Cause Of Sudden Cardiac Death Research Articles

On-device artificial intelligence: mobile solution for detecting severe aortic valve stenosis based on heart sounds

Abstract Background Aortic stenosis is still one of the major causes of sudden cardiac death in the elderly. Noninvasive screening for severe aortic valve stenosis (AS) may result in early cardiac diagnostic leading to an appropriate and timely medical intervention. Purpose The aims of this study were 1) to develop an artificial intelligence to detect severe AS based on heart sounds and 2) to build an application to screen patients using electronic stethoscope and smartphones, which will provide an efficient diagnostic workflow for screening as a complementary tool in daily clinical practice. Methods We enrolled 100 patients diagnosed with severe AS and 200 patients without severe AS (no echocardiographic sign of AS [n=100], mild AS [n=50], moderate AS [n=50]). The heart sounds were recorded in 4000 Hz waveform audio format at the following 3 sites of each patient; the 2nd intercostal right sternal border, the Erb's area and the apex. Each record was divided into multiple data of 4 seconds duration, which built 10800 sound records in total. We developed multiple convolutional neural networks (CNN) designed to recognize severe AS in heart sounds according to the recorded 3 sites. We adopted a stratified 4-fold cross-validation method by which the CNN was trained with 60% of the whole data, validated with 20% data and tested with the remaining 20% data not used during training and validation. As performance metrics we adopted the accuracy, F1 value and the area under the curve (AUC) calculated as the average of all cross-validation folds. For the smartphone application, we combined the best CNN-models from each recorded site for the best performance. Further 40 patients were newly enrolled for its clinical validation (no AS [n=10], mild AS [n=10], moderate AS [n=10], severe AS [n=10]). Results The accuracy, F1 value and AUC of each model were 88.9±5.7%, 0.888±0.006 and 0.953±0.008, respectively. The sensitivity and specificity were 87.9±2.2% and 89.9±2.4%. The recognition accuracy of moderate AS was significantly lower as compared to the other AS grades (moderate AS 74.1±6.1% vs no AS 98.0±1.4%, mild AS 97.6±1.2%, severe AS 87.9±2.2%, respectively, P<0.05). Our smartphone application showed a sensitivity of 100% (10/10), a specificity of 73.3% (22/30), and an accuracy of 80.0% (32/40), which implicated a good utility for screening. In the detailed analysis of 8 mistaken decisions, these were highly affected by the presence of severe mitral or tricuspid valve regurgitation despite of non-severe AS (7/8 [87.5%]). Conclusions This study demonstrated the promising possibility of an end-to-end screening for severe aortic valve stenosis using an electronic stethoscope and a smartphone application. This technology may improve the efficacy of daily medicine particularly where the human resource is limited or support a remote medical consultation. Further investigations are necessary to increase accuracy. Funding Acknowledgement Type of funding sources: None.

FEVER-INDUCED BRUGADA SYNDROME

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Brugada syndrome (BrS) is a rare cause of sudden cardiac death in asymptomatic healthy adults. We present a case of BrS unmasked by fever secondary to COVID-19 infection. CASE PRESENTATION: 38-year-old male with no prior medical history presented with a two-day history of subjective fevers, chills, productive cough, dyspnea, and left-sided pleuritic chest pain. He was noted to be febrile, tachypneic, tachycardic and hypoxic to the low-90s on room air. Bloodwork revealed elevated inflammatory markers with leukocytosis. Imaging and bloodwork were consistent with severe bilateral multifocal pneumonia secondary to COVID-19 infection. EKG on admission showed evidence of sinus tachycardia and type I Brugada pattern in leads V1 and V2 without ischemic changes. He was admitted for treatment of COVID-19 pneumonia with intravenous (IV) Remdesivir, IV steroids, and oxygen supplementation. Despite this, patient continued to be febrile, and interestingly, serial EKGs showed persistent type 1 Brugada pattern, which transformed into type 2 Brugada pattern after day 2 of admission, to persist for the next seven days. Echocardiogram showed normal left ventricular systolic function (ejection fraction 65%) with no significant valvular abnormalities. The Brugada pattern was thought to be induced by the febrile episodes, therefore all fevers were aggressively treated, and patient was closely monitored for any ventricular arrhythmias. Patient was educated on avoiding tricyclic antidepressants and sodium channel blockers as they are contraindicated in BrS. He was discharged home with plans for outpatient electrophysiological study. DISCUSSION: BrS is a clinical entity that can lead to sudden cardiac death and is associated with ECG changes of a 2mm J-point elevation and 1mm ST-segment elevation in two or more of the right precordial leads;type 1 is characterized by coveted-ST elevation in V1 and V2 whereas type 2 involves a saddle-back appearance. Diagnosis is made after excluding all other known causes of ST-segment elevation in right precordial leads, known as phenocopies. Known triggers include fever, intoxication, vagal stimulation, electrolyte imbalances, and various medications. Fever-induced BrS is more common among men in an age group of 30 to 60 years [4], it can precipitate cardiac arrest due to increased arrhythmogenicity of cardiac sodium channels at higher temperatures. Thus, timely and aggressive control of fever is crucial in preventing fatal arrhythmias, with fever-induced BrS leading to cardiac arrest in 18-20% of patients [2,3]. CONCLUSIONS: Clinicians need to be aware of the circumstances that can induce BrS, including fevers and medications, as BrS can be fatal, leading to cardiac arrest in many patients. Early recognition can lead to early intervention, through placement of an implantable pacemaker for documented arrhythmia, to decrease morbidity and mortality. REFERENCE #1: 1. Bayes de Luna A, Brugada J, Baranchuk A, et al. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol. 2012;45:433-442. [PubMed] [Google Scholar] REFERENCE #2: 2. Amin AS, Meregalli PG, Bardai A, Wilde AA, Tan HL. Fever increases the risk for cardiac arrest in the Brugada syndrome. Ann Intern Med. 2008;149:216-218. [PubMed] [Google Scholar] DISCLOSURES: No relevant relationships by Muhammad Hanif, source=Web Response No relevant relationships by Sudheer Konduru, source=Web Response No relevant relationships by Marino Leonardi, source=Web Response No relevant relationships by SANA MULLA, source=Web Response No relevant relationships by Ruqqiya Mustaqeem, source=Web Response No relevant relationships by Vihitha Thota, source=Web Response

Hypertrophic cardiomyopathy in children.

Hypertrophic cardiomyopathy (HCM) characterized by asymmetric ventricular septal hypertrophy, is the commonest cause of sudden cardiac death (SCD) in the young. The underlying etiology of HCM in the childhood and adolescent patients is diverse. Moreover, the prognosis of pediatric HCM depends on the age of presentation and etiology. Despite the complexity of children with obstructive HCM, surgical treatment results in a favorable outcome for carefully selected patients in experienced tertiary referral center in contemporary era. Implantable cardioverter-defibrillator (ICD) remains the most effective and reliable treatment to prevent SCD. New pediatric SCD risk prediction model, which has good discrimination and calibration and can distinguish patients who are most benefit from an ICD implantation, is expected to be further refined in the future.

Preclinical short QT syndrome models: studying the phenotype and drug-screening.

Cardiovascular diseases are the main cause of sudden cardiac death (SCD) in developed and developing countries. Inherited cardiac channelopathies are linked to 5-10% of SCDs, mainly in the young. Short QT syndrome (SQTS) is a rare inherited channelopathy, which leads to both atrial and ventricular tachyarrhythmias, syncope, and even SCD. International European Society of Cardiology guidelines include as diagnostic criteria: (i) QTc ≤ 340 ms on electrocardiogram, (ii) QTc ≤ 360 ms plus one of the follwing, an affected short QT syndrome pathogenic gene mutation, or family history of SQTS, or aborted cardiac arrest, or family history of cardiac arrest in the young. However, further evaluation of the QTc ranges seems to be required, which might be possible by assembling large short QT cohorts and considering genetic screening of the newly described pathogenic mutations. Since the mechanisms underlying the arrhythmogenesis of SQTS is unclear, optimal therapy for SQTS is still lacking. The disease is rare, unclear genotype-phenotype correlations exist in a bevy of cases and the absence of an international short QT registry limit studies on the pathophysiological mechanisms of arrhythmogenesis and therapy of SQTS. This leads to the necessity of experimental models or platforms for studying SQTS. Here, we focus on reviewing preclinical SQTS models and platforms such as animal models, heterologous expression systems, human-induced pluripotent stem cell-derived cardiomyocyte models and computer models as well as three-dimensional engineered heart tissues. We discuss their usefulness for SQTS studies to examine genotype-phenotype associations, uncover disease mechanisms and test drugs. These models might be helpful for providing novel insights into the exact pathophysiological mechanisms of this channelopathy and may offer opportunities to improve the diagnosis and treatment of patients with SQT syndrome.

Sudden Cardiac Death in Athletes.

Sudden Cardiac Death in Athletes.

Whole-heart ventricular arrhythmia modeling moving forward: Mechanistic insights and translational applications.

Ventricular arrhythmias are the primary cause of sudden cardiac death and one of the leading causes of mortality worldwide. Whole-heart computational modeling offers a unique approach for studying ventricular arrhythmias, offering vast potential for developing both a mechanistic understanding of ventricular arrhythmias and clinical applications for treatment. In this review, the fundamentals of whole-heart ventricular modeling and current methods of personalizing models using clinical data are presented. From this foundation, the authors summarize recent advances in whole-heart ventricular arrhythmia modeling. Efforts in gaining mechanistic insights into ventricular arrhythmias are discussed, in addition to other applications of models such as the assessment of novel therapeutics. The review emphasizes the unique benefits of computational modeling that allow for insights that are not obtainable by contemporary experimental or clinical means. Additionally, the clinical impact of modeling is explored, demonstrating how patient care is influenced by the information gained from ventricular arrhythmia models. The authors conclude with future perspectives about the direction of whole-heart ventricular arrhythmia modeling, outlining how advances in neural network methodologies hold the potential to reduce computational expense and permit for efficient whole-heart modeling.

Inherited Arrhythmia Syndromes.

Inherited Arrhythmia Syndromes.

Molecular autopsy and subsequent functional analysis reveal de novo DSG2 mutation as cause of sudden death

Sudden cardiac death (SCD) is a common cause of death in young adults. In up to 80% of cases a genetic cause is suspected. Next-generation sequencing of candidate genes can reveal the cause of SCD, provide prognostic management, and facilitate pre-symptomatic testing and prevention in relatives. Here we present a proband who experienced SCD in his sleep for which molecular autopsy was performed.We performed a post-mortem genetic analysis of a 49-year-old male who died during sleep after competitive kayaking, using a Cardiomyopathy and Primary Arrhythmia next-generation sequencing panel, each containing 51 candidate genes. Autopsy was not performed.Genetic testing of the proband resulted in missense variants in KCNQ1 (c.1449C > A; p.(Asn483Lys)) and DSG2 (c.2979G > T; p.(Gln993His)), both absent from the gnomAD database. Familial segregation analysis showed de novo occurrence of the DSG2 variant and presence of the KCNQ1 variant in the proband's mother and daughter. KCNQ1 p.(Asn483Lys) was predicted to be pathogenic by MutationTaster. However, none of the KCNQ1 variant carrying family members showed long QTc on ECG or Holter. We further functionally analysed this variant using patch-clamp in a heterologous expression system (Chinese Hamster Ovary (CHO) cells) expressing the KCNQ1 mutant in combination with KCNE1 wild type protein and showed no significant changes in electrophysiological function of Kv7.1.Based on the above evidence, we concluded that the DSG2 p.(Gln993His) variant is the most likely cause of SCD in the presented case, and that there is insufficient evidence that the identified KCNQ1 p.(Asn483Lys) variant would confer risk for SCD in his mother and daughter. Fortunately, the DSG2 variant was not inherited by the proband's two children. This case report indicates the added value of molecular autopsy and the importance of subsequent functional study of variants to inform patients and family members about the risk of variants they might carry.

B-PO04-156 TEMPORAL TRENDS IN THE INCIDENCE AND CHARACTERISTICS OF SUDDEN CARDIAC DEATH AMONG YOUNG IN NORTHERN FINLAND DURING 1998-2017

Although the mean age of sudden cardiac death (SCD) victims has increased during recent decades, overall incidence has remained relatively stable. Small but very important proportion of SCDs occur in subjects under 40 years of age and temporal trends in the incidence and characteristics of SCD in young are not well known. We aimed to investigate temporal trends in the incidence and characteristics among young SCD victims. The Fingesture study has prospectively gathered data from 5,869 consecutive autopsy verified SCD victims in Northern Finland during 1998-2017. On the basis of Finnish law, all subjects who die unexpectedly undergo autopsy. Determination of the cause of death was based on medicolegal autopsy, clinical records and questionnaires sent to the next of kin. The reference population in the Northern Finland for every 5-year period was used for incidence calculations. Out of total 5,869 SCDs during the period, 160 occurred in subjects under 40 years of age (2.7%) indicating a total incidence of 1.4/100 000. Incidence decreased during the study period; 2.1/100 000 in 1998-2002, 1.9/100 000 in 2003-2007, 1.3/100 000 in 2008-2012 and 0.7/100 000 in 2013-2017. Coronary artery disease (CAD) was the cause of death in 29% of young SCD victims. Among non-ischemic causes, most common were obesity related hypertrophic myocardial disease (24%), primary myocardial fibrosis (19%), hypertensive myocardial disease (6.3%), myocarditis (5%) and hypertrophic cardiomyopathy (4%). Structurally normal heart was present in 5 subjects (3%). Proportion of CAD as the cause of SCD decreased as follows; 38% in 1998-2002, 33% in 2003-2007, 22% in 2008-2012 and 14% in 2013-2017 (p=0.09). Proportion of male gender (81%) and obesity as a comorbidity (BMI >30 kg/m2, 40%) remained relatively stable during the period (p=0.58 and p=0.79, respectively). The incidence of SCD in young has decreased in Northern Finland during 1998-2017. Most of the deaths are due to non-ischemic myocardial diseases and relative proportion of CAD has decreased.

B-AB01-01 LOCAL REPOLARIZATION HETEROGENEITY IS MORE ARRHYTHMOGENIC THAN STRUCTURAL AND FUNCTIONAL CONDUCTION HETEROGENEITIES IN AN EX VIVO PORCINE MODEL

VF is a major cause of sudden cardiac death. In patients without apparent structural heart disease, J waves are often associated with an increased risk to VF. The mechanisms underlying these ECG patterns and the associated arrhythmogenesis are still debated. To investigate the respective role of repolarization and conduction heterogeneities in J wave’s emergence and in vulnerability to VF. Three porcine right ventricular models of either local (i) repolarization shortening, (ii) conduction slowing, or (iii) structural heterogeneity were created during ex vivo optical mapping experiments by locally perfusing (i) pinacidil (20μM, N=11) or (ii) flecainide (2μM, N=11) via a catheter introduced epicardially into a branch of the right coronary artery, or (iii) by local epicardial tissue destruction through radiofrequency application with a microneedle (9 close lesions at 30W, 1s, N=5). In each model, action potential properties and ECG were assessed. Arrhythmias were mapped and quantified. Bipolar electrograms (EGM) recordings were performed with an HD grid mapping catheter (N=3 in each group). EGM were not impacted in the first model but became locally fragmented in both conduction and structural heterogeneity areas (increased width and peaks number). We observed an increased arrhythmogenicity only in the two first models which presented 82 and 45% more spontaneous arrhythmias (p=0.0001 and 0.01 vs baseline; for (iii) 20% p=0.3), and a reduced pacing frequency threshold to induce arrhythmias (69 and 50 %, p=0.001 and 0.01 respectively vs baseline; for (iii) 25% p=0.1). During arrhythmias, repolarization heterogeneity increased focal activity and rotor number (832 vs 1410 p=0.02; 174 vs 324 p=0.04), while conduction heterogeneity did not affect dynamics and the structural one tended to reduce rotor number (235 vs 149 p=0.06) which tended to last longer. Contrary to structural and functional conduction heterogeneities, repolarization heterogeneity does not lead to EGM fragmentation in our model, but it is nevertheless associated with the highest prevalence of spontaneous VF. In terms of substrate, local repolarization shortening and structural heterogeneities had opposite effects on arrhythmia dynamics.

B-PO02-060 HEALTH RELATED QUALITY OF LIFE IN HYPERTROPHIC CARDIOMYOPATHY PATIENTS WITH IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR

HCM is a leading cause of sudden cardiac death in young patients. Implantable cardioverter-defibrillator (ICD) therapy is highly effective in terminating ventricular arrhythmias in high risk patients. The impact of ICDs on the quality of life of patients with HCM is not well delineated. The purpose of this study is to evaluate the impact of ICD implantation and therapies on QoL in patients with HCM. We posted an online survey that was available to all patients who are enrolled on the HCM website (HCMA, www.4HCM.org). The HCMA is an education and advocacy organization that includes patients with HCM, family members, and clinicians, including approximately 13,000 individuals. 692 patients ranging from age 18-75 years of age with HCM responded. 126 were excluded from the analysis as they did not have an ICD. 99 (17%) reported receiving the ICD at younger than 34 years of age. 102 (18%) reported needing at least one lead replacement over their lifetime. 179 (32%) reported receiving at least one shock over their lifetime with 111 (20%) of them reporting at least one appropriate shock and 74 (13%) reporting at least one inappropriate shock. 64 (11%) reported feeling very nervous either all of the time or a significant portion of the time prior to ICD implantation compared to 82 (14%) post ICD implantation. 39 (7%) reported feeling so depressed that nothing could cheer them either all of the time or a significant portion of the time prior to ICD implantation compared to 52 (9%) post ICD implantation. 46 (8%) reported feeling down or blue either all of the time or a significant portion of the time prior to ICD compared to 50 (9%) post ICD implantation. 383 (68%) reported being a happy person at least a significant portion or all the time prior to ICD implantation compared to 353 (62%) post ICD implantation. Lastly, 181 (32%) reported being in excellent health prior to ICD implantation compared to 162 (29%) post ICD implantation. In our cohort, patients who underwent an ICD implantation reported high percentage of both appropriate and inappropriate shocks. Patients reported a lower QoL post ICD implantation. The QoL data suggests further research is required to better understand the overall impact of ICD therapy on HCM.

Clinical course and surgical outcomes in middle-age adults with anomalous aortic origin of a coronary artery

Abstract Funding Acknowledgements Type of funding sources: None. Background Patients with anomalous aortic origin of a coronary artery (AAOCA) present with a wide range of clinical manifestations, including ischemic symptoms (chest pain or dyspnea) and sudden cardiac death (SCD). Studies have identified coronary anatomic characteristics associated with a higher risk of SCD. However, most of the published literature consists of studies in adolescents and young adults. There is a paucity of data regarding outcomes in middle-aged patients. Current guidelines reveal gaps in evidence for identification of adults are at risk for SCD, and for whom surgery is beneficial. Purpose To study the clinical course and rate of major adverse cardiac events (MACE) in middle-aged adults with AAOCA based on presenting symptoms, coronary anatomy on coronary computed tomography angiography (CCTA), stress test results, and surgical management. Methods We included all patients from January 2013 to December 2019 age > 18 at our institution who were found to have AAOCA. Patients with the following were excluded to minimize confounding factors which could cause MACE: coronary artery disease (CAD) with >50% stenosis in any coronary vessel, CAD requiring revascularization, heart failure with ejection fraction <40%, history of heart transplant, and non-AAOCA congenital heart disease. All patient charts were reviewed for demographics, coronary anatomy on CCTA, presenting symptoms, rationale for pursuing stress testing and CCTA, nature of surgical interventions, post-surgical course, and MACE (cardiovascular death, myocardial infarction, and need for coronary revascularization). All patients underwent PET as well as treadmill stress testing. Results Of 19,367 patients who underwent CCTA, 47 met inclusion criteria, with median age at diagnosis of 54 and median follow-up of 48 months. No patients suffered MACE. Twenty-five patients had AAORCA and 22 had AAOLCA (Table 1). Ten patients with AAORCA and 8 patients with AAOLCA presented with ischemic symptoms and had coronary anatomy characteristics associated with higher risk of SCD, as well as ischemia corresponding to the anomalous artery on stress testing and did not undergo surgery due to personal preference. Five symptomatic patients with stress-induced ischemia corresponding to the anomalous artery underwent surgery and all achieved symptom relief over a median follow up of 5 years. Conclusion As AAOCA is a significant cause of SCD in young adults, it is compelling to observe this adult cohort in which no patients experienced MACE, including 18 symptomatic patients with high-risk anatomy and stress-induced ischemia, as well as a Class I recommendations for surgery. The results suggest that although surgery may be beneficial for symptom relief, it does not necessarily improve mortality over an intermediate follow-up period. Future studies should examine surgical outcomes in middle-aged cohorts with larger sample sizes.

Whole-exome sequencing reveals MYH7 p.R671C mutation in three different phenotypes of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM) is one of the most common types of genetic heart disorder and features high genetic heterogeneity. HCM is a major cause of sudden cardiac death and also an important cause of heart failure-related disability. A pedigree with suspected familial HCM was recruited for the present study to identify genetic abnormalities. HCM was confirmed by echocardiography and clinical data of the family members were collected. Genomic DNA was extracted from the peripheral blood and sequenced based on standard whole-exome sequencing (WES) protocols. Sanger sequencing was further performed to verify mutation sites and their association with HCM. WES and Sanger sequencing revealed a heterozygous missense mutation (c.2011C>T p.R671C) in myosin heavy chain 7 (MYH7) that was identified in three family members. The Arg671Cys mutation was located in exon 18 and, to the best of our knowledge, has not been previously reported in familial HCM. Furthermore, family members carrying the same mutated gene were of different sexes and clinical phenotypes. They included the proband, a 17-year-old survivor of sudden cardiac arrest with ventricular systolic dysfunction, the proband's maternal uncle, who presented with ventricular diastolic dysfunction and the proband's mother, who had no obvious clinical symptoms and did not present with cardiac dysfunction. However, echocardiology indicated that the proband's mother had an enlarged left atrium, slightly thicker right anterior wall and anterior septum and an expanded atrial septum. Therefore, HCM exhibited obvious genetic and phenotypic heterogeneity. To the best of our knowledge, the present study was the first to report such a mutation in the MYH7 gene in familial HCM. In addition, the present study demonstrated that WES is a powerful tool for identifying genetic variants in HCM.

Histopathological Findings in Sudden Cardiac Death: 5-years Autopsy Experience in a Tertiary Hospital in Bandung, Indonesia

Background: Sudden death (SD) is a sudden and unexpected death with an unknown cause. However, it has been assummed that the most common causes of sudden deaths are cardiovascular or non-cardiovascular causes such as gastrointestinal disease, respiratory disease, genitourinary disease, epilepsy, and trauma. This study aimed to portray histopathological findings and causes of sudden cardiac death (SCD) cases based on 5 year autopsy experience in a tertiary hospital in Bandung, Indonesia. Methods: This study was a descriptive cross-sectional study exploring causes of SCD from 2015 to 2019 at Dr. Hasan Sadikin General Hospital, Bandung, Indonesia. All medical records with SCD and histopathology findings were retrieved from September to December 2020. Only cases with histopathological examination results were included.Results: SCD was found in 7 of 16 patients with sudden death. Coronary atherosclerosis was the most common (n=4), followed by myocardial infarction (n=2) and ruptured aortic aneurysm (n=1). Myocarditis and calcific aortic valve diseases were not found.Conclusions: In this study, the most common cause of SCD is coronary atherosclerosis, which is identified mainly in older and male patients.

Ischemic Heart Disease Related Sudden Cardiac Death in Autopsied Cases: An Egyptian perspective.

Diagnosis of the underlying cause of sudden unexpected death in a previously healthy individual remains one of the important challenges in forensic practice. Ischemic heart disease is the most common cause of sudden death. The current study aims to investigate the incidence and pathology of sudden ischemic cardiac death in Egypt. All cases of sudden cardiac death (SCD) examined by different forensic departments throughout Egypt during the period of January 2010 through December 2014 were included. Cases underwent complete autopsy examination including a thorough gross and microscopic examination of the heart and great blood vessels. Of 535 cases of SCD diagnosed during the period of the study, coronary atherosclerosis was the principle finding in 420 (78.5%) cases. The highest numbers of deaths were reported in fifth and sixth decades with male preference. Other causes of SCD included myocarditis, cardiomyopathies, valvular heart disease, and hypertensive heart disease (7.8%, 4.1%, 4.1%, and 2.8%, respectively). There was severe stenosis (>75%) of at least 1 coronary artery in 74% of cases. Type VI atherosclerosis was found in 40.7% of cases. The left anterior descending branch was the most affected artery by atherosclerosis. Acute coronary pathological events were demonstrated in 27.6% of cases. Recent myocardial infarction was evident in 55.5% of cases, whereas old infarcts were demonstrated in 44.5% of cases. Features of hypertensive heart disease were present in 18.3% of cases. In conclusion, ischemic heart disease is the leading cause of SCD in Egypt.

Identification of genes associated with sudden cardiac death: a network- and pathway-based approach.

BackgroundSudden cardiac death (SCD) accounts for a large proportion of the total deaths across different age groups. Although numerous candidate genes related to SCD have been identified by genetic association studies and genome wide association studies (GWAS), the molecular mechanisms underlying SCD are still unclear, and the biological functions and interactions of these genes remain obscure. To clarify this issue, we performed a comprehensive and systematic analysis of SCD-related genes by a network and pathway-based approach.MethodsBy screening the publications deposited in the PubMed and Gene-Cloud Biotechnology Information (GCBI) databases, we collected the genes genetically associated with SCD, which were referred to as the SCD-related gene set (SCDgset). To analyze the biological processes and biochemical pathways of the SCD-related genes, functional analysis was performed. To explore interlinks and interactions of the enriched pathways, pathway crosstalk analysis was implemented. To construct SCD-specific molecular networks, Markov cluster algorithm and Steiner minimal tree algorithm were employed.ResultsWe collected 257 genes that were reported to be associated with SCD and summarized them in the SCDgset. Most of the biological processes and biochemical pathways were related to heart diseases, while some of the biological functions may be noncardiac causes of SCD. The enriched pathways could be roughly grouped into two modules. One module was related to calcium signaling pathway and the other was related to MAPK pathway. Moreover, two different SCD-specific molecular networks were inferred, and 23 novel genes potentially associated with SCD were also identified.ConclusionsIn summary, by means of a network and pathway-based methodology, we explored the pathogenetic mechanism underlying SCD. Our results provide valuable information in understanding the pathogenesis of SCD and include novel biomarkers for diagnosing potential patients with heart diseases; these may help in reducing the corresponding risks and even aid in preventing SCD.

ANABOLICSTEROIDS THERAPY AS A TRIGGER OF CONDUCTION DISORDERS IN ATHLETES

The high prevalence of WPW syndrome among young people dictates the relevance of this topic studying. In the register of causes of sudden cardiac death among athletes, the proportion of this syndrome is about 1%. The frequency of SCD in professional sportsmen cluster of population, according to various authors, varies from 2.3 to 6.5 cases per 100 thousand active athletes that in 2.4 times higher than in the general population.On example of the clinical case demonstrated in this article the importanceof a precise examination of athletes and amateurs, withdetected WPW phenomenon/syndrome, regardless of presencesymptoms, especially on continuous anabolic steroids therapy background. Therefore, it is necessary to control not only the physical activity of people involved in sports, but also the use of pharmacological drugs in preparation for competitions.

Clinical prediction of genotypes in hypertrophic cardiomyopathy: A systematic review.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac condition and the most common cause of sudden cardiac death (SCD) in patients below the age of 35. Genetic testing is a vital part of HCM diagnostics, yet correlation with clinical phenotypes remains complex. Identifying clinical predictors of informative genetic testing may prevent unnecessary investigations and improve cost-effectiveness of services. This article reviews the current literature pertinent to identifying such predictors. Five literature databases were screened using a suitably designed search strategy. Studies investigating the correlation between having a positive genetic test for HCM and a range of clinical and radiological parameters were included in the systematic review. Twenty-nine observational studies of a total of 9,486 patients were included. The main predictors of informative genetic testing were younger age, higher septal thickness, reverse septal curvature, family history of HCM and SCD and the absence of hypertension. Two externally validated scoring systems have also been developed: the Mayo and Toronto scores. Novel imaging markers and complex algorithmic models are emerging predictors. Using clinical predictors to decide whom to test is a feasible alternative to investigating all comers. Nonetheless, currently there is not enough evidence to unequivocally recommend for or against this strategy. Further validation of current predictors and identification of new ones remain open research avenues.

Characterization and modelling of the abnormal electrophysiological response under beta-adrenergic stimulation in hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Introduction Hypertrophic Cardiomyopathy (HCM) is the most common inheritable heart pathology and the main cause of sudden cardiac death in young adults. HCM patients often present an enhanced arrhythmogenicity that can lead to lethal arrhythmias, especially during exercise. Recent studies have shown an abnormal response of HCM myocytes to β-adrenergic stimulation (β-ARS), with prolongation of their action potential duration (APD). The mechanisms underlying this aberrant response to sympathetic stimulation remain unknown. Purpose To investigate the key ionic mechanisms underlying the HCM abnormal response to β-ARS using human-based experimental and computational methodologies. Methods Experimental ionic currents, action potential and calcium transient were recorded in human adult cardiomyocytes from control and HCM patients. Isoproterenol (10-7 mol/L) was used to elicit β-ARS. Whole-cell ruptured patch voltage clamp experiments were conducted to characterise L-type calcium and potassium currents, with recordings performed before and after 3 min of drug exposure. The latest models of human ventricular electrophysiology and beta-adrenergic receptor signalling were integrated and calibrated using the human measured data. Simulations under isoproterenol were performed to quantify the effects of β-ARS on the action potential and calcium transient. The role of the main ion currents affected by β-ARS and by HCM remodelling was evaluated. Results In vitro, isoproterenol shortened APD (-16 ± 3%) in control, while prolonging APD in HCM myocytes (+23 ± 8%). Analysis of the measured data indicated two possible mechanisms contributing to APD prolongation in HCM myocytes. Firstly, a protracted L-type calcium current, presenting slower inactivation kinetics in HCM compared to control. The relative increase of potassium currents under β-ARS was also lower in HCM myocytes. The developed in silico models of β-ARS replicated the behaviour observed in the experimental data, based on slower L-type calcium current inactivation kinetics and a smaller increase of potassium currents in HCM. In absence of β-ARS, simulated HCM cardiomyocytes exhibited prolonged APD compared to control (525 ± 88 vs 281 ± 56 ms, p < 0.001). Under β-ARS, APD in control was reduced (-16.46%), whereas APD was prolonged in HCM (+11.63%). Further analysis showed that the reduction of the potassium currents increment under β-ARS was the main cause of the APD prolongation in HCM myocytes, with L-type calcium inactivation minimally contributing to APD prolongation. Conclusions In this study we assessed the effects of β-ARS on ion currents and APD in control and HCM myocytes. Our modelling results suggest that the increase of potassium repolarising currents under β-ARS is greatly reduced in HCM cardiomyocytes, being the main mechanism underlying their APD prolongation. This APD prolongation may have severe consequences in HCM patients, increasing the risk of exercise-induced arrhythmias. Abstract Figure.

A candidate genetic modifier and autosomal recessive cause of Brugada syndrome that may alter the circadian expression of SCN5A

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by a generous grant from the Newnham College Senior Members Research Support fund. Introduction Inherited cardiac arrhythmias (ICAs) are a major cause of sudden cardiac death (SCD) in the young. ICAs are caused by variants in genes encoding ion channels that predispose individuals to life-threatening arrhythmic events. Early diagnosis to facilitate implementation of effective clinical interventions that greatly reduce SCD risk is critical. ICAs have traditionally been considered monogenic diseases. However, the genomic architecture of ICAs is likely a continuum, ranging from monogenic and near-monogenic (strong genetic factor influenced by a few genetic modifiers) to oligogenic (cumulative effects of coinheritance of many genetic modifiers). The circadian clock, which is predicted to control the expression of one third of the protein-coding genome, has been implicated in contributing to ICAs because the incidence of arrhythmic events in ICA patients oscillates with a period of 24 hours. We therefore hypothesised that it may contribute to oligogenic disease. Purpose To identify variants that may contribute to ICAs and that are located in cis-regulatory motifs that are both functionally predicted to be binding sites for clock transcription factors and located in the promoters of ICA-associated genes predicted to exhibit diurnal rhythmic expression. Methods Genes associated with ICAs and predicted to be rhythmically expressed were identified and the region 1kb upstream of their transcription start sites screened for mammalian circadian motifs. Whole genome sequencing data from participants with ICAs in The 100,000 Genomes Project was interrogated for variants within these motifs. Results Two variants in the SCN5A promoter were significantly associated with Brugada syndrome (BrS) (OR = 2.77, p-value <2.2E-16; OR = 2.11, p-value = 6.23E-14). The variants were found in high linkage disequilibrium (D’=0.988, p-value <2.2E-16). This 2-variant haplotype was enriched in BrS patients who did (OR = 2.43, p-value = 7.07E-08; OR = 1.32, p-value = 0.0204) and did not (OR = 3.00, p-value <2.2E-16; OR = 1.78, p-value = 8.30E-09) have a likely genomic cause, implying that it may be a genetic modifier of BrS. This haplotype in the homozygous state was significantly enriched in individuals with BrS in whom a likely genomic cause had not been identified, suggesting it may be an autosomal recessive cause (OR = 0.102, Fisher’s p-value = 0.0120). Conclusion This haplotype has previously been reported to modulate BrS severity in a large family with a pathogenic SCN5A variant and has demonstrated a trend towards reduced SCN5A expression in murine cardiomyocytes – a molecular mechanism that slows cardiac conduction, predisposing individuals to BrS. Therefore, this 2-variant haplotype, or 1 variant therein, in the SCN5A promoter is a putative genetic modifier and autosomal recessive cause of BrS. Future work includes functional assay in human cardiomyocytes to characterise its molecular consequences on SCN5A expression and the circadian clock.