Search Results (31)

Objective: Sudden infant death syndrome (SIDS), sudden neonatal unexpected death (SNUD), and sudden intrauterine unexpected death (SIUD) are major unsolved, shocking forms of death that occur frequently and without warning. The body of literature on the anatomo-pathological substrates in the cardiac conduction system of SIDS-SIUD and their possible relationship with risk factors and triggers is fragmentary and scarce. The work aims is to analyze the cardiac conduction system findings collected at the national referral center for SIDS-SIUD. Methods: A total of 123 autopsied cases of SIDS (59.35% males, 40.65% females, mean age ± SD: 103.49 ± 67.17 days), 36 cases of SNUD (61.11% males, 38.89% females, mean age ± SD: 8.4 ± 9.17 days), and 127 cases of SIUD (45.67% males, 54.33% females, mean age ± SD: 36 ± 4.59 gestational weeks) were analyzed. In-depth pathological examinations of the cardiac conduction system were performed on serial sections according to the Lino Rossi Research Center’s protocol. Results: Among the studied cases, the following findings were observed: resorptive degeneration (SIDS: 88.7%, SNUD: 88.88%, SIUD: 56.69%), fetal dispersion (SIDS: 73.17%, SNUD: 91.66%, SIUD: 78.74%), Mahaim fibers (SIDS: 40.65%, SNUD: 44.44%, SIUD: 32.28%), cartilaginous meta-hyperplasia (SIDS: 56.91%, SNUD: 25%, SIUD: 33.07%), septated atrio-ventricular junction (AVJ) (SIDS: 21.14%, SNUD: 33.33%, SIUD: 38.58%), AVJ duplicity (SIDS: 6.5%, SNUD: 11.11%, SIUD: 2.36%), intramural bifurcation (SIDS: 3.25%, SNUD: 2.77%, SIUD: 4.72%). Conclusions: The prevalence of cardiac conduction findings was consistent across the SIDS, SNUD and SIUD groups. These findings provide valuable insights into the pathological characteristics of the cardiac conduction system in SIDS-SIUD that are potential morphological substrates for the development of cardiac arrhythmias. Further investigation and study of the conduction system are needed to understand the underlying mechanisms of these forms of death. Full article

Cardiac tumors represent rare neoplasms, but they include a very wide range of neoplasia—first primary benign and malignant cardiac tumors, then cardiac metastases, with these latter ones being far more common in adulthood. These diagnoses may be challenging because of frequently non-specific signs and symptoms; for example, their clinical management may be difficult because of the site and because of possible hemodynamic or arrhythmogenic consequences, independent from their biology. Cardiac tumors may be asymptomatic and incidentally diagnosed, or they may cause heart failure, life-threatening arrhythmias, or even sudden cardiac death. Although they may still represent a post-mortem finding, the evolution and the larger use of cardiac imaging tools, initially echocardiography, has progressively and significantly increased their in vivo detection. Magnetic resonance imaging and computed tomography may give crucial information as to the composition and localization of cardiac masses, useful for investigating them and for planning surgery. Histology is mandatory for the definite and differential diagnosis of the cardiac masses, for assessing predictive factors in malignancies, and for then establishing the appropriate management of patients. Modern techniques applied to histology, including immunohistochemistry and molecular biology, may be required to characterize cardiac tumors, to properly classify them and to assess predictive and/or prognostic markers. Surgical procedures, including minimally invasive surgery, have also dramatically evolved in the last decades, allowing adequate treatment in most cardiac tumors. Finally, biopsy may be useful in selected cases, particularly when radical surgery is not feasible, and histological diagnosis is fundamental for other possible therapeutic approaches. The scope of this review covers advancements in the imaging diagnosis, histology, and treatment of primary and secondary cardiac tumors. Full article

Molecular autopsy is a term employed to describe the investigation of the cause of death through the analysis of genetic information using biological samples collected post-mortem. Its utility becomes evident in situations where conventional medico-legal autopsy methods are not able to identify the cause of death, i.e., in sudden cardiac death (SCD) cases in young individuals, where deaths are commonly due to genetic cardiac conditions, such as cardiomyopathies and channelopathies. The recent advancement in high-throughput sequencing techniques, such as next-generation sequencing (NGS), has allowed the investigation of a high number of genomic regions in a more cost-effective and faster approach. Unlike traditional sequencing methods, which can only sequence one DNA fragment at a time, NGS can sequence millions of short polynucleotide fragments simultaneously. This parallel approach reduces both the time and cost required to generate large-scale genomic data, making it a useful tool for applications ranging from basic research to molecular autopsy. In the forensic context, by enabling the examination of multiple genes or entire exomes and genomes, NGS enhances the accuracy and depth of genetic investigations, contributing to a better understanding of complex inherited diseases. However, challenges remain, such as the interpretation of variants of unknown significance (VUS), the need for standardized protocols, and the high demand for specialized bioinformatics expertise. Despite these challenges, NGS continues to offer significant promise for enhancing the precision of molecular autopsies. The goal of this review is to assess the effectiveness of contemporary advancements in molecular autopsy methodologies when applied to cases of SCD in young individuals and to present an overview of the steps involved in the analysis of NGS data and the interpretation of genetic variants. Full article

Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies have been a part of the Slovenian newborn screening (NBS) program since 2018. We describe a case of early lethal presentation of MTPD/LCHADD in a term newborn. The girl was born after an uneventful pregnancy and delivery, and she was discharged home at the age of 3 days, appearing well. At the age of 4 days, she was found without signs of life. Resuscitation was not successful. The NBS test performed using tandem mass spectrometry (MS/MS) showed a positive screen for MTPD/LCHADD. Genetic analysis performed on a dried blood spot (DBS) sample identified two heterozygous variants in the HADHA gene: a nucleotide duplication introducing a premature termination codon (p.Arg205Ter) and a nucleotide substitution (p.Glu510Gln). Post-mortem studies showed massive macro-vesicular fat accumulation in the liver and, to a smaller extent, in the heart, consistent with MTPD/LCHADD. A neonatal acute cardiac presentation resulting in demise was suspected. We conducted a systematic literature review of early neonatal deaths within 14 days postpartum attributed to confirmed fatty acid oxidation disorders (FAODs), which are estimated to account for 5% of sudden infant deaths. We discuss the pitfalls of the NBS for MTPD/LCHADD. Full article

Hereditary aortopathies are a group of rare genetic diseases affecting the aorta and its major branches, and they represent a cause of sudden cardiac death. These pathologies are classified into syndromic hereditary aortopathies and non-syndromic hereditary aortopathies. The epidemiology of hereditary aortopathies varies according to the specific genetic condition involved; however, these disorders are believed to account for a significant proportion of sudden cardiac death in young individuals with a family history of inherited cardiovascular conditions. The causes of hereditary aortopathies are primarily genetic, with pathogenic variants in various genes encoding structural proteins of the vascular wall, leading to dissection, aneurysms, rupture, and ultimately sudden cardiac death. When the cause of death remains unknown after an autopsy, it is referred to as sudden unexplained death, and post-mortem genetic testing, known as a molecular autopsy, is crucial to confirm hereditary aortopathies and assess the genetic risk in the patient’s relatives. This helps to facilitate diagnostic and therapeutic pathways and/or implement monitoring strategies to prevent sudden cardiac death. In this state-of-the-art review, we focus on syndromic and non-syndromic hereditary aortopathies causing sudden cardiac death in the young and explore preventive strategies for affected family members. Full article

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. Full article

Sudden cardiac death (SCD) is defined as unexpected death due to a cardiac cause that occurs rapidly. Despite the identification of prevention strategies, SCD remains a serious public health problem worldwide, accounting for 15–20% of all deaths, and is therefore a challenge for modern medicine, especially when it affects young people. Sudden cardiac death in young people affects the population aged ≤ 35 years, including athletes and non-athletes, and it is due to various hereditary and non-hereditary causes. After an autopsy, if the cause remains unknown, it is called sudden unexplained death, often attributable to genetic causes. In these cases, molecular autopsy—post-mortem genetic testing—is essential to facilitate diagnostic and therapeutic pathways and/or the monitoring of family members of the cases. This review aims to elaborate on cardiac disorders marked by genetic mutations, necessitating the post-mortem genetic investigation of the deceased for an accurate diagnosis in order to facilitate informed genetic counseling and to implement preventive strategies for family members of the cases. Full article

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder characterized by the progressive fibro-fatty replacement of the right ventricular myocardium, leading to myocardial atrophy. Although the structural changes usually affect the right ventricle, the pathology may also manifest with either isolated left ventricular myocardium or biventricular involvement. As ARVC shows an autosomal dominant pattern of inheritance with variable penetrance, the clinical presentation of the disease is highly heterogeneous, with different degrees of severity and patterns of myocardial involvement even in patients of the same familiar group with the same gene mutation: the pathology spectrum ranges from the absence of symptoms to sudden cardiac death (SCD) sustained by ventricular arrhythmias, which may, in some cases, be the first manifestation of an otherwise silent pathology. An evidence-based systematic review of the literature was conducted to evaluate the state of the art of the diagnostic techniques for the correct post-mortem identification of ARVC. The research was performed using the electronic databases PubMed and Scopus. A methodological approach to reach a correct post-mortem diagnosis of ARVC was described, analyzing the main post-mortem peculiar macroscopic, microscopic and radiological alterations. In addition, the importance of performing post-mortem genetic tests has been underlined, which may lead to the correct identification and characterization of the disease, especially in those ARVC forms where anatomopathological investigation does not show evident morphostructural damage. Furthermore, the usefulness of genetic testing is not exclusively limited to the correct diagnosis of the pathology, but is essential for promoting targeted screening programs to the deceased’s family members. Nowadays, the post-mortem diagnosis of ARVC performed by forensic pathologist remains very challenging: therefore, the identification of a clear methodological approach may lead to both a reduction in under-diagnoses and to the improvement of knowledge on the disease. Full article

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular diseases, and it shows an autosomal dominant pattern of inheritance. HCM can be clinically silent, and sudden unexpected death due to malignant arrhythmias may be the first manifestation. Thus, the HCM diagnosis could be performed at a clinical and judicial autopsy and offer useful findings on morphological features; moreover, it could integrate the knowledge on the genetic aspect of the disease. This review aims to systematically analyze the literature on the main post-mortem investigations and the related findings of HCM to reach a well-characterized and stringent diagnosis; the review was performed using PubMed and Scopus databases. The articles on the post-mortem evaluation of HCM by gross and microscopic evaluation, imaging, and genetic test were selected; a total of 36 studies were included. HCM was described with a wide range of gross findings, and there were cases without morphological alterations. Myocyte hypertrophy, disarray, fibrosis, and small vessel disease were the main histological findings. The post-mortem genetic tests allowed the diagnosis to be reached in cases without morpho-structural abnormalities; clinical and forensic pathologists have a pivotal role in HCM diagnosis; they contribute to a better definition of the disease and also provide data on the genotype–phenotype correlation, which is useful for clinical research. Full article

Brugada syndrome (BrS) is an arrhythmogenic disorder increasing the risk of syncopal episodes and sudden cardiac death. BrS usually runs through families with reduced penetrance and variable expression. We analyzed the multigenerational family of a patient who died after sudden cardiac arrest with post-mortem diagnosis of BrS. We analyzed clinical history, comprehensive arrhythmic risk, genetic findings, and additional tests, including electrocardiogram (ECG), detailed 24-hour Holter ECG results, and standard echocardiography findings, and followed up the patients in the ambulatory clinic. We analyzed a pedigree of 33 members of four generations of the family (19 male and 14 female patients). In this family, we identified 7 patients with BrS (median Modified Shanghai Score and Sieira model: 4.5 (4–6) and 1 (0–4) points, respectively), including both parents of the deceased patient, and 8 relatives with negative sodium channel blocker drug challenge test. Genetic testing revealed a novel mutation in sodium voltage-gated channel alpha subunit 5 (SCN5A) c.941A>G, (p.Tyr314Cys) inherited from the father of the proband. Patients with BrS were characterized by longer P-wave duration (120 (102–155) vs. 92.5 (88–110) ms, p = 0.013) and longer PR intervals (211.3 ±26.3 vs. 161.6 ± 18.9 ms, p = 0.001), along with more frequent positive aVR sign, but did not differ in terms of QRS duration or T-wave characteristics in resting ECGs. BrS patients were characterized by lower mean, minimal, and maximal (for all p ≤ 0.01) heart rates obtained from Holter ECG monitoring, while there was no difference in arrhythmias among investigated patients. Moreover, visual diurnal variability of ST segment changes and fragmented QRS complexes were observed in patients with BrS in Holter ECG monitoring. There were no major arrhythmic events during median follow-up of 68.7 months of alive BrS patients. These results suggest ECG features which may be associated with a diagnosis of BrS and indicate a novel SCN5A variant in BrS patients. Twelve-lead Holter ECG monitoring, with modified precordial leads placement, may be useful in BrS diagnostics and risk stratification in personalized medicine. Full article

Sudden cardiac death (SCD) represents a global emergency, with a high number of cases affecting all age groups every year. The prevention of these fatal events requires an accurate knowledge of etiology and pathogenesis, which can vary. Autopsy is an indispensable tool in cases of SCD for diagnostic purposes, as well as for judicial and preventive purposes for family members. Despite the completion of all routine post-mortem investigations, it is often complicated for the forensic pathologist to define the triggering cause of these events. The study of the proteome is proving to be extremely promising in the field of human cardiovascular disease. This paper aims to offer a literature review on the study of the proteome in post-mortem cadaveric biological samples obtained from SCD cases. The aim of this work is to outline the state of the art of the scientific advances that protein analysis can offer in the diagnosis of SCD and the limits that various studies have traced up to now. In conclusion, the work defines the future perspectives of this field in SCD, suggesting strategies to overcome the reported limits and improve the diagnostics of these events. Full article

Sudden cardiac death (SCD) is an unexpected natural death due to cardiac causes, usually happening within one hour of symptom manifestation or in individuals in good health up to 24 h before the event. Genomic screening has been increasingly applied as a useful approach to detecting the genetic variants that potentially contribute to SCD and helping the evaluation of SCD cases in the post-mortem setting. Our aim was to identify the genetic markers associated with SCD, which might enable its target screening and prevention. In this scope, a case–control analysis through the post-mortem genome-wide screening of 30 autopsy cases was performed. We identified a high number of novel genetic variants associated with SCD, of which 25 polymorphisms were consistent with a previous link to cardiovascular diseases. We ascertained that many genes have been already linked to cardiovascular system functioning and diseases and that the metabolisms most implicated in SCD are the lipid, cholesterol, arachidonic acid, and drug metabolisms, suggesting their roles as potential risk factors. Overall, the genetic variants pinpointed herein might be useful markers of SCD, but the novelty of these results requires further investigations. Full article

Sudden unexpected death (SUD) is a fatal event that occurs in an apparently healthy subject in a way that such an abrupt outcome could have not been predicted. SUD—including sudden intrauterine unexplained death (SIUD), sudden neonatal unexpected death (SNUD), sudden infant death syndrome (SIDS), sudden unexpected death of the young (SUDY), and sudden unexpected death in the adult (SUDA)—occurs as the first manifestation of an unknown underlying disease or within a few hours of the presentation of a disease. SUD is a major unsolved, shocking form of death that occurs frequently and can happen at any time without warning. For each case of SUD, a review of clinical history data and performance of a complete autopsy, particularly focused on the study of the cardiac conduction system, were carried out according to the necropsy protocol devised by the Lino Rossi Research Center, Università degli Studi di Milano, Italy. Research cases collected and selected for this study were represented by 75 SUD victims that were subdivided into 15 SIUD, 15 SNUD, 15 SUDY, and 15 SUDA victims. After a routine autopsy and clinical history analysis, death remained unexplained, and hence a diagnosis of SUD was assigned to 75 subjects, which included 45 females (60%) and 30 (40%) males ranging in age from 27 gestational weeks to 76 years. Serial sections of the cardiac conduction system disclosed frequent congenital alterations of the cardiac conduction system in fetuses and infants. An age-related significant difference in distribution among the five age-related groups was detected for the following anomalies of the conduction system: central fibrous body (CFB) islands of conduction tissue, fetal dispersion, resorptive degeneration, Mahaim fiber, CFB cartilaginous meta-hyperplasia, His bundle septation, sino-atrial node (SAN) artery fibromuscular thickening, atrio-ventricular junction hypoplasia, intramural right bundle branch, and SAN hypoplasia. The results are useful for understanding the cause of death for all SUD cases that were unexpected and would have otherwise remained unexplained, so as to motivate medical examiners and pathologists to perform more in-depth studies. Full article

Background: Myocardial fibrosis is a common postmortem finding among individuals with Sudden Cardiac Death (SCD). Numerous in vivo and in vitro studies have shown that increased galectin-3 (gal3) expression into the myocardium is associated with higher incidence of fibrosis. Although elevated gal3 expression is linked with myocardial fibrosis, its role in predicting the risk of SCD is unknown. Methods: We reviewed the clinical datasets and post-mortem examination of 221 subjects who had died suddenly. We examined myocardial pathology including the extent of cardiac hypertrophy, fibrosis, and the degree of coronary atherosclerosis in these subjects. In a select group of SCD subjects, we studied myocardial gal3 and periostin expression using immunohistochemistry. To further examine if a higher level of circulating gal3 can be detected preceding sudden death, we measured serum gal3 in a porcine model of subtotal coronary artery ligation which shows an increased tendency to develop lethal cardiac arrhythmias, including ventricular tachycardia or fibrillation. Results: Of the total 1314 human subjects screened, 12.7% had SCD. Comparison of age-matched SCD with non-SCD subjects showed that SCD groups had excessive myocardial fibrosis involving both the left ventricular free wall and interventricular septum. In pigs with subtotal coronary artery ligation and SCD, we detected significantly elevated circulating gal3 levels approximately 10 days preceding the SCD event. Immunohistochemistry showed increased myocardial gal3 and periostin expression in pigs that died suddenly, compared to the controls. Conclusion: Our study shows that increased gal3 is associated with a higher risk of myocardial fibrosis and the risk of SCD. This supports the importance of larger translational studies to target gal3 to prevent cardiac fibrosis and attenuate the risk of SCD. Full article