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.

Coronary Artery Dissection and Myocardial Infarction With Nonobstructed Coronary Arteries: Insights From a UK Nationwide Autopsy-Based Registry-Brief Report.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) and myocardial infarction with nonobstructed coronary arteries (MINOCA) are increasingly recognized causes of acute coronary syndrome and potentially of sudden cardiac death (SCD). SCAD has been correlated to coronary fibromuscular dysplasia (FMD), but the prevalence of SCAD and FMD among SCD victims is unclear. Therefore, we sought to assess characteristics of decedents with SCAD found at autopsy and to compare their clinical and pathological profile with MINOCA victims. METHODS: We reviewed a database of 5325 consecutive cases of SCDs referred to our cardiac pathology center between 1994 and 2017. RESULTS: We identified 18 (0.3%) cases with SCAD and 37 (0.7%) with MINOCA. No signs of coronary FMD were found among SCAD and MINOCA victims. Compared to MINOCA, SCAD decedents were mostly females (78% versus 38%, P=0.006) and SCD occurred during peripartum more frequently in SCAD rather than MINOCA female victims (28% versus 3%, P=0.012) Infarcted myocardium was identified in all cases of MINOCA but only in 5 (28%) of SCAD decedents (P<0.001). Premortem cardiac symptoms were present in 100% of SCAD and 49% of MINOCA victims (P<0.001); substances use or abuse was reported in none of SCAD versus 43% of MINOCA decedents (P=0.001). CONCLUSIONS: SCAD and MINOCA are rare causes of SCD. At autopsy, coronary FMD is not present among SCAD victims. Compared to MINOCA, SCAD victims are more frequently females, are linked to pregnancy, and always experienced premortem cardiac symptoms. Among MINOCA victims' substance use or abuse is common.

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.

Sudden arrhythmic death and cardiomyopathy are important causes of sudden cardiac death in the UK: results from a national coronial autopsy database.

AIMS: Sudden cardiac death (SCD) is defined as natural unexpected death in witnessed cases occurring < 1 h and in unwitnessed cases as last seen alive < 24 h. SCD due to ischaemic heart disease (IHD) is frequent in older age groups; in younger people genetic cardiac causes, including channelopathies and cardiomyopathies, are more frequent. This study aimed to present the causes of SCD from a large specialist pathology registry. METHODS AND RESULTS: Cases were examined macroscopically and microscopically by two expert cardiac pathologists. The hearts from 7214 SCD cases were examined between 1994 and 2021. Sudden arrhythmic death syndrome (SADS), a morphologically normal heart, which can be underlaid by cardiac channelopathies, is most common (3821, 53%) followed by the cardiomyopathies (1558, 22%), then IHD (670, 9%), valve disease (225, 3%), congenital heart disease (213, 3%) and myocarditis/sarcoidosis (206, 3%). Hypertensive heart disease (185, 3%), aortic disease (129, 2%), vascular disease (97, 1%) and conduction disease (40, 1%) occur in smaller proportions. DISCUSSION: To our knowledge, this is the largest SCD cohort with autopsy findings ever reported from one country. SADS and cardiomyopathies predominate. This study highlights the importance of the autopsy in SCD, which is a significant public health concern in all age groups. Knowing the true incidence in our population will improve risk stratification and develop preventative strategies for family members. There is now a national pilot study integrating molecular autopsy and family screening into the assessment of SCD victims.

Of Mouse and Man: Cross-Species Characterization of Hypertensive Cardiac Remodeling.

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the disease. While the components of hypertensive remodelling are well established, the timeline and comparative quantification of pathological changes in hypertension have not been shown before. Here, we sought to identify the phasing of cardiac remodelling with hypertension using post-mortem tissue from SCD patients with early and advanced hypertensive heart disease (HHD). In order to study and quantify the progression of phenotypic changes, human specimens were contrasted to a well-described angiotensin-II-mediated hypertensive mouse model. While cardiomyocyte hypertrophy is an early adaptive response in the mouse that stabilises in established hypertension and declines as the disease progresses, this finding did not translate to the human setting. In contrast, optimising fibrosis quantification methods and applying them to each setting identified perivascular fibrosis as the prevailing possible cause for overall disease progression. Indeed, assessing myocardial inflammation highlights CD45+ inflammatory cell infiltration that precedes fibrosis and is an early-phase event in response to elevated arterial pressures that may underscore perivascular remodelling. Along with aetiology insight, we highlight cross-species comparison for quantification of cardiac remodelling in human hypertension. As such, this platform could assist with the development of therapies specific to the disease phase rather than targeting global components of hypertension, such as blood pressure lowering.

Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibrofatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. METHODS: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. After comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed antemortem with dilated cardiomyopathy (n=8) or ACM (n=7). Previous symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Postmortem genetic testing was undertaken in 24 of 202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics criteria. RESULTS: Of 202 ACM decedents (35.4±13.2 years; 82% male), no previous cardiac symptoms were reported in 157 (78%). Forty-one decedents (41/202; 20%) had been participants in competitive sport. The adjusted odds of dying during physical exertion were higher in men than in women (odds ratio, 4.58; 95% CI, 1.54-13.68; P=0.006) and in competitive athletes in comparison with nonathletes (odds ratio, 16.62; 95% CI, 5.39-51.24; P<0.001). None of the decedents with an antemortem diagnosis of dilated cardiomyopathy fulfilled definite 2010 Task Force criteria. The macroscopic appearance of the heart was normal in 40 of 202 (20%) cases. There was left ventricular histopathologic involvement in 176 of 202 (87%). Isolated right ventricular disease was seen in 13%, isolated left ventricular disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibrofatty infiltration were the left ventricular posterobasal (68%) and anterolateral walls (58%). Postmortem genetic testing yielded pathogenic variants in ACM-related genes in 6 of 24 (25%) decedents. CONCLUSIONS: SCD attributable to ACM affects men predominantly, most commonly occurring during exertion in athletic individuals in the absence of previous reported cardiac symptoms. Left ventricular involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM before death.

Can we remove scar and fibrosis from adult human myocardium?

The pathological processes leading to heart failure are characterized by the formation of fibrosis and scar, yet the dynamics of scar production and removal are incompletely understood. Spontaneous disappearance of myocardial collagen is reported in infancy but doubted in adulthood where scar volume constitutes a better prognostic indicator than the conventional parameters of ventricular function. Whilst certain drugs are known to attenuate myocardial fibrosis evidence is emerging that stem cell therapy also has the potential to reduce scar size and improve myocardial viability. Both animal studies and clinical trials support the concept that, as in infancy, cellular processes can be triggered to remove collagen and regenerate injured myocardium. The molecular mechanisms likely involve anti-fibrotic cytokines growth factors and matrix-metalloproteinases. Autologous cardiac, bone-marrow and adipose tissue derived stem cells have each shown efficacy. Specific immune privileged mesenchymal stem cells and genetically modified immunomodulatory progenitor cells may in turn provide an allogenic source for the paracrine effects. Thus autologous and allogenic cells both have the potential through paracrine action to reduce scar volume, boost angiogenesis and improve ventricular morphology. The potential benefit of myocardial cell therapy for routine treatment of heart failure is an area that requires further study.

Insights from examination of hearts from adults dying suddenly to the understanding of congenital cardiac malformations.

Congenital heart disease is a rare but important finding in adults who experience sudden death. Examination of the congenitally malformed heart has historically been considered esoteric and best left to those with expertise. The Cardiac Risk in the Young cardiovascular pathology laboratory based at St George's University of London has now received over 6,000 cases. Of these, 21 congenitally malformed hearts were retained for research and educational purposes. Hearts were assessed using sequential segmental analysis, and causes of death were adjudicated based on thorough macroscopic examination and histology. Congenital malformations that were encountered included atrial septal defects, ventricular septal defects, tetralogy of Fallot, and transposition of the great arteries in both its regular and congenitally corrected variants. Findings also included hearts with mirror-imaged and isomeric atrial appendages. Direct causes of death included myocardial fibrosis, pulmonary hypertension, and hemorrhage. A small but notable proportion did not reveal a substrate for arrhythmia, raising the question of whether the terminal event was due to the congenital heart disease itself, or an underlying channelopathy. Here, we demonstrate the value of simple sequential segmental analysis in describing and categorizing the cases, with the concept of the "morphological method" serving to identify the distinguishing features of the cardiac components. Clin. Anat. 33:394-404, 2020. © 2019 Wiley Periodicals, Inc.

Primary Ovarian Malignant PEComa: A Case Report.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm characterized by expression of both melanocytic and smooth muscle markers. PEComas are rarely encountered in the female genital tract. We report a case of malignant primary PEComa of the ovary, and discuss the differential diagnosis. This represents the first case of primary typical malignant PEComa of the ovary.

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.

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.

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.

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.

Obesity Cardiomyopathy in Sudden Cardiac Death: A Distinct Entity? A Comparative Study.

Background: Obesity cardiomyopathy (OCM) can be associated with sudden cardiac death (SCD) but its pathologic features are not well described. Objectives: The objective of this study was to characterize the clinical and pathological features of OCM associated with SCD. Methods: This was a retrospective case control autopsy study. OCM was identified by an increased heart weight (>550 g in males; >450 g in females) in individuals with obesity (body mass index [BMI] ≥30 kg/m2) in the absence of other causes. Cases of OCM with SCD were compared to sex and age matched SCD controls with obesity or with normal weight (BMI 18.5-24.9 kg/m2) and morphologically normal hearts. Autopsy measures included: heart weight, atrial dimensions, ventricular wall thickness, and epicardial adipose tissue. Fibrosis was assessed microscopically. Results: Of 6,457 SCD cases, 53 cases of OCM were identified and matched to 106 controls with obesity and 106 normal weight controls. The OCM mean age at death of individuals with OCM was 42 ± 12 with a male predominance (n = 34, 64%). Males died younger than females (40 ± 13 vs 45 ± 10, P = 0.036). BMI was increased in OCM cases compared to controls with obesity (42 ± 8 vs 35 ± 5). The average heart weight was 598 ± 93 g in OCM. There were increases in right and left ventricular wall thickness (all P < 0.05) in OCM cases compared to controls. Right ventricular epicardial fat was increased in OCM compared to normal weight controls only. Left ventricular fibrosis was identified in 7 (13%) cases. Conclusions: OCM may be a specific pathological entity associated with SCD. It is most commonly seen in young males with increased BMI.

The role of the bicuspid aortic valve in sudden cardiac death-findings at cardiac autopsy.

BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital cardiac defect in the adult population, with a prevalence of 0.5%-2%. It is well recognized that aortic stenosis (AS), aortic regurgitation (AR) and aertopathy may develop by the fifth or sixth decade of life. There is a paucity of autopsy studies evaluating the hearts of subjects with BAV. The aim of this study is to ascertain the role of BAV in cases of sudden cardiac death. METHODS: A database of 6325 whole hearts referred to a specialist cardiac pathology center between 2004 and 2021 was reviewed to identify a subgroup of 91 subjects with a BAV reported. All cases had a negative full body autopsy and toxicology before being referred and subsequently underwent detailed cardiac evaluation including histological analysis by expert cardiac pathologists. RESULTS: The mean age of death was 37 ± 16 years (84% male). Death was attributed to aortic valve or aortic disease in 57% (n = 52) of cases; AS 30% (n = 27), endocarditis 11% (n = 10), aortic dissection (AD) 9% (n = 8) and AR 8% (n = 7). In the remaining 43% of cases, BAV was an incidental finding. CONCLUSION: The majority of deaths in young individuals with BAV were attributed to complications related to the aortic valve or aorta indicating that BAV is not a benign condition. When a BAV is identified, individuals should be appropriately follow-up with imaging to inform the optimal timing of intervention before a complication develops that may predispose the individual to a premature death.

Effect of sex, age and body measurements on heart weight, atrial, ventricular, valvular and sub-epicardial fat measurements of the normal heart.

AIMS: Descriptive morphological studies of the normal heart are lacking. Previous autopsy studies have focused mainly on heart weight. We characterize the normal heart by providing normal dimensions of the atria, ventricles, valves and sub-epicardial fat, comparing the findings in terms of sex, age and body measurements. METHODS: From 3602 referrals to our cardiovascular pathology unit, pathological criteria used for the classification of a morphologically normal heart were a weight of below 500 grams in males, and below 400 grams in females. Diseased hearts were excluded on anatomical and histological evaluation. RESULTS: We diagnosed 1062 morphologically normal hearts. Mean age at death was 34±12, with a male predominance (701, 66%). Age was similar in females and males (35±13 vs 34±12). Females had a significantly lower heart weight (285±55 vs 374±64). Sex was an independent predictor of most measurements. The atrial and ventricular cavities were significantly larger in males. All ventricular measurements of muscle thickness were larger in males. All valvular circumferences were larger in males. In contrast, sub-epicardial fat was significantly thicker in females in 6 of 7 regions. This is the first study to provide a calculator to give expected values according to sex, age, height and weight. CONCLUSIONS: Major differences between the sexes exist in the morphologically normal heart. These variations should be considered when assessing cardiac structure in imaging for risk stratification and diagnosis in the cardiomyopathies, as well as in treatment outcomes.

Sudden Cardiac Death Among Adolescents in the United Kingdom.

BACKGROUND: Causes and precipitating factors of sudden cardiac death (SCD) in adolescents are poorly understood. OBJECTIVES: The authors sought to investigate the etiologies of SCD and their association with physical activity in a large cohort of adolescents. METHODS: Between 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. RESULTS: A 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%). CONCLUSIONS: Sudden 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.

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.

Genetically determined cardiomyopathies at autopsy: the pivotal role of the pathologist in establishing the diagnosis and guiding family screening.

Cardiomyopathies (CMP) comprise a heterogenous group of diseases affecting primarily the myocardium, either genetic and/or acquired in origin. While many classification systems have been proposed in the clinical setting, there is no internationally agreed pathological consensus concerning the diagnostic approach to inherited CMP at autopsy. A document on autopsy diagnosis of CMP is needed because the complexity of the pathologic backgrounds requires proper insight and expertise. In cases presenting with cardiac hypertrophy and/or dilatation/scarring with normal coronary arteries, a suspicion of inherited CMP must be considered, and a histological examination is essential. Establishing the actual cause of the disease may require a number of tissue-based and/or fluid-based investigations, be it histological, ultrastructural, or molecular. A history of illicit drug use must be looked for. Sudden death is frequently the first manifestation of disease in case of CMP, especially in the young. Also, during routine clinical or forensic autopsies, a suspicion of CMP may arise based on clinical data or pathological findings at autopsy. It is thus a challenge to make a diagnosis of a CMP at autopsy. The pathology report should provide the relevant data and a cardiac diagnosis which can help the family in furthering investigations, including genetic testing in case of genetic forms of CMP. With the explosion in molecular testing and the concept of the molecular autopsy, the pathologist should use strict criteria in the diagnosis of CMP, and helpful for clinical geneticists and cardiologists who advise the family as to the possibility of a genetic disease.

Cardiac arrest with successful cardiopulmonary resuscitation and survival induce histologic changes that correlate with survival time and lead to misdiagnosis in sudden arrhythmic death syndrome.

BACKGROUND: Sudden arrhythmic death syndrome (SADS), defined as sudden cardiac death (SCD) with a morphologically normal heart, is an important cause of sudden death. Hypoperfusion due to cardiac arrest followed by successful cardiopulmonary resuscitation (CPR) may induce histologic changes that mimic pathologic conditions. Detailed characterisation of such features and whether they could confound SADS diagnosis are not described. METHODS: Retrospective observational study analysing all consecutive cases of sudden death prospectively referred to a UK national cardiac pathology centre between 2017 and 2021. Cases showing hypoperfusion features were identified after review of clinical information and examination by expert cardiac pathologists. RESULTS: Out of 2,568 SCD cases, 126 (4.9%) were identified with hypoperfusion changes. Macroscopically, the commonest finding was left ventricular focal or diffuse subendocardial haemorrhage (13.5%). Microscopically, haemorrhage and contraction band necrosis (n = 50, 37.7%), subendocardial acute infarction (n = 44, 34.1%), interstitial mixed inflammatory cell infiltrates (n = 31, 24.9%), healing granulation tissue (n = 9, 7.1%) and subendocardial fibrosis (n = 1, 0.7%) were observed. These changes correlated to duration of survival following resuscitation. In a subcohort of 41 cases, autopsy pathologists misinterpreted such changes as ischaemic myocardial infarction (n = 7; 17%), myocarditis (n = 5; 12.1%), or other pathologies (n = 2; 4.8%) in 14 SADS cases. CONCLUSION: We provide a comprehensive characterisation of hypoperfusion-related changes in the heart following successful CPR with survival, which are time related. These features can lead to diagnostic confusion among pathologists but knowledge of history of resuscitation with survival should help with general and expert pathology assessment and improve SADS diagnostic yield, prompting genetic screening of decedents' relatives.