A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship.

Purpose: The Australian Genomics Cardiovascular Disorders Flagship was a national multidisciplinary collaboration. It aimed to investigate the feasibility of genome sequencing (GS) and functional genomics to resolve variants of uncertain significance (VUS) in the clinical management of patients and families with cardiomyopathies, primary arrhythmias, and congenital heart disease (CHD).

Methods: Between April 2019 and December 2021, 600 probands meeting cardiovascular disorder criteria from 17 cardiology and genetics clinics across Australia were enrolled in the Flagship and underwent GS.

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin () Truncating Variant.

Background: Truncating variants in desmoplakin (tv) 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 tv cardiomyopathy.

Methods: Individuals with tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers.

Cryoablation of Papillary Muscles at Surgery for Malignant Ventricular Arrhythmias Due to Mitral Valve Prolapse.

Background: Mitral valve prolapse (MVP) is relatively common condition and while generally benign a small subset of patient suffers from malignant ventricular arrhythmias (MVA) and sudden cardiac death (SCD).

Method And Material: We report three cases of mitral valve prolapse, mitral regurgitation and malignant ventricular arrhythmias refractory to medical therapy, who had surgical cryoablation at the time of surgery on the mitral valve.

Results: During a follow-up period ranging from 3 to 11 years all three patients have remained free of ventricular arrhythmias and cryoablation lesions targeting the base of the papillary muscles have not caused any detrimental effect on the valve function.

Systematic quantification of histologic ventricular fibrosis in isolated mitral valve prolapse and sudden cardiac death.

Background: Cardiac fibrosis in mitral valve prolapse (MVP) is implicated in the development of sudden cardiac death (SCD); however, the pattern remains poorly characterized.

Objective: The purpose of this study was to systematically quantify left and right ventricular fibrosis in individuals with isolated MVP and SCD (iMVP-SCD), whereby other potential causes of death are excluded, compared to a control cohort.

Methods: Individuals with iMVP-SCD were identified from the Victorian Institute of Forensic Medicine, Australia, and matched for age, sex, and body mass index to control cases with noncardiac death.

Sudden Cardiac Death in Schizophrenia: A Review.

In patients with schizophrenia, cardiovascular disease accounts for nearly 50% of deaths and decreased life expectancy, and the incidence of sudden cardiac death is about four times higher than in the background population. While the majority of sudden deaths are due to ischaemic heart disease and its recognised risk factors, about 10% of sudden deaths are unexplained and are thought to be due to cardiac arrhythmias. This review discusses various factors that might contribute to this increased mortality, such as the effect of antipsychotic drugs on potassium and sodium channel function, increased incidence of Brugada pattern in patients with schizophrenia and the role of the autonomic nervous system.

Characteristic Histopathological Findings and Cardiac Arrest Rhythm in Isolated Mitral Valve Prolapse and Sudden Cardiac Death.

Background The association between mitral valve prolapse (MVP) and sudden death remains controversial. We aimed to describe histopathological changes in individuals with autopsy-determined isolated MVP (iMVP) and sudden death and document cardiac arrest rhythm. Methods and Results The Australian National Coronial Information System database was used to identify cases of iMVP between 2000 and 2018.

Prospective Evaluation of the Utility of Whole Exome Sequencing in Dilated Cardiomyopathy.

Background Dilated cardiomyopathy may be heritable but shows extensive genetic heterogeneity. The utility of whole exome sequencing as a first-line genetic test for patients with dilated cardiomyopathy in a contemporary "real-world" setting has not been specifically established. Using whole exome sequencing with rigorous, evidence-based variant interpretation, we aimed to identify the prevalence of a molecular diagnosis in patients with dilated cardiomyopathy in a clinical setting.

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation.

Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA.

Channelopathies That Lead to Sudden Cardiac Death: Clinical and Genetic Aspects.

Forty per cent (40%) of sudden unexpected natural deaths in people under 35 years of age are associated with a negative autopsy, and the cardiac ion channelopathies are the prime suspects in such cases. Long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are the most commonly identified with genetic testing. The cellular action potential driving the heart cycle is shaped by a specific series of depolarising and repolarising ion currents mediated by ion channels.

Insights into sudden cardiac death: exploring the potential relevance of non-diagnostic autopsy findings.

Aims: Unexplained sudden cardiac death (SCD) may be attributable to cardiogenetic disease. Presence or absence of autopsy anomalies detected following premature sudden death direct appropriate clinical evaluation of at-risk relatives towards inherited cardiomyopathies or primary arrhythmia syndromes, respectively. We investigated the relevance of non-diagnostic pathological abnormalities of indeterminate causality (uncertain) such as myocardial hypertrophy, fibrosis, or inflammatory infiltrates to SCD.

Mitral valve prolapse and sudden cardiac death: a systematic review and meta-analysis.

Objectives: Mitral valve prolapse (MVP) is commonly observed as a benign finding. However, the literature suggests that it may be associated with sudden cardiac death (SCD). We performed a meta-analysis and systematic review to determine the: (1) prevalence of MVP in the general population; (2) prevalence of MVP in all SCD and unexplained SCD; (3) incidence of SCD in MVP and (4) risk factors for SCD.

Arrhythmogenic Right Ventricular Cardiomyopathy: A Review of Living and Deceased Probands.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially life-threatening genetic cardiomyopathy with a spectrum of clinical presentations including sudden cardiac death (SCD).

Methods: Clinical and genetic data of 44 probands referred to a cardiac genetics clinic (2007-2017) who met 2010 Task Force Criteria (TFC) for ARVC diagnosis were included.

Results: Thirty-three (33) (75%) male, 20 (45%) were referred by the Victorian Institute of Forensic Medicine.

A rapid scoring tool to assess mutation probability in patients with inherited cardiac disorders.

Aims: To explore clinical features and relationship with positive mutation ascertainment in inherited heart diseases in order to develop a clinical tool to assist identification of individuals in whom to offer genetic testing. A clinical tool that increases pre test probability of mutation detection would have the benefits of improving patient counselling, prioritising cases for MPS and allowing equity in decision making.

Methods And Results: Consecutive MPS mutation detection testing cases were identified (September 2014 - December 2015, n = 126).

The Electrocardiographic Footprints of Wenckebach Block.

In 1899, Karel Frederik Wenckebach described a cardiac arrhythmia with periodic dropped beats now referred to as a Wenckebach sequence. This was later shown to be due to a block in the atrioventricular node, but today, we identify Wenckebach sequences throughout the heart with most being recognised on the surface electrocardiograph as characteristic footprints. This manuscript will revisit Wenckebach atrioventricular block, the typical features of which only occur in about 15% of cases, with the remainder atypical.

Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.

Background: Mutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural history studies of LMNA-associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain.

Objectives: This study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype.

A Prospective Study of Sudden Cardiac Death among Children and Young Adults.

Background: Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults.

Methods: We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012.

Update on the Diagnosis and Management of Brugada Syndrome.

Brugada Syndrome (BrS) is an autosomal dominant channelopathy with variable penetrance affecting the sodium channel. It reduces the transport of sodium ions essential for proper generation of the cardiac action potential. The resulting inhomogeneous repolarisation in areas of the RV epicardium causes malignant ventricular arrhythmias.

The Cardiac Genetics Clinic: a model for multidisciplinary genomic medicine.

Objectives: To describe patient characteristics, standard operating procedure, and uptake of genetic testing at the multidisciplinary Cardiac Genetics Clinic (CGC) at the Royal Melbourne Hospital during its first 6 years.

Design: Database exploration of referral diagnoses, sex, number of clinic visits and incidence of genetic testing in a population of individuals attending the CGC.

Setting: Tertiary referral hospital (Royal Melbourne Hospital) providing cardiac genetics services to the state of Victoria.

Temporal distribution of arrhythmic events in chronic kidney disease: Highest incidence in the long interdialytic period.

Background: Chronic kidney disease (CKD) patients undergoing hemodialysis (HD) have a high risk of sudden cardiac death (SCD). A unique risk factor may be a longer interval between HD sessions (interdialytic period). Inherent in conventional HD (thrice-weekly) are two 48-hour short breaks (SIDP) and one 72-hour long break (LIDP) between HD sessions.