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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 P 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.

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.

Hypertrophic cardiomyopathy is a genetically determined heart muscle disease, and patients are at an increased risk for sudden cardiac death. We report the case of a 39-year-old White man who was found dead at home unexpectedly. He had a cardiac transplant for congenital heart disease at the age of 12 and his condition was maintained with immunosuppression ever since with good cardiac function and right bundle branch block. At autopsy, the heart was enlarged with a weight of 591 g and had fibrous adhesions of the pericardium with endothelialized sutures in the atria and great vessels in keeping with heart transplant. There was focal septal hypertrophy noted on short axis cut. There was diffuse thickening of the coronary arteries, but no significant stenosis was noted. On microscopic examination of the heart, sections of right and left ventricle showed myocyte hypertrophy with extensive widespread myocyte disarray and replacement fibrosis. The histologic appearance was that of hypertrophic cardiomyopathy, which was responsible for his sudden unexpected death. This postmortem diagnosis of hypertrophic cardiomyopathy in a transplanted heart has major implications for the donor family because of the inherited nature of the condition. Follow-up with the donor family is essential in this unique case. This case highlights the importance of autopsy in transplant death cases. Hypertrophic cardiomyopathy in the donor heart most likely did not manifest phenotypically at the time of transplant in this case because the majority present in adolescence and early adulthood, rarely in childhood. This is first report of such a case.

Background The sole identification of left ventricular hypertrophy (LVH) in a young individual that died suddenly may often lead to an erroneous diagnosis of hypertrophic cardiomyopathy (HCM). Emerging data suggests that idiopathic LVH (ILVH) and HCM may be separate entities. Aim We aimed to report on the prevalence and nature of mitral valve (MV) abnormalities, in a cohort of sudden cardiac death (SCD) victims with a post-mortem examination consistent with HCM and ILVH. Methods We reviewed 6860 consecutive cases of SCD referred to our specialist cardiac pathology centre between 1994 and 2020. SCD was defined as death from a cardiovascular cause within 12 hours of apparent well-being. HCM was defined by the presence of LVH, in the absence of abnormal loading conditions and characterised by myocyte disarray at histology. ILVH was defined as unexplained LVH (heart weight >500 g in males and >400 g in females) and left ventricular (LV) wall thickness >15mm, in the absence of myocardial disarray or secondary causes of LVH. The MV was examined for patency, circumference, thickening, nodularity, ballooning, bulging between cords, perforation, and the presence of impact lesions in the LV outflow tract (LVOT) and aortic outlet. Results Of the total cases of SCD, 264 (4%) were due to HCM (mean age 41±18 years, 78% males, LV maximal wall thickness 19±6 mm) (Figure 1). Ante-mortem symptoms were reported in 44 (17%) cases and for the majority (n=217, 82%) HCM was established at post-mortem. Death was attributed to ILVH in 253 (3%) cases (mean age 43±16 years, 80% males, LV maximal wall thickness 18±4 mm). MV abnormalities were found in 58 (22%) decedents with HCM (mean age 38±17 years; 72% males) and in 13 (5%) decedents with ILVH (mean age 55±15 years; 77% male), p Conclusions MV abnormalities are over four-fold more common in individuals with HCM than those with ILVH and may be considered as additional macroscopic features to differentiate between these two entities. Furthermore, the inherent descriptive terminologies used when assessing the MV, support a greater emphasis on the standardisation and quantification of MV abnormalities as part of the autopsy in victims of SCD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Acknowledgements: We thank the charitable organisation, Cardiac Risk in the Young (CRY) who fund and support the CRY Cardiovascular Pathology Unit and CRY database.

Hypertensive heart disease refers to changes in the myocardium that result from hypertension. The relationship between hypertensive heart disease and sudden cardiac death is well established, but there are few pathological studies. We examined the clinical and pathological features of hypertensive heart disease in sudden cardiac death victims from a national cardiovascular pathology registry. We investigated 5239 cases of sudden cardiac death between 1994 and 2018. Hearts were examined by two expert cardiac pathologists. Diagnostic criteria included history of hypertension, increased heart weight and left ventricular wall thickness in the absence of other causes. Collagen was quantified using picrosirius red staining and imaging software. Of 75 sudden cardiac death cases due to hypertensive heart disease (age at death: 54 ± 16 years; 56% males), 56 (75%) reported no prior cardiac symptoms. Thirty-four (45%) recorded a BMI ≥ 30. Only two (2.7%) had hypertensive heart disease diagnosed antemortem. Four (5%) were diagnosed clinically with hypertrophic cardiomyopathy, but lacked myocyte disarray at autopsy. All hearts showed concentric left ventricular hypertrophy and myocyte hypertrophy. Fibrosis was identified microscopically in 59 cases (81%). The posterior left ventricular wall showed the greatest increase in the percentage of collagen in hypertensive diseased hearts compared to controls (25.2% vs 17.9%, p = 0.034). Most sudden deaths due to hypertensive heart disease occur without prior cardiac symptoms; thus, clinical risk stratification is challenging. Hypertensive heart disease can be misdiagnosed in life as hypertrophic cardiomyopathy which has major implications for relatives. Pathologists require a history of hypertension and histology for a definitive diagnosis of hypertensive heart disease.

Background\ud 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.\ud \ud Methods\ud Retrospective observational study analysing all consecutive cases of sudden death prospectively referred to a UK national cardiac pathology centre between 2017-2021. Cases showing hypoperfusion features were identified after review of clinical information and examination by expert cardiac pathologists.\ud \ud Results\ud 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.\ud \ud Conclusion\ud 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.

This case series assesses the cardiac conditions associated with sudden deaths during or immediately after sexual intercourse.

BACKGROUND: Electrophysiological, imaging, and pathological studies have reported the presence of subtle structural abnormalities in hearts from patients with Brugada syndrome (BrS). However, data concerning disease involvement outside of the right ventricular outflow tract are limited. OBJECTIVES: This study sought to characterize the presence and distribution of ventricular myocardial fibrosis in a cohort of decedents experiencing sudden cardiac death caused by BrS. METHODS: The authors evaluated 28 whole hearts from consecutive sudden cardiac death cases attributed to BrS and 29 hearts from a comparator group comprised of noncardiac deaths (control subjects). Cardiac tissue from 6 regions across the right and left ventricle were stained with Picrosirius red for collagen and tissue composition was determined using image analysis software. Postmortem genetic testing was performed in cases with DNA retained for analysis. RESULTS: Of 28 BrS decedents (75% men; median age of death 25 years), death occurred in sleep or at rest in 24 of 28 (86%). The highest proportion of collagen was observed in the epicardial right ventricular outflow tract of the BrS group (23.7%; 95% CI: 20.8%-26.9%). Ventricular myocardium from BrS decedents demonstrated a higher proportion of collagen compared with control subjects (ratio 1.45; 95% CI: 1.22-1.71; P < 0.001), with no significant interactions with respect to sampling location or tissue layer. There was insufficient evidence to support differences in collagen proportion in SCN5A-positive cases (n = 5) when compared with control subjects (ratio 1.23; 95% CI: 0.75-1.43; P = 0.27). CONCLUSIONS: Brugada syndrome is associated with increased collagen content throughout right and left ventricular myocardium, irrespective of sampling location or myocardial layer.

The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 (Dsg2) in the young murine heart leads to development of AC. Apoptosis was an early cellular phenotype, and RNA sequencing analysis revealed early activation of inflammatory-associated pathways in Dsg2-null (Dsg2−/−) hearts at postnatal day 14 (2 weeks) that were absent in the fibrotic heart of adult mice (10 weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were also upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at the early disease stage suggests cardiac inflammation is an important response and may be one of the mechanisms responsible for AC disease progression.

The mitral valve is composed of leaflets, cords, and papillary muscles which must work in combination for the valve to function properly. The valve leaflets have three distinct layers, the atrialis, the spongiosa, and the fibrosa. Pathological changes affecting these structures may result in either stenosis or regurgitation of the valve and their consequential clinical symptoms and signs.\ud \ud The appearance of the valve changes with increasing age. Age-related changes include thickening of the valve leaflet substance, fatty streaks of the leaflets, nodular thickening along the lines of coaptation, and annular calcification.\ud \ud Diseases affecting the mitral valve include prolapse, rheumatic disease, infectious endocarditis, non-bacterial thrombotic endocarditis, hypertrophic cardiomyopathy, and congenital disease. Both prolapse and rheumatic disease show valve leaflet thickening with calcification, while prolapse shows myxomatous degeneration. Both infectious endocarditis and non-bacterial thrombotic endocarditis show vegetations on the atrial leaflet surfaces. These two conditions may only be distinguished on histology as a diagnosis of non-bacterial thrombotic endocarditis should only be made when the valve is devoid of bacterial colonies and acute inflammation.\ud \ud Advances in mitral valve interventions, both surgical and transvascular, are discussed along with their complications.

The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic Cardiomyopathy (AC) is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 (Dsg2) in the young murine heart leads to development of AC. Cardiomyocyte apoptosis was an early cellular phenotype and RNA-Seq analysis revealed early activation of inflammatory-associated pathways in Dsg2 null (Dsg2−/−) hearts at postnatal day 14 (Two weeks) that were absent in the fibrotic heart of adult mice (Ten weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at different disease stages implicate inflammation related to loss of desmoglein 2 as a major mechanism for disease progression.

Congenital heart disease is a rare but important finding in adults that 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 6000 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 haemorrhage. 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 categorising the cases, with the concept of the "morphological method" serving to identify the distinguishing features of the cardiac components. This article is protected by copyright. All rights reserved.

Myocardial perfusion reserve is impaired in aortic stenosis (AS) even in the absence of epicardial coronary stenosis [(1)][1], which may be due to reduced capillary density and endothelial dysfunction [(2,3)][2]. However, the relationship between histopathological abnormalities of the vasculature

Background Impaired myocardial perfusion reserve occurs in pressure overload hypertrophy such as in severe aortic stenosis (AS) despite unobstructed epicardial coronaries. However the pathological mechanisms underlying this are poorly understood. We sought to assess myocardial perfusion reserve in severe AS by stress perfusion cardiovascular magnetic resonance (CMR), and examine the findings in relation to the histological evidence of vascular changes in the myocardium. Methods Fourteen patients with severe AS and unobstructed epicardial coronaries underwent adenosine stress perfusion CMR before and 6 months after surgical aortic valve replacement (AVR). Myocardial biopsies were obtained during AVR and stained using CD31 +for endothelium, smooth muscle actin (SMA) for smooth muscle, and picrosirius red for fibrosis. Nine age- and sex- matched post-mortem myocardial samples served as histological controls. Results When compared to controls, the myocardium of patients with severe AS had reduced vessel density, total quantity of SMA +ve and CD31 +ve, in addition to the expected increase in fibrosis. There was absence of CD31 +ve endothelium in SMA +ve arterioles, indicating endothelial loss. (Figure 1) Importantly, patients with an aortic valve area (AVA) ≤0.8cm2 had greater endothelial loss compared to those with an AVA >0.8 and≤1.0cm2 (1.34%±0.44% vs 2.84±1.03%, p=0.006), and endothelial loss also correlated with myocardial perfusion reserve index (MPRI), r=0.66, p=0.019. MPRI improved significantly post AVR (from 0.95±0.17 to 1.50±0.43, p=0.018). Conclusion In severe AS, there is microvascular rarefaction and loss of endothelium, which is more pronounced in patients with the most severe aortic valve narrowing. This appears to be an underlying mechanism for reduced myocardial perfusion reserve, which may be reversible post AVR.

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.

Background Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterised by fibrofatty replacement of the ventricular myocardium. It is a leading cause of sudden cardiac death (SCD) in young athletes, where morphological appearances of the right ventricle may overlap with physiological adaptation to regular intense exercise. Purpose Evaluation of sport classification, clinical characteristics, and pathological findings in a retrospective young SCD athletic population. Methods Between 1994–2017, 5205 consecutive cases of SCD were referred to our national cardiac pathology centre. Hearts were examined macroscopically and microscopically by an expert cardiac pathologist. 216 cases were diagnosed with ACM, of which 98 were aged 14­35. Information pertaining to circumstances of death, sporting activity, and symptoms were provided by coroners’ officers and family members. Competitive sport was classified into categories detailing peak static and dynamic components. Results In the young (14–35) ACM cohort, 35/98 individuals (36%) were participants in competitive sport, 26 (74%) of whom engaged in sports with a high dynamic component. Among young competitive athletes (YCA), 31 (89%) died during physical exertion and 25 (71%) died during competitive sport. 26 (74%) had no cardiac symptoms. Heart weight was heavier in YCAs compared to the young non-athletic ACM cohort (474.4g±84.0 vs 394.0g±94.9, p Conclusions Over a third of our young cohort were competitive athletes, principally engaged in sports with a high dynamic component. Sudden death due to ACM was strongly associated with physical exertion in YCAs. Heart weight and RV dimensions were also increased, suggesting a contributory effect from cardiac adaptation to sustained exercise.