Probst, Vincent

Abstract Aims In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT. Methods and results An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22–50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3–12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6–31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1–1.3, P < 0.001) were independently associated with non-adherence. Conclusion The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education.

Abstract In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1–3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype–phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.

Abstract Aims Calmodulinopathy due to mutations in any of the three CALM genes (CALM1–3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. Methods and results The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5–19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Conclusion Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter–defibrillator.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. Methods: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2 -positive probands, and clinical evaluation was performed. Results: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2 -positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). Conclusions: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2 -ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

AbstractBackgroundInfection is a well‐recognized complication of cardiovascular implantable electronic device (CIED) implantation, including the more recently available subcutaneous implantable cardioverter‐defibrillator (S‐ICD). Although the AHA/ACC/HRS guidelines include recommendations for S‐ICD use, currently there are no clinical trial data that address the diagnosis and management of S‐ICD infections. Therefore, an expert panel was convened to develop consensus on these topics.MethodsA process mapping methodology was used to achieve a primary goal – the development of consensus on the diagnosis and management of S‐ICD infections. Two face‐to‐face meetings of panel experts were conducted to recommend useful information to clinicians in individual patient management of S‐ICD infections.ResultsPanel consensus of a stepwise approach in the diagnosis and management was developed to provide guidance in individual patient management.ConclusionAchieving expert panel consensus by process mapping methodology in S‐ICD infection diagnosis and management was attainable, and the results should be helpful in individual patient management.