Primary Electrical Disorders Research Articles

Circulating Autoantibodies Targeting TREK-1 in Patients With Short-Coupled Ventricular Fibrillation.

Short-coupled ventricular fibrillation (SCVF) is increasingly being recognized as a distinct primary electrical disorder and cause of otherwise unexplained cardiac arrest. However, the pathophysiology of SCVF remains largely elusive. Despite extensive genetic screening, there is no convincing evidence of a robust monogenic disease gene, thus raising the speculations for alternative pathogeneses. The role of autoimmune mechanisms in SCVF has not been investigated so far. The objective of this study was to screen for circulating autoantibodies in patients with SCVF and assess their role in arrhythmogenesis. This is a prospective, single-center, case-control study enrolling cardiac arrest survivors diagnosed with SCVF or idiopathic ventricular fibrillation (IVF) between 2019 and 2023 at the Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval Inherited Arrhythmia Clinic in Canada. Plasma samples were screened for autoantibodies targeting cardiac ion channels using peptide microarray technology. Identified target autoantibodies were then purified from pooled plasma samples for subsequent cellular electrophysiological studies. Fourteen patients with SCVF (n=4 [29%] female patients; median age, 45 years [36, 58]; n=14 [100%] non-Hispanic White) and 19 patients with idiopathic ventricular fibrillation (n=8 [42%] female patients; median age, 49 years [38, 57]; n=19 [100%] non-Hispanic White) were enrolled in the study and compared with 38 (n=20 [53%] female subjects; median age, 45 years [29, 66]; n=36 [95%] non-Hispanic White) sex-, age- and ethnicity-matched healthy controls. During the study period, 11 (79%) SCVF probands experienced ventricular fibrillation recurrence after a median of 4.3 months (interquartile range, 0.3-20.7). Autoantibodies targeting cardiac TREK-1 (TWIK [tandem of pore-domains in a weakly inward rectifying potassium channel]-related potassium channel 1 were identified in 7 (50%) patients with SCVF (P=0.049). Patch clamp experiments demonstrated channel-activating properties of anti-TREK-1 autoantibodies that are antagonized by quinidine in both HEK293 cells and human induced pluripotent stem cell-derived cardiomyocytes. Patients with SCVF harbor circulating autoantibodies against the cardiac TREK-1 channel. Anti-TREK-1 autoantibodies not only present the first reported biomarker for SCVF, but our functional studies also suggest a direct implication in the arrhythmogenesis of SCVF.

Out of hospital cardiac arrest - new insights and a call for a worldwide registry and guidelines

IntroductionOut of hospital cardiac arrest (OHCA) is a major public health problem with substantial mortality rates worldwide. Genetic diseases and primary electrical disorders are the most common etiologies at younger ages, while ischemic heart disease and cardiomyopathies are common causes at older ages. Despite improvement in prevention and treatment in recent years, OHCA is still a major cause of cardiovascular death.MethodWe report prospective data regarding etiology, characteristics, clinical course, and outcomes of patients with OHCA who were admitted to a tertiary care center intensive cardiac care unit (ICCU) between 2020–2023.ResultsA total of 92 patients admitted after OHCA were included in the cohort. Mean age was 63.8 ± 13.8 years and 75 (82%) were males. The most common etiology of OHCA was acute coronary syndrome (ACS) in 54 (59%) patients, of whom 46 (85%) patients had ST elevation myocardial infarction and 8 (15%) had non-ST elevation myocardial infarction. During hospitalization, 42 (46%) patients underwent targeted temperature management and 13 (14%) received mechanical circulatory support. Interestingly, 77 (84%) patients underwent coronary angiography, while only 51 (55%) received percutaneous coronary intervention (PCI). Neurologic status was favorable in 49 (53%) patients with Cerebral Performance Category score of 1–2. Overall, mortality rates were relatively low, with 15 (16%) in-hospital deaths and 24 (26%) deaths at 30-day follow-up.ConclusionAlthough ACS was the most common etiology for OHCA, only 55% of patients underwent PCI. Most OHCA patients admitted to the ICCU survived hospitalization and were discharged. Increased awareness, public education, worldwide registries, and specific evidence-based guidelines for the treatment of OHCA patients may lead to improved outcomes for these patients who often carry poor prognoses.

Systematic analysis of SCN5A variants associated with inherited cardiac diseases

BackgroundSCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes or pleiotropy, which have not been systematically described. In addition, the involvement of SCN5A in dilated cardiomyopathies (DCMs) remains controversial. ObjectiveWe aimed to evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and to determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers. MethodsThe DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced with a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped. ResultsThe study included 170 P/LP variants found in 495 patients. Of them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, 6 with progressive cardiac conduction disease, 4 with multifocal ectopic Purkinje-related premature contractions, and 3 with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Of those, 8 were carried by 8 patients presenting with DCM with a debatable causative genotype/phenotype link. ConclusionMost P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960) if not questionable.

Identification of Arrhythmia-Associated Gene Mutations in Chinese Patients with Primary Electrical Disorders or Sudden Cardiac Death

Background: Sudden cardiac death (SCD), unexpected death based on sudden cardiac ejection cessation, accounts for 15–20% of unnatural deaths in developed countries. Primary electrical disorders (PEDs), a group of cardiac rhythm abnormalities without detectable structural heart disease, are a major cause of SCD in people younger than 35 years of age. Cardiac muscle contraction and relaxation are triggered by the action potential (AP), which is generated by ionic changes across the cell membrane. Thus, PEDs are influenced by mutations in AP-associated genes, such as KCNE1 and RYR2. Methods: We recruited six patients with SCD and 42 patients with arrhythmia with onset under the age of 25, and used targeted sequencing to determine the genetic etiologies. Results: We identified five mutations (RYR2: c.12269C>T, p.P4090L; KCNE1: c.169T>C, p.F57L; KCNQ1: c.853A>C, p.K285Q; KCNH2: c.793T>C, p.C265R, and TRPM4: c.2985_3012del, p.E996Gfs*118) in five families with PED/SCD. Conclusions: We detected five mutations and expanded the mutation spectrum of PED-associated genes, thus contributing to the clinical diagnosis of PED.

Human Genetics of Cardiac Arrhythmias.

Inherited forms of cardiac arrhythmias mostly are rare diseases (prevalence <1:2000) and considered to be either "primary electrical heart disorders" due to the absence of structural heart abnormalities or "cardiac ion channel disorders" due to the myocellular structures involved. Precise knowledge of the electrocardiographic features of these diseases and their genetic classification will enable early disease recognition and prevention of cardiac events including sudden cardiac death.The genetic background of these diseases is complex and heterogeneous. In addition to the predominant "private character" of a mutation in each family, locus heterogeneity involving many ion channel genes for the same familial arrhythmia syndrome is typical. Founder pathogenic variants or mutational hot spots are uncommon. Moreover, phenotypes may vary and overlap even within the same family and mutation carriers. For the majority of arrhythmias, the clinical phenotype of an ion channel mutation is restricted to cardiac tissue, and therefore, the disease is nonsyndromic.Recent and innovative methods of parallel DNA analysis (so-called next-generation sequencing, NGS) will enhance further mutation and other variant detection as well as arrhythmia gene identification.

Assessment of Sudden Cardiac Death Risk in Pediatric Primary Electrical Disorders: A Comprehensive Overview

Sudden cardiac death (SCD) in children is a devastating event, often linked to primary electrical diseases (PED) of the heart. PEDs, often referred to as channelopathies, are a group of genetic disorders that disrupt the normal ion channel function in cardiac cells, leading to arrhythmias and sudden cardiac death. This paper investigates the unique challenges of risk assessment and stratification for channelopathy-related SCD in pediatric patients—Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, long QT syndrome, Anderson–Tawil syndrome, short QT syndrome, and early repolarization syndrome. We explore the intricate interplay of genetic, clinical, and electrophysiological factors that contribute to the complex nature of these conditions. Recognizing the significance of early identification and tailored management, this paper underscores the need for a comprehensive risk stratification approach specifically designed for pediatric populations. By integrating genetic testing, family history, and advanced electrophysiological evaluation, clinicians can enhance their ability to identify children at the highest risk for SCD, ultimately paving the way for more effective preventive strategies and improved outcomes in this vulnerable patient group.

Lessons Learnt from Case Series of Out-of-hospital Cardiac Arrest and Unexpected Death after COVID-19 Vaccination.

Vaccination against COVID-19 has raised concerns about myocarditis in young men, as out-of-hospital cardiac arrest (OHCA) or sudden death after vaccination has been reported sporadically. Common features of these cases are occurrence in young men, within a few weeks after vaccination, in patients with no structural heart diseases. Cases of unexplained nocturnal death showed fibrotic or hypertrophied myocardium, and one case of OHCA presented ventricular fibrillation (VF) triggered by a prominent J wave on an automated external defibrillator and histopathologic findings compatible with myocarditis. Both myocarditis and J waves are prevalent in young men, and these cases imply that myocarditis augments J waves, which trigger VFs, and primary electrical disorders are a leading cause of death. To prevent such issues, artificial intelligence (AI)-assisted interpretation of historical electrocardiogram findings may help predict future J wave formation leading to VF, as digital ECG findings are well suited for AI interpretation.

A Typical, Relapsing Case of Brugada Syndrome

Brugada Syndrome (BrS) is a channelopathy classified as a primary electrical disorder that has been a subject of study in the past three decades because of its association with cases of Sudden Cardiac Death (SCD) in young, asymptomatic, and apparently healthy patients. The typical manifestations are syncope and cardiac arrest accompanied by characteristic electrocardiographic patterns. In the latest advances to understand this syndrome, it has been identified genes and multiple mutations that have allowed the elaboration of hypotheses related to repolarization and depolarization which aim to explain the physiopathological mechanisms. In this article, a case of a 32-year-old man with no history of cardiovascular disease who debuted with syncope and electrocardiographic changes in the right precordial leads suggestive of type II and type I Brugada pattern (after ajmaline test), is presented. Also, a review of the literature is carried out in terms of definition, classification, pathophysiology, genetics, prognosis and treatment for this entity.

Outcome of a nationwide screening programme in young individuals

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Cardiac Risk in the Young. Background Sudden cardiac death (SCD) seemingly affects young, healthy individuals and is therefore recognised as an important public health concern for athletes and non-athletes. However, systematic population screening is not recommended in the United Kingdom (UK). Concerns include the low reported incidence of SCD in young individuals, the efficacy of the electrocardiogram (ECG) and the lack of robust evidence on cardiac screening. We sought to determine the diagnostic yield of a nationwide cardiac screening programme in young individuals. Importantly, we sought to report on the frequency of false-negative screen-test results, which is underrecognized in the literature, and the incidence of sudden cardiac arrest (SCA) and SCD amongst individuals who underwent screening. Methods From 2007 through 2018, 104,369 consecutive individuals, aged 14 to 35 years, underwent voluntary cardiac screening (62% were male, 91% were non-athletes). Initial evaluation consisted of a health questionnaire (HQ), ECG, and clinical consultation. Selective on-site echocardiography was available at the discretion of the consulting physician. Clinical outcomes were sourced from the Office for National Statistics-Hospital-Episode-Statistics database and an online HQ. Results During screening 280 (0.27%) individuals were found to have a cardiac condition associated with SCA/SCD and 115 received potentially life-saving treatments. A further 166 (0.16%) with congenital or valvular abnormalities were identified. During a mean follow-up of 6.2 ± 2.5 years, an additional 86 individuals, considered to have normal screening, were found to have a cardiac condition associated with SCA/SCD.After screening there were 86 deaths. Cardiac disorders accounted for 20 deaths (23%), all of which were sudden. In addition, 15 individuals survived a SCA. Primary electrical disorders accounted for 21 (60%) of the 35 cases of SCA/SCD, followed by cardiomyopathies (n=6), and congenital or acquired coronary artery disease (n=5). On the basis of a total of 626,550 person-years (PY), the combined incidence of SCA/SCD was 1:17,901 PY (5.6 per 100,000 PY). Males were at 3.5-fold higher risk than females (1:12,488 PY vs 1:44,067 PY, p &amp;lt; 0.01). For prevention of SCA/SCD the programme’s sensitivity was 19.4% with a specificity of 97.5%. For identifying conditions associated with SCD, the programme’s sensitivity was 76.5% with a specificity was 97.8%. Conclusion Diseases that are associated with SCD were identified in 0.27% of young individuals who underwent cardiac screening. A further 86 (0.08%) conditions were identified after screening. The incidence of SCA and SCD was 5.6 per 100,000 person-years, which is considerable higher than previous estimates in the general population. Most of these events were due to confirmed or presumed primary electrical disorders that had not been detected on screening.

Subepicardial Cardiomyopathy: A Disease Underlying J-Wave Syndromes and Idiopathic Ventricular Fibrillation.

Brugada syndrome (BrS), early repolarization syndrome (ERS), and idiopathic ventricular fibrillation (iVF) have long been considered primary electrical disorders associated with malignant ventricular arrhythmia and sudden cardiac death. However, recent studies have revealed the presence of subtle microstructural abnormalities of the extracellular matrix in some cases of BrS, ERS, and iVF, particularly within right ventricular subepicardial myocardium. Substrate-based ablation within this region has been shown to ameliorate the electrocardiographic phenotype and to reduce arrhythmia frequency in BrS. Patients with ERS and iVF may also exhibit low-voltage and fractionated electrograms in the ventricular subepicardial myocardium, which can be treated with ablation. A significant proportion of patients with BrS and ERS, as well as some iVF survivors, harbor pathogenic variants in the voltage-gated sodium channel gene, SCN5A, but the majority of genetic susceptibility of these disorders is likely to be polygenic. Here, we postulate that BrS, ERS, and iVF may form part of a spectrum of subtle subepicardial cardiomyopathy. We propose that impaired sodium current, along with genetic and environmental susceptibility, precipitates a reduction in epicardial conduction reserve, facilitating current-to-load mismatch at sites of structural discontinuity, giving rise to electrocardiographic changes and the arrhythmogenic substrate.

Next-Generation Sequencing in Genetic Testing of Kazakhstani Sudden Cardiac Death Cases

<h3>Purpose</h3> The use of next-generation sequencing (NGS) enables a rapid analysis of many genes associated with sudden cardiac death (SCD). It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. SCD most commonly occurs in patients with coronary heart disease, whereas inherited cardiomyopathies and primary electrical disorders prevail in younger SCD victims (up to 30% of all SCD in the young). The aim of the study was to elucidate the mutational spectrum in Kazakhstani SCD victims revealed by NGS of 96 genes associated with cardiac diseases and compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. <h3>Methods</h3> We screened 37 suspected SCD cases (<45 years) using the customized HaloPlex Target Enrichment System (Agilent) and NGS for 96 genes associated with inherited cardiac syndromes and cardiomyopathies. 27 cases had non-diagnostic structural cardiac abnormalities and 10 cases, diagnosed with a cardiomyopathy post-mortem. ACMG/AMP guidelines were applied for variant interpretation of clinical significance. <h3>Results</h3> 31 rare variants were identified in 17 (63%) of the deceased individuals with non-diagnostic structural cardiac abnormalities. Among them pathogenic variants in KCNQ1, KCNJ2, SCN5A, RYR2 genes were identified. The corresponding frequency in deceased individuals with cardiomyopathies was 35%. The most abundant mutations observed in MYBPC3, LAMA2, MYH6 and GAA. <h3>Conclusion</h3> Genetic screening revealed variants with likely functional effects at high rates, in 63% and 35% of the SCD cases with non-diagnostic and diagnostic cardiac abnormalities, respectively. Targeted NGS screening can support the forensic investigation and help the cardiologist's decision to offer counselling and clinical evaluation to relatives of young SCD victims. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the clinical interpretation of the large number of variants of unknown significance detected in each individual. Study was supported by a grant from the Ministry Education and Science, Republic of Kazakhstan (AP09563474).

Generation of two induced pluripotent stem cell (iPSC) lines (BBANTWi006-A, BBANTWi007-A) from Brugada syndrome patients carrying an SCN5A mutation

Brugada syndrome (BrS) is an inherited primary electrical disorder of the heart. 25% of BrS patients carry a mutation in the SCN5A gene, encoding the cardiac specific voltage-gated sodium channel Nav1.5. Here we report two iPSC lines (BBANTWi006-A, BBANTWi007-A) of a brother and a sister carrying an SCN5A mutation (c.4813 + 3_4813 + 6dupGGGT) causing BrS. iPSCs were generated from dermal fibroblasts and reprogrammed with the Cytotune®-iPS 2.0 Sendai Reprogramming Kit (Invitrogen). The generated iPSCs showed a normal karyotype, expressed pluripotency markers, were differentiated into cells of the three germ layers and carried the original genotype.

Management of Long QT Syndrome in Women Before, During, and After Pregnancy

Congenital long QT syndrome (LQTS) is a primary genetic and electrical disorder that increases risk for torsades de pointes, syncope, and sudden death. Post-pubertal women with LQTS require specialized multidisciplinary management before, during, and after pregnancy involving cardiology and obstetrics to reduce risk for cardiac events in themselves and their fetuses and babies. The risk of potentially life-threatening events is lower during pregnancy but increases significantly during the 9-month postpartum period. Treatment of women with LQTS with a preferred β-blocker at optimal doses along with close monitoring are indicated throughout pregnancy and during the high-risk postpartum period.

Long-term evolution of echocardiography parameters in Brugada syndrome patients

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ESC Research Grant Background Brugada syndrome is a heritable disorder with a high risk of sudden death. Although being a primary electrical disorder, subtle structural changes have repeatedly been described. Little is known about the long-term structural evolution in Brugada syndrome. Purpose We aimed to assess the evolution of echocardiographic parameters in Brugada syndrome and the presence of markers of structural evolution. Methods Brugada syndrome patients with minimum two complete transthoracic echocardiographic examinations were included. Clinical data were collected retrospectively. We analyzed all available echocardiographic examinations and assessed the evolution of cardiac parameters over time and its association with patient characteristics. Results The study included 113 Brugada syndrome patients [47 (33-55) years, 59 (52%) female, spontaneous type 1 ECG in 26 (23%)], with a total of 258 echocardiographies, collected over a period of 6.8 (6.6-7.1) years. Proximal and distal right ventricular outflow tract and basal right ventricular diameter dilated at a rate of 0.2 (0.1-0.3) mm/year (p = 0.004), 0.4 (0.3-0.5) mm/year (p &amp;lt; 0.001) and 0.6 (0.4-0.8) mm/year (p &amp;lt; 0.001) respectively (Figure). Left ventricular mechanical dispersion increased from 38 (±11) ms to 42 (±12) ms (p = 0.001). Neither male sex, nor presenting a spontaneous type 1 ECG pattern were associated with worse structural evolution. Conclusion We observed progressive right ventricular outflow tract and basal right ventricle dilation and an increasing contractile dyssynchrony in Brugada syndrome, potentially indicating a progressive structural affection. Further research is warranted to unravel underlying mechanisms and possible clinical implications of progressive structural changes in Brugada syndrome. Abstract Figure.

Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?

Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to the risk of sudden cardiac death and characterized by right precordial lead ST elevation. Early description of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. We propose that the final common pathway for BrS could be viewed as a disease of 'reduced RVOT conduction reserve'.

Inherited Ventricular Arrhythmia in Zebrafish: Genetic Models and Phenotyping Tools.

In the last years, the field of inheritable ventricular arrhythmia disease modelling has changed significantly with a push towards the use of novel cellular cardiomyocyte based models. However, there is a growing need for new in vivo models to study the disease pathology at the tissue and organ level. Zebrafish provide an excellent opportunity for in vivo modelling of inheritable ventricular arrhythmia syndromes due to the remarkable similarity between their cardiac electrophysiology and that of humans. Additionally, many state-of-the-art methods in gene editing and electrophysiological phenotyping are available for zebrafish research. In this review, we give a comprehensive overview of the published zebrafish genetic models for primary electrical disorders and arrhythmogenic cardiomyopathy. We summarise and discuss the strengths and weaknesses of the different technical approaches for the generation of genetically modified zebrafish disease models, as well as the electrophysiological approaches in zebrafish phenotyping. By providing this detailed overview, we aim to draw attention to the potential of the zebrafish model for studying arrhythmia syndromes at the organ level and as a platform for personalised medicine and drug testing.

Calmodulinopathy in inherited arrhythmia syndromes.

Calmodulin (CaM) is a ubiquitous intracellular calcium sensor that controls and regulates key cellular functions. In all vertebrates, three CaM genes located on separate chromosomes encode an identical 149 amino acid protein, implying an extraordinarily high level of evolutionary importance and suggesting that CaM mutations would be possibly fatal. Inherited arrhythmia syndromes comprise a spectrum of primary electrical disorders caused by mutations in genes encoding ion channels or associated proteins leading to various cardiac arrhythmias, unexplained syncope, and sudden cardiac death. CaM mutations have emerged as an independent entity among inherited arrhythmia syndromes, referred to as calmodulinopathies. The most common clinical presentation associated with calmodulinopathy is congenital long QT syndrome, followed by catecholaminergic polymorphic ventricular tachycardia, both of which significantly increase the possibility of repeated syncope, lethal arrhythmic events, and sudden cardiac death, especially in young individuals. Here, we aim to give an overview of biochemical and structural characteristics of CaM and progress toward updating current known CaM mutations and associated clinical phenotypes. We also review the possible mechanisms underlying calmodulinopathy, based on several key in vitro studies. We expect that further experimental studies are needed to explore the complexity of calmodulinopathy.

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.

Optical Mapping in hiPSC-CM and Zebrafish to Resolve Cardiac Arrhythmias

Inherited cardiac arrhythmias contribute substantially to sudden cardiac death in the young. The underlying pathophysiology remains incompletely understood because of the lack of representative study models and the labour-intensive nature of electrophysiological patch clamp experiments. Whereas patch clamp is still considered the gold standard for investigating electrical properties in a cell, optical mapping of voltage and calcium transients has paved the way for high-throughput studies. Moreover, the development of human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) has enabled the study of patient specific cell lines capturing the full genomic background. Nevertheless, hiPSC-CMs do not fully address the complex interactions between various cell types in the heart. Studies using in vivo models, are therefore necessary. Given the analogies between the human and zebrafish cardiovascular system, zebrafish has emerged as a cost-efficient model for arrhythmogenic diseases. In this review, we describe how hiPSC-CM and zebrafish are employed as models to study primary electrical disorders. We provide an overview of the contemporary electrophysiological phenotyping tools and discuss in more depth the different strategies available for optical mapping. We consider the current advantages and disadvantages of both hiPSC-CM and zebrafish as a model and optical mapping as phenotyping tool and propose strategies for further improvement. Overall, the combination of experimental readouts at cellular (hiPSC-CM) and whole organ (zebrafish) level can raise our understanding of the complexity of inherited cardiac arrhythmia disorders to the next level.

Rate, Time Course, and Predictors of Implantable Cardioverter Defibrillator Infections: An Analysis From the SIMPLE Trial

BackgroundThe number of implantable cardioverter defibrillator (ICD) infections is increasing due to an increased number of ICD implants, higher-risk patients, and more frequent replacement procedures, which carry a higher risk of infection. Reducing the morbidity, mortality, and cost of ICD-related infections requires an understanding of the current rate of this complication and its predictors. MethodsThe Shock Implant Evaluation Trial (SIMPLE) trial randomized 2500 ICD recipients to defibrillation testing or not. Over an average of 3.1 years, patients were seen every 6 months and examined for evidence of ICD infection, which was defined as requiring device removal and/or intravenous antibiotics. ResultsWithin 24 months, 21 patients (0.8%) developed infection. Fourteen patients (67%) with infection presented within 30 days, 20 patients by 12 months, and only 1 patient beyond 12 months. Univariate analysis demonstrated that patients with primary electrical disorders (3 patients, P = 0.009) and those with a secondary prevention indication (13 patients, P = 0.0009) were more likely to develop infection. Among the 2.2% of patients who developed an ICD wound hematoma, 10.4% developed an infection. Among the 8.3% of patients requiring an ICD reintervention, 1.9% developed an infection. ConclusionsThis cohort of ICD recipients at high-volume centres have a low risk of device-related infection. However; strategies to reduce wound hematoma and the need for ICD reintervention could further reduce the rate of infection.