Search Results (164)

Background: Cardiac channelopathies are rare but potentially life-threatening disorders that may present with syncope or seizure-like episodes in children, often leading to misdiagnosis and delayed recognition. Other arrhythmia-associated cardiac conditions may also present with similar clinical manifestations and require careful cardiac evaluation. Objective: To evaluate the prevalence of cardiac channelopathies and inherited arrhythmogenic cardiac disorders in pediatric patients presenting with syncope and seizure-like events and to identify associated clinical and electrocardiographic features. Methods: This retrospective cross-sectional study included pediatric patients presenting with syncope, presyncope, seizures, or seizure-like episodes who underwent cardiac evaluation at Ankara Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research Hospital between January 2015 and April 2019. Cardiac evaluation was performed using a standard 12-lead electrocardiogram and was complemented by additional investigations, including 24 h Holter monitoring, exercise testing, pharmacological provocation, electrophysiological studies, and genetic analysis, when clinically indicated. Demographic, clinical, and diagnostic parameters were systematically evaluated. Results: A total of 363 patients were included in the final analysis. The mean age was 12.2 ± 4.7 years, and 58.7% were female. The most common diagnosis was vasovagal syncope (n = 160, 44.1%), followed by epilepsy (n = 53, 14.6%). Cardiac channelopathies, and arrhythmogenic right ventricular dysplasia (ARVD) were identified in 18 patients, corresponding to 4.9% of the pediatric cardiology-evaluated patients and 0.82% of the initial screened population. These diagnoses included long QT syndrome (n = 8), Brugada syndrome (n = 3), short QT syndrome (n = 3), catecholaminergic polymorphic ventricular tachycardia (n = 2), ARVD (n = 1), and malignant-type early repolarization (n = 1). Compared with other patients, those with cardiac channelopathies, malignant-type early repolarization, and ARVD more frequently had exercise-related triggers (p < 0.001), ventricular extrasystoles and ventricular tachycardia (p < 0.001), and abnormal exercise test findings (p < 0.001). Conclusions: Cardiac channelopathies are not uncommon in pediatric patients presenting with syncope and seizure-like events and should be considered in the differential diagnosis. Clinical triggers, family history, and electrocardiographic abnormalities may serve as important clues for early identification. A multidisciplinary approach, including detailed cardiac evaluation, is essential to prevent misdiagnosis and reduce the risk of sudden cardiac death. Full article

Background: Channelopathies represent a heterogeneous group of rare inherited cardiac diseases associated with life-threatening arrhythmias. Our knowledge of their epidemiology in childhood is limited. The aim of this study is to evaluate the epidemiology of pediatric channelopathies on a Mediterranean island (Crete, Greece). Methods: Retrospective study of children < 18 years followed in the Regional Tertiary Pediatric Cardiology Unit during a 24-year period (2002–2025) and meeting the disease-specific diagnostic criteria. Results: A total of 43 children (32 families) were enrolled, corresponding to an average annual incidence of 1.43 (95% C.I.: 1.03–1.92) and a cumulative prevalence of 31.1 (95% C.I.: 22.1–42.5) cases per 100, 000 children, with significant regional incidence differences. Long QT syndrome (n = 38) was predominant; rare cases of Brugada syndrome (n = 3) and Catecholaminergic polymorphic tachycardia (n = 2) were recorded. The diagnosis was based on symptomatic presentation (n = 15, 35%), while asymptomatic patients (n = 28, 65%) were diagnosed during cascade family screening (n = 22, 51%) and preparticipation screening (n = 6, 14%). They represented the first diagnosis within affected families (index cases) in 21/43 (49%) of cases. Genetic testing was performed in 35/43 (81%) channelopathy cases and it was positive in 33/43 (77%) of them, specifically in 30 out of 38 (79%) LQT cases with a genotype of LQT2 in 15 (39%), LQT1 in 10 (26%), LQT3 in one (3%) and LQT5 in two (5%) cases. Conclusions: The incidence of pediatric channelopathies on the Mediterranean island of Crete seems comparable to that reported in the literature, with regional clusters of significantly increased incidence. Further study of the epidemiology of pediatric channelopathies is needed, to document any regional or ethnic differences and for the best design of large-scale screening programs. Full article

Congenital Long QT Syndrome (LQTS) is a hereditary cardiac channelopathy defined by delayed ventricular repolarization and an elevated risk of life-threatening ventricular arrhythmias. Recent echocardiographic studies using speckle-tracking and strain imaging have identified subtle abnormalities in ventricular and atrial mechanics among LQTS patients, including reduced global longitudinal strain, impaired diastolic function, enlarged left atrial volumes and a consistently negative electromechanical window. These findings challenge the traditional concept of LQTS as solely an electrical disease and support evolving evidence of a subclinical cardiomyopathic phenotype. Left atrial remodeling, although less studied, may represent an underrecognized component of LQTS with potential implications for arrhythmia vulnerability and diastolic dysfunction. This review summarizes current evidence on electromechanical and structural cardiac involvement in congenital LQTS, highlights its diagnostic and clinical implications, and outlines future directions for research in this evolving field. Full article

The hERG potassium channel is critical for cardiac ventricular repolarization and a core target in pre-clinical drug safety screening. A robust, stable cell line with uniform, high hERG expression is essential for high-throughput assessments. In this study, we established a functional stable HEK293T cell line with high hERG expression. The hERG gene was subcloned into Lenti-HA-hERG-P2A-EGFP plasmid, in which GFP serves as a selection marker via a P2A self-cleaving peptide. GFP-positive monoclonal cells were isolated by fluorescence-activated cell sorting (FACS). Confocal imaging confirmed that hERG localized predominantly to the cell membrane, consistent with its physiological role. Manual patch-clamp revealed canonical hERG current properties: a small, stable current during depolarization to 20 mV, followed by a large outward tail current upon repolarization to −40 mV-a hallmark of hERG channel gating. Automated patch-clamp (APC)-based current profiling showed 93.5% of stable hERG cells exhibited peak tail currents > 50 pA (87% > 100 pA, with 49.5% > 400 pA), whereas 100% of blank HEK293T cells showed peak tail currents < 50 pA. Pharmacological validation with E-4031 demonstrated concentration-dependent inhibition of hERG currents, with an IC₅₀ of 29.8 nM, which is consistent with literature-reported values. The stable hERG-expressing HEK293T cell line developed here exhibits consistent hERG expression, canonical channel function, and physiological sensitivity to hERG blockers. When paired with high-throughput APC systems, this cell model provides a robust, standardized platform for pre-clinical drug-induced hERG inhibition evaluation, aiding early detection of long QT syndrome risks and safer drug development. Full article

Kv11.1 (hERG1) channels, encoded by KCNH2, mediate the rapid delayed rectifier potassium current (I_Kr) crucial for cardiac repolarization. Disruptions, via mutations or antiarrhythmic drugs like dofetilide cause severe arrhythmogenic disorders, including Long QT Syndrome Type 2 (LQT2), Brugada Syndrome (BrS), and Torsades de Pointes (TdP). While Kv11.1’s role in channelopathies and drug-induced arrhythmias is established, understanding its complex regulation and therapeutic targeting remains a challenge. This review synthesizes the structural, functional, and regulatory aspects of Kv11.1 channels and their clinical implications. Recent studies using iPSC-derived cardiomyocytes highlight regulation by PI3K/Akt, PKC, and PKA signaling via phosphorylation (Ser283, Ser890) and interactions with proteins like 14-3-3. Beyond electrophysiology, Kv11.1 influences pathological hypertrophy and non-cardiac functions including insulin secretion. Pharmacological efforts focus on activators to shorten action potential duration and suppress TdP, and blockers with overdose risks. Mutation heterogeneity, exemplified by trafficking impairment (G785D) in LQT2 and gain-of-function (R397C) in BrS, complicates precision therapy. Clinically, systematic risk stratification using electrocardiographic parameters and genotype-specific approaches enables personalized management. Beta-blockers remain first-line therapy for LQTS2, while rigorous avoidance of QT-prolonging medications and electrolyte monitoring form the cornerstones of preventive care. Advancing Kv11.1-targeted therapies with approaches like CRISPR-Cas9 and pharmacological chaperones (e.g., lumacaftor) holds promise for personalized treatments, ultimately reducing arrhythmic events and sudden cardiac death. Full article

Sudden cardiac death (SCD) is a major global health issue, defined as sudden natural death presumed to be of cardiac cause. While in the elderly SCD is commonly associated with coronary artery disease, in the younger population it is linked to inherited cardiomyopathies or channelopathies, even though SCD can remain unexplained even after a comprehensive autopsy in a substantial proportion of cases. In this context, genetic testing has gained importance, supported by the widespread availability of techniques such as next-generation and whole-exome/genome sequencing and their reduced costs. This state-of-the-art review summarizes the genetic bases of sudden cardiac death among cardiomyopathies, channelopathies and in sudden unexplained death presumed to be of arrhythmic cause. Among the structural causes, inherited cardiomyopathies such as hypertrophic, dilated, non-dilated left ventricular, arrhythmogenic right ventricular and restrictive ones represent major substrates for malignant ventricular arrhythmias mostly arising from variants in sarcomeric or desmosomal genes. Channelopathies (long or short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia) are caused by variants in genes encoding cardiac ion channels and/or regulatory proteins, which equally predispose to high risk of life-threatening ventricular arrhythmias. In sudden arrhythmic death syndrome, with a structurally normal heart, post-mortem genetic testing (molecular autopsy) can uncover an underlying inherited condition. However, variants of uncertain significance are detected in more than half of the cases, underscoring the need for a multidisciplinary approach. Genetic testing also plays a key role in cascade screening of first-degree relatives. While monogenic variants drive risk in inherited cardiac disorders, emerging evidence suggests that polygenic contributions may modulate SCD susceptibility, highlighting future roles for polygenic risk scores in risk stratification. Full article

Neonatal arrhythmias, though relatively uncommon, can range from benign self-limiting conditions to life-threatening disorders requiring intensive management. Data on their clinical spectrum, management, and outcomes remain limited. This study aimed to evaluate the types, frequency, clinical characteristics, treatment strategies, and prognosis of neonatal arrhythmias in a tertiary pediatric cardiac center. We retrospectively reviewed neonates diagnosed with arrhythmia within the first 28 days of life at Basaksehir Cam and Sakura City Hospital between 1 January 2021 and 1 May 2025. Demographic data, electrocardiographic and echocardiographic findings, treatment modalities, recurrence, morbidity, and mortality were analyzed. Patients were categorized as having benign or non-benign arrhythmias. A total of 65 neonates (57% male, mean weight 3.2 kg) were included. Non-benign arrhythmias were more frequent (77%) compared to benign arrhythmias (23%). Supraventricular tachycardia (35%) was the most common non-benign arrhythmia, followed by long QT syndrome (10.7%) and complete atrioventricular block (9.2%). Antiarrhythmic therapy was required in 55% of patients. Pacemaker implantation was performed in seven infants with conduction disorders. Recurrence occurred in 3% of cases, exclusively among patients with supraventricular tachycardia. During a median follow-up of 12.8 months, no mortality was observed. Prenatal diagnosis and early management contribute to favorable outcomes, as reflected in the absence of mortality in this cohort. Larger, prospective studies are warranted to define optimal management strategies and treatment durations for neonatal arrhythmias. Full article

Deleterious variants in SCN5A lead to a wide clinical spectrum that includes pathologies characterized by life-threatening cardiac events (CEs). In the pediatric population, early identification, management, and risk stratification of these pathologies are the main current challenges. This study analyzed a Spanish pediatric cohort (≤18 years) carrying rare SCN5A variants to explore genotype–phenotype correlations. A retrospective descriptive cohort study, including clinical, demographic, and genetic data of probands and their relatives, was conducted. Out of 100 children studied, 69 had definitively deleterious SCN5A variants (26 females, 38%; median age: 3 years, IQR 1–12). The main diagnoses were isolated Brugada syndrome (BrS) (31; 45%); isolated long QT syndrome type 3 (LQT3) (5; 7%); isolated progressive cardiac conduction disease (PCCD) (1; 2%); isolated familial atrial fibrillation (1; 2%); overlapping phenotypes (7; 10%) including: BrS-PCCD (2; 2.8%); BrS-LQT3 (1; 1.4%); premature ventricular contraction-dilated cardiomyopathy (1; 1.4%); BrS-LQT3-PCCD (1; 1.4%); BrS-PCCD-sick sinus syndrome (SSS) (1; 1.4%) and BrS-PCCD-SSS-familial atrial fibrillation (1; 1.4%). Of them, 13 (19%) patients presented with CEs (cardiogenic syncope, ventricular tachycardia/fibrillation, sudden cardiac arrest/death, and appropriate implantable cardio defibrillator shock). These findings underscore the utility of genetic testing for early diagnosis, risk stratification, and personalized management, enhancing preventive strategies for CE prevention in pediatrics. Full article

Long QT associated with pheochromocytoma is rare but clinically significant. A 43-year-old woman presented with palpitations, chest pain, and recurrent syncope. ECG showed ST-segment elevation, while coronary angiography revealed normal arteries but Takotsubo-like left ventricular dysfunction. Hypertension and tachycardia raised suspicion for pheochromocytoma, later confirmed by imaging and biochemical tests. The patient exhibited QT prolongation (QTc 570 ms) in parallel with Takotsubo episodes. Following adrenalectomy, both QT duration and ventricular function normalized. The European Society of Cardiology now classifies pheochromocytoma-induced cardiomyopathy within the Takotsubo spectrum. Early recognition is crucial due to the risk of sudden cardiac death. Full article

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as SCN5A for Brugada syndrome, and MYH7 and MYBPC3 for hypertrophic cardiomyopathy, which have revolutionized diagnosis, risk stratification, and medical management. Nonetheless, issues such as variable expressivity and penetrance, low yield of genetic testing, and relative lack of disease-modifying therapies remain significant hurdles for clinical management. The revolution of genome-wide association studies GWASs has transformed our understanding of inherited arrhythmias and cardiomyopathies, shifting the view of these disorders from a monogenic Mendelian inheritance towards a more complex, often polygenic inheritance with nuanced interplay between genetics and environment. Moreover, GWASs have enabled the quantification of polygenic predisposition to disease using polygenic risk scores, which are often complementary to and independent of monogenic risk. In this review, we highlight how GWASs have transformed the field of inherited arrhythmias and cardiomyopathies, with a particular focus on the polygenic risk scores developed and their clinical utility for the four disorders which have been impacted by GWASs—hypertrophic cardiomyopathy, dilated cardiomyopathy, Brugada syndrome, and long QT syndrome. Full article

Introduction: Clinical variability within families harbouring disease-causing genetic variants hampers clinical care and risk stratification. We studied a multigenerational family presenting with sinus bradycardia and long QT syndrome type 2 (LQTS2). The family harboured a pathogenic variant in KCNH2, which co-segregated with the observed LQTS2. We studied the genetic cause of the high occurrence of sinus bradycardia in this family. Methods: Clinical data was collected, including heart rate, QT-interval, symptoms, and echocardiographic parameters. QTc was calculated using the Bazett and the Fridericia formula. Sanger sequencing of HCN4 was performed, followed by segregation analysis of the identified variant with sinus bradycardia. The biophysiological consequences of two variants, KCNH2-p.L69P (c.206T>C) and HCN4-p.R666W (c.1996C>T), were assessed by patch-clamp experiments. Therefore, a heterologous model was generated by transfection of HEK293A or CHO-k1 cells, respectively. Results: Sanger sequencing of HCN4 identified HCN4-p.R666W (c.1996C>T), which has a stronger segregation with the observed sinus bradycardia than KCNH2-p.L69P. Patch-clamp experiments revealed that KCNH2-p.L69P and HCN4-p.R666W lead to a decrease in the corresponding current densities, which explains the LQTS and sinus bradycardia observed in the patients. Carriers of both genetic variants have a more severe LQTS2 phenotype, reflected in longer QT and higher incidence of syncope. Conclusions: We identified two (likely) pathogenic variants, KCNH2-p.L69P and HCN4-p.R666W, co-segregating with LQTS2 and sinus bradycardia, respectively. Patients carrying both variants showed a more severe phenotype. These findings highlight the importance of additional genetic testing when discordant features are present, thereby enabling more accurate diagnosis, risk prediction, and management. Full article

Calmodulin (CaM) plays a central role in cardiac excitation–contraction coupling by regulating ion channels, including the L-type calcium (Ca²⁺) channel Ca_v1.2 and the voltage-gated potassium (K⁺) channel K_v7.1. Mutations in CaM are linked to severe arrhythmogenic disorders such as Long QT syndrome (LQTS), yet the molecular mechanisms remain incompletely understood. Here, we investigate the structural and functional consequences of the arrhythmia-associated CaM variant D133H. Biophysical analysis revealed that D133H destabilises Ca²⁺ binding at the C-terminal lobe of CaM, altering its Ca²⁺-dependent conformational changes. Electrophysiological recordings demonstrated that CaM D133H impairs Ca²⁺-dependent inactivation (CDI) of Ca_v1.2, prolonging Ca²⁺ influx, while also reducing activation of K_v7.1, thereby limiting repolarising K⁺ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS. Our findings establish that CaM D133H perturbs both Ca²⁺ and K⁺ channel regulation, highlighting a shared pathway by which calmodulinopathy mutations disrupt cardiac excitability. Full article

Background: Artificial Intelligence (AI) is a transformative innovation designed to enable machines to perform tasks typically requiring human intelligence. Among various medical fields, cardiology—and particularly electrophysiology—has seen rapid integration of AI technologies. The ability of AI to analyze large and complex datasets is reshaping diagnostic and therapeutic approaches. Objectives: This review aims to provide a comprehensive overview of AI models and their applications in cardiac electrophysiology. The focus is on understanding how AI contributes to clinical practice through ECG interpretation, arrhythmia detection, atrial mapping, and catheter ablation, while also exploring its limitations and future potential. Methods: The review discusses various AI approaches, including Machine Learning (ML) and Deep Learning (DL), and highlights relevant literature illustrating their implementation in electrophysiological settings. Key clinical applications are examined thematically, with a narrative synthesis of current capabilities, technologies, and outcomes. Results: AI-based tools have demonstrated effectiveness in identifying supraventricular arrhythmias like atrial fibrillation (AF) and atrial flutter (AFL), as well as complex conditions such as ventricular tachycardias (VTs) and long QT syndrome (LQTS). In procedural contexts, AI enhances electro-anatomical mapping, reduces operative time, and supports tailored post-ablation management. Discussion: While AI offers clear advantages in diagnostic accuracy and procedural efficiency, challenges remain regarding data security, ethical transparency, and clinical adoption. Addressing these limitations will be crucial for integrating AI into routine electrophysiology and maximizing its potential in future cardiology practice. Full article

Background: Long QT syndrome (LQTS) is characterized by delayed myocardial repolarization, predisposing to malignant arrhythmias such as torsades de pointes, ventricular fibrillation, and cardiac arrest. Recent reports suggest that acquired LQTS (aLQTS) may represent an early manifestation of hypopituitarism, potentially contributing to its increased cardiovascular mortality, although evidence remains limited to 16 published case reports. Objective: The objective was to investigate the relationship between hypopituitarism and corrected QT (QTc) interval. Methods: We retrospectively analyzed data from 185 patients (121 males) with hypothalamic–pituitary disorders who underwent a 12-lead electrocardiogram between April 2023 and September 2024. Clinical characteristics, hormone replacement therapy, and same-day laboratory parameters (electrolytes, fT3, fT4, IGF-I, testosterone) were recorded. QTc was calculated using Bazett’s formula. Multivariate logistic regression identified predictors of QTc prolongation. Results: Age (OR 1.07–1.09, p = 0.02) was a significant predictor in 5 of 8 models. The presence of expansive lesions other than pituitary adenomas, craniopharyngiomas, and Rathke’s cleft cysts was also associated with QTc prolongation (OR 8.35–17.73, p < 0.05 and p = 0.03). Potassium (OR 0.14–0.17, p = 0.09) and albumin-corrected calcium levels (OR 0.0003, p = 0.06) showed consistent, though borderline, associations. Conclusions: Age and the presence of expansive lesions other than pituitary adenomas, craniopharyngiomas, and Rathke’s cleft cysts are the main predictors of QTc duration in patients with hypothalamic–pituitary disease. Electrolyte imbalances—particularly low potassium and albumin-corrected calcium—may further contribute. The influence of specific pituitary deficiencies remains uncertain, likely due to adequate replacement therapy in most patients. Full article

Background and Objectives: Spinal anesthesia is a common anesthetic method for cesarean delivery. However, it is associated with spinal hypotension, which can negatively impact both the mother and the fetus. We hypothesized that parturients with preoperatively prolonged corrected QT interval (QTc) would have a lower incidence of developing spinal hypotension. Materials and Methods: This prospective observational study analyzed eighty-five parturients undergoing cesarean delivery. The participants were divided into two groups based on their baseline QTc, which was measured automatically using a patient monitor in the operating room rather than using a standardized 12-lead electrocardiogram: <440 ms (n = 42) or ≥440 ms (n = 43). Following combined spinal-epidural anesthesia, the incidence of spinal hypotension until delivery was analyzed and the vasopressor requirements within 30 min were compared between the QTc groups. The area under the receiver operating characteristic curve was measured to identify the optimal QTc cut-off for predicting spinal hypotension. Results: Spinal hypotension was observed in 37/43 parturients (86.0%) with QTc < 440 ms, compared to 17/42 (40.5%) with QTc ≥ 440 ms (p < 0.001). The total amount of phenylephrine significantly differed between groups (300 μg [100–400] vs. 100 μg [0–300], p = 0.009). The area under the ROC curve for spinal hypotension prediction was 0.75 (95% confidence interval [CI] 0.64–0.86). The optimal QTc cut-off interval, determined using the maximum Youden index (J = 0.510), which corresponded to the best combination of sensitivity and specificity, was 441 ms. Conclusions: These preliminary patient-monitor-based findings indicate an association between preoperative QTc and spinal hypotension, which should be validated using standardized electrocardiographic methods. Full article