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01 februari 2023, Item does not contain fulltext, BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

BACKGROUND: Administrative coding of out-of-hospital cardiac arrest (OHCA) is heterogeneous, with the prevalence of noninformative diagnoses uncertain. AIM: To characterize the prevalence and type of non-informative diagnoses in a young cardiac arrest population. METHODS: Hospital discharge diagnoses provided to a statewide OHCA registry were characterised as either 'informative' or 'noninformative.' Informative diagnoses stated an OHCA had occurred or defined OHCA as occurring due to coronary artery disease, cardiomyopathy, channelopathy, definite noncardiac cause, or no known cause. Noninformative diagnoses were blank, stated presenting cardiac rhythm only, provided irrelevant information or presented a complication of the OHCA as the main diagnosis. Characteristics of patients receiving informative versus noninformative diagnoses were compared. RESULTS: Of 1479 patients with OHCA aged 1 to 50 years, 290 patients were admitted to 15 hospitals. Ninety diagnoses (31.0%) were noninformative (arrest rhythm = 50, blank = 21, complication = 10 and irrelevant = 9). Two hundred diagnoses (69.0%) were informative (cardiac arrest = 84, coronary artery disease = 54, noncardiac diagnosis = 48, cardiomyopathy = 8, arrhythmia disorder = 4 and unascertained = 2). Only 10 diagnoses (3.5%) included both OHCA and an underlying cause. Patients receiving a noninformative diagnosis were more likely to have survived OHCA or been referred for forensic assessment (P = 0.011) and had longer median length of stay (9 vs 5 days, P = 0.0019). CONCLUSION: Almost one third of diagnoses for young patients discharged after an OHCA included neither OHCA nor any underlying cause. Underestimating the burden of OHCA impacts ongoing patient and at-risk family care, data sampling strategies, international statistics and research funding.

To develop a suite of quality indicators (QIs) for the management of patients with ventricular arrhythmias (VA) and the prevention of sudden cardiac death (SCD). The Working Group comprised experts in heart rhythm management including Task Force members of the 2022 European Society of Cardiology (ESC) Clinical Practice Guidelines for the management of patients with VA and the prevention of SCD, members of the European Heart Rhythm Association, international experts, and a patient representative. We followed the ESC methodology for QI development, which involves (i) the identification of the key domains of care for the management of patients with VA and the prevention of SCD by constructing a conceptual framework of care, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified-Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. We identified eight domains of care for the management of patients with VA and the prevention of SCD: (i) structural framework, (ii) screening and diagnosis, (iii) risk stratification, (iv) patient education and lifestyle modification, (v) pharmacological treatment, (vi) device therapy, (vii) catheter ablation, and (viii) outcomes, which included 17 main and 4 secondary QIs across these domains. Following a standardized methodology, we developed 21 QIs for the management of patients with VA and the prevention of SCD. The implementation of these QIs will improve the care and outcomes of patients with VA and contribute to the prevention of SCD.

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.

BACKGROUND: While athletes are generally very fit, intense exercise can increase the risk of atrial fibrillation. Moreover, other arrhythmias such as atrial flutter or supraventricular tachycardia can cause distressing, exercise-related symptoms. Given symptoms are infrequent and may occur during intense exertion, traditional monitoring devices are often impractical to use during exercise. Smartphone electrocardiograms (ECGs) such as the Alivecor Kardia device may be the portable and reliable tool required to help identify arrhythmias in this challenging population. This case series highlights the use of such devices in aiding the diagnosis of arrhythmias in the setting of exercise-related symptoms in athletes. CASE SUMMARY: The six cases in this series included one elite non-endurance athlete, two elite cricketers, one amateur middle-distance runner, and two semi-elite ultra-endurance runners, with an age range of 16-48 years. An accurate diagnosis of an arrhythmia was obtained in five cases (atrial fibrillation/flutter and supraventricular tachycardias) using the smartphone ECG, which helped guide definitive treatment. No arrhythmia was identified in the final case despite using the device during multiple symptomatic events. DISCUSSION: The smartphone ECG was able to accurately detect arrhythmias and provide a diagnosis in cases where traditional monitoring had not. The utility of detecting no arrhythmia during symptoms in one case was also highlighted, providing the athlete with the confidence to continue exercising. This reassurance and confidence across all cases is perhaps the most valuable aspect of this device, where clinicians and athletes can be more certain of reaching a diagnosis and undertaking appropriate management.

Objective To codesign an online support intervention for families after sudden cardiac death (SCD) in the young (<35 years). Design Codesign of an SCD family intervention by stakeholder focus groups. Setting Families and healthcare professionals with experience in SCD in the young. Participants Semistructured online focus groups were held with key stakeholders, that is, family members who had experienced young SCD, healthcare professionals and researchers based in New South Wales, Australia. Guided discussions were used to develop an online support intervention. Thematic analysis of discussions and iterative feedback on draft materials guided content development. Results Four focus groups were held (4-6 participants per group, 12 unique participants). Stakeholder involvement facilitated development of high-level ideas and priority issues. Creative content and materials were developed based on user preference for stories, narratives and information reflecting everyday experience of families navigating the legal and medical processes surrounding SCD, normalising and supporting grief responses in the context of family relationships and fostering hope. Emphasis on accessibility led to the overarching need for digital information and online engagement. These insights allowed development of an online intervention - COPE-SCD: A COmmunity suPporting familiEs after Sudden Cardiac Death - which includes a website and online support programme. Conclusion Using codesign with stakeholders we have developed a support intervention that addresses the needs of SCD families and aims to fill a large gap in existing healthcare. We will evaluate COPE-SCD to determine whether this is an effective intervention for support of families following a young SCD.

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in epilepsy. The underlying pathological mechanisms are likely to be multifactorial. Cardiac arrhythmia has been suggested as a cause of death in some patients with SUDEP. SCN5A encodes the cardiac Nav 1.5 sodium channel. SCN5A variants that result in either loss or gain of channel function cause cardiac arrhythmias. Rare SCN5A variants have been reported in SUDEP cases, but the impact of these variants on channel function is unknown. Here, we use whole-cell voltage clamp recordings to perform functional analyses of rare SCN5A SUDEP variants, p.V223G, p.I397V, and p.R523C. Expression and biophysical properties, including activation, inactivation, and recovery from inactivation, were probed. Each SCN5A variant significantly impacted human NaV 1.5 channel function, indicating that they could cause cardiac arrhythmias. The patient carrying the p.R523C variant was on lamotrigine, an antiseizure medication implicated in SUDEP. Therapeutic concentration of lamotrigine caused a slowing of the rate of recovery from inactivation and a hyperpolarizing shift in the voltage of inactivation of human NaV 1.5 wild-type, but not p.R523C channels, implicating a gene-by-drug interaction. These data suggest that SCN5A arrhythmogenic variants may confer increased risk of sudden death in individuals with epilepsy.

OBJECTIVE: To contextualize obesity rates in young sudden cardiac death (SCD) against the age-matched national population, and identify clinical and pathologic features in WHO class II and III obesity. METHODS: A prospective state-wide out-of-hospital cardiac arrest registry included all SCDs in Victoria, Australia from 2019-2021. Body mass indices (BMIs) of patients 18-50 years were compared to age-referenced general population. Characteristics of SCD patients with WHO Class II obesity (BMI ≥30kg/m2) and non-obesity (BMI<30kg/m2) were compared. Clinical characteristics of people with BMI>50kg/m2 were assessed. RESULTS: 504 patients were included. Obesity was strongly over-represented in young SCD compared to the age-matched general population (55.0% vs 28.7%, p<0.0001). Obese SCD patients more frequently had hypertension, diabetes and obstructive sleep apnoea (p<0.0001, p=0.009 and p=0.001 respectively), ventricular fibrillation as their arrest rhythm (p=0.008) and left ventricular hypertrophy (LVH) (p<0.0001). Obese patients were less likely to have toxicology positive for illicit substances (22.0% vs 32.6%, p=0.008) or history of alcohol abuse (18.8% vs 26.9%, p=0.030). Patients with BMI>50 kg/m2 represented 8.5% of young SCD. LVH (n=26, 60.5%) was their predominant cause of death and only 10 (9.3%) patients died from coronary disease. CONCLUSION: Over half of young Australian SCD patients are obese, with all obesity classes over-represented compared to the general population. Obese patients had more cardiac risk factors. Almost two thirds of patients with BMI>50 kg/m2 died from LVH, with fewer than 10% dying from coronary disease.