Unexplained Sudden Cardiac Death Research Articles

Abstract 4126987: A Case of Recurrent Neurocardiogenic Syncope in a COVID-19 Patient

Background: COVID-19 infection has been associated with a broad range of clinical manifestations. There are very few reported cases of COVID-19 patients presenting with syncope as an initial symptom. We present an extraordinary case of recurrent neurocardiogenic syncope in a COVID-19 patient. Case: A 66-year-old male presented after experiencing two episodes of syncope. He denied any prodromal or anginal symptoms. His medications included propranolol 10 mg twice daily for essential tremors. He had no family history of unexplained syncope or sudden cardiac death. He was hemodynamically stable and had one episode of fever at 102°F. Telemetry recording showed vagal-mediated sinus arrest and pauses without escape. Blood work showed normal cell counts, electrolytes, thyroid-stimulating hormone, and erythrocyte sedimentation rate, with a slightly elevated C-reactive protein of 22.2 mg/L. He tested positive for COVID-19 and had negative Lyme and Ehrlichia serologies. Decision Making: Due to symptomatic long sinus pauses, propranolol was discontinued, and he received a temporary pacemaker set at 50 beats per minute (bpm). He had another syncopal episode while being paced at 50 bpm, suggesting a neurocardiogenic mechanism, so the pacing rate was increased to 70 bpm. An echocardiogram showed a normal ejection fraction without any significant valvular disease. The syncope was determined to be vasovagal due to autonomic dysfunction in the setting of COVID-19. After 72 hours without further syncope, the temporary pacemaker was removed, and he was discharged home with an implantable loop recorder (ILR). A one-month follow-up showed no syncope, and ILR interrogation showed no bradycardia or pauses. Conclusion: Neurocardiogenic syncope with prolonged asystole and sinus pauses is an uncommon presentation of COVID-19 infection. The clinical course of autonomic dysfunction following COVID-19 is not very clear, and monitoring with an ILR is reasonable before considering permanent pacemaker implantation.

Prevalence and characteristics of the catecholamine induced QT prolongation syndrome

Abstract Background We have recently described large families of idiopathic ventricular fibrillation characterised by catecholamine-induced QT interval prolongation (CIQTP). The patient presented with a normal QT duration at rest but an abnormal QT prolongation during a mental stress test (MST). Objective The aim of this study was to investigate the role of this new syndrome in inherited arrhythmic diseases. Methods Consecutive patients and their relatives, identified after unexplained familial sudden cardiac death or sudden cardiac arrest, were enrolled in the study in the presence of: - no other diagnosis after cardiac ultrasound, stress test, pharmacological test with adrenaline and ajmaline. - positive MST defined by a prolongation of the QT interval (>-11ms) during MST (as previously published). Results 134 families with unexplained SCD were examined. CIQTP was diagnosed in 15 families, representing a prevalence of 11.2%. Family screening of these 15 families identified a total of 43 individuals. Seven (16%) had symptoms prior to diagnosis, including sudden cardiac arrest in one. At baseline, the QTc interval was measured at 440+/-23 ms. MST increased the QTc interval by 49+/-33 ms. The identification of QT interval prolongation was less important in the exercise test (delta QTc 17+/-52 ms at 4 minutes after exercise) and the epinephrine test (delta QTc 19+/-36 at 1 minute according to the Krahn protocol). Treatment with beta-blockers was initiated in 19 patients (44%) on the basis of symptoms and major prolongation of the QT interval during the MST. After a mean follow-up of 7+/-2 years, only one patient developed ventricular fibrillation. This episode occurred during a short period when he was no observant for the treatment. Since then, there has been no recurrence of the arrhythmia on beta-blocker therapy. All other patients, including those who were previously symptomatic remained symptom-free on treatment. Conclusion CIQTP may explain a significant part of sudden cardiac arrest or syncope in young patients. Conventional screening using ECG, exercise test and epinephrine challenge may not be able to unmask CIQTP. Then MST may be systematically proposed for the screening of patient and their family. In CIQTP patients beta blocker therapy appears to be highly efficient to prevent symptoms.

Teclistamab in Relapsed/Refractory Multiple Myeloma: Real-World Outcomes at a Single Academic Center in the Midwest

CONCLUSIONS BCMA-directed CAR T-cell therapy is only available at certain academic centers in the Midwest and requires several weeks for manufacturing, leading to a bottleneck of patients who need therapy for relapsed/refractory multiple myeloma (R/R MM). Teclistamab is an off-the-shelf BCMA-directed bispecific T-cell engager (BiTE) that could help alleviate this bottleneck. The MajesTEC-1 trial was a phase I/II study of teclistamab in patients with R/R MM. Even in patients with triple class-exposed disease, teclistamab showed deep and durable responses. However, clinical trials generally enroll fitter patients, especially when compared to the typical MM patient at the late stages of their disease. We sought to describe the real-world treatment outcomes of patients with R/R MM who received teclistamab at Indiana University (IU). This study was conducted retrospectively at a single center. Patients who received teclistamab between October 25 th, 2022, and July 1 st, 2023, were included. Patients were hospitalized during step-up dosing. The teclistamab dosing and schedule were per standard of care. Response was assessed after each cycle based on the IMWG Uniform Response Criteria. CRS and ICANS were graded per Lee 2020, while other side effects were evaluated using CTCAE 5.0. Demographic information, response, and adverse events were reported descriptively, and survival outcomes were estimated using Kaplan-Meier analysis with Prism GraphPad 10.0. The baseline clinical characteristics are summarized in Table 1. Compared to MajesTEC-1, patients treated in this study were older and more heavily pretreated with a higher baseline burden of disease. Many exhibited organ dysfunction and poor performance status, and 20 of 33 patients were previously exposed to BCMA-directed therapy (BDT). The median follow-up duration was 17.6 weeks. The overall response rate (ORR) was 45.5%, including one-third of patients who achieved a very good partial response (VGPR) or better. When stratified by prior exposure to BDT, ORR was 35% in previously exposed patients and was 61.5% in naïve patients. Thirteen patients died during follow-up (9 from disease progression, 3 from infection, and 1 unexplained sudden cardiac death). Median overall survival in the entire cohort was 17.7 weeks. As shown in the Kaplan-Meier analysis in Figure 2, the median OS was not reached for patients who achieved a response, while patients who did not respond had a median OS of 16.7 weeks (p=.05). CRS was observed in 12 patients (36%), with one grade 3 event requiring tocilizumab, dexamethasone, and ICU transfer for hypoxemic respiratory failure - this patient ultimately died from a hospital-acquired infection. ICANS was observed in 5 patients (15.2%), with one grade 3 event - this patient became unresponsive, requiring intubation and mechanical ventilation. Sixteen of 33 patients had an infectious complication (48.5%), while 3 patients died of a treatment-related infection (Pseudomonas pneumonia, hospital-acquired pneumonia, and sepsis from a urinary source). Grade 3 or 4 neutropenia occurred in 12.1%. In a real-world cohort of heavily pretreated myeloma patients, including those with poor organ function, poor performance status, and prior exposure to BCMA-directed therapy, overall response to teclistamab was lower than previously observed in the MajesTEC-1 study. Achieving a PR or better led to a significantly improved OS, while survival among non-responders was poor. Receipt of prior BCMA-directed therapy led to a lower response rate. The incidence of CRS in the current study was lower than that seen in MajesTEC-1, while the rate of neurotoxicity was similar. High grade CRS and ICANS were infrequent but led to poor patient outcomes in our cohort. Despite a low rate of grade 3 or 4 neutropenia, there was a high rate of infection, even with use of prophylactic IVIG for hypogammaglobulinemia. There were 3 infection-related fatalities. This highlights the severely immunocompromised state of the patient population and the need for early recognition and improved strategies for infection prevention. The early use of BCMA BiTEs may improve access and tolerability. However, there is still a need for better understanding of resistance mechanisms.

The burden of splice-disrupting variants in inherited heart disease and unexplained sudden cardiac death

There is an incomplete understanding of the burden of splice-disrupting variants in definitively associated inherited heart disease genes and whether these genes can amplify from blood RNA to support functional confirmation of splicing outcomes. We performed burden testing of rare splice-disrupting variants in people with inherited heart disease and sudden unexplained death compared to 125,748 population controls. ClinGen definitively disease-associated inherited heart disease genes were amplified using RNA extracted from fresh blood, derived cardiomyocytes, and myectomy tissue. Variants were functionally assessed and classified for pathogenicity. We found 88 in silico-predicted splice-disrupting variants in 128 out of 1242 (10.3%) unrelated participants. There was an excess burden of splice-disrupting variants in PKP2 (5.9%), FLNC (2.7%), TTN (2.8%), MYBPC3 (8.2%) and MYH7 (1.3%), in distinct cardiomyopathy subtypes, and KCNQ1 (3.6%) in long QT syndrome. Blood RNA supported the amplification of 21 out of 31 definitive disease-associated inherited heart disease genes. Our functional studies confirmed altered splicing in six variants. Eleven variants of uncertain significance were reclassified as likely pathogenic based on functional studies and six were used for cascade genetic testing in 12 family members. Our study highlights that splice-disrupting variants are a significant cause of inherited heart disease, and that analysis of blood RNA confirms splicing outcomes and supports variant pathogenicity classification.

Cardiac hereditary diseases: genetic insights from a single center 15-year experience

Abstract Funding Acknowledgements Type of funding sources: None. Background In the last decades, the implementation of high-throughput next-generation (NGS) technologies has profoundly changed the landscape of human genome sequencing. However, the molecular diagnosis in cardiac hereditary diseases is still hampered by the incomplete penetrance, variable expressivity, and genetic heterogeneity of the diseases. Objective We report our 15-year experience on a cohort of consecutive patients (pts) with suspicion of cardiac hereditary disease referred to the specialized cardiogenetic outpatient clinic of our center. Methods We retrospectively reviewed DNA sequencing results of pts referred to our center from July 1st 2007 through December 31st 2021, who were tested with NGS technologies for suspected cardiac hereditary diseases including channelopathies, inherited cardiomyopathies and unexplained sudden cardiac death. Results Among the 488 tested pts, the most frequent clinical indication were presymptomatic screening (37.3%) for a known familial variant, followed by suspected arrhythmic syndrome (28.3%) and hereditary cardiomyopathy (26.8%). A likely pathogenic/pathogenic variant was found in 198 pts for an overall diagnostic yield of 40.6% and of 23.6% considering only index cases. The rate of identified mutation-carriers was higher among pts with cardiomyopathy (45.8%) than among pts with inherited arrhythmic syndromes (37%). Panel A and B display variant distribution in arrhythmic syndromes and cardiomyopathies respectively. In particular, the highest diagnostic yield was observed among pts with suspected hypertrophic cardiomyopathy (60.7%) and catecholaminergic polymorphic ventricular tachycardia (50%), followed by congenital long QT syndrome (48.6%). The pathogenic variants were mainly identified in genes with definitive scientific evidence of causal association with the disease. Conclusions The 15-year experience of our specialized cardiogenetic outpatient clinic has demonstrated the pivotal role of genetic analysis for the diagnostic confirmation and, hence for the therapeutic management of pts with suspected cardiac hereditary disease.

PO-05-173 PREVALENCE OF MITRAL VALVE PROLAPSE IN PATIENTS WITH SUDDEN CARDIAC DEATH

The growing interest in the prevention of sudden cardiac death (SCD) has drawn attention to MVP as a possible substrate of cardiac arrest. Although poorly understood, the current understanding of arrhythmogenesis in MVP involves the development of a substrate for arrhythmias (cardiac fibrosis) combined with a trigger for arrhythmias. In general, MVP has a low prevalence; its prevalence in patients who died from sudden cardiac death (SCD) remains unclear. We aimed to assess the prevalence of MVP in patients with autopsy-proven SCD. A systematic search, without language restriction, using PubMed, EMBASE, SCOPUS, Google Scholar, and ClinicalTrials.gov was performed. The meta-analysis was performed using a meta-package for R version 4.0/RStudio version 1.2 and Freeman Tukey double arcsine method to establish the variance of raw proportions. The outcomemeasured was the prevalence of MVP in patients who died with SCD, proven by autopsy. We also aimed to evaluate prevalence stratified by region. This systematic review of nineteen studies (seven from North America, eleven from Europe, and one from Asia) incorporated a total of 6,642 patients with autopsy-proven SCD (mean age 38.4±16.1 years, 80% men). Fifteen studies exclusively incorporated the general population, three included young athletes, and one included military recruits. Of all SCDs, the prevalence of MVP was 2.2% (95% CI 1.2-3.5%) with a high degree of heterogeneity I2=88%, Χ2 p<0.01). When stratified by region, the prevalence of MVP among SCD patients was 6.7% (95% CI 3.5-10.9%) in Italy, 2.85% (95% 1-5.6%) in the United States, 2.4% (95% CI 1.6-3.3%) in the United Kingdom and 1.7% (95% CI 0.2-6%) in Israel. The overrepresentation of MVP in unexplained SCD cohorts indicates an ‘at-risk’ subset and poses significant concern in light of the large MVP population in the general population.

Prospective observational study on the accuracy of predictors of high-grade atrioventricular conduction block after transcatheter aortic valve implantation (CONDUCT-TAVI): study protocol, background and significance

IntroductionAortic stenosis is the most common cardiac valve pathology worldwide and has a mortality rate of over 50% at 5 years if left untreated. Transcatheter aortic valve implantation (TAVI) is...

Sudden Cardiac Death in Young Individuals: A Current Review of Evaluation, Screening and Prevention.

Sudden cardiac death (SCD) can affect all age groups, including young persons. While less common in the age < 35 population, the occurrence of SCD in the young raises concern, with multiple possible etiologies and often unanswered questions. While coronary artery disease is the leading cause in those > 35 years of age, the younger population faces a different subset of pathologies associated with SCD, including arrhythmias and cardiomyopathies. The tragic nature of SCD in the young entails that we explore and implement available screening methods for this population, and perform the necessary investigations such as electrocardiography (ECG) and echocardiography. In this review, we not only explore the vast etiology associated with SCD in those age < 35, but emphasize evaluation methods, who is at risk, and delve into screening of SCD in potential victims and their family members, in an attempt to prevent this traumatic event. Future research must work towards establishing preventative measures in order to reduce SCD, particularly unexplained SCD in the young.

313 BRUGADA SYNDROME MIMICRY: THE IMPORTANCE OF AN EXTENDED FOLLOW-UP

Abstract Introduction Brugada Syndrome (BrS) is a genetically inherited condition associated with the risk of fatal arrhythmias and sudden cardiac death (SCD) occurring in a structurally normal heart. This disorder was historically related to mutations in the SCN5A gene, but recent observations suggest a more complex genetic inter-play, highlighting the possible overlap with structural cardiomyopathies, including hypertrophic cardiomyopathy (HCM). Case Presentation In May 2005, an asymptomatic 56-year-old man with a family history of unexplained SCD was referred to our outpatient clinic. A 12-lead ECG showed a type 2 Brugada pattern whilst transthoracic echocardiogram (TTE) was normal. Ventricular fibrillation (VF) was induced during an elective electrophysiological study and a transvenous implantable cardioverter-defibrillator (ICD) was implanted for primary prevention. More than 10 years later, in March 2022, our patient was admitted to the hospital because of palpitations. The ECG revealed a typical atrial flutter with a high ventricular rate, successfully treated with catheter ablation. Post-procedural ECG showed the persistence of type 2 Brugada pattern in association with new-onset T wave inversion in inferolateral leads and signs of ventricular hypertrophy. TTE revealed asymmetric left ventricular hypertrophy, with left ventricular outflow tract (LVOT) obstruction determined by mitral systolic anterior motion and preserved LV systolic function. The patient was treated with optimal medical therapy with symptom improvement and reduction of LVOT obstruction at a 3-month follow-up TTE. Discussion The distinction between Brugada phenocopy and BrS electrocardiogram patterns is not obvious, and according to our experience a Brugada type 2 pattern could be an early ECG marker of a concealed HCM which became manifest over an extended follow-up. Brugada ECG phenocopies are clinical entities characterized by type 1 or type 2 Brugada patterns elicited by an underlying condition, the disappearance of the pattern with the resolution of the condition and the absence of classical symptoms. Several pathogenic variants involving other and different genes have been recently reported suggesting a possible overlap with structural cardiomyopathies. Recently, two other cases of incidental findings of a Brugada ECG pattern in the context of HCM were described. Both patients had a common pathogenetic splicing mutation in the MYBPC3 sarcomeric gene (encoding for the cardiac myosin-binding protein C) responsible for HCM with no genetic mutations associated with Brugada syndrome. This fact suggests that patients are not simultaneously affected by BrS and HCM but a clinically manifest HCM with a specific genetic background can lead to an early BrS electrical manifestation. Conclusion Our experience confirms that a Brugada type 2 ECG pattern could be a very early sign of a concealed HCM manifested over 10 years later. The importance of proper risk stratification and regular follow-up has thus crucial implications in patient clinical management. However, whether Brugada pattern associated with structural heart disease is linked to an increased risk of sudden cardiac death is still unknown and needs further investigations.

Ventricular activation time as a marker for complex ventricular arrhythmias, sudden cardiac death and ICD implantation in hypertrophic cardiomyopathy

Abstract Background Identification of patients with hypertrophic cardiomyopathy (HCM) who are at high risk of sudden cardiac death (SCD) is essential, as life-threatening ventricular arrhythmias (VAs) can be effectively prevented with an implantable cardioverter defibrillator (ICD). Risk stratification using HCM Risk-SCD score is recommended in the 2014 ESC guidelines for the management of patients with HCM. However, the role of electrocardiogram (ECG) in risk stratification is less well established. Purpose We investigated the association between the ventricular activation time (VAT), an ECG marker of the duration of ventricular depolarization, with the HCM Risk-SCD score, the presence of complex VAs, the implantation of an ICD and ICD-therapy for VAs. Methods Patients with a history of HCM, documented by echocardiography, were studied. The 12-lead ECG and echocardiography were performed on the same day. On ECG, we evaluated the VAT in milliseconds, between the onset of the QRS complex to the peak of R wave on V5 or V6 precordial ECG leads. A careful personal and family history for unexplained syncope and SCD was obtained, respectively. The presence of non-sustained ventricular tachycardia (NSVT) and ICD therapy were assessed either with 48h ECG recording or ICD interrogation. HCM Risk-SCD score was calculated by the corresponding ESC online calculator. Statistical analysis was performed using the SPSS software. Results Thirty-three patients with HCM were included (mean age 51±12 years, 78.8% male). According to the HCM Risk-SCD score, HCM patients were divided into three groups: low-risk (&amp;lt;4, 45.5%), intermediate-risk (4 to &amp;lt;6, 24.2%) and high-risk (&amp;gt;6, 30.3%) for SCD. Approximately half of the HCM patients had episodes of NSVT (48.5%) and an ICD (48.5%). Ventricular activation time was significantly prolonged in high-risk group compared either with intermediate-risk (74±24.5 vs 48.7±16.4, p=0.006) or low-risk (74±24.5 vs 44.3±12.6, p&amp;lt;0.001). HCM patients with NSVT had a significantly prolonged VAT compared with those without NSVT (62.19±25.2 vs 47.06±15.3, p=0.022). Moreover, HCM patients with an ICD had a higher VAT than those without an ICD (62.1±25.2 vs 47±15.3, p=0.003). VAT was also significantly prolonged in the group with appropriate ICD therapy for VAs compared with that without ICD therapy (82.8±22.1 vs 52.2±16.4, p=0.007). Finally, there was a significant positive correlation between VAT and NSVT (r=0.352, p=0.044), history of syncope (r=0.604, p&amp;lt;0.001), HCM risk-SCD score (r=0.493, p=0.004), ICD implantation (r=0.508, p=0.003) and ICD therapy (r=0.648, p=0.007) for VAs while there was not a correlation with the family history of SCD. Conclusion Prolongation of VAT is associated with NSVT, HCM risk score for SCD, ICD implantation and ICD therapy for VAs in patients with HCM and it seems to be a novel, easy to measure, ECG marker for risk stratification. Funding Acknowledgement Type of funding sources: None.

Implantable defibrillators in primary prevention of genetic arrhythmias. A shocking choice?

Many previously unexplained life-threatening ventricular arrhythmias and sudden cardiac deaths (SCDs) in young individuals are now recognized to be genetic in nature and are ascribed to a growing number of distinct inherited arrhythmogenic diseases. These include hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (VT), and short QT syndrome. Because of their lower frequency compared to coronary disease, risk factors for SCD are not very precise in patients with inherited arrhythmogenic diseases. As randomized studies are generally non-feasible and may even be ethically unjustifiable, especially in the presence of effective therapies, the risk assessment of malignant arrhythmic events such as SCD, cardiac arrest due to ventricular fibrillation (VF), appropriate implantable cardioverter defibrillator (ICD) interventions, or ICD therapy on fast VT/VF to guide ICD implantation is based on observational data and expert consensus. In this document, we review risk factors for SCD and indications for ICD implantation and additional therapies. What emerges is that, allowing for some important differences between cardiomyopathies and channelopathies, there is a growing and disquieting trend to create, and then use, semi-automated systems (risk scores, risk calculators, and, to some extent, even guidelines) which then dictate therapeutic choices. Their common denominator is a tendency to favour ICD implantation, sometime with reason, sometime without it. This contrasts with the time-honoured approach of selecting, among the available therapies, the best option (ICDs included) based on the clinical judgement for the specific patient and after having assessed the protection provided by optimal medical treatment.

Latent Causes of Sudden CardiacArrest.

Inherited arrhythmia syndromes are a common cause of apparently unexplained cardiac arrest or sudden cardiac death. These include long QT syndrome and Brugada syndrome, with a well-recognized phenotype in most patients with sufficiently severe disease to lead to cardiac arrest. Less common and typically less apparent conditions that may not be readily evident include catecholaminergic polymorphic ventricular tachycardia, short QT syndrome and early repolarization syndrome. In cardiac arrest patients whose extensive testing does not reveal an underlying etiology, a diagnosis of idiopathic ventricular fibrillation or short-coupled ventricular fibrillation is assigned. This review summarizes our current understanding of the less common inherited arrhythmia syndromes and provides clinicians with a practical approach to diagnosis and management.

PO-717-07 A FAMILY WITH SUDDEN CARDIAC DEATH, LEFT VENTRICULAR FIBROSIS AND MITRAL VALVE PROLAPSE

Arrhythmic mitral valve prolapse (AMVP) is a rare cause of sudden cardiac death (SCD) however, the prevalence of MVP in victims of unexplained SCD is 11.7%. Mechanisms of arrhythmia include tugging of the prolapsing valve, which can tigger premature ventricular beats, polymorphic ventricular tachycardia (VT) and ventricular fibrillation. This may lead to fibrosis of the myocardium over time and re-entrant arrhythmia. No guidelines exist on SCD risk stratification and treatment of AMVP.

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.

Research Progress on Molecular Markers Related to Unexplained Sudden Cardiac Death and Its Forensic Application.

Routine pathological examination of unexplained sudden cardiac death (USCD) lacks significant morphological characteristics. In the field of forensic medicine, molecular biology methods have been used to find the cause of death by detecting genes and research related to the mechanism of sudden cardiac death has been carried out. From the molecular pathology point of view, the application of multiple levels of biomarkers to resolve the causes of USCD has already shown potential and provides an important path for forensic identification of USCD. This article reviews the latest research progress on USCD-related genes, RNA, proteins and USCD, and summarizes forensic application.

Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals

Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined. To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

KCNE2 gene mutation and Brugada syndrome

KCNE2 gene mutations have been associated with atrial fibrillation, long QT syndrome, Brugada syndrome and unexplained sudden cardiac death. Herein, we describe a case of Brugada syndrome carrying an heterozygous variant in the KCNE2 gene [NM_172201.2:c.161 T > C, p.(Met54Thr, M54T)]. Gain of function of the Ito current possibly explains the Brugada ECG phenotype in this case.

Long-term follow-up in patients with Brugada Syndrome in South China.

ObjectiveTo evaluate the presence of Brugada electrocardiogram (ECG) pattern, clinical characteristics, treatment, and long‐term prognosis of Brugada syndrome in southern Chinese population.MethodsThis prospective study consisted of a consecutive series of patients with diagnostic coved type I Brugada ECG pattern at baseline between January 2007 and February 2020. Histories of symptoms including ventricular tachycardia (VT)/ventricular fibrillation (VF) episode, syncope, and family history of Brugada Syndrome (BrS) or unexplained sudden cardiac death were collected. Electrophysiological study and implantable cardioverter‐defibrillator (ICD) were performed. All patients included in this study were followed up in the outpatient department every 6 months after baseline evaluation. Occurrences of syncope, VF, and sudden death were independently analyzed by two cardiologists.Results45 (56.3%) patients were diagnosed with BrS. During a mean follow‐up of 7.9 ± 3.6 years, six patients had experienced documented VF/sudden cardiac death (SCD) or recurrent syncope. Two patients experienced episodes of syncope more than once. Two patients experienced onset of electrical storm with a total of 11 episodes of VF. There were 50% of these events occurring in fever status. One of patient with BrS died of SCD.ConclusionThere was a very low prevalence of Brugada syndrome in southern Chinese population. The risk of arrhythmic events was low in asymptomatic patients. ICD was high effective in preventing SCD without adverse device outcome in long‐term follow‐up. Fever can lead to predispose to malignant arrhythmia, and aggressive treatment of febrile state in Brugada syndrome was recommended.

Characterization of clinically relevant copy-number variants from exomes of patients with inherited heart disease and unexplained sudden cardiac death

PurposeCopy-number variant (CNV) analysis is increasingly performed in genetic diagnostics. We leveraged recent gene curation efforts and technical standards for interpretation and reporting of CNVs to characterize clinically relevant CNVs in patients with inherited heart disease and sudden cardiac death. MethodsExome sequencing data were analyzed for CNVs using eXome-Hidden Markov Model tool in 48 established disease genes. CNV breakpoint junctions were characterized. CNVs were classified using the American College of Medical Genetics and Genomics technical standards. ResultsWe identified eight CNVs in 690 unrelated probands (1.2%). Characterization of breakpoint junctions revealed nonhomologous end joining was responsible for four deletions, whereas one duplication was caused by nonallelic homologous recombination between duplicated sequences in MYH6 and MYH7. Identifying the precise breakpoint junctions determined the genomic involvement and proved useful for interpreting the clinical relevance of CNVs. Three large deletions involving TTN, MYBPC3, and KCNH2 were classified as pathogenic in three patients. Haplotype analysis of a deletion in ACTN2, found in two families, suggests the deletion was caused by an ancestral event. ConclusionCNVs infrequently cause inherited heart diseases and should be investigated when standard genetic testing does not reveal a genetic diagnosis.

Concealed Cardiomyopathy as a Cause of Sudden Cardiac Death

Inherited cardiomyopathies can present with malignant arrhythmias prior to overt structural changes, so called “concealed cardiomyopathy”. However, current guidelines recommend only “arrhythmia-syndrome focused” genetic testing following unexplained sudden cardiac death (SCD).