Rafik Tadros

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: Early repolarization syndrome (ERS) is diagnosed in survivors of unexplained cardiac arrest (UCA) who exhibit a distinct ECG pattern of early repolarization (ER), defined as J-point elevation ≥0.1 mV in ≥2 contiguous inferolateral leads. UCA survivors without ER or another identifiable cause are classified as idiopathic ventricular fibrillation (IVF). This study evaluated long-term outcomes in ERS compared with IVF. METHODS: This retrospective cohort study analyzed patients from the CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) who survived UCA and had structurally normal hearts with an Implantable Cardioverter Defibrillator. Of 709 patients, 186 with explanatory diagnoses and no ER pattern were excluded. The remaining 523 were categorized as ERS (n=48), IVF (n=463), or UCA with ER plus an additional diagnosis (Dx+ER, n=12). Patients were followed for the primary outcome of appropriate Implantable Cardioverter Defibrillator therapy, and logistic regression identified predictors of arrhythmia recurrence. RESULTS: Corrected QT interval intervals were significantly shorter in ERS than in IVF (412±25 ms versus 431±41 ms; P P =0.09), with incidence rates of 3.0 and 1.5 per 100 person-years, respectively. Four deaths occurred (0.8%), with no significant difference between groups ( P =0.39). In Dx+ER, appropriate Implantable Cardioverter Defibrillator therapies occurred in 42% of patients (incidence rate, 4.5 per 100 person-years). Arrhythmia-free survival was lower in ERS than in IVF ( P =0.03). After adjusting for age, sex, and ethnicity, ER was an independent predictor of arrhythmia recurrence (odds ratio, 2.59 [95% CI, 1.33–4.85]; P =0.004). CONCLUSIONS: ERS is associated with shorter corrected QT interval intervals and reduced arrhythmia-free survival compared with IVF, with an incidence rate of 3.0 per 100 person-years. These findings underscore the importance of careful ECG review in patients with apparent UCA, to detect ER and undertake individualized risk assessment in affected individuals.

Diastolic heart failure (HF) in primary cardiomyopathy is under-recognized and often diagnosed late, particularly in children. While recent studies have advanced understanding of HF with preserved ejection fraction in older adults, the prevalence, outcomes and molecular drivers of diastolic HF in pediatric and young adult cardiomyopathy remain poorly defined, where disease is typically driven by primary myocardial disease rather than acquired co-morbidities. The Canadian Cardiomyopathy Collaborative (C3) was assembled to leverage three of Canada’s leading pediatric and adult cardiomyopathy biobank registries. Its flagship initiative, Artificial Intelligence to Model Diastolic Heart Failure (AID-HF), aims to integrate deep phenotyping - including comprehensive diastolic function assessment - with genomics, lipidomics and proteomics and apply machine learning to identify biological and clinical signatures that drive cardiac function and outcomes in cardiomyopathy. Harmonized phenotyping and multiomics protocols across registries will create a uniquely integrated national data resource and enable the goals of AID-HF i.e., earlier diagnosis and new therapeutic targets for diastolic HF in cardiomyopathy.

Background and Aims: Adults with repaired tetralogy of Fallot (TOF) face long-term risks of ventricular tachycardia (VT) and sudden cardiac death (SCD). There is no consensus on arrhythmia management during surgical pulmonary valve replacement (PVR). This study assessed whether pre-operative electrophysiological (EP) testing with targeted intraoperative cryoablation of identified anatomical isthmuses during PVR is associated with a reduction in post-operative VT inducibility and long-term risk of clinical VT/SCD. Methods: In this prospective multicentre cohort study, consecutive adults with TOF undergoing surgical PVR (2005–22) underwent standardized pre-operative EP studies. Surgical ablation strategy (EP-guided vs empiric) was at the discretion of the treating team. Post-operative EP studies assessed residual inducibility; clinical VT/SCD were evaluated during follow-up. Results: Among 204 patients (age 35.5 ± 13.1 years, 43.1% female), 91 (45.1%) had inducible VT. Among those undergoing surgical ablation, post-operative VT was non-inducible in 74.1% with EP-guided vs 15.0% with empiric ablation [adjusted odds ratio 20.4, 95% confidence interval (CI) 4.5–91.8, P < .0001]. Persistent post-operative inducibility was associated with increased hazard of VT/SCD compared to patients without inducible VT pre-operatively [adjusted hazard ratio (HR) 5.3, 95% CI 1.8–16.0, P = .003], over a median 10.2-year follow-up. Compared to patients without inducible VT pre-operatively, empiric ablation was associated with a significantly higher hazard of VT/SCD (HR 5.2, 95% CI 1.6–16.5, P = .005), whereas EP-guided ablation was not (HR 2.8, 95% CI 0.8–10.3, P = .228). Conclusions: In adults with repaired TOF undergoing PVR, inducible VT is common. An EP-guided surgical strategy is associated with greater post-operative non-inducibility and improved long-term arrhythmic outcomes compared with empiric ablation.

Background: Hypertrophic cardiomyopathy (HCM) is a common inherited disease and a leading known cause of sudden cardiac arrest in young adults and athletes. While genetic testing has advanced rapidly in the past decade, the yield of genetic testing remains low. The Clinical Genome Resource (ClinGen) initiative has become a leading resource for defining the clinical relevance of genetic variants with expert groups focusing on evaluating the strength of evidence for each HCM implicated gene. With the rise of large biobanks and population databases, genetic discovery has been significantly advanced. However, whether these databases can be used to validate gene–disease associations curated by ClinGen and provide evidence for novel gene–disease associations remains unclear. Objectives: Here, we utilized a publicly available database containing 748,879 individuals across three large biobanks (All of Us, UK biobank, Mass General Brigham biobank). Methods: We tested the association of rare coding variants in each gene in the HCM ClinGen panel with HCM. In total, 38 genes were tested, and Bonferroni correction was applied accordingly. Results: Of the 12 genes with definitive evidence for HCM (e.g., MYBPC3, MYH7, TNNT2, ALPK3), 8 (67%) demonstrated nominally significant association with HCM on a population level, and 5 (42%) remained significant after Bonferroni correction, further supporting the validity of these genes in HCM panels. Several definitive genes which are much less commonly affected in HCM (CSRP3, MYL3, ACTC1, TPM1, FHOD3, MYL2, and TNNC1) did not pass our Bonferroni corrected-significance threshold, but all had positively associated effect sizes with HCM. No genes deemed to have moderate or limited evidence had any significant associations with HCM even before Bonferroni correction. Conclusions: Altogether, we show that large biobanks and population databases generally recapitulate established gene–disease associations for HCM and support the ClinGen group’s gene curations. The utilization of such publicly accessible databases represents an additional tool for assessing gene validity in monogenic cardiac disorders with an established phenotype, although it may have limited sensitivity and should not be solely relied on.