Unexplained Sudden Cardiac Arrest Research Articles

Molecular genetic screening after non-ischaemic sudden cardiac arrest and no overt cardiomyopathy in real life: A major tool for the aetiological diagnostic work-up

BackgroundWith the development of advanced sequencing techniques, genetic testing has emerged as a valuable tool for the work-up of non-ischaemic sudden cardiac arrest (SCA). AimsTo evaluate the effectiveness of genetic testing in patients with unexplained SCA, according to clinical phenotype. MethodsAll patients who underwent molecular genetic testing for non-ischaemic SCA with no left ventricular cardiomyopathy between 2012 and 2021 in two French university hospitals were included. ResultsOf 66 patients (mean age 36.7±11.9years, 54.5% men), 21 (31.8%; 95% confidence interval 22.4–45.3%) carried a genetic variant: eight (12.1%) had a pathogenic or likely pathogenic (P/LP) variant and 13 (19.7%) had a variant of uncertain significance (VUS). Among 37 patients (56.1%) with no phenotypic clues, genetic testing identified a P/LP variant in five (13.5%), mainly in RYR2 (n=3) and SCN5A (n=2), and a VUS in nine (24.3%). None of the nine patients with phenotypic evidence of channelopathies had P/LP variants, but two had VUS in RYR2 and NKX2.5. Among the 20 patients with suspected arrhythmogenic cardiomyopathy, three P/LP variants (15.0%) and two VUS (10.0%) were found in DSC2, PKP2, SCN5A and DSG2, TRPM4, respectively. Genetic testing was performed sooner after cardiac arrest (P<0.001) and results were obtained more rapidly (P=0.02) after versus before 2016. ConclusionThis study highlights the utility of molecular genetic testing with a genetic variant of interest identified in one-third of patients with unexplained SCA. Genetic testing was beneficial even in patients without phenotypic clues, with one-fourth of patients carrying a P/LP variant that could have direct implications.

Prolonged follow-up after apparently unexplained sudden cardiac arrest: A retrospective study

BackgroundWe hypothesized that a prolonged follow-up of survivors of unexplained sudden cardiac arrest (USCA) would subsequently unmask electrical heart disorders in a significant proportion of cases. Patients and methodsWe retrospectively analyzed all out-of-hospital cardiac arrest (OHCA) admitted alive in our cardiac arrest center over 20-years (2002–2022). The diagnosis of USCA was made when no etiology was found after thorough initial hospital investigations. We identified all the new diagnoses established during follow-up, and compared outcomes according to underlying heart diseases. ResultsOut of the 2482 OHCA patients, 68 (2.7%) were initially classified as USCA and 30 (1.2%) with electrical heart disorders. Compared to other cardiac etiologies of OHCA, both USCA and electrical heart disorders patients were younger (mean age 48.5 and 43.5 year-old respectively, versus 62.5 year-old; p < 0.0001), with a higher rate of family history of SCA (17.6 and 23.3% respectively versus 9.2%; p = 0.003). Six patients in each group were lost to follow-up at discharge (6/68, 8.8% in the USCA group, 6/30 20% in the electrical heart disorders group). During a mean follow-up of 8.1 ± 6.3 years, a diagnosis was eventually established in 24.3% of USCA patients (9/35), most of them as electrical heart disorders (55.6%, 5/9). No post-discharge death occurred in both USCA and electrical heart disorders groups, with approximately 10% of appropriate therapy delivered by the implantable cardioverter defibrillator. ConclusionOur findings emphasized that approximately a quarter of patients who had been initially considered as having apparently USCA after index hospital stay actually reveal heart conditions, especially electrical heart disorders.

Abstract 12083: Highly Caffeinated Energy Drinks and Genetic Heart Disease-Associated Sudden Cardiac Arrest

Background: Highly caffeinated energy drinks (HCEDs) can trigger life-threatening cardiac arrhythmias in individuals with and without an underlying genetic predisposition. Though the mechanism(s) responsible for these events remain unclear, it has been postulated that high caffeine may alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a manner that is pro-arrhythmic. Objective: To describe our experience regarding sudden cardiac arrest (SCA) events occurring in proximity to HCED consumption in patients with underling genetic heart diseases. Methods: All SCA survivors referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for clinical and/or molecular evaluation were reviewed to identify those with a history of HCED consumption prior to their event. Patient demographics, clinical characteristics, documented HCED consumption, and temporal relationship of HCED consumption to SCA were extracted from the electronic medical record. Results: Among 144 SCA survivors with a structurally normal heart, 8 (6 females; mean age at event 28 ± 8 years) experienced an unexplained SCA associated temporally with HCED consumption. Of these, 5 (63%) had either long QT syndrome (n=3) or catecholaminergic polymorphic ventricular tachycardia (n=2). The remaining 3 were diagnosed with unexplained SCA/idiopathic ventricular fibrillation after a comprehensive evaluation. Three patients (37%) were habitual HCED consumers while 5 (63%) imbibed for the first time with consumption ranging from several hours to a few minutes before the SCA. Seven patients (88%) required a rescue shock (average 2 ± 2 shocks/patient) while 1 was manually resuscitated. Upon follow-up, 6 (75%) were dismissed with an implantable cardioverter defibrillator, 1 (13%) on pharmacologic therapy, and 1 (13%) underwent denervation surgery. All SCA survivors have quit drinking HCEDs and have been event-free since. Conclusion: Overall, 8/144 (5.6%) of SCA survivors evaluated in our program experienced a SCA in proximity to consuming a HCED. Although larger cohort studies are needed to elucidate the precise mechanism for HCED-triggered/associated SCA and quantify its precise pro-arrhythmic risk, it seems prudent to sound an early warning.

Characteristics and prognosis of the catecholamine induced QT prolongation syndrome

Abstract Background We have recently demonstrated association of unexplained sudden cardiac arrest (SCA) with inheritance of catecholamine induced QT prolongation (CIQTP). Objective We here aim to describe incidence, characteristics and prognosis of this new syndrome in young patients with unexplained SCA or their relatives. Methods We reviewed the medical screening of all consecutive patients or their first-degree relatives explore from 2015 after the occurrence of a SCA before age 45. Structural heart disease or inherited arrhythmia diseases were excluded. A mental stress test was performed, as previously described, for each family members. All families with a positive mental stress were included in the study. Genetic screening was performed in at least one positive patient per family using targeted sequencing on a panel of 109 genes associated with inherited arrhythmias and cardiomyopathies. Results Among 456 patients screened (24 after SCA, 432 for familial screening) of 153 families, we identified 10 families (6.5%) with a catecholamine induced QT prolongation. No mutation was identified in these families. One hundred and ten patients were screened in CIQTP families. Thirty-four patients (30.9%) presented a CIQTP (mean age 42±20 yo, 64.7% of women). Five (14.7%) patients presented with previous symptoms (including 4 syncope and 1 SCA). Two patients (5.9%) were implanted with an ICD and eleven (32.3%) were treated with beta blocker therapy mainly because of QT prolongation &amp;gt;500 ms after mental stress test or previous symptoms. After a 3.6±1.8 years of follow up, no sudden cardiac death nor syncope occurred on beta blocker therapy except for one patient implanted with an ICD after a SCA. Under beta blocker treatment the patient was asymptomatic for 5 years. After a suddenly stop of the beta blocker treatment, the patient underwent VF. For 3 years now the patient is asymptomatic under beta blocker treatment. Conclusions In our experience, CIQTP families represent 6.5% of cases of unexplained SCD and suggest systematic screening with a mental stress test for family screening after the occurrence of a SCA. Beta blocker therapy is very efficient to reduce the risk of SCA. Funding Acknowledgement Type of funding sources: None.

The Arrhythmogenic Face of COVID-19: Brugada ECG Pattern in SARS-CoV-2 Infection.

In 1992, Brugada syndrome (BS) was first described; an often unrecognized cardiac conduction disorder mainly associated with unexplained sudden cardiac arrest and consecutive syncope. Nevertheless, the pathomechanism of BS and sudden cardiac death remains mainly explained. Mutations in the cardiac sodium channels, which cause a reduction or functional loss of these channels, are associated with characteristic electrocardiographic (ECG) abnormalities and malignant arrhythmia. The majority of affected people are previously healthy and unaware of their genetic predisposition for BS and might experience ventricular tachyarrhythmias and cardiac arrest potentially triggered by several factors (e.g., alcohol, sodium channel blockers, psychotropic drugs, and fever). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was firstly identified in Wuhan in early December 2019 and rapidly spread worldwide as coronavirus disease (COVID-19). COVID-19 is typically characterized by a severe inflammatory response, activation of the immune system, and high febrile illness. Due to this condition, symptomatic COVID-19 infection or vaccination might serve as inciting factor for unmasking the Brugada pattern and represents a risk factor for developing proarrhythmic complications. The aim of this narrative review was to detail the association between virus-related issues such as fever, electrolyte disturbance, and inflammatory stress of COVID-19 infection with transient Brugada-like symptoms and ECG-pattern and its susceptibility to proarrhythmogenic episodes.

Exome Sequencing Highlights a Potential Role for Concealed Cardiomyopathies in Youthful Sudden Cardiac Death.

Sudden cardiac arrest (SCA) and sudden unexplained death (SUD) are feared sequelae of many genetic heart diseases. In rare circumstances, pathogenic variants in cardiomyopathy-susceptibility genes may result in electrical instability leading to SCA/SUD before any structural manifestations of underlying cardiomyopathy are evident. Collectively, 38 unexplained SCA survivors (21 males; mean age at SCA 26.4±13.1 years), 68 autopsy-inconclusive SUD cases (46 males; mean age at death 20.4±9.0 years) without disease-causative variants in the channelopathy genes, and 973 ostensibly healthy controls were included. Following exome sequencing, ultrarare (minor allele frequency ≤0.00005 in any ethnic group within Genome Aggregation Database [gnomAD, N=141 456 individuals]) nonsynonymous variants identified in 24 Clinical Genome Resource adjudicated definitive/strong evidence cardiomyopathy-susceptibility genes were analyzed. Eligible variants were adjudicated as pathogenic, likely pathogenic, or variant of uncertain significance in accordance with current American College of Medical Genetics and Genomics guidelines. Overall, 7 out of 38 (18.4%) SCA survivors and 14 out of 68 (20.5%) autopsy-inconclusive, channelopathic-negative SUD cases had at least one pathogenic/likely pathogenic or a variant of uncertain significance nonsynonymous variant within a strong evidence, cardiomyopathy-susceptibility gene. Following American College of Medical Genetics and Genomics criterion variant adjudication, a pathogenic or likely pathogenic variant was identified in 3 out of 38 (7.9%; P=0.05) SCA survivors and 8 out of 68 (11.8%; P=0.0002) autopsy-inconclusive SUD cases compared to 20 out of 973 (2.1%) European controls. Interestingly, the yield of pathogenic/likely pathogenic variants was significantly greater in autopsy-inconclusive SUD cases with documented interstitial fibrosis (4/11, 36%) compared with only 4 out of 57 (7%, P<0.02) SUD cases without ventricular fibrosis. Our data further supports the inclusion of strong evidence cardiomyopathy-susceptibility genes on the genetic testing panels used to evaluate unexplained SCA survivors and autopsy-inconclusive/negative SUD decedents. However, to avoid diagnostic miscues, the careful interpretation of genetic test results in patients without overt phenotypes is vital.

Abstract 13281: Idiopathic Ventricular Fibrillation Endophenotype Determines the Yield of Ultra-Rare RYR2 Variants in Youthful Unexplained Sudden Cardiac Arrest

Introduction: Loss-of-function variants in the RYR2-encoded cardiac calcium release channel underlie a small number of unexplained sudden cardiac arrest and death (SCA/SCD) cases. Objective: To determine if the yield of ultra-rare RYR2 variants in unexplained SCA patients with a default diagnosis of idiopathic ventricular fibrillation (IVF) depends on pre-defined IVF endophenotype and whether RYR2 variant-positive IVF cases have a discernible electrocardiographic phenotype. Methods: All SCA cases referred to Mayo Clinic’s Windland Smith Rice Genetic Heart Rhythm Clinic between 01/2000 and 04/2021 were reviewed. After exclusion of 116 cases where a probable SCA root cause was identified and/or RYR2 genetic testing was not pursued, a total of 64 unexplained SCA cases (36% female; 26 ± 11 years at the time of SCA) were included. Clinical data was extracted from the medical record and patients classified as having i) IVF (no diagnostic clues), N=38 (59%) ii) PVC-triggered ventricular fibrillation (PTVF; documented short coupled PVC-triggered ventricular arrhythmias), N=19 (30%), or iii) early repolarization syndrome (ERS; J-point elevation ≥0.1 mV in ≥2 contiguous leads, excluding leads V 1 -V 3 ), N=7 (11%). The yield of ultra-rare, non-synonymous RYR2 variants (MAF&lt;0.0001 in the Genome Aggregation Database) and electrocardiographic profiles were then compared. Results: Overall, a qualifying, ultra-rare RYR2 non-synonymous variant was identified in 5 out of 64 (7.8%) unexplained SCA patients. Of note, the yield of ultra-rare RYR2 missense variants was significantly higher in individuals with an PTVF endophenotype than those without [4/19 (21%) versus 1/45 (2.2%), p=0.02]. Interestingly, the majority of ultra-rare RYR2 variant-positive unexplained SCA survivors [3/5 (60%)] displayed an exercise stress test pattern characterized by the onset of ventricular ectopy at ~120 bpm with suppression at heart rates ≥140 bpm. Conclusions: The burden of ultra-rare RYR2 variants is higher in unexplained SCA patients with documented PTVF. Collectively, this data suggests that i) a subset of PTVF may have an underlying genetic basis and ii) some IVF- and PTVF-associated RYR2 variants may result in an identifiable electrocardiographic profile.

The emerging role of reassessment of genetic testing results in the diagnosis of the unexplained sudden cardiac arrest's causes

Abstract Background The most common cause of Unexplained Sudden Cardiac Arrest (USCA) are hereditary primary arrhythmic syndromes and subclinical forms of cardiomyopathies. Both of them may be difficult to diagnose. Objective The aim of this study was to re-examine the role of genetic testing in patients after USCA during follow-up. Methods In the years 2014–2017 we studied 44 unrelated patients (pts) (23 men (53%), mean age 36 years) after USCA. All pts underwent cardiac evaluation including ECG, Holter, echo, coronary angiography, stress exercise test and, if necessary cardiac MRI and provocative drug testing. Standard diagnostic criteria were used according to currently available ESC guidelines. We performed next generation sequencing with panel covered coding regions of &amp;gt;4800 genes (26pts), 194 genes (5pts) and whole exome sequencing &amp;gt;2ehab724.3204 genes (5pts). Variants of frequency no greater than 0,001 in existing variants' databases and classified as damaging by at least 3 of applied software algorithms were assessed for pathogenicity according to ACMG standards. The enrolled patients were followed up. During the follow up, the classification of rare variants according to ACMG standards was repeated. Results Based on applicable standards and the clinical data collected, clinical diagnosis was made in 17 (39%) probands (Long QT Syndrome 21%, Brugada Syndrome 7%, Short QT Syndrome 7%, Early Repolarization Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia 2%, both). Genetic tests were performed in 36 pts. We identified 27 rare variants in 22 pts, in genes associated with inherited arrhythmia or cardiomyopathies, of these 23 rare variants were identified in years 2014–2017. The first classification was in 2017, then only 2 variants (in FLNC) were considered pathogenic and the remaining 21 were classified as Variants of Unknown Significance (VUS). During the years 2019–2021, 23 earlier identified rare variants were reclassified according to The American College of Medical Genetics and Genomics (ACMG) standards, of these 5 VUS became pathogenic/likely pathogenic variants. In addition, we performed genetic tests in next 5 pts – we identified 4 rare variants – 3 pathogenic and 1 VUS. Detection of certain hereditary background of SCA increased from 6,5% in years 2014–2017, to 25% in years 2019–2021. The median follow-up period was 2366 days (interquartile range 1785–2903 days). 17/44 (39%) pts had adequate discharge of ICD. Two pts were observed with reduction of left ventricular contractility and the development of the initial stages of dilated cardiomyopathy. Conclusion This study shows clinical utility of extensive clinical assessment and follow-up of patient after USCA. Routine genetic testing by next generation sequencing in the patients can help in diagnosis and re-evaluation of rare variants should be made during the follow-up. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): grant of National Institute of Cardiology, Warsaw, Poland

Molecular Diagnosis of Inherited Cardiac Diseases in the Era of Next-Generation Sequencing: A Single Center's Experience Over 5 Years.

Molecular diagnosis in inherited cardiac diseases is challenging because of the significant genetic and clinical heterogeneity. We present a detailed molecular investigation of a cohort of 4185 patients with referrals for inherited cardiac diseases. Patients suffering from cardiomyopathies (3235 probands), arrhythmia syndromes (760 probands), or unexplained sudden cardiac arrest (190 cases) were analyzed using a next-generation sequencing (NGS) workflow based on a panel of 105 genes involved in sudden cardiac death. (Likely) pathogenic variations were identified for approximately 30% of the cohort. Pathogenic copy number variations (CNVs) were detected in approximately 3.1% of patients for whom a (likely) pathogenic variation were identified. A (likely) pathogenic variation was also detected for 21.1% of patients who died from sudden cardiac death. Unexpected variants, including incidental findings, were present for 28 cases. Pathogenic variations were mainly observed in genes with definitive evidence of disease causation. Our study, which comprises over than 4000 probands, is one of most important cohorts reported in inherited cardiac diseases. The global mutation detection rate would be significantly increased by determining the putative pathogenicity of the large number of variants of uncertain significance. Identification of "unexpected" variants also showed the clinical utility of genetic testing in inherited cardiac diseases as they can redirect clinical management and medical resources toward a meaningful precision medicine. In cases with negative result, a WGS approach could be considered, but would probably have a limited impact on mutation detection rate as (likely) pathogenic variations were essentially clustered in genes with strong evidence of disease causation.

Potential Role of Life Stress in Unexplained Sudden Cardiac Arrest

BackgroundThe etiology of sudden cardiac arrest (SCA) in individuals without known cardiovascular heart disease remains elusive in nearly half of all patients after systematic testing. We investigated the relationship between stressful life events and SCA risk in cases of explained and unexplained SCA (USCA) events. MethodsIndividuals who previously experienced SCA were enrolled prospectively and divided into a USCA or explained SCA (ESCA) subgroup dependent on whether a diagnosis was ascribed after SCA. Participants completed either the 1997 Recent Life Changes Questionnaire, Student Stress Scale, or Social Re-adjustment Rating Scale for Non-Adults recalling events during the year preceding their SCA, depending on age at SCA presentation; all measure stress in life change units (LCUs). SCA group scores were compared with an age- and sex-matched control group. ResultsWe compared 36 SCA group participants (22 USCA, 14 ESCA, age 47 ± 15 years, age at SCA 40 ± 14 years, 50% male) with 36 control participants (age 47 ± 15 years, 50% male). There was no significant difference in LCU score between the control group and the SCA group (248 ± 181 LCU vs 252 ± 227 LCU; P > .05). The ESCA subgroup had significantly lower mean LCU scores than the USCA subgroup (163 ± 183 LCU vs 308 ± 237 LCU; P = .030). ConclusionsStressful life events, especially those producing chronic stress, might predispose otherwise healthy individuals to lethal arrhythmias. Further investigation into the role of stress in SCA precipitation is warranted.

“Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest

Abstract Background Current genetic testing guidelines recommend against broad, multi-phenotype genetic testing in survivors of sudden cardiac arrest (SCA) where no cause is identified on clinical screening. Recent reports describe malignant arrhythmic events preceding detectable structural changes in patients with pathogenic variants in cardiomyopathy genes, who go on to demonstrate structural changes in follow up. Purpose We sought to investigate the utility of a broad genetic testing approach, sequencing genes implicated in both arrhythmia syndromes and cardiomyopathy, in SCA survivors where no cause was identified after thorough clinical evaluation. Methods We retrospectively reviewed the clinical and genetic profiles of SCA survivors referred to a specialised genetic heart disease multidisciplinary team in Australia. Multi-phenotype genetic testing included analysis of 174 cardiac genes associated with arrhythmia or cardiomyopathy. Results The cohort was comprised of 86 SCA survivors. A clinical diagnosis was made in 46 (53%) patients while 40 (47%) cases were considered idiopathic, with no cause of arrest identified despite thorough clinical investigation. Thirty-two survivors of idiopathic SCA (80%) underwent broad, multi-phenotype genetic testing through genome (n=1), exome (n=26) or extended panel (n=5) analysis. The majority of the cohort were male (62.5%, n=25) and ≤35 years of age at time of arrest (60%, n=24). Events in this group most commonly occurred at rest or sleep (65.8%, n=25) and 5 patients had a family history of sudden death (12.5%). Seven disease causing variants were identified with a testing yield of 21.9%. There was no difference in demographic or clinical factors between those with and without a disease-causing variant. Six (85.7%) of these clinically actionable variants were identified in genes associated with cardiomyopathy (PKP2, MYBPC3, DES, DSP and ACTN2) that would not have been analysed on a standard commercial cardiac arrhythmia panel. Cardiac magnetic resonance (CMR) imaging was performed prior to genetic testing in 4 of the 6 cases found to have disease-causing variants in cardiomyopathy genes (2 patients did not have CMR performed due to the presence of cardiac devices), with 2 (50%) showing sub-diagnostic changes while 2 (50%) revealed a structurally normal heart. Conclusion A broad approach to genetic testing in idiopathic SCA can improve care for patients and their families by identifying clinically actionable variants that would be missed by phenotype specific gene panels and thus significantly increase the rate of diagnosis. “Concealed cardiomyopathy” represents a clinical challenge in how to manage patients and their relatives who carry a pathogenic cardiomyopathy variant, have no overt signs of structural disease, yet have an important risk of sudden cardiac arrest. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Cardiac Society of Australia and New Zealand; National Health and Medical Research Council (Australia)

Idiopathic ventricular fibrillation: the ongoing quest for diagnostic refinement

Prior to the recognition of distinct clinical entities, such as Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome, all sudden cardiac arrest (SCA) survivors with ventricular fibrillation (VF) and apparently structurally normal hearts were labelled as idiopathic ventricular fibrillation (IVF). Over the last three decades, the definition of IVF has changed substantially, mostly as result of the identification of the spectrum of SCA-predisposing genetic heart diseases (GHDs), and the molecular evidence, by post-mortem genetic analysis (aka, the molecular autopsy), of cardiac channelopathies as the pathogenic basis for up to 35% of unexplained cases of sudden cardiac death (SCD) in the young. The evolution of the definition of IVF over time has led to a progressively greater awareness of the need for an extensive diagnostic assessment in unexplained SCA survivors. Nevertheless, GHDs are still underdiagnosed among SCA survivors, due to the underuse of pharmacological challenges (i.e. sodium channel blocker test), misrecognition of electrocardiogram (ECG) abnormalities/patterns (i.e. early repolarization pattern or exercise-induced ventricular bigeminy) or errors in the measurement of ECG parameters (e.g. the heart-rate corrected QT interval). In this review, we discuss the epidemiology, diagnostic approaches, and the controversies related to role of the genetic background in unexplained SCA survivors with a default diagnosis of IVF.

“Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest

BackgroundGenetic heart disease is a common cause of sudden cardiac arrest (SCA) in the young and those without an ischaemic precipitant. Identifying a cause of SCA in these patients allows for targeted care and family screening. Current guidelines recommend limited, phenotype-guided genetic testing in SCA survivors where a specific genetic condition is suspected and genetic testing is not recommended in clinically-idiopathic SCA survivors. ObjectiveTo investigate the diagnostic utility of broad, multi-phenotype genetic testing in clinically-idiopathic SCA survivors. MethodsClinically-idiopathic SCA survivors underwent analysis of genes known to be associated with either cardiomyopathy or primary arrhythmia syndromes, following referral to a specialised genetic heart disease clinic in Sydney, Australia between 1997 and 2019. Comprehensive review of clinical records, investigations and re-appraisal of genetic data according to current variant classification criteria was performed. ResultsIn total, 22% (n = 8/36) of clinically-idiopathic SCA survivors (mean age 36.9 ± 16.9 years, 61% male) had a disease-causing variant identified on broad genetic testing. Of these, 7 (88%) variants resided in cardiomyopathy-associated genes (ACTN2, DES, DSP, MYBPC3, MYH7, PKP2) despite structurally normal hearts or sub-diagnostic structural changes at the time of arrest, so-called “concealed cardiomyopathy”. Only one SCA survivor had a variant identified in a channelopathy associated gene (SCN5A). ConclusionExtended molecular analysis with multi-phenotype genetic testing can identify a “concealed cardiomyopathy”, and increase the diagnosis rate for clinically-idiopathic SCA survivors.

Unexplained sudden cardiac arrest in children: clinical and genetic characteristics of survivors.

Unexplained sudden cardiac arrest in children: clinical and genetic characteristics of survivors.

Unmasking latent preexcitation of a right-sided accessory pathway with intravenous adenosine after unexplained sudden cardiac arrest.

Intravenous adenosine is a simple test that can uncover latent preexcitation via an accessory pathway and is useful in the diagnostic workup of sudden cardiac arrest survivors without an identifiable cause. Latent preexcitation is usually associated with left free wall pathways but may also occur in right-sided accessory pathways with slow antegrade conduction. Although intermittent ECG evidence of preexcitation is generally considered a marker of low risk for sudden death, if this is due to an accessory pathway with long atrioventricular conduction time and short effective refractory period (rather than true intermittent conduction via the pathway), the risk for sudden death may be equal to those accessory pathways with manifest preexcitation.

Prevalence and electrophysiological phenotype of rare SCN5A genetic variants identified in unexplained sudden cardiac arrest survivors.

To determine the prevalence and in vitro electrophysiological (EP) phenotype of ultra-rare SCN5A variants of uncertain significance (VUS) identified in unexplained sudden cardiac arrest (SCA) survivors. Retrospective review of 73 unexplained SCA survivors was used to identify all patients that underwent a form of genetic testing that included comprehensive SCN5A analysis. Ultra-rare SCN5A variants (minor allele frequency < 0.005) were adjudicated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Variants designated as VUS were expressed heterologously and characterized using the whole-cell patch clamp technique. Overall, 60/73 (82%; the average age at SCA 28 ± 12 years) unexplained SCA survivors had received SCN5A genetic testing. Of these, 5/60 (8.3%) had an ultra-rare SCN5A variant. All SCN5A variants were classified as VUS. Whereas the single SCN5A VUS (p.Asp872Asn-SCN5A) identified in an unexplained SCA survivor with PR interval prolongation and inferior early repolarization conferred a loss-of-function phenotype (46.2% reduction in peak current density; 16 ms slower recovery from inactivation), the four other SCN5A VUS (p.Glu30Gly-SCN5A, p.Gln245Lys-SCN5A, p.Pro648Leu-SCN5A, and p.Glu1240Gln-SCN5A) identified in unexplained SCA survivors without early repolarization/conduction delay were indistinguishable from wild-type Nav1.5 channels. In the absence of a phenotype(s) potentially attributable to sodium channel dysfunction, all SCN5A VUS identified in unexplained SCA survivors conferred a wild-type EP phenotype in vitro. As the background rate of SCN5A genetic variation is not trivial, great care must be taken to avoid prioritizing genotype over phenotype when attempting to ascertain the root cause of an individual's SCA.

Sudden cardiac arrest in patients without overt heart disease: a limited value of next generation sequencing.

INTRODUCTION Unexplained sudden cardiac arrest (SCA), occurs in up to 10% of patients and is often attributed to an inherited arrhythmia syndrome. Family screening and genetic testing may help clarify the cause of unexplained SCA. OBJECTIVES We aimed to assess the usefulness of clinical evaluation and genetic testing in patients after unexplained SCA and in their families. PATIENTS AND METHODS In the years 2014-2017, we studied 44 unrelated patients after unexplained SCA and 96 of their relatives. All patients and relatives underwent comprehensive cardiac evaluation. In 31 patients with SCA, next generation sequencing (NGS) was performed. The Kaplan-Meier survival curve was constructed to compare the event-free survival depending on clinical diagnosis or genotype. An adverse event was defined as an adequate implantable cardioverter-defibrillator discharge. RESULTS Based on the clinical evaluation, diagnosis was established in 39% of probands (long QT syndrome 21%; short QT syndrome 7%; Brugada syndrome 7%; catecholaminergic polymorphic ventricular tachycardia, 2%; and early repolarization syndrome, 2%). Ventricular arrhythmia was identified in the relatives of 19% of probands. In 18 of the 31 probands (54.8%), 23 rare gene variants were identified, of which only 2 were classified as pathogenic. The event-free survival over a median of 4.5 years was similar in patients with or without clinical diagnosis and in carriers and noncarriers of a rare genetic variant. CONCLUSIONS This study shows the significance of an extensive clinical assessment in unexplained SCA victims and their relatives. Routine genetic testing by NGS has low diagnostic and prognostic value.

Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real-world setting: focus on idiopathic ventricular fibrillation.

AimsRecent studies have shown that in more than half of apparently unexplained sudden cardiac arrests (SCA), a specific aetiology can be unmasked by a careful evaluation. The characteristics and the extent to which such cases undergo a systematic thorough investigation in real-life practice are unknown.Methods and resultsData were analysed from an ongoing study, collecting all cases of out-of-hospital cardiac arrest in Paris area. Investigations performed during the index hospitalization or planned after discharge were gathered to evaluate the completeness of assessment of unexplained SCA. Between 2011 and 2016, among the 18 622 out-of-hospital cardiac arrests, 717 survivors (at hospital discharge) fulfilled the definition of cardiac SCA. Of those, 88 (12.3%) remained unexplained after electrocardiogram, echocardiography, and coronary angiography. Cardiac magnetic resonance imaging yielded the diagnosis in 25 (3.5%) cases, other investigations accounted for 14 (2.4%) additional diagnoses, and 49 (6.8%) patients were labelled as idiopathic ventricular fibrillation (IVF) (48.7 ± 15 years, 69.4% male). Among those labelled IVF, only 8 (16.3%) cases benefited from a complete workup (including pharmacological testing). Younger patients [odds ratio (OR) 6.00, 95% confidence interval (CI) 1.80–22.26] and those admitted to university centres (OR 3.60, 95% CI 1.12–12.45) were more thoroughly investigated. Genetic testing and family screening were initiated in only 9 (18.4%) and 12 (24.5%) cases, respectively.ConclusionOur findings suggest that complete investigations are carried out in a very low proportion of unexplained SCA. Standardized, systematic approaches need to be implemented to ensure that opportunities for specific therapies and preventive strategies (including relatives) are not missed.

Sex Differences in Cardiac Arrhythmias: Clinical and Research Implications.

Sex differences have the potential to impact diagnostic and therapeutic interventions in a wide variety of medical conditions, and cardiac arrhythmias are no exception.1 Studies evaluating pathophysiology, disease course, and therapeutic options for cardiac arrhythmias have been performed predominantly in male patients. However, catheter and device-based therapies coupled with landmark clinical trials have contributed to an improved understanding of this important aspect. The objective of this review is to present the current state of knowledge on sex differences in cardiac arrhythmias with a focus on clinical management, while highlighting gaps in knowledge that would benefit from future investigation. ### Atrial Fibrillation and Atrial Flutter #### Disease Burden Atrial fibrillation (AF) and atrial flutter (AFL) are the most commonly encountered tachyarrhythmias in clinical practice, with significant implications for public health and healthcare costs. Stroke, hospitalization, and loss of productivity are the major consequences of AF.2 The incidence of AF (per 1000 person-years) is reported to be between 1.6 and 2.7 in women and between 3.8 and 4.7 in men.2 The age-adjusted incidence and prevalence of AF is lower in women compared with that in men, and accordingly, the lifetime risk of AF from the Framingham Heart Study at 40 years of age was higher in men (26.0% for men versus 23.0% for women).3 Another analysis from the Framingham Heart Study demonstrated no significant sex differences in the risk of developing AFL.4 The prevalence of AF continues to rise among both men and women. In a study investigating the global burden of disease from 1980 to 2010, there was not only an increase in overall burden, incidence, and prevalence of AF, but most importantly an increase in AF-associated mortality in both men and women (Figure 1).5 The age-adjusted mortality for women was consistently higher compared with that for men from 1990 to 2010 (Figure …

0396: Sensitivity of sodium channel blocker in Brugada syndrome

Brugada syndrome (BS) is characterized by a typical ECG pattern. To carrying out the diagnosis in patients without a spontaneous ECG pattern, sodium channel blocker (SCB) is used. However, the value of this test is not well known, particulary its sensibility because of a complex genetic model do not allowing the use of any mutation as a gold standard. To clarify the value of this test, we analyzed a database of 680 SCB performed in families affected by the syndrome, considering the mandatory transmitters (MT) as a true positive. All patients who underwent a SCB and belonging to a family with at least 2 subjects with the syndrome were included. The MT was defined by an individual with at least one descendant in the first degree and an ascendant with a BS or unexplained sudden cardiac arrest. All the ECG data at baseline and at diagnosis was reviewed by two expert, blinded to the clinical and genetical status. Of the 137 selected families, 85 MT were identified. Excluding individuals who have not benefited from the SCB, sensitivity of test was calculated at 91% (42/46). According to the molecule used, the sensitivity was significantly better for ajmaline than flecainide with a sensitivity of 97% and 75% respectively (p =0.048). Among the 680 individuals who benefited a SBC, the duration of the S wave in DII, DIII and V5 and the R wave in aVR were significantly elongated at both baseline and diagnosis, in individuals with a positive SBC. Complications occurred in 1.6% of patients (11/680) including 4 required an electrical cardioversion. Risk factors present a complication was the youngest age and the occurrence of a complication with a member of his family. This study demonstrates for the first time, the excellent sensitivity of SCB in BS, particulary with the use of ajmaline. Complications are rare and doesn’t appeared to be linked with QRS enlargement but with familial history of ventricular arythmia during the test