The purpose of this study was to investigate the cause of death in subjects with α-synucleinopathies (ASs) and the confirmed presence of cardiac α-synuclein (α-syn), compared to non-AS disorders in a neuropathologically confirmed cohort. In total, 78 neuropathologically confirmed AS cases positive for cardiac α-syn were included in the study. Individuals with other neurocognitive diseases, having no α-syn in the brainstem or above, nor in cardiac nerves, served as controls (n = 53). Data regarding the cause of death, cardiac α-syn, pathological cardiac findings, and cardio- and cerebrovascular disease were assembled from autopsy reports and medical records. In the AS group, there was a significantly higher prevalence of sudden cardiac death ([SCD]; n = 40, 51.3%) compared to the control group (n = 12, 22.6%, p < 0.001). No statistically significant differences between the groups were reported regarding other cardiac conditions on autopsy or regarding cardio- and cerebrovascular disease from the medical records. The most prevalent cause of death in the AS group was SCD, which differed significantly from the control group. This suggests that α-syn deposits in cardiac nerves may cause lethal alterations in cardiac function, warranting further research.

Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.

Cardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need. Because right ventricular (RV) dysfunction increases the risk for sudden cardiac death, we examined responses to RV stress in mice. Among immune cells accumulated in the RV after pressure overload-induced by pulmonary artery banding, interfering with macrophages caused sudden death from severe arrhythmias. We show that cardiac macrophages crucially maintain cardiac impulse conduction by facilitating myocardial intercellular communication through gap junctions. Amphiregulin (AREG) produced by cardiac macrophages is a key mediator that controls connexin 43 phosphorylation and translocation in cardiomyocytes. Deletion of Areg from macrophages led to disorganization of gap junctions and, in turn, lethal arrhythmias during acute stresses, including RV pressure overload and β-adrenergic receptor stimulation. These results suggest that AREG from cardiac resident macrophages is a critical regulator of cardiac impulse conduction and may be a useful therapeutic target for the prevention of sudden death.

Cardiac hypertrophy, which develops in middle-aged and older individuals as a consequence of hypertension and obesity, is an established risk factor for sudden cardiac death (SCD). However, it is sometimes difficult to differentiate SCD with acquired cardiac hypertrophy (SCH) from compensated cardiac hypertrophy (CCH), at autopsy. We aimed to elucidate the proteomic alteration in SCH, which can be a guideline for future postmortem diagnosis.

The benefits of exercise for cardiovascular and general health are many. However, sudden cardiac death (SCD) may occur in apparently healthy athletes who perform at the highest levels. A diverse spectrum of diseases is implicated in SCD in athletes, and while atherosclerotic coronary artery disease predominates in individuals of >35 years of age, primary cardiomyopathies and ion channelopathies are prevalent in young individuals. Prevention of SCD in athletes relies on the implementation of health policies aimed at the early identification of arrhythmogenic diseases (such as cardiac screening) and successful resuscitation (such as widespread utilization of automatic external defibrillators and training members of the public on cardiopulmonary resuscitation). This review will focus on the epidemiology and aetiologies of SCD in athletes, and examine fallacies in the approach to this controversial field. Furthermore, potential strategies to prevent these tragic events will be discussed, analysing current practice, gaps in knowledge and future directions.

Cathepsins are the major lysosomal proteases that maintain intracellular homeostasis. Herein, we investigated the alterations in myocardial cathepsin expression during aging, cardiac hypertrophy, and sudden cardiac death (SCD). Cardiac tissue and blood were sampled from autopsy cases. Subjects were classified into three groups: SCD with cardiac hypertrophy (SCH), compensated cardiac hypertrophy (CCH), and control. Immunoblotting was performed for the major cardiac cathepsins and their targets: cathepsin B, D, and L (CTSB/D/L), p62, ATP synthase subunit c (ATPSC), and α-synuclein (ASNC). Immunohistochemical analysis and ELISA using serum samples were performed for CTSD. Cardiac CTSB and CTSD were upregulated with age (r = 0.63 and 0.60, respectively), whereas the levels of CTSL, p62, ATPSC, and ASNC remained unchanged. In age-matched groups, cardiac CTSD was significantly downregulated in SCH (p = 0.006) and CTSL was moderately downregulated in CCH (p = 0.021); however, p62, ATPSC, and ASNC were not upregulated in cardiac hypertrophy. Immunohistochemistry also revealed decreased myocardial CTSD levels in SCH, and serum CTSD levels were relatively lower in SCH cases. Overall, these results suggest that upregulation of cardiac CTSB and CTSD with age may compensate for the elevated proteolytic demand, and that downregulation of CTSD is potentially linked to SCH.

Background The relationship between mitral valve prolapse ( MVP ) and sudden cardiac death ( SCD ) remains controversial. In this systematic review, we evaluate the relationship between isolated MVP and SCD to better define a potential high-risk subtype. In addition, we determine whether premortem parameters could predict SCD in patients with MVP and the incidence of SCD in MVP . Methods and Results Electronic searches were conducted in PubMed and Embase for all English literature articles published between 1960 and 2018 regarding MVP and SCD or cardiac arrest. We also identified articles investigating predictors of ventricular arrhythmias or SCD and cohort studies reporting SCD outcomes in MVP . From 2180 citations, there were 79 articles describing 161 cases of MVP with SCD or cardiac arrest. The median age was 30 years and 69% of cases were female. Cardiac arrest occurred during situations of stress in 47% and was caused by ventricular fibrillation in 81%. Premature ventricular complexes on Holter monitoring (92%) were common. Most cases had bileaflet involvement (70%) with redundancy (99%) and nonsevere mitral regurgitation (83%). From 22 articles describing predictors for ventricular arrhythmias or SCD in MVP , leaflet redundancy was the only independent predictor of SCD . The incidence of SCD with MVP was estimated at 217 events per 100 000 person-years. Conclusions Isolated MVP and SCD predominantly affects young females with redundant bileaflet prolapse, with cardiac arrest usually occurring as a result of ventricular arrhythmias. To better understand the complex relationship between MVP and SCD , standardized reporting of clinical, electrophysiological, and cardiac imaging parameters with longitudinal follow-up is required.

Background and Objectives: Sudden cardiac death (SCD), particular among elite footballers, has attracted much attention in recent times. However, limited information exists on football-related SCD in Turkey. Autopsy-based studies of sports-related sudden deaths in Turkey are rare and often have small sample sizes. To address this, this study aimed to determine the population-based incidence and profile of football-related SCD nationally in Turkey. Materials and Methods: Due to a lack of national data on this issue, football-related SCD (non-elite competitive or recreational football) between 1 January 2011, and 31 December 2019 were identified by dual, independent identification and screening of online media reports. Deaths were explored by sex, age group, season, and phase of exercise. Descriptive statistics were utilised. Age-specific mortality rates and proportional mortality rates were calculated. Results: In total, 118 football-related SCD were identified, a crude mortality rate of 0.41 per 100,000 population. All fatalities were males and the mean age was 35.5 years ± 10.4. Those aged 40-49 years recorded the highest mortality rate (0.67/100,000), three times the risk of those aged 50-59 years (RR = 3.1; 95%CI:1.5-6.4). Those aged 30-39 recorded the highest age-specific proportional mortality rate (0.86/1000 deaths). The highest risk occurred while playing football (n = 97; 82.2%), with another 15% of deaths (n = 18) occurring within 1 h of play. Almost all fatalities (n = 113; 95.8%) occurred during participation in recreational football. Conclusions: This study has identified football-related SCD most commonly occurs during recreational football among males aged 30-49 years. It is recommended males of this age participating in recreational football be encouraged to seek pre-participation heart health checks. Given the value of automated external defibrillators (AEDs) in responding to out-of-hospital cardiac arrest, future research should explore the feasibility and effectiveness of AEDs in preventing football-related SCD in Turkey including training of first responders in cardiopulmonary resuscitation and AED use.

Molecular autopsy is the process of investigating sudden death through genetic analysis. It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. The final goal of molecular autopsy in SUD cases is to aid medico-legal inquiries and to guide cascade genetic screening of the victim's relatives. Early attempts of molecular autopsy relied on Sanger sequencing, which, despite being accurate and easy to use, has a low throughput and can only be employed to analyse a small panel of genes. Conversely, the recent adoption of next-generation sequencing (NGS) technologies has allowed exome/genome wide examination, providing an increase in detection of pathogenic variants and the discovery of newer genotype-phenotype associations. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the clinical interpretation of the large number of variants of unknown significance detected in each individual.

We aimed to identify and assess cardiac abnormalities by cardiovascular magnetic resonance (CMR) in a non-ischaemic aborted sudden cardiac death (SCD) population and to establish possible predictors of SCD.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death.

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.

The epidemiology of sudden cardiac death (SCD) after heart transplantation (HTx) remains imprecisely described. We aimed to assess the incidence and determinants of SCD in a large cohort of HTx recipients, compared with the general population.

Cardiovascular pathology in patients with superinvasive opisthorchiasis is characterized by severe changes in haemodynamics and myocardial metabolism, impaired automatism, excitability, and conduction of the heart muscle. An analysis of 578 cases (medical and outpatient records and reports of pathoanatomical and forensic autopsies) recorded in healthcare facilities treating opisthorchiasis patients with a hyperendemic focus was carried out. We identified a set of cardiac changes in patients with hypereosinophilic syndrome associated with superinvasive opisthorchiasis infection, classified the pathological processes in accordance with ICD-10, and described their pathogenesis.

Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP.

Background and objectives: Anabolic-androgenic steroids (AASs) are a group of synthetic molecules derived from testosterone and its related precursors. AASs are widely used illicitly by adolescents and athletes, especially by bodybuilders, both for aesthetic uses and as performance enhancers to increase muscle growth and lean body mass. When used illicitly they can damage health and cause disorders affecting several functions. Sudden cardiac death (SCD) is the most common medical cause of death in athletes. SCD in athletes has also been associated with the use of performance-enhancing drugs. This review aimed to focus on deaths related to AAS abuse to investigate the cardiac pathophysiological mechanism that underlies this type of death, which still needs to be fully investigated. Materials and Methods: This review was conducted using PubMed Central and Google Scholar databases, until 21 July 2020, using the following key terms: "((Sudden cardiac death) OR (Sudden death)) AND ((androgenic anabolic steroid) OR (androgenic anabolic steroids) OR (anabolic-androgenic steroids) OR (anabolic-androgenic steroid))". Thirteen articles met the inclusion and exclusion criteria, for a total of 33 reported cases. Results: Of the 33 cases, 31 (93.9%) were males while only 2 (61%) were females. Mean age was 29.79 and, among sportsmen, the most represented sports activity was bodybuilding. In all cases there was a history of AAS abuse or a physical phenotype suggesting AAS use; the total usage period was unspecified in most cases. In 24 cases the results of the toxicological analysis were reported. The most detected AASs were nandrolone, testosterone, and stanozolol. The most frequently reported macroscopic alterations were cardiomegaly and left ventricular hypertrophy, while the histological alterations were foci of fibrosis and necrosis of the myocardial tissue. Conclusions: Four principal mechanisms responsible for SCD have been proposed in AAS abusers: the atherogenic model, the thrombosis model, the model of vasospasm induced by the release of nitric oxide, and the direct myocardial injury model. Hypertrophy, fibrosis, and necrosis represent a substrate for arrhythmias, especially when combined with exercise. Indeed, AAS use has been shown to change physiological cardiac remodeling of athletes to pathophysiological cardiac hypertrophy with an increased risk of life-threatening arrhythmias.

Cardiac hypertrophy is a well-known risk factor for heart failure and sudden cardiac death (SCD). On the other hand, physiological cardiac hypertrophy is often observed in young healthy men, and it is difficult to predict SCD in cardiac hypertrophy subjects who do not show symptoms of heart failure. MicroRNAs (miRNAs) widely regulate biological activity and play pivotal roles in heart failure progression. In this study, we investigated whether miRNA expression is altered in SCD with cardiac hypertrophy (SCH).

Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na+ and K+ ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.

Cardiomyopathy and cardiac conduction defects are common manifestations of mitochondrial disease. Previous studies suggest that clinically asymptomatic individuals harbouring pathogenic mitochondrial DNA (mtDNA) mutations in the cardiac muscle may have sudden cardiac death (SCD) as the first manifestation of mitochondrial disease. We investigated the contribution of pathogenic mtDNA point mutations and mtDNA haplogroups in cardiac muscle in a cohort of 280 Finnish subjects that had died from non-ischaemic SCD with the median age of death at 59 years and in 537 population controls. We did not find any common or novel pathogenic mutations, but the frequency of haplogroup H1 was higher in the SCD subjects than that in 537 population controls (odds ratio: 1.76, confidence interval 95%: 1.02-3.04). We conclude that, at the population level, pathogenic point mutations in mtDNA do not contribute to non-ischaemic SCD, but natural variation may modify the risk.

To summarise studies describing incidence of sudden cardiac death in a general population of young individuals to inform screening policy.