Elijah Raphael Behr

BACKGROUND: PPA2 encodes for inorganic pyrophosphatase 2, a mitochondrial enzyme that hydrolyzes inorganic pyrophosphates into orthophosphate. Biallelic loss-of-function variants cause PPA2 deficiency, an emerging recessive cardiac condition that causes heart failure and sudden cardiac death in infants and young people. METHODS: Using published case reports and large-scale genomics resources, we defined the clinical and molecular spectrum of this disease, classified variants using a customized American College of Medical Genetics and Genomics pipeline, assessed genotype-phenotype correlations, calculated predicted prevalence using the gnomAD GenIE tool, and investigated monoallelic associations in the UK Biobank. RESULTS: A total of 63 cases from 37 families were identified from 12 publications. The natural history of this disease is characterized by clinical heterogeneity and high mortality (79% by 20 years of age), typically presenting as a highly arrhythmogenic cardiomyopathy with 2 distinct risk periods: in infancy, where viral infections can lead to heart failure, and in adolescence, where minimal alcohol exposure can trigger sudden cardiac death. The disease is genetically heterogeneous, with 29 distinct variants described (18 of which were classified as [likely] pathogenic), usually in compound heterozygosity. As complete gene knockout appears to be incompatible with life, PPA2 deficiency is caused by biallelic variants within a particular loss-of-function window, with deficiency mitigated by hypomorphic effects, variants in nonconstitutive exons, and particular compound heterozygous combinations. The spectrum of phenotypic effect extends to monoallelic carriers of pathogenic variants, which demonstrate an apparent mitohormesis-like compensatory protection from heart failure. The disease has an estimated prevalence of at least 1/135 000 in European ancestry populations. CONCLUSIONS: PPA2 deficiency is a genetically complex and clinically severe disease. Given the potential for effective life-saving interventions, PPA2 may warrant inclusion in emerging newborn genomic screening programs.

Background: Dysfunction of the KCND3 -encoded K _v 4.3 channel, which carries the transient outward potassium current ( I _to ), has long been suspected to contribute to the pathophysiology of Brugada Syndrome (BrS). Although recent genome-wide association studies (GWAS) have implicated KCND3 , the role of rare variation in this gene remains uncertain and clinically unactionable. Methods: Genome sequencing was performed in 983 BrS probands from Europe and Thailand. Putative gain-of-function (GoF) rare variants in KCND3 identified in patients were functionally characterized by patch-clamp analysis of K _v 4.3 current properties using a HEK293 cell heterozygous model. Biobank datasets were utilized to evaluate rare-common variant interaction at the KCND3 locus. Results: Eight BrS cases carried six different rare KCND3 variants which clustered at the K _v 4.3 C-terminus, with terminal exon rare variants significantly enriched in cases versus study (p=0.004) and population (p=2.0e ⁻⁶ ) controls. Four of the five KCND3 case variants studied demonstrated significant GoF effects versus wild-type and putative benign variants, including increased I _to amplitude (p.Leu586Val, p.Ala634Thr) and slower inactivation (p.Gly600Arg, p.Ala654Thr, p.Ala634Thr). Analysis of p.Gly600Arg carriers in the UK Biobank and All of Us revealed a significant enrichment of the protective KCND3 expression-reducing allele of the GWAS lead single-nucleotide polymorphism rs12090194, suggesting a possible epistatic common-rare variant interaction modifies penetrance in carriers. Conclusions: GoF rare variants at the C-terminus of KCND3 are associated with BrS in a small proportion of cases. Determination of the rare and common variant status in BrS patients and their relatives may provide information about disease risk.

Background Exercise has the potential to unmask ventricular arrhythmias in arrhythmogenic cardiomyopathy (ACM). The aim of the study was to assess the prevalence and prognostic significance of exercise-induced ventricular arrhythmias (EIVAs) during exercise tests. Methods Clinical data of patients with a definitive diagnosis of ACM as well as individuals harbouring a pathogenic or likely pathogenic (P/LP) gene variant associated with ACM who exhibited a negative or borderline phenotype were retrospectively analysed. Patients were stratified into ‘lower’ and ‘higher’ exercise groups based on exercise intensity performed after the diagnosis. EIVAs were adjudicated on revision of the exercise test (exercise tolerance test (ETT) or cardiopulmonary exercise test (CPET)). Peak VO₂ was obtained via CPET or estimated from metabolic equivalents. The primary endpoint was a composite of sustained ventricular tachycardia/fibrillation, appropriate implantable cardioverter-defibrillator therapy, sudden cardiac arrest and sudden death. Results Of 202 patients followed at our centre, 157 (mean age 48±16 years, 57% men) underwent ETT or CPET at baseline; 80 (51%) patients harboured a P/LP variant, most commonly in plakophilin-2 (n=43), desmoplakin (n=18) and filamin C (n=11) genes. Mean peak VO₂ was 41.4±10.6 mL/kg/min. EIVAs were observed in 61 (39%) cases. Patients demonstrating EIVA exhibited lower peak VO₂ (38.2 ± 10.2 vs 43.0 ± 10.4 mL/kg/min, p=0.019) and a numerically higher prevalence of myocardial fibrosis (MF) on cardiac magnetic resonance (52% vs 37%, p=0.071) with respect to counterparts. Among 65 patients with a baseline normal ECG, 9 (14%) exhibited EIVA; among 29 genotype-positive individuals with a negative or borderline phenotype, 6 (20%) showed EIVA. The prevalence of EIVA was comparable between the lower-exercise and higher-exercise groups (31% vs 30%, respectively). MF (HR 6.05, 95% CI 1.70 to 21.54; p=0.005) and EIVA (HR 2.8, 95% CI 1.1 to 7.3; p=0.03) were independently associated with the primary arrhythmic endpoint at multivariable analysis, with similar direction of effect after accounting for beta-blocker therapy in sensitivity analyses. The combination of the two risk factors—EIVA and MF (score 2) significantly stratified prognosis in comparison to none or one risk factor (score 0–1), pConclusions EIVAs occurred in nearly 40% of patients with ACM and were associated with adverse arrhythmic outcomes, alongside MF. These findings support the integration of exercise testing into routine risk stratification.

Very rare and ultra-rare primary inherited arrhythmia syndromes (IAS) represent a heterogeneous group of disorders associated with a significant risk of sudden cardiac death, often manifesting from foetal life to early adulthood. Current guidelines primarily address more common IAS and provide limited, non-specific recommendations for these rare entities, particularly in paediatric populations. This European Heart Rhythm Association Clinical Consensus Statement, developed in collaboration with the Association of Cardiovascular Nursing and Allied Professions and endorsed by the Association for European Paediatric and Congenital Cardiology, integrates available evidence with expert opinion. Recommendations were formulated through structured discussion and voting, following ESC consensus methodology, with a focus on clinically actionable gene-disease associations. The document provides a comprehensive framework for the diagnosis and management of very rare IAS, including calmodulinopathies, Andersen–Tawil syndrome, Timothy syndrome, TRDN-related disease, calcium release deficiency syndrome, and other atypical channelopathies. It highlights age-specific clinical presentations, the importance of genetic testing, and tailored therapeutic strategies, including pharmacological treatments, left cardiac sympathetic denervation, and selective use of implantable cardioverter-defibrillators. Special attention is given to paediatric considerations, foetal diagnosis, and the role of multidisciplinary care. The document also addresses arrhythmic risk in metabolic and cardiomyopathic conditions, as well as the importance of molecular autopsy and family screening in sudden unexplained death. This consensus document fills a critical gap by providing expert-driven, pragmatic guidance for the management of very rare IAS across the lifespan. It underscores the need for specialized care, international collaboration, and prospective registries to improve evidence generation, risk stratification, and patient outcomes in this vulnerable population.

Background: The coexistence of persistent atrial fibrillation (AF) and heart failure with reduced left ventricular ejection fraction is associated with greater morbidity and death than either condition alone. Catheter ablation improves outcomes in selected patients, yet results in persistent AF remain unsatisfactory. Convergent hybrid ablation may offer more durable rhythm control by integrating epicardial and endocardial techniques to achieve homogeneous, transmural pulmonary vein and posterior wall isolation. However, randomized data comparing ablation strategies in patients with reduced left ventricular ejection fraction are lacking, leaving a critical evidence gap. Methods: HALT AF (Hybrid Ablation for Atrial Fibrillation With Heart Failure) is an investigator‐initiated, multicenter, prospective, open‐label, randomized controlled trial with blinded outcome assessment. A total of 120 patients with nonparoxysmal AF, left ventricular ejection fraction 30 seconds at 12 months and off class I/III antiarrhythmic drugs, excluding a 3‐month blanking period. The primary safety end point is major adverse cardiovascular events within 30 days. Secondary end points assess cardiac remodeling, biomarkers, symptoms, and quality of life. Conclusions: HALT AF will be the first randomized trial to compare convergent hybrid ablation and catheter ablation in patients with persistent AF and reduced left ventricular function. By enrolling only patients with reduced left ventricular ejection fraction and dilated atria and by equating lesion sets, HALT AF is designed to provide critical evidence to inform rhythm‐control strategies and guideline recommendations in this high‐risk, underrepresented population. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05411614.

SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalisation of management and has the potential to guide preventative therapies.

J‐wave syndromes (JWS)—comprising Brugada syndrome (BrS) and early repolarization syndrome (ERS)—are important causes of malignant ventricular arrhythmias and sudden cardiac death in patients whose hearts appear structurally normal. Since the 2016 consensus, advances in genetics, pathophysiology, and therapy have redefined both understanding and management. BrS, once viewed as a purely electrical disorder, is now recognized along a microstructural–electrical continuum, with sodium‐channel dysfunction and subtle epicardial fibrosis of the right ventricular outflow tract as key contributors. Likewise, ERS—historically considered benign—carries significant risk when inferolateral J‐waves coexist with arrhythmic events. Genetically, SCN5A remains the sole gene with definitive disease association, while polygenic susceptibility materially modulates risk, underscoring complex inheritance. Risk stratification remains challenging: patients with prior cardiac arrest or arrhythmic syncope are highest risk, whereas asymptomatic individuals warrant multiparametric assessment integrating clinical features, ECG markers, electrophysiologic studies, and genetics. For decades, treatment centered on implantable cardioverter‐defibrillators and quinidine, both limited by availability, tolerance, and device complications. More recently, epicardial substrate ablation has emerged as a transformative therapy, with large registries and randomized trials demonstrating durable suppression of ventricular fibrillation and acceptable safety. This APHRS‐organized international consensus updates and extends the 2016 Expert Consensus and the 2022 ESC Guidelines, providing contemporary diagnostic frameworks, pragmatic risk‐stratification tools, and treatment algorithms for BrS and ERS. It emphasizes JWS as a microstructural–electrical disease spectrum and elevates substrate ablation as a major therapeutic advance, while outlining priorities for genetics, risk‐stratification and treatment algorithms.

Background: Dilated cardiomyopathy has a diverse aetiology. Around 20% of cases have an underlying genetic cause. A subset of patients with dilated cardiomyopathy is prone to arrhythmia (‘arrhythmogenic’ cardiomyopathy). (Likely) Pathogenic variants of SCN5A, the gene coding for the alpha subunit of the main cardiac sodium voltage-gated channel, are a known cause of this subset. Case summary: A 17-year-old male presents with new-onset severe left ventricular systolic dysfunction with atrial flutter and significant ventricular ectopy. Despite medical therapy, his management was challenging. A LifeVest was fitted to allow outpatient optimization of his medications whilst bridging to a decision about implantable cardioverter defibrillator implantation. Specialist genetic testing revealed a pathogenic variant in SCN5A (p.R814W) leading to gain of function. This prompted the use of a sodium channel blocker, hydroquinidine. Hydroquinidine resulted in complete resolution of arrhythmia and improvement of ventricular size and function. Its effect was confirmed on accidental withdrawal of hydroquinidine due to supply issues, resulting in recurrence of atrial arrhythmia. Discussion: This atypical presentation of a cardiomyopathy was driven, at least in part, by the patient’s extensive arrhythmia. Previous research has shown variable, short-term effects of sodium channel antagonists in familial p.R814W variants. Contrastingly, in our patient, sustained and long-term improvement was observed with the use of hydroquinidine. Close multidisciplinary team working and early genetic testing facilitated personalized care in our patient’s case, resulting in a favourable outcome.