1
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Li N, Wang L, Hu X, Xu H, Yang B, Zhan L, Cai Y, Gu Y, Chen X, Zheng Y, Liu T, Gao Z, Xiong B. Conformational restriction enables discovering a series of chroman derivatives as potent and selective Na V1.8 inhibitors with improved pharmacokinetic properties. Eur J Med Chem 2025; 293:117697. [PMID: 40347793 DOI: 10.1016/j.ejmech.2025.117697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/16/2025] [Accepted: 04/25/2025] [Indexed: 05/14/2025]
Abstract
Voltage-gated sodium channel 1.8 (NaV1.8) is a promising analgesic target due to its unique biophysical characteristics and specific role in nociceptive sensation. VX-150 initially completed proof-of-concept studies in clinical trials, but with high dosages and frequent administration. Herein, based on VX-150, we report the design, synthesis and structure-activity relationship (SAR) study aiming to identify novel, potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties. Conformational restriction strategy and subsequent optimization led to the identification of the chroman derivative (R)-40 as the most promising hNaV1.8 inhibitor showing an IC50 value of 5.9 ± 1.0 nM and good selectivity over other tested NaV channels and hERG channel. More importantly, (R)-40 showed good in vitro metabolic stability in liver microsomes across multiple species and excellent in vivo PK profiles in rats and dogs. Notably, (R)-40 exerted dose-dependent analgesic activities in both rat models with postoperative and inflammatory pain, and a wide safety margin in neurotoxicity evaluation. Overall, these results confirmed conformational restriction as an effective strategy to improve PK profile, and our detailed study provided a valuable foundation for developing novel NaV1.8 inhibitors.
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Affiliation(s)
- Na Li
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China
| | - Linlin Wang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xinyuan Hu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Haiyan Xu
- Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Bowen Yang
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Li Zhan
- Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yongjie Cai
- Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yueling Gu
- Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xueqin Chen
- Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yueming Zheng
- Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Tongchao Liu
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Zhaobing Gao
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Bing Xiong
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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2
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Dahlberg P, Pozzi S, Bulmer L, Golluscio A, Nilsson M, Nygren A, Larsson HP, Pantazis A, Gummesson A. Clinical and electrophysiological characterization of a SCN5A gain-of-function mutation associated with CPVT-like arrhythmia. J Mol Cell Cardiol 2025; 203:47-58. [PMID: 40209984 DOI: 10.1016/j.yjmcc.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/20/2025] [Accepted: 04/06/2025] [Indexed: 04/12/2025]
Abstract
The present study aimed to characterize the SCN5A variant I1333V, found in five families with a history of suspected catecholaminergic polymorphic ventricular tachycardia (CPVT). SCN5A encodes the pore-forming subunit of the cardiac voltage-gated sodium channel NaV1.5. Gain of SCN5A function causes long QT syndrome type 3 (LQT3), but its involvement in CPVT is disputed. Nineteen patients harboring the I1333V variant were identified across five families, commonly presenting with exercise-induced arrhythmia, including polymorphic premature ventricular contractions, ventricular bigeminy, couplets, and ventricular tachycardias. Prolonged QT interval was a less consistent finding, and structural myocardial changes were absent. Human NaV1.5/β1 complexes were expressed in Xenopus laevis oocytes, using RNA combinations to emulate homozygous wild-type, heterozygous and homozygous I1333V-mutant conditions. Cells were studied using the cut-open oocyte Vaseline gap voltage-clamp to evaluate effects of I1333V on NaV1.5 function. NaV1.5(I1333V) channels required less depolarization to activate, classifying this variant as gain-of-function. Fast inactivation was unaffected, and action-potential (AP) clamp showed no significant differences in late Na+ current. A computational model of human ventricular myocyte excitability predicted no effect of I1333V on AP duration; instead, it showed stronger Na+ influx during the AP upstroke, concurrent with elevated Ca2+ import via the sodium‑calcium exchanger. Finally, NaV1.5(I1333V) channels exhibited a diminished response to cAMP (emulating adrenergic stimulation), which also likely contributes to arrhythmogenesis. In conclusion, I1333V is a gain-of-function variant of SCN5A with a unique set of functional consequences. It is associated with cardiac arrhythmia disease characterized by overlapping CPVT-like and LQT3 features. Our findings support that SCN5A should be considered in genetic screening of suspected CPVT.
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Affiliation(s)
- Pia Dahlberg
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Serena Pozzi
- Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Linda Bulmer
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Alessia Golluscio
- Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Michelle Nilsson
- Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Anders Nygren
- Pediatric Heart Center, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - H Peter Larsson
- Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Antonios Pantazis
- Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden; Wallenberg Center for Molecular Medicine, Linköping University, Linköping, Sweden.
| | - Anders Gummesson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Feng S, Liang SH. Novel Sulfonamide Derivatives as Nav1.5 Sodium Channel Blockers for Treating Atrial Fibrillation. ACS Med Chem Lett 2025; 16:748-749. [PMID: 40365389 PMCID: PMC12067141 DOI: 10.1021/acsmedchemlett.5c00192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Indexed: 05/15/2025] Open
Abstract
This highlight describes a novel class of sulfonamide-based Nav1.5 sodium channel blockers. These compounds preferentially inhibit Nav1.5 in atrial cardiomyocytes, extending the effective refractory period and preventing arrhythmic, rapid contraction of the atria. The novel Nav1.5 blockers possess the potential to treat Atrial Fibrillation without affecting the function of the rest of the heart.
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Affiliation(s)
- Siyan Feng
- Department of Radiology and Imaging
Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States
| | - Steven H. Liang
- Department of Radiology and Imaging
Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States
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Pateda AZ, Azzahra AA, Sumargo KZ, Siregar MNI. Effectiveness of resveratrol in inducing adeno-associated virus as a potential definitive therapy for SCN5A mutation in Brugada syndrome: a narrative review. Egypt Heart J 2025; 77:43. [PMID: 40338408 PMCID: PMC12061799 DOI: 10.1186/s43044-025-00640-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Accepted: 04/15/2025] [Indexed: 05/09/2025] Open
Abstract
OBJECTIVES Brugada syndrome (BrS) is a hereditary channelopathy that affects cardiac electrical signal transmission, with SCN5A gene mutation being the most common cause. Current BrS therapy primarily relies on Implantable Cardioverter Defibrillators, which are limited to arrhythmia prevention. Recent research has explored gene therapy as an alternative approach for managing BrS. Resveratrol, a non-ketone polyphenol compound, exhibits cardioprotective effects due to its antioxidant properties, which can influence gene expression through cellular signaling pathways, thereby modulating adeno-associated virus (AAV). This study aims to evaluate the effectiveness of resveratrol in enhancing the induction of AAV-based viral vectors as a potential definitive therapy for SCN5A mutations in BrS patients. METHODS A comprehensive literature search was conducted across multiple databases, including PubMed, Google Scholar, ScienceDirect, and PLOS ONE. The final stage involved assessing the eligibility of 47 studies, followed by a full-text review, which included seven studies for further analysis. RESULTS The findings indicate that this therapeutic approach highlights resveratrol's crucial role as an activator of deacetylase proteins, influencing DNA repair processes, cell cycle regulation, and energy metabolism. Resveratrol facilitates the modulation of Voltage-Gated Calcium Channels, enabling calcium ion (Ca2⁺) influx into cardiomyocytes, thereby maintaining normal cardiac rhythm. Resveratrol enhances AAV-mediated gene delivery and expression through p53 pathway activation. CONCLUSION Experimental studies have demonstrated that AAV-MOG1 gene therapy can restore sodium channel function, improve cardiac electrophysiological abnormalities, and ameliorate the clinical manifestations of BrS. Thus, resveratrol is potentially an inducer of AAV-mediated gene therapy for BrS.
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Affiliation(s)
- Andin Zahrani Pateda
- Medical Study Program, Faculty of Medicine, State University of Gorontalo, Gorontalo, Indonesia
| | - Andi Alika Azzahra
- Medical Study Program, Faculty of Medicine, State University of Gorontalo, Gorontalo, Indonesia
| | - Kuni Zakiyyah Sumargo
- Medical Study Program, Faculty of Medicine, State University of Gorontalo, Gorontalo, Indonesia
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5
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Balla C, Canovi L, Zuin M, Di Lenno L, Berloni ML, de Carolis B, Di Domenico A, Tonet E, Vitali F, Malagu M, Boriani G, Bertini M. Cardiac Conduction Disorders Due to Acquired or Genetic Causes in Young Adults: A Review of the Current Literature. J Am Heart Assoc 2025; 14:e040274. [PMID: 40314370 DOI: 10.1161/jaha.124.040274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
Cardiac conduction disorders can manifest in young adults in isolated forms, associated with myocardial diseases or as part of a multiorgan disorder. Underlying causes of cardiac conduction disorders may be genetically determined or acquired. Cardiac conduction disorder in young adults is a complex and often underestimated and underrecognized disease that may need of a multidisciplinary team for the diagnosis, treatment, and long-term management of these patients. Therefore, it is crucial to raise clinicians' awareness of this condition. In this review, we provide a comprehensive update on the cause, diagnosis, and treatment of young adults with cardiac conduction disorders, also suggesting potential strategies to improve the current clinical management of these patients.
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Affiliation(s)
- Cristina Balla
- Cardiology Unit Azienda Ospedaliero-Universitaria di Ferrara Cona FE Italy
| | - Luca Canovi
- Cardiology Unit Azienda Ospedaliero-Universitaria di Ferrara Cona FE Italy
| | - Marco Zuin
- Cardiology Unit Azienda Ospedaliero-Universitaria di Ferrara Cona FE Italy
| | - Luca Di Lenno
- Pediatric Cardiology and Adult Congenital Heart Disease Program, Department of Cardio-Thoracic and Vascular Medicine IRCCS Azienda Ospedaliero-Universitaria di Bologna Bologna Italy
| | - Maria L Berloni
- Cardiology Unit Azienda Ospedaliero-Universitaria di Ferrara Cona FE Italy
| | | | | | - Elisabetta Tonet
- Cardiology Unit Azienda Ospedaliero-Universitaria di Ferrara Cona FE Italy
| | - Francesco Vitali
- Cardiology Unit Azienda Ospedaliero-Universitaria di Ferrara Cona FE Italy
| | - Michele Malagu
- Cardiology Unit Azienda Ospedaliero-Universitaria di Ferrara Cona FE Italy
| | - Giuseppe Boriani
- Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia, Policlinico di Modena Modena Italy
| | - Matteo Bertini
- Cardiology Unit Azienda Ospedaliero-Universitaria di Ferrara Cona FE Italy
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6
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Alsaloum M, Dib-Hajj SD, Page DA, Ruben PC, Krainer AR, Waxman SG. Voltage-gated sodium channels in excitable cells as drug targets. Nat Rev Drug Discov 2025; 24:358-378. [PMID: 39901031 DOI: 10.1038/s41573-024-01108-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 02/05/2025]
Abstract
Excitable cells - including neurons, muscle cells and cardiac myocytes - are unique in expressing high densities of voltage-gated sodium (NaV) channels. This molecular adaptation enables these cells to produce action potentials, and is essential to their function. With the advent of the molecular revolution, the concept of 'the' sodium channel has been supplanted by understanding that excitable cells in mammals can express any of nine different forms of sodium channels (NaV1.1-NaV1.9). Selective expression in particular types of cells, together with a key role in controlling action potential firing, makes some of these NaV subtypes especially attractive molecular targets for drug development. Although these different channel subtypes display a common overall structure, differences in their amino acid sequences have provided a basis for the development of subtype-specific drugs. This approach has resulted in exciting progress in the development of drugs for epilepsy, cardiac disorders and pain. In this Review, we discuss recent progress in the development of drugs that selectively target each of the sodium channel subtypes.
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Affiliation(s)
- Matthew Alsaloum
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | | | - Dana A Page
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Peter C Ruben
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
| | | | - Stephen G Waxman
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
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7
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Bukaeva AA, Blokhina AV, Kharlap MS, Zaicenoka M, Zotova ED, Petukhova AV, Garbuzova EV, Zharikova AA, Divashuk MG, Kiseleva AV, Ershova AI, Meshkov AN, Drapkina OM. A Novel Bradycardia-Associated Variant in HCN4 as a Candidate Modifier in Type 3 Long QT Syndrome: Case Report and Deep In Silico Analysis. Biomedicines 2025; 13:1008. [PMID: 40299689 PMCID: PMC12025296 DOI: 10.3390/biomedicines13041008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 05/01/2025] Open
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 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.
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Affiliation(s)
- Anna A. Bukaeva
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Anastasia V. Blokhina
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Maria S. Kharlap
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Marija Zaicenoka
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
- Moscow Center for Advanced Studies, 123592 Moscow, Russia
| | - Evgenia D. Zotova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Anna V. Petukhova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Elizaveta V. Garbuzova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Anastasia A. Zharikova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Mikhail G. Divashuk
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
- All-Russia Research Institute of Agricultural Biotechnology, 127550 Moscow, Russia
| | - Anna V. Kiseleva
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Alexandra I. Ershova
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Alexey N. Meshkov
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
| | - Oxana M. Drapkina
- National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia; (A.V.B.); (M.S.K.); (M.Z.); (A.V.P.); (E.V.G.); (A.A.Z.); (M.G.D.); (A.V.K.); (A.I.E.); (A.N.M.); (O.M.D.)
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8
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Gerritse M, van Ham WB, Denning C, van Veen TAB, Maas RGC. Characteristics and pharmacological responsiveness in hiPSC models of inherited cardiomyopathy. Pharmacol Ther 2025; 272:108845. [PMID: 40250811 DOI: 10.1016/j.pharmthera.2025.108845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/17/2025] [Accepted: 03/24/2025] [Indexed: 04/20/2025]
Abstract
Inherited cardiomyopathies are a major cause of heart failure in all age groups, often with an onset in adolescence or early adult life. More than a thousand variants in approximately one hundred genes are associated with cardiomyopathies. Interestingly, many genetic cardiomyopathies display overlapping phenotypical defects in patients, despite the diversity of the initial pathogenic variants. Understanding how the underlying pathophysiology of genetic cardiomyopathies leads to these phenotypes will improve insights into a patient's disease course, and creates the opportunity for conceiving treatment strategies. Moreover, therapeutic strategies can be used to treat multiple cardiomyopathies based on shared phenotypes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer reliable, high-throughput models for studying molecular and cellular characteristics of hereditary cardiomyopathies. hiPSC-CMs are produced relatively easily, either by directly originating them from patients, or by introducing patient-specific genetic variants in healthy lines. This review evaluates 90 studies on 24 cardiomyopathy-associated genes and systematically summarises the morphological and functional phenotypes observed in hiPSC-CMs. Additionally, treatment strategies applied in cardiomyopathic hiPSC-CMs are compiled and scored for effectiveness. Multiple overlapping phenotypic defects were identified in cardiomyocytes with different variants, whereas certain characteristics were only associated with specific genetic variants. Based on these findings, common mechanisms, therapeutic prospects, and considerations for future research are discussed with the aim to improve clinical translation from hiPSC-CMs to patients.
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Affiliation(s)
- Merel Gerritse
- Utrecht Regenerative Medicine Center, Circulatory Health Research Center, University Utrecht, 3584 CS Utrecht, the Netherlands; Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, the Netherlands.
| | - Willem B van Ham
- Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, the Netherlands.
| | - Chris Denning
- Department of Stem Cell Biology, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
| | - Toon A B van Veen
- Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, the Netherlands.
| | - Renee G C Maas
- Utrecht Regenerative Medicine Center, Circulatory Health Research Center, University Utrecht, 3584 CS Utrecht, the Netherlands; Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
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9
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Yang SH, Zhang SN, Li XZ. Advances in Therapeutic Targets and Traditional Chinese Medicine for Cardiomyopathy. Phytother Res 2025. [PMID: 40219655 DOI: 10.1002/ptr.8494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/21/2025] [Accepted: 03/15/2025] [Indexed: 04/14/2025]
Abstract
Cardiomyopathy is a kind of heart disease caused by multiple factors of myocardial structure and function disorders. In this paper, we summarized and found the targets and mechanisms with therapeutic potential by querying the relevant literature on cardiomyopathy in the past 10 years from databases. Numerous pieces of literature have proven the significant efficacy of traditional Chinese medicine (TCM) in the treatment of cardiomyopathy. Through effective screening methods, we quickly identified a variety of commonly used Chinese herbs such as Astragalus, Danggui, Danshen, Pueraria Root, and ginseng, and further analyzed the active ingredients that play key roles in the treatment of cardiomyopathy. Specifically, our study revealed significant interaction activity at the molecular level of active ingredients such as calycosin, formononetin, and beta-sitosterol, which were strongly validated by sophisticated molecular docking experiments. These active ingredients can be precisely combined with 14 core targets (such as AKT1, TP53, IL6, and other key proteins), which not only reveals their potential therapeutic mechanisms but also provides direct and solid scientific support for the application of TCM in the treatment of cardiomyopathy. It is helpful to develop new TCM preparations further and provide more treatment options for patients with cardiomyopathy.
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Affiliation(s)
- Si-Hui Yang
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guian New Area, People's Republic of China
| | - Shuai-Nan Zhang
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guian New Area, People's Republic of China
| | - Xu-Zhao Li
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guian New Area, People's Republic of China
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10
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Han S, Zhang YY, Geng J. Case Report: A novel variant of the TTN gene and two other rare variants in a Chinese patient with dilated cardiomyopathy. Front Cardiovasc Med 2025; 12:1527544. [PMID: 40271130 PMCID: PMC12014737 DOI: 10.3389/fcvm.2025.1527544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 03/17/2025] [Indexed: 04/25/2025] Open
Abstract
Genetic factors are estimated to cause approximately 30%-50% of dilated cardiomyopathy (DCM) cases, with Titin (TTN) being the most commonly implicated gene, accounting for 20%-25% of genetic causes. Many DCM-causing TTN mutations are heterozygous truncating variants, including frameshift, non-sense, and essential splice site mutations. SCN5A mutations are associated with arrhythmias, while pathogenic variants in the low-density lipoprotein receptor (LDLR) gene are associated with familial hypercholesterolemia. Here, we report a case of DCM with a novel TTN variant, as well as two rare variants in the SCN5A and LDLR genes. It is rare for a patient to have three rare genetic variations and this may expand the genetic map of DCM and TTN, offering important insights for future studies on their genetic and disease relationships.
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Affiliation(s)
| | - Ying-Yi Zhang
- Department of Cardiology, Chest Hospital, Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin University, Tianjin, China
| | - Jie Geng
- Department of Cardiology, Chest Hospital, Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin University, Tianjin, China
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11
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Wang X, Lang Z, Yan Z, Xu J, Zhang J, Jiao L, Zhang H. Dilated cardiomyopathy: from genes and molecules to potential treatments. Mol Cell Biochem 2025:10.1007/s11010-025-05269-0. [PMID: 40155570 DOI: 10.1007/s11010-025-05269-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 03/22/2025] [Indexed: 04/01/2025]
Abstract
Dilated cardiomyopathy is a myocardial condition marked by the enlargement of the heart's ventricular chambers and the gradual decline in systolic function, frequently resulting in congestive heart failure. Dilated cardiomyopathy has obvious familial characteristics, and mutations in related pathogenic genes can account for about 50% of patients with dilated cardiomyopathy. The most common genes related to dilated cardiomyopathy include TTN, LMNA, MYH7, etc. With more and more research on these genes, it will undoubtedly provide more potential targets and therapeutic pathways for the treatment of dilated cardiomyopathy. In addition, myocardial inflammation, myocardial metabolism abnormalities and cardiomyocyte apoptosis all have an important impact on the pathogenesis of dilated cardiomyopathy. Approximately half of sudden deaths among children and adolescents, along with the majority of patients undergoing heart transplantation, stem from cardiomyopathy. Therefore, precise and prompt clinical diagnosis holds paramount importance. Currently, diagnosis primarily hinges on the patient's medical background and imaging tests, with the significance of genetic testing steadily gaining prominence. The primary treatment for dilated cardiomyopathy remains heart transplantation. However, the scarcity of donors and the risk of severe immune rejection underscore the pressing need for novel therapies. Presently, research is actively exploring preclinical treatments like stem cell therapy as potential solutions.
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Affiliation(s)
- Xiumei Wang
- Department of Anesthesiology and Operating Theater, The First Hospital of Lanzhou University, Lanzhou, 730000, The People's Republic of China
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, The People's Republic of China
| | - Zekun Lang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, The People's Republic of China
| | - Zeyi Yan
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, The People's Republic of China
| | - Jing Xu
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, The People's Republic of China
| | - Jinyuan Zhang
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, The People's Republic of China
| | - Lianhang Jiao
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, The People's Republic of China
| | - Haijun Zhang
- Department of Anesthesiology and Operating Theater, The First Hospital of Lanzhou University, Lanzhou, 730000, The People's Republic of China.
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, The People's Republic of China.
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12
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Ghazal R, Wang M, Liu D, Tschumperlin DJ, Pereira NL. Cardiac Fibrosis in the Multi-Omics Era: Implications for Heart Failure. Circ Res 2025; 136:773-802. [PMID: 40146800 PMCID: PMC11949229 DOI: 10.1161/circresaha.124.325402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Cardiac fibrosis, a hallmark of heart failure and various cardiomyopathies, represents a complex pathological process that has long challenged therapeutic intervention. High-throughput omics technologies have begun revolutionizing our understanding of the molecular mechanisms driving cardiac fibrosis and are providing unprecedented insights into its heterogeneity and progression. This review provides a comprehensive analysis of how techniques-encompassing genomics, epigenomics, transcriptomics, proteomics, and metabolomics-are providing insight into our understanding of cardiac fibrosis. Genomic studies have identified novel genetic variants and regulatory networks associated with fibrosis susceptibility and progression, and single-cell transcriptomics has unveiled distinct cardiac fibroblast subpopulations with unique molecular signatures. Epigenomic profiling has revealed dynamic chromatin modifications controlling fibroblast activation states, and proteomic analyses have identified novel biomarkers and potential therapeutic targets. Metabolomic studies have uncovered important alterations in cardiac energetics and substrate utilization during fibrotic remodeling. The integration of these multi-omic data sets has led to the identification of previously unrecognized pathogenic mechanisms and potential therapeutic targets, including cell-type-specific interventions and metabolic modulators. We discuss how these advances are driving the development of precision medicine approaches for cardiac fibrosis while highlighting current challenges and future directions in translating multi-omic insights into effective therapeutic strategies. This review provides a systems-level perspective on cardiac fibrosis that may inform the development of more effective, personalized therapeutic approaches for heart failure and related cardiovascular diseases.
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Affiliation(s)
- Rachad Ghazal
- Departments of Cardiovascular Diseases (R.G., N.L.P.), Mayo Clinic, Rochester, MN
| | - Min Wang
- Molecular Pharmacology and Experimental Therapeutics (M.W., D.L., N.L.P.), Mayo Clinic, Rochester, MN
| | - Duan Liu
- Molecular Pharmacology and Experimental Therapeutics (M.W., D.L., N.L.P.), Mayo Clinic, Rochester, MN
| | | | - Naveen L. Pereira
- Departments of Cardiovascular Diseases (R.G., N.L.P.), Mayo Clinic, Rochester, MN
- Molecular Pharmacology and Experimental Therapeutics (M.W., D.L., N.L.P.), Mayo Clinic, Rochester, MN
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13
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Panicker JS, Chiramel SJ. Co-existence of RBM20 and KCNQ1 gene mutations in a patient with long QT syndrome and dilated cardiomyopathy. "Which came first: Chicken or the egg?". Indian Pacing Electrophysiol J 2025:S0972-6292(25)00023-3. [PMID: 40158693 DOI: 10.1016/j.ipej.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/02/2025] Open
Abstract
A 60-year-old female patient was taken to the emergency department with a history of syncope. ECG revealed polymorphic ventricular tachycardia which necessitated recurrent DC cardioversion. Post-reversion ECG showed sinus rhythm with prolonged corrected QTc. Bedside transthoracic echocardiogram revealed features suggestive of dilated cardiomyopathy (DCM) with severe left ventricular dysfunction. Next reversion to VT was managed with intravenous propranolol and DC cardioversion after which she remained in sinus rhythm. After the initiation of beta-blocker, she developed sinus bradycardia followed by complete heart block. The concern we had while managing this case was whether the DCM caused the VT {then why long QTc?} OR was the long QTc causing DCM {due to same gene mutation}. Genetic analysis revealed the simultaneous occurrence of KCNQ1 and RBM20 mutation. Regarding the treatment given to our patient, we continued beta-blocker, left bundle branch optimized implantable cardioverter defibrillator {LOT - Dx ICD} was done with atrial sensing, the right ventricular coil as the defibrillator, and left bundle branch area pacing. In our patient, any of the two mutations could explain the occurrence of both DCM and long QTc. However genetic analysis revealed the simultaneous presence of both RBM20 and KCNQ1 mutation. To the best of our knowledge, this is the first report in the medical literature on the co-existence of RBM20 and KCNQ1 mutation.
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Affiliation(s)
- Jithin S Panicker
- Department of Cardiology, Government Medical College, Kozhikode, Kerala, India.
| | - Sam Jacob Chiramel
- Department of Cardiology, Government Medical College, Kozhikode, Kerala, India.
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14
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Shao W, Liu L, Gu J, Yang Y, Wu Y, Zhang Z, Xu Q, Wang Y, Shen Y, Gu L, Cheng Y, Zhang H. Spotlight on mechanism of sudden unexpected death in epilepsy in Dravet syndrome. Transl Psychiatry 2025; 15:84. [PMID: 40097380 PMCID: PMC11914262 DOI: 10.1038/s41398-025-03304-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 02/17/2025] [Accepted: 03/06/2025] [Indexed: 03/19/2025] Open
Abstract
Dravet syndrome (DS) is a severe and catastrophic epilepsy with childhood onset. The incidence and prevalence of sudden unexpected death in epilepsy (SUDEP) are significantly higher in DS patients than in general epileptic populations. Although extensive research conducted, the underlying mechanisms of SUDEP occurring in DS patients remain unclear. This review focuses on the link between DS and SUDEP and analyzes the potential pathogenesis. We summarize the genetic basis of DS and SUDEP and elucidate the pathophysiological mechanisms of SUDEP in DS. Furthermore, given the drug-resistant nature of this disorder, the pharmacological approach has limited efficacy and often causes side effects, therefore, the non-pharmacological approaches and precise treatment can reduce the risk of SUDEP in this condition, open a new window to cure this disease, and provide a widened landscape of treatment options for patients.
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Affiliation(s)
- WeiHui Shao
- Department of Anesthesiology, the Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Lu Liu
- Department of Anesthesiology, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - JiaXuan Gu
- Department of Anesthesiology, the Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Yue Yang
- Department of Anesthesiology, the Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - YaXuan Wu
- Department of Anesthesiology, the Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - ZhuoYue Zhang
- Department of Anesthesiology, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qing Xu
- Department of Anesthesiology, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - YuLing Wang
- Department of Anesthesiology, the Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Yue Shen
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, 310006, China
| | - LeYuan Gu
- Department of Anesthesiology, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yuan Cheng
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, 310006, China.
| | - HongHai Zhang
- Department of Anesthesiology, the Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China.
- Department of Anesthesiology, Zhejiang University School of Medicine, Hangzhou, 310006, China.
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, 310006, China.
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15
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Li R, Zheng D, Lin C, Chen Y, Bai Y, Zhou N, Zhao Q, Wei W, Wu Q, Deng J, Zhao S, Yao H, Tang S, Luo B, Liu S, Quan L, Liu X, Cheng J, Huang E. Characterization of a novel SCN5A mutation associated with long QT syndrome and arrhythmogenic right ventricular cardiomyopathy in a family. Forensic Sci Med Pathol 2025; 21:33-41. [PMID: 39133258 DOI: 10.1007/s12024-024-00863-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2024] [Indexed: 08/13/2024]
Abstract
Sudden cardiac death represents a significant diagnostic challenge for forensic pathologists, particularly in inherited arrhythmia syndromes or cardiomyopathies resulting from genetic defects. Molecular autopsies can reveal the underlying molecular etiology in such cases. In this study, we investigated a family with a history of sudden cardiac death to elucidate the molecular basis responsible for sudden cardiac death. The proband underwent a comprehensive forensic examination. Family members received thorough clinical evaluations, including electrocardiogram, Holter monitoring, echocardiography, and cardiac magnetic imaging. Whole exome sequencing and genetic analysis were performed on the deceased and her parents. In addition, Western blotting and patch-clamp recordings were employed to evaluate the expression and function of the mutant protein in vitro. Forensic examination diagnosed arrhythmogenic right ventricular cardiomyopathy (ARVC) as the cause of sudden death. Genetic analysis identified a novel missense mutation in SCN5A (p.V1323L), which was assessed as likely pathogenic by the ACMG guideline. Another family member carrying the mutation manifested long QT syndrome and mild cardiac fibrosis. The cellular electrophysiological study demonstrated that the mutation resulted in an enhanced late sodium current, suggesting it was a gain-of-function mutation. This study characterizes a novel SCN5A mutation that putatively causes long QT syndrome and may contribute to the development of ARVC. Our work expands the pathogenic spectrum of SCN5A variants and underscores the importance of molecular autopsy in sudden death cases, especially in those with suspected genetic disorders.
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Affiliation(s)
- Rui Li
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Da Zheng
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chunxi Lin
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, Guangdong, China
| | - Yili Chen
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, Guangdong, China
| | - Yang Bai
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Nan Zhou
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China
- Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China
- Guangzhou Key Laboratory of Molecular Mechanisms and Translation in Major Cardiovascular Disease, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qianhao Zhao
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenzhao Wei
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qiuping Wu
- Division of Forensic Medicine, Department of Pathology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiacheng Deng
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuquan Zhao
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hui Yao
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuangbo Tang
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bin Luo
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuiping Liu
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Li Quan
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaoshan Liu
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Jianding Cheng
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Erwen Huang
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
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16
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Hu RC, Zhang Y, Nitschke L, Johnson SJ, Hurley AE, Lagor WR, Xia Z, Cooper TA. MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model. J Clin Invest 2025; 135:e186416. [PMID: 39932794 PMCID: PMC11957708 DOI: 10.1172/jci186416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explored MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile dysfunction, hypertrophy, and misregulated alternative splicing and gene expression. While robust, the rescue was partial compared with reduced CUGexp RNA and plateaued with increased exogenous MBNL expression. These findings demonstrate that MBNL loss is a major contributor to DM1 cardiac manifestations and suggest that additional mechanisms play a role, highlighting the complex nature of DM1 pathogenesis.
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Affiliation(s)
- Rong-Chi Hu
- Department of Pathology and Immunology, and
- Department of Integrative Physiology, Baylor College of Medicine, Houston, Texas, USA
| | - Yi Zhang
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA
| | | | - Sara J. Johnson
- Department of Pathology and Immunology, and
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Ayrea E. Hurley
- Department of Integrative Physiology, Baylor College of Medicine, Houston, Texas, USA
| | - William R. Lagor
- Department of Integrative Physiology, Baylor College of Medicine, Houston, Texas, USA
| | - Zheng Xia
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA
- Center for Biomedical Data Science, Oregon Health and Science University, Portland, Oregon, USA
| | - Thomas A. Cooper
- Department of Pathology and Immunology, and
- Department of Integrative Physiology, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
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17
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Aizawa T, Makiyama T, Huang H, Imamura T, Fukuyama M, Sonoda K, Kato K, Hisamatsu T, Nakamura Y, Hoshino K, Ozawa J, Suzuki H, Yasuda K, Aoki H, Kurita T, Yoshida Y, Suzuki T, Nakamura Y, Ogawa Y, Yamagami S, Morita H, Yuasa S, Fukuda M, Ono M, Kondo H, Takahashi N, Ohno S, Nakagawa Y, Ono K, Horie M. SCN5A variant type-dependent risk prediction in Brugada syndrome. Europace 2025; 27:euaf024. [PMID: 39931825 PMCID: PMC11844247 DOI: 10.1093/europace/euaf024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 01/18/2025] [Indexed: 02/22/2025] Open
Abstract
AIMS The variant in SCN5A with the loss of function (LOF) effect in the cardiac Na+ channel (Nav1.5) is the definitive cause for Brugada syndrome (BrS), and the functional analysis data revealed that LOF variants are associated with poor prognosis. However, which variant types (e.g. missense or non-missense) affect the prognoses of those variant carriers remain unelucidated. METHODS AND RESULTS We defined SCN5A LOF variants as all non-missense and missense variants that produce peak INa < 65% of wild-type previously confirmed by patch-clamp studies. The study population consisted of 76 Japanese BrS patients (74% patients were male and the median age [IQR] at diagnosis was 28 [14-45] years) with LOF type of SCN5A variants: 40 with missense and 36 with non-missense variants. Non-missense variant carriers presented significantly more severe cardiac conduction disorder compared to the missense variant carriers. During follow-up periods of 9.0 [5.0-14.0] years, compared to missense variants, non-missense variants were significant risk factors of lifetime lethal arrhythmia events (LAEs) (P = 0.023). When focusing only on the missense variants that produce no peak INa, these missense variant carriers exhibited the same clinical outcomes as those with non-missense (log-rank P = 0.325). After diagnosis, however, both variant types were comparable in risk of LAEs (P = 0.155). CONCLUSION We identified, for the first time, that SCN5A non-missense variants were associated with higher probability of LAE than missense variants in BrS patients though it did not change significantly after diagnosis.
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Affiliation(s)
- Takanori Aizawa
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Takeru Makiyama
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hai Huang
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomohiko Imamura
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Megumi Fukuyama
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Keiko Sonoda
- Medical Genome Center, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Koichi Kato
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Takashi Hisamatsu
- Department of Public Health, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Yuko Nakamura
- Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan
| | - Kenji Hoshino
- Department of Cardiology, Saitama Children’s Medical Center, Saitama, Japan
| | - Junichi Ozawa
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hiroshi Suzuki
- Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Kazushi Yasuda
- Department of Pediatric Cardiology, Aichi Children’s Health and Medical Center, Obu, Japan
| | - Hisaaki Aoki
- Department of Pediatric Cardiology, Osaka Women’s and Children’s Hospital, Izumi, Japan
| | - Takashi Kurita
- Division of Cardiovascular Center, Kindai University School of Medicine, Osakasayama, Japan
| | - Yoko Yoshida
- Division of Pediatric Cardiology and Electrophysiology, Osaka City General Hospital, Osaka, Japan
| | - Tsugutoshi Suzuki
- Division of Pediatric Cardiology and Electrophysiology, Osaka City General Hospital, Osaka, Japan
| | - Yoshihide Nakamura
- Division of Pediatric Cardiology and Electrophysiology, Osaka City General Hospital, Osaka, Japan
| | - Yoshiharu Ogawa
- Division of Cardiology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan
| | | | - Hiroshi Morita
- Department of Cardiovascular Therapeutics, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Shinsuke Yuasa
- Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masakazu Fukuda
- Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Makoto Ono
- Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hidekazu Kondo
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu, Japan
| | - Naohiko Takahashi
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu, Japan
| | - Seiko Ohno
- Medical Genome Center, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Yoshihisa Nakagawa
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Koh Ono
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Minoru Horie
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan
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18
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Tunca Sahin G, Kurt CC, Kafali HC, Sevinc Sengul F, Haydin S, Ozgur S, Guzeltas A, Ergul Y. Sinus node dysfunction in children: different aetiologies, similar clinical course in two-centre experience. Cardiol Young 2025; 35:297-302. [PMID: 39555893 DOI: 10.1017/s1047951124025952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
AIM This study aims to evaluate the clinical characteristics and outcomes of children diagnosed with sinus node dysfunction. METHODS This was a retrospective review of patients diagnosed with sinus node dysfunction in two tertiary paediatric cardiology centres in Turkey from January 2011 to June 2022. RESULTS In all, 77 patients (50, 64.9% males) were included, with a mean age of 8.2 ± 6.3 years and a mean weight of 28.2 ± 18.8 kg. While age-incompatible bradycardia and pauses were the most common rhythm disturbances, syncope, presyncope, and dizziness (n:33, 43%) were the most frequent initial symptoms. Structural heart disease was present in 58 (75.3%) of the 77 patients, 47 (61%) of whom were congenital. The most commonly associated CHDs were transposition of the great arteries (n:8), atrial septal defect (n:7), and atrioventricular septal defect (n:5). Seven of them also had left atrial isomerism. The remaining 19 patients were isolated. Four patients had SCN5A mutation (two of them were siblings) and two of them had Emery-Dreifuss muscular dystrophy. CONCLUSION Although sinus node dysfunction is rare in children, it has been diagnosed with increasing frequency with structural heart disease, especially in patients who have undergone corrective cardiac surgery related to atrial tissue. Since sinus node dysfunction can occur at any time postoperatively, these patients should be kept under constant control. If symptomatic sinus node dysfunction is confirmed, permanent pacing is an effective therapeutic modality.
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Affiliation(s)
- Gulhan Tunca Sahin
- Department of Paediatric Cardiology, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Cemil Cihad Kurt
- Department of Paediatric Cardiology, Etlik City Hospital, University of Health Sciences, Ankara, Turkey
| | - Hasan Candas Kafali
- Department of Paediatric Cardiology, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Fatma Sevinc Sengul
- Department of Paediatric Cardiology, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Sertac Haydin
- Department of Paediatric Cardiovascular Surgery, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Senem Ozgur
- Department of Paediatric Cardiology, Etlik City Hospital, University of Health Sciences, Ankara, Turkey
| | - Alper Guzeltas
- Department of Paediatric Cardiology, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Yakup Ergul
- Department of Paediatric Cardiology, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
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19
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Vouloagkas I, Agbariah A, Zegkos T, Gossios TD, Tziomalos G, Parcharidou D, Didagelos M, Kamperidis V, Ziakas A, Efthimiadis GK. The many faces of SCN5A pathogenic variants: from channelopathy to cardiomyopathy. Heart Fail Rev 2025; 30:247-256. [PMID: 39465469 DOI: 10.1007/s10741-024-10459-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/18/2024] [Indexed: 10/29/2024]
Abstract
The SCN5A gene encodes the alpha subunit of the cardiac sodium channel, which plays a fundamental role in the generation and propagation of the action potential in the heart muscle. During the past years our knowledge concerning the function of the cardiac sodium channel and the diseases caused by mutations of the SCN5A gene has grown. Although initially SCN5A pathogenic variants were mainly associated with channelopathies, increasing recent evidence suggests an association with structural heart disease in the form of heart muscle disease. The pathways leading to a cardiomyopathic phenotype remain unclear and require further elucidation. The aim of the present review is to provide a concise summary regarding the mechanisms through which SCN5A pathogenic variants result in heart disease, focusing in cardiomyopathy, highlighting along the way the complex role of the SCN5A gene at the intersection of cardiac excitability and contraction networks.
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Affiliation(s)
- Ioannis Vouloagkas
- Department of Medicine, Cantonal Hospital of Winterthur, Winterthur, Switzerland
| | - Andrea Agbariah
- Department of Cardiology, Università Degli Studi Di Verona, Verona, Italy
| | - Thomas Zegkos
- Cardiomyopathies Laboratory, 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece
| | - Thomas D Gossios
- Cardiomyopathies Laboratory, 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece.
| | - Georgios Tziomalos
- Cardiomyopathies Laboratory, 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece
| | - Despoina Parcharidou
- Cardiomyopathies Laboratory, 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece
| | - Matthaios Didagelos
- 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece
| | - Vasileios Kamperidis
- 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece
| | - Antonios Ziakas
- 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece
| | - Georgios K Efthimiadis
- Cardiomyopathies Laboratory, 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece
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20
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Hespe S, Gray B, Puranik R, Peters S, Sweeting J, Ingles J. The role of genetic testing in management and prognosis of individuals with inherited cardiomyopathies. Trends Cardiovasc Med 2025; 35:34-44. [PMID: 39004295 DOI: 10.1016/j.tcm.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024]
Abstract
Inherited cardiomyopathies are a heterogeneous group of heart muscle conditions where disease classification has traditionally been based on clinical characteristics. However, this does not always align with genotype. While there are well described challenges of genetic testing, understanding the role of genotype in patient management is increasingly required. We take a gene-by-gene approach, reviewing current evidence for the role of genetic testing in guiding prognosis and management of individuals with inherited cardiomyopathies. In particular, focusing on causal variants in genes definitively associated with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy. This review identifies genotype-specific disease sub-groups with strong evidence supporting the use of genetics in clinical management and highlights that at present, the spectrum of clinical utility is not reflected in current guidelines. Of 13 guideline or expert consensus statements for management of cardiomyopathies, there are seven gene-specific therapeutic recommendations that have been published from four documents. Understanding how genotype influences phenotype provides evidence for the role of genetic testing for prognostic and therapeutic purposes, moving us closer to precision-medicine based care.
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Affiliation(s)
- Sophie Hespe
- Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Australia
| | - Belinda Gray
- Faculty of Medicine and Health, The University of Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Rajesh Puranik
- Faculty of Medicine and Health, The University of Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Stacey Peters
- Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia
| | - Joanna Sweeting
- Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, Australia
| | - Jodie Ingles
- Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
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21
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Ohya H, Inaba O, Inamura Y, Kato K, Ohno S, Sasano T. Episodic long-lasting atrial standstill associated with an SCN5A variant resulting in atrial pacing failure: Is an atrial lead necessary for familial atrial standstill? HeartRhythm Case Rep 2025; 11:56-60. [PMID: 40330691 PMCID: PMC12049724 DOI: 10.1016/j.hrcr.2024.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2025] Open
Affiliation(s)
- Hiroaki Ohya
- Department of Cardiology, Japanese Red Cross Saitama Hospital, Saitama, Japan
| | - Osamu Inaba
- Department of Cardiology, Japanese Red Cross Saitama Hospital, Saitama, Japan
| | - Yukihiro Inamura
- Department of Cardiology, Japanese Red Cross Saitama Hospital, Saitama, Japan
| | - Koichi Kato
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Seiko Ohno
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan
- Medical Genome Center, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Tetsuo Sasano
- Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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22
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Matteucci A, Mariani MV, Sgarra L, Bonanni M, Frazzetto M, La Fazia VM, Pierucci N, Lavalle C, Pandozi C, Nardi F, Colivicchi F. Epicardial Ablation for Arrhythmogenic Disorders in Patients with Brugada Syndrome. Biomedicines 2024; 13:27. [PMID: 39857610 PMCID: PMC11762830 DOI: 10.3390/biomedicines13010027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 12/23/2024] [Accepted: 12/25/2024] [Indexed: 01/27/2025] Open
Abstract
Brugada syndrome (BrS) is an inherited arrhythmogenic disorder characterized by distinct electrocardiographic patterns and an increased risk of sudden cardiac death due to ventricular arrhythmias. Effective management of BrS is essential, particularly for high-risk patients with recurrent arrhythmias. While implantable cardioverter-defibrillator (ICD) is effective in terminating life-threatening arrhythmias, it does not prevent arrhythmia onset and can lead to complications such as inappropriate shocks. Epicardial ablation has emerged as a promising treatment option for patients with recurrent ventricular arrhythmias and frequent ICD interventions. This review examines the latest advancements in the management of Brugada syndrome, focusing on the role and rationale of epicardial ablation for the treatment of patients at risk of sudden cardiac death.
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Affiliation(s)
- Andrea Matteucci
- Clinical and Rehabilitation Cardiology Division, San Filippo Neri Hospital, 00135 Rome, Italy
- Department of Experimental Medicine, Tor Vergata University, 00133 Rome, Italy
| | - Marco Valerio Mariani
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences “Sapienza” University of Rome, 00185 Rome, Italy
| | - Luca Sgarra
- Cardiology Department, Regional General Hospital “F. Miulli”, 70021 Bari, Italy
| | - Michela Bonanni
- Department of Experimental Medicine, Tor Vergata University, 00133 Rome, Italy
- Fondazione Toscana G. Monasterio, Ospedale del Cuore, 54100 Massa, Italy
| | - Marco Frazzetto
- Division of Cardiology, Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | | | - Nicola Pierucci
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences “Sapienza” University of Rome, 00185 Rome, Italy
| | - Carlo Lavalle
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences “Sapienza” University of Rome, 00185 Rome, Italy
| | - Claudio Pandozi
- Clinical and Rehabilitation Cardiology Division, San Filippo Neri Hospital, 00135 Rome, Italy
| | - Federico Nardi
- Santo Spirito Hospital, Casale Monferrato, 15033 Alessandria, Italy
| | - Furio Colivicchi
- Clinical and Rehabilitation Cardiology Division, San Filippo Neri Hospital, 00135 Rome, Italy
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23
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Kingsmore SF, Wright M, Smith LD, Liang Y, Mowrey WR, Protopsaltis L, Bainbridge M, Baker M, Batalov S, Blincow E, Cao B, Caylor S, Chambers C, Ellsworth K, Feigenbaum A, Frise E, Guidugli L, Hall KP, Hansen C, Kiel M, Van Der Kraan L, Krilow C, Kwon H, Madhavrao L, Lefebvre S, Leipzig J, Mardach R, Moore B, Oh D, Olsen L, Ontiveros E, Owen MJ, Reimers R, Scharer G, Schleit J, Shelnutt S, Mehtalia SS, Oriol A, Sanford E, Schwartz S, Wigby K, Willis MJ, Yandell M, Kunard CM, Defay T. Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection. Am J Hum Genet 2024; 111:2618-2642. [PMID: 39642867 PMCID: PMC11639087 DOI: 10.1016/j.ajhg.2024.10.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 12/09/2024] Open
Abstract
Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives. We used the phenomenon of purifying hyperselection, which acts to decrease the frequency of SCGD causal diplotypes, to reduce false positives. Training of gene-disease-inheritance mode-diplotype tetrads in 618,290 control and affected subjects identified 293 variants or haplotypes and seven genes with variable inheritance contributing higher positive diplotype counts than consistent with purifying hyperselection and with little or no evidence of SCGD causality. With these changes, 2.0% of UKB470K adults were positive. In contrast, gNBS was positive in 7.2% of 3,118 critically ill children with suspected SCGDs and 7.9% of 705 infant deaths. When compared with rapid diagnostic genome sequencing (RDGS), gNBS had 99.1% recall. In eight true-positive children, gNBS was projected to decrease time to diagnosis by a median of 121 days and avoid life-threatening disease presentations in four children, organ damage in six children, ∼$1.25 million in healthcare cost, and ten (1.4%) infant deaths. Federated training predicated on purifying hyperselection provides a general framework to attain high precision in population screening. Federated training across many biobanks and clinical trials can provide a privacy-preserving mechanism for qualification of gNBS in diverse genetic ancestries.
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Affiliation(s)
- Stephen F Kingsmore
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA.
| | - Meredith Wright
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Laurie D Smith
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | - Yupu Liang
- Alexion, AstraZeneca Rare Disease, Boston, MA 02210, USA
| | | | - Liana Protopsaltis
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Matthew Bainbridge
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Mei Baker
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA
| | - Sergey Batalov
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Eric Blincow
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Bryant Cao
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Sara Caylor
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Christina Chambers
- Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA
| | - Katarzyna Ellsworth
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Annette Feigenbaum
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA; Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA
| | - Erwin Frise
- Fabric Genomics, Inc., Oakland, CA 94612, USA
| | - Lucia Guidugli
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | | | - Christian Hansen
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Mark Kiel
- Genomenon Inc., Ann Arbor, MI 48108, USA
| | - Lucita Van Der Kraan
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | | | - Hugh Kwon
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Lakshminarasimha Madhavrao
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | | | | | - Rebecca Mardach
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA; Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA
| | - Barry Moore
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84132, USA
| | - Danny Oh
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Lauren Olsen
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Eric Ontiveros
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Mallory J Owen
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Rebecca Reimers
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Scripps Research Translational Institute, La Jolla, CA 92037, USA
| | - Gunter Scharer
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | - Jennifer Schleit
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | | | | | - Albert Oriol
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Erica Sanford
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | | | - Kristen Wigby
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Mary J Willis
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | - Mark Yandell
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84132, USA
| | | | - Thomas Defay
- Alexion, AstraZeneca Rare Disease, Boston, MA 02210, USA
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24
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Zhang X, Qiao K, Cui R, Xu M, Cai S, Huang Q, Liu Z. Tetrodotoxin: The State-of-the-Art Progress in Characterization, Detection, Biosynthesis, and Transport Enrichment. Mar Drugs 2024; 22:531. [PMID: 39728106 DOI: 10.3390/md22120531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/21/2024] [Accepted: 11/21/2024] [Indexed: 12/28/2024] Open
Abstract
Tetrodotoxin (TTX) is a neurotoxin that binds to sodium channels and blocks sodium conduction. Importantly, TTX has been increasingly detected in edible aquatic organisms. Because of this and the lack of specific antidotes, TTX poisoning is now a major threat to public health. However, it is of note that ultra-low dose TTX is an excellent analgesic with great medicinal value. These contradictory effects highlight the need for further research to elucidate the impacts and functional mechanisms of TTX. This review summarizes the latest research progress in relation to TTX sources, analogs, mechanisms of action, detection methods, poisoning symptoms, therapeutic options, biosynthesis pathways, and mechanisms of transport and accumulation in pufferfish. This review also provides a theoretical basis for reducing the poisoning risks associated with TTX and for establishing an effective system for its use and management to ensure the safety of fisheries and human health.
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Affiliation(s)
- Xinxin Zhang
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Kun Qiao
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, National Research and Development Center for Marine Fish Processing, Xiamen 361021, China
| | - Ruimin Cui
- College of Food Science and Technology, Zhejiang Ocean University, Zhoushan 316022, China
| | - Min Xu
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, National Research and Development Center for Marine Fish Processing, Xiamen 361021, China
| | - Shuilin Cai
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, National Research and Development Center for Marine Fish Processing, Xiamen 361021, China
| | - Qilin Huang
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhiyu Liu
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, National Research and Development Center for Marine Fish Processing, Xiamen 361021, China
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25
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Huang S, Li J, Li Q, Wang Q, Zhou X, Chen J, Chen X, Bellou A, Zhuang J, Lei L. Cardiomyopathy: pathogenesis and therapeutic interventions. MedComm (Beijing) 2024; 5:e772. [PMID: 39465141 PMCID: PMC11502724 DOI: 10.1002/mco2.772] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 10/29/2024] Open
Abstract
Cardiomyopathy is a group of disease characterized by structural and functional damage to the myocardium. The etiologies of cardiomyopathies are diverse, spanning from genetic mutations impacting fundamental myocardial functions to systemic disorders that result in widespread cardiac damage. Many specific gene mutations cause primary cardiomyopathy. Environmental factors and metabolic disorders may also lead to the occurrence of cardiomyopathy. This review provides an in-depth analysis of the current understanding of the pathogenesis of various cardiomyopathies, highlighting the molecular and cellular mechanisms that contribute to their development and progression. The current therapeutic interventions for cardiomyopathies range from pharmacological interventions to mechanical support and heart transplantation. Gene therapy and cell therapy, propelled by ongoing advancements in overarching strategies and methodologies, has also emerged as a pivotal clinical intervention for a variety of diseases. The increasing number of causal gene of cardiomyopathies have been identified in recent studies. Therefore, gene therapy targeting causal genes holds promise in offering therapeutic advantages to individuals diagnosed with cardiomyopathies. Acting as a more precise approach to gene therapy, they are gradually emerging as a substitute for traditional gene therapy. This article reviews pathogenesis and therapeutic interventions for different cardiomyopathies.
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Affiliation(s)
- Shitong Huang
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Jiaxin Li
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Qiuying Li
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Qiuyu Wang
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Xianwu Zhou
- Department of Cardiovascular SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Jimei Chen
- Department of Cardiovascular SurgeryGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Cardiovascular SurgeryGuangdong Provincial Key Laboratory of South China Structural Heart DiseaseGuangzhouChina
| | - Xuanhui Chen
- Department of Medical Big Data CenterGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Abdelouahab Bellou
- Department of Emergency Medicine, Institute of Sciences in Emergency MedicineGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Emergency MedicineWayne State University School of MedicineDetroitMichiganUSA
| | - Jian Zhuang
- Department of Cardiovascular SurgeryGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Cardiovascular SurgeryGuangdong Provincial Key Laboratory of South China Structural Heart DiseaseGuangzhouChina
| | - Liming Lei
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Cardiovascular SurgeryGuangdong Provincial Key Laboratory of South China Structural Heart DiseaseGuangzhouChina
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26
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Cazzato F, Coll M, Grassi S, Fernàndez-Falgueras A, Nogué-Navarro L, Iglesias A, Castellà J, Oliva A, Brugada R. Investigating cardiac genetic background in sudden infant death syndrome (SIDS). Int J Legal Med 2024; 138:2229-2237. [PMID: 38849547 PMCID: PMC11490465 DOI: 10.1007/s00414-024-03264-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 05/30/2024] [Indexed: 06/09/2024]
Abstract
Sudden infant death syndrome (SIDS) is still the leading cause of death for newborns in developed countries. The pathophysiological mechanisms have not been fully clarified, but in some of SIDS cases variants of genes associated with inherited cardiac conditions are found. In this study, an analysis of SCD-related genes was performed to determine the prevalence of rare pathogenic (P) or likely pathogenic (LP) variants that could provide an unambiguous explanation for the fatal event. A cohort of 76 SIDS cases underwent Next-Generation Sequencing (NGS) analysis with a custom panel of SCD-related genes. Rare variants were classified according to the guidelines provided by the American College of Medical Genetics and Genomics (ACMG) and the specifications of the ClinGen association. Post-mortem genetic testing identified 50 (65.8%) carriers of at least one variant in SCD genes. 104 rare genetic variants were found, 65.4% in genes encoding structural proteins. Only 4 out of 76 cases (5.3%) hosted at least a P or LP variant found in genes with structural or structural/arrhythmogenic functions (SLC22A5, SCN5A, MYL3and TTN). 99 variants were classified as of uncertain significance (VUS). The difference in the distribution of variants between gene groups by function was not statistically significant (chi square, p = 0,219). Despite this, most of the variants concerned structural genes that were supposed to have a close interaction with ion channels, thus providing an explanation for the arrhythmic event. Segregation analysis, reclassification of VUS variants and identification of new associated genes could clarify the implications of the current findings.
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Affiliation(s)
- Francesca Cazzato
- Department of Health Surveillance and Bioethics, Section of Legal Medicine, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
| | - Mònica Coll
- Cardiovascular Genetics Centre, University of Girona-IDIBGI, 17190, Salt, Spain
| | - Simone Grassi
- Department of Health Sciences, Section of Forensic Medical Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy.
| | | | - Laia Nogué-Navarro
- Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic 08500, Can Baumann, Spain
| | - Anna Iglesias
- Cardiovascular Genetics Centre, University of Girona-IDIBGI, 17190, Salt, Spain
| | - Josep Castellà
- Forensic Pathology Service, Institut Medicina Legal Ciències Mèdiques Catalunya, Barcelona, Spain
| | - Antonio Oliva
- Department of Health Surveillance and Bioethics, Section of Legal Medicine, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
| | - Ramon Brugada
- Cardiovascular Genetics Centre, University of Girona-IDIBGI, 17190, Salt, Spain
- Cardiology Department, Hospital Universitari Doctor Josep Trueta, 17003, Girona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain
- Medical Science Department, School of Medicine, University of Girona, 17003, Girona, Spain
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27
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Newman NA, Burke MA. Dilated Cardiomyopathy: A Genetic Journey from Past to Future. Int J Mol Sci 2024; 25:11460. [PMID: 39519012 PMCID: PMC11546582 DOI: 10.3390/ijms252111460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation. Cases without an identified secondary cause are classified as idiopathic dilated cardiomyopathy (IDC). Over the last 35 years, many cases of IDC have increasingly been recognized to be genetic in etiology with a core set of definitively causal genes in up to 40% of cases. While over 200 genes have been associated with DCM, the evidence supporting pathogenicity for most remains limited. Further, rapid advances in sequencing and bioinformatics have recently revealed a complex genetic spectrum ranging from monogenic to polygenic in DCM. These advances have also led to the discovery of causal and modifier genetic variants in secondary forms of DCM (e.g., alcohol-induced cardiomyopathy). Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies (e.g., device placement in LMNA cardiomyopathy). The future of genetics in DCM will likely involve polygenic risk scores, direct-to-consumer testing, and pharmacogenetics, requiring providers to have a thorough understanding of this rapidly developing field. Herein we outline three decades of genetics in DCM, summarize recent advances, and project possible future avenues for the field.
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Affiliation(s)
- Noah A. Newman
- Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Michael A. Burke
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA
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28
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Tarantino A, Ciconte G, Melgari D, Frosio A, Ghiroldi A, Piccoli M, Villa M, Creo P, Calamaio S, Castoldi V, Coviello S, Micaglio E, Cirillo F, Locati ET, Negro G, Boccellino A, Mastrocinque F, Ćalović Ž, Ricagno S, Leocani L, Vicedomini G, Santinelli V, Rivolta I, Anastasia L, Pappone C. NaV1.5 autoantibodies in Brugada syndrome: pathogenetic implications. Eur Heart J 2024; 45:4336-4348. [PMID: 39078224 PMCID: PMC11491155 DOI: 10.1093/eurheartj/ehae480] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/22/2024] [Accepted: 07/15/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND AND AIMS Patients suffering from Brugada syndrome (BrS) are predisposed to life-threatening cardiac arrhythmias. Diagnosis is challenging due to the elusive electrocardiographic (ECG) signature that often requires unconventional ECG lead placement and drug challenges to be detected. Although NaV1.5 sodium channel dysfunction is a recognized pathophysiological mechanism in BrS, only 25% of patients have detectable SCN5A variants. Given the emerging role of autoimmunity in cardiac ion channel function, this study explores the presence and potential impact of anti-NaV1.5 autoantibodies in BrS patients. METHODS Using engineered HEK293A cells expressing recombinant NaV1.5 protein, plasma from 50 BrS patients and 50 controls was screened for anti-NaV1.5 autoantibodies via western blot, with specificity confirmed by immunoprecipitation and immunofluorescence. The impact of these autoantibodies on sodium current density and their pathophysiological effects were assessed in cellular models and through plasma injection in wild-type mice. RESULTS Anti-NaV1.5 autoantibodies were detected in 90% of BrS patients vs. 6% of controls, yielding a diagnostic area under the curve of .92, with 94% specificity and 90% sensitivity. These findings were consistent across varying patient demographics and independent of SCN5A mutation status. Electrophysiological studies demonstrated a significant reduction specifically in sodium current density. Notably, mice injected with BrS plasma showed Brugada-like ECG abnormalities, supporting the pathogenic role of these autoantibodies. CONCLUSIONS The study demonstrates the presence of anti-NaV1.5 autoantibodies in the majority of BrS patients, suggesting an immunopathogenic component of the syndrome beyond genetic predispositions. These autoantibodies, which could serve as additional diagnostic markers, also prompt reconsideration of the underlying mechanisms of BrS, as evidenced by their role in inducing the ECG signature of the syndrome in wild-type mice. These findings encourage a more comprehensive diagnostic approach and point to new avenues for therapeutic research.
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Affiliation(s)
- Adriana Tarantino
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- School of Medicine, University Vita-Salute San Raffaele, Via Olgettina, 58, 20132 Milan, Italy
| | - Giuseppe Ciconte
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- School of Medicine, University Vita-Salute San Raffaele, Via Olgettina, 58, 20132 Milan, Italy
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Dario Melgari
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Anthony Frosio
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Andrea Ghiroldi
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Marco Piccoli
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Marco Villa
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Pasquale Creo
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Serena Calamaio
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Valerio Castoldi
- Experimental Neurophysiology Unit, Institute of Experimental Neurology-INSPE, IRCCS Ospedale San Raffaele, Via Olgettina, 58, 20132 Milan, Italy
| | - Simona Coviello
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Emanuele Micaglio
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Federica Cirillo
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Emanuela Teresina Locati
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Gabriele Negro
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Antonio Boccellino
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Flavio Mastrocinque
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Žarko Ćalović
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Stefano Ricagno
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Letizia Leocani
- School of Medicine, University Vita-Salute San Raffaele, Via Olgettina, 58, 20132 Milan, Italy
- Experimental Neurophysiology Unit, Institute of Experimental Neurology-INSPE, IRCCS Ospedale San Raffaele, Via Olgettina, 58, 20132 Milan, Italy
| | - Gabriele Vicedomini
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Vincenzo Santinelli
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
| | - Ilaria Rivolta
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900 Monza, Italy
| | - Luigi Anastasia
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- School of Medicine, University Vita-Salute San Raffaele, Via Olgettina, 58, 20132 Milan, Italy
| | - Carlo Pappone
- Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
- School of Medicine, University Vita-Salute San Raffaele, Via Olgettina, 58, 20132 Milan, Italy
- Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan, 2, 20097 San Donato Milanese, Milan, Italy
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Nitschke L, Hu RC, Miller AN, Cooper TA. Rescue of Scn5a mis-splicing does not improve the structural and functional heart defects of a DM1 heart mouse model. Hum Mol Genet 2024; 33:1789-1799. [PMID: 39126705 PMCID: PMC11458005 DOI: 10.1093/hmg/ddae117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/04/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant multisystemic disorder for which cardiac features, including conduction delays and arrhythmias, are the second leading cause of disease mortality. DM1 is caused by expanded CTG repeats in the 3' untranslated region of the DMPK gene. Transcription of the expanded DMPK allele produces mRNAs containing long tracts of CUG repeats, which sequester the Muscleblind-Like family of RNA binding proteins, leading to their loss-of-function and the dysregulation of alternative splicing. A well-characterized mis-regulated splicing event in the DM1 heart is the increased inclusion of SCN5A exon 6A rather than the mutually exclusive exon 6B that normally predominates in adult heart. As previous work showed that forced inclusion of Scn5a exon 6A in mice recapitulates cardiac DM1 phenotypes, we tested whether rescue of Scn5a mis-splicing would improve the cardiac phenotypes in a DM1 heart mouse model. We generated mice lacking Scn5a exon 6A to force the expression of the adult SCN5A isoform including exon 6B and crossed these mice to our previously established CUG960 DM1 heart mouse model. We showed that correction Scn5a mis-splicing does not improve the DM1 heart conduction delays and structural changes induced by CUG repeat RNA expression. Interestingly, we found that in addition to Scn5a mis-splicing, Scn5a expression is reduced in heart tissues of CUG960 mice and DM1-affected individuals. These data indicate that Scn5a mis-splicing is not the sole driver of DM1 heart deficits and suggest a potential role for reduced Scn5a expression in DM1 cardiac disease.
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Affiliation(s)
- Larissa Nitschke
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
| | - Rong-Chi Hu
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
| | - Andrew N Miller
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
| | - Thomas A Cooper
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
- Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
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30
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Wang XC, Zhou Y, Chen HX, Hou HT, He GW, Yang Q. ER stress modulates Kv1.5 channels via PERK branch in HL-1 atrial myocytes: Relevance to atrial arrhythmogenesis and the effect of tetramethylpyrazine. Heliyon 2024; 10:e37767. [PMID: 39318794 PMCID: PMC11420496 DOI: 10.1016/j.heliyon.2024.e37767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/05/2024] [Accepted: 09/09/2024] [Indexed: 09/26/2024] Open
Abstract
Endoplasmic reticulum (ER) stress is implicated in cardiac arrhythmia whereas the associated mechanisms remain inadequately understood. Kv1.5 channels are essential for atrial repolarization. Whether ER stress affects Kv1.5 channels is unknown. This study aimed to elucidate the response of Kv1.5 channels to ER stress by clarifying the unfolded protein response (UPR) branch responsible for the channel modulation. In addition, the effect of tetramethylpyrazine (TMP) on Kv1.5 channels was studied. Patch clamp and western-blot results revealed that exposure of HL-1 atrial myocytes to ER stress inducer tunicamycin upregulates Kv1.5 expression, increases Kv1.5 channel current (I Kur ) (14.91 ± 1.11 vs. 6.11 ± 1.31 pA/pF, P < 0.001), and shortened action potential duration (APD) (APD90: 82.79 ± 5.25 vs.121.11 ± 6.72 ms, P < 0.01), which could be reverted by ER stress inhibitors. Blockade of the PERK branch while not IRE1 and ATF6 branches of UPR downregulated Kv1.5 expression, accompanied by a decreased I Kur (9.03 ± 0.99 pA/pF) and a prolonged APD90 (113.69 ± 4.41 ms) (P < 0.01). PERK-mediated increases of Kv1.5 expression and I Kur were also observed in HL-1 cells incubated with thapsigargin. TMP suppressed the enhancement of I Kur (10.52 ± 0.97 vs. 17.52 ± 2.25 pA/pF, P < 0.05), prevented the shortening of APD (APD90: 110.16 ± 5.36 vs. 84.84 ± 4.58 ms, P < 0.05), and inhibited the upregulation of Kv1.5 triggered by ER stress. Our study suggests that ER stress induces upregulation and activation of Kv1.5 channels in atrial myocytes through the PERK branch of UPR. TMP prevents Kv1.5 upregulation/activation and the resultant APD shortening by inhibiting ER stress. These results may shed light on the mechanisms of atrial arrhythmogenesis and the antiarrhythmic effect of the traditional Chinese herb TMP.
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Affiliation(s)
- Xiang-Chong Wang
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin, 300457, China
- Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China
- Department of Pharmacology, Hebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Hebei International Cooperation Center for Ion channel Function and Innovative Traditional Chinese Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050091, China
- School of Medicine, Nankai University, Tianjin, 300457, China
| | - Yang Zhou
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin, 300457, China
- Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China
| | - Huan-Xin Chen
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin, 300457, China
- Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China
| | - Hai-Tao Hou
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin, 300457, China
- Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China
| | - Guo-Wei He
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin, 300457, China
- Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China
| | - Qin Yang
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin, 300457, China
- Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China
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31
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Akbari Ahangar A, Elhanafy E, Blanton H, Li J. Mapping structural distribution and gating-property impacts of disease-associated mutations in voltage-gated sodium channels. iScience 2024; 27:110678. [PMID: 39286500 PMCID: PMC11404175 DOI: 10.1016/j.isci.2024.110678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 06/18/2024] [Accepted: 08/02/2024] [Indexed: 09/19/2024] Open
Abstract
Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, cardiac arrhythmia, and pain disorders. Yet, the effects of more variants remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications are frequently employed to interpret mutations' effects and guide therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar GoF/LoF effects can stem from unique molecular mechanisms. Utilizing UniProt data, we mapped over 2,400 disease-associated missense mutations across Nav channels. This analysis pinpoints key mutation hotspots and maps patterns of gating-property impacts for the mutations, respectively, located around the selectivity filter, activation gate, fast inactivation region, and voltage-sensing domains. This study shows great potential to enhance prediction accuracy for mutational effects based on the structural context, paving the way for targeted drug design in precision medicine.
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Affiliation(s)
- Amin Akbari Ahangar
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
| | - Eslam Elhanafy
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
| | - Hayden Blanton
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
| | - Jing Li
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
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32
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Djemai M, Jalouli M, Chahine M. Impacts of DCM-linked gating pore currents on the electrophysiological characteristics of hiPSC-CM monolayers. Biochem Biophys Res Commun 2024; 723:150175. [PMID: 38820625 DOI: 10.1016/j.bbrc.2024.150175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND Variants of the SCN5A gene, which encodes the NaV1.5 cardiac sodium channel, have been linked to arrhythmic disorders associated with dilated cardiomyopathy (DCM). However, the precise pathological mechanisms remain elusive. The present study aimed to elucidate the pathophysiological consequences of the DCM-linked Nav1.5/R219H variant, which is known to generate a gating pore current, using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cultured in monolayers. METHODS Ventricular- and atrial-like hiPSC-CM monolayers were generated from DCM patients carrying the R219H SCN5A variant as well as from healthy control individuals. CRISPR-corrected hiPSC-CMs served as isogenic controls. Simultaneous optical mapping of action potentials (APs) and calcium transients (CaTs) was employed to measure conduction velocities (CVs) and AP durations (APDs) and served as markers of electrical excitability. Calcium handling was evaluated by assessing CaT uptake (half-time to peak), recapture (tau of decay), and durations (TD50 and TD80). A multi-electrode array (MEA) analysis was conducted on hiPSC-CM monolayers to measure field potential (FP) parameters, including corrected Fridericia FP durations (FPDc). RESULTS Our results revealed that CVs were significantly reduced by more than 50 % in both ventricular- and atrial-like hiPSC-CM monolayers carrying the R219H variant compared to the control group. APDs were also prolonged in the R219H group compared to the control and CRISPR-corrected groups. CaT uptake, reuptake, and duration were also markedly delayed in the R219H group compared to the control and CRISPR-corrected groups in both the ventricular- and the atrial-like hiPSC-CM monolayers. Lastly, the MEA data revealed a notably prolonged FPDc in the ventricular- and atrial-like hiPSC-CMs carrying the R219H variant compared to the control and isogenic control groups. CONCLUSIONS These findings highlight the impact of the gating pore current on AP propagation and calcium homeostasis within a functional syncytium environment and offer valuable insights into the potential mechanisms underlying DCM pathophysiology.
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Affiliation(s)
| | - Maroua Jalouli
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
| | - Mohamed Chahine
- CERVO Brain Research Centre, Quebec City, Quebec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada.
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Verkerk L, Verkerk AO, Wilders R. Zebrafish as a Model System for Brugada Syndrome. Rev Cardiovasc Med 2024; 25:313. [PMID: 39355588 PMCID: PMC11440409 DOI: 10.31083/j.rcm2509313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 04/22/2024] [Accepted: 04/28/2024] [Indexed: 10/03/2024] Open
Abstract
Brugada syndrome (BrS) is an inheritable cardiac arrhythmogenic disease, associated with an increased risk of sudden cardiac death. It is most common in males around the age of 40 and the prevalence is higher in Asia than in Europe and the United States. The pathophysiology underlying BrS is not completely understood, but several hypotheses have been proposed. So far, the best effective treatment is the implantation of an implantable cardioverter-defibrillator (ICD), but device-related complications are not uncommon. Therefore, there is an urgent need to improve diagnosis and risk stratification and to find new treatment options. To this end, research should further elucidate the genetic basis and pathophysiological mechanisms of BrS. Several experimental models are being used to gain insight into these aspects. The zebrafish (Danio rerio) is a widely used animal model for the study of cardiac arrhythmias, as its cardiac electrophysiology shows interesting similarities to humans. However, zebrafish have only been used in a limited number of studies on BrS, and the potential role of zebrafish in studying the mechanisms of BrS has not been reviewed. Therefore, the present review aims to evaluate zebrafish as an animal model for BrS. We conclude that zebrafish can be considered as a valuable experimental model for BrS research, not only for gene editing technologies, but also for screening potential BrS drugs.
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Affiliation(s)
- Leonie Verkerk
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Arie O Verkerk
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Department of Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Ronald Wilders
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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Chen SP, Hsu CL, Chen TH, Pan LLH, Wang YF, Ling YH, Chang HC, Chen YM, Fann CSJ, Wang SJ. A genome-wide association study identifies novel loci of vertigo in an Asian population-based cohort. Commun Biol 2024; 7:1034. [PMID: 39174713 PMCID: PMC11341872 DOI: 10.1038/s42003-024-06603-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 07/18/2024] [Indexed: 08/24/2024] Open
Abstract
The contributing genetic factors of vertigo remain poorly characterized, particularly in individuals of non-European ancestries. Here we show the genetic landscape of vertigo in an Asian population-based cohort. In a two-stage genome-wide association study (Ncase = 6199; Ncontrol = 54,587), we identify vertigo-associated genomic loci in DROSHA and ZNF91/LINC01224, with the latter replicating the findings in European ancestries. Gene-based association testing corroborates these findings. Interestingly, both genes are enriched in cerebellum, a key structure receiving sensory input from the vestibular system. Subjects carrying risk alleles from lead SNPs of DROSHA and ZNF91 incur a 1.74-fold risk of vertigo than those without. Moreover, composite clinical-polygenic risk scores allow differentiation between patients and controls, yielding an area under receiver operating characteristic curve of 0.69. This study identified novel genomic loci for vertigo in an Asian population-based cohort, which may help identifying high risk subjects and provide mechanistic insight in understanding the pathogenesis of vertigo.
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Affiliation(s)
- Shih-Pin Chen
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Lin Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ting-Huei Chen
- Department of Mathematics & Statistics, Laval University, Quebec City, QC, Canada
- Cervo Brain Research Centre, Quebec City, QC, Canada
| | - Li-Ling Hope Pan
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen-Feng Wang
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Hsiang Ling
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsueh-Chen Chang
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Ming Chen
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Translational Research, Department of Medical Research, Taichung Veterans General Hospital, Taipei, Taiwan
| | | | - Shuu-Jiun Wang
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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Balla C, Margutti A, De Carolis B, Canovi L, Di Domenico A, Vivaldi I, Vitali F, De Raffele M, Malagù M, Sassone B, Biffi M, Selvatici R, Ferlini A, Gualandi F, Bertini M. Cardiac conduction disorders in young adults: Clinical characteristics and genetic background of an underestimated population. Heart Rhythm 2024; 21:1363-1369. [PMID: 38467355 DOI: 10.1016/j.hrthm.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 03/04/2024] [Accepted: 03/05/2024] [Indexed: 03/13/2024]
Abstract
BACKGROUND Cardiac conduction disorder (CCD) in patients <50 years old is a rare and mostly unknown condition. OBJECTIVE We aimed to assess clinical characteristics and genetic background of patients <50 years old with CCD of unknown origin. METHODS We retrospectively reviewed a consecutive series of patients with a diagnosis of CCD before the age of 50 years referred to our center between January 2019 and December 2021. Patients underwent complete clinical examination and genetic evaluation. RESULTS We enrolled 39 patients with a median age of 40 years (28-47 years) at the onset of symptoms. A cardiac implantable electronic device was implanted in 69% of the patients. In 15 of 39 CCD index patients (38%), we found a total of 13 different gene variations (3 pathogenic, 6 likely pathogenic, and 4 variants of uncertain significance), mostly in 3 genes (SCN5A, TRPM4, and LMNA). In our cohort, genetic testing led to the decision to implant an implantable cardioverter-defibrillator in 2 patients for the increased risk of sudden cardiac death. CONCLUSION Patients with the occurrence of CCD before the age of 50 years present with a high rate of pathologic gene variations, mostly in 3 genes (SCN5A, TRPM4, and LMNA). The presence of pathogenic variations may add information about the prognosis and lead to an individualized therapeutic approach.
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Affiliation(s)
- Cristina Balla
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (Ferrara), Italy.
| | - Alice Margutti
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Beatrice De Carolis
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (Ferrara), Italy
| | - Luca Canovi
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (Ferrara), Italy
| | - Assunta Di Domenico
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (Ferrara), Italy
| | - Ilaria Vivaldi
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Francesco Vitali
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (Ferrara), Italy
| | - Martina De Raffele
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (Ferrara), Italy
| | - Michele Malagù
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (Ferrara), Italy
| | - Biagio Sassone
- Division of Cardiology, SS.ma Annunziata Hospital, Department of Emergency, AUSL Ferrara, Cento (Ferrara), Italy
| | - Mauro Biffi
- Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Rita Selvatici
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Alessandra Ferlini
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Francesca Gualandi
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Matteo Bertini
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (Ferrara), Italy
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Huttelmaier MT, Fischer TH. [Cardiac channelopathies in the context of hereditary arrhythmia syndromes]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2024; 65:787-797. [PMID: 38977442 PMCID: PMC11269359 DOI: 10.1007/s00108-024-01751-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/26/2024] [Indexed: 07/10/2024]
Abstract
Genetic arrhythmia disorders are rare diseases; however, they are a common cause of sudden cardiac death in children, adolescents, and young adults. In principle, a distinction can be made between channelopathies and cardiomyopathies in the context of genetic diseases. This paper focuses on the channelopathies long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Early diagnosis of these diseases is essential, as drug therapy, behavioral measures, and if necessary, implantation of a cardioverter defibrillator can significantly improve the prognosis and quality of life of patients. This paper highlights the pathophysiological and genetic basis of these channelopathies, describes their clinical manifestations, and comments on the principles of diagnosis, risk stratification and therapy.
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MESH Headings
- Humans
- Arrhythmias, Cardiac/genetics
- Arrhythmias, Cardiac/diagnosis
- Arrhythmias, Cardiac/therapy
- Arrhythmias, Cardiac/physiopathology
- Channelopathies/genetics
- Channelopathies/diagnosis
- Channelopathies/therapy
- Brugada Syndrome/genetics
- Brugada Syndrome/diagnosis
- Brugada Syndrome/physiopathology
- Brugada Syndrome/therapy
- Tachycardia, Ventricular/genetics
- Tachycardia, Ventricular/therapy
- Tachycardia, Ventricular/diagnosis
- Tachycardia, Ventricular/physiopathology
- Adolescent
- Child
- Long QT Syndrome/genetics
- Long QT Syndrome/diagnosis
- Long QT Syndrome/therapy
- Long QT Syndrome/physiopathology
- Death, Sudden, Cardiac/prevention & control
- Death, Sudden, Cardiac/etiology
- Adult
- Defibrillators, Implantable
- Electrocardiography
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Affiliation(s)
- Moritz T Huttelmaier
- Medizinische Klinik 1, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland
| | - Thomas H Fischer
- Medizinische Klinik 1, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland.
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Ishihara Y, Noma T, Takeuchi M, Tani R, Ohara M, Minamino T. Inappropriate ventricular pacing-induced ventricular fibrillation in a long QT type 3 syndrome patient with implantable cardioverter-defibrillator. HeartRhythm Case Rep 2024; 10:557-560. [PMID: 39155908 PMCID: PMC11328552 DOI: 10.1016/j.hrcr.2024.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/20/2024] Open
Affiliation(s)
- Yu Ishihara
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Takahisa Noma
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Masaki Takeuchi
- Department of Clinical Engineering, Kagawa University Hospital, Kagawa, Japan
| | - Ryosuke Tani
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Minako Ohara
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tetsuo Minamino
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Tamayo-Trujillo R, Paz-Cruz E, Cadena-Ullauri S, Guevara-Ramirez P, Ruiz-Pozo VA, Ibarra-Castillo R, Laso-Bayas JL, Zambrano AK. Exploring Atrial Fibrillation: Understanding the Complex Relation Between Lifestyle and Genetic Factors. J Med Cases 2024; 15:186-194. [PMID: 39091575 PMCID: PMC11287905 DOI: 10.14740/jmc4250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 06/21/2024] [Indexed: 08/04/2024] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death worldwide across diverse ethnic groups. Among these, atrial fibrillation (AF) stands as one of the most prevalent types of arrhythmias and the primary cause of stroke. Risk factors associated with AF include alcohol consumption, aging, high blood pressure, hypertension, inflammation, and genetic factors. A family history of CVD could indicate an increased risk. Consequently, genetic, and genomic testing should be performed to identify the molecular etiology of CVDs and assess at-risk patients. It is important to note that CVDs are the results of the complex interplay of genes and environmental factors, including ethnicity. In this case, the proband's clinic story includes a history of smoking abuse for 10 years (10 cigarettes per day), obesity, hypertension, and an associated familial history. These risk factors, along with genetic variants, could trigger the early onset of AF. In recent years, genetic and genomic studies have significantly advanced our understanding of CVD etiology, given that next-generation sequencing (NGS) allows for the identification of genetic variants that could contribute to these pathologies. Furthermore, NGS facilitates early diagnosis, personalized pharmacological approaches, and identification of novel biomarkers. Thus, NGS is a valuable tool in CVD management. However, such studies are limited in Ecuador, a low- and middle-income country. Several challenges contribute to this gap, encompassing economic, infrastructural, and educational obstacles. Notably, the cost of genetic and genomic studies may also pose a barrier, restricting access to a portion of the population. In this case report, we present a 56-year-old Ecuadorian woman, who has been diagnosed with AF; however, after performing NGS no disease-associated variants were found, despite having strong clinical signs and symptoms. In summary, this case report contributes valuable insights into the complex interplay between genetic and lifestyle factors in the development and management of AF. The case report aims to underscore the potential impact of genetic variants on disease risk, even when classified as variants of uncertain significance, and the importance of an integral approach to patient care that includes genetic screening, lifestyle interventions, and tailored pharmacological treatment.
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Affiliation(s)
- Rafael Tamayo-Trujillo
- Centro de Investigacion Genetica y Genomica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
- These authors contributed equally to this work and share first authorship
| | - Elius Paz-Cruz
- Centro de Investigacion Genetica y Genomica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
- These authors contributed equally to this work and share first authorship
| | - Santiago Cadena-Ullauri
- Centro de Investigacion Genetica y Genomica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
- These authors contributed equally to this work and share first authorship
| | - Patricia Guevara-Ramirez
- Centro de Investigacion Genetica y Genomica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
- These authors contributed equally to this work and share first authorship
| | - Viviana A. Ruiz-Pozo
- Centro de Investigacion Genetica y Genomica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | | | | | - Ana Karina Zambrano
- Centro de Investigacion Genetica y Genomica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
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Ventrella N, Bianchini L, Riva S, Pizzamiglio F, Dessanai MA, Tundo F, Sattin T, De Lio F, Cellucci S, Tondo C. Novel SCN5A gene mutation in a patient affected by multifocal ectopic premature Purkinje-related contractions syndrome. ESC Heart Fail 2024; 11:2399-2404. [PMID: 38504463 PMCID: PMC11287344 DOI: 10.1002/ehf2.14677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 12/10/2023] [Accepted: 12/28/2023] [Indexed: 03/21/2024] Open
Abstract
We report the case of a 36-year-old woman who presented to the emergency department complaining of palpitations and asthenia. Investigations showed frequent ventricular ectopy and severe left ventricular ejection fraction impairment. She was diagnosed with a peculiar condition defined multifocal ectopic premature Purkinje-related contractions syndrome, which in some cases can be associated with a dilated cardiomyopathy phenotype. Genetic testing showed a novel mutation in the SCN5A gene (c.673C > G). In the context of acute left ventricular dysfunction in a young patient, we discuss the clinical presentation of this rare condition and its clinical management, as well as its genetic substrate.
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Affiliation(s)
- Nicoletta Ventrella
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Lorenzo Bianchini
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Stefania Riva
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Francesca Pizzamiglio
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Maria Antonietta Dessanai
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Fabrizio Tundo
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Tommaso Sattin
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Francesca De Lio
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Selene Cellucci
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
| | - Claudio Tondo
- Department of Clinical Electrophysiology and Cardiac PacingCentro Cardiologico Monzino, IRCCSMilanItaly
- Department of Biomedical, Surgical and Dental SciencesUniversity of MilanMilanItaly
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Cadena-Ullauri S, Guevara-Ramírez P, Ruiz-Pozo VA, Tamayo-Trujillo R, Paz-Cruz E, Simancas-Racines D, Ibarra-Castillo R, Laso-Bayas JL, Zambrano AK. Genomic analysis of an Ecuadorian individual carrying an SCN5A rare variant. BMC Cardiovasc Disord 2024; 24:388. [PMID: 39068398 PMCID: PMC11282620 DOI: 10.1186/s12872-024-04049-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 07/15/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Ion channels, vital transmembrane protein complexes, regulate ion movement within cells. Germline variants in channel-encoding genes lead to channelopathies. The sodium channels in cardiac cells exhibit a structure of an alpha subunit and one to two beta subunits. The alpha subunit, encoded by the SCN5A gene, comprises four domains. CASE PRESENTATION A fifteen-year-old Ecuadorian female with atrial flutter and abnormal sinus rhythm with no familial history of cardiovascular disease underwent NGS with the TruSight Cardio kit (Illumina). A likely pathogenic SCN5A gene variant (NM_188056.2:c.2677 C > Tp. Arg893Cys) was identified, associated with arrhythmias, long QT, atrial fibrillation, and Brugada syndrome. Ancestral analysis revealed a predominant European component (43.9%), followed by Native American (35.7%) and African (20.4%) components. CONCLUSIONS The participant presents atrial flutter and conduction disorders, despite lacking typical cardiovascular risk factors. The proband carries a SCN5A variant that has not been previously reported in Latin America and may be associated to her phenotype. The documented arginine-to-cysteine substitution at position 893 in the protein is crucial for various cellular functions. The subject's mixed genetic composition highlights potential genetic contributors to atrial flutter, emphasizing the need for comprehensive genetic studies, particularly in mixed populations like Ecuadorians. This case underscores the importance of genetic analysis for personalized treatment and the significance of studying diverse genetic backgrounds in understanding cardiovascular diseases.
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Affiliation(s)
- Santiago Cadena-Ullauri
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Patricia Guevara-Ramírez
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Viviana A Ruiz-Pozo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Rafael Tamayo-Trujillo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Elius Paz-Cruz
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Daniel Simancas-Racines
- Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | | | | | - Ana Karina Zambrano
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador.
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Arnautu DA, Cozma D, Lala IR, Arnautu SF, Tomescu MC, Andor M. Risk Assessment and Personalized Treatment Options in Inherited Dilated Cardiomyopathies: A Narrative Review. Biomedicines 2024; 12:1643. [PMID: 39200108 PMCID: PMC11351202 DOI: 10.3390/biomedicines12081643] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 07/18/2024] [Accepted: 07/19/2024] [Indexed: 09/01/2024] Open
Abstract
Considering the worldwide impact of heart failure, it is crucial to develop approaches that can help us comprehend its root cause and make accurate predictions about its outcome. This is essential for lowering the suffering and death rates connected with this widespread illness. Cardiomyopathies frequently result from genetic factors, and the study of heart failure genetics is advancing quickly. Dilated cardiomyopathy (DCM) is the most prevalent kind of cardiomyopathy, encompassing both genetic and nongenetic abnormalities. It is distinguished by the enlargement of the left ventricle or both ventricles, accompanied by reduced contractility. The discovery of the molecular origins and subsequent awareness of the molecular mechanism is broadening our knowledge of DCM development. Additionally, it emphasizes the complicated nature of DCM and the necessity to formulate several different strategies to address the diverse underlying factors contributing to this disease. Genetic variants that can be transmitted from one generation to another can be a significant contributor to causing family or sporadic hereditary DCM. Genetic variants also play a significant role in determining susceptibility for acquired triggers for DCM. The genetic causes of DCM can have a large range of phenotypic expressions. It is crucial to select patients who are most probable to gain advantages from genetic testing. The purpose of this research is to emphasize the significance of identifying genetic DCM, the relationships between genotype and phenotype, risk assessment, and personalized therapy for both those affected and their relatives. This approach is expected to gain importance once treatment is guided by genotype-specific advice and disease-modifying medications.
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Affiliation(s)
- Diana-Aurora Arnautu
- Multidisciplinary Heart Research Center, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania; (D.-A.A.); (M.-C.T.)
- Department of Internal Medicine I, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Dragos Cozma
- Department of Cardiology, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Ioan-Radu Lala
- Department of Cardiology, Western University Vasile Goldis, 310025 Arad, Romania
| | - Sergiu-Florin Arnautu
- Department of Internal Medicine I, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Mirela-Cleopatra Tomescu
- Multidisciplinary Heart Research Center, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania; (D.-A.A.); (M.-C.T.)
- Department of Internal Medicine I, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Minodora Andor
- Multidisciplinary Heart Research Center, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania; (D.-A.A.); (M.-C.T.)
- Department of Internal Medicine I, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Park NK, Choi SW, Park SJ, Woo J, Kim HJ, Kim WK, Moon SH, Park HJ, Kim SJ. Requirement of β subunit for the reduced voltage-gated Na + current of a Brugada syndrome patient having novel double missense mutation (p.A385T/R504T) of SCN5A. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2024; 28:313-322. [PMID: 38926839 PMCID: PMC11211759 DOI: 10.4196/kjpp.2024.28.4.313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/02/2024] [Accepted: 04/02/2024] [Indexed: 06/28/2024]
Abstract
Mutations within the SCN5A gene, which encodes the α-subunit 5 (NaV1.5) of the voltage-gated Na+ channel, have been linked to three distinct cardiac arrhythmia disorders: long QT syndrome type 3, Brugada syndrome (BrS), and cardiac conduction disorder. In this study, we have identified novel missense mutations (p.A385T/R504T) within SCN5A in a patient exhibiting overlap arrhythmia phenotypes. This study aims to elucidate the functional consequences of SCN5A mutants (p.A385T/R504T) to understand the clinical phenotypes. Whole-cell patch-clamp technique was used to analyze the NaV1.5 current (INa) in HEK293 cells transfected with the wild-type and mutant SCN5A with or without SCN1B co-expression. The amplitude of INa was not altered in mutant SCN5A (p.A385T/R504T) alone. Furthermore, a rightward shift of the voltage-dependent inactivation and faster recovery from inactivation was observed, suggesting a gain-of-function state. Intriguingly, the coexpression of SCN1B with p.A385T/R504T revealed significant reduction of INa and slower recovery from inactivation, consistent with the loss-of-function in Na+ channels. The SCN1B dependent reduction of INa was also observed in a single mutation p.R504T, but p.A385T co-expressed with SCN1B showed no reduction. In contrast, the slower recovery from inactivation with SCN1B was observed in A385T while not in R504T. The expression of SCN1B is indispensable for the electrophysiological phenotype of BrS with the novel double mutations; p.A385T and p.R504T contributed to the slower recovery from inactivation and reduced current density of NaV1.5, respectively.
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Affiliation(s)
- Na Kyeong Park
- Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Seong Woo Choi
- Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Korea
- Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Korea
| | - Soon-Jung Park
- Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Korea
| | - JooHan Woo
- Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Korea
- Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Korea
| | - Hyun Jong Kim
- Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Korea
- Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Korea
| | - Woo Kyung Kim
- Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Korea
- Department of Internal Medicine Graduate School of Medicine, Dongguk University, Goyang 10326, Korea
| | - Sung-Hwan Moon
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Hun-Jun Park
- Division of Cardiology, Department of Internal Medicine, Uijeonbu St.Mary’s Hospital, The Catholic University of Korea, Seoul 11765, Korea
| | - Sung Joon Kim
- Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Physiology & Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
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43
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Zhu X, Lv M, Cheng T, Zhou Y, Yuan G, Chu Y, Luan Y, Song Q, Hu Y. Bibliometric analysis of atrial fibrillation and ion channels. Heart Rhythm 2024; 21:1161-1169. [PMID: 38280618 DOI: 10.1016/j.hrthm.2024.01.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 01/29/2024]
Abstract
Atrial fibrillation (AF) is a common clinical malignant arrhythmia with an increasing global incidence. Ion channel dysfunction is an important mechanism in the development of AF. In this study, we used bibliometrics to analyze the studies of ion channels and AF, aiming to provide inspiration and reference for researchers. A total of 3179 literature citations were obtained from Web of Science core databases. Analysis software included Excel 2019, VOSviewer 1.6.16, and CiteSpace 5.7.R2. This field of research has been growing since 1985. The most active country is the United States. The University of Montreal is the most important research institution. The journal Cardiovascular Research has published the largest number of articles in this field. Stanley Nattel and Dobromir Dobrev are the most frequently cited authors. The most cited literature was published in Nature and Science. Cardiac electrophysiology, gene expression, pathogenesis of AF, and AF prevention and treatment are the hot topics for this field research. Cardiac fibrillation and catheter ablation may be future research hotspots in this field.
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Affiliation(s)
- Xueping Zhu
- Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Meng Lv
- Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tao Cheng
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Yan Zhou
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Guozhen Yuan
- Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuguang Chu
- Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yujie Luan
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Qingqiao Song
- Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Yuanhui Hu
- Guang 'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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44
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Jnani J, Gruber D, Mtisi T, Saleh M, Azari BM. Identification of a SCN5A Genetic Variant Associated With Type 1 Brugada Syndrome (BrS) in a Family. Cureus 2024; 16:e64883. [PMID: 39156269 PMCID: PMC11330683 DOI: 10.7759/cureus.64883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/16/2024] [Indexed: 08/20/2024] Open
Abstract
The Brugada pattern is associated with a genetic disorder characterized by ST-segment elevation in the right precordial leads on electrocardiogram (EKG) in the absence of structural heart disease. Patients with the Brugada pattern have an increased risk for ventricular tachyarrhythmia and sudden cardiac death. Loss-of-function mutations in the SCN5A gene which encodes the alpha subunit of the cardiac sodium channel have been associated with Brugada syndrome (BrS). We report a case of a patient who was found to have a spontaneous type 1 Brugada pattern on a routine EKG done prior to travel. He underwent electrophysiological testing (EPS) which provoked ventricular tachycardia and underwent implantable cardioverter defibrillator (ICD) placement. His family history revealed a history of sudden cardiac death, abnormal EKG, syncope, dilated cardiomyopathy, and BrS. Genetic testing revealed a variant of uncertain significance (VUS) in the SCN5A gene in the proband and six of his relatives. The SCN5A VUS in this clinical context and segregation with the disease in his family supports its reclassification to pathogenic.
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Affiliation(s)
- Jack Jnani
- Internal Medicine, North Shore University Hospital, Manhasset, USA
| | - Dorota Gruber
- Pediatrics and Cardiology, Zucker School of Medicine at Hofstra/Northwell, Manhasset, USA
| | - Tafadzwa Mtisi
- Cardiology, North Shore University Hospital, Manhasset, USA
| | - Moussa Saleh
- Cardiology, North Shore University Hospital, Manhasset, USA
| | - Bani M Azari
- Cardiovascular Institute, Northwell Health, New Hyde Park, USA
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45
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Nasilli G, Verkerk AO, O’Reilly M, Yiangou L, Davis RP, Casini S, Remme CA. Chronic Mexiletine Administration Increases Sodium Current in Non-Diseased Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Biomedicines 2024; 12:1212. [PMID: 38927420 PMCID: PMC11200762 DOI: 10.3390/biomedicines12061212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
A sodium current (INa) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on INa in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on INa and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak INa of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Nav1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak INa density, or the INa voltage dependence of (in)activation. Importantly, the increase in the peak INa density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases INa density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore INa and cardiac conduction.
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Affiliation(s)
- Giovanna Nasilli
- Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (A.O.V.)
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, 1105 AZ Amsterdam, The Netherlands
| | - Arie O. Verkerk
- Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (A.O.V.)
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, 1105 AZ Amsterdam, The Netherlands
- Department of Medical Biology, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Molly O’Reilly
- Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (A.O.V.)
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, 1105 AZ Amsterdam, The Netherlands
| | - Loukia Yiangou
- Department of Anatomy and Embryology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
| | - Richard P. Davis
- Department of Anatomy and Embryology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
| | - Simona Casini
- Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (A.O.V.)
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, 1105 AZ Amsterdam, The Netherlands
| | - Carol Ann Remme
- Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (A.O.V.)
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, 1105 AZ Amsterdam, The Netherlands
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46
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Tariq U, Sarkar S, Malladi N, Kumar R, Bugga P, Chakraborty P, Banerjee SK. Knockdown of SCN5A alters metabolic-associated genes and aggravates hypertrophy in the cardiomyoblast. Mol Biol Rep 2024; 51:661. [PMID: 38758505 DOI: 10.1007/s11033-024-09594-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/29/2024] [Indexed: 05/18/2024]
Abstract
SCN5A mutations have been reported to cause various cardiomyopathies in humans. Most of the SCN5A mutations causes loss of function and thereby, alters the overall cellular function. Therefore, to understand the loss of SCN5A function in cardiomyocytes, we have knocked down the SCN5A gene (SCN5A-KD) in H9c2 cells and explored the cell phenotype and molecular behaviors in the presence and absence of isoproterenol (ISO), an adrenergic receptor agonist that induces cardiac hypertrophy. Expression of several genes related to hypertrophy, inflammation, fibrosis, and energy metabolism pathways were evaluated. It was found that the mRNA expression of hypertrophy-related gene, brain (B-type) natriuretic peptide (BNP) was significantly increased in SCN5A-KD cells as compared to 'control' H9c2 cells. There was a further increase in the mRNA expressions of BNP and βMHC in SCN5A-KD cells after ISO treatment compared to their respective controls. Pro-inflammatory cytokine, tumor necrosis factor-alpha expression was significantly increased in 'SCN5A-KD' H9c2 cells. Further, metabolism-related genes like glucose transporter type 4, cluster of differentiation 36, peroxisome proliferator-activated receptor alpha, and peroxisome proliferator-activated receptor-gamma were significantly elevated in the SCN5A-KD cells as compared to the control cells. Upregulation of these metabolic genes is associated with increased ATP production. The study revealed that SCN5A knock-down causes alteration of gene expression related to cardiac hypertrophy, inflammation, and energy metabolism pathways, which may promote cardiac remodelling and cardiomyopathy.
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Affiliation(s)
- Ubaid Tariq
- Non-communicable Disease Group, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India
| | - Soumalya Sarkar
- Non-communicable Disease Group, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India
| | - Navya Malladi
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, 781101, India
| | - Roshan Kumar
- Non-communicable Disease Group, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India
| | - Paramesha Bugga
- Non-communicable Disease Group, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India
| | - Praloy Chakraborty
- Department of Cardiac Electrophysiology, Adult Cardiology, Toronto General Hospital, Toronto, ON, Canada
| | - Sanjay K Banerjee
- Non-communicable Disease Group, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India.
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, 781101, India.
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47
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Li Z, Liu X, Lin L, Jiang M, Hou J, Wang S, Chai Q, Li L, Liu Q. The grading diagnostic strategy of molecular autopsy combined with pathological autopsy in the forensic diagnosis of cardiomyopathy. Leg Med (Tokyo) 2024; 68:102380. [PMID: 38237273 DOI: 10.1016/j.legalmed.2023.102380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/04/2023] [Accepted: 12/20/2023] [Indexed: 05/08/2024]
Abstract
The diagnosis of cardiomyopathy often relies on the subjective judgment of pathologists due to the variety of morphologic changes in the condition and its low specificity. This uncertainty can contribute to unexplained sudden cardiac deaths (USCD). To enhance the accuracy of hereditary cardiomyopathy diagnosis in forensic medicine, we proposed a combination of molecular autopsy and pathologic autopsy. By analyzing 16 deceased patients suspected of cardiomyopathy, using whole exome sequencing (WES) in molecular autopsy, and applying a combined diagnostic strategy, the study found pathogenic or likely pathogenic variants in 6 cases. Out of the 16 cases, cardiomyopathy was confirmed in 3, while 3 exhibited conditions consistent with it. Data for 4 cases was inconclusive, and cardiomyopathy was ruled out in 6. Notably, a novel variant of the TTN gene was identified. This research suggests that a grading diagnostic strategy, combining molecular and pathological evidence, can improve the accuracy of forensic cardiomyopathy diagnosis. This approach provides a practical model and strategy for precise forensic cause-of-death determination, addressing the limitations of relying solely on morphologic assessments in cardiomyopathy cases, and integrating genetic information for a more comprehensive diagnosis.
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Affiliation(s)
- Zehao Li
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Genetics, Genomics, and Bioinformatics Program, University of California, Riverside, CA, USA
| | - Xiang Liu
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Lihua Lin
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Min Jiang
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Jiaqi Hou
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Shujuan Wang
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Qianqian Chai
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Lianjie Li
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Qian Liu
- Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
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48
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Zhou Q, Hao G, Xie W, Chen B, Lu W, Wang G, Zhong R, Chen J, Ye J, Shen J, Cao P. Exenatide reduces atrial fibrillation susceptibility by inhibiting hKv1.5 and hNav1.5 channels. J Biol Chem 2024; 300:107294. [PMID: 38636665 PMCID: PMC11109313 DOI: 10.1016/j.jbc.2024.107294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 04/02/2024] [Accepted: 04/12/2024] [Indexed: 04/20/2024] Open
Abstract
Exenatide, a promising cardioprotective agent, protects against cardiac structural remodeling and diastolic dysfunction. Combined blockade of sodium and potassium channels is valuable for managing atrial fibrillation (AF). Here, we explored whether exenatide displayed anti-AF effects by inhibiting human Kv1.5 and Nav1.5 channels. We used the whole-cell patch-clamp technique to investigate the effects of exenatide on hKv1.5 and hNav1.5 channels expressed in human embryonic kidney 293 cells and studied the effects of exenatide on action potential (AP) and other cardiac ionic currents in rat atrial myocytes. Additionally, an electrical mapping system was used to explore the effects of exenatide on electrical properties and AF activity in isolated rat hearts. Finally, a rat AF model, established using acetylcholine and calcium chloride, was employed to evaluate the anti-AF potential of exenatide in rats. Exenatide reversibly suppressed IKv1.5 with IC50 of 3.08 μM, preferentially blocked the hKv1.5 channel in its closed state, and positively shifted the voltage-dependent activation curve. Exenatide also reversibly inhibited INav1.5 with IC50 of 3.30 μM, negatively shifted the voltage-dependent inactivation curve, and slowed its recovery from inactivation with significant use-dependency at 5 and 10 Hz. Furthermore, exenatide prolonged AP duration and suppressed the sustained K+ current (Iss) and transient outward K+ current (Ito), but without inhibition of L-type Ca2+ current (ICa,L) in rat atrial myocytes. Exenatide prevented AF incidence and duration in rat hearts and rats. These findings demonstrate that exenatide inhibits IKv1.5 and INav1.5in vitro and reduces AF susceptibility in isolated rat hearts and rats.
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Affiliation(s)
- Qian Zhou
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Guoliang Hao
- Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, China; Henan SCOPE Research Institute of Electrophysiology Co Ltd, Kaifeng, China; Burdon Sanderson Cardiac Science Centre and BHF Centre of Research Excellence, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Wensen Xie
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bin Chen
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Nanjing Research Institute for Comprehensive Utilization of Wild Plants, Nanjing, China
| | - Wuguang Lu
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Gongxin Wang
- Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, China; Henan SCOPE Research Institute of Electrophysiology Co Ltd, Kaifeng, China
| | - Rongling Zhong
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiao Chen
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Ye
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianping Shen
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Cao
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China; Animal-Derived Chinese Medicine and Functional Peptides International Collaboration Joint Laboratory, Nanjing University of Chinese Medicine, Nanjing, China; Shandong Academy of Chinese Medicine, Jinan, China.
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49
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Zhang Y, Yao B, Guo Y, Huang S, Liu J, Zhang Y, Liang C, Huang J, Tang Y, Wang X. Sorafenib reduces the production of epoxyeicosatrienoic acids and leads to cardiac injury by inhibiting CYP2J in rats. Biochem Pharmacol 2024; 223:116169. [PMID: 38548244 DOI: 10.1016/j.bcp.2024.116169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/15/2024] [Accepted: 03/25/2024] [Indexed: 04/22/2024]
Abstract
Sorafenib, an important cancer drug in clinical practice, has caused heart problems such as hypertension, myocardial infarction, and thrombosis. Although some mechanisms of sorafenib-induced cardiotoxicity have been proposed, there is still more research needed to reach a well-established definition of the causes of cardiotoxicity of sorafenib. In this report, we demonstrate that sorafenib is a potent inhibitor of the CYP2J enzyme. Sorafenib significantly inhibited the production of epoxyeicosatrienoic acids (EETs) in rat cardiac microsomes. The in vivo experimental results also showed that after the administration of sorafenib, the levels of 11,12-EET and 14,15-EET in rat plasma were significantly reduced, which was similar to the results of CYP2J gene knockout. Sorafenib decreased the levels of EETs, leading to abnormal expression of mitochondrial fusion and fission factors in heart tissue. In addition, the expression of mitochondrial energy metabolism factors (Pgc-1α, Pgc-1β, Ampk, and Sirt1) and cardiac mechanism factors (Scn5a and Prkag2) was significantly reduced, increasing the risk of arrhythmia and heart failure. Meanwhile, the increase in injury markers Anp, CK, and CK-MB further confirmed the cardiotoxicity of sorafenib. This study is of great significance for understanding the cardiotoxicity of sorafenib, and is also a model for studying the cardiotoxicity of other drugs that inhibit CYP2J activity.
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Affiliation(s)
- Yanfang Zhang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Bingyi Yao
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yuanqing Guo
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Shengbo Huang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Jie Liu
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yuanjin Zhang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Chenmeizi Liang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Junze Huang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yu Tang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Xin Wang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China.
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50
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Gallego-Delgado M, Cámara-Checa A, Rubio-Alarcón M, Heredero-Jung D, de la Fuente-Blanco L, Rapún J, Plata-Izquierdo B, Pérez-Martín S, Cebrián J, Moreno de Redrojo L, García-Berrocal B, Delpón E, Sánchez PL, Villacorta E, Caballero R. Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families. Int J Mol Sci 2024; 25:4686. [PMID: 38731905 PMCID: PMC11083067 DOI: 10.3390/ijms25094686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/05/2024] [Accepted: 04/10/2024] [Indexed: 05/13/2024] Open
Abstract
A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.
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Affiliation(s)
- María Gallego-Delgado
- Department of Cardiology, CSUR Cardiopatías Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), 37007 Salamaca, Spain; (M.G.-D.)
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
| | - Anabel Cámara-Checa
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
- Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain
| | - Marcos Rubio-Alarcón
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
- Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain
| | - David Heredero-Jung
- Department of Biochemistry, CSUR Cardiopatías Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), 37007 Salamaca, Spain
| | - Laura de la Fuente-Blanco
- Department of Cardiology, CSUR Cardiopatías Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), 37007 Salamaca, Spain; (M.G.-D.)
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
| | - Josu Rapún
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
- Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain
| | - Beatriz Plata-Izquierdo
- Department of Pediatrics, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Leon (SACYL), CIBERCV, 37007 Salamaca, Spain;
| | - Sara Pérez-Martín
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
- Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain
| | - Jorge Cebrián
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
- Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain
| | - Lucía Moreno de Redrojo
- Department of Cardiology, CSUR Cardiopatías Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), 37007 Salamaca, Spain; (M.G.-D.)
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
| | - Belén García-Berrocal
- Department of Biochemistry, CSUR Cardiopatías Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), 37007 Salamaca, Spain
| | - Eva Delpón
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
- Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain
| | - Pedro L. Sánchez
- Department of Cardiology, CSUR Cardiopatías Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), 37007 Salamaca, Spain; (M.G.-D.)
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
| | - Eduardo Villacorta
- Department of Cardiology, CSUR Cardiopatías Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), 37007 Salamaca, Spain; (M.G.-D.)
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
| | - Ricardo Caballero
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain (M.R.-A.); (J.R.); (J.C.); (R.C.)
- Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain
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