Cardiac Channelopathies Research Articles

Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes.

Congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS remains the domain of cardiologists, cardiac electrophysiologists and specialised centres, the much more frequently acquired LQTS is the domain of physicians and other members of healthcare teams required to make therapeutic decisions. This paper reviews the electrophysiological mechanisms of acquired LQTS, its ECG characteristics, clinical presentation, and management. The paper concludes with a comprehensive review of the electrophysiological mechanisms of torsade de pointes.

Prevalence, Clinical Presentation, and Management of Channelopathies and Cardiomyopathies, Long QT Syndrome, Brugada Syndrome, Arrhythmogenic Cardiomyopathy, and Hypertrophic Cardiomyopathy

With this paper, we aim to summarize the knowledge on gender differences in the most common inheritable channelopathies and cardiomyopathies, focusing on aspects that are of clinical importance for patient management and follow-up. Despite autosomal dominant inheritance patterns in most of the inheritable cardiac channelopathies and cardiomyopathies, there is increasing awareness that there are important gender differences in disease penetrance and severity, affecting prevalence, clinical presentation, and patient management. Important gender differences are present in Long QT syndrome, Brugada syndrome, arrhythmogenic cardiomyopathy, and hypertrophic cardiomyopathy. In LQTS, genotype-specific differences are important, and female LQT2 patients have higher arrhythmic risk compared with male. In the remaining inheritable channelopathies and cardiomyopathies discussed in this review, male patients are more likely to have penetrant disease and experience arrhythmic events. Mechanistic explanations for the observed gender differences are sparse, but in channelopathies, hormonal effects are thought to be important. Although treatment strategies in inheritable channelopathies and cardiomyopathies are similar in men and women with the notable exception of women with LQT2, the differences between the sexes are important to be aware of in patient management.

Mexiletine Shortens the QT Interval in Patients With Potassium Channel-Mediated Type 2 Long QT Syndrome.

Long QT syndrome is a potentially lethal yet highly treatable cardiac channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel blockers, like mexiletine, is often utilized for patients with sodium channel-mediated type 3 long QT syndrome (LQT3). The potential role of sodium channel blockers in patients with potassium channel-mediated long QT syndrome (ie, LQT1 and LQT2) has not been investigated in detail. We performed a retrospective chart review on 12 patients (5 females; median age at diagnosis 14.1 years (interquartile range [IQR], 7.7-23; range, 0-59, median heart rate-corrected QT interval [QTc] at diagnosis 557 ms (IQR, 529-605) with genetically established LQT2 (10) or a combination of LQT1/LQT2 (1) or LQT2/LQT3 (1), who received mexiletine. Data were collected on symptomatic status, treatments, and breakthrough cardiac events after diagnosis and initiation of treatment. Additionally, 12-lead ECGs were collected at diagnosis, before initiation of mexiletine and following mexiletine to evaluate the drug's effect on QTc. Before diagnosis, 6 patients were symptomatic and, before initiation of mexiletine, 4 patients experienced ≥1 breakthrough cardiac event on β-blocker. Median age at first mexiletine dose was 24.3 years (IQR, 14-32.4). After mexiletine, the median QTc decreased by 65±45 ms from 547 ms (IQR, 488-558) premexiletine to 470 ms (IQR, 409-529) postmexiletine ( P=0.0005) for all patients. In 8 patients (67%), the QTc decreased by ≥ 40 ms with a mean decrease in QTc of 91 ms ( P < 0.008). For the 11 patients maintained on mexiletine therapy, there have been no breakthrough cardiac events during follow-up. Although commonly prescribed in patients with LQT3, mexiletine also shortens the QTc significantly in two-thirds of a small subset of patients with potassium channel-mediated LQT2. In patients with LQT2, pharmacological targeting of the physiological late sodium current may provide added therapeutic efficacy to β-blocker therapy.

The Atrial Phenotype of the Inherited Primary Arrhythmia Syndromes.

Over the past two decades, our understanding of inherited primary arrhythmia syndromes has been enriched by studies that have aimed to define the clinical characteristics and the genetic, cellular and molecular features predisposing patients to an enhanced risk of ventricular arrhythmias. In contrast, very little is known about the causative role of inherited cardiac channelopathies on atrial conduction abnormalities possibly leading to different atrial tachyarrhythmias. The diagnostic and therapeutic management of patients with an inherited cardiac channelopathy presenting with atrial arrhythmias remains highly challenging and is in urgent need of improvement. This review will assess the current knowledge on atrial electrical abnormalities affecting patients with different forms of inherited primary arrhythmia syndromes, including long and short QT syndromes, early repolarisation syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome.

Optical Recording of Action Potentials in Human Induced Pluripotent Stem Cell-Derived Cardiac Single Cells and Monolayers Generated from Long QT Syndrome Type 1 Patients.

Induced pluripotent stem cells (iPSCs) from type 1 long QT (LQT1) patients can differentiate into cardiomyocytes (CMs) including ventricular cells to recapitulate the disease phenotype. Although optical recordings using membrane potential dyes to monitor action potentials (APs) were reported, no study has investigated the disease phenotypes of cardiac channelopathy in association with the cardiac subtype at the single-cell level. We induced iPSC-CMs from three control and three LQT1 patients. Single-cell analysis using a fast-responding dye confirmed that ventricular cells were the dominant subtype (control-iPSC-CMs: 98%, 88%, 91%; LQT1-iPSC-CMs: 95%, 79%, 92%). In addition, LQT1-iPSC-ventricular cells displayed an increased frequency of early afterdepolarizations (pvalue = 0.031). Cardiomyocyte monolayers constituted mostly of ventricular cells derived from LQT1-iPSCs showed prolonged AP duration (APD) (pvalue = 0.000096). High-throughput assays using cardiomyocyte monolayers in 96-well plates demonstrated that IKr inhibitors prolonged APDs in both control- and LQT1-iPSC-CM monolayers. We confirmed that the optical recordings of APs in single cells and monolayers derived from control- and LQT1-iPSC-CMs can be used to assess arrhythmogenicity, supporting the feasibility of membrane potential dye-based high-throughput screening to study ventricular arrhythmias caused by genetic channelopathy or cardiotoxic drugs.

The advance on the prenatal diagnosis and management of fetal long QT syndrome

Long QT syndrome (LQTS) is a rare and inherited cardiac channelopathy with high lethality, which is characterized by prolonged QTc interval and frequent malignant arrhythmia, the cause of the disease is that mutations of genes coding for cardiac ion channel subunit or channel associated proteins.Since some fetal LQTS may die in utero or neonatal period, thus, prenatal suspicion or diagnosis of fetal LQTS may improve their outcome and prognosis.Therefore, this review prepares to discuss around the prenatal diagnosis and management of fetal LQTS. Key words: Long QT syndrome; Malignant arrhythmia; Fetus; Diagnosis; Treatment; Management

Autoimmune and inflammatory K+ channelopathies in cardiac arrhythmias: Clinical evidence and molecular mechanisms

Cardiac K+ channelopathies account for a significant proportion of arrhythmias and sudden cardiac death (SCD) in subjects without structural heart disease. It is well recognized that genetic defects are key factors in many cases, and in practice, the term cardiac channelopathies currently coincides with inherited cardiac channelopathies. However, mounting evidence demonstrate that not only genetic alterations but also autoimmune and inflammatory factors can cause cardiac K+-channel dysfunction and arrhythmias in the setting of a structurally normal heart. In particular, it has been demonstrated that specific autoantibodies as well as inflammatory cytokines can modulate expression and/or function of different K+ channels in the heart, resulting in a disruption of the cardiac action potential and arrhythmias/sudden cardiac death. Awareness about the existence of these newly recognized forms is essential to identify and adequately manage affected patients. In the present review, we focus on autoimmune and inflammatory K+ channelopathies as a novel mechanism for cardiac arrhythmias and analyze the recent advancements in this topic, providing complementary basic, clinical, and population health perspectives.

Lethal immunoglobulins: Autoantibodies and sudden cardiac death.

Sudden cardiac death (SCD) is an unexpected death due to cardiac causes that occurs in a short time period (generally within 1 h of symptom onset) in a person with known or unknown cardiac disease. Patients with cardiomyopathies, myocarditis, ischemic heart disease and cardiac channelopathies are at risk of SCD. However, a certain percentage of autopsy-negative cases of SCD in the young (<35 years) remain unexplained even after a post-mortem genetic testing. Autoantibodies against cardiac proteins may be potentially involved in the pathogenesis of different heart diseases and in the occurrence of unexplained SCD. In this review we analyze clinical and animal studies that elucidate the prevalence of these autoantibodies in patients with different cardiac diseases and their pathophysiological relevance. We propose a classification of the autoantibodies associated with heart diseases and focus on their molecular and cellular effects. Anti-beta adrenergic receptor antibodies and anti-muscarinic acetylcholine receptor antibodies affect myocardial electrophysiological properties and were reported to be the independent predictors of SCD in patients with different heart diseases. Autoimmune mechanism is proposed for cardiac-related adverse reactions following human papillomavirus (HPV) vaccination. The pentapeptid sharing between HPV's antigens, adrenergic receptors and muscarinic acetylcholine receptors supports this assumption. The dysregulating effects of the autoantibodies against calcium and potassium ion channels can be the basis for autoimmune phenocopies of genetic cardiac channelopathies, which are also associated with SCD.

Idiopathic Ventricular Fibrillation and Otherwise Normal Electrocardiograms

Background: Idiopathic ventricular fibrillation (IVF) in patients with normal baseline electrocardiograms (ECGs) is a rare disease. Little information is available on the clinical features and long-term follow-up of out-of-hospital cardiac arrest (OHCA) survivors presenting with true IVF and 12-lead ECGs that remain normal over time. Objective: To define the clinical and ECG characteristics, as well as long-term clinical outcomes of a large cohort of survivors of OHCA due to true IVF. Methods: OHCA survivors with VF as the presenting rhythm, normal baseline and follow-up ECGs with no signs of cardiac channelopathy including early repolarization or atrioventricular (AV) conduction abnormalities, and without structural heart disease were included in a registry. Results: A total of 245 OHCA survivors with IVF (median age: 38 years; males 59%) were recruited from 25 centres. All had normal baseline and follow-up ECGs, and no evidence of structural heart disease. An implantable cardioverter-defibrillator (ICD) was implanted in 226 patients (92%), while 18 patients (8%) were treated with drug therapy only. Over a median follow-up of 63 months (interquartile range: 25-110 months), 12 patients died (5%); in 4 of them (1.6%) the lethal event was of cardiac origin. Patients treated with antiarrhythmic drugs (AADs) only had a higher rate of cardiovascular death compared to patients who received an ICD (16% vs. 0.4%, p=0.001). The ECG and echocardiogram of all patients remained unchanged over time. Fifty-two patients (21%) experienced an arrhythmic recurrence. Age ≤ 16 years at the time of the first ventricular arrhythmia was the only predictor of arrhythmic recurrence on multivariable analysis (HR 0.41, 95% CI 0.18-0.92, p=0.03). Discussion: OHCA survivors of true IVF with normal baseline and follow-up ECGs frequently have arrhythmic recurrences, but a good prognosis when treated with an ICD. Children are a category of IVF patients at higher risk of arrhythmic recurrences. Funding: The study was supported by a grant of the Swiss Heart Foundation. Declaration of Interest: G.C. has received a research grant from the Swiss National Foundation. P.L. has received speaker fees and research grants from Boston Scientific, Abbott and Medtronic Research support from UCLH Biomedicine NIHR. F.L. is consultant and has received research support from Medtronic Plc, Abbott, Boston Scientific and Microport. S.B. has received speaker’s bureau from Medtronic and Microport. C.P. has received research grant from Biotronik and Biosense Webster. P.B. is consultant for Biotronik. A.A. is consultant to Abbott, Biosense Webster, Daiichi-Sankyo, Boston Scientific, Medtronic, Microport-CRM; and has received speaker fee from Daiichi-Sankyo, Boston Scientific, Medtronic, Microport-CRM Ethics Approval Statement: Data were collected in accordance with regulations set by the local Institutional Ethics Committee and/or Institutional Review Board.

Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth.

The incidence of stillbirth in Sweden has essentially remained constant since the 1980’s, and despite thorough investigation, many cases remain unexplained. It has been suggested that a proportion of stillbirth cases is caused by heart disease, mainly channelopathies. The aim of this study was to analyze DNA from 290 stillbirth cases without chromosomal abnormalities for pathogenic single nucleotide variants (SNVs) in 70 genes associated with cardiac channelopathies and cardiomyopathies. The HaloPlex Target Enrichment System (Agilent Technologies) was utilized to prepare sequencing libraries which were sequenced on the Illumina NextSeq platform. We found that 12.1% of the 290 investigated stillbirth cases had one (n = 31) or two (n = 4) variants with evidence supporting pathogenicity, i.e. loss-of-function variants (nonsense, frameshift, splice site substitutions), evidence from functional studies, or previous identification of the variants in affected individuals. Regarding identified putative pathogenic variants in genes associated with channelopathies, the prevalence was significantly higher in the stillbirth cohort (n = 23, 7.93%) than the corresponding prevalence of the same variants in the non-Finnish European population of the Exome Aggregation Consortium (2.70%, p<0.001) and SweGen, (2.30%, p<0.001). Our results give further support to the hypothesis that cardiac channelopathies might contribute to stillbirth. Screening for pathogenic SNVs in genes associated with heart disease might be a valuable complement for stillbirth cases where today’s conventional investigation does not reveal the underlying cause of fetal demise.

Human ether‑à‑go‑go‑related gene mutation L539fs/47‑hERG leads to cell apoptosis through the endoplasmic reticulum stress pathway.

Congenital long QT syndrome (LQTS) is a cardiac channelopathy that often results in fatal arrhythmias. LQTS mutations not only lead to abnormal myocardial electrical activities but are associated with heart contraction abnormalities, cardiomyopathy and congenital heart defects. In vivo and in vitro studies have found that LQTS mutations are associated with cardiomyocyte apoptosis, cardiac developmental disorders and even embryonic mortality. Cardiac delayed rectifier potassium channel dysfunction due to the human ether-à-go-go-related gene (hERG) mutation causes congenital LQTS type 2. The majority of LQTS 2 mutations are characterized by mutant protein accumulation in the endoplasmic reticulum (ER). Unfolded or misfolded protein retention in the ER causes an unfolded protein reaction, which is characteristic of ER stress (ERS). Therefore, the present study hypothesized that LQTS mutations can cause cardiac structural abnormalities via ERS-mediated cardiomyocyte apoptosis. To test this hypothesis, 293 cells were transiently transfected with an L539fs/47-hERG plasmid to generate an LQTS 2 model. L539fs/47-hERG is an LQTS 2 mutation, which consists of a 19-bp deletion at 1619-1637 and a point mutation at 1692. Using confocal laser scanning microscopy analysis, it was verified that the L539fs/47-hERG protein was retained in the ER. Hoechst 33342 apoptosis staining indicated that apoptosis was increased in the L539fs/47-hERG-transfected cells, and this be reversed by treatment with 4-phenyl butyric acid. Western blot analysis revealed increased expression levels of the ERS chaperone glucose regulated protein 78 and pro-apoptotic ERS-induced factors, including protein kinase R-like endoplasmic reticulum kinase, eukaryotic translation-initiation factor-2α and C/EBP homologous protein, in the L539fs/47-hERG-transfected cells. The B-cell lymphoma (Bcl-2)-associated X protein/Bcl-2 ratio and caspase-12 were also increased in the mutated cells. These results demonstrate that L539fs/47-hERG induces cell apoptosis and the potential molecular mechanism involves the activation of ERS and ERS-mediated cell apoptosis.

Recurrent syncope in a child and video assisted thoracoscopic surgery - The long and short of it

Long QT syndrome (LQTS) is a myocardial repolarisation disorder caused by cardiac ion channelopathy and one of its common presentations is recurrent syncope. This reduced repolarisation reserve in LQTS can be unmasked by perioperative factors like electrolyte imbalance, drugs, hypothermia and changes in cardiac autonomic tone. We report the anaesthetic management of left thoracoscopic sympathectomy in a 5-year-old child with LQTS and epicardial pacemaker in situ. It is very challenging to isolate the lung on one hand and prevent the predisposition to torsadogenic potential on the other.

Clinical and genetic profile of congenital long QT syndrome in Hong Kong: a 20-year experience in paediatrics.

Congenital long QT syndrome (LQTS) is a genetically transmitted cardiac channelopathy that can lead to sudden cardiac death. This study aimed to report the clinical and genetic characteristics of all young patients diagnosed with LQTS in the only tertiary paediatric cardiology centre in Hong Kong. This is a retrospective review of all paediatric and young adult patients diagnosed at our centre with LQTS from January 1997 to December 2016. The diagnosis of LQTS was established with a corrected QT interval (QTc) ≥480 ms, Schwartz score of >3 points, or the presence of a pathogenic mutation. Fifty-nine patients (33 males) from 52 families were included, with a mean age of 8.17 years (range, 0.00-16.95 years) at presentation. Five patients had concomitant congenital heart diseases. The mean follow-up duration was 5.33 ± 4.65 years. The mean QTc in the cohort was 504 ± 47 ms. They presented with syncope and convulsion (49%), cardiac arrest (10%), bradycardia and neonatal atrioventricular block (12%). Fifteen (25%) patients were asymptomatic at diagnosis. Thirty-eight (64.4%) patients were confirmed to have a pathogenic mutation for LQTS genes. Forty-five (76.3%) patients received beta blocker therapy. Thirteen (22.0%) patients required implantable cardioverter defibrillator. There was no mortality in the study period. The 1-, 5-, and 10-year breakthrough cardiac event-free rates were 93.0%, 80.7%, and 72.6%, respectively. Identification of the disorder, administration of beta blockers, and lifestyle modification can prevent subsequent cardiac events in LQTS. Genotyping in patients with LQTS is essential in guiding medical therapy and improving prognosis.

Turning a negative into a positive

In this volume of The Journal, Tester et al described the results of a large study employing whole exome sequencing for rare variants in sudden infant death syndrome (SIDS). These investigators carried out whole exome sequencing on 278 cases of SIDS and compared the results to 973 ethnic-matched controls. One Reviewer remarked, “Many of us have been waiting for this paper after its initial presentation in oral form. There was a sharp intake of breath around the room as an essentially negative report came out.” Indeed, while no exome-wide significant differences (P < 2.5 × 10−6) in burden of ultra-rare variants was detected for any genes this is still a notable effort. This was a substantial undertaking and represents important results for the research community, the clinical community, and the families of patients with sudden infant death syndrome. Although this negative result suggests that there is not a readily discernible monogenic cause of SIDS, it does not rule out genetics per se. Many complex disorders are due to alterations in multiple genes in networks and pathways. That remains to be explored in SIDS. The authors also note that there are some rare “monogenic causes of SIDS including mutations in ion-channel genes, SCN5A and SCN4A.” Thus ultra-rare genetic variations in the exome do not represent an abundant explanation underlying the etiology of SIDS. It is possible that additional studies may identify SIDS susceptibility genes with varying penetrance but it remains likely from these data that monogenic disorders stemming from cardiac channelopathies and other established sudden death pathways will comprise less than 10% of all SIDS. This very substantial effort, albeit negative, has contributed important work in this field. Negative findings have garnered great controversy and publicity in science. The longstanding bias against publication of negative findings is beginning to be reversed by recognition of the importance of such results. A recent Editorial describing negative studies in cancer research has pointed out the importance of recognition of negative trials (JAMA Oncol 2016;2:865-6). Obvious benefits include dissuading individuals from unnecessary duplication. Negative trials may identify treatments with less morbidity and less cost compared to newer, more intensive therapies that turn out to lack benefit. Negative trials in intensive therapy for breast cancer have led to improvements and recognition that, in some patients, more radical treatments are unnecessary. The authors of the Editorial recommend that, for negative trials, it is important to include their impact on patient care. In the case of this negative result for SIDS, family appreciation of, in this case lack of, genetic etiologies for the great majority of SIDS cases may provide some comfort or at least enhanced understanding. Article page 423 ▶ Exome-Wide Rare Variant Analyses in Sudden Infant Death SyndromeThe Journal of PediatricsVol. 203PreviewTo determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. Full-Text PDF

Emerging Arrhythmic Risk of Autoimmune and Inflammatory Cardiac Channelopathies.

Cardiac arrhythmias are associated with high morbidity and mortality.1 Specifically, malignant arrhythmias are a recognized leading cause of sudden cardiac death (SCD) in the Western countries. It has been estimated that every day >1000 SCDs occur in the United States.1, 2 Although structural heart diseases, particularly coronary artery disease and heart failure,2, 3 are the prevalent underlying causes of cardiac arrhythmias and SCD, structural alterations are not identified at the postmortem examination in 5% to 15% of patients, increasing up to 40% in subjects aged <40 years.1, 2 The discovery that, in the absence of structural heart defects, mutations in the genes encoding for cardiac ion channels and/or associated regulatory proteins can promote arrhythmias led to the recognition of a new group of inherited arrhythmogenic diseases, accounting for a significant proportion of the unexplained cases.4 The term cardiac channelopathies has been used to designate a collection of genetically mediated syndromes, including long‐QT syndrome (LQTS), short‐QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), early repolarization syndrome (ERS), idiopathic ventricular fibrillation (IVF), and progressive cardiac conduction disease.5 All these disorders are caused by the dysfunction (loss or gain of function) of specific cardiomyocyte ion channels, resulting in a disruption of the cardiac action potential (AP).4 Such electrical abnormalities lead to an increased susceptibility to develop arrhythmias, syncope, seizures, or SCD, precipitated by episodes of polymorphic ventricular tachycardia (torsade de pointes [TdP]) or ventricular fibrillation (VF), typically in the presence of a structurally normal heart.4 Thus, although the term cardiac channelopathies does not per se imply a genetic origin, it currently coincides with that of inherited cardiac channelopathies.1, 5 Accumulating recent evidence demonstrated that factors other than genetic mutations can promote arrhythmias by causing a selective cardiac ion channel dysfunction in the absence of any structural heart defect. In addition to a well‐recognized list of drugs directly interfering with cardiac ion channel function,6 immunologic and inflammatory factors can cause cardiac channelopathies.7, 8 In fact, besides the established role of cardiac inflammation, often of autoimmune origin, in promoting arrhythmias in the presence of an autopsy/biopsy‐proven inflammatory cell tissue infiltration,9, 10, 11, 12, 13 it is increasingly recognized that systemically released autoantibodies and cytokines can be per se arrhythmogenic, regardless of evident histologic changes in the heart.14, 15, 16 Several arrhythmogenic autoantibodies targeting calcium, potassium, or sodium channels in the heart have been identified, and the term autoimmune cardiac channelopathies has been proposed.7 Moreover, evidence exists that inflammatory cytokines, mainly tumor necrosis factor (TNF)‐α, interleukin‐1, and interleukin‐6, can modulate expression and/or function of ion channels, both by directly acting on cardiomyocytes8, 17 and/or inducing systemic effects (fever).17 A careful consideration of these, to date, largely overlooked factors is highly relevant because they are potentially involved in several unexplained arrhythmias/SCD that are negative for genetic factors.2 In patients with unexplained cause of death after a comprehensive postmortem genetic testing of blood/tissue samples (the so‐called “molecular autopsy”), a genetic cause is demonstrated in no more than ≈30% of cases.2 As such, a novel and more comprehensive classification of cardiac channelopathies is herein proposed, distinguishing the “classic” inherited forms, related to genetic mutations, from the acquired forms, including drug‐induced and more recently recognized autoimmune and inflammatory/fever‐induced cardiac channelopathies (Figure 1). In this review, we focus on autoimmune and inflammatory/fever‐induced channelopathies and their emerging impact on arrhythmic risk, providing both basic and clinical perspectives. Open in a separate window Figure 1 Classification of arrhythmogenic cardiac channelopathies. Besides the “classic” inherited forms of cardiac channelopathies related to genetic mutations, a wider spectrum of acquired forms includes not only drug‐induced, but also autoimmune and inflammatory/fever‐induced, cardiac channelopathies.

Video-Assisted Thoracoscopic Left Cardiac Sympathetic Denervation in Chinese Patients with Long QT Syndrome.

Long QT syndrome is a rare but potentially lethal cardiac channelopathy. The primary aim of the study was to investigate the long-term effects of video-assisted thoracoscopic (VATS) left cardiac sympathetic denervation (LCSD) in Chinese patients with long QT syndrome.VATS-LCSD was performed in eight Chinese patients with LQTS. Twelve-lead ECGs and 24-hour Holter monitoring ECGs were recorded before and after surgery. The medical charts were reviewed to obtain patient data, and the patients who had been lost to follow-up were contacted through telephone.The average QTc was shortened from 534 ± 52.7 to 503 ± 43.7 ms (P = 0.030) 24 hours post-surgery and down to 486 ± 34.8 ms (P = 0.021) 1 week post-surgery, with the heart rate unchanged. The average QT dispersion was reduced from 67 ± 17.5 to 21 ± 3.9 ms (P < 0.001) 24 hours post-surgery and remained shortened 1 week later (30 ± 8.1 ms, P < 0.001). Moreover, the 24-hour ECG showed that the QTc was shortened from 552 ± 95.9 to 497 ± 19.7 ms at the minimum heart rate (P = 0.008), and was decreased from 594 ± 144 to 495 ± 74.1 ms at the maximum heart rate (P= 0.04), while the minimum and maximum heart rates were comparable before and after surgery. No death was observed during the follow-up period and the clinical symptoms improved in all patients. The annual event rate decreased from 4 ± 3.50 to 0.63 ± 1.37 events/year (P = 0.034) after surgery.These findings indicate that LCSD shortens the QTc, with the heart rate remaining unchanged. QTd might be a useful parameter for evaluating the efficacy of VATS-LCSD. LCSD could improve patients' life quality by reducing cardiac events.

A New Cardiac Channelopathy: From Clinical Phenotypes to Molecular Mechanisms Associated With Nav1.5 Gating Pores.

Voltage gated sodium channels (NaV) are broadly expressed in the human body. They are responsible for the initiation of action potentials in excitable cells. They also underlie several physiological processes such as cognitive, sensitive, motor, and cardiac functions. The NaV1.5 channel is the main NaV expressed in the heart. A dysfunction of this channel is usually associated with the development of pure electrical disorders such as long QT syndrome, Brugada syndrome, sinus node dysfunction, atrial fibrillation, and cardiac conduction disorders. However, mutations of Nav1.5 have recently been linked to the development of an atypical clinical entity combining complex arrhythmias and dilated cardiomyopathy. Although several Nav1.5 mutations have been linked to dilated cardiomyopathy phenotypes, their pathogenic mechanisms remain to be elucidated. The gating pore may constitute a common biophysical defect for all NaV1.5 mutations located in the channel's VSDs. The creation of such a gating pore may disrupt the ionic homeostasis of cardiomyocytes, affecting electrical signals, cell morphology, and cardiac myocyte function. The main objective of this article is to review the concept of gating pores and their role in structural heart diseases and to discuss potential pharmacological treatments.

Higher Dispersion Measures of Conduction and Repolarization in Type 1 Compared to Non-type 1 Brugada Syndrome Patients: An Electrocardiographic Study From a Single Center.

Background: Brugada syndrome (BrS) is a cardiac ion channelopathy that predisposes affected individuals to sudden cardiac death (SCD). Type 1 BrS is thought to take a more malignant clinical course than non-type 1 BrS. We hypothesized that the degrees of abnormal repolarization and conduction are greater in type 1 subjects and these differences can be detected by electrocardiography (ECG).Methods: Electrocardiographic data from spontaneous type 1 and non-type 1 BrS patients were analyzed. ECG parameters were measured from leads V1 to V3. Values were expressed as median [lower quartile-upper quartile] and compared using Kruskal-Wallis ANOVA.Results: Compared to non-type 1 BrS patients (n = 29), patients with spontaneous type 1 patterns (n = 22) showed similar (P > 0.05) heart rate (73 [64–77] vs. 68 [62–80] bpm), QRS duration (136 [124–161] vs. 127 [117–144] ms), uncorrected QT (418 [393–443] vs. 402 [386–424] ms) and corrected QT intervals (457 [414–474] vs. 430 [417–457] ms), JTpeak intervals (174 [144–183] vs. 174 [150–188] ms), Tpeak− Tend intervals (101 [93–120] vs. 99 [90–105] ms), Tpeak− Tend/QT ratios (0.25 [0.23–0.27] vs. 0.24 [0.22–0.27]), Tpeak− Tend/QRS (0.77 [0.62–0.87] vs. 0.77 [0.69–0.86]), Tpeak− Tend/(QRS × QT) (0.00074 [0.00034–0.00096] vs. 0.00073 [0.00048–0.00012] ms−1), index of Cardiac Electrophysiological Balance (iCEB, QT/QRS, marker of wavelength: 3.14 [2.56–3.35] vs. 3.21 [2.85–3.46]) and corrected iCEB (QTc/QRS: 3.25 [2.91–3.73] vs. 3.49 [2.99–3.78]). Higher QRS dispersion was seen in type 1 subjects (QRSd: 34 [24–66] vs. 24 [12–34] ms) but QT dispersion (QTd: 48 [39–71] vs. 43 [22–94] ms), QTc dispersion (QTcd: 52 [41–79] vs. 46 [23–104] ms), JTpeak dispersion (44 [23–62] vs. 45 [30–62] ms), Tpeak− Tend dispersion (28 [15–34] vs. 29 [22–53] ms) or Tpeak− Tend/QT dispersion (0.06 [0.03–0.08] vs. 0.08 [0.04–0.12]) did not differ between the two groups. Type 1 subjects showed higher (QRSd × Tpeak− Tend)/QRS (25 [19–44] vs. 19 [9–30] ms) but similar iCEB dispersion (0.83 [0.49–1.14] vs. 0.61 [0.34–0.92]) and iCEBc dispersion (0.93 [0.51–1.15] vs. 0.65 [0.39–0.96]).Conclusion: Higher levels of dispersion in conduction and repolarization are found in type 1 than non-type 1 BrS patients, potentially explaining the higher incidence of ventricular arrhythmias in the former group.

GW29-e0961 Video-Assisted Thoracoscopic Left Cardiac Sympathetic Denervation in Chinese Patients with long QT syndrome

Long QT syndrome is a rare but potentially lethal cardiac channelopathy. The primary aim of the study was to investigate the long-term effects of Video-assisted thoracoscopic left cardiac sympathetic denervation in Chinese patients with long QT syndrome. Video-assisted thoracoscopic left cardiac

Identification novel LQT syndrome-associated variants in Polish population and genotype-phenotype correlations in eight families

Congenital long QT syndrome (LQTS) is a primary cardiac channelopathy. Genetic testing has not only diagnostic but also prognostic and therapeutic implications. At present, 15 genes have been associated with the disease, with most mutations located in 3 major LQTS-susceptibility genes. During a routine genetic screening for KCNQ1, KCNH2 and SCN5A genes in index cases with LQTS, seven novel variants in KCNH2 and SCN5A genes were found. Genotype-phenotype correlations were analysed in these patients and their families. An open reading frame and splice site analysis of the exons was conducted using next-generation sequencing. In novel variants, phenotypes of carriers and their affected relatives were analysed. In 39 unrelated patients, 40 pathogenic/putative pathogenic mutations were found. Thirty-three of them, predominantly missense, were reported previously: 11 were in the KCNQ, 17 in the KCNH2 and 5 in the SCN5A gene. Seven novel missense variants were found in eight families. Among them, four variants were in typical for LQTS location. Two variants in the KCNH2 gene (p.D803Y and p.D46F) and one in the SCN5A gene (G1391R) were in amino acid (AA) position which up to present has not been reported in LQTS. Phenotype analysis showed the life-threatening course of the disease in index cases with a history of sudden cardiac death in six families. Mutation carriers presented with ECG abnormalities and some of them received beta-blocker therapy. We report three novel variants (KCNQ1 p.46, KCNH2 p.D803Y, SCN5A p.G1391R) which have never been reported for this AA location in LQTS; the phenotype-genotype correlation suggests their pathogenicity.