Basis Of Sudden Cardiac Death Research Articles

Risk stratification in cardiomyopathies (dilated, hypertrophic, and arrhythmogenic cardiomyopathy) by cardiac magnetic resonance imaging.

Cardiac magnetic resonance imaging (CMR) is a non-invasive, multiplanar, and high spatial resolution imaging technique, which represents the current gold standard for the evaluation of biventricular volumes and function. Furthermore, unlike other methods, it has the great advantage of characterizing the myocardial tissue by identifying the presence of alterations, such as oedema and focal and diffuse fibrosis. In particular, the late gadolinium enhancement technique makes it possible to identify areas of focal fibrosis that often constitute the substrate for the triggering of threatening ventricular arrhythmias at the basis of sudden cardiac death. For this reason, the use of CMR in the study of cardiomyopathies has become of primary importance, both for the differential diagnosis and for patient risk stratification. In this brief review, the ability of CMR in prognostic stratification of patients with dilated, hypertrophic, and arrhythmogenic cardiomyopathy will be analysed. In particular, the role of CMR in the prediction of arrhythmic risk and in the decision-making process for the implantation of a cardiac defibrillator will be examined.

Genetics of Sudden Cardiac Death, the Channelopathies: Today's Perspective and the Future

Channelopathy constitute significant proportion of SCD worldwide (around 10% or 370000 deaths annually). Besides LQTS, the channelopathies include Brugada syndrome (BrS), short QT syndrome, Early Repolarization Syndrome (ERS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and congenital sick sinus syndrome. It was constituting a mysterious group of disease until the second half of the last century when Anton Jervell and Fred Lange-Nielsen described Jervell Lange-Nielsen syndrome in 1957.It was late until 1995 where genetic characterization commenced. Later on, the massive genetic information obtained in the field with discovery of genetic heterogeneity and allelic heterogeneity were all part of our new understanding and clues to solve the historical conundrum of channelopathies. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels. Diving deep into the genetic details of those syndromes enable us to improve our knowdelege and decode the pathophysiology of those malignant arrhythmias. The ultimate ambition is prevention of channelopathy based sudden cardiac death and associated disorders in human.

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

BackgroundThe 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.

The Hidden Fragility in the Heart of the Athletes: A Review of Genetic Biomarkers.

Sudden cardiac death (SCD) is a devastating event which can also affect people in apparent good health, such as young athletes. It is known that intense and continuous exercise along with a genetic background that predisposes a person to the risk of fatal arrhythmias is a trigger for SCD. Therefore, knowledge of the athlete’s genetic conditions underlying the onset of SCD must be extended, in order to develop new effective prevention and/or therapeutic strategies. Arrhythmic features occur across a broad spectrum of cardiac diseases, sometimes presenting with overlapping phenotypes. The genetic basis of arrhythmogenic disorders has been greatly highlighted in the last 30 years, and has shown marked heterogeneity. The advent of next-generation sequencing has constantly updated our understanding of the genetic basis of arrhythmogenic diseases and is laying the foundation for precision medicine. With the exception of a few clinical cases involving a single athlete showing a highly suspected phenotype for the presence of a heart disease, there are few studies to date that analysed the applicability of genetic testing on cohorts of athletes. This evidence shows that genetic testing can contribute to the diagnosis of up to 13% of athletes; however, the presence of clinical markers is essential. This review aims to provide a reference collection on current knowledge of the genetic basis of sudden cardiac death in athletes and to review updated evidence on the effectiveness of genetic testing in early identification of athletes at risk for SCD.

Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young.

Unexplained sudden death in the young is cardiovascular in most cases. Structural and conduction defects in cardiac-related genes can conspire to underlie sudden cardiac death. Here we report aclinical investigation and an extensive genetic assessment of aTunisian family with sudden cardiac death in young members. In order to identify the family-genetic basis of sudden cardiac death, we performed Whole Exome Sequencing (WES), read depth copy-number-variation (CNV) screening and segregation analysis. We identify6 ultra-rare pathogenic heterozygous variants in OBSCN, RYR2, DSC2, AKAP9, CACNA1C and RBM20 genes, and one homozygous splicing variant in TECRL gene consistent with an oligogenic model of inheritance. CNV analysis did not reveal any causative CNV consistent with the family phenotype. Overall, our results are highly suggestive for acumulative effect of heterozygous missense variants as disease causation and to account for agreater disease severity among offspring. Our study further confirms the complexity of the inheritance of sudden cardiac death and highlights the utility of family-based WES and segregation analysis in the identification of family specific mutations within different cardiac genes pathways.

Molecular Autopsy for Sudden Cardiac Death: Current State and Considerations

The study of the genetic basis of sudden cardiac death has been impacted by advances in sequencing technology, gene variant interpretation, and additional evaluation into the ideal clinical approach to assessing cause of death and the medical and psychological risks of surviving family members. This short review aims to summarize recent publications as well as provide context for future directions for the care of families faced with sudden cardiac death. The molecular autopsy is a critical method in determining cause of death, particularly in autopsy-negative sudden cardiac death. Although the cost and availability of exome sequencing have improved in the past few years, its utility in the postmortem evaluation has not significantly improved yield. This is primarily due to the increase in genetic variants detected through this sequencing modality and the difficulty in interpreting these results. Medical examiners are essential in the proper identification and referral of surviving relatives to multidisciplinary clinics that include an expert cardiologist, cardiac genetic counselor, and clinical psychologist that can provide appropriate education, clinical evaluation, and psychological support. Future studies need to build on the improvement in variant interpretation and appropriate education and support of medical examiners. This will ensure family members are referred to appropriate providers such that they can receive medical and psychological care that will improve overall health outcomes and reduce the incidence of subsequent sudden cardiac death in the family.

Molecular genetic basis of sudden cardiac death in the young with cardiomyopathy of various origins

This paper provides a review of the modern literature devoted to the problem of forensic medical interpretation of the molecular genetic research of the young who died suddenly. The authors attempted to draw a parallel between the morphological markers of different variants of cardiomyopathy as the most common disease in sudden death at a young age and the association with genetic mutations in the genes responsible for the synthesis of sarcomer proteins, desmos and membrane channels. Based on the results of the analysis, further research is proposed to improve the accuracy of forensic diagnosis in cases of young deaths.

Genetics of sudden cardiac death.

Sudden cardiac death occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Genetic studies conducted during the past 20 years have markedly illuminated the genetic basis of the inherited cardiac disorders associated with sudden cardiac death. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels, and the cardiomyopathies, which have been attributed to mutations in genes encoding a broader category of proteins, including those of the sarcomere, the cytoskeleton, and desmosomes. We discuss the challenges currently faced in unraveling genetic factors that predispose to sudden cardiac death in the setting of sequela of coronary artery disease and present the genome-wide association studies conducted in recent years on electrocardiographic parameters, highlighting their potential in uncovering new biological insights into cardiac electric function.

Molecular and genetic basis of sudden cardiac death

The abrupt cessation of effective cardiac function due to an aberrant heart rhythm can cause sudden and unexpected death at any age, a syndrome called sudden cardiac death (SCD). Annually, more than 300,000 cases of SCD occur in the United States alone, making this a major public health concern. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of heart rhythm. This knowledge has helped shape the current diagnosis and treatment of inherited arrhythmia susceptibility syndromes associated with SCD and has provided a pathophysiological framework for understanding more complex conditions predisposing to this tragic event. This Review presents an overview of the molecular basis of SCD, with a focus on monogenic arrhythmia syndromes.

State of the Art in Forensic Investigation of Sudden Cardiac Death

The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death. Many of the causes of sudden death are due to genetic heart disorders, which can lead to both structural (eg, hypertrophic cardiomyopathy) and arrhythmogenic abnormalities (eg, familial long QT syndrome, Brugada syndrome). Most commonly, sudden cardiac death can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is this a tragic event for those involved, but it also presents a great challenge to the forensic pathologist involved in the management of the surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist, a genetic counselor, and the forensic pathologist directly involved in the sudden death case. This multifaceted cardiac genetic service is crucial in the evaluation and management of the clinical, genetic, psychological, and social complexities observed in families in which there has been a young sudden cardiac death. The present study will address the spectrum of structural substrates of cardiac sudden death with particular emphasis given to the possible role of forensic molecular biology techniques in identifying subtle or even merely functional disorders accounting for electrical instability.

Genetic predisposition to sudden cardiac death

Sudden cardiac death (SCD) is a major public health burden, and evidence from family history and from molecular studies on inherited arrhythmogenic syndromes indicates that genetic factors are important contributors to the risk of SCD. This review discusses recent advances on the genetic predisposition to SCD, with a specific focus on primary ventricular fibrillation and channelopathies. Coronary artery disease is the major determinant of SCD, and its predisposing genetic background is complex. Very recently, a first genome-wide association study on primary ventricular fibrillation was published but the results are not conclusive and further studies with greater numbers are needed. Among channelopathies, long QT syndrome and Brugada syndrome are those in which more significant advances have been reported in the last year. Of note is the recently described early repolarization syndrome and the proposed classification of J wave syndromes. Revision of current guidelines for autopsy investigation has introduced molecular autopsy as a standard requirement for adequate assessment of SCD. Interesting data on the genetic basis of sudden cardiac death have been published in the past year, and, whereas in the field of channelopathies research findings have been partially recognized by current guidelines and translated into clinical practice, in the field of coronary artery disease further advances are still needed.

Genetic basis of sudden cardiac death due to emotional trauma in apparently healthy individuals: Commentary

In this issue of the journal, Yalta et al. [1] propose an elegant alternative solution to our report of the epidemic of sudden deaths caused by the demise of a popular politician in India [2]. Emotional trauma causing sudden deaths has been previously reported, although the reason behind such events has not been widely examined. Suggested causes include acute coronary events due to rupture of a previously silent atherosclerotic plaque, caused by stress-induced hemodynamic, autonomic and prothrombotic responses [3].

Genetic basis of sudden cardiac death due to emotional trauma in apparently healthy individuals

Abstract Several mechanisms underlying sudden deaths due to emotional trauma have been propounded. Emotional trauma has been known to be associated with hyperactivation of some physiyological systems including sympathetic system that may directly trigger malign arrhythmic events in arrhythmia-prone subjects or lead to some clinically serious conditions including acute coronary syndromes, Tako-tsubo cardiomyopathy (TTC) etc. that may have the potential to trigger sudden cardiac death (SCD). Besides these well known effects, emotional trauma may be associated with SCDs due to some genetically determined arrhythmogenic conditions including ion channelopathies (overt or obscure), particularly in relatively young victims with no apparent etiology of SCD suggesting thorough evaluation and genetic screening of family members of these victims for prevention of SCD.

Genetics and tragady

The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death (SCD) in the young. Many of the causes of SCD in the young are due to genetic heart disorders, which can lead to both structural (e.g., hypertrophic cardiomyopathy) and arrhythmogenic (e.g. familial long QT syndrome) abnormalities. Most commonly, SCD in the young can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is the tragic event for those involved, but it also presents a medical challenge to the clinician involved in the management of the surviving family members. Given the complex problem of SCD in the young, a co-ordinated multidisciplinary team approach to the investigation of such deaths is required, including expert pathology, cardiology, clinical and molecular genetic assessment, grief and genetic counselling, and involvement of patient support groups. The TRAGADY Network (Trans-Tasman Response AGAinst Sudden Death in the Young) was established in 2005, and comprises a group of highly motivated Australian and New Zealand health professionals, scientists and patient advocates who share the aim of reducing SCD in the young, principally by understanding the molecular, genetic and pathological basis of genetic heart diseases. The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death (SCD) in the young. Many of the causes of SCD in the young are due to genetic heart disorders, which can lead to both structural (e.g., hypertrophic cardiomyopathy) and arrhythmogenic (e.g. familial long QT syndrome) abnormalities. Most commonly, SCD in the young can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is the tragic event for those involved, but it also presents a medical challenge to the clinician involved in the management of the surviving family members. Given the complex problem of SCD in the young, a co-ordinated multidisciplinary team approach to the investigation of such deaths is required, including expert pathology, cardiology, clinical and molecular genetic assessment, grief and genetic counselling, and involvement of patient support groups. The TRAGADY Network (Trans-Tasman Response AGAinst Sudden Death in the Young) was established in 2005, and comprises a group of highly motivated Australian and New Zealand health professionals, scientists and patient advocates who share the aim of reducing SCD in the young, principally by understanding the molecular, genetic and pathological basis of genetic heart diseases.

Sudden cardiac death in the young: a clinical genetic approach

The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death in the young. Many of the causes of sudden death in the young are due to genetic heart disorders, which can lead to both structural (e.g. hypertrophic cardiomyopathy) and arrhythmogenic (e.g. familial long QT syndrome) abnormalities. Most commonly, sudden cardiac death in the young can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is this a tragic event for those involved, but it also presents a medical challenge to the clinician involved in the management of the surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist, a genetic counsellor and the forensic pathologist directly involved in the sudden death case. This multifaceted cardiac genetic service is crucial in the evaluation and management of the clinical, genetic, psychological and social complexities observed in families in which there has been a young sudden cardiac death.

Molecular genetic basis of sudden cardiac death

In this review, the up-to-date understanding of the molecular basis of disorders causing sudden death will be described. Two arrhythmic disorders causing sudden death have recently been well described at the molecular level, the long QT syndromes (LQTS) and Brugada syndrome, and in this article we will review the current scientific knowledge of each disease. A third disorder, hypertrophic cardiomyopathy (HCM), a myocardial disorder causing sudden death, has also been well studied. Finally, a disorder in which both myocardial abnormalities and rhythm abnormalities coexist, arrhythmogenic right ventricular dysplasia (ARVD) will also be described. The role of the pathologist in these studies will be highlighted.

The pathologic basis of sudden death

The innumerable conditions associated with or causing sudden unexpected death are reviewed, with particular attention to the pathologic basis of sudden cardiac death. Diseases of the cardiovascular system account for the majority of sudden deaths, and coronary artery disease is considered to be responsible for most cases of sudden cardiac death. It was emphasized that a proportion of sudden cardiac deaths exhibit no significant myocradial or coronary artery pathology which might reasonably account for death, and the validity of including such cases in the category of sudden death due to ischemic heart disease has been questioned. It is suggested that the category, sudden unexpected death due to ischemic heart disease be more carefully and critically defined for future epidemiological studies, and that alternate pathophysiological mechanisms which might account for sudden cardiac death be rigorously sought and studied. The potential importance of pathologic lesions in the conduction system has been discussed, and it is recommended that an examination of the conduction system and its blood supply become a routine in all cases of sudden death. Additionally, the role of microvascular disease, including coronary micro-embolism has been stressed as a potential mechanism for sudden cardiac death, and the need for research studies in this area has been emphasized.