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.' 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.

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. For confirmed cardiac causes of OHCA, circumstances and cardiac history were collected. National time-use data was used to contextualize circumstances. 1319 OHCAs were included. 725 (55.0%) cases had a cardiac aetiology of OHCA, with coronary disease (n = 314, 23.8%) the most common pathology. Drug toxicity (n = 226, 17.1%) was the most common non-cardiac cause of OHCA and the second-most common cause overall. OHCAs were most likely to occur in sleep (n = 233, 41.2%). However, when compared to the typical Australian day, OHCAs occurred disproportionately more commonly during exercise (9% of patients vs. 1.3% of typical day, P = 0.018) and less commonly while sedentary (39.6 vs. 54.6%, P = 0.047). 38.2% of patients had known standard modifiable cardiovascular risk factors. 77% of patients with a cardiac cause of OHCA had not reported cardiac symptoms nor been evaluated by a cardiologist prior to their OHCA. CONCLUSION: Approximately half of OHCAs in the young have a cardiac cause, with coronary disease and drug toxicity dominant aetiologies. OHCAs disproportionately occur during exercise. Of patients with cardiac cause of OHCA, almost two-thirds have no standard modifiable cardiovascular risk factors, and more than three-quarters had no prior warning symptoms or interaction with a cardiologist.

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. For OHCAs with confirmed cardiac aetiology, cardiovascular risk profiles were compared. SETTING: A state-wide prospective OHCA registry (combining ambulance, hospital and forensic data) in the state of Victoria, Australia (population 6.5 million). PARTICIPANTS: Victorians aged 1-50 years old experienced an OHCA between April 2019 and April 2020. MAIN OUTCOME MEASURES: Rates and underlying causes of OHCA in young rural and metropolitan Victorians. RESULTS: Rates of young OHCA were higher in rural areas (OHCA 22.5 per 100 000 rural residents vs. 13.4 per 100 000 metropolitan residents, standardised incidence ratio 168 (95% CI 101-235); confirmed cardiac cause of arrest 12.1 per 100 000 rural residents versus 7.5 per 100 000 metropolitan residents, standardised incidence ratio 161 (95% CI 71-251). The underlying causation of the OHCA and cardiovascular risk factor burden did not differ between rural and metropolitan areas. CONCLUSION: Higher rates of OHCA occur in young rural patients, with standardised incidence ratio of 168 compared to young metropolitan residents. Rural status did not influence causes of cardiac arrest or known cardiovascular risk factor burden in young patients experiencing OHCA.

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. The registry will support clear pathways of cardiac assessment, epidemiological profiling and routine family screening and psychological support.

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. The CAC score was calculated in a blinded manner from post-mortem CTs performed on all cases. CAC scores were assessable in 97 non-decomposed cases (feasibility 97%). The median CAC score was 88 Agatston units [IQR 0-286] in patients deceased from ischemic heart disease vs 0 [IQR 0-0] in patients deceased from other causes (p < 0.0001). Presence of any coronary calcification differed significantly between ischemic heart disease and non-ischemic groups (adjusted odds ratio 10.7, 95% CI 3.2-35.5). All cases with a CAC score > 100 (n = 22) had ischemic heart disease as the cause of death. Fifteen cases had a CAC score of zero but severe coronary disease at post-mortem examination. Post-mortem CAC scoring is highly feasible. An elevated CAC score in cases 18-50 years old with sudden death predicts ischemic heart disease at post-mortem examination. However, a CAC score of zero does not exclude significant coronary artery disease. Post-mortem CAC score may be considered as a further assessment tool to help predict likely cause of death when there is an objection to or unavailability of post-mortem examination.

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. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. RESULTS: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. CONCLUSIONS: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

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. Statistical analyses focused on overall levels of function and across-group comparisons adjusted for age. RESULTS: From 6/2018 to 2/2020, 252 parents provided information for one or more functional domains. Median age was 7.2 years (interquartile range (IQR): 3.9 to 11.8), and 128 (51%) were females. DEE groups were Dravet syndrome (N = 72), KCNQ2-DEE (N = 80), KCNB1-DEE, (N = 33), Lennox-Gastaut syndrome (LGS; N = 26), electrographic status epilepticus in sleep (ESES; N = 15), and others (N = 26). Overall, functional hand grasp was absent in 48 (20%). Of children ≥2 years old, 60/214 (28%) could not walk independently, 85 (40%) were dependent on someone else for feeding, and 153 (73%) did not effectively communicate with unfamiliar people. Impairments entailing absence or near absence of independent function (profound impairment) were observed in 0, 1, 2, 3, and 4 domains for 58 (25%), 78 (34%), 40 (17%), 33 (14%), and 22 (10%) children, respectively. After adjustment for age, impairment levels varied substantially across DEE group for mobility (p < 0.0001), feeding (p < 0.0001), communication (p < 0.0001), hand grasp (p < 0.0001), and number of profoundly impaired domains (p < 0.0001). Three or four profoundly affected domains were reported in 44% of KCNQ2-DEE participants, followed by LGS (29%), KCNB1-DEE (27%), ESES (7%), and Dravet syndrome (6%). CONCLUSIONS: Many children with DEEs experience severe functional impairments, and few children have typical function. As precision therapies will emphasize nonseizures consequences of DEEs, understanding the nature of abilities and impairments will be critical to selecting appropriate outcome measures in therapeutic trials.

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. METHODS AND RESULTS: At-risk relatives of unexplained SCD cases aged 1-64 years without prior cardiac disease (n = 98) with either normal and negative (40%, true sudden arrhythmic death syndrome; SADS) or isolated non-diagnostic (60%, uncertain sudden unexplained death; SUD) cardiac histological autopsy findings at a central forensic pathology unit were referred to the regional unexplained SCD clinic for clinical cardiac phenotyping. Uncertain SUD were older than true SADS cases (31.8 years vs. 21.1 years, P < 0.001). A cardiogenetic diagnosis was established in 24 families (24.5%) following investigation of 346 referred relatives. The proportions of uncertain SUD and true SADS explained by familial cardiogenetic diagnoses were similar (20% vs. 31%, P = 0.34, respectively), with primary arrhythmia syndromes predominating. Unexplained SCD cases were more likely than matched non-cardiac premature death controls to demonstrate at least one uncertain autopsy finding (P < 0.001). CONCLUSION: Primary arrhythmia syndromes predominate as familial cardiogenetic diagnoses amongst both uncertain SUD and true SADS cases. Non-diagnostic or uncertain histological findings associate with SUD, though cannot be attributed a causative status. At-risk relatives of uncertain SUD cases should be evaluated for phenotypic evidence of both ion channel disorders and cardiomyopathies.

Managing Care Transitions to the Community During a Pandemic.

This column discusses the establishment of a multidisciplinary model for care transition of COVID-19-positive patients from hospital to community. The pandemic has presented challenging issues for discharge transition. A tiered patient identification and clinical messaging referral system was developed. The use of the COVID-19 transition model provided support to patients and physicians during the 30-day discharge period and can serve as a model for emerging public health issues in the future.

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. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation. RESULTS: A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred. CONCLUSIONS: The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).

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. Over the course of 40 ECP treatments, hemolysis was observed on five occasions. An extensive investigation found an association between hemolysis and apheresis RBC (A-RBC). Of 46 RBC units dispensed for blood priming, hemolysis occurred with 22% (4 of 18) of A-RBC and accounted for 80% (4 of 5) of all hemolysis episodes. Hemolysis was significantly higher with A-RBC when compared with RBC collected by whole blood donations (WB-RBC: 3.5% [1 of 28]; P = .049). A comparison of RBC attributes, including unit age, showed that hemolyzed A-RBC units tended to be younger than both nonhemolyzed RBC (6.5 vs 10.3 days, P = .018) and WB-RBC (8.5 days, P = .10). We hypothesize that A-RBC may exhibit "sublethal" RBC damage following prior exposure to centrifugal shear and negative forces at the time of collection, leading to a decrease in RBC deformability and increased susceptibility to hemolysis. This is the first report showing an increased susceptibility to hemolysis with A-RBC during priming of the Cellex.

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. Presentation that lead to diagnosis included ARVC-related SCD (n=19), SCD due to alternate cause of death (n=1), aborted cardiac arrest (n=6), stable symptomatic ventricular tachycardia (n=14), palpitations (n=3) and presyncope (n=1). Left ventricular involvement (50%) was more common in the SCD subgroup (84% vs 21%, p<0.001). Genetic testing (n=39) revealed a pathogenic mutation in 16 (commonest: plakophillin-2 (n=9)), a variant of uncertain significance (VUS) in 15, with no abnormality in eight. In the SCD subgroup, median age at death was 44.7 years and 74% were male. Genetic testing (n=16) in this subgroup revealed a pathogenic mutation in six patients (commonest: desmoplakin (n=4)). Comparison of the two commonest mutations (PKP2 and desmoplakin [DSP]) showed DSP mutation was more frequently associated with SCD (p<0.01) and LV involvement (p<0.001). Screening of 117 relatives has lead to ARVC diagnosis in 29 patients. CONCLUSIONS: Arrhythmogenic right ventricular cardiomyopathy has a heterogeneous and often severe clinical presentation. Sudden cardiac death and aborted cardiac arrest (ACA) are common, demonstrating electrical abnormalities appear early in the ARVC phenotype. Left ventricular involvement was common and may reflect a worse prognosis. Genetic testing is essential in family screening and may be helpful in risk assessment. Desmoplakin mutation is associated with LV involvement and may be indicative of worse prognosis and increased risk of SCD. Genetic screening of proband family members in a specialised multidisciplinary clinic is essential in early diagnosis of affected family members.

Lynch syndrome and cervical cancer.

Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age-specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6 fold (95% CI: 2.3-13.8; p = 0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9-10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0-46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p = 0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome.

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. PARTICIPANTS: All individuals initially attending the clinic between July 2007 and July 2013, either as the proband or as an at-risk family member. MAIN OUTCOME MEASURES: Classification of patients into diagnostic categories, number of probands and at-risk relatives assessed, incidence and outcomes of genetic testing. RESULTS: 1170 individuals were seen for the first time over the 6-year period; 57.5% made only one visit. The median age was 39 years. Most were encompassed within four broad diagnostic categories: cardiomyopathy (315 patients), aortopathy (303 patients), arrhythmia disorders (203 patients) and resuscitated cardiac arrest and/or family history of sudden cardiac death (341 patients); eight patients had "other" diagnoses. Genetic testing (mutation detection or predictive testing) was undertaken in 381 individuals (32.6%), and a pathogenic mutation was identified in 47.6% of tests, representing 15.3% of the total population. CONCLUSION: The CGC fulfils an important role in assisting clinicians and patients by reviewing genetic cardiac diagnoses. Clinical practice during the study period moved from a selected candidate gene approach to broader gene panel-based testing. This move to next-generation sequencing may increase the detection of mutations and variants of unknown significance. A major contribution by the clinic to the care of these individuals and their families is the provision (or negating) of a diagnosis, and of a plan for managing risks of predictable cardiac disease.

Characterization of L1 retrotransposition with high-throughput dual-luciferase assays.

Recent studies employing genome-wide approaches have provided an unprecedented view of the scope of L1 activities on structural variations in the human genome, and further reinforced the role of L1s as one of the major driving forces behind human genome evolution. The rapid identification of novel L1 elements by these high-throughput approaches demands improved L1 functional assays. However, the existing assays use antibiotic selection markers or fluorescent proteins as reporters; neither is amenable to miniaturization. To increase assay sensitivity and throughput, we have developed a third generation assay by using dual-luciferase reporters, in which firefly luciferase is used as the retrotransposition indicator and Renilla luciferase is encoded on the same or separate plasmid for normalization. This novel assay is highly sensitive and has a broad dynamic range. Quantitative data with high signal-to-noise ratios can be obtained from 24- up to 96-well plates in 2-4 days after transfection. Using the dual-luciferase assays, we have characterized profiles of retrotransposition by various human and mouse L1 elements, and detailed the kinetics of L1 retrotransposition in cultured cells. Its high-throughput and short assay timeframe make it well suited for routine tests as well as large-scale screening efforts.

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. METHODS: The End Unexplained Cardiac Death (EndUCD) prospective state-wide registry compared people aged 15 to 50 years with and without schizophrenia who experienced SCD within a 2-year time period and were referred for forensic evaluation. RESULTS: We identified 579 individuals, of whom 65 (11.2%) had schizophrenia. Patients with schizophrenia were more commonly smokers (46.2% vs 23.0%; P < 0.0001), consumed excess alcohol (32.3% vs 21.4%; P = 0.05), and used QTc-prolonging medications (69.2% vs 17.9%; P < 0.0001). They were less likely to arrest while exercising (0.0% vs 6.4%; P = 0.04). Unfavorable arrest-related factors included lower rates of witnessed arrest (6.2% vs 23.5%; P < 0.0001), more likely to be found in asystole (92.3% vs 73.3%; P < 0.0001), and being more likely to be found as part of a welfare check after a prolonged period of time (median 42 hours vs 12 hours; P = 0.003). There was more frequent evidence of decomposition, and they more commonly underwent autopsy (41.2% vs 26.4%; P = 0.04 and 93.8% vs 82.5%; P = 0.05), with a diagnosis of nonischemic cardiomyopathy being more common (29.2% vs 18.1%; P = 0.04). CONCLUSIONS: People with schizophrenia account for 11% of young SCD patients referred for forensic investigations, exceeding population rates by 11-fold. They have a higher preexisting cardiac risk factor burden, unfavorable resuscitation profiles, and higher rates of nonischemic cardiomyopathy. Strategies targeting biopsychosocial support may deliver not only psychological benefits, but also help to decrease unwitnessed cardiac arrest.

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

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.

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). METHODS: A prospective 2-year analysis of in-hospital deaths following OHCA in Victoria, Australia, was conducted using a statewide registry combining data from ambulance, hospital, and forensic resources. RESULTS: OHCA caused 26.3% of all deaths (n = 1301) in Victorians aged 1-50 years. Rates of prehospital and in-hospital referral to coronial services were 95.0% and 59.5%, respectively. Factors independently predicting in-hospital coronial referral were age <40 years, death in the emergency department, and rural status (odds ratios 4.07, 8.91, and 3.43, respectively). Establishing a diagnosis of coronary disease in-hospital substantially reduced odds of coronial referral (odds ratio 0.07). Of 107 SCD patients referred to the coroner from hospitals, 25 (23.3%) had illicit substances identified on toxicologic analysis. Eighty-one patients (75.7%) underwent autopsy, with cause of death determined in 65 cases (80.2%). Sixteen deaths (19.8%) remained unascertained after autopsy and ancillary investigations. CONCLUSION: More than one-fourth of young Victorian deaths result from OHCA. Approximately half of patients dying in-hospital following OHCA are referred to the coroner. Patients referred are younger, more likely to die in the emergency department, and reside rurally. Forensic assessment identifies high rates of illicit drug use in young SCD patients and provides a definitive cause of death for most patients.

Obesity in young sudden cardiac death: Rates, clinical features, and insights into people with body mass index >50kg/m2.

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.

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. Of 1,477 patients who experienced cardiac arrest during the study period, 490 underwent autopsy and were confirmed to have experienced SCD. Of these 490 patients, 5 (1%) had a CAA identified, with 3 having anomalies of coronary origin and 2 having anomalies of coronary course. In no cases were the CAA deemed responsible for the SCD. In 2 cases, severe coronary disease and intra-coronary thrombus with histological evidence of acute myocardial infarction were identified. In the third, critical coronary disease was found, the fourth had an unrelated thoracic aortic dissection, and the fifth had cardiomegaly in the setting of illicit drug use. Of 27 patients who experienced their SCD during exercise, only 1 had a CAA identified (the patient with thoracic aortic dissection). In conclusion, in this prospective cohort of consecutive young patients with SCD who underwent autopsy, CAAs occurred in 1% of patients and did not cause any deaths. The role of CAAs in causing young and middle-aged SCD appears to be less significant than previously hypothesized.