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.

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.

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.

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.

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.

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. Pre-SCA employment status of all patients was modelled using age and gender-matched Australian economic data. A Markov state-transition model with a five-year horizon calculated health and economic impact in years of life lived (YLL), productivity-adjusted life years (PALYs) and gross domestic product (GDP) lost. A counterfactual Markov state-transition model assessed outcomes of an identical cohort of patients who did not experience SCA. All values were discounted by 5%. RESULTS: In 12 months, 4637 people suffered SCAs in Victoria, of whom 1516 (32.7%) were working at the time. 695 patients (15.0%) survived to hospital, 325 (7.0%) to discharge, and 303 (6.5%) to 12 months. In five years following their SCA, the cohort lost 15,922 years of life and 2327 PALYs. Reduced productivity led to GDP losses of AUD$448 million (92.8% relative reduction). Extrapolated to the 20,000 SCAs occurring across all of Australia, total GDP losses approached AUD$2 billion. CONCLUSION: The health and economic burden of SCAs is high, predominantly underpinned by very high mortality. Annual national losses approach AUD$2 billion (USD$1.42 billion) and are comparable to productivity losses from all cancers combined. Prioritising research and state-of-the-art care for SCA patients appears economically sound.

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. Most genetic consultations occurred in a clinic setting (90%), followed by inpatient (6%) and Telehealth (4%). Queensland had the highest proportion of Telehealth consultations (9% of state total). Sixty-six percent of patients had a clinical diagnosis of a cardiomyopathy, 28% a primary arrhythmia, and 0.7% congenital heart disease. The reason for diagnosis was most commonly as a result of investigations of symptoms (73%). Most patients were referred by a cardiologist (85%), followed by a general practitioner (9%) and most genetic tests were funded by the state Genetic Health Service (73%). Nationally, 29% of genetic tests identified a pathogenic or likely pathogenic gene variant; 32% of cardiomyopathies, 26% of primary arrhythmia syndromes, and 25% of congenital heart disease. CONCLUSION: We provide important information describing the current models of care for genetic heart diseases throughout Australia. These baseline data will inform the implementation and impact of whole genome sequencing in the Australian healthcare landscape.

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.

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.

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.

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.

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. Methods: Biomedical and public search engines were searched with the terms 'registry cardio*'; 'sudden cardiac death registry' and 'cardiac arrest registry'. Registries were categorised as either CA, SCD registries or 'other' according to prespecified criteria. SCD registry coordinators were contacted for contemporaneous data regarding registry details. Results: Our search strategy identified 49 CA registries, 15 SCD registries and 9 other registries (ie, epistries). Population coverage of contemporary CA and SCD registries is highly variable with registries densely concentrated in North America and Western Europe. Existing SCD registries (n=15) cover a variety of age ranges and subpopulations, with some enrolling surviving patients (n=8) and family members (n=5). Genetic data are collected by nine registries, with the majority of these (n=7) offering indefinite storage in a biorepository. Conclusions: Many CA registries exist globally, although with inequitable population coverage. Comprehensive multisource surveillance SCD registries are fewer in number and more challenging to design and maintain. Challenges identified include maximising case identification and case verification. Trial registration number: CRD42019118910.

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. Methods and Results Whole exome sequencing was performed in eligible patients (n=83) with idiopathic or familial dilated cardiomyopathy. Variants were prioritized for curation in up to 247 genes and classified using American College of Medical Genetics and Genomics-based criteria. Ten (12%) had a pathogenic or likely pathogenic variant. Eight (10%) participants had truncating TTN variants classified as variants of uncertain significance. Five (6%) participants had variants of unknown significance according to strict American College of Medical Genetics and Genomics criteria but classified as either pathogenic or likely pathogenic by other clinical laboratories. Pathogenic or likely pathogenic variants were found in 8 genes (all within tier 1 genes), 2 (20%) of which are not included in a standard commercially available dilated cardiomyopathy panel. Using our bioinformatics pipeline, there was an average of 0.74 variants of uncertain significance per case with ≈0.75 person-hours needed to interpret each of these variants. Conclusions Whole exome sequencing is an effective diagnostic tool for patients with dilated cardiomyopathy. With stringent classification using American College of Medical Genetics and Genomics criteria, the rate of detection of pathogenic variants is lower than previous reports. Efforts to improve adherence to these guidelines will be important to prevent erroneous misclassification of nonpathogenic variants in dilated cardiomyopathy genetic testing and inappropriate cascade screening.

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.

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.

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.