A randomized controlled trial of eplerenone in asymptomatic phospholamban p.Arg14del carriers

Phospholamban (PLN; p.Arg14del) cardiomyopathy is an inherited disease caused by the pathogenic p.Arg14del variant in the PLN gene. Clinically, it is characterized by malignant ventricular arrhythmias and progressive heart failure.1,2 Cardiac fibrotic tissue remodelling occurs early on in PLN p.Arg14del carriers.3,4 Eplerenone was deemed a treatment candidate because of its beneficial effects on ventricular remodelling and antifibrotic properties.5,6 We conducted the multicentre randomized trial ‘intervention in PHOspholamban RElated CArdiomyopathy STudy’ (i-PHORECAST) to assess whether treatment with eplerenone of asymptomatic PLN p.Arg14del carriers attenuates disease onset and progression

Low-Dose Amiodarone for Maintenance of Sinus Rhythm After Cardioversion of Atrial Fibrillation or Flutter

Objective.-To study efficacy and safety of low-dose amiodarone for maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation or flutter. Design.-Nonrandomized trial; mean duration of follow-up, 20.7 months. Setting.-Referral center; institutional practice; both hospitalized and ambulatory care. Patients.-Eighty-nine consecutive patients having chronic atrial fibrillation or flutter and eligible for cardioversion. Patients had failed previous treatment aimed at maintaining sinus rhythm. During follow-up one patient was withdrawn because of side effects; all patients were available for follow-up. Intervention.-Before cardioversion, patients received 600 mg of amiodarone daily during a 4-week loading period. After conversion, the daily maintenance dose was 204+/-66 mg (mean+/-SD). Main Outcome Measures.-Arrhythmia recurrence and adverse effects causing drug discontinuation. Results.-During loading, 15 patients (16%) converted, and after electrical cardioconversion, 90% of all patients had sinus rhythm. Actuarially, 53% of these patients were still in sinus rhythm after 3 years. In patients with compromised left ventricular function, 93% maintained sinus rhythm after 6 months. One patient died due to congestive heart failure. Intolerable side effects occurred in one patient. No proarrhythmia was observed. Logistic regression analysis revealed that amiodarone was ineffective in patients with mitral stenosis or chronic arrhythmia. Conclusions.-Low-dose amiodarone is effective for maintaining sinus rhythm in patients with difficult to treat chronic atrial fibrillation or flutter and is associated with a low incidence of serious side effects

Initial experience with pulsed field ablation for atrial fibrillation

Introduction: Pulsed field ablation (PFA) was recently introduced for the treatment of symptomatic atrial fibrillation (AF) with the claim of selectively ablating the myocardium while sparing surrounding tissues. We present our initial experience with a PFA catheter for pulmonary vein isolation (PVI) and describe procedural findings and peri-procedural safety of the first 100 patients. Materials and methods: We investigated 100 patients treated for symptomatic AF using the FARAWAVE PFA catheter (Farapulse, Menlo Park, CA, USA) between July 2021 and March 2022. Procedure workflow and electrophysiological findings at the time of ablation, peri-procedural complications, and operator learning curves are described. Results: The mean age of patients was 62.9 ± 9.4 years, 62% were male subjects and 80% had paroxysmal AF. The median CHA2DS2-VASc score was 1.5 (IQR: 1.0–2.0) and the mean left atrial volume index was 35.7 ± 9.6 ml/m2. In 88 (88%) patients, PVI alone was performed and in 12 (12%) patients additional ablation of the posterior wall was performed. 3D-electroanatomic mapping was performed in 18 (18%) patients. Procedures without mapping lasted for 52.3 ± 16.6 min. The mean number of applications per pulmonary vein (PV) was 8.1 ± 0.6. In all patients (100%), all PVs were confirmed to be isolated. The learning curves of the two operators who performed > 20 procedures showed a negligible variation of performance over time and practice did not significantly predict procedure time [Operator 1 (senior): R2 = 0.034, p = 0.35; Operator 2 (junior): R2 = 0.004, p = 0.73]. There was no difference between the procedure times between senior and junior operators (Operator 1: 46.9 ± 9.7 min vs. Operator 2: 45.9 ± 9.9 min; p = 0.73). The only complications observed were two cases of bleeding at the site of percutaneous access. Conclusion: Our initial experience shows that use of the PFA catheter for pulmonary vein isolation (PVI) is safe, fast, and easy to learn

Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans

Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel α subunit NaV1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel β1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, β1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when NaV1.5 was coexpressed with mutant β1 or β1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility

Genotype-phenotype analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy:Follow-up of a large series of dutch index-patients and family members

Background: In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) causative mutations in genes encoding 5 desmosomal proteins or TMEM43 are found in the majority of patients. One of the primary clinical challenges in ARVD/C is timely diagnosis of those still asymptomatic. However, previous studies mainly involved overt ARVD/C index-patients. Follow-up data on relatives are scarce. Therefore, we sequenced all 6 genes in a large cohort of ARVD/C families and correlated results with clinical follow-up. Methods: 149 ARVD/C index-patients (111 men, age 49±13 years) according to 2010 Task Force Criteria (TFC) and 302 family members from 93 different families (282 asymptomatic, 135 men, age 44±13 years) were clinically and genetically analyzed. DNA analysis comprised sequencing of PKP2, DSC2, DSG2, DSP, JUP and TMEM43 and multiple ligation-dependent probe amplification (MLPA) to identify large PKP2 deletions. Results: Pathogenic mutations were found in 87 of 149 index-patients (58%): 90% PKP2 and multiple mutations in 4 cases. MLPA revealed 3 large PKP2 deletions (2%). Mutation carriers presented at younger age than non-carriers (35±12 vs 40±14 years; p=0.042). Familial cases were identified in 42 of 93 (45%) of index-patients with relatives screened: 90% with mutations. In total, 57 of 282 asymptomatic relatives (20%) showed signs of ARVD/C (age 47±18 years, 48 with mutations). See table 2. Terminal activation duration (TAD) 7ge;55ms occurred more than negative T waves in V1-3 (12 vs 7%), especially in those age

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

International audienceBACKGROUND:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain.OBJECTIVE:The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients.METHODS:We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders.RESULTS:Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy.CONCLUSION:Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias