias. The toxicological results showed a level of 4.8 mg/L amiodarone and 2.98 mg/L flecainide. He was successfully treated in the ED using a large dose of sodium bicarbonate and lipid emulsion therapy. After hospital admission, he remained stable, with no need for exceptional therapeutic measures such as mechanical circulatory support, cardiac pacing or ECMO. We emphasize the importance of an early start of pharmacological therapies in the ED, which might improve the outcome in antiarrhythmic acute poisoning. [ABSTRACT FROM AUTHOR]

Transcatheter ablation was increasingly and successfully used to treat symptomatic drug refractory patients affected by supraventricular arrhythmias. Antiarrhythmic drug treatment still plays a major role in patient management, alone or combined with non-pharmacological therapies. Flecainide is an IC antiarrhythmic drug approved in 1984 from the Food and Drug Administration for the suppression of sustained ventricular tachycardia and later for acute cardioversion of atrial fibrillation and for sinus rhythm maintenance. Currently, flecainide is mostly used for sinus rhythm maintenance in atrial fibrillation (AF) patients without structural cardiomyopathy although recent studies enrolling different patient populations have demonstrated a good effectiveness and safety profile. How should we interpret the results of the CAST after the latest evidence? Is it possible to expand the indications of flecainide, and therefore, its use? This review aims to highlight the main characteristics of flecainide, as well as its optimal clinical use, delineating drug indications and contraindications and appropriate monitoring, based on the most recent evidence. [ABSTRACT FROM AUTHOR]

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL. [ABSTRACT FROM AUTHOR]

Evidence on cellular/molecular mechanisms leading to atrial fibrillation (AF) are scanty. Increased expression of Rho kinase (ROCK) and myosin-phosphatase-target subunit-1 (MYPT-1), ROCK activity's marker, were shown in AF patients, which correlated with connexin 40 (Cx40) expression, membrane protein of heart gap junctions, key for rapid action potential's cell–cell transfer. AF is the most frequent arrhythmia in dialysis patients who present increased MYPT-1 phosphorylation, which correlates with left ventricular (LV) mass. Given ROCK's established role in cardiovascular–renal remodeling, induction of impaired cell-to-cell coupling/potential conduction promoting AF initiation/perpetuation, we evaluated in dialysis patients with AF, MYPT-1 phosphorylation, Cx40 expression, and their relationships to support their involvement in AF. Mononuclear cells' MYPT-1 phosphorylation, Cx40 expression, and the ROCK inhibitor fasudil's effect were assessed in dialysis patients with AF (DPAFs), dialysis patients with sinus rhythm (DPs), and healthy subjects (C) (western blot). M-mode echocardiography assessed LV mass and left atrial systolic volume. DPAF's phospho-MYPT-1 was increased vs. that of DPs and C (1.57 ± 0.17 d.u. vs. 0.69 ± 0.04 vs. 0.51 ± 0.05 respectively, p < 0.0001). DP's phospho-MYPT-1 was higher vs. that of C, p = 0.009. DPAF's Cx40 was higher vs. that of DPs and C (1.23 ± 0.12 vs. 0.74 ± 0.03 vs. 0.69 ± 0.03, p < 0.0001). DPAF's phospho-MYPT-1 correlated with Cx40 (p < 0.001), left atrial systolic volume (p = 0.013), and LV mass (p = 0.014). In DPAFs, fasudil reduced MYPT-1 phosphorylation (p < 0.01) and Cx40 expression (p = 0.03). These data point toward ROCK and Cx40's role in the mechanism(s) leading to AF in dialysis patients. Exploration of the ROCK pathway in AF could contribute to AF generation's mechanistic explanations and likely identify potential pharmacologic targets for translation into treatment. [ABSTRACT FROM AUTHOR]

Background: Sarcoplasmic reticulum Ca2+ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. Objective: The aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome. Methods: Patient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca2+ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied. Results: Exercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca2+ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2. Conclusion: We identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband's resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]