Cardiac Death In Young Adults Research Articles

Genetics in the diagnosis and treatment of cardiovascular diseases

Cardiovascular diseases (CVDs) remain one of the leading causes of morbidity and mortality worldwide, with genetics being a major risk factor. Genetic cardiovascular disease can occur either because of single variant (Mendelian) or polygenic influences and has been linked to inherited cardiovascular conditions (ICC) such as arrhythmias, cardiomyopathies, dyslipidemias, and aortopathies which are significant factors leading to sudden cardiac death in young adults. Timely screening, diagnosis, and management of ICC can not only provide life-saving treatment to a patient, but also identify at-risk family members. The field of pharmacogenomics (PGx) helped to understand the variable action of medications such as clopidogrel, aspirin, warfarin, and statin according to genotype. Newer technologies such as multi-omics can combine data from multiple sources such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome. These advancements can contribute to the development of polygenic prediction scores and precision medicine tailored to individual genotypes. Substantial strides have been made in genetic-based therapeutics, gene editing technologies, and drug delivery systems, which have significantly expanded treatment options for patients with acquired or inherited CVDs. Although variable, the country- and society-specific guidelines on genetic testing for ICC and PGx and treatment are being continuously updated to keep up with ongoing research in the field. Along with appropriate knowledge, other factors including cost and availability of genetic testing play a vital role in the usage by both physicians and patients. With the advent of newer genetic testing for CVDs, a key factor is the availability of genetic counselors (GCs) who are specifically trained in cardiovascular genomics. The current review provides a concise summary of the major influences of genetics in the diagnosis and treatment of CVDs.

Acute Adenoviral Infection Elicits an Arrhythmogenic Substrate Prior to Myocarditis.

Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate before significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species specificity, models of infection are lacking, and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse adenovirus type-3 was previously reported as cardiotropic, yet it has not been utilized to understand the mechanisms of cardiac infection and pathology. We have developed mouse adenovirus type-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart before an appreciable immune response or gross cardiomyopathy. Optical mapping of infected hearts exposes decreases in conduction velocity concomitant with increased Cx43Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43Ser368 are protected against mouse adenovirus type-3-induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of mouse adenovirus type-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreased IK1 and IKs current density. Turning to human systems, we find human adenovirus type-5 increases phosphorylation of Cx43Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes, indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data. Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.

Association between anti-cardiac autoantibodies in acute myocarditis and downstream clinical outcomes

Abstract Introduction Myocarditis is an inflammatory heart muscle disease that can result in cardiac dysfunction and arrhythmias. Its aetiology includes infectious, toxic or autoimmune causes. Myocarditis is responsible for sudden cardiac death in young adults (1) and can result in heart failure due to dilated cardiomyopathy in 20% of patients (2). The pathogenesis of myocarditis may involve immune system dysregulation leading to a cascade of inflammation and myocardial damage (3). For those patients that rapidly progress to end-stage dilated cardiomyopathy, an important dilemma is whether there is any prospect of heart function recovery. Therefore, there is an unmet need for a better understanding of key causal pathways and for developing a biological signature of disease progression. Hypothesis The progression of acute myocarditis depends on a persistent adaptive immune response against the heart, leading to ongoing inflammation, myocardial fibrosis and ultimately tissue destruction and remodelling. Aims We sought to explore anti-cardiac IgG serum levels, their temporal profile throughout follow up and their association with clinical and imaging data, in patients presenting with acute myocarditis. Methods We prospectively recruited 80 patients with a clinical diagnosis of acute myocarditis. We measured their total anti-cardiac IgG levels at admisssion, 3- and 12-months follow-up using an enzyme-linked immunosorbent assay (ELISA). We explored the association between the anti-cardiac IgG levels, cardiac MRI parameters (CMR) and clinical data. Results We detect an adaptive immune response against the heart in a subgroup of patients with acute myocarditis. 20% of patients develop high systemic titres of anti-cardiac IgG (OD threshold >0.65), within the first 7 days of presentation (Figure 1a). These patients continue to have persistent and significantly higher anti-cardiac IgG levels at 12 months (Figure 1b). Importantly, patients that mount a strong initial adaptive immune response against the heart, are more likely to show evidence of persistent oedema on CMR at 12 months(Figure 1c). Clinical event rates in our cohort have remained low at five-year follow-up. A small signal exists to indicate potentially higher rates of persistent symptoms (70% vs 47%), hospitalisations for heart failure (12% vs 8%) and new heart failure diagnosis (18% vs 11%), in patients that mount a strong adaptive immune response compared to those that do not. Conclusion A subset of patients with acute myocarditis develops a strong and persistent adaptive immune response against the heart. This may be associated with more myocardial oedema on cardiac MRI, persistent symptoms and higher rates of heart failure diagnoses and hospitalisations. Further work Plasma proteomics (targeted and un-targeted discovery) with validation in myocardial tissue. Analysis of CMR data with a focus on fibrosis assessment. ELISA for IgG subtypes and total IgG against myosin and troponin I.

Sudden cardiac death and thymic hyperplasia in adults: myth or reality? A case report

BackgroundSudden cardiac death is a major public health concern. The incidence of sudden cardiac death in young adults remains unclear and is generally underestimated.Case presentationThis is a case report of a 24-year-old man with a silent pathological history, who suddenly collapsed in a restaurant during dinner with his workmates. Autopsy and ancillary examination revealed focal atrioventricular node fibrosis and thymic hyperplasia.ConclusionsThymic hyperplasia has been considered a cause of sudden death in the past century. The mode of death was explained through nosographic entities such as status lymphaticus or thymic asthma, which are currently consigned to history books. Nevertheless, recent studies have sought to determine the relationship between thymic hyperplasia and sudden unexpected deaths in adults. Moreover, isolated fibrosis of the atrioventricular node is a rare condition that can remain undiagnosed even after a full autopsy. This report aims to provide a concise review of the existing literature concerning sudden cardiac death and discuss the so-called “thymic death” theory, which is now considered a myth. Was the finding of thymic hyperplasia and atrioventricular node fibrosis a coincidence? Should the myth surrounding “thymic death” be re-examined?

Revitalizing myocarditis treatment through gut microbiota modulation: unveiling a promising therapeutic avenue.

Numerous studies have demonstrated that gut microbiota plays an important role in the development and treatment of different cardiovascular diseases, including hypertension, heart failure, myocardial infarction, arrhythmia, and atherosclerosis. Furthermore, evidence from recent studies has shown that gut microbiota contributes to the development of myocarditis. Myocarditis is an inflammatory disease that often results in myocardial damage. Myocarditis is a common cause of sudden cardiac death in young adults. The incidence of myocarditis and its associated dilated cardiomyopathy has been increasing yearly. Myocarditis has gained significant attention on social media due to its association with both COVID-19 and COVID-19 vaccinations. However, the current therapeutic options for myocarditis are limited. In addition, little is known about the potential therapeutic targets of myocarditis. In this study, we review (1) the evidence on the gut-heart axis, (2) the crosslink between gut microbiota and the immune system, (3) the association between myocarditis and the immune system, (4) the impact of gut microbiota and its metabolites on myocarditis, (5) current strategies for modulating gut microbiota, (6) challenges and future directions for targeted gut microbiota in the treatment of myocarditis. The approach of targeting the gut microbiota in myocarditis is still in its infancy, and this is the study to explore the gut microbiota-immune system-myocarditis axis. Our findings are expected to pave the way for the use of gut microbiota as a potential therapeutic target in the treatment of myocarditis.

"Sudden Cardiac Death in Young Adults: Population Aspects in Bihor County, Romania"

Sudden cardiac death in young adults represents a worldwide health risk, sometimes producing deaths within minutes after the onset of the symptoms. The purpose of our study is to establish population aspects of sudden cardiac death in young adults, in Bihor County, Romania, to evaluate concordance and discordance between macroscopic and microscopic aspects of the heart and to offer a possible solution for diagnosing acute cardiovascular pathology.

Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation-Contraction Coupling.

Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, and metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem-cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features, which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology, as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease.

Application of Magnetocardiography to Screen for Inflammatory Cardiomyopathy and Monitor Treatment Response.

Background Inflammatory cardiomyopathy is one of the most common causes of sudden cardiac death in young adults. Diagnosis of inflammatory cardiomyopathy remains challenging, and better monitoring tools are needed. We present magnetocardiography as a method to diagnose myocardial inflammation and monitor treatment response. Methods and Results A total of 233 patients were enrolled, with a mean age of 45 (±18) years, and 105 (45%) were women. The primary analysis included 209 adult subjects, of whom 66 (32%) were diagnosed with inflammatory cardiomyopathy, 17 (8%) were diagnosed with cardiac amyloidosis, and 35 (17%) were diagnosed with other types of nonischemic cardiomyopathy; 91 (44%) did not have cardiomyopathy. The second analysis included 13 patients with inflammatory cardiomyopathy who underwent immunosuppressive therapy after baseline magnetocardiography measurement. Finally, diagnostic accuracy of magnetocardiography was tested in 3 independent cohorts (total n=23) and 1 patient, who developed vaccine-related myocarditis. First, we identified a magnetocardiography vector to differentiate between patients with cardiomyopathy versus patients without cardiomyopathy (vector of ≥0.051; sensitivity, 0.59; specificity, 0.95; positive predictive value, 93%; and negative predictive value, 64%). All patients with inflammatory cardiomyopathy, including a patient with mRNA vaccine-related myocarditis, had a magnetocardiography vector ≥0.051. Second, we evaluated the ability of the magnetocardiography vector to reflect treatment response. We observed a decrease of the pathologic magnetocardiography vector toward normal in all 13 patients who were clinically improving under immunosuppressive therapy. Magnetocardiography detected treatment response as early as day 7, whereas echocardiographic detection of treatment response occurred after 1 month. The magnetocardiography vector decreased from 0.10 at baseline to 0.07 within 7 days (P=0.010) and to 0.03 within 30 days (P<0.001). After 30 days, left ventricular ejection fraction improved from 42.2% at baseline to 53.8% (P<0.001). Conclusions Magnetocardiography has the potential to be used for diagnostic screening and to monitor early treatment response. The method is valuable in inflammatory cardiomyopathy, where there is a major unmet need for early diagnosis and monitoring response to immunosuppressive therapy.

Characterisation of patients referred to a tertiary-level inherited cardiac condition clinic with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC)

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy is a rare inherited disease with incomplete penetrance and an environmental component. Although a rare disease, ARVC is a common cause of sudden cardiac death in young adults. Data on the different stages of ARVC remains scarce. The purpose of this study is to describe the initial presentation and cardiac phenotype of definite and non-definite ARVC for patients seen at a tertiary service.MethodsThis is a single centre, observational cohort study of patients with definite and non-definite ARVC seen at the Inherited Cardiac Conditions services at University Hospital Birmingham (UHB) in the period 2010–2021. Patients were identified by interrogation of digital health records, medical history, imaging and by examining 12-lead electrocardiograms (ECG).ResultThe records of 1451 patients were reviewed; of those, 165 patients were at risk of ARVC (mean age 41 ± 17 years, 56% male). 60 patients fulfilled task force criteria for definite ARVC diagnosis (n = 40, 67% males), and 38 (72%) of them carried a known pathogenic variant. The remaining 105 patients (50% males) were non-definite, and of these 45 (62%) carried a known pathogenic variant. Patients in the definite group were more symptomatic, with palpitations (57% vs. 17%), syncope (35% vs. 6%) and shortness of breath (28% vs. 5%, p < 0.001). T-wave inversion in V1-V3 and epsilon waves were observed only in the definite group. Both PR interval and QRS duration were longer in the definite (170 ± 34 ms and 100 ± 19 ms, p < 0.001) compared to (149 ± 25 and 91 ± 14 ms, p = 0.005). Patients with definite ARVC had significantly larger RV end diastolic areas and significantly reduced biventricular function (RVEDA = 27 ± 10 cm2, RVFAC = 37 ± 11% and EF = 56 ± 12%) compared to the non-definite group (RVEDA = 18 ± 4 cm2, RVFAC 49 ± 6% and LVEF 64 ± 7%, p < 0.001). Sustained ventricular tachycardia (VT) occurred more frequently in the definite group compared to the non-definite group (27% vs. 2%, p < 0.001). Ventricular fibrillation was observed in the definite group only (8 of 60 patients, 13%).ConclusionOur study showed differences between definite and non-definite ARVC patients in terms of clinical, electrophysiological and imaging features. Major adverse cardiac events occurred more commonly in the definite group, but also were observed in non-definite ARVC. This single centre observational cohort study forms a basis for further prospective multicentre interventional studies.

Abstract 12554: Hipsc Derived Cardiomyocytes for Mechanistic, Patient Tailored Treatment in a Novel Mutation Linked to Cpvt

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a disease related to altered ryanodine receptor (RyR) mediated SR Ca 2+ leak and associated with sudden cardiac death in young adults. We recently identified a family with a mixed phenotype of CPVT and long-QT-syndrome (CPVT3*) related to a novel mutation in the trans-2.3-enyol-CoA reductase-like (TECRL) gene. Ventricular arrhythmia burden varies greatly between individual CPVT3* patients. Methods/Results: We generated human induced pluripotent stem cell derived cardiomyocytes (iPSc-CM) from a control and CPVT3* patient to explore underlying mechanisms and individualize pharmacological treatment. iPSc-CM were studied using confocal Ca 2+ imaging (fluo-4). Ca 2+ signaling during excitation-contraction coupling was studied in the presence of different clinically available modulators of RyR mediated SR Ca 2+ leak. In particular, cardiomyocyte function and arrythmias were tested upon addition of the class Ic antiarrhythmic flecainide (10μM), the RyR stabilizer dantrolene (1μM), the betablocker R-Carvedilol (1μM), the kinase inhibitor Rimacalib (10μM) and the RyR-Calstabin interaction stabilizer S107 (10μM). Under baseline conditions, CPVT3* iPSc-CM showed significantly decreased Ca 2+ transient (CaT) amplitudes and increased CaT duration. Upon addition of the beta-agonist isoproterenol (ISO, 100nM), CaT amplitudes and pro-arrhythmogenic Ca 2+ release (i.e. Ca 2+ sparks) significantly increased in CPVT3* as compared to control. All pharmaceuticals altered Ca 2+ signaling in CPVT3* in a substance dependent manner and pro-arrhythmogenic Ca 2+ release was particularly mitigated upon addition of flecainide. Treatment of the CPVT3* patient with flecainide significantly reduced ventricular premature beats as determined by 24 hour holter-ECG monitoring. Conclusion: We quantitatively assessed drugs targeting RyR mediated SR Ca 2+ leak in a CPVT3* patient with a novel TECRL mutation using iPSc-CM. Favorable in-vitro results of flecainide were mirrored in a significant reduction of ventricular arrhythmia in-vivo. Our results underscore the potential of iPSc-CM for the development of patient-tailored treatment in genetic arrhythmia syndromes.

КЛИНИЧЕСКИЕ И МОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКИЕ ОСНОВЫ ВНЕЗАПНОЙ СЕРДЕЧНОЙ СМЕРТИ ПРИ ПЕРВИЧНЫХ ЭЛЕКТРИЧЕСКИХ ЗАБОЛЕВАНИЯХ СЕРДЦА У ДЕТЕЙ

Primary electrical heart diseases (PEHDs) are hereditary orphan life-threatening conditions leading to a sudden cardiac death in young adults in the absence of structural heart disease. Among the most common and studied diseases of this group are: long QT syndrome (LQTS), catecholaminergic ventricular tachycardia, Brugada syndrome, short QT syndrome, early ventricular repolarization syndrome. Also, this group of diseases includes congenital sick sinus syndrome, progressive cardiac conduction defect, idiopathic ventricular fibrillation, familial atrial fibrillation and a number of cases (from 5 to 10%) of the sudden cardiac death syndrome in infants. The total prevalence of PEHDs in the pediatric population is quite high and is about 1:2000, mainly due to long QT syndrome. PEHDs are poorly identified by the standard clinical approach, at the same time a delay in diagnosing and prescribing specific therapy may lead to fatal consequences and sudden cardiac death of the child at the first-ever syncope. The vast majority of PEHDs genes identified to date encode subunits of cardiac ion channels or proteins, which interact with ion channels and regulate their functions. The advent of the next generation sequencing led to a shift in most DNA diagnostics laboratories from screening single genes or small gene panels to examining of whole exome or whole genome data. These diseases, especially LQTS, have become unique cardiological models for clinical and genetic studies, analysis of genotype-phenotype correlations and the development of a modern strategy of multi-level hybrid therapy and the prevention of sudden cardiac death (SCD) in people of young age. The most PEHDs can and should be diagnosed in childhood, which now makes it possible to effectively prevent life-threatening arrhythmias. More and more patients are surviving into adulthood, as yet, and patients are interacting with traditional risk factors and obviously should have higher cardiovascular risks. Due to the high prevalence in the population, the association with the SCD, the polymorphism of clinical and genetic manifestations, high technology medicine, the research of PEHDs has become one of the priority places in both pediatric and adult cardiology, and the diseases have now become models for development of gene therapies. The paper outlines the clinical and genetic characteristics, the basics of diagnostics and up-to-date therapeutic, interventional and surgical technologies for the treatment of the most common PEHDs in childhood.

Adenovirus increases arrhythmia susceptibility during acute cardiac infection

Myocarditis is responsible for 42% of sudden cardiac death in young adults, yet mechanisms underlying virally induced arrhythmia remain elusive. Adenovirus is a leading etiological agent of myocarditis but species‐specificity has limited development of animal disease models. Normal electrical impulse propagation in the heart is achieved through intercellular coupling via gap junctions, composed primarily of connexin43 (Cx43). Changes in Cx43 expression, localization, and/or function underlie the arrhythmias of sudden cardiac death. Given that gap junctions also propagate innate and adaptive antiviral immune responses, we hypothesized that adenovirus would target Cx43 to facilitate replication. Our prior work has demonstrated that Cx43 expression and function are indeed reduced rapidly during adenoviral infection limiting gap junction communication in human epithelial and cardiac cells. We are now employing a recently described cardiotropic strain of mouse adenovirus, MAdV‐3, to develop our work into whole animal studies and investigate virally‐induced alterations in cardiac electrophysiology and the molecular mechanisms of the resulting arrhythmogenic substrate. Adult mice were inoculated with MAdV‐3 and sampled after 7 days to model acute cardiac infection. We find MAdV‐3 viral genomes are specifically enriched in heart tissue, confirming cardiotropism. No cardiomyopathy was apparent by echocardiography or histopathology, consistent with human acute myocarditis patients. We find reductions in cardiac ion channel and connexin mRNA transcript levels after infection, and at the protein level, Cx43 is phosphorylated at residues known to reduce function. Ex vivo optical mapping experiments illustrate decreased conduction velocity in infected hearts. Turning to primary adult mouse cardiomyocytes, we detect prolonged action potential duration and impaired K+ current in infected cells by patch clamping. Confocal and super‐resolution localization microscopy of infected cardiac tissue and isolated cardiomyocytes reveals remodeling of gap junctions with alterations in complexing with scaffolding proteins and other ion channels at the cell‐cell junction. Finally, employing human iPSC‐derived cardiomyocytes and human adenovirus type‐5, we find increased Cx43 phosphorylation and, using optical mapping, perturbation of intercellular coupling during infection, just as we see with MAdV‐3. Our data demonstrate that reduced cellular coupling and ion channel function during adenoviral infection generates an arrhythmogenic substrate prior to an appreciable immune response or cardiomyopathy development. MAdV‐3 infection therefore provides a novel model of cardiac infection and myocarditis and provides physiologically relevant insight into mechanisms of virally‐induced arrhythmias.

BS-514-04 ADENOVIRUS INCREASES ARRHYTHMIA SUSCEPTIBILITY DURING ACUTE CARDIAC INFECTION

Myocarditis underlies 42% of sudden cardiac death in young adults, yet viral arrhythmogenic mechanisms remain elusive. Adenovirus is a leading cause but species-specificity has limited disease modeling in mice. Gap junctions, composed primarily of connexin43 (Cx43), enable electrical impulse propagation in the heart. Changes in Cx43 expression, localization, and/or function cause arrhythmias. Gap junctions propagate innate and adaptive antiviral responses, and our prior work has demonstrated that Cx43 expression and function are reduced during human adenoviral infection.

Anomalía de Ebstein como causa de muerte súbita. Presentación del primer caso de autopsia forense en panamá

Sudden cardiac death in young adults is often the first manifestation of an underlying cardiac disease not diagnosed previously. We present the case of sudden death in a 33-year-old male which occurred immediately after significant physical exertion. The autopsy revealed the existence of Ebstein´s disease that had not been diagnosed during the patient´s lifetime. Ebstein´s anomaly is a very rare congenital malformation that affects the tricuspid valve and is characterized, among other findings, by a severe dilatation of the right atrium with displacement of the septal and posterior leaflets towards the apex of the right ventricle with atrialization of part of it. As far as we know, this is the first case diagnosed after forensic autopsy in Panama. Due to its low frequency, this anomaly presents diagnostic challenges so it is not usually identified in life. Therefore, it is necessary for pathologists and forensic specialists to be familiar with it and to bear in mind among the differential diagnoses in cases of sudden death, especially in adolescents and young adults. Finally, a historical journey through the interesting life and work of Dr. Wilhelm Ebstein is carried out.

Arterial fibromuscular dysplasia as a factor in sudden cardiac death in young adults

The objective of the study is to consider the problem of diagnostics of a rare vasculopathy, fibromuscular dysplasia of coronary arteries, by the case study of a 19-year-old serviceman, an athlete with sudden death occurred during slight physical exertion. After repeated histological examination as part of the forensic medical examination, the diagnosis was made: «multifocal fibromuscular dysplasia of the coronary arteries and ascending aortic arch, complicated by acute left ventricular failure.» This disease often manifests with the acute coronary syndrome in people of young age. Therefore, special attention was given to the macroscopic and histological features of fibromuscular dysplasia of arteries.

CHARACTERISATION OF HYPERTROPHIC CARDIOMYOPATHY BY CARDIAC MAGNETIC RESONANCE IMAGING

Background: There are many causes of left ventricular hypertrophy which can result in arrhythmias and sudden cardiac death. Hypertrophic cardiomyopathy (HCM) is one of the commonly encountered cause of sudden cardiac death in young adults. Aim: Identifying the role of Cardiac MRI in characterising the diagnostic parameters of HCM. Materials and methods: 125 patients with clinical suspicion or genetic evidence of HCM referred for cardiac MRI between June 2013 to June 2021 were included under the study. Image interpretations were done by fellowship qualified cardiac imaging radiologist. Categorical variables were expressed using frequency and percentage. Numerical variables were presented using mean and standard deviation. Results: Out of the total population, 119 patients (95 %) had LV wall thickness &gt; 13 mm, 48 patients (38.4%) had Left ventricle outflow tract obstruction (LVOTO) and 32 patients (25.6 %) had mid cavity obstruction, 39 patients (37.9 %) had myocardial scar &gt; 15 % and asymmetric septal hypertrophy was the most frequently encountered left ventricle morphology Conclusion: Cardiac MRI detected HCM has a statistically significant association with the final diagnosis (histopathological and genetic correlation). CMRI hence serves as a reliable tool in identifying and characterising the various diagnostic and non- diagnostic parameters of HCM.

Abstract 13258: Transcriptomic Remodeling of Brugada Syndrome Arises During in vitro Cardiac Development

Introduction: Recent genetic data suggest that abnormal cardiac development participate to the pathogenesis of Brugada Syndrome (BrS), a rare inherited arrhythmia responsible for sudden cardiac death in young adults. In vitro cardiac differentiation of human induced pluripotent stem cells (hiPSCs) mimics cardiac development at the cellular level up to a prenatal stage. Objective: This study aims at defining whether BrS impairs cardiac differentiation of hiPSCs. Methods &amp; Results: Transcriptomic kinetics (daily bulk 3’RNA-seq from day 0 to day 30 of in vitro cardiac differentiation) were generated in triplicate for 2 control hiPSC lines and 2 BrS-patient hiPSC lines. First, global analysis unveiled that BrS and control kinetics start to diverge as early as day 8, coinciding with the emergence of beating cells. The 500 most differentially expressed genes between BrS and control kinetics revealed 7 main distinct expression profiles. Interestingly, in one of the clusters (Cluster 2), enriched in genes involved in ventricular development ( e.g. IRX4 , NKX2-5 ), the expression levels were higher in BrS as compared to control, starting at day 8. Inversely, another cluster (Cluster 4), enriched in genes involved in atrial development ( e.g. TBX18 , PITX2 ), displayed an opposite expression profile. Cell-type annotation of single-cell RNA-seq data obtained at day 30 of cardiac differentiation for 1 control (n=2; 11,499 cells) and 1 BrS hiPSCs line (n=2; 12,142 cells) confirmed this ventricular-to-atrial imbalance with an average ventricular-to-atrial cell number ratio of 0.97 and 8.27 for control and BrS lines, respectively. Conclusion: This first transcriptomic kinetic study supports the hypothesis of an early developmental defect in BrS. Altogether, our data show that BrS hiPSCs are more prone to ventricular specification as compared to control cells. This suggests that an abnormal cell fate during cardiac differentiation may participate to BrS pathogeny.

A Simulation Study on Electrical Activity of Ventricular Endocardial Tissue due to SCN5A L812Q Mutation.

Brugada Syndrome is a rare arrhythmia, hereditary in nature. It is caused due to mutation in genes that encodes sodium ion channels and it results sudden cardiac death in young adults. This paper aims to model a two dimensional SCN5A L812Q mutated endocardial tissue by modifying the model equations for sodium ion channel in the Ten Tusscher model for human ventricular tissue. Results show that the propagation of electrical activity in the mutated cells is slower when compared to the normal cells of the endocardial tissue. From this it is concluded that there is a large reduction of sodium current in the mutated region of the endocardial tissue. This leads to reduction in the total ionic current as well and further reduces the membrane potential. It also leads to the slower propagation of action potential in the mutated region when compared to the normal endocardial tissue.Clinical Relevance- This establishes the propagation of electrical activity in endocardial tissue for SCN5A L812Q gene mutation that results in arrhythmia called Brugada Syndrome.

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 &amp;lt; 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.

Asymptomatic Adult Type ALCAPA Syndrome Coexisting with Bicuspid Aortic Valve- A Case Report

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA), also known as Bland-White-Garland syndrome (BWGS) is a rare variant of the congenital anomalies of the coronary arteries. Two forms, the infantile (most common) and the adult types (rare) of these syndromic manifestations have been reported in the literature. Affected infants present with myocardial infarction and congestive heart failure. Few of them survive the first year of life, without appropriate surgical intervention. Adult type ALCAPA syndrome is one of the important causes of malignant cardiac arrhythmias, acute coronary syndromes, valvular pathologies and sudden cardiac death in young adults and adults. Asymptomatic adult type ALCAPA is uncommon, much more so its coexistence with bicuspid aortic valve (BAV). We present a 65-year-old patient with ALCAPA and BAV, who was largely asymptomatic. She had ligation of the ALCAPA, and aortic valve replacement, with a very good outcome.