Arrhythmogenic Disease Research Articles

Interpreting the actionable clinical role of rare variants associated with short QT syndrome

Genetic testing is recommended in the diagnosis of short QT syndrome. This rare inherited lethal entity is characterized by structural normal hearts with short QT intervals in the electrocardiogram. Few families diagnosed with this arrhythmogenic disease have been reported worldwide so far, impeding a comprehensive understanding of this syndrome. Unraveling the origin of the disease helps to the early identification of genetic carriers at risk. However, only rare variants with a definite deleterious role should be actionable in clinical practice. Our aim was to perform a comprehensive update and reinterpretation, according to the American College of Medical Genetics and Genomics recommendations of all rare variants currently associated with short QT syndrome. We identified 34 rare variants. Reanalysis showed that only nine variants played a deleterious role associated with a definite short QT syndrome phenotype. These variants were located in the four main genes: KCNQ1, KCNH2, KCNJ2 or SLC4A3. Additional rare variants located in other genes were associated with other conditions with phenotypic shortened QT intervals, but not definite diagnosis of short QT syndrome. Periodically updating of rare variants, especially those previously classified as unknown, helps to clarify the role of rare variants and translate genetic data into clinical practice.

Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases.

Ryanodine receptor type 2 (RyR2) is the principal intracellular calcium release channel in the cardiac sarcoplasmic reticulum (SR). Pathological RyR2 hyperactivity generates arrhythmia risk in genetic and structural heart diseases. RYR2 gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia. In structural heart diseases (i.e., heart failure), posttranslation modifications render RyR2 channels leaky, resulting in pathologic calcium release during diastole, contributing to arrhythmogenesis and contractile dysfunction. Hence, RyR2 represents a therapeutic target in arrhythmogenic heart diseases. We provide an overview of the structure and function of RyR2, and then review US Food and Drug Administration-approved and investigational RyR2 inhibitors. A therapeutic classification of RyR2 inhibitors is proposed based on their mechanism of action. Class I RyR2 inhibitors (e.g., flecainide) do not change SR calcium content and are primarily antiarrhythmic. Class II RyR2 inhibitors (e.g., dantrolene) increase SR calcium content, making them less effective as antiarrhythmics but preferable in conditions with reduced SR calcium content such as heart failure.

Zebrafish as a Model System for Brugada Syndrome.

Brugada syndrome (BrS) is an inheritable cardiac arrhythmogenic disease, associated with an increased risk of sudden cardiac death. It is most common in males around the age of 40 and the prevalence is higher in Asia than in Europe and the United States. The pathophysiology underlying BrS is not completely understood, but several hypotheses have been proposed. So far, the best effective treatment is the implantation of an implantable cardioverter-defibrillator (ICD), but device-related complications are not uncommon. Therefore, there is an urgent need to improve diagnosis and risk stratification and to find new treatment options. To this end, research should further elucidate the genetic basis and pathophysiological mechanisms of BrS. Several experimental models are being used to gain insight into these aspects. The zebrafish (Danio rerio) is a widely used animal model for the study of cardiac arrhythmias, as its cardiac electrophysiology shows interesting similarities to humans. However, zebrafish have only been used in a limited number of studies on BrS, and the potential role of zebrafish in studying the mechanisms of BrS has not been reviewed. Therefore, the present review aims to evaluate zebrafish as an animal model for BrS. We conclude that zebrafish can be considered as a valuable experimental model for BrS research, not only for gene editing technologies, but also for screening potential BrS drugs.

"Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders"

BackgroundGenetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders.MethodsGenomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts.ResultsWe identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017–2019, with rates ranging from 50 to 60%.ConclusionThe results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.

Screening for arrhythmogenic heart disease in school age children-a pilot study

Screening for arrhythmogenic heart disease in school age children-a pilot study

MiRNAs as a tool for the diagnosis of suspected Brugada Syndrome

Abstract Background/Introduction Brugada syndrome (BrS) is a life-threatening arrhythmogenic disease that can lead to sudden unexplained death/cardiac arrest in otherwise healthy individuals. ECG represents the gold standard for the diagnosis. In 30% of cases, however, the syndrome is diagnosed only after a provocative test with sodium channel blockers [1]. Among the different approaches to support diagnosis, circulating biomarkers such as miRNAs may represent a tool that can provide a biological signature of the syndrome in patients with suspected BrS. Purpose Within the BrS and Artificial Intelligence Applications to Diagnosis system study, we collected and analyzed blood samples from patients with suspected BrS undergoing provocative tests aiming to assess whether miRNAs may be potential markers to identify the syndrome. Methods Patients undergoing provocative tests with sodium channel blockers (i.e., ajmaline, flecainide) were classified as positive (15 patients) and negative (13 patients) based on the test results. Blood samples were obtained when a Type-1 ECG pattern developed (for positive) or at the end of the provocative test without any electrographic changes (negative). miRNAs were extracted from circulating exosomes, obtained by blood samples, using a dedicated and innovative assay (exoRNeasy mini/midi kit, QIAGEN). They were quantified and quality tested by Agilent 2100 Bioanalyzer RNA assay; miRNA-seq was carried out with NovaSeq 6000 (Illumina, San Diego, CA). Data were analyzed through web-based platforms for network visual analytics (mirNET 2.0). Results The presence of 8 small RNAs up-regulated was reported in the positive group (hsa-miR-155-5p ,hsa-miR-10a-5p, hsa-miR-29a-3p, hsa-miR-142-5p, hsa-miR-30a-5p, hsa-miR-126-5p, hsa-miR-95-3p, hsa-miR-126-3p), with a log fold-change between 6.4 (as for hsa-miR-95-3p) and up to 615.0 (as for hsa-miR-126-3p) (Table 1). The network analysis results (Figure 1) on this group of miRNAs showed their involvement, among the others, in response to cytokine and muscle development (in terms of function analysis) and Ca2+pathway modulation (in terms of pathway analysis). Conclusion(s) In this work, a miRNA analysis of patients undergoing provocative tests for Type-1 BrS diagnosis was performed. Our results show a set of potential miRNAs that could be used to identify Type 1 BrS patients in whom the typical ECG pattern is basally lacking. Although further experiments and validation on a larger number of samples are necessary, our results could identify these miRNAs as potential early markers in patients with a suspected Type-1 BrS diagnosis.Upregulated miRNAs in BrS patientsMiRNA network analysis

Arrhythmogenic Manifestations of Chagas Disease: Perspectives From the Bench to Bedside.

Chagas cardiomyopathy caused by infection with the intracellular parasite Trypanosoma cruzi is the most common and severe expression of human Chagas disease. Heart failure, systemic and pulmonary thromboembolism, arrhythmia, and sudden cardiac death are the principal clinical manifestations of Chagas cardiomyopathy. Ventricular arrhythmias contribute significantly to morbidity and mortality and are the major cause of sudden cardiac death. Significant gaps still exist in the understanding of the pathogenesis mechanisms underlying the arrhythmogenic manifestations of Chagas cardiomyopathy. This article will review the data from experimental studies and translate those findings to draw hypotheses about clinical observations. Human- and animal-based studies at molecular, cellular, tissue, and organ levels suggest 5 main pillars of remodeling caused by the interaction of host and parasite: immunologic, electrical, autonomic, microvascular, and contractile. Integrating these 5 remodeling processes will bring insights into the current knowledge in the field, highlighting some key features for future management of this arrhythmogenic disease.

Discovery and Structure-Activity Relationship of a Ryanodine Receptor 2 Inhibitor.

Ryanodine receptor 2 (RyR2) is a large Ca2+-release channel in the sarcoplasmic reticulum (SR) of cardiac muscle cells. It serves to release Ca2+ from the SR into the cytosol to initiate muscle contraction. RyR2 overactivation is associated with arrhythmogenic cardiac disease, but few specific inhibitors have been reported so far. Here, we identified an RyR2-selective inhibitor 1 from the chemical compound library and synthesized it from glycolic acid. Synthesis of various derivatives to investigate the structure-activity relationship of each substructure afforded another two RyR2-selective inhibitors 6 and 7, among which 6 was the most potent. Notably, compound 6 also inhibited Ca2+ release in cells expressing the RyR2 mutants R2474S, R4497C and K4750Q, which are associated with cardiac arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). This inhibitor is expected to be a useful tool for research on the structure and dynamics of RyR2, as well as a lead compound for the development of drug candidates to treat RyR2-related cardiac disease.

Engineered tissue geometry and Plakophilin-2 regulate electrophysiology of human iPSC-derived cardiomyocytes.

Engineered heart tissues have been created to study cardiac biology and disease in a setting that more closely mimics in vivo heart muscle than 2D monolayer culture. Previously published studies suggest that geometrically anisotropic micro-environments are crucial for inducing "in vivo like" physiology from immature cardiomyocytes. We hypothesized that the degree of cardiomyocyte alignment and prestress within engineered tissues is regulated by tissue geometry and, subsequently, drives electrophysiological development. Thus, we studied the effects of tissue geometry on electrophysiology of micro-heart muscle arrays (μHM) engineered from human induced pluripotent stem cells (iPSCs). Elongated tissue geometries elicited cardiomyocyte shape and electrophysiology changes led to adaptations that yielded increased calcium intake during each contraction cycle. Strikingly, pharmacologic studies revealed that a threshold of prestress and/or cellular alignment is required for sodium channel function, whereas L-type calcium and rapidly rectifying potassium channels were largely insensitive to these changes. Concurrently, tissue elongation upregulated sodium channel (NaV1.5) and gap junction (Connexin 43, Cx43) protein expression. Based on these observations, we leveraged elongated μHM to study the impact of loss-of-function mutation in Plakophilin 2 (PKP2), a desmosome protein implicated in arrhythmogenic disease. Within μHM, PKP2 knockout cardiomyocytes had cellular morphology similar to what was observed in isogenic controls. However, PKP2-/- tissues exhibited lower conduction velocity and no functional sodium current. PKP2 knockout μHM exhibited geometrically linked upregulation of sodium channel but not Cx43, suggesting that post-translational mechanisms, including a lack of ion channel-gap junction communication, may underlie the lower conduction velocity observed in tissues harboring this genetic defect. Altogether, these observations demonstrate that simple, scalable micro-tissue systems can provide the physiologic stresses necessary to induce electrical remodeling of iPS-CM to enable studies on the electrophysiologic consequences of disease-associated genomic variants.

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3.

Short QT syndrome type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to a lack of inward-going rectification and increased IK1 at voltages positive to -80 mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80 mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer.

Loss of sodium current caused by a Brugada syndrome–associated variant is determined by patient-specific genetic background

BackgroundBrugada syndrome (BrS) is an inherited cardiac arrhythmogenic disease that predisposes patients to sudden cardiac death. It is associated with mutations in SCN5A, which encodes the cardiac sodium channel alpha subunit (NaV1.5). BrS-related mutations have incomplete penetrance and variable expressivity within families. ObjectiveThe purpose of this study was to determine the role of patient-specific genetic background on the cellular and clinical phenotype among carriers of NaV1.5_p.V1525M. MethodsWe studied sodium currents from patient-specific human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and heterologously transfected human embryonic kidney (HEK) tsA201 cells using the whole-cell patch-clamp technique. We determined gene and protein expression by quantitative polymerase chain reaction, RNA sequencing, and western blot and performed a genetic panel for arrhythmogenic diseases. ResultsOur results showed a large reduction in INa density in hiPSC-CM derived from 2 V1525M single nucleotide variant (SNV) carriers compared with hiPSC-CM derived from a noncarrier, suggesting a dominant-negative effect of the NaV1.5_p.V1525M channel. INa was not affected in hiPSC-CMs derived from a V1525M SNV carrier who also carries the NaV1.5_p.H558R polymorphism. Heterozygous expression of V1525M in HEK-293T cells produced a loss of INa function, not observed when this variant was expressed together with H558R. In addition, the antiarrhythmic drug mexiletine rescued INa function in hiPSC-CM. SCN5A expression was increased in the V1525M carrier who also expresses NaV1.5_p.H558R. ConclusionOur results in patient-specific hiPSC-CM point to a dominant-negative effect of NaV1.5_p.V1525M, which can be reverted by the presence of NaV1.5_p.H558R. Overall, our data points to a role of patient-specific genetic background as a determinant for incomplete penetrance in BrS.

Associations between Selected ADRB1 and CYP2D6 Gene Polymorphisms in Children with Ventricular and Supraventricular Arrhythmias.

Background and Objectives: Tachycardia is a common cardiovascular disease. Drugs blocking β1-adrenergic receptors (ADRB1) are used in the therapy of arrhythmogenic heart diseases. Disease-related polymorphisms can be observed within the ADRB1 gene. The two most important are Ser49Gly and Arg389Gly, and they influence the treatment efficacy. The family of the cytochrome P450 system consists of the isoenzyme CYP2D6 (Debrisoquine 4-hydroxylase), which is involved in phase I metabolism of almost 25% of clinically important drugs, including antiarrhythmic drugs. A study was conducted to detect the ADRB1 and CYP2D6 gene polymorphisms. Materials and Methods: The material for the test was whole blood from 30 patients with ventricular and supraventricular tachycardia and 20 controls. The samples were obtained from the Department of Pediatric Cardiology. The first to be made was the extraction of DNA using a GeneMATRIX Quick Blood DNA Purification Kit from EURx. The selected ADRB1 and CYP2D6 gene polymorphisms were detected by high-resolution melting polymerase chain reaction (HRM-PCR) analysis. Results: Based on the analysis of melt profile data for each PCR product, the identification of polymorphisms was carried out. Heterozygotes and homozygotes were found in the examined alleles. Conclusions: The frequency of the Arg389Gly polymorphism differs statistically significantly between the control group and patients with supraventricular and ventricular arrhythmias, as well as between these two groups of patients. Moreover, the Arg389Gly polymorphism was statistically more prevalent in the group of girls with SVT arrhythmia compared to girls with VT. A few carriers of homozygous and heterozygous systems of the S49G polymorphism were detected among patients with arrhythmias, as well as control group. The percentage of individuals carrying the CYP2D6 4 allele as either homozygous or heterozygous was observed in the study and control groups. The high prevalence of the CYP2D6*4 allele carriers in both groups prompts the optimization of beta-1 blocker therapy.

Abstract 15106: Echocardiography versus Cardiac Magnetic Resonance-Quantification of Right Ventricular Function to Stratify the Risk of Appropriate Defibrillator Therapy

Background: Right ventricular dysfunction is recently referred as an independent predictor of sudden cardiac death. The purpose of this study was to evaluate the efficiency of risk stratification methods for appropriate implantable cardiac defibrillator (ICD) therapy using two different modalities to quantify the right ventricular function. Methods: Consecutive patients undergoing ICD implantations who completed both preprocedural echocardiography and cardiac magnetic resonance (CMR) were retrospectively enrolled. Any channelopathy or arrhythmogenic right ventricular disease were excluded. The right ventricular fractional area change (RVFAC) and estimated pulmonary artery pressure (EPAP) were calculated from echocardiography. The contraction-pressure index (CPI) was defined as the quotient of the RVFAC divided by EPAP. The right ventricular ejection fraction (RVEF) was automatically provided by CMR. Both were evaluated to predict the initial appropriate ICD therapy. Results: In total, 111 patients (59.5±14.9 years, 79 males) including 20 with ischemic cardiomyopathy were retrospectively enrolled. Fifty-six patients received an ICD as secondary prophylaxis. The mean RVFAC, CPI, and RVEF were 36.7±8.9%, 1.4±0.7%, and 39.9±13.8%, respectively. Regarding appropriate ICD therapy events, the best cut-off value of the RVFAC was 34.8 (specificity 0.63, sensitivity 0.65, ROC-AUC 0.64), CPI 1.59 (specificity 0.42, sensitivity 0.94, ROC-AUC 0.61) and RVEF 43.0 (specificity 0.48, sensitivity 0.87, ROC-AUC 0.64). The hazard ratio of a low RVFAC was 3.13 (95%CI: 1.32-7.44, P<0.01, concordance=0.62), that of low CPI was 9.60 (95%CI: 1.27-72.4, P=0.03, c=0.65), and that of reduced RVEF was 5.55 (95%CI: 1.64-18.7, P<0.01, c=0.67). Conclusion: CPI and RVEF were similarly associated with an increased appropriate ICD therapy. The CPI seemed to provide an equivalent stratification for the risk of appropriate ICD therapy as compared to a CMR indicator.

Athletes and suspected catecholaminergic polymorphic ventricular tachycardia: Awareness and current knowledge.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac inherited arrhythmogenic disease potentially leading to sudden cardiac death that is determined by electrical instability exacerbated by acute adrenergic tone. Despite its life-threatening nature, CPVT remains potentially unnoticed since diagnosis may be difficult especially in apparently healthy athletes. This review summarizes current knowledge and shortcomings of CPVT, focusing on genetics, arrhythmic mechanisms, sport preparticipation screening, and current recommendations. The paper captures the importance of CPVT athletes regarding the necessity of risk stratification, as well as the importance of maintaining a healthy lifestyle.

From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies.

In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1-3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype-phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.

Catheter ablation of ventricular tachycardia: strategies to improve outcomes.

Catheter ablation of ventricular arrhythmias has evolved considerably since it was first described more than 3 decades ago. Advancements in understanding the underlying substrate, utilizing pre-procedural imaging, and evolving ablation techniques have improved the outcomes of catheter ablation. Ensuring safety and efficacy during catheter ablation requires adequate planning, including analysis of the 12 lead ECG and appropriate pre-procedural imaging. Defining the underlying arrhythmogenic substrate and disease eitology allow for the developed of tailored ablation strategies, especially for patients with non-ischemic cardiomyopathies. During ablation, the type of anesthesia can affect VT induction, the quality of the electro-anatomic map, and the stability of the catheter during ablation. For high risk patients, appropriate selection of hemodynamic support can increase the success of VT ablation. For patients in whom VT is hemodynamically unstable or difficult to induce, substrate modification strategies can aid in safe and successful ablation. Recently, there has been an several advancements in substrate mapping strategies that can be used to identify and differentiate local late potentials. The incorporation of high-definition mapping and contact-sense technologies have both had incremental benefits on the success of ablation procedures. It is crucial to harness newer technology and ablation strategies with the highest level of peri-procedural safety to achieve optimal long-term outcomes in patients undergoing VT ablation.

Arrhythmogenic mechanism of a novel ryanodine receptor mutation underlying sudden cardiac death.

The ryanodine receptor 2 (RyR2) is essential for cardiac muscle excitation-contraction coupling; dysfunctional RyR2 participates in the development of inherited arrhythmogenic cardiac disease. In this study, a novel RyR2 mutation A690E is identified from a patient with family inheritance of sudden cardiac death, and we aimed to investigate the pathogenic basis of the mutation. We generated a mouse model that carried the A690E mutation. Mice were characterized by adrenergic-induced ventricular arrhythmias similar to clinical manifestation of the patient. Optical mapping studies revealed that isolated A690E hearts were prone to arrhythmogenesis and displayed frequency-dependence calcium transient alternans. Upon β-adrenoceptor challenge, the concordant alternans was shifted towards discordant alternans that favour triggering ectopic beats and Ca2+ re-entry; similar phenomenon was also found in the A690E cardiomyocytes. In addition, we found that A690E cardiomyocytes manifested abnormal Ca2+ release and electrophysiological disorders, including an increased sensitivity to cytosolic Ca2+, an elevated diastolic RyR2-mediated Ca2+ leak, and an imbalance between Ca2+ leak and reuptake. Structural analyses reveal that the mutation directly impacts RyR2-FK506 binding protein interaction. In this study, we have identified a novel mutation in RyR2 that is associated with sudden cardiac death. By characterizing the function defects of mutant RyR2 in animal, whole heat, and cardiomyocytes, we demonstrated the pathogenic basis of the disease-causing mutation and provided a deeper mechanistic understanding of a life-threatening cardiac arrhythmia.

An unconventional dose of epinephrine for a diagnostic test of catecholaminergic polymorphic ventricular tachycardia: A case report

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare heritable arrhythmogenic disease, and the Mayo Clinic protocol-guided epinephrine test is commonly used for diagnostic purposes. Whether the Mayo Clinic protocol is enough for patients who are insensitive to catecholamine remains an unknown question. Our patient was a19-year-old female who presented with recurrent stress-induced syncope and was saved by cardiopulmonary resuscitation. The initial physical examination and complementary tests (ECG, blood laboratory, cardiac ultrasound, and cranial magnetic resonance angiography) showed no abnormalities on admission. Treadmill exercise testing shows non-sustained and polymorphic tachycardia. A subsequent epinephrine test was performed, and polymorphic ventricular tachycardia was not induced until using a high dose of epinephrine above Mayo Clinic protocol. Therefore, it is suggested that an unconventional dose of epinephrine may be needed fordiagnostic tests of CPVT for some insensitive individuals.

P11 RISK STRATIFICATION IN ATHLETES: AN "IRREDUCIBLE" MASTER ATHLETE

Abstract We describe the clinical case of a 48–year–old master athlete, runner (marathon runner), always asymptomatic at rest and during effort, with a family history of ischemic heart disease and no other known cardiovascular risk factors. On the occasion of the pre–partecipation screening visit, he presented an altered baseline electrocardiogram with low peripheral voltages and T wave inversion in V1–V5 leads and inferior leads. The echocardiogram documented morphofunctional alterations in the right ventricle and raises the suspicion of arrhythmogenic cardiomyopathy, later confirmed by cardiac magnetic resonance with Gadolinium. During effort, even repetitive premature ventricular beats LBBB with superior axis morphology appeared. Also, torsade de pointes episode with presyncopal sensation. He was hospitalized with a diagnosis of threatening arrhythmias in right ventricular arrhythmogenic heart disease. Coronary angiography was negative. We recommend beta–blocker therapy, genetic analysis, screening of family members. A subcutaneus defibrillator has been placed. The patient, against the advice of the Physicians, continued to train even at high intensity until he has a syncopal episode with correct intervention of the device on ventricular fibrillation. Since the patient has requested specific indications to continue training independently, an exercise test in beta–blocker therapy is repeated and the training thresholds are calculated. The case of this master athlete highlights the issue of the difficulty of screening the master athlete with frequent omission of symptoms (the patient already had syncopal/presyncopal episodes at home which he had omitted), poor adherence to therapeutic indications, possible negative effects of high intensity physical training on the evolution of arrhythmogenic cardiomyopathy.

The Role of Electrophysiological Study in the Risk Stratification of Brugada Syndrome.

Brugada syndrome (BrS) is a complex arrhythmogenic disease associated with an increased risk of sudden cardiac death (SCD). The role of electrophysiological study (EPS) for risk stratification purposes of asymptomatic BrS patients remains still controversial. This study aims to summarize the existing data about the role of electrophysiological study for arrhythmic risk stratification of BrS patients without a prior history of aborted SCD or fatal arrhythmic event. Two independent investigators (G.B. and G.T.) performed a systematic search in the MedLine database and Cochrane library from their inception until April 2022 without any limitations. The reference lists of the relevant research studies as well as the relevant review studies and meta-analyses were manually searched. Nineteen studies were included in the final analysis. The included studies enrolled 6218 BrS patients (mean age: 46.9 years old, males: 76%) while 4265 (68.6%) patients underwent an EPS. The quantitative synthesis showed that a positive EPS study was significantly associated with arrhythmic events in BrS patients (RR, 1.74 [1.23-2.45]; P = 0.002; I2 = 63%]. By including the studies that provided data on the association of EPS with arrhythmic events during follow-up in patients without a prior history of aborted SCD or fatal arrhythmic event, the association between positive EPS study and future arrhythmic events remained significant (RR, 1.60 [1.08-2.36]; P = 0.02; I2 = 19%). In conclusion, EPS is a useful invasive tool for the risk stratification of BrS patients and can be used to identify the population of BrS patients who may be candidates for primary prevention of SCD with implantable cardioverter-defibrillator (ICD) implantation.