Etiology Of Sudden Cardiac Death Research Articles

Morphological Changes Of The Heart In Sudden Death Psychiatric Patients

Although sudden cardiac death is often reported in epileptic or psychiatric patients, the etiologyis not fully understood. The aim of this study was to examine whether morphological changes of the heart contribute to sudden cardiac death in epileptic or psychiatric patients, compared with control decedents.Cases of sudden cardiac deathsdue to fatal arrhythmia in patients with epilepsy or psychiatric disease were selected from forensic autopsies performed at the Shiga Prefecture from 2014 to 2021.As the control group, autopsied healthy decedents were selected. The heart weight to normal heart weight ratio, ventricular wall thickness, cardiomyocyte width, nuclear diameter and nuclear density of the left and right ventricle and interventricular septum were examined. The left and right ventricular wall thickness and cardiomyocyte to be smaller in epileptic patients, however, no significant differences were found. The nuclear diameter/body surface area of the left ventricle was significantly smaller in epileptic and psychiatric patients than in control patients.The smaller nuclei of cardiomyocytes in epileptic and psychiatric patients may relate to the etiology of sudden cardiac death.

A method of identifying the high-risk mutations of sudden cardiac death at KCNQ1 and KCNH2 genes

Sudden Cardiac Death (SCD) often shows negative anatomy results after a systemic autopsy and the gene mutations of potassium channel play a key role in the etiology of SCD. We established a feasible system to detect SCD-related mutations and investigated the mutations at KCNQ1 and KCNH2 genes in the Chinese population. We established a mutation detection system combined with multiplex PCR, SNaPshot technique, and capillary electrophoresis. We genotyped 101 putative mutations at KCNQ1 and KCNH2 genes in 60 SCD of negative anatomy and 50 controls using the established assay and compared Odd Ratio (OR). Four coding variants were identified in the KCNQ1 gene: S546S, I145I, P448R, and G643S. The mutations of I145I and S546S did not differ significantly in the SCD compared with controls. 21 SCD individuals (35 %) and 1 control individual (2 %) showed a genotype of C/G at P448R (OR = 17.5, 95 % CI [2.40–127.82]). 24 SCD individuals (40 %) and 1 control individual (2 %) showed a genotype of C/G at G643S (OR = 20.0, 95 % CI [2.75–145.25]). We established a robust assay for rapid screening the putative SCD-related mutations in KCNQ1 and KCNH2 genes. The new assay in our study is easily amenable to the majority of laboratories without the need for new specialized equipment. Our method will meet the increasing requirement of mutation screening for SCD in regular DNA laboratories and will help screen mutations in those dead of SCD and their relatives.

Ethnicity and sudden cardiac death in athletes: insights from a large United Kingdom registry.

The relationship between ethnicity and causes of sudden cardiac death (SCD) in athletes is poorly understood. To investigate aetiology of SCD among different ethnicities in a large cohort of athletes. Between 1994 and November 2022, 7880 cases of SCD were consecutively referred from all over the United Kingdom to our national cardiac pathology centre; 848 (11%) were athletes. All cases underwent detailed autopsy evaluation by expert cardiac pathologists. Clinical information was obtained from referring coroners. Most of athletes were white (n = 758; 89%). Black and Asian athletes were in number of 51 (6%) and 39 (5%), respectively. A structurally normal heart, indicative of sudden arrhythmic death syndrome (SADS) was the most common autopsy finding (n = 385; 45%), followed by myocardial diseases (n = 275; 32%), atherosclerotic coronary artery disease (CAD) (n = 58; 7%), and coronary artery anomalies (n = 29; 3%). In most of cases, death occurred during exercise (n = 737; 87%). Arrhythmogenic cardiomyopathy (ACM) was more common in black (n = 13; 25%) than in white (n = 109; 14%) and Asian (n = 3; 8%) athletes (P = 0.03 between black and white athletes; P = 0.04 between black and Asian athletes); in contrast, CAD was more common in Asians (n = 6; 15% vs. n = 51; 7% in whites vs. n = 1; 2%; in blacks, P = 0.02 between Asian and black athletes). Among white athletes, ACM was more common in individuals who died during exercise than in the ones who died at rest (P = 0.005). Such a difference was not observed in Asian and black athletes. In Asian athletes, CAD was the diagnosis at autopsy in 18% of individuals who died during exercise and in none of individuals who died at rest. A structurally normal heart at autopsy and myocardial diseases are the most common findings in athletes who died suddenly. While ACM is more common in black athletes, atherosclerotic CAD is more common in Asian athletes, with a strong association with exercise-induced SCD. ACM appears to be a driver of exercise-induced SCD in white athletes, however this is not the case in black and Asian athletes.

Cardiac magnetic resonance imaging in athletes with suspected structural myocardial disease: results of a high volume single-center study

Abstract Introduction Structural heart disease is one of the leading causes of sudden cardiac death in athletes. Cardiac magnetic resonance imaging (CMR) has a key role in the diagnosis, providing accurate functional and morphological information. Aim To investigate the prevalence of structural heart disease and the etiology of sudden cardiac death (SCD) in athletes. Methods We enrolled athletes (training ≥6 hours/week) who underwent CMR due to suspected structural myocardial disease at our Heart and Vascular Center between 2009 and 2022. We also performed cardiogenetic testing with new-generation sequencing (174 genes) in athletes with confirmed structural heart disease and/or malignant arrhythmia who gave consent. Results CMR was performed on a total of 556 athletes (445 male, 24±10 age). The indications for CMR were as follows: aborted sudden cardiac death/sustained ventricular tachycardia (3%), ECG (46%) or echocardiographic abnormality (36%), positive family history of SCD or cardiomyopathy (CMP) (3%), or athletes' complaints (31%). Structural myocardial abnormalities were confirmed in 99 athletes: hypertrophic (HCM) in 27, arrhythmogenic (AC) in 11, dilated (DCM) CMP in 7, and left ventricular non-compaction (LVNC) in 9 cases. MR images consistent with Fabry disease were found in 5 patients. We have discovered post-myocardial infarction scars in 10 cases, and atypical non-ischemic scarring (excluding hinge point fibrosis) was observed in 32 athletes. Besides pathological abnormalities, minor alterations were identified in 76 patients. Among the athletes examined after aborted sudden cardiac death/sustained ventricular tachycardia (n=18), we found structural heart disease in 14 patients, AC was confirmed in 7, HCM in two, non-ischemic fibrosis in three cases and LVNC in one athlete. Cardiogenetic test was performed in 26 athletes, we found pathogenic or likely pathogenic mutations in 5 cases, typical of HCM, AC, DCM (MYBPC3, PKP2, LMNA, TTN). The genetic test showed VUS (variant of unknown significance) in 15 additional athletes. Conclusions HCM was identified as the most frequent CMP, whereas AC and nonischaemic scar was the leading cause of SCD or SVT in our athletes.Figure A)Short axis late gadolinium ehancement CMR image of a 26-year-old female tennis player with hypertrophic cardiomyopathy and nonischemic fibrosis (arrow) and MYBPC3 pathogenic variant.Figure B)Short axis late gadolinium enhancement CMR image of a 40-year-old male elite discus thrower with sustained ventricular tacchycardia and nonischaemic scar formation (arrows). LMNA and titin pathogenic variants could be detected.

Clinical profile and outcomes of young patients treated with implantable cardioverter defibrillators at a South African tertiary hospital: a review of two decades of implantable cardioverter defibrillator implantation and follow up.

In young patients without atherosclerotic coronary artery disease, the aetiology of sudden cardiac death (SCD) has been described in Europe and North America. However, there are important regional variations and there are limited data on the aetiology and outcome of SCD in South Africa. The objective of this study was to determine the profile and outcomes of young patients treated with implantable cardioverter defibrillators (ICDs) at a South African tertiary hospital. This study was designed as a retrospective review of patients aged 35 years or younger implanted with ICDs at Groote Schuur Hospital. During the study period, 38 patients younger than 35 years were implanted with ICDs. The mean (standard deviation) age at ICD implantation was 25.1 (7.6) years and 63.2% were male. A secondary-prevention ICD was implanted in 57.9% of the patient population, and primary prevention in the remaining 42.1%. Patients with secondary-prevention ICDs presented with ventricular tachycardia (59.1%), ventricular fibrillation (31.8%) and receipt of cardiopulmonary resuscitation but no recorded electrocardiograms (9.1%). Arrhythmogenic right ventricular cardiomyopathy (ARVC) was the leading cause of SCD in the secondary-prevention patient population (36.4%). Idiopathic dilated cardiomyopathy accounted for 50% of the primary-prevention patient population. After a median (interquartile range) follow up 32 (14-90) months, 7.9% died and 5.2% received a heart transplant; 42.1% of the study population received appropriate ICD shock therapies and 18.4% received inappropriate shock therapies. In this single-centre study from South Africa, ARVC and repaired congenital heart disease were the leading causes of SCD in patients younger than 35 years treated with secondary-prevention ICDs. Primary-prevention ICDs were frequently implanted for idiopathic dilated cardiomyopathy.

Causes and characteristics of sudden cardiac death in octogenarians/nonagenarians

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation Introduction The risk for sudden cardiac death (SCD) increases with ageing. Methods We evaluated causes and characteristics of unexpected SCD in SCD victims aged ≥ 80 years in a consecutive series of 5,869 SCD victims who underwent medico-legal autopsy. Results Among SCD victims ≥ 80 years, 91.0% of SCDs were due to ischemic heart disease (IHD) determined in autopsy and 9.0% due to non-ischemic heart disease (NIHD), whereas among those < 80 years, only 72.6% of SCDs were due to IHD and 27.4% due to NIHD (P<.001). Severe fibrosis in myocardium was more common whereas heart weight and liver weight, body mass index and abdominal fat thickness, were lower among SCD victims aged ≥ 80 years than among victims aged < 80 years. In those with IHD as etiology of SCD, at least 75% stenosis in one or more major coronary vessels was more common in SCD victims aged ≥ 80 years than among victims aged < 80 years (P=.001). Dying in sauna was more common among those ≥ 80 years than among those < 80 years (5.5% vs. 2.6%, P<.001). Conclusion In victims of unexpected SCD aged ≥ 80 years, the autopsy-based etiology of SCD was more commonly IHD than in those aged < 80 years. In SCD victims aged ≥ 80 years, severe fibrosis in myocardium, representing arrhythmic substrate, was more common than in the younger ones.

Causes and characteristics of unexpected sudden cardiac death in octogenarians/nonagenarians.

The risk for sudden cardiac death (SCD) increases with ageing. We evaluated causes and characteristics of unexpected SCD in SCD victims aged ≥ 80 years in a consecutive series of 5,869 SCD victims in Northern Finland. All the victims underwent medico-legal autopsy as medico-legal autopsy is mandatory in cases of unexpected sudden death in Finland. All the non-cardiac deaths such as pulmonary embolism and cerebral hemorrhage were excluded from the study, as were unnatural deaths such as intoxications. Among SCD victims ≥ 80 years, 91.0% of SCDs were due to ischemic heart disease (IHD) determined in autopsy and 9.0% due to non-ischemic heart disease (NIHD), whereas among those < 80 years, only 72.6% of SCDs were due to IHD and 27.4% due to NIHD (P < .001). Severe fibrosis in myocardium was more common whereas heart weight and liver weight, body mass index and abdominal fat thickness, were lower among SCD victims aged ≥ 80 years than among victims aged < 80 years. In those with IHD as etiology of SCD, at least 75% stenosis in one or more major coronary vessels was more common in SCD victims aged ≥ 80 years than among victims aged < 80 years (P = .001). SCD victims 80 years or older were less likely to die during physical activity than those under 80 years old (5.6% vs. 15.9%, P < .001). Dying in sauna was more common among those ≥ 80 years than among those < 80 years (5.5% vs. 2.6%, P < .001). In victims of unexpected SCD aged ≥ 80 years, the autopsy-based etiology of SCD was more commonly IHD than in those aged < 80 years. In SCD victims aged ≥ 80 years, severe fibrosis in myocardium, representing arrhythmic substrate, was more common than in the younger ones.

Sudden Cardiac Death Among Adolescents in the United Kingdom

BackgroundCauses and precipitating factors of sudden cardiac death (SCD) in adolescents are poorly understood. ObjectivesThe authors sought to investigate the etiologies of SCD and their association with physical activity in a large cohort of adolescents. MethodsBetween 1994 and June 2022, 7,675 cases of SCD were consecutively referred to our national cardiac pathology center; 756 (10%) were adolescents. All cases underwent detailed autopsy evaluation by expert cardiac pathologists. Clinical information was obtained from referring coroners. ResultsA structurally normal heart, indicative of sudden arrhythmic death syndrome was the most common autopsy finding (n = 474; 63%). Myocardial diseases were detected in 163 cases (22%), including arrhythmogenic cardiomyopathy (n = 36; 5%), hypertrophic cardiomyopathy (n = 31; 4%), idiopathic left ventricular hypertrophy (n = 31; 4%), and myocarditis (n = 30; 4%). Coronary artery anomalies were identified in 17 cases (2%). Decedents were competitive athletes in 128 cases (17%), and 159 decedents (21%) died during exercise. Arrhythmogenic cardiomyopathy was diagnosed in 8% of athletes compared with 4% of nonathletes (P = 0.05); coronary artery anomalies were significantly more common in athletes (9% vs 1%; P < 0.001), as well as commotio cordis (5% compared with 1% in nonathletes; P = 0.001). The 3 main comorbidities were asthma (n = 58; 8%), epilepsy (n = 44; 6%), and obesity (n = 40; 5%). ConclusionsSudden arrhythmic death syndrome and myocardial diseases are the most common conditions diagnosed at autopsy in adolescent victims of SCD. Among causes of SCD, arrhythmogenic cardiomyopathy, coronary artery anomalies, and commotio cordis are more common in young athletes than in similar age sedentary individuals.

Significance of postmortem biomarkers and multimarker strategy in sudden cardiac death

The most common cause in the etiology of sudden cardiac death (SCD) is ischemic heart disease due to atherosclerosis. Postmortem diagnosis can be made by histopathological examinations, but routine histopathological examinations are limited, especially in the early period of postmortem ischemia. For this reason, many methods are being investigated for the postmortem diagnosis of ischemia, and postmortem biochemical studies are promising. In our study, we evaluated the biochemical markers; hs-cTnT, NT-proBNP, H-FABP, pentraxin-3, copeptin, ischemic modified albumin (IMA), and PAPP-A in postmortem serums. In forensic pathology practice, it was investigated whether it would be useful to go to the diagnosis by measuring more than one marker in a single biological fluid in SCD cases. The study included 35 sudden cardiac death cases and 24 control cases and as a result of our study, hs-cTnT, NT-proBNP, and H-FABP values were found to be significantly higher in the SCD group than in the control group. Within the scope of the multi-marker strategy, models were tried to be developed in which the markers were used together, and it was concluded that the model consisting of the myocardial ischemia marker hs-cTnT, the myocardial stress marker NT-proBNP, and the inflammation marker pentraxin 3 was the most accurate combination by correctly classifying the cases at a rate of 94.9%. As a result, it was thought that it would be appropriate to use the multi-marker strategy which is widely used in clinical applications, also in forensic medicine applications.

Clinicopathological correlates of out-of-hospital cardiac arrests.

BackgroundSudden cardiac arrest with or without sudden cardiac death (SCD) represents a heterogeneous spectrum of underlying etiology but is often a catastrophic event. Despite improvements in pre‐hospital response and post‐resuscitation care, outcomes remain grim. Thus, we aim to evaluate the predictors of survival in out‐of‐hospital cardiac arrests (OHCAs) and describe autopsy findings of those with the uncertain cause of death (COD).MethodsThis is a subgroup analysis of the Singapore cohort from the Pan Asian Resuscitation Outcome Study which studied 933 OHCAs admitted to two Singapore tertiary hospitals from April 2010 to May 2012.ResultsOf the patients analysed, 30.2% (n = 282) had an initial return of spontaneous circulation (ROSC) at the emergency department, 18.0% (n = 168) had sustained ROSC with subsequent admission and 3.4% (n = 32) had survival to discharge. On multivariate analysis, an initial shockable rhythm, a witnessed event, prehospital defibrillation, and shorter time to hospital predicted ROSC as well as survival to discharge. A total of 163 (17.5%) autopsies were performed of which a cardiac etiology of SCD was noted in 92.1% (n = 151). Ischemic heart disease accounted for 54.3% (n = 89) of the autopsy cohort, with acute myocardial infarction (26.9%, n = 44) and myocarditis (3.7%, n = 6) rounding out the top three causes of demise.ConclusionOHCA remains a clinical presentation that portends a poor prognosis. Of those with uncertain COD, cardiac etiology appears to predominate from autopsy study. Identification of prognostic factors will play an important role in improving individual‐level and systemic‐level variables to further optimize outcomes.

A novel echocardiographic approach for assessing coronary artery origins.

Anomalous aortic origin of a coronary artery (AAOCA) is a potential etiology of sudden cardiac death (SCD) in physically active individuals. Identification of coronary artery origins is an essential part of comprehensive pre-participation athletic screening. Although echocardiography is an established method for identifying AAOCA, current imaging protocols are time intensive and readers frequently have low confidence in coronary artery identification. Echocardiographic images from a sample of 110 patients from a database of competitive athletes ages 13-22years from the Kansas City metropolitan area were reviewed by six echocardiographers of varying experience. Coronary artery images were provided to the readers in the conventional single plane for all the patients; then biplane images of the same patients were presented to the readers. While reviewing the images, readers recorded perceived confidence level of identifying the coronary artery from 1 (least confident) to 5 (most confident). Ratings and differences between ratings were summarized descriptively by means and standard deviations across all readings as well as by individual reader. The mean confidence level of echocardiogram readers in identifying coronary artery origins increased by 0.4 points (P=.05) on a five-point confidence scale when using biplane imaging rather than single plane imaging. When assessing the variability of confidence of readers on the same patient, the between-reader variability improved from 25.9% to 10.3%. Biplane echocardiographic imaging increases the confidence of readers in identifying coronary artery origins.

Causes of sudden cardiac death in young athletes and nonathletes: systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. The etiology of sudden cardiac death (SCD) in young people is still debated. The aim of this meta-analysis was to identify the most frequent causes of SCD in individuals aged ≤35 years, the differences between athletes and nonathletes and among geographic areas. Methods. Studies published between 01/01/1990 and 01/31/2020 and evaluating post-mortem the etiology of SCD in young individuals (≤35 years) were included. Individuals were divided in athletes and nonathletes. Studies that did not report separately data between athletes and nonathletes were excluded. Results. Thirty-four studies met the inclusion criteria and a total population of 5,060 victims of SCD were analysed (2,890 athletes, 2,170 nonathletes). Structurally normal heart, hypertrophic cardiomyopathy (HCM), idiopathic left ventricular hypertrophy, and anomalous origin of coronary arteries (AOCA) were the most frequent causes of SCD in athletes while coronary artery disease (CAD), arrhythmogenic cardiomyopathy (ACM), and channelopathies were frequent causes of SCD in nonathletes. The number of SCDs due to ischemic heart disease (19.6% vs. 9.1%, p = 0.009), ACM (11.5% vs. 4.7%, p = 0.03) and channelopathies (8.4% vs. 1.9%, p = 0.02) was higher in nonathletes comparing with athletes. SCD due to non-ischemic left ventricular scar (5.1% vs. 1.1%, p = 0.01) was more frequent in athletes. HCM (p = 0.01) and AOCA (p = 0.004) were more frequently cause of SCD in US while ACM (p = 0.001), structurally normal heart (p = 0.02), and channelopathies (p = 0.02) in Europe. Conclusions. Structurally normal heart, HCM, AOCA were frequent causes of SCD in athletes while CAD, ACM and channelopathies in nonathletes. The causes of SCD differ between US and Europe.

Sudden Cardiac Death-A New Insight Into Potentially Fatal Genetic Markers.

Sudden cardiac death (SCD) is an unexpected and dramatic event. It draws special attention especially in young, seemingly healthy athletes. Our scientific paper is based on the death of a young, 23-year-old professional footballer, who died on the football field after a two-year history of cardiac symptoms. In this study we analyzed clinical, ECG and laboratory data, as well as results of genetic testing analysis in family members. To elucidate potential genetic etiology of SCD in this family, our analysis included 294 genes related to various cardiac conditions.

Abstract 15641: Fever. The True Unmasker of My Disease

Introduction: The most common etiology of sudden cardiac death (SCD) from ventricular tachyarrhythmias (VTA) is an acute ischemic event from coronary artery disease (CAD; followed by genetic syndromes, including Brugada Syndrome (BS). The presentation of SCD with an ECG showing RBBB pattern with ST segment elevation (STSE) in leads V1-V3 in healthy patients and in the absence electrolyte imbalances, CAD, or structural heart disease is known as BS. It can be triggered by abundant meals, excessive alcohol intake, cocaine, local anesthetics, tricyclic antidepressants, lithium, propofol and fevers. Case Presentation: 29 y/o woman presenting with atypical chest pain, malaise, and a remote history of a syncopal episode. She denied family history of SCD. She was febrile to 100.4 o F, tachycardic, with regular heart sounds and no murmurs. Laboratory work up was normal. ECG from two years ago showed nonspecific interventricular conduction delay. ECG on admission showed STSE in anterior precordial leads which disappeared with resolution of her fever. Due to the Brugada-like pattern in her ECG and remote history of syncope, AICD placement was recommended. Flecainide challenge was not pursued, since the patient was amenable to AICD. Genetic counseling and testing were provided to her family members. Discussion: Most patients with BS are healthy adults between 30-40 y/o without significant medical history. A defect in the sodium channel SCN5A, results in a loss of homogeneity in the myocardial action potential. This mutant channel may be exaggerated when exposed to supraphysiologic temperatures, unmasking BS and elevating the risk of VTA and SCD. BS is carried through generations in an autosomal dominant fashion. Medical management alone is ineffective and not recommended. AICD is the only effective treatment for prevention of SCD. Conclusion: BS is an identifiable and preventable cause of death. In patients presenting with multiple syncopal episodes or aborted VTA’s, in the absence of significant cardiovascular history, and with known or equivocal family history of SCD, the diagnosis of BS must be considered. Health providers across all practice settings should have the skill of identifying its clinical and ECG presentation in order to decrease the rate of SCD.

The diagnostic value of cardiac magnetic resonance in athletes with suspected structural myocardial diseases

Abstract Introduction Sudden cardiac death (SCD) is the leading cause of death in athletes occurring usually during intensive training. Cardiac magnetic resonance (CMR) is a reliable technique to assess ventricular volumes and function. Furthermore, it provides tissue-specific information and has a crucial role in detecting structural myocardial diseases. Aim We aimed to investigate the prevalence of myocardial structural heart diseases and the etiology of sudden cardiac death in highly trained athletes and their outcome during follow-up. Method We examined athletes (training ≥6 hours/week) who underwent CMR due to suspected structural myocardial disease at Semmelweis University Heart and Vascular Center between 2009 and 2019. Cine movie images and late gadolinium enhanced (LGE) images were performed. Athletes with structural myocardial alterations were followed for the endpoint of all-cause-mortality. Results CMR was performed on a total of 338 athletes (280 male, 24±11 age). The indications for CMR were as follows: aborted sudden cardiac death/sustained ventricular tachycardia (SVT) (4%), ECG alterations (36%), echocardiographic alterations (32%), positive family history of SCD or cardiomyopathies (CMP) (3%), and patients' complaints, e.g. palpitation, syncope, dyspnoea, chest complaints (25%). CMR confirmed structural myocardial disease in 82 athletes with the following distribution: 20 hypertrophic (HCM), 10 arrhythmogenic (AC), 8 dilated (DCM), and 7 non-compact (NCCMP) CMP. The CMR images of three patients indicated Fabry disease. We found post-myocardial infarction scars in 7 cases, and atypical non-ischemic scars in 28 athletes. Besides pathological conditions, we identified minor alterations in 58 patients (51 male, 25±12 age) such as: increased trabeculation, nonspecific LGE in left ventricular insertion point and myocardial crypts. Among athletes examined after aborted sudden cardiac death or SVT we found structural heart disease in 11 males and one female: AC (n=7), HCM (n=1), NCCMP (n=1) and atypical non-ischemic scars (n=3, in two patients the localisation was lateral subepicardial) were diagnosed. During the median follow up of five years one patient died in whom CMR showed lateral scar formation and only mildly reduced left ventricular ejection fraction (50%). Conclusions The most common structural alteration was non-ischaemic scar, the most common CMP was HCM, and the leading cause of sudden cardiac death or SVT in our competitive athletes was AC and lateral subepicardial scar formation. LGE pattern in various cardiomyopathies Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Project no. NVKP_16-1-2016-0017 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme. This project was supported by a grant from the National Research, Development and Innovation Office (NKFIH) of Hungary (K 120277).

Comparison of variant detection rate in genes between two cohorts of Czech living patients versus victims of sudden cardiac death with clinical / post mortem diagnosis of non-ischemic cardiomyopathy

Abstract Introduction Hereditary cardiomyopathy is associated with an increased risk of ventricular arrhythmia and sudden cardiac death (SCD). Genetic stratification substantiates risk assessment and enables the primary prevention of SCD in relatives at risk. We have analyzed the genetic aetiology of SCD in a representative Czech cohort with post mortem diagnosis of various forms of cardiomyopathy and compared it to living cases with these cardiac disorders. Patients and methods Between 2018 and 2019, altogether 47 victims of SCD with post mortem diagnosis of hypertrophic- (HCM; 18/47), arrhythmogenic- (ACM; 19/47) and dilated cardiomyopathy (DCM; 10/47) were identified. Concurrently, genetic testing was performed in 114 living patients (HCM 54/114, ACM 22/114, DCM 38/114). Genetic counselling and cardiologic examination had been carried out in first-degree relatives in all patients/SCD victims. Massively parallel sequencing (MiSeq platform; Illumina.com) was utilized for a custom-made panel comprising 100 candidate genes (Sophia Genetics, Switzerland). The presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results The causative detection rate (according to ACMG.net classes 4 or 5) in SCD victims with DCM was 60% (6/10) and in living patients with DCM 47.4% (18/38). Variants in TTN, RBM20, DES and FLNC (mainly truncating variants) prevailed in both groups. The detection rate in ACM was 5% (1/19 in SCN5A gene) in SCD victims and 31.8% (7/22) in living patients. Interestingly, the most prevalent mutated gene PKP2 in living patients was not detected in SCD victims. The detection rate in SCD victims with post mortem diagnosis of HCM was 16% (3/18) and in living patients 35% (19/54). The most prevalent gene was MYBPC3 in both groups, while PRKAG2 was detected in one SCD victim and in one living case who survived cardiac arrest. Conclusion Post-mortem genetic analysis in DCM yields a high detection rate and allows potentially effective primary prevention of SCD in relatives at risk. In contrast, the molecular autopsy of HCM and ACM renders a much lower yield which is below the mutation detection rate in living phenotype positive individuals. The results help to improve the genetic counselling in affected families in Czech Republic. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic

Association of isolated T inversion and sudden cardiac death – etiology and gender differences

Abstract Background Inferolateral T wave inversion has been associated with increased risk of mortality and sudden cardiac death (SCD) in general population. However, the association between isolated T inversion and SCD is still unclear. Purpose The purpose of this study was to examine whether isolated T inversion associates with SCD, and find out possible gender differences. Methods FinGesture Study has systematically collected clinical data and medico-legal autopsy data from 5,869 consecutive SCD victims (mean age 64.9±12.4 yrs.) in Northern of Finland between years 1998 and 2017. Previously recorded electrocardiograms (ECG) were available and analyzed in 1,101 subjects. The control group consisted of 7,217 subjects representative of Finnish general population (mean age 51.5±12.4 yrs.). T inversion was interpreted isolated if there was at least two T inversions ≥−0.1 mV in at least two contiguous leads, and there were no ECG signs of left ventricular hypertrophy (LVH) defined by Sokolow-Lyon criteria or bunchle brand block (BBB) attached to it. Results In a current study, isolated T inversion was more common finding among SCD victims compared to general population: isolated T inversion in any leads 10.9% vs. 0.9% (SCD vs. general population, p&amp;lt;0.001), laterally 7.7% vs. 0.1% (p&amp;lt;0.001), inferiorly 3.2% vs. 0.5% (p&amp;lt;0.001) and anteriorly 2.9% vs. 0.4% (p&amp;lt;0.001). Particularly, isolated T inversion seemed to assoaciate with ischemic SCD taking into account that 61.5% of the total isolated T inversions were seen in ischemic SCD victims (p=0.018). In addition, 62.1% of the inferior isolated T inversions (p=0.023) and 61.7% of the lateral isolated T inversions (p=0.031) were in ischemic SCD victims versus 37.9% and 38.3% in non-ischemic SCD victims, respectively. The prevalence of isolated T inversion in any lead was also higher among male SCD victims compared to female victims (12.8% vs. 8.2%, p&amp;lt;0.001, respectively). There was no statistically significant difference in the prevalence of LVH and strain changes between the populations. Among bundle branch blocks left BBB was predictably more typical in SCD victims (5.8% vs. 0.5%, p&amp;lt;0.001). Conclusion We noticed an association between isolated T inversion and SCD. The association was most prominent in males and in those with ischemic etiology of SCD. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Finnish Medical Foundation, Finnish Foundation for Cardiovascular Research

Sudden cardiac death in athletes

Exercise is generally a good thing. However, for some it holds hidden danger. The following review discusses the incidence and aetiology of sudden cardiac death (SCD) and measures to reduce the burden of SCD.

P1107First results of molecular autopsy examinations in sudden cardiac death drawn from nationwide multidisciplinary and multicentric collaboration in the Czech Republic

Abstract Funding Acknowledgements Supported by Ministry of Health of the Czech Republic, grant nr. NV18-02-00237. All rights reserved." Introduction "Molecular autopsy" in sudden cardiac death (SCD) is an important diagnostic tool for primary prevention of cardiac arrest in victim´s relatives and requires multicentric and multidisciplinary collaboration. Purpose To establish a national network for SCD diagnostics, to assess the acceptance of genetic testing in at risk relatives and to elucidate the genetic etiology of SCD in a representative Czech cohort aged below 45 years. Patients and Methods Between 2016 and 2019 we ascertained 70 SCD (50 M / 20 F), with positive family history for cardiac arrest in 8/70 cases. Only one family did not agree with molecular autopsy. Genetic counselling and cardiological screening examination was carried out in first degree relatives of SCD survivors accompanied by custom-made targeted panel massively parallel DNA sequencing comprising 100 cardiac conditions-related genes. Presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results According to post-mortem diagnosis most victims died of HCM (17/70), ACM (16/70), no structural heart disease was found in 15/70 cases, DCM/LVNC in 9/70, 6/70 were SIDS cases, other rare diagnoses comprised aortic dissection, or myocarditis. Most of victims died at sleep, only 9/70 victims died during strenuous activities. About 50% of SCD victims did not have cardiac complaints before death. Very likely or certain molecular etiology (i.e. based on presence of ACMG.net Class 4 to 5 variants) was disclosed in 12/70 (17%) in RYR2, FLNC, TTN, KCNH2 and KCNQ1 genes, whilst potentially causative DNA variants (Classes 3-4) were observed in 13/70 (18%) cases. In SIDS we did not find any pathogenic variants. Interestingly, the KCNE1 p.Asp85Asn (LQT 5 lite) variant, was detected in 3/70 cases as a recognized risk factor for ventricular arrhythmias. Conclusion The multidisciplinary cooperation in Czech Republic has been established, family survivors are willing to receive genetic and cardiological care, while centralised molecular genetic analysis enables reliable results which are in accordance with other multicentric studies. The molecular autopsy should, especially in SIDS, be expanded to whole exome sequencing.

Sudden cardiac death in children and young adults without structural heart disease: a comprehensive review

Sudden cardiac death (SCD) is a rare clinical encounter in pediatrics, but its social impact is immense because of its unpredicted and catastrophic nature in previously healthy individuals. Unlike in adults where the primary cause of SCD is related to ischemic heart disease, the etiology is diverse in young SCD victims. Although certain structural heart diseases may be identified during autopsy in some SCD victims, autopsy-negative SCD is more common in pediatrics, which warrants the diagnosis of sudden arrhythmic death syndrome (SADS) based upon the assumption that the usual heart rhythm is abruptly replaced by lethal ventricular arrhythmia. Despite current advances in molecular genetics, the causes of more than half of SADS cases remain unanswered even after postmortem genetic testing. Moreover, the majority of these deaths occur at rest or during sleep even in the young. Recently, sudden unexpected death in epilepsy (SUDEP) has emerged as another etiology of SCD in children and adults, suggesting critical involvement of the central nervous system (CNS) in SCD. Primary cardiac disorders may not be solely responsible for SCD; abnormal CNS function may also contribute to the unexpected lethal event. In this review article, we provide an overview of the complex pathogenesis of SADS and its diverse clinical presentation in the young and postulate that SADS is, in part, induced by unfortunate miscommunication between the heart and CNS via the autonomic nervous system.