Autopsy of all young sudden death cases is important to increase survival in family members left behind.

Sudden cardiac death (SCD) is an important public health problem worldwide, accounting for an estimated 6 to 20% of total mortality. A significant proportion of SCD is caused by inherited heart disease, especially among the young. An autopsy is crucial to establish a diagnosis of inherited heart disease, allowing for subsequent identification of family members who require cardiac evaluation. Autopsy of cases of unexplained sudden death in the young is recommended by both the European Society of Cardiology and the American Heart Association. Overall autopsy rates, however, have been declining in many countries across the globe and there is a lack of skilled trained pathologists able to carry out full autopsies. Recent studies show that not all cases of sudden death in the young are autopsied, likely due to financial, administrative, and organizational limitations as well as awareness among police, legal authorities, and physicians. Consequently, diagnoses of inherited heart disease are likely missed, along with the opportunity for treatment and prevention among surviving relatives. This article reviews the evidence for the role of autopsy in sudden death, how the cardiologist should interpret the autopsy-record and how this can be integrated and implemented in clinical practice. Finally, we identify areas for future research along with potential for healthcare reform aimed at increasing autopsy awareness and ultimately reducing mortality from SCD.

Sudden Cardiac Death, Post-Mortem Investigation: A Proposing Panel of First Line and Second Line Genetic Tests.

Investigating the causes of Sudden cardiac death (SCD) is always difficult; in fact, genetic cardiac conditions associated with SCD could be "silent" even during autopsy investigation. In these cases, it is important to exclude other aetiology and assist to ask for genetic investigations. Herein, the purpose of this review is to collect the most-implicated genes in SCD and generate a panel with indications for first line and second line investigations. A systematic review of genetic disorders that may cause SCD in the general population was carried out according to the Preferred Reporting Item for Systematic Review (PRISMA) standards. We subsequently listed the genes that may be tested in the case of sudden cardiac death when the autopsy results are negative or with no evidence of acquired cardiac conditions. To make genetic tests more specific and efficient, it is useful and demanded to corroborate autopsy findings with the molecular investigation as evident in the panel proposed. The genes for first line investigations are HCM, MYBPC3, MYH7, TNNT2, TNNI3, while in case of DCM, the most implicated genes are LMNA and TTN, and in second line for these CDM, ACTN2, TPM1, C1QPB could be investigated. In cases of ACM/ARVC, the molecular investigation includes DSP, DSG2, DSC2, RYR2, PKP2. The channelopathies are associated with the following genes: SCN5A, KCNQ1, KCNH2, KCNE1, RYR2. Our work underlines the importance of genetic tests in forensic medicine and clinical pathology; moreover, it could be helpful not only to assist the pathologists to reach a diagnosis, but also to prevent other cases of SCD in the family of the descendant and to standardise the type of analysis performed in similar cases worldwide.

Ethnicity and Sudden Cardiac Death in Athletes: Insights from a Large United Kingdom Registry.

BACKGROUND AND AIMS: The relationship between ethnicity and causes of sudden cardiac death (SCD) in athletes is poorly understood. OBJECTIVES: To investigate etiology of SCD among different ethnicities in a large cohort of athletes. METHODS: 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. RESULTS: Most of athletes were white (n = 758; 89%). Black and Asian athletes were 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%) cases, 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 2% n = 1; 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. CONCLUSIONS: 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.

A sudden death in an athlete is an uncommon but highly tragic event which appears almost paradoxical, as athletes epitomize the healthiest segment of society. Inherited and familiar cardiac conditions are the main causes of sudden death in young individuals and athletes. Studies on this matter have mainly focused on Caucasian athletes and the frequency or the causes of sudden death in athletes of other ethnicities is largely unknown. Our study focusses on this aspect and reveals that causes of sudden death may highly vary among athletes of different race. The circumstances of death differ significantly among various ethnicities, even looking at the same underlying cardiac condition.

Angiotensinogen as a Therapeutic Target for Cardiovascular and Metabolic Diseases.

AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.

Incidence of quadricuspid pulmonary valves at postmortem examination.

Quadricuspid pulmonic valve is a rare congenital abnormality and because of its difficult non-invasive assessment, it is usually discovered incidentally at autopsies (reported prevalence in post-mortem specimens ranges from 1 in 400 to 1 in 2000). Unlike a bicuspid pulmonary valve, it rarely presents with clinical complications, such as valvular insufficiency or stenosis. Abnormal function is rarely reported in cases that are not associated with other congenital heart disease. With increased sophistication of imaging coincidental quadricuspid valves autopsy studies are important to understand the anatomical consequences of this finding. Our case series identified 21 QPV cases from the Victorian Institute of Forensic Medicine, Melbourne and St George's University of London, Department of Cardiovascular Pathology. Cases were identified through local database searches and review of autopsy/cardiac examination reports over a 20-year period. Available photographs were also systematically examined. Fifteen cases had causes of death with no direct causality to cardiac valvular pathology alone. Six cases were considered unascertained or similar (sudden arrhythmic death syndrome and sudden unexpected death in epilepsy). The presence of QPV in these instances were uncertain but thought to be unlikely contributory to death, due to the absence of pulmonary valvular complications.

Assessment of gait mechanics and muscle strength in hypermobile Ehlers Danlos Syndrome.

BACKGROUND: Hypermobile Ehlers Danlos Syndrome, a heritable connective tissue disorder, is associated with muscle dysfunction, joint subluxations and pain. The impact of hypermobile Ehlers Danlos Syndrome on musculoskeletal mechanics is understudied. Therefore, the aim of this study was to assess the effects of hypermobile Ehlers Danlos Syndrome on lower extremity gait mechanics and muscle strength. METHODS: Eleven people with hypermobile Ehlers Danlos Syndrome and 11 asymptomatic controls underwent a 3D gait analysis and isometric hip and knee muscle strength assessment. Joint subluxations were self-reported by the hypermobile Ehlers Danlos syndrome group. Independent t-tests and Mann Whitney U tests were used to analyze joint mechanics, muscle strength, and patient report outcomes (p < 0.05). FINDINGS: Both groups exhibited similar walking speeds as well as similar hip, knee, and ankle joint kinematics. The hypermobile Ehlers Danlos Syndrome group walked with a lower peak hip extensor moment (hypermobile Ehlers Danlos Syndrome: -0.52 ± 0.28 Nmˑkg-1, Control: -0.83 ± 0.26 Nmˑkg-1, p = 0.01) yet similar knee and ankle joint moments. The hypermobile Ehlers Danlos Syndrome group exhibited a 40% deficit in peak hip extensor strength (hypermobile Ehlers Danlos Syndrome:1.07 ± 0.53 Nmˑkg-1, Control: 1.77 ± 0.79 Nmˑkg-1, p = 0.04). Approximately 73%, 55% and 45% of the hypermobile Ehlers Danlos Syndrome cohort self-reported hip, knee/patella and ankle joint subluxations, respectively, at least once a week. INTERPRETATION: Patients with hypermobile Ehlers Danlos Syndrome ambulated with altered hip extensor moments and exhibit hip extensor weakness. Future work should investigate the underlying mechanisms of hip extensor weakness and corresponding effects on joint health in people with hypermobile Ehlers Danlos Syndrome.

Seasonal Variation in Sudden Cardiac Death: Insights from a Large United Kingdom Registry.

BACKGROUND: Sudden cardiac death (SCD) is relatively common and may occur in apparently healthy individuals. The role of seasonal variation as a risk factor for SCD is poorly understood. The aim of this study was to investigate whether SCD exhibits a predilection for specific seasons. METHODS: We reviewed a database of 4751 cases of SCD (mean age 38 ± 17 years) referred to our Center for Cardiac Pathology at St George's University of London between 2000 and 2018. Clinical information was obtained from referring coroners who were asked to complete a detailed questionnaire. All cases underwent macroscopic and histological evaluation of the heart, by expert cardiac pathologists. RESULTS: SCD was more common during winter (26%) and rarer during summer (24%), p = 0.161. Significant seasonal variation was not observed among cases of sudden arrhythmic death syndrome (SADS, 2910 cases) in which the heart is structurally normal. In contrast, a significant difference in seasonal distribution among decedents exhibiting cardiac structural abnormalities at the post-mortem examination (n = 1841) was observed. In this subgroup, SCDs occurred more frequently during winter (27 %) compared to summer (22%) (p = 0.007). In cases diagnosed with a myocardial disease (n = 1399), SCD was most common during the winter (27%) and least common during the summer (22%) (p = 0.027). CONCLUSIONS: While SADS occurs throughout the year with no seasonal variation, SCD due to structural heart disease appears to be more common during the winter. Bio-meteorological factors may be potential triggers of SCD in individuals with an underlying structural cardiac abnormality.

Sudden Cardiac Death in Young Athletes: JACC State-of-the-Art Review.

Athletes epitomize the healthiest segment of society. Despite this premise, sudden cardiac death may occur in apparently healthy athletes, attracting significant attention not only in the medical community but also in laypersons and media. The incidence of sudden cardiac death is variably reported, and epidemiological burden differs among cohorts. Athletes appear to be at risk of developing fatal arrhythmias when harboring a quiescent cardiac disorder. Primary cardiomyopathies, ion channelopathies, and coronary artery anomalies are prevalent causes in young individuals. Cardiac assessment of athletes can be challenging because these individuals exhibit a plethora of electrical, structural, and functional physiological changes that overlap with cardiac pathology. A diagnosis of cardiac disease in a young athlete is not necessarily an indication to terminate competition and sports participation. International guidelines, traditionally focused on disqualification of individuals with cardiac disease, have recently adopted a more liberal attitude, based on a careful assessment of the risk and on a shared-decision making approach.

Insights into malignant mitral valve degenerative disease from a sudden cardiac death cohort highlighting significant measurement differences from normal.

AIMS: Mitral valve prolapse (MVP) is an accepted cause of sudden cardiac death (SCD) in most autopsy series. Diagnosis at autopsy relies upon subjective assessment with no established objective pathological criteria. This study set out to establish objective measurements to help pathologists dealing with SCD. METHODS: We diagnosed 120 (1.5%) cases of MVP in 8108 cases of SCD. We measured the mitral annulus, anterior and posterior leaflets, rough zone and mitral annular disjunction (MAD) in 27 MVP cases and compared them to 54 age- and sex-matched normal mitral valves. RESULTS: Age of death was 39 ± 16 years, with 59 females and 61 males. History of mild MV disease was present in 19 (16%). Eleven (9%) died associated with exertion. Left ventricular hypertrophy was present in nine (15%) females and 10 (16%) males. Both MV leaflets showed thickening and ballooning in all individuals. MVP showed highly significantly increased annular circumference, elongation and thickening of both leaflets as well as increased MAD (all P < 0.001). Left ventricular fibrosis was present in 108 (90%), with interstitial fibrosis in the posterolateral wall and papillary muscle in 88 (81%) and coexisting replacement fibrosis in 40 (37%). CONCLUSION: This is the largest MVP associated with SCD series highlighting a young cohort with equal representation of males and females. There is involvement of both leaflets with significant annular dilatation, elongation and thickening of both leaflets with MAD. Left ventricular fibrosis explains arrhythmia. Our quantitative measurements should serve as a reference for pathologists assessing post-mortem hearts for MVP.

Yield of molecular autopsy in sudden cardiac death in athletes: data from a large registry in the UK.

AIMS: Sudden cardiac death (SCD) may occur in apparently healthy individuals, including athletes. The aim was to investigate the diagnostic role of post-mortem genetic testing, molecular autopsy (MA), in elucidating the cause of SCD in athletes. METHODS AND RESULTS: We reviewed a database of 6860 consecutive cases of SCD referred to our specialist cardiac pathology centre. All cases underwent detailed cardiac autopsy, and 748 were deemed to be athletes. Of these, 42 (6%) were investigated with MA (28 using a targeted sequencing, 14 exome sequencing). Variants were classified as pathogenic, likely pathogenic, or variant of unknown significance using international guidelines. Clinical information was obtained from referring coroners who completed a detailed health questionnaire. Out of the 42 decedents (average age 35 years old, 98% males) who were investigated with MA, the autopsy was in keeping with a structurally normal heart [sudden arrhythmic death syndrome (SADS)] in n = 33 (78%) cases, followed by arrhythmogenic cardiomyopathy (ACM) in eight (19%) individuals and idiopathic left ventricular fibrosis in one (2%). Death occurred during exercise and at rest in 26 (62%) and 16 (38%) individuals, respectively. Variants that were adjudicated clinically actionable were present in seven cases (17%). There was concordance between the genetic and phenotypic findings in two cases of ACM (in FLNC and TMEM43 genes). None of the variants identified in SADS cases were previously linked to channelopathies. Clinically actionable variants in cardiomyopathy-associated genes were found in five cases of SADS. CONCLUSION: The yield of MA in athletes who died suddenly is 17%. In SADS cases, clinically actionable variants were found in cardiomyopathy-associated genes and not in channelopathy-associated genes. Arrhythmogenic cardiomyopathy is a common cause of SCD in athletes, and one in four decedents with this condition had a clinically actionable variant in FLNC and TMEM43 genes.

Detailed study of collagen, vasculature, and innervation in the human cardiac conduction system.

BACKGROUND: The cardiac conduction system (CCS) creates and propagates electrical signals generating the heartbeat. This study aimed to assess the collagen content, vasculature, and innervation in the human sinoatrial and atrioventricular CCS, and surrounding tissue. MATERIALS AND METHODS: Ten sinoatrial and 17 atrioventricular CCS samples were collected from 17 adult human autopsied hearts. Masson trichrome stain was used to examine collagen, cardiomyocytes, and fat proportions. Immunohistochemically, vessels and lymphatics were studied by CD31 (pan-endothelial marker) and D2-40 (lymphatic endothelium marker) antibodies. General nerve densities were assessed by S100, while sympathetic nerves were studied using tyrosine hydroxylase, parasympathetic nerves with choline acetyltransferase, and GAP43 (neural growth marker) antibodies looked at these components. All components were quantified with QuPath software (Queens University, Belfast, Northern Ireland). RESULTS: Interstitial collagen was more than two times higher in the sinoatrial vs. atrioventricular CCS (55% vs. 22%). The fat content was 6.3% in the sinoatrial CCS and 6.5% in the atrioventricular CCS. The lymphatic vessel density was increased in the sinoatrial and atrioventricular CCS compared to the surrounding tissue and was lower in the sinoatrial vs. atrioventricular CCS (P=.043). The overall vasculature density did not differ between the SA and AV CCS. The overall innervation and neural growth densities were significantly increased in the CCS compared to the surrounding tissue. The overall innervation was higher in the atrial vs. ventricular CCS (P=.018). The neural growth was higher in the atrial vs. ventricular CCS (P=.018). The sympathetic neural supply was dominant in all the studied regions with the highest density in the sinoatrial CCS. CONCLUSIONS: Our results provide new insights into the unique morphology of the human CCS collagen, fat, vasculature, and innervation. A deeper understanding of the CCS anatomical components and morphologic substrates' role will help in elucidating the causes of cardiac arrhythmias and provide a basis for further therapeutic interventions.

Innate immune signaling in hearts and buccal mucosa cells of patients with arrhythmogenic cardiomyopathy.

Background: Nuclear factor κB (NF-κB) signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy (ACM) by mobilizing CCR2-expressing macrophages that promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with ACM. Objectives: We sought to determine if persistent innate immune signaling via NF-κB occurs in cardiac myocytes in patients with ACM and if this is associated with myocardial infiltration of proinflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NF-κB signaling. Methods: We analyzed myocardium from ACM patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NF-κB signaling. We also counted myocardial CCR2-expressing cells. Results: RelA/p65 signal was seen in numerous cardiac myocyte nuclei in 34 of 36 cases of ACM but not in 19 age-matched control individuals. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NF-κB signaling. NF-κB signaling was observed in buccal cells in young subjects with active disease. Conclusions: Patients with clinically active ACM exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells, reflecting a local and systemic inflammatory process. Such individuals may benefit from anti-inflammatory therapy.

An mTORC1-Dependent Mouse Model for Cardiac Sarcoidosis.

Background Sarcoidosis is an inflammatory, granulomatous disease of unknown cause affecting multiple organs, including the heart. Untreated, unresolved granulomatous inflammation can lead to cardiac fibrosis, arrhythmias, and eventually heart failure. Here we characterize the cardiac phenotype of mice with chronic activation of mammalian target of rapamycin (mTOR) complex 1 signaling in myeloid cells known to cause spontaneous pulmonary sarcoid-like granulomas. Methods and Results The cardiac phenotype of mice with conditional deletion of the tuberous sclerosis 2 (TSC2) gene in CD11c+ cells (TSC2fl/flCD11c-Cre; termed TSC2KO) and controls (TSC2fl/fl) was determined by histological and immunological stains. Transthoracic echocardiography and invasive hemodynamic measurements were performed to assess myocardial function. TSC2KO animals were treated with either everolimus, an mTOR inhibitor, or Bay11-7082, a nuclear factor-kB inhibitor. Activation of mTOR signaling was evaluated on myocardial samples from sudden cardiac death victims with a postmortem diagnosis of cardiac sarcoidosis. Chronic activation of mTORC1 signaling in CD11c+ cells was sufficient to initiate progressive accumulation of granulomatous infiltrates in the heart, which was associated with increased fibrosis, impaired cardiac function, decreased plakoglobin expression, and abnormal connexin 43 distribution, a substrate for life-threatening arrhythmias. Mice treated with the mTOR inhibitor everolimus resolved granulomatous infiltrates, prevented fibrosis, and improved cardiac dysfunction. In line, activation of mTOR signaling in CD68+ macrophages was detected in the hearts of sudden cardiac death victims who suffered from cardiac sarcoidosis. Conclusions To our best knowledge this is the first animal model of cardiac sarcoidosis that recapitulates major pathological hallmarks of human disease. mTOR inhibition may be a therapeutic option for patients with cardiac sarcoidosis.

Innate Immune Signaling in Hearts and Buccal Mucosa Cells of Patients with Arrhythmogenic Cardiomyopathy.

Objectives: We sought to determine if persistent innate immune signaling via NFκB occurs in cardiac myocytes in patients with arrhythmogenic cardiomyopathy and if this is associated with myocardial infiltration of pro-inflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NFκB signaling. Background: NFκB signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing CCR2-expressing macrophages which promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with arrhythmogenic cardiomyopathy. Methods: We analyzed myocardium from arrhythmogenic cardiomyopathy patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NFκB signaling. We also counted myocardial CCR2-expressing cells. Results: NFκB signaling was seen in cardiac myocytes in 34 of 36 cases of arrhythmogenic cardiomyopathy but in none of 19 age-matched controls. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NFκB signaling. NFκB signaling also occurred in buccal cells in young subjects with active disease. Conclusions: Patients with clinically active arrhythmogenic cardiomyopathy exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells reflecting an inflammatory process that fails to resolve. Such individuals may benefit from anti-inflammatory therapy. CONDENSED ABSTRACT: NFκB signaling in cardiac myocytes causes arrhythmias and myocardial injury in a mouse model of arrhythmogenic cardiomyopathy by mobilizing pro-inflammatory CCR2-expressing macrophages to the heart. Based on these new mechanistic insights, we analyzed hearts of arrhythmogenic cardiomyopathy patients who died suddenly or required cardiac transplantation. We observed active NFκB signaling in cardiac myocytes associated with marked infiltration of CCR2-expressing cells. We also observed NFκB signaling in buccal mucosa cells obtained from young subjects with active disease. Thus, anti-inflammatory therapy may be effective in arrhythmogenic cardiomyopathy. Screening buccal cells may be a reliable way to identify patients most likely to benefit. HIGHLIGHTS: Inflammation likely contributes to the pathogenesis of arrhythmogenic cardiomyopathy but the responsible mechanisms and the roles of specific classes of immune cells remain undefined.NFκB signaling in cardiac myocytes is sufficient to cause disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing injurious myeloid cells expressing CCR2 to the heart.Here, we provide evidence of persistent NFκB signaling in cardiac myocytes and increased CCR2-expressing cells in hearts of patients with arrhythmogenic cardiomyopathy. We observed a close correlation between the number of cardiac myocytes with active NFκB signaling and the number of CCR2-expressing cells in patient hearts.We also provide evidence of active NFκB signaling in buccal mucosa cells associated with initial onset of disease and/or disease progression in young subjects with arrhythmogenic cardiomyopathy alleles.