Cardiac Ion Channel Disease Research Articles

Artificial Intelligence ECG Analysis in Patients with Short QT Syndrome to Predict Life-Threatening Arrhythmic Events

Short QT syndrome (SQTS) is an inherited cardiac ion-channel disease related to an increased risk of sudden cardiac death (SCD) in young and otherwise healthy individuals. SCD is often the first clinical presentation in patients with SQTS. However, arrhythmia risk stratification is presently unsatisfactory in asymptomatic patients. In this context, artificial intelligence-based electrocardiogram (ECG) analysis has never been applied to refine risk stratification in patients with SQTS. The purpose of this study was to analyze ECGs from SQTS patients with the aid of different AI algorithms to evaluate their ability to discriminate between subjects with and without documented life-threatening arrhythmic events. The study group included 104 SQTS patients, 37 of whom had a documented major arrhythmic event at presentation and/or during follow-up. Thirteen ECG features were measured independently by three expert cardiologists; then, the dataset was randomly divided into three subsets (training, validation, and testing). Five shallow neural networks were trained, validated, and tested to predict subject-specific class (non-event/event) using different subsets of ECG features. Additionally, several deep learning and machine learning algorithms, such as Vision Transformer, Swin Transformer, MobileNetV3, EfficientNetV2, ConvNextTiny, Capsule Networks, and logistic regression were trained, validated, and tested directly on the scanned ECG images, without any manual feature extraction. Furthermore, a shallow neural network, a 1-D transformer classifier, and a 1-D CNN were trained, validated, and tested on ECG signals extracted from the aforementioned scanned images. Classification metrics were evaluated by means of sensitivity, specificity, positive and negative predictive values, accuracy, and area under the curve. Results prove that artificial intelligence can help clinicians in better stratifying risk of arrhythmia in patients with SQTS. In particular, shallow neural networks’ processing features showed the best performance in identifying patients that will not suffer from a potentially lethal event. This could pave the way for refined ECG-based risk stratification in this group of patients, potentially helping in saving the lives of young and otherwise healthy individuals.

The mechanism of sudden unexpected death in epilepsy: A mini review.

Sudden unexpected death in epilepsy (SUDEP) is defined as a sudden, unexpected, non-traumatic, non-drowning death in a person with epilepsy. SUDEP is generally considered to result from seizure-related cardiac dysfunction, respiratory depression, autonomic nervous dysfunction, or brain dysfunction. Frequency of generalized tonic clonic seizures (GTCS), prone posture, and refractory epilepsy are considered risk factors. SUDEP has also been associated with inherited cardiac ion channel disease and severe obstructive sleep apnea. Most previous studies of SUDEP mechanisms have focused on cardiac and respiratory dysfunction and imbalance of the neural regulatory system. Cardiac-related mechanisms include reduction in heart rate variability and prolongation of QT interval, which can lead to arrhythmias. Laryngospasm and amygdala activation may cause obstructive and central apnea, respectively. Neural mechanisms include impairment of 5-HT and adenosine neuromodulation. The research to date regarding molecular mechanisms of SUDEP is relatively limited. Most studies have focused on p-glycoprotein, catecholamines, potassium channels, and the renin-angiotensin system, all of which affect cardiac and respiratory function.

Deciphering Common Long QT Syndrome Using CRISPR/Cas9 in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

From carrying potentially pathogenic genes to severe clinical phenotypes, the basic research in the inherited cardiac ion channel disease such as long QT syndrome (LQTS) has been a significant challenge in explaining gene-phenotype heterogeneity. These have opened up new pathways following the parallel development and successful application of stem cell and genome editing technologies. Stem cell-derived cardiomyocytes and subsequent genome editing have allowed researchers to introduce desired genes into cells in a dish to replicate the disease features of LQTS or replace causative genes to normalize the cellular phenotype. Importantly, this has made it possible to elucidate potential genetic modifiers contributing to clinical heterogeneity and hierarchically manage newly identified variants of uncertain significance (VUS) and more therapeutic options to be tested in vitro. In this paper, we focus on and summarize the recent advanced application of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9 (CRISPR/Cas9) in the interpretation for the gene-phenotype relationship of the common LQTS and presence challenges, increasing our understanding of the effects of mutations and the physiopathological mechanisms in the field of cardiac arrhythmias.

Combining multi-dimensional molecular fingerprints to predict the hERG cardiotoxicity of compounds

Recently, drug toxicity has become a critical problem with heavy medical and economic burdens. Acquired long QT syndrome (acLQTS) is an acquired cardiac ion channel disease caused by drugs blocking the hERG channel. Therefore, it is necessary to avoid cardiotoxicity in drug design, and computer models have been widely used to fix this predicament. In this study, we collected a hERG inhibitor dataset containing 8671 compounds, and then, these compounds were featurized by traditional molecular fingerprints (including Baseline2D, ECFP4, PropertyFP, and 3DFP) and the newly proposed molecular dynamics fingerprint (MDFP). Subsequently, regression prediction models were established by using four machine learning algorithms based on these fingerprints and the combined multi-dimensional molecular fingerprints (MultiFP). After cross-validation and independent test dataset validation, the results show that the best model was built by the consensus of four algorithms with MultiFP, and this model bests recently published methods in terms of hERG cardiotoxicity prediction with a RMSE of 0.531 and a R2 of 0.653 on the test dataset. Feature importance analysis and correlation analysis identified some novel structural features and molecular dynamics features that are highly associated with the hERG inhibition of compounds. Our findings provide new insight into multi-dimensional molecular fingerprints and consensus models for hERG cardiotoxicity prediction.

Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different Na v1.5-subunit mutations.

Brugada syndrome (BrS) is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death. Considering that its heterogeneity in clinical manifestations may result from genetic background, the application of patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) may help to reveal cell phenotype characteristics underlying different genetic variations. Here, to verify and compare the pathogenicity of mutations (SCN5A c.4213G>A andSCN1B c.590C>T) identified from two BrS patients, we generated two novel BrS iPS cell lines that carried missense mutations inSCN5A or SCN1B, compared their structures and electrophysiology, and evaluated the safety of quinidine in patient-specific iPSC-derived CMs. Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration, and varying degrees of decreased Vmax, but no structural difference. After applying different concentrations of quinidine, drug-induced cardiotoxicity was not observed within 3-fold unbound effective therapeutic plasma concentration (ETPC). The data presented proved that iPSC-CMs with variants in SCN5A c.4213G>A orSCN1B c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.

An Unusual Case of Brugada Syndrome in an 82-Year Old Black Hypertensive Man

Rationale: Brugada syndrome (BrS) is a cardiac ion channel disease that is caused by an autosomal dominant genetic abnormality. It is frequently seen among young and middle-aged adults of Asian descent and rarely in blacks. Patient Concerns: We report an extremely rare case of an 82-year-old male known hypertensive with poor drug compliance, who suffered recurrent palpitations and pre-syncope. His electrocardiogram showed an unusual right bundle branch block with coved ST segment elevation in leads V1-V3. Diagnoses: The patient was eventually diagnosed with Brugada Syndrome with background hypertensive heart disease. He could not have genetic testing due to unavailability and cost. Interventions: The patient was treated with antihypertensives but could not afford a device implant. He was counseled to avoid risk factors such as fever, extreme physical and emotional exertions etc. Outcomes: At his last clinic visit two months post diagnosis he still had similar symptoms but no syncope nor sudden cardiac arrest. Lessons: To the best of our knowledge, this is possibly the first reported case of BrS in an elderly African with hypertensive heart disease.

GW29-e1547 Nonhuman disease model in researches of cardiac ion channel dysfunction

As many cardiac diseases have a substrate of abnormal cardiac ion channel function, there is an increasing attention to the cardiac ion channel dysfunction. An appropriate and reliable disease model is essential to improving our understanding of the pathophysiology of cardiac ion channel disease, as

The gender difference of utilization of cardiac implantable electronic device in China: data from Arrhythmia Interventional Therapy Data Registry.

BackgroundCardiac implantable electronic devices (CIEDs) greatly improve survival and life quality of patients. However, there are gender differences regarding both the utilization and benefit of these devices. In this prospective CIED registry, we aim to appraise the gender differences in CIED utilization in China.MethodsTwenty centers from 14 provinces in China were included in our registry study. All patients who underwent a CIED implantation in these twenty centers between Jan 2015 and Dec 2016 were included.ResultsA total of 8570 patients were enrolled in the baseline cohort, including 7203 pacemaker, 664 implantable cardiac defibrillators (ICD) implants and 703 cardiac resynchronization therapy device (CRT/D). Totally, 4117 (48.0%) CIED patients were female, and more than 59% pacemaker patients were female, but women account only one third of ICD or CRT/D implantation in this registry. There were significant differences between genders at pacemaker and ICD indications. Female was more likely received a pacemaker due to sick sinus syndrome (SSS) (63.9% vs. 51.0%, P < 0.001). Female patients receiving an ICD were more likely due to cardiac ion channel disease (29.2% vs. 4.2%, P < 0.001). The percentage of utilization of dual-chamber pacemaker in female patients was significantly higher than male (85.3% vs. 81.1%, P < 0.001). But male patients were more likely received a cardiac resynchronization therapy devices with defibrillator than female (56.5% vs. 41.9%, P = 0.001). In pacemaker patient, male was more likely to have structure heart disease (31.3% vs. 28.0%, P = 0.002). In ICD patient, male patients were more likely to have ischemic heart disease (48.2% vs. 29.2%, P < 0.001). The mean age of women at the time of CRT/D implantation was older than men (P = 0.014). Nonischemic cardiomyopathy (70.9%) was the most common etiology in the patients who underwent the treatment of CRT/D, no matter male or female.ConclusionsIn real-world setting, female do have different epidemiology, pathophysiology and clinical presentation of many cardiac rhythm disorders when compared with male, and all these factors may affect the utilization of CIED implantation. But it also possibility that cultural and socioeconomic features may play a role in this apparent discrimination.

Andersen-Tawil syndrome: a review of its clinical and genetic diagnosis with emphasis on cardiac manifestations

The Andersen-Tawil syndrome is a cardiac ion channel disease that is inherited in an autosomal dominant way and is classified as type 7 of the congenital long QT syndromes. Affected gene is KCNJ2, which forms the inward rectifier potassium channel designated Kir2.1. This protein is involved in stabilizing the resting membrane potential and controls the duration of the action potential in skeletal muscle and heart. It also participates in the terminal repolarization phase of the action potential in ventricular myocytes and is a major component responsible for the correction in the potassium current during phase 3 of the action potential repolarization. Kir 2.1 channel has a predominant role in skeletal muscle, heart and brain. Alterations in this channel produce flaccid paralysis, arrhythmias, impaired skeletal development primarily in extremities and facial area. In this review we address the disease from the point of view of clinical and molecular diagnosis with emphasis on cardiac manifestations.

Brugada Syndrome: Current Clinical Aspects and Risk Stratification

Brugada syndrome is a primary electrical disease of the heart that causes sudden cardiac death or life-threatening ventricular arrhythmias, especially in younger men. Genetic analysis supports that this syndrome is a cardiac ion channel disease. A typical electrocardiographic finding consists of a right bundle branch block pattern and ST-segment elevation in the right precordial leads. The higher intercostal space V(1) to V(3) lead electrocardiogram could be helpful in detecting Brugada patients. Although two types of the ST-segment elevation are present, the coved type is more relevant to the syndrome than the saddle-back type. These patterns can be present permanently or intermittently. Recent data suggest that the Brugada-type electrocardiogram is more prevalent than the manifest Brugada syndrome. Asymptomatic individuals have a much lower incidence of future cardiac events than the symptomatic patients. Although risk stratification for the Brugada syndrome is still incomplete, the inducibility of sustained ventricular arrhythmias has been proposed as a good outcome predictor in this syndrome. In noninvasive techniques, some clinical evidence supports that late potentials detected by signal-averaged electrocardiography are a useful index for identifying patients at risk. The available data recommend prophylactic implantation of an implantable cardioverter defibrillator to prevent sudden cardiac death. This review summarizes recent information of the syndrome by reviewing most of new clinical reports and speculates on its risk stratification.