Cardiac Channelopathies Research Articles

Epilepsy duration is an independent factor for electrocardiographic changes in pediatric epilepsy.

ObjectiveCardiac alterations represent a potential epilepsy‐associated comorbidity. Whether cardiac changes occur as a function of epilepsy duration is not well understood. We sought to evaluate whether cardiac alterations represented a time‐dependent phenomenon in pediatric epilepsy.MethodsWe retrospectively followed pediatric epilepsy patients without preexisting cardiac conditions or ion channelopathies who had history of pediatric intensive care unit admission for convulsive seizures or status epilepticus between 4/2014 and 7/2017. All available 12‐lead electrocardiograms (ECGs) from these patients between 1/2006 and 5/2019 were included. We examined ECG studies for changes in rhythm; PR, QRS, or corrected QT intervals; QRS axis or morphology; ST segment; or T wave. Data were analyzed using multivariable models containing covariates associated with ECG changes or epilepsy duration from the univariate analyses.Results127 children with 323 ECGs were included in the analyses. The median epilepsy duration was 3.9 years (IQR 1.3‐8.4 years) at the time of an ECG study and a median of 2 ECGs (IQR 1‐3) per subject. The clinical encounters associated with ECGs ranged from well‐child visits to status epilepticus. We observed changes in 171 ECGs (53%), with 83 children (65%) had at least 1 ECG with alterations. In a multivariable logistic regression model adjusting for potentially confounding variables and accounting for clustering by patient, epilepsy duration was independently associated with altered ECGs for each year of epilepsy (OR: 1.1, 95% CI: 1.0‐1.2, P = .002). Extrapolating from this model, children with epilepsy durations of 10 and 15 years had 2.9 and 4.9 times the odds of having ECG changes, respectively.SignificanceCardiac alterations may become more common with increasing epilepsy duration in select pediatric epilepsy patients. Future studies are needed to determine the potential clinical implications and the generalizability of these observations.

Ventricular Tachyarrhythmia Risk in Paediatric/Young vs. Adult Brugada Syndrome Patients: A Territory-Wide Study.

Introduction: Brugada syndrome (BrS) is a cardiac ion channelopathy with a higher prevalence in Asia compared to the Western populations. The present study compared the differences in clinical and electrocardiographic (ECG) presentation between paediatric/young (≤25 years old) and adult (>25 years) BrS patients.Method: This was a territory-wide retrospective cohort study of consecutive BrS patients presenting to public hospitals in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF).Results: The cohort consists of 550 consecutive patients (median age of initial presentation = 51 ± 23 years; female = 7.3%; follow-up period = 83 ± 80 months), divided into adult (n = 505, mean age of initial presentation = 52 ± 19 years; female = 6.7%; mean follow-up period = 83 ± 80 months) and paediatric/young subgroups (n = 45, mean age of initial presentation = 21 ± 5 years, female = 13.3%, mean follow-up period = 73 ± 83 months). The mean annual VT/VF incidence rate were 17 and 25 cases per 1,000 patient-year, respectively. Multivariate analysis showed that initial presentation of type 1 pattern (HR = 1.80, 95% CI = [1.02, 3.15], p = 0.041), initial asymptomatic presentation (HR = 0.26, 95% CI = [0.07, 0.94], p = 0.040) and increased P-wave axis (HR = 0.98, 95% CI = [0.96, 1.00], p = 0.036) were significant predictors of VT/VF for the adult subgroup. Only initial presentation of VT/VF was predictive (HR = 29.30, 95% CI = [1.75, 492.00], p = 0.019) in the paediatric/young subgroup.Conclusion: Clinical and ECG presentation of BrS vary between the paediatric/young and adult population in BrS. Risk stratification and management strategies for younger patients should take into consideration and adopt an individualised approach.

Correction to: Sex-Related Differences in Cardiac Channelopathies: Implications for Clinical Practice.

Correction to: Sex-Related Differences in Cardiac Channelopathies: Implications for Clinical Practice.

Does the Age of Sudden Cardiac Death in Family Members Matter in Brugada Syndrome?

BackgroundBrugada syndrome is an inherited cardiac channelopathy associated with major arrhythmic events (MAEs). The presence of a positive family history of sudden cardiac death (SCD) as a risk predictor of MAE remains controversial. We aimed to examine the association between family history of SCD and MAEs stratified by age of SCD with a systematic review and meta‐analysis.Methods and ResultsWe searched the databases of MEDLINE and EMBASE from January 1992 to January 2020. Data from each study were combined using the random‐effects model. Fitted metaregression was performed to evaluate the association between the age of SCD in families and the risk of MAE. Twenty‐two studies from 2004 to 2019 were included in this meta‐analysis involving 3386 patients with Brugada syndrome. The overall family history of SCD was not associated with increased risk of MAE in Brugada syndrome (pooled odds ratio [OR], 1.11; 95% CI, 0.82–1.51; P=0.489, I2=45.0%). However, a history of SCD in family members of age younger than 40 years of age did increase the risk of MAE by ≈2‐fold (pooled OR, 2.03; 95% CI, 1.11–3.73; P=0.022, I2=0.0%). When stratified by the age of cut point at 50, 45, 40, and 35 years old, a history of SCD in younger family member was significantly associated with a higher risk of MAE (pooled OR, 0.49, 1.30, 1.51, and 2.97, respectively; P=0.046).ConclusionsA history of SCD among family members of age younger than 40 years was associated with a higher risk of MAE.

Andersen-Tawil Syndrome with High Risk of Sudden Cardiac Death in Four Mexican Patients. Cardiac and Extra-Cardiac Phenotypes.

Andersen-Tawil syndrome (ATS) is a cardiac channelopathy that is inherited in an autosomal dominant way, and it is characterized by a triad of periodic paralysis, ventricular arrhythmias, and includes some dysmorphic features with incom- plete penetrance and variable expression that result in a challenging diagnosis. The objective of the study was to describe the cardiac and extra-cardiac phenotype in a cohort of patients with ATS at risk of sudden cardiac death (SCD) to improve its early clinical identification. In an observational, transversal study, with a deviant case sampling, four female patients with ATS at high risk of SCD were included in the study. They carried the heterozygous pathogenic variants c.407C>T [p.Ser136Phe], c.652C>T [p.Arg218Trp] (n=2), and c.431G>C [p.Gly144Ala] in the KCNJ2 gene. Patients were evaluated by a cardiologist, a clinical geneticist, and a physiatrist. One patient had the classical facial phenotype and the other three had subtle manifestations. The group of patients presented a diverse set of clinical data such as: triangular face, broad forehead, broadening of medial eyebrows, auricular pits, low-set ears, eyelid ptosis, thin lips, mandibular hypoplasia, and diverse types of dental alterations, single transverse palmar crease, camptodactyly, and syndactyly. Long-exercise test showed a decrement in the percentage amplitude up to 44%, classifying patients in IV or V types according to Fournier's scale. Extra- cardiac manifestations were a common finding in this series of ATS type1 at high risk of SCD. Its recognition could help the clinician in the early identification of patients with ATS, especially for the cardiologist since they are commonly referred only for evaluation of ventricular arrhythmias.

Genetic investigations of 100 inherited cardiac disease-related genes in deceased individuals with schizophrenia.

Cardiac diseases and sudden cardiac death (SCD) are more prevalent in individuals diagnosed with schizophrenia compared to the general population, with especially coronary artery disease (CAD) as the major cardiovascular cause of death. Antipsychotic medications, genetics, and lifestyle factors may contribute to the increased SCD in individuals with schizophrenia. The role of antipsychotic medications and lifestyle factors have been widely investigated, while the genetic predisposition to inherited cardiac diseases in schizophrenia is poorly understood. In this study, we examined 100 genes associated with inherited cardiomyopathies and cardiac channelopathies in 97 deceased individuals diagnosed with schizophrenia for the prevalence of genetic variants associated with SCD. The deceased individuals had various causes of death and were included in the SURVIVE project, a prospective, autopsy-based study of mentally ill individuals in Denmark. This is the first study of multiple inherited cardiac disease-related genes in deceased individuals with diagnosed schizophrenia to shed light on the genetic predisposition to SCD in individuals with schizophrenia. We found no evidence for an overrepresentation of rare variants with high penetrance in inherited cardiac diseases, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG) consensus guidelines. However, we found that the deceased individuals had a statistically significantly increased polygenic burden caused by variants in the investigated heart genes compared to the general population. This indicates that common variants with smaller effects in heart genes may play a role in schizophrenia.

Med Check: Qelbree and ADHD; Lacmital and Heart Disease; FDA and Atogepant; Azstarys and ADHD; FDA and CBD; Daridorexant and Insonnia

Med Check: Qelbree and ADHD; Lacmital and Heart Disease; FDA and Atogepant; Azstarys and ADHD; FDA and CBD; Daridorexant and Insonnia

Imperacalcin‐Induced Reduction of Sarcoplasmic Reticulum Ca 2+ in Intact Mouse Heart

Introduction Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac channelopathy, that often leads to sudden death due to arrhythmogenic episodes triggered by adrenergic stimulation. Previous studies have shown that CPVT is associated with mutations in the Ca2+ release channel of the sarcoplasmic reticulum (SR), the ryanodine receptor type-2 (RyR2). Loss of function mutations in the RyR2 result in abnormally low Ca2+ release which leads to an increase in SR Ca2+ content. It has been proposed that SR Ca2+ overload precipitates CPVT events by over activating the Na-Ca exchanger (NCX) which favors the development of arrhythmogenic delayed afterdepolarizations (DADs). Previous studies from our group and others have shown that the scorpion-derived peptide, imperacalcin (IpCa) is an effective agent to prevent/revert DADs in CPVT mouse models. The overall goal of this study was to test the hypothesis that the IpCa protects against CPVT by partially reducing SR Ca2+ content, therefore preventing the development of Ca2+ overload. To test this hypothesis, IpCa effect on SR Ca2+ content was evaluated by measuring SR Ca2+ restitution, which is the time-dependent recovery of SR Ca2+ release as a function of the stimulation frequency. If indeed, IpCa reduces SR Ca2+ content due to RyR2-mediated Ca2+ leak, SR Ca2+ restitution would be significantly shorter than in its absence. As a positive control, a known RyR2 agonist like caffeine, was used to define the effects of reducing SR Ca2+ content on SR Ca2+ restitution. Methods To test IpCa effects on SR Ca2+ restitution the pulsed local field fluorescence microscopy was used. Rhod-2AM-loaded hearts were perfused with either Tyrode, caffeine (1 mM), or IpCa (1 µM) and were stimulated at 2, 3, 4, 5, 6, 7, and 8 Hz while action potentials and intracellular Ca2+ transients were simultaneously recorded. SR Ca2+restitution was calculated from the ratio of the Ca2+ transient amplitude before and after the premature stimulation at the tested frequencies. Results At a constant stimulation frequency of 2 Hz, IpCa (1 µM; n=8) induced a 36% reduction of the Ca2+ transients amplitude, without affecting their kinetics or basal Ca2+. In contrast, caffeine (1 mM; n=10) affected basal Ca2+ (~3-fold increase), Ca2+ transients amplitude (~50% reduction), and their kinetics (~65% longer rise time & ~70% shorter decay & half-duration). As a function of the stimulation frequency, the SR Ca2+ exponential recovery (control t = 206±5 ms; n=6) was slightly accelerated by IpCa (t = 198±3 ms; n=4), & by caffeine (t = 183±4 ms; n=6). Conclusion Our results indicate that in intact mouse heart, the effects of IpCa on the intracellular Ca2+ dynamics are similar to those induced by caffeine in terms of reduction of SR Ca2+ content, without affecting the Ca2+ transient kinetics. Consistent with previous observations, our SR Ca2+ restitution results support the notion that IpCa partially depletes SR Ca2+ content, providing a plausible mechanism for its antiarrhythmic effects.

MODELING LONG QT SYNDROME IN IPS-DERIVED CARDIOMYOCYTES FROM A PATIENT HARBORING THE KCNQ1- I588T MUTATION

<h3>Background</h3> Human induced pluripotent stem (iPS) cell-derived cardiomyocytes (hiPSC‐CMs) technology offers an unprecedented tool to study cardiac diseases. Long QT syndrome type 1 (LQT1) is an inherited cardiac channelopathy caused by mutations in KCNQ1, which encodes the main subunit of the potassium channel Kv 7.1, leading to delayed repolarizations and imposing potentially fatal arrhythmias on patients. Therefore, the in vitro patient-specific modeling of LQT1 is crucial to test the pathogenicity of the KCNQ1- I588T mutation. <h3>Objective</h3> The purpose of this study was to test a cellular model of LQT1 based on a KCNQ1-I588T mutation using hiPSC‐CMs. <h3>Methods</h3> Peripheral blood was collected from a proband (a 15-year-old LQT1 symptomatic patient carrying KCNQ1-I588T mutation), a carrier donor (non-symptomatic familial carrying KCNQ1 mutation), and an unrelated control donor. The erythroblast enriched fraction was reprogrammed into iPS using Sendai virus vector. iPS were characterized for pluripotency markers by RT-PCR and flow cytometry, in vitro spontaneous differentiation, and karyotype stability. iPS were differentiated into cardiomyocytes and electrophysiological studies were performed. <h3>Results</h3> The proband was clinically diagnosed with LQT1 with resting corrected QT interval equal to 516 ms. The KCNQ1 mutation (c.1763T>C; p.I588T) was identified by NGS in the proband DNA sample. By Sanger, the same mutation was identified in the familial carrier while it was absent in the control subject. Erythroblasts were successfully reprogrammed into iPS. All iPS expressed the 13 different pluripotent markers evaluated, differentiated into three germ layers and presented a normal chromosomic profile. The differentiation protocol generated cells positive for cardiac troponin T. As expected, proband hiPSC‐CMs exhibited prolongation of action potential duration (APD90 = 312 ± 79 ms) when compared to carrier donor and control donor hiPS-CMs (APD90 = 177 ± 68 and 271 ± 71 ms, respectively). Since the mutation is the same in both the proband and the carrier, a protective/damaging molecular regulation must be involved. We speculate that a polymorphism identified only in the proband (SCN5A c.1673A>G; p.H558R) may be involved in this mechanism. <h3>Conclusions</h3> We identified an LQT1 causative variant that successfully recapitulated LQT1 proband phenotype by in vitro modeling. We also propose the existence of a second variant with a damaging effect on LQT1 symptom development.

Precision Medicine and cardiac channelopathies: when dreams meet reality.

Precision Medicine (PM) is an innovative approach that, by relying on large populations’ datasets, patients’ genetics and characteristics, and advanced technologies, aims at improving risk stratification and at identifying patient-specific management through targeted diagnostic and therapeutic strategies. Cardiac channelopathies are being progressively involved in the evolution brought by PM and some of them are benefiting from these novel approaches, especially the long QT syndrome. Here, we have explored the main layers that should be considered when developing a PM approach for cardiac channelopathies, with a focus on modern in vitro strategies based on patient-specific human-induced pluripotent stem cells and on in silico models. PM is where scientists and clinicians must meet and integrate their expertise to improve medical care in an innovative way but without losing common sense. We have indeed tried to provide the cardiologist’s point of view by comparing state-of-the-art techniques and approaches, including revolutionary discoveries, to current practice. This point matters because the new approaches may, or may not, exceed the efficacy and safety of established therapies. Thus, our own eagerness to implement the most recent translational strategies for cardiac channelopathies must be tempered by an objective assessment to verify whether the PM approaches are indeed making a difference for the patients. We believe that PM may shape the diagnosis and treatment of cardiac channelopathies for years to come. Nonetheless, its potential superiority over standard therapies should be constantly monitored and assessed before translating intellectually rewarding new discoveries into clinical practice.

The updated view on induced pluripotent stem cells for cardiovascular precision medicine.

Cardiovascular diseases have consistently been one of the leading causes of mortality, despite investigations by many scientists and clinicians. Animal models are versatile platforms to illustrate various mechanisms of different diseases, but are lacking in accurately portraying cardiovascular disease phenotypes. The advent of human pluripotent stem cells (PSCs) has led to much development in the construction of cardiovascular disease models. In this review, we provide a brief overview of the history and utilization of PSCs for cardiovascular precision medicine, including disease modeling, drug screening, and gene editing, and elaborate on the current updated research status of patient-specific induced pluripotent stem cell (iPSC)-based disease models for cardiac channelopathies, cardiomyopathies, and other cardiovascular diseases. Furthermore, we highlight the development of novel human iPSC-derived engineered heart tissues for cardiovascular disease modeling. Finally, we put forward our own views on the existing advantages and difficulties for moving forward in this field.

Sex-Related Differences in Cardiac Channelopathies: Implications for Clinical Practice.

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.

Cardiac channelopathies: diagnosis and contemporary management

### Learning objectives The inherited arrhythmia (IA) syndromes are a group of disorders characterised by an increased risk of sudden cardiac death (SCD), abnormal cardiac electrical function and typically, a...

Territory-Wide Chinese Cohort of Long QT Syndrome: Random Survival Forest and Cox Analyses.

Introduction: Congenital long QT syndrome (LQTS) is a cardiac ion channelopathy that predisposes affected individuals to spontaneous ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD). The main aims of the study were to: (1) provide a description of the local epidemiology of LQTS, (2) identify significant risk factors of ventricular arrhythmias in this cohort, and (3) compare the performance of traditional Cox regression with that of random survival forests.Methods: This was a territory-wide retrospective cohort study of patients diagnosed with congenital LQTS between 1997 and 2019. The primary outcome was spontaneous VT/VF.Results: This study included 121 patients [median age of initial presentation: 20 (interquartile range: 8–44) years, 62% female] with a median follow-up of 88 (51–143) months. Genetic analysis identified novel mutations in KCNQ1, KCNH2, SCN5A, ANK2, CACNA1C, CAV3, and AKAP9. During follow-up, 23 patients developed VT/VF. Univariate Cox regression analysis revealed that age [hazard ratio (HR): 1.02 (1.01–1.04), P = 0.007; optimum cut-off: 19 years], presentation with syncope [HR: 3.86 (1.43–10.42), P = 0.008] or VT/VF [HR: 3.68 (1.62–8.37), P = 0.002] and the presence of PVCs [HR: 2.89 (1.22–6.83), P = 0.015] were significant predictors of spontaneous VT/VF. Only initial presentation with syncope remained significant after multivariate adjustment [HR: 3.58 (1.32–9.71), P = 0.011]. Random survival forest (RSF) model provided significant improvement in prediction performance over Cox regression (precision: 0.80 vs. 0.69; recall: 0.79 vs. 0.68; AUC: 0.77 vs. 0.68; c-statistic: 0.79 vs. 0.67). Decision rules were generated by RSF model to predict VT/VF post-diagnosis.Conclusions: Effective risk stratification in congenital LQTS can be achieved by clinical history, electrocardiographic indices, and different investigation results, irrespective of underlying genetic defects. A machine learning approach using RSF can improve risk prediction over traditional Cox regression models.

Patients with coronary heart disease, dilated cardiomyopathy and idiopathic ventricular tachycardia share overlapping patterns of pathogenic variation in cardiac risk genes

BackgroundVentricular tachycardia (VT) is a major cause of sudden cardiac death (SCD). Clinical investigations can sometimes fail to identify the underlying cause of VT and the event is classified as idiopathic (iVT). VT contributes significantly to the morbidity and mortality in patients with coronary artery disease (CAD) and dilated cardiomyopathy (DCM). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility screening for disease-predisposing variants could improve VT diagnostics and prevent SCD in patients.MethodsNinety-two patients diagnosed with coronary heart disease (CHD), DCM, or iVT were included in our study. We evaluated genetic profiles and variants in known cardiac risk genes by targeted next generation sequencing (NGS) using a newly designed custom panel of 96 genes. We hypothesized that shared morphological and phenotypical features among these subgroups may have an overlapping molecular base. To our knowledge, this was the first study of the deep sequencing of 96 targeted cardiac genes in Kazakhstan. The clinical significance of the sequence variants was interpreted according to the guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015. The ClinVar and Varsome databases were used to determine the variant classifications.ResultsTargeted sequencing and stepwise filtering of the annotated variants identified a total of 307 unique variants in 74 genes, totally 456 variants in the overall study group. We found 168 mutations listed in the Human Genome Mutation Database (HGMD) and another 256 rare/unique variants with elevated pathogenic potential. There was a predominance of high- to intermediate pathogenicity variants in LAMA2, MYBPC3, MYH6, KCNQ1, GAA, and DSG2 in CHD VT patients. Similar frequencies were observed in DCM VT, and iVT patients, pointing to a common molecular disease association. TTN, GAA, LAMA2, and MYBPC3 contained the most variants in the three subgroups which confirm the impact of these genes in the complex pathogenesis of cardiomyopathies and VT. The classification of 307 variants according to ACMG guidelines showed that nine (2.9%) variants could be classified as pathogenic, nine (2.9%) were likely pathogenic, 98 (31.9%) were of uncertain significance, 73 (23.8%) were likely benign, and 118 (38.4%) were benign. CHD VT patients carry rare genetic variants with increased pathogenic potential at a comparable frequency to DCM VT and iVT patients in genes related to sarcomere function, nuclear function, ion flux, and metabolism.ConclusionsIn this study we showed that in patients with VT secondary to coronary artery disease, DCM, or idiopathic etiology multiple rare mutations and clinically significant sequence variants in classic cardiac risk genes associated with cardiac channelopathies and cardiomyopathies were found in a similar pattern and at a comparable frequency.

Frequency of syncope as a presenting symptom in channelopathies diagnosed in childhood. Can the multivariable EGSYS score unmask these children?

Pediatric syncope raises cardiac etiology concern as it might be the first sign of life-threatening arrhythmia syndromes. Our aim was to study the incidence of syncope as the presenting symptom in children with arrhythmia syndromes, and if known, warning signs are helpful to reveal the arrhythmic origin. All data on children with channelopathy was followed by a tertiary pediatric cardiac center between 2000 and 2018 and data were reviewed retrospectively. Forty-eight patients were enrolled, representing long QT syndrome (n = 39), catecholaminergic polymorphic ventricular tachycardia (n = 5), and Brugada syndrome (n = 4). Presenting symptoms were syncope in 13 cases [27%] (including 7 initially mislabeled as epilepsy) and sudden cardiac arrest (SCA) in 9 cases [19%]. In the rest of the group, the concern for arrhythmic etiology was raised by either an abnormal ECG during sports medicine screening (n = 13) [27%] or a positive family history of channelopathy (n = 13) [27%]. None of the patients presenting with SCA had a prior syncopal history. Six patients presenting with syncope and afterward treated with ICD had an appropriate shock. Description of witnessed syncope was available in eight out of thirteen children presenting with syncope. Multivariable EGSYS score suggested cardiac origin (≥ 3 points) in 7 out of 8 (88%) patients.Conclusions: Syncope was a relatively uncommon presenting symptom of channelopathies in this sample and did not always precede sudden cardiac arrests. However, we found that multivariable EGSYS score can identify syncope of arrhythmic origin, raising suspicion for pediatric channelopathies even in patients previously misdiagnosed with epilepsy. What is known: • Cardiac syncope is rare in children but can be the first sign of a potentially fatal primary arrhythmia syndrome and is frequently misdiagnosed as atypical/therapy-resistant epilepsy. • Multivariate EGSYS score is effective to diagnose cardiac syncope in adults. What is new: • Cardiac syncope as a presenting symptom is not common in children with cardiac channelopathies and is not often present before sudden cardiac arrest. • Multivariable EGSYS score might identify cardiac syncope in children with a hereditary and secondary channelopathy.

Chapter 17 - Neurologic complications of genetic channelopathies

This chapter describes what a channelopathy is and how mutations in the genes result in different types of clinical abnormalities. It provides a description of common types of cardiac channelopathies with examples of how there are some areas of overlap with sensory-neuromuscular channelopathies. We describe the cardiac channelopathies of Jervell and Lange-Nielson syndrome, Andersen-Tawil syndrome, Timothy syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and sinoatrial node dysfunction and deafness. We also discuss sudden unexpected death in epilepsy and how it could relate to some cardiac channelopathies.

Biophysical Characterization of a Novel SCN5A Mutation Associated With an Atypical Phenotype of Atrial and Ventricular Arrhythmias and Sudden Death.

BackgroundSudden cardiac death (SCD) is an unexpected death that occurs within an hour of the onset of symptoms. Hereditary primary electrical disorders account for up to 1/3 of all SCD cases in younger individuals and include conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT). These disorders are caused by mutations in the genes encoding cardiac ion channels, hence they are known as cardiac channelopathies. We identified a novel variant, T1857I, in the C-terminus of Nav1.5 (SCN5A) linked to a family with a CPVT-like phenotype characterized by atrial tachy-arrhythmias and polymorphic ventricular ectopy occurring at rest and with adrenergic stimulation, and a strong family history of SCD.ObjectiveOur goal was to functionally characterize the novel Nav1.5 variant and determine a possible link between channel gating and clinical phenotype.MethodsWe first used electrocardiogram recordings to visualize the patient cardiac electrical properties. Then, we performed voltage-clamp of transiently transfected CHO cells. Lastly, we used the ventricular/atrial models to visualize gating defects on cardiac excitability.ResultsVoltage-dependences of both activation and inactivation were right-shifted, the overlap between activation and inactivation predicted increased window currents, the recovery from fast inactivation was slowed, there was no significant difference in late currents, and there was no difference in use-dependent inactivation. The O’Hara-Rudy model suggests ventricular after depolarizations and atrial Grandi-based model suggests a slight prolongation of atrial action potential duration.ConclusionWe conclude that T1857I likely causes a net gain-of-function in Nav1.5 gating, which may in turn lead to ventricular after depolarization, predisposing carriers to tachy-arrhythmias.

Inherited Cardiac Arrhythmia Syndromes: Focus on Molecular Mechanisms Underlying TRPM4 Channelopathies.

The Transient Receptor Potential Melastatin 4 (TRPM4) is a transmembrane N-glycosylated ion channel that belongs to the large family of TRP proteins. It has an equal permeability to Na+ and K+ and is activated via an increase of the intracellular calcium concentration and membrane depolarization. Due to its wide distribution, TRPM4 dysfunction has been linked with several pathophysiological processes, including inherited cardiac arrhythmias. Many pathogenic variants of the TRPM4 gene have been identified in patients with different forms of cardiac disorders such as conduction defects, Brugada syndrome, and congenital long QT syndrome. At the cellular level, these variants induce either gain- or loss-of-function of TRPM4 channels for similar clinical phenotypes. However, the molecular mechanisms associating these functional alterations to the clinical phenotypes remain poorly understood. The main objective of this article is to review the major cardiac TRPM4 channelopathies and recent advances regarding their genetic background and the underlying molecular mechanisms.

Efficacy and safety of implantable cardioverter-defibrillator implantation in pediatric tachycardia cases

Objective: To analyze the indication, efficacy and complications of implantable cardioverter-defibrillator (ICD) implantation in children with severe tachycardia. Methods: The retrospective study collected the clinical data of 6 patients who accepted ICD implantation in Shanghai Children's Medical Center from January 2009 to January 2020. The etiologies of tachycardia, procedure of the ICD implantation and the operation associated complications were analyzed. Results: The 6 patients aged from 6 years and 5 months to 16 years and 2 months, and their weight were from 15.4 kg to 49.8 kg. Three patients were diagnosed with long QT syndrome, and the remaining three with catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy and lethal cardiac channelopathy, respectively. All the patients suffered from drug-resistant ventricular tachycardia or ventricular vibration before the operation. After the ICD implantation, 3 patients had electric storm, which was alleviated after analgesics-sedatives treatment with chlorpromazine, dexmedetomidine or midazolam combined with fentanyl, as well as reset of the ICD parameters and support from psychological consultation. The other 3 patients did not undergo any complications as the above comprehensive strategies were given after the operation prophylactically. All patients continued anti-arrhythmic medicine after the operation and all survived at the end of the follow-up period lasted from 1 month to 7 years. Two patients had ventricular tachycardia (VT) and ventricular vibration, which were successfully recognized and defibrillated by ICD. Conclusions: ICD implantation is safe and effective in children and adolescent patients. The electric storm may happen after operation, which could be prevented by the comprehensive strategies including appropriate ICD parameter-setting, analgesics-sedatives treatment and psychological support.