Hallazgos histopatológicos en la disección y rotura de la aorta torácica. Estudio de 54 casos de autopsia / Histopathological findings in dissection and rupture of the thoracic aorta. Study of 54 autopsy cases

Introducción la disección/rotura de la aorta torácica tiene una alta mortalidad, constituyendo de 3,9 a 5,4% de las muertes súbitas en series forenses. Los hallazgos histopatológicos de la media asociados a estas entidades han recibido múltiples términos y definiciones. En 2016, la Asociación Europea de Patología Cardiovascular junto con la Sociedad de Patología Cardiovascular publicaron un documento de consenso, aplicado a muestras quirúrgicas, para unificar criterios. El objetivo de este trabajo es valorar su aplicación en las autopsias forenses. Un objetivo secundario es estudiar cambios inflamatorios útiles para la datación. Material y métodos se revisaron las preparaciones histológicas de aorta de 54 casos de muertes súbitas por rotura/disección aórtica estudiados entre 2019 y 2022. Resultados se observó degeneración de la media en 49 casos (90,8%) (severa en 42,9%). Por lesiones, el orden de frecuencia fue: fragmentación y/o pérdida de las fibras elásticas (74,1%); acúmulo de matriz mucoide extracelular (61,1%); pérdida de núcleos de células musculares lisas (48,1%) y colapso de la media (44,4%). Algunas lesiones del documento no pudieron ser valoradas. No se encontraron diferencias significativas por edad; presencia o no de colagenopatías; o válvulas aórticas bi/tricúspides. Se observó tejido de granulación o infiltrado neutrofílico en los fallecidos con dolor de varios días o <24 h antes de la muerte, respectivamente. Conclusión con la aplicación del documento se encuentran lesiones en la media en >90% de los casos y pueden estudiarse las lesiones fundamentales. La respuesta inflamatoria frente a la rotura/disección parece correlacionarse con el momento de la disección/rotura. (AU)

Introduction Thoracic aortic dissection/rupture has a high mortality, constituting 3.9-5.4% of sudden deaths in forensic series. Medial histopathological findings associated with these entities have received multiple terms and definitions. In 2016, the European Association for Cardiovascular Pathology and the Society for Cardiovascular Pathology published a consensus document, applied to surgical specimens, to unify criteria. The aim of this work is to assess its application in forensic autopsies. A secondary objective is to study inflammatory changes useful for dating. Material and methods Aortic histological preparations of the 54 cases of sudden deaths due to aortic rupture/dissection studied between 2019 and 2022 were reviewed. Results Medial degeneration was observed in 49 cases (90.8%) (severe in 42.9%). By lesions, the order of frequency was: fragmentation and/or loss of elastic fibers (74.1%); accumulation of extracellular mucoid matrix (61.1%); loss of smooth muscle cell nuclei (48.1%) and collapse of the media (44.4%). Some lesions of the consensus paper could not be assessed. No significant differences were found by age; presence or not of collagenopathies; or bi/tricuspid aortic valves. Granulation tissue or neutrophilic infiltrate was observed in those deceased with pain several days or <24 h before death, respectively. Conclusion With the application of the document, lesions in the media are found in >90% of cases and fundamental lesions can be studied. The inflammatory response to rupture/dissection appears to correlate with the timing of dissection/rupture. (AU)

Accumulation of Lewy-Related Pathology Starts in Middle Age: The Tampere Sudden Death Study.

When effective treatments against neurodegenerative diseases become a reality, it will be important to know the age these pathologies begin to develop. We investigated alpha-synuclein pathology in brain tissue of the Tampere Sudden Death Study-unselected forensic autopsies on individuals living outside hospital institutions in Finland. Of 562 (16-95 years) participants, 42 were positive for Lewy-related pathology (LRP). The youngest LRP case was aged 54 years, and the frequency of LRP in individuals aged ≥50 years was 9%. This forensic autopsy study indicates LRP starts already in middle age and is more common than expected in the ≥50 years-of-age non-hospitalized population. ANN NEUROL 2024;95:843-848.

Hidden Coronary Artery Ostium and Sudden Death.

A 1-week-old girl died suddenly and unexpectedly. At autopsy the major finding was of a right dominant coronary artery circulation with an inapparent left coronary artery ostium. After careful examination, an anomalous origin of the left coronary artery was found with the ostium located in the non-coronary cusp immediately adjacent to the commissure of the non- and left coronary cusps. The ostium was of small caliber with an obliquely oriented artery (<45°) with no ostial ridges. The artery coursed anteriorly past the left coronary cusp between the aorta and the left atrial appendage to then follow its usual course inferiorly along the anterior aspect of the left ventricle. The reminder of the autopsy was unremarkable. Death was, therefore, attributed to an anomalous and hypoplastic left coronary artery (and ostium) with an acute angle of take-off. Tracing coronary arteries in the very young may be technically difficult due to their small size, thus identifying the location of ostia is important. This may be difficult when the ostium was located close to a commissure.

A sudden death, an aortic rupture, and an unexpected cause: a report about suspected child abuse.

All unexpected deaths of children require an autopsy to determine the cause of death. In cases of aortic rupture, the immediate cause of death is easily identified at autopsy. Although the majority of aortic ruptures are caused by high-energy trauma, other causes should not be missed.We present and discuss the case of a 29-month-old child who died suddenly at home. Her recent medical history and the ecchymotic lesions observed on external examination of the body appeared potentially suspicious of physical abuse. The autopsy concluded that death was due to complete rupture of the abdominal aorta with associated vertebral disjunction. At first glance, the overall forensic picture could suggest a traumatic death. However, careful inspection of the retroperitoneum revealed a discrete atypical mass of infiltrative tissue within the hematoma. Histopathological examinations confirmed tumor proliferation of the soft tissues, triggering vascular and spinal injuries. Other paraneoplastic elements or metastases were ultimately revealed (orbital and subcutaneous). Overall, this was a rare and fatal case of abdominal aortic rupture induced by tumors. Due to the mechanisms and the forces needed to cause vertebral dislocations and aortic rupture, the combination of the two is highly suggestive of child abuse when an accidental traumatic history is absent or inconsistent with the injuries. Nevertheless, this case illustrates the importance of a systematic and rigorous forensic examination, rather than ignoring other possible diagnoses.

Sudden unexpected death from subvalvular hemorrhagic cyst complicated with coronary heart disease in an adult.

Cardiac blood cysts are rare benign tumors. It is commonly found in the heart valve and left ventricle of newborns by autopsy and is rarely seen in adults [1, 2]. The typical histopathology of cardiac blood cysts is a closed, round, blood-containing cystic mass attached to the heart valve or endocardium. This article reports a rare case of sudden death due to a giant subaortic cardiac blood cyst with coronary heart disease in an adult patient and summarizes the pathological features, aiming to provide a reference for the forensic pathological identification of cardiac blood cysts.

Hemorragia Intracerebral Imprevisible en un Hombre Joven: La Importancia de la Tomografía computarizada craneal post-mortem / Unpredictable Intracerebral Hemorrhage in a Young Male: The Importance of Post-Mortem Cranial Computed Tomography

La muerte súbita es aquella que ocurre dentro de las 24 horas posteriores al inicio de los síntomas y se caracteriza por ser clínicamente inexplicable, inesperada y repentina. Debido a la naturaleza de la muerte súbita, no es posible llegar a un diagnóstico preciso sin una autopsia. En esta comunicación breve, evaluaremos el caso de un empleado de crucero de 33 años, sin historial médico/farmacológico previo, el cual falleció súbitamente mientras reposaba en su camarote. Debido a las sospechas iniciales de una posible muerte causada por una sobredosis de cocaína, se le realizó un panel toxicológico abarcador el cual resultó negativo. Empero, una tomografía computarizada (TC) craneal sin contraste revirtió la hipótesis inicial y la autopsia neuropatológica -sorpresivamente- confirmó que la verdadera causa de muerte fue la ruptura de un aneurisma sacular desconocido en el polígono de Willis.

Sudden death occurs within 24 hours after the onset of symptoms and is characterized by being clinically inexplicable, sudden, and unexpected. Due to the nature of sudden death, it is not possible an accurate diagnosis without performing an autopsy. In this brief communication, we will evaluate the case of a 33-year-old cruise employee, with no prior medical/pharmacological history, who suddenly died while resting in his cabin. Due to initial suspicions of a possible cocaine overdose death, a comprehensive toxicology panel was performed, although yielding a negative result. A cranial computed tomography without contrast reversed the initial hypothesis and the neuropathological autopsy -surprisingly- confirmed that the true cause of death was the rupture of an unknown saccular aneurysm in the Circle of Willis.

Sudden death after fatal percussion of the cervical neurovascular bundle.

Background: Atypical compression of the neck may be classified as asphyxia in which the external compression on the cervical anatomical structures occurs in a peculiar manner. In such cases, death occurs due to the combination of several pathophysiological phenomena, such as respiratory, vascular, and nervous. When the mechanical action on the neck is violent and rapid, it is more correct to use the word percussion rather than compression. Usually there are no skin lesions of special significance in this type of neck percussion, unlike the cases of choking, strangulation, and hanging, and the diagnosis is challenging. It is important to carefully evaluate the body during the autopsy to identify which pathophysiological mechanism caused the death. Case report: A young woman died immediately after being struck by a concrete beam at the level of her neck. The woman was on vacation with her boyfriend and decided to hang from a concrete beam suspended between two columns to take a souvenir photo when the beam suddenly broke and fell on her. The autopsy revealed multiple abrasions, swelling, and lacerations to the face, neck, and chest. Internal examination revealed primarily the presence of hemorrhagic infiltration in the anterior cervical compartments and lacerations of various organs, including the trachea. Conclusion: Based on all the obtained data, including toxicological and histological, the cause of death was atypical ab extrinsic percussion of the neck, directed particularly at the right cervical neurovascular bundle.

Hamartoma of mature cardiac myocytes: systematic review.

BACKGROUND: While primary cardiac tumors are rare, it has been increasingly recognized due to improvement in screening measures. However, the hamartoma of mature cardiac myocytes has been underrecognized compared to other cardiac tumors, such as cardiac myxomas and papillary fibroelastomas, and is still potentially associated with critical consequences such as sudden death. This systematic review aims to summarize the evidence regarding the hamartoma of mature cardiac myocytes and characterize the presentations and symptoms for clinicians. METHODS: Following the PRISMA statement, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including "hamartoma of mature cardiac myocytes" from their inception to January 2, 2023. RESULTS: We included 25 articles, including 34 cases, in this systematic review. Patients with hamartoma of mature cardiac myocytes commonly presented with nonspecific symptoms such as dyspnea (35.3%), although a few presented with sudden death and syncope. The left ventricle was the common site of origin (41.2%), followed by the right atrium and ventricle. Surgery was commonly pursued for diagnosis and treatment, while a few required cardiac transplants (8.8%), and 29.4% were diagnosed with autopsy or expired. CONCLUSION: Hamartoma of mature cardiac myocytes is a potentially underrecognized primary cardiac tumor associated with treatable yet potentially critical consequences. Given the challenges of differentiating it from malignancy such as angiosarcoma, multimodal imaging needs to be utilized to pursue a diagnosis. Future studies are warranted to develop a noninvasive diagnosis mode for cardiac tumor.

Forensic Analysis of 9 Cases of Sudden Unexpected Death in Epilepsy.

OBJECTIVES: To analyze the case, scene and forensic pathological characteristics of sudden unexpected death in epilepsy (SUDEP), to provide a practical basis for forensic identification. METHODS: A total of 9 autopsy cases of SUDEP were collected. The basic information of the cases, the scene characteristics, the forensic pathological changes, the common drugs and antiepileptic drug test results, and pericardial fluid biochemical test results were analyzed. RESULTS: All of the 9 cases were male epilepsy patients died during sleep at night, the age of death was (37.1±8.6) years, and the course of epilepsy was (21.3±5.6) years. Six corpses were in prone position and three in left lateral position. The hemorrhage of the sternocleidomastoid muscle, sternal thyroid muscle and sternohyoid muscle were found with 8 cases, 5 cases and 4 cases, respectively, all of them were unilateral. Six cases had bilateral hemorrhage of pectoralis minor muscle. Brain edema, phagocytosis of frontotemporal neurons and gliosis, cardiac fibers bend in wavy patterns and eosinophilic staining enhancement, pulmonary edema, pulmonary congestion, alveolar hemorrhage, pulmonary small bronchiole wall shrinking, tubular proteinuria and pancreatic parenchymal hemorrhage were the common histopathological changes. The biochemical test results of pericardial fluid indicated that there were myocardial ischemic damage. CONCLUSIONS: Young male, early onset, long course of disease, sleep in the prone position, poor drug compliance or combination, epileptic seizure may be the risk factors of SUDEP. Cardiac dysfunction and respiratory depression might be the main death mechanism of SUDEP.

Vertebral artery dissection induced lateral medullary syndrome characterized with severe bradycardia: a case report and review of the literature.

BACKGROUND: Lateral medullary syndrome is the most common type of brainstem infarction. Lateral medullary syndrome results in damage to the corresponding cranial nerve nuclei and the nucleus tractus solitarius, with vertigo, ipsilateral ataxia, crossed sensory disturbances, Horner's sign, bulbar palsy, and other underlying symptoms or signs. However, cases with cardiac arrhythmia and other autonomic dysfunctions as the primary manifestations are less common. Clinically, sudden death occasionally occurs in patients with lateral medullary syndrome, which may be associated with severe cardiac arrhythmia. These patients may suffer in life-threatening arrhythmia and even cardiac arrest, and vital signs should be closely monitored to prevent sudden death. In younger patients, vertebral artery dissection is the most common cause. CASE DESCRIPTION: Here, we present a case of lateral medullary syndrome caused by vertebral artery dissection with severe bradycardia. The patient was a 49-year-old man who was admitted with "sudden onset of numbness in the left limbs and right side of the face for 1 hour". Electrocardiogram (ECG) monitoring showed a repeated heart rate decrease to as low as 23 beats/min, followed by a gradual increase in heart rate to 35-55 beats/min after 2-3 seconds. Head magnetic resonance imaging (MRI) examination revealed right dorsolateral cerebral infarction of the medulla oblongata. Digital subtraction angiography (DSA) revealed a right vertebral artery dissecting aneurysm. We performed an emergency placement of a temporary pacemaker, followed by conservative treatment with platelet aggregation inhibitors, vascular softening agents and improved collateral circulation. Elective spring coil embolization of the vertebral artery dissecting aneurysm and stent implantation were performed. At outpatient follow-up, the patient had a good prognosis. CONCLUSIONS: Clinical management of patients with lateral medullary syndrome should be prioritized, with close cardiac monitoring at the early stages of observation and pacemaker placement and tracheal intubation as required to prevent adverse events.

Post-Mortem Cardiac Magnetic Resonance in Explanted Heart of Patients with Sudden Death.

BACKGROUND: We sought to evaluate the diagnostic accuracy of post-mortem cardiac magnetic resonance (PMCMR) of explanted hearts to detect the cardiac causes of sudden death. METHODS: PMCMR was performed in formalin-fixed explanted hearts of 115 cases of sudden death. Histological sampling of myocardium was performed using two different approaches: (1) guideline-based sampling; (2) guideline-based plus PMCMR-driven sampling. RESULTS: Forensic diagnosis of cardiac cause of death was ascertained in 72 (63%) patients. When the guideline-driven histological sampling was used, the PMCMR interpretation matched with final forensic diagnosis in 93 out of 115 cases (81%) with sensitivity of 88% (79-95%), specificity of 65% (47-80%), PPV of 84% (78-90%), NPV of 73% (58-84%), accuracy of 81% (72-88%), and AUC of 0.77 (0.68-0.84). When a PMCMR-driven approach was added to the guideline-based one, the matching increased to 102 (89%) cases with a PMCMR sensitivity of 89% (80-94%), a specificity of 86% (67-96%), PPV of 95% (89-98%), NPV of 73% (59-83%), accuracy of 89% (81-93%), and AUC of 0.88 (0.80-0.93). CONCLUSIONS: PMCMR has high accuracy to identify the cardiac cause of sudden death and may be considered a valid auxilium for forensic diagnosis. PMCMR could improve histological diagnosis in conditions with focal myocardial involvement or demonstrating signs of myocardial ischemia.

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood.

Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10-15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10-21, z = - 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10-6, z = 2.65) and CA1-3 (p = 4.7 × 10-6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10-5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10-3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10-5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10-3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.

Blinded review of hippocampal neuropathology in sudden unexplained death in childhood reveals inconsistent observations and similarities to explained paediatric deaths.

AIMS: Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls. METHODS: Hippocampal haematoxylin and eosin (H&E) slides (n = 67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by nine blinded reviewers: three board-certified forensic pathologists, three neuropathologists and three dual-certified neuropathologists/forensic pathologists. RESULTS: Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (52.5% SUDC, 53.0% controls), with no difference by cause of death (COD) (p = 0.16) or febrile seizure history (p = 0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' κ = 0.014, p = 0.47). Within reviewer groups, there were no findings more frequent in SUDC compared with controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p = 0.41). CONCLUSIONS: The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal maldevelopment associated with sudden death (HMASD). These findings underscore a need for larger studies to standardise evaluation of hippocampal findings, identifying the range of normal variation and changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.

Sudden death due to non-traumatic rupture of splenic artery aneurysm.

INTRODUCTION: Splenic artery aneurysm is a rare form of vascular pathology that carries a high risk of mortality once it gets ruptured. It has a prevalence of 1% and occurs due to thinning and dilatation of the arterial wall. CASE: We describe a case of a 35-year-old policeman who died suddenly. At medico-legal autopsy, intraperitoneal clotted blood about 1000 g and liquid blood about 3000 ml were seen. On further exploration, ruptured splenic artery aneurysm about 2.0 cm in diameter became visible near the hilum. CONCLUSION: Rare cases typically present as sudden and unexpected death with intraperitoneal bleed and may be confused with blunt trauma abdomen. Therefore, splenic artery aneurysm is an appropriate differential diagnosis for sudden deaths and intraperitoneal bleeding, respectively.

Forensic Analysis of 9 Cases of Sudden Unexpected Death in Epilepsy / 法医学杂志

OBJECTIVES@#To analyze the case, scene and forensic pathological characteristics of sudden unexpected death in epilepsy (SUDEP), to provide a practical basis for forensic identification.@*METHODS@#A total of 9 autopsy cases of SUDEP were collected. The basic information of the cases, the scene characteristics, the forensic pathological changes, the common drugs and antiepileptic drug test results, and pericardial fluid biochemical test results were analyzed.@*RESULTS@#All of the 9 cases were male epilepsy patients died during sleep at night, the age of death was (37.1±8.6) years, and the course of epilepsy was (21.3±5.6) years. Six corpses were in prone position and three in left lateral position. The hemorrhage of the sternocleidomastoid muscle, sternal thyroid muscle and sternohyoid muscle were found with 8 cases, 5 cases and 4 cases, respectively, all of them were unilateral. Six cases had bilateral hemorrhage of pectoralis minor muscle. Brain edema, phagocytosis of frontotemporal neurons and gliosis, cardiac fibers bend in wavy patterns and eosinophilic staining enhancement, pulmonary edema, pulmonary congestion, alveolar hemorrhage, pulmonary small bronchiole wall shrinking, tubular proteinuria and pancreatic parenchymal hemorrhage were the common histopathological changes. The biochemical test results of pericardial fluid indicated that there were myocardial ischemic damage.@*CONCLUSIONS@#Young male, early onset, long course of disease, sleep in the prone position, poor drug compliance or combination, epileptic seizure may be the risk factors of SUDEP. Cardiac dysfunction and respiratory depression might be the main death mechanism of SUDEP.

An autopsy case of unexpected death due to Addison's disease caused by adrenal tuberculosis.

BACKGROUND: Adrenal tuberculosis is difficult to diagnose due to non-specific symptom. Unexpected death due to adrenal insufficiency after trauma surgery is rare. CASE PRESENTATION: A 45-year-old man, who was admitted to hospital because of trauma to the right hand, died unexpectedly on the 13th day after replantation of amputated fingers. He was diagnosed with brain edema and diluted hyponatremia. Autopsy and histopathologic examination revealed severe brain edema combined with cerebellar tonsillar hernia, extensive destruction of adrenal gland caused by bilateral adrenal tuberculosis and right lung invasive pulmonary tuberculosis. CONCLUSIONS: Trauma and pulmonary tuberculosis complicated with adrenal tuberculosis induced the adrenal crisis, which eventually lead to severe cerebral edema and hernia, and finally death from respiratory and circulatory failure. This autopsy and histopathologic examination suggested a possible pathophysiologic mechanism of sudden death due to diluted hyponatremia after trauma surgery.

Myocarditis-induced Sudden Death after BNT162b2 mRNA COVID-19 Vaccination in Korea: Case Report Focusing on Histopathological Findings.

We present autopsy findings of a 22-year-old man who developed chest pain 5 days after the first dose of the BNT162b2 mRNA vaccine and died 7 hours later. Histological examination of the heart revealed isolated atrial myocarditis, with neutrophil and histiocyte predominance. Immunohistochemical C4d staining revealed scattered single-cell necrosis of myocytes which was not accompanied by inflammatory infiltrates. Extensive contraction band necrosis was observed in the atria and ventricles. There was no evidence of microthrombosis or infection in the heart and other organs. The primary cause of death was determined to be myocarditis, causally-associated with the BNT162b2 vaccine.

Genomic Autopsy of Sudden Deaths in Young Individuals.

Importance: Postmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information. Objective: To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families. Design, Setting, and Participants: Pathological and whole-genome sequence analysis was conducted in a cohort referred from a national network of medical examiners. Cases were accrued prospectively from May 2015 to March 2019 across 24 US states. Analysis began September 2016 and ended November 2020. Exposures: Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation. Results: A total of 103 decedents (mean [SD] age at death, 23.7 [11.9] years; age range, 1-44 years), their surviving family members, and 140 sex- and genetic ancestry-matched controls were analyzed. Among 103 decedents, autopsy and clinical data review categorized 36 decedents with postmortem diagnoses, 23 decedents with findings of uncertain significance, and 44 with sudden unexplained death. Pathogenic/likely pathogenic (P/LP) genetic variants in arrhythmia or cardiomyopathy genes were identified in 13 decedents (12.6%). A multivariable analysis including decedent phenotype, ancestry, and sex demonstrated that younger decedents had a higher burden of P/LP variants and select variants of uncertain significance (effect size, -1.64; P = .001). These select, curated variants of uncertain significance in cardiac genes were more common in decedents than controls (83 of 103 decedents [86%] vs 100 of 140 controls [71%]; P = .005), and decedents harbored more rare cardiac variants than controls (2.3 variants per individual vs 1.8 in controls; P = .006). Genetic testing of 31 parent-decedent trios and 14 parent-decedent dyads revealed 8 transmitted P/LP variants and 1 de novo P/LP variant. Incomplete penetrance was present in 6 of 8 parents who transmitted a P/LP variant. Conclusions and Relevance: Whole-genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes. Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort.

Significances of viable synergistic autophagy-associated cathepsin B and cathepsin D (CTSB/CTSD) as potential biomarkers for sudden cardiac death.

BACKGROUND: The Cathepsins family, including cathepsin B and cathepsin D, potentially affects the entire processes involved in atherosclerosis. Although coronary heart disease (CHD) has been widely studied as the basis of Sudden Cardiac Death (SCD), the relationship between CHD and CTSB/D remains unclear. METHODS: We screened for differentially expressed proteins (DEPs) associated with autophagy by limma package in R. For the genes corresponding to the DEPs after screening, we used various databases to carry out functional enrichment of related DEGs to explore their possible influence on a specific aspect of the disease. Functional enrichment analysis of DEGs was performed by DAVID, Metascape and GSEA. STRING and Cytoscape were obtained the hub genes, the analysis of interaction networks through the GENMANIA and Networkanalyst. Western Blot was used to validate the protein expression level of target genes. TF and miRNA prediction were performed using Networkanalyst and visualized using Cytoscape. RESULTS: The expression levels of members of the cathepsin family were up regulated in CHD tissues compared with the control. GO and KEGG revealed that cathepsin was markedly enriched in endopeptidase activities, immune responses, lysosome pathways, et al. The correlation analysis showed that in patients with CHD, the CTSB/CTSD expression were negatively correlated with ATG4D and BNIP3, but positively with BCL2L1, CAPNS1, and TP53. In the TF-mRNA-miRNA network, has-miR-24-3p and has-miR-128-3p had higher degrees, CTSB/CTSD could be targeted by them. CONCLUSIONS: Our findings elucidated the expression and regulatory role of cathepsins in coronary heart disease induced SCD and might further explore the potential mechanisms of autophagy in CHD.