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Keywords = long-QT syndrome

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26 pages, 1474 KiB  
Review
Gene Therapy for Cardiac Arrhythmias: Mechanisms, Modalities and Therapeutic Applications
by Paschalis Karakasis, Panagiotis Theofilis, Panayotis K. Vlachakis, Nikias Milaras, Kallirhoe Kalinderi, Dimitrios Patoulias, Antonios P. Antoniadis and Nikolaos Fragakis
Med. Sci. 2025, 13(3), 102; https://doi.org/10.3390/medsci13030102 - 30 Jul 2025
Viewed by 477
Abstract
Cardiac arrhythmias remain a major source of morbidity and mortality, often stemming from molecular and structural abnormalities that are insufficiently addressed by current pharmacologic and interventional therapies. Gene therapy has emerged as a transformative approach, offering precise and durable interventions that directly target [...] Read more.
Cardiac arrhythmias remain a major source of morbidity and mortality, often stemming from molecular and structural abnormalities that are insufficiently addressed by current pharmacologic and interventional therapies. Gene therapy has emerged as a transformative approach, offering precise and durable interventions that directly target the arrhythmogenic substrate. Across the spectrum of inherited and acquired arrhythmias—including long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, atrial fibrillation, and post-infarction ventricular tachycardia—gene-based strategies such as allele-specific silencing, gene replacement, CRISPR-mediated editing, and suppression-and-replacement constructs are showing growing translational potential. Advances in delivery platforms, including cardiotropic viral vectors, lipid nanoparticle-encapsulated mRNA, and non-viral reprogramming tools, have further enhanced the specificity and safety of these approaches. Additionally, innovative applications such as biological pacemaker development and mutation-agnostic therapies underscore the versatility of genetic modulation. Nonetheless, significant challenges remain, including vector tropism, immune responses, payload limitations, and the translational gap between preclinical models and human electrophysiology. Integration of patient-derived cardiomyocytes, computational simulations, and large-animal studies is expected to accelerate clinical translation. This review provides a comprehensive synthesis of the mechanistic rationale, therapeutic strategies, delivery platforms, and translational frontiers of gene therapy for cardiac arrhythmias. Full article
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39 pages, 514 KiB  
Review
A Comprehensive Review of a Mechanism-Based Ventricular Electrical Storm Management
by Alina Gabriela Negru, Diana Carina Iovanovici, Ana Lascu, Alexandru Silviu Pescariu, Gabriel Cismaru, Simina Crișan, Ștefan Ailoaei, Diana Luiza Bebec, Caius Glad Streian, Mariela Romina Bîrza, Andrei Raul Manzur, Silvia Ana Luca, Dana David, Svetlana Moșteoru, Dan Gaiță and Constantin Tudor Luca
J. Clin. Med. 2025, 14(15), 5351; https://doi.org/10.3390/jcm14155351 - 29 Jul 2025
Viewed by 391
Abstract
The electrical ventricular storm (VES) is defined as multiple sustained ventricular arrhythmias arising in a short time, often refractory to standard antiarrhythmic treatment. The three pillars of the physiopathogenesis of the VES are autonomic dysfunction, triggers, and an altered ventricular substrate. Incessant or [...] Read more.
The electrical ventricular storm (VES) is defined as multiple sustained ventricular arrhythmias arising in a short time, often refractory to standard antiarrhythmic treatment. The three pillars of the physiopathogenesis of the VES are autonomic dysfunction, triggers, and an altered ventricular substrate. Incessant or highly recurrent ventricular arrhythmia impacts the hemodynamic status by worsening heart failure and increasing mortality. A stepwise, team-based, and tailored therapeutic approach is required to stop ventricular arrhythmia and regain the hemodynamic and electric stability of the patient. The authors focused on describing all currently available therapeutic approaches for VES, intending to establish the best VES therapeutic approaches. This process involves considering the patient’s specific condition, responses to previous treatments, and the potential risks and benefits of each approach. The options range from adjusting antiarrhythmic therapy to reprogramming of the ICD, sedation, epidural anaesthesia, stellate ganglia anaesthetic block, and the use of ECMO or left ventricular assist devices and radiofrequency catheter ablation. Particular attention is paid to the detailed management of genetic primary arrhythmia syndromes like long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome and Wolff–Parkinson–White syndrome, early repolarisation syndrome, right ventricular arrhythmogenic dysplasia, and idiopathic ventricular fibrillation. After overcoming the acute events of VES and obtaining hemodynamic stability, the treatment should shift toward an optimal balance of heart failure therapy, controlling the substrate by revascularisation procedures and resolving other pathology-generating ventricular arrhythmias. This article provides a comprehensive overview of ESV’s current management options using the most efficient strategies known to date. Full article
(This article belongs to the Section Cardiology)
25 pages, 5252 KiB  
Article
Predicting the Damaging Potential of Uncharacterized KCNQ1 and KCNE1 Variants
by Svetlana I. Tarnovskaya and Boris S. Zhorov
Int. J. Mol. Sci. 2025, 26(14), 6561; https://doi.org/10.3390/ijms26146561 - 8 Jul 2025
Viewed by 361
Abstract
Voltage-gated potassium channels Kv7.1, encoded by the gene KCNQ1, play critical roles in various physiological processes. In cardiomyocytes, the complex Kv7.1-KCNE1 mediates the slow component of the delayed rectifier potassium current that is essential for the action potential repolarization. Over 1000 [...] Read more.
Voltage-gated potassium channels Kv7.1, encoded by the gene KCNQ1, play critical roles in various physiological processes. In cardiomyocytes, the complex Kv7.1-KCNE1 mediates the slow component of the delayed rectifier potassium current that is essential for the action potential repolarization. Over 1000 KCNQ1 missense variants, many of which are associated with long QT syndrome, are reported in ClinVar and other databases. However, over 600 variants are of uncertain clinical significance (VUS), have conflicting interpretations of pathogenicity, or lack germline information. Computational prediction of the damaging potential of such variants is important for the diagnostics and treatment of cardiac disease. Here, we collected 1750 benign and pathogenic missense variants of Kv channels from databases ClinVar, Humsavar, and Ensembl Variation and tested 26 bioinformatics tools in their ability to identify known pathogenic or likely pathogenic (P/LP) variants. The best-performing tool, AlphaMissense, predicted the pathogenicity of 195 VUSs in Kv7.1. Among these, 79 variants of 66 wildtype residues (WTRs) are also reported as P/LP variants in sequentially matching positions of at least one hKv7.1 paralogue. In available cryoEM structures of Kv7.1 with activated and deactivated voltage-sensing domains, 52 WTRs form intersegmental contacts with WTRs of ClinVar-listed variants, including 21 WTRs with P/LP variants. ClinPred and paralogue annotation methods consistently predicted that 21 WTRs of KCNE1 have 34 VUSs with damaging potential. Among these, 8 WTRs are contacting 23 Kv7.1 WTRs with 13 ClinVar-listed variants in the AlphaFold3 model. Analysis of intersegmental contacts in CryoEM and AlphaFold3 structures suggests atomic mechanisms of dysfunction for some VUSs. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases: 2nd Edition)
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14 pages, 286 KiB  
Review
The Diagnostic Value of Copy Number Variants in Genetic Cardiomyopathies and Channelopathies
by Valerio Caputo, Virginia Veronica Visconti, Enrica Marchionni, Valentina Ferradini, Clara Balsano, Pasquale De Vico, Leonardo Calò, Ruggiero Mango, Giuseppe Novelli and Federica Sangiuolo
J. Cardiovasc. Dev. Dis. 2025, 12(7), 258; https://doi.org/10.3390/jcdd12070258 - 4 Jul 2025
Viewed by 576
Abstract
Sudden cardiac death represents an unexpected death for which a strong underlying genetic background has been described. The primary causes are identified in cardiomyopathies and channelopathies, which are heart diseases of the muscle and electrical system, respectively, without coronary artery disease, hypertension, valvular [...] Read more.
Sudden cardiac death represents an unexpected death for which a strong underlying genetic background has been described. The primary causes are identified in cardiomyopathies and channelopathies, which are heart diseases of the muscle and electrical system, respectively, without coronary artery disease, hypertension, valvular disease, and congenital heart malformations. Genetic variants, especially single nucleotide variants and short insertions/deletions impacting essential myocardial functions, have shown that cardiomyopathies display high heritability. However, genetic heterogeneity, incomplete penetrance, and variable expression may complicate the interpretation of genetic findings, thus delaying the management of seriously at-risk patients. Moreover, recent studies show that the diagnostic yield related to genetic cardiomyopathies ranges from 28 to 40%, raising the need for further research. In this regard, investigating the occurrence of structural variants, especially copy number variants, may be crucial. Based on these considerations, this review aims to provide an overview of copy number variants identified in cardiomyopathies and discuss them, considering diagnostic yield. This review will ultimately address the necessity of incorporating copy number variants into routine genetic testing for cardiomyopathies and channelopathies, a process increasingly enabled by advances in next-generation sequencing technologies. Full article
(This article belongs to the Section Genetics)
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13 pages, 1167 KiB  
Article
A New High Penetrant Intronic Pathogenic Variant Related to Long QT Syndrome Type 2
by Manuel Rodríguez-Junquera, Alberto Alén, Francisco González-Urbistondo, José Julián Rodríguez-Reguero, Bárbara Fernández, Rut Álvarez-Velasco, Daniel Vazquez-Coto, Lorena M. Vega-Prado, Pablo Avanzas, Eliecer Coto, Juan Gómez and Rebeca Lorca
J. Clin. Med. 2025, 14(13), 4646; https://doi.org/10.3390/jcm14134646 - 1 Jul 2025
Viewed by 373
Abstract
Background/Objectives: Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy linked to pathogenic variants in the KCNH2 gene, which encodes the Kv11.1 potassium channel, essential for cardiac repolarization. Variants affecting splice sites disrupt potassium ion flow, prolong QT interval, and increase [...] Read more.
Background/Objectives: Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy linked to pathogenic variants in the KCNH2 gene, which encodes the Kv11.1 potassium channel, essential for cardiac repolarization. Variants affecting splice sites disrupt potassium ion flow, prolong QT interval, and increase the risk of arrhythmias and sudden cardiac death (SCD). Understanding genotype–phenotype correlations is key, given the variability of clinical manifestations even within families sharing the same variant. We aimed to evaluate new pathogenic variants by analyzing genotype–phenotype correlations in informative families. Methods: Genetic and clinical assessments were performed on index cases and family members carrying KCNH2 pathogenic variants, referred for genetic testing between 2010 and June 2023. The next-generation sequencing (NGS) of 210 cardiovascular-related genes was conducted. Clinical data, including demographic details, family history, arrhythmic events, electrocardiographic parameters, and treatments, were collected. Results: Among 390 patients (152 probands) tested for LQTS, only 2 KCNH2 variants had over 5 carriers. The detailed clinical information of 22 carriers of this KCNH2 p.Ser261fs. has already been reported by our research group. Moreover, we identified 12 carriers of the KCNH2 c.77-2del variant, predicted to disrupt a splice site and not previously reported. Segregation analysis showed its high penetrance, supporting its classification as pathogenic. Conclusions: The newly identified KCNH2 c.77-2del variant is a pathogenic, as strongly supported by the segregation analysis. Our findings underscore the importance of further research into splice site variants to enhance clinical management and genetic counseling for affected families. Full article
(This article belongs to the Section Cardiology)
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33 pages, 15086 KiB  
Review
Broad Electrocardiogram Syndromes Spectrum: From Common Emergencies to Particular Electrical Heart Disorders—Part II
by Alexandr Ceasovschih, Anastasia Balta, Victorița Șorodoc, Krishnaraj Rathod, Ahmed El Gohary, Serghei Covantsev, Richárd Masszi, Yusuf Ziya Şener, Alexandru Corlăteanu, Syed Haseeb Raza Naqvi, Alexandra Grejdieru, Nicholas G. Kounis and Laurențiu Șorodoc
Diagnostics 2025, 15(12), 1568; https://doi.org/10.3390/diagnostics15121568 - 19 Jun 2025
Viewed by 2664
Abstract
The electrocardiogram (ECG) remains a cornerstone of modern cardiology, providing rapid, non-invasive, and widely accessible diagnostic insights. While ECG interpretation is an essential skill for clinicians, certain patterns can be subtle or atypical, posing diagnostic challenges. In our previous review (doi.org/10.3390/jpm12111754), we explored [...] Read more.
The electrocardiogram (ECG) remains a cornerstone of modern cardiology, providing rapid, non-invasive, and widely accessible diagnostic insights. While ECG interpretation is an essential skill for clinicians, certain patterns can be subtle or atypical, posing diagnostic challenges. In our previous review (doi.org/10.3390/jpm12111754), we explored several uncommon ECG syndromes with significant clinical implications. However, the spectrum of electrocardiographic abnormalities extends far beyond those initially discussed. In this second installment, we expand our discussion of rare and underrecognized ECG syndromes, including Long QT, Jervell and Lange-Nielsen, Romano–Ward, Andersen–Tawil, Timothy, Short QT, and Twiddler’s syndromes, as well as Noonan, Barlow’s, Bundgaard, BRASH, Carvajal, Naxos, and Danon disease. We highlight their clinical context, characteristic findings, and implications for diagnosis and management. These conditions range from acute, life-threatening emergencies requiring immediate intervention to chronic electrical disorders necessitating long-term monitoring and risk stratification. By broadening our focus, we aim to enhance awareness and recognition of these entities, ultimately improving patient outcomes through timely and accurate diagnosis. Full article
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16 pages, 7349 KiB  
Article
Cardiac Electrophysiological Effects of the Sodium Channel-Blocking Antiepileptic Drugs Lamotrigine and Lacosamide
by Julian Wolfes, Philipp Achenbach, Felix K. Wegner, Benjamin Rath, Lars Eckardt, Gerrit Frommeyer and Christian Ellermann
Pharmaceuticals 2025, 18(5), 726; https://doi.org/10.3390/ph18050726 - 15 May 2025
Viewed by 759
Abstract
Background: The two antiepileptic drugs lacosamide and lamotrigine exert their antiepileptic effect by inhibiting sodium channels. Lacosamide enhances the inactivation of sodium channels, while lamotrigine inhibits the activation of the channel. Interactions with sodium channels also play an interesting role in cardiac pro- [...] Read more.
Background: The two antiepileptic drugs lacosamide and lamotrigine exert their antiepileptic effect by inhibiting sodium channels. Lacosamide enhances the inactivation of sodium channels, while lamotrigine inhibits the activation of the channel. Interactions with sodium channels also play an interesting role in cardiac pro- and antiarrhythmia, with inhibition of inactivation, in particular, being regarded as potentially proarrhythmic. Therefore, the ventricular electrophysiologic effects of lacosamide and lamotrigine were investigated in an established experimental whole-heart model. Methods: A total of 67 rabbit hearts were allocated to four groups. Retrograde aortic perfusion was performed using the Langendorff setup. The action potential duration at 90% repolarization (APD90), QT intervals, spatial dispersion of repolarization, effective refractory period, post-repolarization refractoriness, and VT incidence were determined. The electrophysiological effects of lacosamide and lamotrigine were investigated in increasing concentrations on the natively perfused heart. On the other hand, perfusion with the IKr-blocker sotalol was performed to increase arrhythmia susceptibility, followed by perfusion with lacosamide or lamotrigine to investigate the effects of both in a setting of increased arrhythmia susceptibility. Perfusion with lacosamide and lamotrigine tended to decrease APD90 and QT-interval. As expected, perfusion with sotalol led to a significant increase in APD90, QT interval, and arrhythmia incidence. Additive perfusion with lacosamide led to a further increase in arrhythmia incidence, while additive perfusion with lamotrigine led to a decrease in VT incidence. Conclusions: In this model, lacosamide showed proarrhythmic effects, especially in the setting of an additive prolonged QT interval. Lamotrigine showed no significant proarrhythmia under baseline conditions and rather antiarrhythmic effects with additive QT prolongation. Full article
(This article belongs to the Section Pharmacology)
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20 pages, 20625 KiB  
Review
Sudden Cardiac Death in Pregnant Women—Literature Review and Autopsy Findings
by Ioana Radu, Anca Otilia Farcas, Laura Cimpan, Corina-Lacramioara Platon, Victoria Nyulas, Bogdan Andrei Suciu, Ioana Hălmaciu, Carmen Corina Radu and Klara Brînzaniuc
Diagnostics 2025, 15(9), 1108; https://doi.org/10.3390/diagnostics15091108 - 27 Apr 2025
Viewed by 1287
Abstract
Cardiovascular diseases increase among pregnant women and complicate 1–4% of pregnancies worldwide. The incidence of maternal deaths due to cardiovascular causes has increased dramatically, rising from 3% three decades ago to 15% in recent years. The aim of this study is to provide [...] Read more.
Cardiovascular diseases increase among pregnant women and complicate 1–4% of pregnancies worldwide. The incidence of maternal deaths due to cardiovascular causes has increased dramatically, rising from 3% three decades ago to 15% in recent years. The aim of this study is to provide a comprehensive overview of the current status of knowledge in sudden maternal death (SMD) described in the literature and to present two cases of autopsy findings in sudden cardiac death in pregnant women. Among the most common causes of sudden maternal deaths are peripartum cardiomyopathies, aortic dissection, acute myocardial infarction, arrhythmias, ischemic heart disease, and coronary artery dissection, and among the less common causes, we list coronary artery dissection, congenital heart diseases, valvulopathies, hypertension, fibroelastosis, and borderline myocarditis. The Centers for Disease Control and Prevention (CDC) reported that over 80% of pregnancy-related deaths were preventable. To reduce the number of maternal deaths caused by cardiovascular diseases, the implementation of specialized multidisciplinary teams has been proposed. Molecular biology techniques are proving their effectiveness in forensic medicine. PCR or DNA sequencing can be utilized in “molecular autopsy”, which holds particular value in cases of sudden death where the forensic autopsy is negative but there is a suspicion that death was caused by arrhythmia. Susceptibility genes can be analyzed, such as KCNQ1, KCNH2, KCNE1, and KCNE2, which are involved in long QT syndrome, the RYR2 gene implicated in catecholaminergic polymorphic ventricular tachycardia type 1, or the SCN5A gene associated with Brugada syndrome. Early identification of risk factors involved in sudden maternal death prenatally and during pregnancy is essential. At the same time, genetic determinations and molecular biology techniques are absolutely necessary to prevent the occurrence of sudden deaths among close relatives. Full article
(This article belongs to the Special Issue Diagnosis and Management of Cardiovascular Disorders)
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13 pages, 2296 KiB  
Case Report
A Novel Bradycardia-Associated Variant in HCN4 as a Candidate Modifier in Type 3 Long QT Syndrome: Case Report and Deep In Silico Analysis
by Anna A. Bukaeva, Anastasia V. Blokhina, Maria S. Kharlap, Marija Zaicenoka, Evgenia D. Zotova, Anna V. Petukhova, Elizaveta V. Garbuzova, Anastasia A. Zharikova, Mikhail G. Divashuk, Anna V. Kiseleva, Alexandra I. Ershova, Alexey N. Meshkov and Oxana M. Drapkina
Biomedicines 2025, 13(4), 1008; https://doi.org/10.3390/biomedicines13041008 - 21 Apr 2025
Viewed by 563
Abstract
Background: Genetic testing for long QT syndrome (LQTS) is straightforward in many families; however, in severe and complex cases, a single disease-causing variant may not be enough to explain all clinical features. In such cases, the search for genetic modifiers may be beneficial [...] Read more.
Background: Genetic testing for long QT syndrome (LQTS) is straightforward in many families; however, in severe and complex cases, a single disease-causing variant may not be enough to explain all clinical features. In such cases, the search for genetic modifiers may be beneficial for precise diagnosis and management. Case presentation: We describe a three-generational family affected with clinically heterogeneous LQTS type 3 and bradycardia in which a novel missense variant p.V642M in HCN4 was identified in addition to the known pathogenic variant p.E1784K in SCN5A. We performed the detailed clinical investigation of the family and a deep in silico analysis of the discovered variants, showing the causal role of a new HCN4 variant in sinus bradycardia and its possible contribution to the phenotypic heterogeneity of LQTS type 3. Conclusions: This case is the first description of a functional variant in HCN4 as a candidate modifier in LQTS type 3 and demonstrates the importance of analyzing additional genetic variations in families with complex LQTS phenotypes. Full article
(This article belongs to the Special Issue Cardiovascular Diseases in the Era of Precision Medicine)
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20 pages, 6059 KiB  
Review
The Prenatal Diagnosis and Perinatal Management of Congenital Long QT Syndrome: A Comprehensive Literature Review and Recent Updates
by Stefani Samples, Sara Cherny, Nitin Madan, Jeff Hong, Sheena A. Mansukhani, Janette F. Strasburger, Michael R. Carr and Sheetal R. Patel
J. Cardiovasc. Dev. Dis. 2025, 12(4), 156; https://doi.org/10.3390/jcdd12040156 - 14 Apr 2025
Viewed by 923
Abstract
Congenital long QT syndrome (LQTS) is a group of heritable conditions that are associated with cardiac repolarization abnormalities characterized by QT prolongation on electrocardiogram and the risk of life-threatening arrhythmias. The prenatal detection of LQTS presents significant challenges for clinicians, and a multidisciplinary [...] Read more.
Congenital long QT syndrome (LQTS) is a group of heritable conditions that are associated with cardiac repolarization abnormalities characterized by QT prolongation on electrocardiogram and the risk of life-threatening arrhythmias. The prenatal detection of LQTS presents significant challenges for clinicians, and a multidisciplinary approach is required for optimal prenatal and postnatal management. In this comprehensive literature review, we describe strategies for the fetal diagnosis of LQTS with variable initial presentation, genetic testing in suspected fetal LQTS, the utility of fetal magnetocardiography as an additional diagnostic tool, prenatal management, and postnatal treatment. We focus on a multidisciplinary team approach including fetal cardiology, adult and pediatric electrophysiology, neonatology, maternal–fetal medicine, and genetic counselors, all playing vital roles in the comprehensive prenatal management and orchestration of postnatal treatment to optimize neonatal outcomes. Full article
(This article belongs to the Special Issue Recent Advances in Fetal Cardiology)
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19 pages, 1338 KiB  
Article
Activation of Small Conductance Ca2+-Activated K+ Channels Suppresses Electrical and Calcium Alternans in Atrial Myocytes
by Giedrius Kanaporis and Lothar A. Blatter
Int. J. Mol. Sci. 2025, 26(8), 3597; https://doi.org/10.3390/ijms26083597 - 11 Apr 2025
Viewed by 522
Abstract
Small conductance Ca2+-activated K+ (SK) channels are expressed in atria and ventricles. However, the data on the contribution of SK channels to atrial action potential (AP) repolarization are inconsistent. We investigated the effect of SK channel modulators on AP morphology [...] Read more.
Small conductance Ca2+-activated K+ (SK) channels are expressed in atria and ventricles. However, the data on the contribution of SK channels to atrial action potential (AP) repolarization are inconsistent. We investigated the effect of SK channel modulators on AP morphology in rabbit atrial myocytes and tested the hypothesis that pharmacological activation of SK channels suppresses pacing-induced Ca2+ transient (CaT) and AP duration (APD) alternans. At the cellular level, alternans are observed as beat-to-beat alternations in contraction, APD, and CaT amplitude, representing a risk factor for arrhythmias, including atrial fibrillation. Our results show that SK channel inhibition by apamin did not affect atrial APD under basal conditions. However, SK channel activation by NS309 significantly shortened APD, indicating the expression of functional SK channels. Moreover, the activation of SK channels reduced CaT amplitude and sarcoplasmic reticulum Ca2+ load. Activation of SK channels also suppressed pacing-induced CaT and APD alternans. KV7.1 potassium channel inhibition, simulating long QT syndrome type-1 conditions, increased the risk of atrial CaT alternans, which was abolished by the activation of SK channels. In summary, our data suggest that pharmacological modulation of SK channels can potentially reduce atrial arrhythmia risk arising from pathological APD prolongation. Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)
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13 pages, 1317 KiB  
Article
Clinical, Electrical, and Mechanical Parameters in Potassium Channel-Mediated Congenital Long QT Syndrome
by Neringa Bileišienė, Violeta Mikštienė, Eglė Preikšaitienė, Ieva Kažukauskienė, Gabrielė Tarutytė, Diana Zakarkaitė, Rita Kramena, Germanas Marinskis, Audrius Aidietis and Jūratė Barysienė
J. Clin. Med. 2025, 14(8), 2540; https://doi.org/10.3390/jcm14082540 - 8 Apr 2025
Viewed by 492
Abstract
Background: Congenital long QT syndrome (LQTS) is a rare cardiac disorder caused by repolarization abnormalities in the myocardium that predisposes to ventricular arrhythmias and sudden cardiac death. Potassium channel-mediated LQT1 and LQT2 are the most common types of channelopathy. Recently, LQTS has been [...] Read more.
Background: Congenital long QT syndrome (LQTS) is a rare cardiac disorder caused by repolarization abnormalities in the myocardium that predisposes to ventricular arrhythmias and sudden cardiac death. Potassium channel-mediated LQT1 and LQT2 are the most common types of channelopathy. Recently, LQTS has been acknowledged as an electromechanical disease. Methods: A total of 87 genotyped LQT1/LQT2 patients underwent cardiac evaluation. A comparison between LQT1 and LQT2 electrical and mechanical parameters was performed. Results: LQT2 patients had worse electrical parameters at rest: a longer QTc interval (p = 0.007), a longer Tpe in lead V2 (p = 0.028) and in lead V5 (p < 0.001), and a higher Tpe/QT ratio in lead V2 (p = 0.011) and in lead V5 (p = 0.005). Tpe and Tpe/QT remained significantly higher in the LQT2 group after brisk standing. Tpe was longer in LQT2 patients compared with LQT1 patients during peak exercise (p = 0.007) and almost all recovery periods in lead V2 during EST. The mid-cavity myocardium mean radial contraction duration (CD) was longer in LQT2 patients (p = 0.02). LQT2 patients had a longer mean radial CD in mid-septal (p = 0.015), mid-inferior (p = 0.034), and mid-posterior (p = 0.044) segments. Conclusions: Potassium channel-mediated LQTS has different effects on cardiac electromechanics with a more pronounced impact on LQT2 patients. Tpe was more prominent in the LQT2 cohort, not only at rest and brisk standing but also during EST exercise and at recovery phases. The altered mean radial CD in the mid-cavity myocardium was also specific for LQT2 patients. Full article
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18 pages, 2776 KiB  
Article
Electrocardiographic Discrimination of Long QT Syndrome Genotypes: A Comparative Analysis and Machine Learning Approach
by Martina Srutova, Vaclav Kremen and Lenka Lhotska
Sensors 2025, 25(7), 2253; https://doi.org/10.3390/s25072253 - 2 Apr 2025
Cited by 1 | Viewed by 511
Abstract
Long QT syndrome (LQTS) presents a group of inheritable channelopathies with prolonged ventricular repolarization, leading to syncope, ventricular tachycardia, and sudden death. Differentiating LQTS genotypes is crucial for targeted management and treatment, yet conventional genetic testing remains costly and time-consuming. This study aims [...] Read more.
Long QT syndrome (LQTS) presents a group of inheritable channelopathies with prolonged ventricular repolarization, leading to syncope, ventricular tachycardia, and sudden death. Differentiating LQTS genotypes is crucial for targeted management and treatment, yet conventional genetic testing remains costly and time-consuming. This study aims to improve the distinction between LQTS genotypes, particularly LQT3, through a novel electrocardiogram (ECG)-based approach. Patients with LQT3 are at elevated risk due to arrhythmia triggers associated with rest and sleep. Employing a database of genotyped long QT syndrome E-HOL-03-0480-013 ECG signals, we introduced two innovative parameterization techniques—area under the ECG curve and wave transformation into the unit circle—to classify LQT3 against LQT1 and LQT2 genotypes. Our methodology utilized single-lead ECG data with a 200 Hz sampling frequency. The support vector machine (SVM) model demonstrated the ability to discriminate LQT3 with a recall of 90% and a precision of 81%, achieving an F1-score of 0.85. This parameterization offers a potential substitute for genetic testing and is practical for low frequencies. These single-lead ECG data could enhance smartwatches’ functionality and similar cardiovascular monitoring applications. The results underscore the viability of ECG morphology-based genotype classification, promising a significant step towards streamlined diagnosis and improved patient care in LQTS. Full article
(This article belongs to the Special Issue Sensors for Heart Rate Monitoring and Cardiovascular Disease)
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12 pages, 587 KiB  
Case Report
Long QT Interval Syndrome and Female Sex—Review and Case Report
by Lana Maričić, Livija Sušić, Damir Mihić and Nikolina Šego
Reports 2025, 8(1), 32; https://doi.org/10.3390/reports8010032 - 17 Mar 2025
Viewed by 908
Abstract
Background and Clinical Significance: Congenital LQTS is a life-threatening condition, resulting from a mutation of the gene encoding the cardiac ion channels, which results in prolongation of the ventricular action potential. Genetic screening of family members in symptomatic and asymptomatic patients is crucial [...] Read more.
Background and Clinical Significance: Congenital LQTS is a life-threatening condition, resulting from a mutation of the gene encoding the cardiac ion channels, which results in prolongation of the ventricular action potential. Genetic screening of family members in symptomatic and asymptomatic patients is crucial for the prevention of sudden cardiac death. There are a number of detected mutations of congenital LQTS, of which the three forms LQT1, LQT2, and LQT3 are the best described. In addition to the described ECG morphology, the key triggers and treatment approach are described. This emphasizes even more the importance of timely screening of these patients, and the decision for therapy. It should be emphasized that the phenotypic manifestations significantly depend on the affected genes. The guidelines in the treatment approach are very clear, although it should be emphasized that beta blockers are the first and basic treatment therapy. The therapeutic choice is narrowed especially if they are not effective. Case Presentation: This is a case report of a young woman diagnosed with LQTS who was confirmed to have KCNH2 mutations through genetic analysis. The same mutation was also confirmed in her children. Changes in the therapeutic approach are described, and the use of beta blockers, depending on the symptoms and drug tolerance. Especially in the postpartum period, due to reduced progesterone levels, in this case, the patient was implanted with a cardioverter defibrillator. Conclusions: It should be emphasized that timely recognition is essential for early diagnosis, regular control, timely initiation of treatment, and prevention of adverse events. Full article
(This article belongs to the Section Cardiology/Cardiovascular Medicine)
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10 pages, 1181 KiB  
Article
Electrocardiogram May Fail to Identify Proportion of High-Risk Individuals: Analysis of Series of 50 Sudden Death Cases
by Mariela Salar-Alcaraz, Pablo Peñafiel-Verdú, Francisco J. Castro-García, Francisco A. Pastor-Quirante, Carmen Muñoz-Esparza, José M. López-Ayala, Juan Martínez-Sánchez, Juan J. Sánchez-Muñoz, Arcadi García-Alberola, María Sabater-Molina and Juan R. Gimeno-Blanes
Cardiogenetics 2025, 15(1), 5; https://doi.org/10.3390/cardiogenetics15010005 - 10 Feb 2025
Viewed by 902
Abstract
Background: An electrocardiogram (ECG) is an essential and easily available diagnostic test in the management of cardiomyopathies and channelopathies. Different strategies based on ECG have been recommended for general population and athlete screening. Objectives: The purpose of this study was to explore the [...] Read more.
Background: An electrocardiogram (ECG) is an essential and easily available diagnostic test in the management of cardiomyopathies and channelopathies. Different strategies based on ECG have been recommended for general population and athlete screening. Objectives: The purpose of this study was to explore the value of the ECG for the diagnosis of sudden cardiac death (SCD) cases. Methods: ECGs from 50 (aged 37.6 ± 19.9 years, 37 men) resuscitated cardiac arrest (26, 52%) and SCD cases (24, 48%) were analyzed. Relevant medical history and results from clinical tests were reviewed. ECG findings were compared with the final diagnosis. Results: Final ECG classification was as follows: 9 (18%) normal, 15 (30%) unspecific, 14 (28%) suggestive, and 12 (24%) diagnostic. Amongst 13 hypertrophic cardiomyopathy patients, ECGs were diagnostic in 6 (46%) and suggestive in 1 (8%). Arrhythmogenic right ventricular cardiomyopathy was diagnosed in seven patients, two (28%) with suggestive ECG. Dilated cardiomyopathy was diagnosed in four patients, two (50%) with suggestive ECG. Six patients had Brugada syndrome: four (66%) had diagnostic ECGs, and two (33%) had suggestive ECG. Long QT syndrome was diagnosed in four cases; only one (25%) had a diagnostic ECG. Three patients had other cardiomyopathies. After the complete study, 13 (26%) patients remained with a non-conclusive diagnosis; their ECGs were unspecific or normal. Conclusion: ECG can be unspecific or normal in an important percentage of SCD cases (48%). Furthermore, a significant proportion of SCD cases after a comprehensive study remain without a definite diagnosis (26%). These findings should be considered when planning SCD preventive strategies. Full article
(This article belongs to the Section Sport Cardiology)
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