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.

Sudden Cardiac Death in People With Schizophrenia: Higher Risk, Poorer Resuscitation Profiles, and Differing Pathologies.

Background: People with schizophrenia account for approximately 1.0% of the population and seem to experience increased rates of sudden cardiac death (SCD).

Objectives: This study sought to determine characteristics of increased SCD in people with schizophrenia.

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.

Causes, circumstances, and potential preventability of cardiac arrest in the young: insights from a state-wide clinical and forensic registry.

Aims: The causes, circumstances, and preventability of young sudden cardiac arrest remain uncertain.

Methods And Results: A prospective state-wide multi-source registry identified all out-of-hospital cardiac arrests (OHCAs) in 1-50 year olds in Victoria, Australia, from 2019 to 2021. Cases were adjudicated using hospital and forensic records, clinic assessments and interviews of survivors and family members.

Inconsistent discharge diagnoses for young cardiac arrest episodes: insights from a statewide registry.

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.

Obesity in young sudden cardiac death: Rates, clinical features, and insights into people with body mass index >50kg/m.

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.

Higher rates but similar causes of young out-of-hospital cardiac arrest in rural Australian patients.

Objective: To determine whether young rural Australians have higher rates or different underlying causes of out-of-hospital cardiac arrest (OHCA).

Design: A case-control design identified patients experiencing an OHCA, then compared annual OHCA rates and underlying causes in rural versus metropolitan Victoria. OHCA causes were defined as either cardiac or non-cardiac, with specific aetiologies including coronary disease, cardiomyopathy, unascertained cause of arrest, drug toxicity, respiratory event, neurological event and other cardiac and non-cardiac.

Prevalence of Coronary Artery Anomalies in Young and Middle-Aged Sudden Cardiac Death Victims (from a Prospective State-Wide Registry).

Coronary artery anomalies (CAAs) have been previously implicated as a major cause of young sudden cardiac death (SCD), particularly in exercise-related SCD, with a prevalence of up to 33%. A state-wide prospective out-of-hospital cardiac arrest registry identified all patients aged 1 to 50 years who experienced an SCD and underwent autopsy from April 2019 to April 2021. Rates of normal anatomy, normal variants, and CAAs were identified, and circumstances and causes of death for patients with CAAs examined.

Predictors and outcomes of in-hospital referrals for forensic investigation after young sudden cardiac death.

Background: Forensic investigations are recommended following sudden cardiac death (SCD) to determine cause of death and identify living relatives at potential risk. Not all young SCD patients are referred to coronial services.

Objective: The purpose of this study was to identify referral rates, predictors, and outcomes of young SCD patients who die in-hospital following out-of-hospital cardiac arrest (OHCA).

The economic impact of sudden cardiac arrest.

Background: There are 20,000 sudden cardiac arrests (SCAs) in Australia annually, with 90% case-fatality.

Objective: The present study calculated both the health and economic impact of SCAs in Victoria, Australia.

Methods: Data on all SCAs attended by Ambulance Victoria from July 2017 to June 2018 were collected regarding age, gender, and survival to hospital, discharge and 12 months.

Investigation of current models of care for genetic heart disease in Australia: A national clinical audit.

Background: This sub-study of the Australian Genomics Cardiovascular Genetic Disorders Flagship sought to conduct the first nation-wide audit in Australia to establish the current practices across cardiac genetics clinics.

Method: An audit of records of patients with a suspected genetic heart disease (cardiomyopathy, primary arrhythmia, autosomal dominant congenital heart disease) who had a cardiac genetics consultation between 1st January 2016 and 31 July 2018 and were offered a diagnostic genetic test.

Results: This audit included 536 records at multidisciplinary cardiac genetics clinics from 11 public tertiary hospitals across five Australian states.

The End Unexplained Cardiac Death (EndUCD) Registry for Young Australian Sudden Cardiac Arrest.

In 2019, the first multi-source registry of sudden cardiac arrest and death for patients aged 1-50 years launched in Victoria, Australia. Sudden cardiac arrest (SCA) affects approximately fifteen hundred younger Victorians per year. The End Unexplained Cardiac Death (EndUCD) Registry enrols SCA/death (D) cases aged 1-50 years, providing family screening, access to psychological support through clinical sites and creating a genetic biorepository for whole-genome sequencing.

Can post-mortem coronary artery calcium scores aid diagnosis in young sudden death?

This study sought to explore the feasibility and utility of post-mortem coronary artery calcium (CAC) scoring in identifying patients with ischemic heart disease as cause of sudden death. 100 deceased patients aged 18-50 years underwent post-mortem examination in the setting of sudden death. At post-mortem, fifty cases were determined to have ischemic heart disease, and fifty had death attributed to trauma or unascertained causes.

Nonseizure consequences of Dravet syndrome, KCNQ2-DEE, KCNB1-DEE, Lennox-Gastaut syndrome, ESES: A functional framework.

Rationale: Developmental epilepsies and encephalopathies (DEEs) are characterized by many severe developmental impairments, which are not well-described. A functional framework could facilitate understanding of their nature and severity and guide the selection instruments to measure improvements in therapeutic trials.

Methods: An online survey administered through several parent-organized foundations utilized accepted functional classifications and questionnaires derived from common instruments to determine levels of mobility, fine motor, communication, and feeding functions.

Cardiac arrest and sudden cardiac death registries: a systematic review of global coverage.

Background: Sudden cardiac death (SCD) is a major global health problem, accounting for up to 20% of deaths in Western societies. Clinical quality registries have been shown in a range of disease conditions to improve clinical management, reduce variation in care and improve outcomes.

Aim: To identify existing cardiac arrest (CA) and SCD registries, characterising global coverage and methods of data capture and validation.

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.

Apheresis red blood cells associated with repeated hemolysis during blood priming of the Cellex Photopheresis System.

Extracorporeal photopheresis (ECP) in young pediatric patients has a risk for procedural hypotension and anemia due to extracorporeal fluid shifts. A standard mitigation policy in these patients is to prime the device with packed red blood cells (RBC) or whole blood. We now report multiple episodes of hemolysis while attempting to prime the Therakos Cellex in a pediatric transplant patient undergoing a course of ECP for severe graft-vs-host-disease.

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.

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.

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.

Roadmap for creating an accelerated three-year medical education program.

Unlabelled: Medical education is undergoing significant transformation. Many medical schools are moving away from the concept of seat time to competency-based education and introducing flexibility in the curriculum that allows individualization. In response to rising student debt and the anticipated physician shortage, 35% of US medical schools are considering the development of accelerated pathways.

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).

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.