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Elhanafy E, Akbari Ahangar A, Roth R, Gamal El-Din TM, Bankston JR, Li J. The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels. J Gen Physiol 2025; 157:e202413669. [PMID: 39820972 PMCID: PMC11740781 DOI: 10.1085/jgp.202413669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/27/2024] [Accepted: 12/25/2024] [Indexed: 01/19/2025] Open
Abstract
Voltage-gated sodium (Nav) channels are pivotal for cellular signaling, and mutations in Nav channels can lead to excitability disorders in cardiac, muscular, and neural tissues. A major cluster of pathological mutations localizes in the voltage-sensing domains (VSDs), resulting in either gain-of-function, loss-of-function effects, or both. However, the mechanism behind this functional diversity of mutations at equivalent positions remains elusive. Through hotspot analysis, we identified three gating charges (R1, R2, and R3) as major mutational hotspots in VSDs. The same amino acid substitutions at equivalent gating-charge positions in VSDI and VSDII of the cardiac sodium channel Nav1.5 show differential gating property impacts in electrophysiology measurements. We conducted molecular dynamics (MD) simulations on wild-type channels and six mutants to elucidate the structural basis of their differential impacts. Our 120-µs MD simulations with applied external electric fields captured VSD state transitions and revealed the differential structural dynamics between equivalent R-to-Q mutants. Notably, we observed transient leaky conformations in some mutants during structural transitions, offering a detailed structural explanation for gating-pore currents. Our salt-bridge network analysis uncovered VSD-specific and state-dependent interactions among gating charges, countercharges, and lipids. This detailed analysis revealed how mutations disrupt critical electrostatic interactions, thereby altering VSD permeability and modulating gating properties. By demonstrating the crucial importance of considering the specific structural context of each mutation, our study advances our understanding of structure-function relationships in Nav channels. Our work establishes a robust framework for future investigations into the molecular basis of ion channel-related disorders.
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Affiliation(s)
- Eslam Elhanafy
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, USA
| | - Amin Akbari Ahangar
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, USA
| | - Rebecca Roth
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | - John R Bankston
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jing Li
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, USA
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2
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Wang J, Verkerk AO, Wilders R, Zhang Y, Zhang K, Prakosa A, Rivaud MR, Marsman EMJ, Boender AR, Klerk M, Fokkert L, de Jonge B, Neef K, Kirzner OF, Bezzina CR, Remme CA, Tan HL, Boukens BJ, Devalla HD, Trayanova NA, Christoffels VM, Barnett P, Boink GJJ. SCN10A-short gene therapy to restore conduction and protect against malignant cardiac arrhythmias. Eur Heart J 2025:ehaf053. [PMID: 39973098 DOI: 10.1093/eurheartj/ehaf053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 05/27/2024] [Accepted: 01/23/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND AND AIMS Life-threatening arrhythmias are a well-established consequence of reduced cardiac sodium current (INa). Gene therapy approaches to increase INa have demonstrated potential benefits to prevent arrhythmias. However, the development of such therapies is hampered by the large size of sodium channels. In this study, SCN10A-short (S10s), a short transcript encoding the carboxy-terminal domain of the human neuronal sodium channel, was evaluated as a gene therapy target to increase INa and prevent arrhythmias. METHODS Adeno-associated viral vector overexpressing S10s was injected into wild type and Scn5a-haploinsufficient mice on which patch-clamp studies, optical mapping, electrocardiogram analyses, and ischaemia reperfusion were performed. In vitro and in silico studies were conducted to further explore the effect of S10s gene therapy in the context of human hearts. RESULTS Cardiac S10s overexpression increased cellular INa, maximal action potential upstroke velocity, and action potential amplitude in Scn5a-haploinsufficient cardiomyocytes. S10s gene therapy rescues conduction slowing in Scn5a-haploinsufficient mice and prevented ventricular tachycardia induced by ischaemia-reperfusion in wild type mice. S10s overexpression increased maximal action potential upstroke velocity in human inducible pluripotent stem cell-derived cardiomyocytes and prevented inducible arrhythmias in simulated human heart models. CONCLUSIONS S10s gene therapy may be effective to treat cardiac conduction abnormalities and associated arrhythmias.
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Affiliation(s)
- Jianan Wang
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Arie O Verkerk
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Ronald Wilders
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Yingnan Zhang
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Kelly Zhang
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Adityo Prakosa
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Mathilde R Rivaud
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - E Madelief J Marsman
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Arie R Boender
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
| | - Mischa Klerk
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Lianne Fokkert
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Berend de Jonge
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Klaus Neef
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
- Netherlands Heart Institute, Moreelsepark 1, Utrecht 3511 EP, The Netherlands
| | - Osne F Kirzner
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
- Department of Anaesthesiology, Amsterdam University Medical Centers, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands
| | - Connie R Bezzina
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Carol Ann Remme
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Hanno L Tan
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
- Netherlands Heart Institute, Moreelsepark 1, Utrecht 3511 EP, The Netherlands
| | - Bastiaan J Boukens
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, Maastricht 6229 ER, The Netherlands
| | - Harsha D Devalla
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Natalia A Trayanova
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
- Alliance for Cardiovascular Diagnostic and Treatment Innovation, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Vincent M Christoffels
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Phil Barnett
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Gerard J J Boink
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
- Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
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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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Martin S, Jenewein T, Geisen C, Scheiper-Welling S, Kauferstein S. "Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders". BMC Cardiovasc Disord 2024; 24:390. [PMID: 39068400 PMCID: PMC11282671 DOI: 10.1186/s12872-024-04065-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: 04/28/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Genetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders. METHODS Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts. RESULTS We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017-2019, with rates ranging from 50 to 60%. CONCLUSION The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.
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Affiliation(s)
- Sarah Martin
- Centre for Sudden Cardiac Death and Familial Arrhythmias, Institute of Legal Medicine, University Hospital Frankfurt, Goethe-University, Frankfurt/Main, Germany.
| | - Tina Jenewein
- Centre for Sudden Cardiac Death and Familial Arrhythmias, Institute of Legal Medicine, University Hospital Frankfurt, Goethe-University, Frankfurt/Main, Germany
- German Red Cross Blood Center, Institute of Transfusion Medicine and Immunohaematology, University Hospital Frankfurt, Frankfurt, Germany
| | - Christof Geisen
- German Red Cross Blood Center, Institute of Transfusion Medicine and Immunohaematology, University Hospital Frankfurt, Frankfurt, Germany
| | - Stefanie Scheiper-Welling
- Centre for Sudden Cardiac Death and Familial Arrhythmias, Institute of Legal Medicine, University Hospital Frankfurt, Goethe-University, Frankfurt/Main, Germany
| | - Silke Kauferstein
- Centre for Sudden Cardiac Death and Familial Arrhythmias, Institute of Legal Medicine, University Hospital Frankfurt, Goethe-University, Frankfurt/Main, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Rhein-Main, Frankfurt, Germany
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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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Chimatapu SN, Schachter JL, Batra AS, Sirignano R, Okawa ER. A Pediatric Case of Refractory Torsades de Pointes in Autoimmune Hypothyroidism. JCEM CASE REPORTS 2024; 2:luae124. [PMID: 39011403 PMCID: PMC11247166 DOI: 10.1210/jcemcr/luae124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Indexed: 07/17/2024]
Abstract
Hypothyroidism can have a significant impact on cardiac contractility, vascular resistance, blood pressure, and cardiac rhythm. Ventricular arrhythmias induced by hypothyroidism are infrequently reported, especially in pediatric cases. A 15-year-old girl with autoimmune hypothyroidism experienced pulseless ventricular arrhythmias on 2 separate occasions because of nonadherence to levothyroxine medication. Subsequent investigations revealed an SCN5A mutation associated with Brugada syndrome. A loop recorder captured polymorphic ventricular tachycardia (PMVT), specifically Torsades de Pointes during her second event. Both arrhythmias were addressed only after stabilizing her thyroid hormone levels with replacement therapy. Although rare, patients with uncontrolled hypothyroidism may present with ventricular arrhythmias, particularly PMVT. The cornerstone of treatment for hypothyroidism-induced ventricular arrhythmia is thyroid replacement therapy. The identification of an SCN5A mutation unmasked by overt hypothyroidism emphasizes the need for a comprehensive cardiac evaluation in patients with hypothyroidism being assessed for PMVT.
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Affiliation(s)
- Sri Nikhita Chimatapu
- University of California, Los Angeles, Mattel Children's Hospital, Los Angeles, CA 90095, USA
| | - Jessica L Schachter
- Department of Cardiology, University of California Irvine Medical Center, Orange, CA 92868, USA
| | - Anjan S Batra
- Department of Cardiology, University of California Irvine Medical Center, Orange, CA 92868, USA
| | - Rachel Sirignano
- Children's Heart Institute, Memorial Care Miller Children's & Women's Hospital, Long Beach, CA 90806, USA
| | - Erin R Okawa
- University of California, Los Angeles, Mattel Children's Hospital, Los Angeles, CA 90095, USA
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Marchal GA, Rivaud MR, Wolswinkel R, Basso C, van Veen TAB, Bezzina CR, Remme CA. Genetic background determines the severity of age-dependent cardiac structural abnormalities and arrhythmia susceptibility in Scn5a-1798insD mice. Europace 2024; 26:euae153. [PMID: 38875491 PMCID: PMC11203918 DOI: 10.1093/europace/euae153] [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: 02/09/2024] [Accepted: 05/12/2024] [Indexed: 06/16/2024] Open
Abstract
AIMS Patients with mutations in SCN5A encoding NaV1.5 often display variable severity of electrical and structural alterations, but the underlying mechanisms are not fully elucidated. We here investigate the combined modulatory effect of genetic background and age on disease severity in the Scn5a1798insD/+ mouse model. METHODS AND RESULTS In vivo electrocardiogram and echocardiograms, ex vivo electrical and optical mapping, and histological analyses were performed in adult (2-7 months) and aged (8-28 months) wild-type (WT) and Scn5a1798insD/+ (mutant, MUT) mice from the FVB/N and 129P2 inbred strains. Atrio-ventricular (AV) conduction, ventricular conduction, and ventricular repolarization are modulated by strain, genotype, and age. An aging effect was present in MUT mice, with aged MUT mice of both strains showing prolonged QRS interval and right ventricular (RV) conduction slowing. 129P2-MUT mice were severely affected, with adult and aged 129P2-MUT mice displaying AV and ventricular conduction slowing, prolonged repolarization, and spontaneous arrhythmias. In addition, the 129P2 strain appeared particularly susceptible to age-dependent electrical, functional, and structural alterations including RV conduction slowing, reduced left ventricular (LV) ejection fraction, RV dilatation, and myocardial fibrosis as compared to FVB/N mice. Overall, aged 129P2-MUT mice displayed the most severe conduction defects, RV dilatation, and myocardial fibrosis, in addition to the highest frequency of spontaneous arrhythmia and inducible arrhythmias. CONCLUSION Genetic background and age both modulate disease severity in Scn5a1798insD/+ mice and hence may explain, at least in part, the variable disease expressivity observed in patients with SCN5A mutations. Age- and genetic background-dependent development of cardiac structural alterations furthermore impacts arrhythmia risk. Our findings therefore emphasize the importance of continued assessment of cardiac structure and function in patients carrying SCN5A mutations.
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Affiliation(s)
- Gerard A Marchal
- Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
- OptoCARD Lab, Institute of Clinical Physiology (IFC-CNR), Florence, Italy
| | - Mathilde R Rivaud
- Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
| | - Rianne Wolswinkel
- Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
| | - Cristina Basso
- Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Padua, Italy
| | - Toon A B van Veen
- Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Connie R Bezzina
- Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
| | - Carol Ann Remme
- Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands
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8
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Ahangar AA, Elhanafy E, Blanton H, Li J. Mapping Structural Distribution and Gating-Property Impacts of Disease-Associated Missense Mutations in Voltage-Gated Sodium Channels. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.20.558623. [PMID: 37781633 PMCID: PMC10541146 DOI: 10.1101/2023.09.20.558623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision 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 phenotypic effects can stem from unique molecular mechanisms. Our results show a high biophysical agreement (86%) between homologous disease-associated variants in different Nav genes, significantly surpassing the 60% phenotype (GoFo/LoFo) agreement among homologous mutants, suggesting the need for more nuanced disease categorization and treatment based on specific gating-property changes. Using UniProt data, we mapped over 2,400 disease-associated missense variants across nine human Nav channels and identified three clusters of mutation hotspots. Our findings indicate that mutations near the selectivity filter generally diminish the maximal current amplitude, while those in the fast inactivation region lean towards a depolarizing shift in half-inactivation voltage in steady-state activation, and mutations in the activation gate commonly enhance persistent current. In contrast to mutations in the PD, those within the VSD exhibit diverse impacts and subtle preferences on channel activity. This study shows great potential to enhance prediction accuracy for variant effects based on the structural context, laying the groundwork 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
| | - Eslam Elhanafy
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi
| | - Hayden Blanton
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi
| | - Jing Li
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi
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9
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Hoeksema WF, Amin AS, Bezzina CR, Wilde AAM, Postema PG. Novelties in Brugada Syndrome: Complex Genetics, Risk Stratification, and Catheter Ablation. Card Electrophysiol Clin 2023; 15:273-283. [PMID: 37558298 DOI: 10.1016/j.ccep.2023.05.002] [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] [Indexed: 08/11/2023]
Abstract
Brugada syndrome (BrS) is an inherited arrhythmia syndrome with distinctive electrocardiographic abnormalities in the right precordial leads and predisposes to ventricular arrhythmias and sudden cardiac death in otherwise healthy patients. Its complex genetic architecture and pathophysiological mechanism are not yet completely understood, and risk stratification remains challenging, particularly in patients at intermediate risk of arrhythmic events. Further understanding of its complex genetic architecture may help improving future risk stratification, and advances in management may contribute to alternatives to implantable cardioverter-defibrillators. Here, the authors review the latest insights and developments in BrS.
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Affiliation(s)
- Wiert F Hoeksema
- Department of Clinical Cardiology, Amsterdam UMC, Location University of Amsterdam, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 9, Amsterdam, the Netherlands
| | - Ahmad S Amin
- Department of Clinical Cardiology, Amsterdam UMC, Location University of Amsterdam, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 9, Amsterdam, the Netherlands
| | - Connie R Bezzina
- Department of Experimental Cardiology, Amsterdam UMC, Location University of Amsterdam, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 9, Amsterdam, the Netherlands
| | - Arthur A M Wilde
- Department of Clinical Cardiology, Amsterdam UMC, Location University of Amsterdam, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 9, Amsterdam, the Netherlands
| | - Pieter G Postema
- Department of Clinical Cardiology, Amsterdam UMC, Location University of Amsterdam, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 9, Amsterdam, the Netherlands.
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Liantonio A, Bertini M, Mele A, Balla C, Dinoi G, Selvatici R, Mele M, De Luca A, Gualandi F, Imbrici P. Brugada Syndrome: More than a Monogenic Channelopathy. Biomedicines 2023; 11:2297. [PMID: 37626795 PMCID: PMC10452102 DOI: 10.3390/biomedicines11082297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/10/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Brugada syndrome (BrS) is an inherited cardiac channelopathy first diagnosed in 1992 but still considered a challenging disease in terms of diagnosis, arrhythmia risk prediction, pathophysiology and management. Despite about 20% of individuals carrying pathogenic variants in the SCN5A gene, the identification of a polygenic origin for BrS and the potential role of common genetic variants provide the basis for applying polygenic risk scores for individual risk prediction. The pathophysiological mechanisms are still unclear, and the initial thinking of this syndrome as a primary electrical disease is evolving towards a partly structural disease. This review focuses on the main scientific advancements in the identification of biomarkers for diagnosis, risk stratification, pathophysiology and therapy of BrS. A comprehensive model that integrates clinical and genetic factors, comorbidities, age and gender, and perhaps environmental influences may provide the opportunity to enhance patients' quality of life and improve the therapeutic approach.
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Affiliation(s)
- Antonella Liantonio
- Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (A.L.); (A.M.); (G.D.); (M.M.); (A.D.L.)
| | - Matteo Bertini
- Cardiological Center, Sant’Anna University Hospital of Ferrara, 44121 Ferrara, Italy; (M.B.); (C.B.)
| | - Antonietta Mele
- Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (A.L.); (A.M.); (G.D.); (M.M.); (A.D.L.)
| | - Cristina Balla
- Cardiological Center, Sant’Anna University Hospital of Ferrara, 44121 Ferrara, Italy; (M.B.); (C.B.)
| | - Giorgia Dinoi
- Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (A.L.); (A.M.); (G.D.); (M.M.); (A.D.L.)
| | - Rita Selvatici
- Medical Genetics Unit, Department of Mother and Child, Sant’Anna University Hospital of Ferrara, 44121 Ferrara, Italy;
| | - Marco Mele
- Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (A.L.); (A.M.); (G.D.); (M.M.); (A.D.L.)
- Cardiothoracic Department, Policlinico Riuniti Foggia, 71122 Foggia, Italy
| | - Annamaria De Luca
- Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (A.L.); (A.M.); (G.D.); (M.M.); (A.D.L.)
| | - Francesca Gualandi
- Medical Genetics Unit, Department of Mother and Child, Sant’Anna University Hospital of Ferrara, 44121 Ferrara, Italy;
| | - Paola Imbrici
- Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (A.L.); (A.M.); (G.D.); (M.M.); (A.D.L.)
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11
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Remme CA. SCN5A channelopathy: arrhythmia, cardiomyopathy, epilepsy and beyond. Philos Trans R Soc Lond B Biol Sci 2023; 378:20220164. [PMID: 37122208 PMCID: PMC10150216 DOI: 10.1098/rstb.2022.0164] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/31/2022] [Indexed: 05/02/2023] Open
Abstract
Influx of sodium ions through voltage-gated sodium channels in cardiomyocytes is essential for proper electrical conduction within the heart. Both acquired conditions associated with sodium channel dysfunction (myocardial ischaemia, heart failure) as well as inherited disorders secondary to mutations in the gene SCN5A encoding for the cardiac sodium channel Nav1.5 are associated with life-threatening arrhythmias. Research in the last decade has uncovered the complex nature of Nav1.5 distribution, function, in particular within distinct subcellular subdomains of cardiomyocytes. Nav1.5-based channels furthermore display previously unrecognized non-electrogenic actions and may impact on cardiac structural integrity, leading to cardiomyopathy. Moreover, SCN5A and Nav1.5 are expressed in cell types other than cardiomyocytes as well as various extracardiac tissues, where their functional role in, e.g. epilepsy, gastrointestinal motility, cancer and the innate immune response is increasingly investigated and recognized. This review provides an overview of these novel insights and how they deepen our mechanistic knowledge on SCN5A channelopathies and Nav1.5 (dys)function. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
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Affiliation(s)
- Carol Ann Remme
- Department of Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam, The Netherlands
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12
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ter Bekke RMA, de Schouwer K, Conti S, Claes GRF, Vanoevelen J, Gommers S, Helderman-van den Enden ATJM, Brunner-LaRocca HP. Juvenile-onset multifocal atrial arrhythmias, atrial standstill and compound heterozygosity of genetic variants in TAF1A: sentinel event for evolving dilated cardiomyopathy-a case report. Eur Heart J Case Rep 2023; 7:ytad255. [PMID: 37501913 PMCID: PMC10371049 DOI: 10.1093/ehjcr/ytad255] [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: 11/11/2022] [Revised: 02/20/2023] [Accepted: 05/19/2023] [Indexed: 07/29/2023]
Abstract
Background Juvenile onset of extensive atrial electromechanical failure, including atrial standstill, is a rare disease entity that may precede ventricular cardiomyopathy. Genetic variants associated with early-onset atrioventricular (AV) cardiomyopathy are increasingly recognized. Case summary A 16-year-old patient presented with atrial brady- and tachyarrhythmias and concomitant impaired atrial electromechanical function (atrial standstill). The atrial phenotype preceded the development of a predominantly right-sided AV dilated cardiomyopathy with pronounced myocardial fibrosis. A His-bundle pacemaker was installed for high-degree AV conduction block and sinus arrest. Using familial-based whole-exome sequencing, a missense mutation and a copy number variant deletion (compound heterozygosity) of the TAF1A gene (involved in ribosomal RNA synthesis) were identified. Discussion Juvenile onset of severe atrial electromechanical failure with atrial arrhythmias should prompt deep pheno- and genotyping and calls for vigilance for downstream cardiomyopathic deterioration.
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Affiliation(s)
| | - Koen de Schouwer
- Department of Cardiology, Cardiovascular Center Onze-Lieve-Vrouwziekenhuis Hospital, Aalst, Belgium
| | - Sergio Conti
- Department of Cardiac Electrophysiology, ARNAS Civico Hospital, Palermo, Italy
| | - Godelieve R F Claes
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jo Vanoevelen
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Suzanne Gommers
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
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13
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Marchal GA, Remme CA. Subcellular diversity of Nav1.5 in cardiomyocytes: distinct functions, mechanisms and targets. J Physiol 2023; 601:941-960. [PMID: 36469003 DOI: 10.1113/jp283086] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/24/2022] [Indexed: 12/11/2022] Open
Abstract
In cardiomyocytes, the rapid depolarisation of the membrane potential is mediated by the α-subunit of the cardiac voltage-gated Na+ channel (NaV 1.5), encoded by the gene SCN5A. This ion channel allows positively charged Na+ ions to enter the cardiomyocyte, resulting in the fast upstroke of the action potential and is therefore crucial for cardiac excitability and electrical propagation. This essential role is underscored by the fact that dysfunctional NaV 1.5 is associated with high risk for arrhythmias and sudden cardiac death. However, development of therapeutic interventions regulating NaV 1.5 has been limited due to the complexity of NaV 1.5 structure and function and its diverse roles within the cardiomyocyte. In particular, research from the last decade has provided us with increased knowledge on the subcellular distribution of NaV 1.5 as well as the proteins which it interacts with in distinct cardiomyocyte microdomains. We here review these insights, detailing the potential role of NaV 1.5 within subcellular domains as well as its dysfunction in the setting of arrhythmia disorders. We furthermore provide an overview of current knowledge on the pathways involved in (microdomain-specific) trafficking of NaV 1.5, and their potential as novel targets. Unravelling the complexity of NaV 1.5 (dys)function may ultimately facilitate the development of therapeutic strategies aimed at preventing lethal arrhythmias. This is not only of importance for pathophysiological conditions where sodium current is specifically decreased within certain subcellular regions, such as in arrhythmogenic cardiomyopathy and Duchenne muscular dystrophy, but also for other acquired and inherited disorders associated with NaV 1.5.
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Affiliation(s)
- Gerard A Marchal
- Department of Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.,National Institute of Optics, National Research Council (CNR-INO), Sesto Fiorentino, Florence, Italy
| | - Carol Ann Remme
- Department of Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
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14
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Plijter IS, Verkerk AO, Wilders R. The Antidepressant Paroxetine Reduces the Cardiac Sodium Current. Int J Mol Sci 2023; 24:ijms24031904. [PMID: 36768229 PMCID: PMC9915920 DOI: 10.3390/ijms24031904] [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: 12/13/2022] [Revised: 01/05/2023] [Accepted: 01/13/2023] [Indexed: 01/21/2023] Open
Abstract
A considerable amount of literature has been published on antidepressants and cardiac ion channel dysfunction. The antidepressant paroxetine has been associated with Brugada syndrome and long QT syndrome, albeit on the basis of conflicting findings. The cardiac voltage-gated sodium channel (NaV1.5) is related to both of these syndromes, suggesting that paroxetine may have an effect on this channel. In the present study, we therefore carried out patch clamp experiments to examine the effect of paroxetine on human NaV1.5 channels stably expressed in human embryonic kidney 293 (HEK-293) cells as well as on action potentials of isolated rabbit left ventricular cardiomyocytes. Additionally, computer simulations were conducted to test the functional effects of the experimentally observed paroxetine-induced changes in the NaV1.5 current. We found that paroxetine led to a decrease in peak NaV1.5 current in a concentration-dependent manner with an IC50 of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the NaV1.5 current as well as a significant increase in its rate of inactivation. Paroxetine (3 µM) affected the action potential of the left ventricular cardiomyocytes, significantly decreasing its maximum upstroke velocity and amplitude, both of which are mainly regulated by the NaV1.5 current. Our computer simulations demonstrated that paroxetine substantially reduces the fast sodium current of human left ventricular cardiomyocytes, thereby slowing conduction and reducing excitability in strands of cells, in particular if conduction and excitability are already inhibited by a loss-of-function mutation in the NaV1.5 encoding SCN5A gene. In conclusion, paroxetine acts as an inhibitor of NaV1.5 channels, which may enhance the effects of loss-of-function mutations in SCN5A.
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Affiliation(s)
- Ingmar S. Plijter
- 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
- Correspondence:
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15
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Kekenes-Huskey PM, Burgess DE, Sun B, Bartos DC, Rozmus ER, Anderson CL, January CT, Eckhardt LL, Delisle BP. Mutation-Specific Differences in Kv7.1 ( KCNQ1) and Kv11.1 ( KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes. Int J Mol Sci 2022; 23:7389. [PMID: 35806392 PMCID: PMC9266926 DOI: 10.3390/ijms23137389] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 11/16/2022] Open
Abstract
The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano-Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the "benign" to a "pathogenic" binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene- and mutation-specific differences in K+ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals.
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Affiliation(s)
- Peter M. Kekenes-Huskey
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Don E. Burgess
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; (D.E.B.); (E.R.R.)
| | - Bin Sun
- Department of Pharmacology, Harbin Medical University, Harbin 150081, China;
| | | | - Ezekiel R. Rozmus
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; (D.E.B.); (E.R.R.)
| | - Corey L. Anderson
- Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (C.L.A.); (C.T.J.); (L.L.E.)
| | - Craig T. January
- Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (C.L.A.); (C.T.J.); (L.L.E.)
| | - Lee L. Eckhardt
- Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (C.L.A.); (C.T.J.); (L.L.E.)
| | - Brian P. Delisle
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; (D.E.B.); (E.R.R.)
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16
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Leveraging FHF modulation to inhibit arrhythmogenic late sodium current. NATURE CARDIOVASCULAR RESEARCH 2022; 1:548-549. [PMID: 39195863 DOI: 10.1038/s44161-022-00077-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
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17
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Song Y, Zheng Z, Lian J. Deciphering Common Long QT Syndrome Using CRISPR/Cas9 in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Front Cardiovasc Med 2022; 9:889519. [PMID: 35647048 PMCID: PMC9136094 DOI: 10.3389/fcvm.2022.889519] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
From carrying potentially pathogenic genes to severe clinical phenotypes, the basic research in the inherited cardiac ion channel disease such as long QT syndrome (LQTS) has been a significant challenge in explaining gene-phenotype heterogeneity. These have opened up new pathways following the parallel development and successful application of stem cell and genome editing technologies. Stem cell-derived cardiomyocytes and subsequent genome editing have allowed researchers to introduce desired genes into cells in a dish to replicate the disease features of LQTS or replace causative genes to normalize the cellular phenotype. Importantly, this has made it possible to elucidate potential genetic modifiers contributing to clinical heterogeneity and hierarchically manage newly identified variants of uncertain significance (VUS) and more therapeutic options to be tested in vitro. In this paper, we focus on and summarize the recent advanced application of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9 (CRISPR/Cas9) in the interpretation for the gene-phenotype relationship of the common LQTS and presence challenges, increasing our understanding of the effects of mutations and the physiopathological mechanisms in the field of cardiac arrhythmias.
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Affiliation(s)
- Yongfei Song
- Department of Cardiovascular, Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
- Yongfei Song
| | - Zequn Zheng
- Department of Cardiovascular, Medical College, Ningbo University, Ningbo, China
- Department of Cardiovascular, Lihuili Hospital Affiliated to Ningbo University, Ningbo, China
| | - Jiangfang Lian
- Department of Cardiovascular, Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
- Department of Cardiovascular, Medical College, Ningbo University, Ningbo, China
- Department of Cardiovascular, Lihuili Hospital Affiliated to Ningbo University, Ningbo, China
- *Correspondence: Jiangfang Lian
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18
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SCN5A Overlap Syndromes: an open-minded approach. Heart Rhythm 2022; 19:1363-1368. [DOI: 10.1016/j.hrthm.2022.03.1223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 03/07/2022] [Accepted: 03/22/2022] [Indexed: 12/19/2022]
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19
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Papagiannis J, Yang T, Glazer AM, Tisma-Dupanovic S, Avramidis D, Kannankeril PJ, Viskin S, Walsh EP, Roden DM. Incessant atrial and ventricular tachycardias associated with an SCN5A mutation. HeartRhythm Case Rep 2021; 7:806-811. [PMID: 34987964 PMCID: PMC8695285 DOI: 10.1016/j.hrcr.2021.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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20
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Novel presentation of SCN5A nonsense mutation as SCN5A overlap syndrome. HeartRhythm Case Rep 2021; 8:209-213. [PMID: 35492839 PMCID: PMC9039685 DOI: 10.1016/j.hrcr.2021.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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21
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Santilli R, Saponaro V, Carlucci L, Perego M, Battaia S, Borgarelli M. Heart rhythm characterization during sudden cardiac death in dogs. J Vet Cardiol 2021; 38:18-30. [PMID: 34710652 DOI: 10.1016/j.jvc.2021.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 09/20/2021] [Accepted: 09/22/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION/OBJECTIVES Inherited or acquired arrhythmic disorders and cardiac disease have been associated with sudden cardiac death (SCD) in dogs. The electrical mechanism related to death in most of these cases is unknown. This retrospective study aimed to describe arrhythmic events in dogs that experienced SCD during Holter monitoring. ANIMALS, MATERIALS AND METHODS Nineteen client-owned dogs that experienced SCD during Holter examination were included. Clinical records from a Holter service database were reviewed, and both the rhythm preceding death and the dominant rhythm causing SCD were analysed. Clinical data, Holter diaries and echocardiographic diagnosis were also evaluated. RESULTS Structural heart disease was identified in 12/19 dogs (dilated cardiomyopathy in five dogs, arrhythmogenic right ventricular cardiomyopathy in four dogs, myxomatous mitral valve disease in two dogs, and suspected myocarditis in one dog), five of which had concurrent congestive heart failure. Sudden cardiac death was related to ventricular premature complexes or monomorphic ventricular tachycardia degenerating into ventricular fibrillation in 42% of dogs, polymorphic ventricular tachycardia, or torsade de pointes-like inducing ventricular fibrillation in 21%, and asystole or presumptive agonal pulseless electrical activity triggered by malignant bradyarrhythmias in 37%. CONCLUSIONS The most common rhythm associated with SCD in our population of dogs was ventricular tachycardia leading to ventricular fibrillation, although bradyarrhythmia-related SCD, possibly related to inappropriate vagal reflexes, was also a notable cause.
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Affiliation(s)
- R Santilli
- Clinica Veterinaria Malpensa, AniCura, Via G. Marconi 27, Samarate, Varese, 21017, Italy; Department of Clinical Sciences, Cornell University College of Veterinary Medicine, 930 Campus Road, Ithaca, NY, 14853, USA.
| | - V Saponaro
- Centre Hospitalier Universitaire Vétérinaire d'Alfort (CHUVA), Ecole Nationale Vétérinaire d'Alfort, 7 avenue du Général de Gaulle, Maisons-Alfort, F-94700, France
| | - L Carlucci
- Scuola Superiore Sant'Anna, Istituto Scienze della Vita, Via Martiri della Libertà, 33, Pisa, 56100, Italy
| | - M Perego
- Clinica Veterinaria Malpensa, AniCura, Via G. Marconi 27, Samarate, Varese, 21017, Italy; Ospedale Veterinario I Portoni Rossi, Via Roma 57, Zola Predosa, Bologna, 40069, Italy
| | - S Battaia
- Clinica Veterinaria Malpensa, AniCura, Via G. Marconi 27, Samarate, Varese, 21017, Italy; Ospedale Veterinario I Portoni Rossi, Via Roma 57, Zola Predosa, Bologna, 40069, Italy
| | - M Borgarelli
- Virginia-Maryland College of Veterinary Medicine, 205 Duck Pond Dr, Blacksburg, VA, 24060, USA
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22
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Leventopoulos G, Perperis A, Karelas D, Almpanis G. You cannot ablate the Lernaean Hydra: SCN5A mutation in a patient with multifocal ectopic Purkinje-related premature contractions syndrome treated with Flecainide and an implant of a subcutaneous defibrillator—a case report. Eur Heart J Case Rep 2021; 5:ytab158. [PMID: 33959699 PMCID: PMC8086419 DOI: 10.1093/ehjcr/ytab158] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/28/2020] [Accepted: 04/12/2021] [Indexed: 12/19/2022]
Abstract
Background SCN5A mutations may present with different clinical phenotypes such as Brugada syndrome, long QT3 syndrome, sick sinus syndrome, atrial fibrillation, dilated cardiomyopathy, and the least known multifocal ectopic Purkinje-related premature contractions syndrome. Case summary We report a case of a 29-year-old woman with palpitations due to multifocal premature ventricular complexes (PVCs) and a family history of sudden death. The previous electrophysiological study had shown that PVCs arose from Purkinje fibres but catheter ablation was unsuccessful. Cardiac magnetic resonance (CMR) imaging demonstrated non-ischaemic areas of subendocardial fibrosis at multiple left ventricular (LV) segments with concomitant dilatation and mild systolic impairment. Amiodarone suppressed the ectopy but caused hyperthyroidism. Due to recent pregnancy, she received no antiarrhythmics which resulted in PVC burden increase and further deterioration of the ejection fraction (EF). After gestation, amiodarone was reinitiated and switched to flecainide after implantation of a subcutaneous defibrillator as a safety net. At follow-up, LV function had almost normalized. Genetic analysis confirmed an SCN5A mutation. Discussion Multifocal ectopic Purkinje-related premature contractions syndrome is associated with SCN5A mutation which in our case (R222Q) is the most common described. Flecainide can be an appropriate treatment option when ablation is ineffective. Defibrillator—even a subcutaneous type—could be implanted in cases of LV dysfunction or scar. PVCs suppression by flecainide and restoration of EF implies an arrhythmia—induced mechanism of LV impairment.
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Sasaki T, Ikeda K, Nakajima T, Kawabata-Iwakawa R, Iizuka T, Dharmawan T, Tamura S, Niwamae N, Tange S, Nishiyama M, Kaneko Y, Kurabayashi M. Multiple arrhythmic and cardiomyopathic phenotypes associated with an SCN5A A735E mutation. J Electrocardiol 2021; 65:122-127. [PMID: 33610078 DOI: 10.1016/j.jelectrocard.2021.01.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 01/29/2021] [Accepted: 01/29/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND SCN5A mutations are associated with multiple arrhythmic and cardiomyopathic phenotypes including Brugada syndrome (BrS), sinus node dysfunction (SND), atrioventricular block, supraventricular tachyarrhythmias (SVTs), long QT syndrome (LQTS), dilated cardiomyopathy and left ventricular noncompaction. Several single SCN5A mutations have been associated with overlap of some of these phenotypes, but never with overlap of all the phenotypes. OBJECTIVE We encountered two pedigrees with multiple arrhythmic phenotypes with or without cardiomyopathic phenotypes, and sought to identify a responsible mutation and reveal its functional abnormalities. METHODS Target panel sequencing of 72 genes, including inherited arrhythmia syndromes- and cardiomyopathies-related genes, was employed in two probands. Cascade screening was performed by Saner sequencing. Wild-type or identified mutant SCN5A were expressed in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp techniques. RESULTS We identified an SCN5A A735E mutation in these probands, but did not identify any other mutations. All eight mutation carriers exhibited at least one of the arrhythmic phenotypes. Two patients exhibited multiple arrhythmic phenotypes: one (15-year-old girl) exhibited BrS, SND, and exercise and epinephrine-induced QT prolongation, the other (4-year-old boy) exhibited BrS, SND, and SVTs. Another one (30-year-old male) exhibited all arrhythmic and cardiomyopathic phenotypes, except for LQTS. One male suddenly died at age 22. Functional analysis revealed that the mutant did not produce functional INa. CONCLUSIONS A non-functional SCN5A A735E mutation could be associated with multiple arrhythmic and cardiomyopathic phenotypes, although there remains a possibility that other unidentified factors may be involved in the phenotypic variability of the mutation carriers.
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Affiliation(s)
- Takashi Sasaki
- Department of Cardiovascular Medicine, Japanese Red Cross Maebashi Hospital, Maebashi, Gunma, Japan
| | - Kentaro Ikeda
- Department of Cardiology, Gunma Children's Medical Center, Shibukawa, Gunma, Japan
| | - Tadashi Nakajima
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
| | - Reika Kawabata-Iwakawa
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Gunma, Japan
| | - Takashi Iizuka
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Tommy Dharmawan
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Shuntaro Tamura
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Nogiku Niwamae
- Department of Cardiovascular Medicine, Japanese Red Cross Maebashi Hospital, Maebashi, Gunma, Japan
| | - Shoichi Tange
- Department of Cardiovascular Medicine, Japanese Red Cross Maebashi Hospital, Maebashi, Gunma, Japan
| | | | - Yoshiaki Kaneko
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Masahiko Kurabayashi
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
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24
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Lorenzini M, Burel S, Lesage A, Wagner E, Charrière C, Chevillard PM, Evrard B, Maloney D, Ruff KM, Pappu RV, Wagner S, Nerbonne JM, Silva JR, Townsend RR, Maier LS, Marionneau C. Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites. J Gen Physiol 2021; 153:211660. [PMID: 33410863 PMCID: PMC7797897 DOI: 10.1085/jgp.202012646] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 10/23/2020] [Accepted: 12/03/2020] [Indexed: 12/16/2022] Open
Abstract
Phosphorylation of the voltage-gated Na+ (NaV) channel NaV1.5 regulates cardiac excitability, yet the phosphorylation sites regulating its function and the underlying mechanisms remain largely unknown. Using a systematic, quantitative phosphoproteomic approach, we analyzed NaV1.5 channel complexes purified from nonfailing and failing mouse left ventricles, and we identified 42 phosphorylation sites on NaV1.5. Most sites are clustered, and three of these clusters are highly phosphorylated. Analyses of phosphosilent and phosphomimetic NaV1.5 mutants revealed the roles of three phosphosites in regulating NaV1.5 channel expression and gating. The phosphorylated serines S664 and S667 regulate the voltage dependence of channel activation in a cumulative manner, whereas the nearby S671, the phosphorylation of which is increased in failing hearts, regulates cell surface NaV1.5 expression and peak Na+ current. No additional roles could be assigned to the other clusters of phosphosites. Taken together, our results demonstrate that ventricular NaV1.5 is highly phosphorylated and that the phosphorylation-dependent regulation of NaV1.5 channels is highly complex, site specific, and dynamic.
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Affiliation(s)
- Maxime Lorenzini
- Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France
| | - Sophie Burel
- Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France
| | - Adrien Lesage
- Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France
| | - Emily Wagner
- Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO
| | - Camille Charrière
- Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France
| | - Pierre-Marie Chevillard
- Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France
| | - Bérangère Evrard
- Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France
| | - Dan Maloney
- Bioinformatics Solutions Inc., Waterloo, Ontario, Canada
| | - Kiersten M Ruff
- Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO
| | - Rohit V Pappu
- Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO
| | - Stefan Wagner
- Department of Internal Medicine II, University Heart Center, University Hospital Regensburg, Regensburg, Germany
| | - Jeanne M Nerbonne
- Department of Developmental Biology, Washington University Medical School, St. Louis, MO.,Department of Medicine, Washington University Medical School, St. Louis, MO
| | - Jonathan R Silva
- Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO
| | - R Reid Townsend
- Department of Medicine, Washington University Medical School, St. Louis, MO.,Department of Cell Biology and Physiology, Washington University Medical School, St. Louis, MO
| | - Lars S Maier
- Department of Internal Medicine II, University Heart Center, University Hospital Regensburg, Regensburg, Germany
| | - Céline Marionneau
- Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France
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25
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Marchal GA, Verkerk AO, Mohan RA, Wolswinkel R, Boukens BJD, Remme CA. The sodium channel Na V 1.5 impacts on early murine embryonic cardiac development, structure and function in a non-electrogenic manner. Acta Physiol (Oxf) 2020; 230:e13493. [PMID: 32386467 PMCID: PMC7539970 DOI: 10.1111/apha.13493] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/15/2020] [Accepted: 05/01/2020] [Indexed: 12/19/2022]
Abstract
AIM The voltage-gated sodium channel NaV 1.5, encoded by SCN5A, is essential for cardiac excitability and ensures proper electrical conduction. Early embryonic death has been observed in several murine models carrying homozygous Scn5amutations. We investigated when sodium current (INa ) becomes functionally relevant in the murine embryonic heart and how Scn5a/NaV 1.5 dysfunction impacts on cardiac development. METHODS Involvement of NaV 1.5-generated INa in murine cardiac electrical function was assessed by optical mapping in wild type (WT) embryos (embryonic day (E)9.5 and E10.5) in the absence and presence of the sodium channel blocker tetrodotoxin (30 µmol/L). INa was assessed by patch-clamp analysis in cardiomyocytes isolated from WT embryos (E9.5-17.5). In addition, cardiac morphology and electrical function was assessed in Scn5a-1798insD-/- embryos (E9.5-10.5) and their WT littermates. RESULTS In WT embryos, tetrodotoxin did not affect cardiac activation at E9.5, but slowed activation at E10.5. Accordingly, patch-clamp measurements revealed that INa was virtually absent at E9.5 but robustly present at E10.5. Scn5a-1798insD-/- embryos died in utero around E10.5, displaying severely affected cardiac activation and morphology. Strikingly, altered ventricular activation was observed in Scn5a-1798insD-/- E9.5 embryos before the onset of INa , in addition to reduced cardiac tissue volume compared to WT littermates. CONCLUSION We here demonstrate that NaV 1.5 is involved in cardiac electrical function from E10.5 onwards. Scn5a-1798insD-/- embryos displayed cardiac structural abnormalities at E9.5, indicating that NaV 1.5 dysfunction impacts on embryonic cardiac development in a non-electrogenic manner. These findings are potentially relevant for understanding structural defects observed in relation to NaV 1.5 dysfunction.
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Affiliation(s)
- Gerard A. Marchal
- Department of Experimental Cardiology Amsterdam UMC (location Academic Medical Center) Amsterdam the Netherlands
| | - Arie O. Verkerk
- Department of Experimental Cardiology Amsterdam UMC (location Academic Medical Center) Amsterdam the Netherlands
- Department of Medical Biology Amsterdam UMC (location Academic Medical Center) Amsterdam the Netherlands
| | - Rajiv A. Mohan
- Department of Experimental Cardiology Amsterdam UMC (location Academic Medical Center) Amsterdam the Netherlands
- Department of Medical Biology Amsterdam UMC (location Academic Medical Center) Amsterdam the Netherlands
| | - Rianne Wolswinkel
- Department of Experimental Cardiology Amsterdam UMC (location Academic Medical Center) Amsterdam the Netherlands
| | - Bastiaan J. D. Boukens
- Department of Medical Biology Amsterdam UMC (location Academic Medical Center) Amsterdam the Netherlands
| | - Carol Ann Remme
- Department of Experimental Cardiology Amsterdam UMC (location Academic Medical Center) Amsterdam the Netherlands
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26
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Tse G, Lee S, Liu T, Yuen HC, Wong ICK, Mak C, Mok NS, Wong WT. Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong. Front Physiol 2020; 11:574590. [PMID: 33071830 PMCID: PMC7531256 DOI: 10.3389/fphys.2020.574590] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 08/26/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The aim of this study is to report on the genetic composition of Brugada syndrome (BrS) patients undergoing genetic testing in Hong Kong. METHODS Patients with suspected BrS who presented to the Hospital Authority of Hong Kong between 1997 and 2019, and underwent genetic testing, were analyzed retrospectively. RESULTS A total of 65 subjects were included (n = 65, 88% male, median presenting age 42 [30-54] years old, 58% type 1 pattern). Twenty-two subjects (34%) showed abnormal genetic test results, identifying the following six novel, pathogenic or likely pathogenic mutations in SCN5A: c.674G > A, c.2024-11T > A, c.2042A > C, c.4279G > T, c.5689C > T, c.429del. Twenty subjects (31%) in the cohort suffered from spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) and 18 (28%) had incident VT/VF over a median follow-up of 83 [Q1-Q3: 52-112] months. Univariate Cox regression demonstrated that syncope (hazard ratio [HR]: 4.27 [0.95-19.30]; P = 0.059), prior VT/VF (HR: 21.34 [5.74-79.31; P < 0.0001) and T-wave axis (HR: 0.970 [0.944-0.998]; P = 0.036) achieved P < 0.10 for predicting incident VT/VF. After multivariate adjustment, only prior VT/VF remained a significant predictor (HR: 12.39 [2.97-51.67], P = 0.001). CONCLUSION This study identified novel mutations in SCN5A in a Chinese cohort of BrS patients.
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Affiliation(s)
- Gary Tse
- Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, China
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Sharen Lee
- Laboratory of Cardiovascular Physiology, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Ho Chuen Yuen
- Department of Medicine and Geriatrics, Princess Margaret Hospital, Kowloon, China
| | - Ian Chi Kei Wong
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China
- School of Pharmacy, University College London, London, United Kingdom
| | - Chloe Mak
- Department of Pathology, Hong Kong Children’s Hospital, Kowloon, China
| | - Ngai Shing Mok
- Department of Medicine and Geriatrics, Princess Margaret Hospital, Kowloon, China
| | - Wing Tak Wong
- State Key Laboratory of Agrobiotechnology (CUHK), School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
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27
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Glazer AM, Wada Y, Li B, Muhammad A, Kalash OR, O'Neill MJ, Shields T, Hall L, Short L, Blair MA, Kroncke BM, Capra JA, Roden DM. High-Throughput Reclassification of SCN5A Variants. Am J Hum Genet 2020; 107:111-123. [PMID: 32533946 PMCID: PMC7332654 DOI: 10.1016/j.ajhg.2020.05.015] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/19/2020] [Indexed: 12/19/2022] Open
Abstract
Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence data in clinical care. We selected 83 variants: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada syndrome-associated variants, selected on the basis of their frequency in the general population and in individuals with Brugada syndrome. We used high-throughput automated patch clamping to study the function of the 83 variants, with the goal of reclassifying variants with functional data. The ten previously studied controls had functional properties concordant with published manual patch clamp data. All 10 suspected benign variants had wild-type-like function. 22 suspected BrS variants had loss of channel function (<10% normalized peak current) and 22 variants had partial loss of function (10%-50% normalized peak current). The previously unstudied variants were initially classified as likely benign (n = 2), likely pathogenic (n = 10), or VUSs (n = 61). After the patch clamp studies, 16 variants were benign/likely benign, 45 were pathogenic/likely pathogenic, and only 12 were still VUSs. Structural modeling identified likely mechanisms for loss of function including altered thermostability and disruptions to alpha helices, disulfide bonds, or the permeation pore. High-throughput patch clamping enabled reclassification of the majority of tested VUSs in SCN5A.
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Affiliation(s)
- Andrew M Glazer
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Yuko Wada
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Bian Li
- Department of Biological Sciences, Center for Structural Biology, and Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA
| | - Ayesha Muhammad
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Olivia R Kalash
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Matthew J O'Neill
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Tiffany Shields
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Lynn Hall
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Laura Short
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Marcia A Blair
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Brett M Kroncke
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - John A Capra
- Department of Biological Sciences, Center for Structural Biology, and Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA
| | - Dan M Roden
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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28
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Musa H, Marcou CA, Herron TJ, Makara MA, Tester DJ, O'Connell RP, Rosinski B, Guerrero-Serna G, Milstein ML, Monteiro da Rocha A, Ye D, Crotti L, Nesterenko VV, Castelletti S, Torchio M, Kotta MC, Dagradi F, Antzelevitch C, Mohler PJ, Schwartz PJ, Ackerman MJ, Anumonwo JM. Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk. Am J Physiol Heart Circ Physiol 2020; 318:H1357-H1370. [PMID: 32196358 DOI: 10.1152/ajpheart.00481.2019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 (DLG1) variants that were associated with inherited arrhythmogenic disease. The murine model of cardiac-specific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no DLG1 mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human DLG1 mutation resulting in an increase in Kv4.3 current (Ito) as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, DLG1 joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease.NEW & NOTEWORTHY The gene encoding SAP97 (DLG1) joins a growing list of genes encoding ion channel-interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1-encoded SAP97's candidacy as a minor Brugada syndrome susceptibility gene.
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Affiliation(s)
- Hassan Musa
- Departments of Internal Medicine and of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio.,Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan
| | - Cherisse A Marcou
- Division of Heart Rhythm Services, Department of Cardiovascular Diseases; Division of Pediatric Cardiology, Department of Pediatrics; and Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
| | - Todd J Herron
- Departments of Internal Medicine and of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio.,Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan.,Cardiovascular Regeneration Core Laboratory, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan
| | - Michael A Makara
- Departments of Internal Medicine and of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - David J Tester
- Division of Heart Rhythm Services, Department of Cardiovascular Diseases; Division of Pediatric Cardiology, Department of Pediatrics; and Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
| | - Ryan P O'Connell
- Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan
| | - Brad Rosinski
- Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan
| | - Guadalupe Guerrero-Serna
- Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan
| | - Michelle L Milstein
- Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan
| | - André Monteiro da Rocha
- Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan.,Cardiovascular Regeneration Core Laboratory, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan
| | - Dan Ye
- Division of Heart Rhythm Services, Department of Cardiovascular Diseases; Division of Pediatric Cardiology, Department of Pediatrics; and Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
| | - Lia Crotti
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,IRCCS Istituto Auxologico Italiano, San Luca Hospital, Milan, Italy.,IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy
| | | | - Silvia Castelletti
- IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy
| | - Margherita Torchio
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy
| | - Maria-Christina Kotta
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy
| | - Federica Dagradi
- IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy
| | | | - Peter J Mohler
- Departments of Internal Medicine and of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio.,Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio
| | - Peter J Schwartz
- IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy
| | - Michael J Ackerman
- Division of Heart Rhythm Services, Department of Cardiovascular Diseases; Division of Pediatric Cardiology, Department of Pediatrics; and Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
| | - Justus M Anumonwo
- Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan
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29
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Li KHC, Lee S, Yin C, Liu T, Ngarmukos T, Conte G, Yan GX, Sy RW, Letsas KP, Tse G. Brugada syndrome: A comprehensive review of pathophysiological mechanisms and risk stratification strategies. IJC HEART & VASCULATURE 2020; 26:100468. [PMID: 31993492 PMCID: PMC6974766 DOI: 10.1016/j.ijcha.2020.100468] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 01/01/2020] [Accepted: 01/02/2020] [Indexed: 12/17/2022]
Abstract
Brugada syndrome (BrS) is an inherited ion channel channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Originally believed to be predominantly associated with mutations in SCN5A encoding for the cardiac sodium channel, mutations of 18 genes other than SCN5A have been implicated in the pathogenesis of BrS to date. Diagnosis is based on the presence of a spontaneous or drug-induced coved-type ST segment elevation. The predominant electrophysiological mechanism underlying BrS remains disputed, commonly revolving around the three main hypotheses based on abnormal repolarization, depolarization or current-load match. Evidence from computational modelling, pre-clinical and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening ventricular arrhythmic events. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers. Current treatment options include pharmacological therapy to reduce the occurrence of arrhythmic events or to abort these episodes, and interventions such as implantable cardioverter-defibrillator insertion or radiofrequency ablation of abnormal arrhythmic substrate.
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Affiliation(s)
- Ka Hou Christien Li
- Faculty of Medicine, Newcastle University, Newcastle, United Kingdom.,Laboratory of Cardiovascular Physiology, Li Ka Shing Institute of Health Sciences, Hong Kong, SAR, PR China
| | - Sharen Lee
- Laboratory of Cardiovascular Physiology, Li Ka Shing Institute of Health Sciences, Hong Kong, SAR, PR China
| | - Chengye Yin
- School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, PR China
| | - Tachapong Ngarmukos
- Department of Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University, Bangkok, Thailand
| | - Giulio Conte
- Division of Cardiology, Cardiocentro Ticino, Lugano, Switzerland
| | - Gan-Xin Yan
- Lankenau Institute for Medical Research and Lankenau Medical Center, Wynnewood, PA, USA
| | - Raymond W Sy
- Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.,Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia
| | - Konstantinos P Letsas
- Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, Evangelismos General Hospital of Athens, Athens, Greece
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, PR China.,Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, China
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30
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Doisne N, Waldmann V, Redheuil A, Waintraub X, Fressart V, Ader F, Fossé L, Hidden-Lucet F, Gandjbakhch E, Neyroud N. A novel gain-of-function mutation in SCN5A responsible for multifocal ectopic Purkinje-related premature contractions. Hum Mutat 2020; 41:850-859. [PMID: 31930659 DOI: 10.1002/humu.23981] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 12/13/2019] [Accepted: 01/02/2020] [Indexed: 12/19/2022]
Abstract
Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy (DCM). Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and DCM. After failure of antiarrhythmic drugs and an attempt of radiofrequency catheter ablation showing three exit-sites of PVCs, all with presystolic Purkinje potentials, a treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs and normalization of cardiac function. Electrophysiological studies showed that Nav 1.5-A204E mutant channels exhibited a significant leftward shift of 8 mV of the activation curve, leading to a larger hyperpolarized window current when compared to wild-type. Action potential modeling using Purkinje fiber and ventricular cell models predicted an arrhythmogenic effect predominant in Purkinje fibers for the A204E mutation. Comparison with other MEPPC-associated Nav 1.5 mutations revealed a common electrophysiological pattern of abnormal voltage-dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of this syndrome. These features of the mutant sodium channels are likely to be responsible for the hyperexcitability of the fascicular-Purkinje system observed in patients with MEPPC.
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Affiliation(s)
- Nicolas Doisne
- Faculté de Médecine, Sorbonne Université, Paris, France.,INSERM, UMR_S1166, Hôpital Pitié-Salpêtrière, Paris, France.,ICAN, Institute of Cardiometabolism and Nutrition, Paris, France
| | - Victor Waldmann
- Département de Cardiologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Alban Redheuil
- Faculté de Médecine, Sorbonne Université, Paris, France.,ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.,Département d'Imagerie Cardiovasculaire, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Xavier Waintraub
- ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.,Département de Cardiologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Véronique Fressart
- Faculté de Médecine, Sorbonne Université, Paris, France.,INSERM, UMR_S1166, Hôpital Pitié-Salpêtrière, Paris, France.,ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.,Département de Biochimie métabolique, Cardiogénétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Flavie Ader
- Faculté de Médecine, Sorbonne Université, Paris, France.,INSERM, UMR_S1166, Hôpital Pitié-Salpêtrière, Paris, France.,ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.,Département de Biochimie métabolique, Cardiogénétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Lucie Fossé
- Faculté de Médecine, Sorbonne Université, Paris, France.,INSERM, UMR_S1166, Hôpital Pitié-Salpêtrière, Paris, France
| | - Françoise Hidden-Lucet
- ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.,Département de Cardiologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Estelle Gandjbakhch
- Faculté de Médecine, Sorbonne Université, Paris, France.,INSERM, UMR_S1166, Hôpital Pitié-Salpêtrière, Paris, France.,ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.,Département de Cardiologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Nathalie Neyroud
- Faculté de Médecine, Sorbonne Université, Paris, France.,INSERM, UMR_S1166, Hôpital Pitié-Salpêtrière, Paris, France.,ICAN, Institute of Cardiometabolism and Nutrition, Paris, France
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Glazer AM, Kroncke BM, Matreyek KA, Yang T, Wada Y, Shields T, Salem JE, Fowler DM, Roden DM. Deep Mutational Scan of an SCN5A Voltage Sensor. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2020; 13:e002786. [PMID: 31928070 DOI: 10.1161/circgen.119.002786] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Variants in ion channel genes have classically been studied in low throughput by patch clamping. Deep mutational scanning is a complementary approach that can simultaneously assess function of thousands of variants. METHODS We have developed and validated a method to perform a deep mutational scan of variants in SCN5A, which encodes the major voltage-gated sodium channel in the heart. We created a library of nearly all possible variants in a 36 base region of SCN5A in the S4 voltage sensor of domain IV and stably integrated the library into HEK293T cells. RESULTS In preliminary experiments, challenge with 3 drugs (veratridine, brevetoxin, and ouabain) could discriminate wild-type channels from gain- and loss-of-function pathogenic variants. High-throughput sequencing of the pre- and postdrug challenge pools was used to count the prevalence of each variant and identify variants with abnormal function. The deep mutational scan scores identified 40 putative gain-of-function and 33 putative loss-of-function variants. For 8 of 9 variants, patch clamping data were consistent with the scores. CONCLUSIONS These experiments demonstrate the accuracy of a high-throughput in vitro scan of SCN5A variant function, which can be used to identify deleterious variants in SCN5A and other ion channel genes.
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Affiliation(s)
- Andrew M Glazer
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Arrhythmia Research and Therapeutics (A.M.G., B.M.K., T.Y., Y.W., T.S., J.-E.S., D.M.R.), Vanderbilt University Medical Center, Nashville, TN
| | - Brett M Kroncke
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Arrhythmia Research and Therapeutics (A.M.G., B.M.K., T.Y., Y.W., T.S., J.-E.S., D.M.R.), Vanderbilt University Medical Center, Nashville, TN
| | - Kenneth A Matreyek
- Department of Genome Sciences, University of Washington, Seattle (K.A.M., D.M.F.)
| | - Tao Yang
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Arrhythmia Research and Therapeutics (A.M.G., B.M.K., T.Y., Y.W., T.S., J.-E.S., D.M.R.), Vanderbilt University Medical Center, Nashville, TN
| | - Yuko Wada
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Arrhythmia Research and Therapeutics (A.M.G., B.M.K., T.Y., Y.W., T.S., J.-E.S., D.M.R.), Vanderbilt University Medical Center, Nashville, TN
| | - Tiffany Shields
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Arrhythmia Research and Therapeutics (A.M.G., B.M.K., T.Y., Y.W., T.S., J.-E.S., D.M.R.), Vanderbilt University Medical Center, Nashville, TN
| | - Joe-Elie Salem
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Arrhythmia Research and Therapeutics (A.M.G., B.M.K., T.Y., Y.W., T.S., J.-E.S., D.M.R.), Vanderbilt University Medical Center, Nashville, TN.,Department of Clinical Pharmacology, APHP, Sorbonne Université, INSERM, CIC-1421, Hôpital Pitié-Salpêtrière, Paris, France (J.-E.S.)
| | - Douglas M Fowler
- Department of Genome Sciences, University of Washington, Seattle (K.A.M., D.M.F.)
| | - Dan M Roden
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Arrhythmia Research and Therapeutics (A.M.G., B.M.K., T.Y., Y.W., T.S., J.-E.S., D.M.R.), Vanderbilt University Medical Center, Nashville, TN.,Department of Biomedical Informatics (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.,Department of Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, TN
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Neubauer J, Wang Z, Rougier JS, Abriel H, Rieubland C, Bartholdi D, Haas C, Medeiros-Domingo A. Functional characterization of a novel SCN5A variant associated with long QT syndrome and sudden cardiac death. Int J Legal Med 2019; 133:1733-1742. [DOI: 10.1007/s00414-019-02141-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 08/06/2019] [Indexed: 12/14/2022]
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33
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Nieto-Marín P, Jiménez-Jáimez J, Tinaquero D, Alfayate S, Utrilla RG, Rodríguez Vázquez del Rey MDM, Perin F, Sarquella-Brugada G, Monserrat L, Brugada J, Tercedor L, Tamargo J, Delpón E, Caballero R. La expresividad variable del síndrome de QT largo de una familia española se explica por la heterocigosis digénica en SCN5A y CACNA1C. Rev Esp Cardiol (Engl Ed) 2019. [DOI: 10.1016/j.recesp.2018.03.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Dehghani-Samani A, Madreseh-Ghahfarokhi S, Dehghani-Samani A. Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias. ACTA CARDIOLOGICA SINICA 2019; 35:99-110. [PMID: 30930557 PMCID: PMC6434417 DOI: 10.6515/acs.201903_35(2).20181028a] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 10/28/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Arrhythmias as important malfunctions of heart are known as abnormal rhythm of heart. Several causes can make arrhythmias and most of them are related to generation and/or conduction of action potential in heart. Action potential in myocytes results from the sequential opening and closing of ion channel proteins that span the plasma membrane of individual myocytes. Action potential's conduction through the heart is depended on electrical coupling between myocytes, which is mediated by gap junctions. Generation and conduction of action potentials are related to perfect action of ionic channels in heart. OBJECTIVES This novel review comprehensively addressed the ionic mechanisms of the arrhythmogenic mutations in cardiac voltage-gated ionic channels including: CACNA1C, CACNA1D, KCNA5, KCND2, KCND3, KCNE1, KCNE2, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4A, SCN5A, SCN1B, SCN2B, SCN3B and SCN4B. METHODS Current study, for the first time, review and discuses about relation between cardiac arrhythmias and whole of important voltage gated ionic channels from different families, altogether and at the same time. RESULTS This review clears that mutations in voltage-gated ionic channels play important roles in generation of severe cardiac arrhythmias, and among them it is looked that mutations in voltage-gated potassium channels are more important. CONCLUSIONS Most of induced arrhythmias due to voltage-gated ionic channels mutations result in action potentials prolongation and long QT syndromes. Study on ionic channel regulators can be considered as a subject for future research.
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Affiliation(s)
- Amir Dehghani-Samani
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord
| | - Samin Madreseh-Ghahfarokhi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad
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35
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Pan Z, Ai T, Chang PC, Liu Y, Liu J, Maruyama M, Homsi M, Fishbein MC, Rubart M, Lin SF, Xiao D, Chen H, Chen PS, Shou W, Li BY. Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12. Am J Physiol Heart Circ Physiol 2019; 316:H371-H379. [PMID: 30499712 PMCID: PMC6397388 DOI: 10.1152/ajpheart.00486.2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 11/19/2018] [Accepted: 11/19/2018] [Indexed: 12/19/2022]
Abstract
Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.
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Affiliation(s)
- Zhenwei Pan
- Department of Pharmacology, Harbin Medical University, Heilonjiang, China
- Krannert Institute for Cardiology and the Division of Cardiology, Indiana University School of Medicine , Indianapolis, Indiana
| | - Tomohiko Ai
- Krannert Institute for Cardiology and the Division of Cardiology, Indiana University School of Medicine , Indianapolis, Indiana
| | - Po-Cheng Chang
- Krannert Institute for Cardiology and the Division of Cardiology, Indiana University School of Medicine , Indianapolis, Indiana
- The Second Section of Cardiology, Departments of Medicine, Chang Gung Memorial Hospital and Chang Gung University School of Medicine , Taoyuan , Taiwan
| | - Ying Liu
- Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, Indiana
| | - Jijia Liu
- Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, Indiana
- The Second Xiangya Hospital, South Central University School of Medicine , China
| | - Mitsunori Maruyama
- Krannert Institute for Cardiology and the Division of Cardiology, Indiana University School of Medicine , Indianapolis, Indiana
| | - Mohamed Homsi
- Krannert Institute for Cardiology and the Division of Cardiology, Indiana University School of Medicine , Indianapolis, Indiana
| | - Michael C Fishbein
- Department of Pathology and Laboratory Medicine, University of California , Los Angeles, California
| | - Michael Rubart
- Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, Indiana
| | - Shien-Fong Lin
- Krannert Institute for Cardiology and the Division of Cardiology, Indiana University School of Medicine , Indianapolis, Indiana
| | - Deyong Xiao
- Fountain Valley Biotechnology, Inc., Dalian Hi-Tech District, Dalian , China
| | - Hanying Chen
- Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, Indiana
| | - Peng-Sheng Chen
- Krannert Institute for Cardiology and the Division of Cardiology, Indiana University School of Medicine , Indianapolis, Indiana
| | - Weinian Shou
- Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, Indiana
| | - Bai-Yan Li
- Department of Pharmacology, Harbin Medical University, Heilonjiang, China
- Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, Indiana
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Skinner JR, Winbo A, Abrams D, Vohra J, Wilde AA. Channelopathies That Lead to Sudden Cardiac Death: Clinical and Genetic Aspects. Heart Lung Circ 2019; 28:22-30. [DOI: 10.1016/j.hlc.2018.09.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 09/20/2018] [Accepted: 09/23/2018] [Indexed: 12/19/2022]
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Wilders R. Cellular Mechanisms of Sinus Node Dysfunction in Carriers of the SCN5A-E161K Mutation and Role of the H558R Polymorphism. Front Physiol 2018; 9:1795. [PMID: 30618807 PMCID: PMC6305593 DOI: 10.3389/fphys.2018.01795] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 11/29/2018] [Indexed: 12/16/2022] Open
Abstract
Background: Carriers of the E161K mutation in the SCN5A gene, encoding the NaV1.5 pore-forming α-subunit of the ion channel carrying the fast sodium current (INa), show sinus bradycardia and occasional exit block. Voltage clamp experiments in mammalian expression systems revealed a mutation-induced 2.5- to 4-fold reduction in INa peak current density as well as a +19 mV shift and reduced steepness of the steady-state activation curve. The highly common H558R polymorphism in NaV1.5 limits this shift to +13 mV, but also introduces a -10 mV shift in steady-state inactivation. Aim: We assessed the cellular mechanism by which the E161K mutation causes sinus node dysfunction in heterozygous mutation carriers as well as the potential role of the H558R polymorphism. Methods: We incorporated the mutation-induced changes in INa into the Fabbri-Severi model of a single human sinoatrial node cell and the Maleckar et al. human atrial cell model, and carried out simulations under control conditions and over a wide range of acetylcholine levels. Results: In absence of the H558R polymorphism, the E161K mutation increased the basic cycle length of the sinoatrial node cell from 813 to 866 ms. In the simulated presence of 10 and 25 nM acetylcholine, basic cycle length increased from 1027 to 1131 and from 1448 to 1795 ms, respectively. The increase in cycle length was the result of a significant slowing of diastolic depolarization. The mutation-induced reduction in INa window current had reduced the contribution of the mutant component of INa to the net membrane current during diastolic depolarization to effectively zero. Highly similar results were obtained in presence of the H558R polymorphism. Atrial excitability was reduced, both in absence and presence of the H558R polymorphism, as reflected by an increase in threshold stimulus current and a concomitant decrease in capacitive current of the atrial cell. Conclusion: We conclude that the experimentally identified mutation-induced changes in INa can explain the clinically observed sinus bradycardia and potentially the occasional exit block. Furthermore, we conclude that the common H558R polymorphism does not significantly alter the effects of the E161K mutation and can thus not explain the reduced penetrance of the E161K mutation.
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Affiliation(s)
- Ronald Wilders
- Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, Netherlands
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38
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van Mil A, Balk GM, Neef K, Buikema JW, Asselbergs FW, Wu SM, Doevendans PA, Sluijter JPG. Modelling inherited cardiac disease using human induced pluripotent stem cell-derived cardiomyocytes: progress, pitfalls, and potential. Cardiovasc Res 2018; 114:1828-1842. [PMID: 30169602 PMCID: PMC6887927 DOI: 10.1093/cvr/cvy208] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/06/2018] [Accepted: 08/28/2018] [Indexed: 12/17/2022] Open
Abstract
In the past few years, the use of specific cell types derived from induced pluripotent stem cells (iPSCs) has developed into a powerful approach to investigate the cellular pathophysiology of numerous diseases. Despite advances in therapy, heart disease continues to be one of the leading causes of death in the developed world. A major difficulty in unravelling the underlying cellular processes of heart disease is the extremely limited availability of viable human cardiac cells reflecting the pathological phenotype of the disease at various stages. Thus, the development of methods for directed differentiation of iPSCs to cardiomyocytes (iPSC-CMs) has provided an intriguing option for the generation of patient-specific cardiac cells. In this review, a comprehensive overview of the currently published iPSC-CM models for hereditary heart disease is compiled and analysed. Besides the major findings of individual studies, detailed methodological information on iPSC generation, iPSC-CM differentiation, characterization, and maturation is included. Both, current advances in the field and challenges yet to overcome emphasize the potential of using patient-derived cell models to mimic genetic cardiac diseases.
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Affiliation(s)
- Alain van Mil
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Geerthe Margriet Balk
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Klaus Neef
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Jan Willem Buikema
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Folkert W Asselbergs
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Faculty of Population Health Sciences, Institute of Cardiovascular Science, University College London, London, UK
- Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands
- Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK
| | - Sean M Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Pieter A Doevendans
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Joost P G Sluijter
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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Chorin E, Taub R, Medina A, Flint N, Viskin S, Benhorin J. Long-term flecainide therapy in type 3 long QT syndrome. Europace 2018; 20:370-376. [PMID: 28339995 DOI: 10.1093/europace/euw439] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 12/26/2016] [Indexed: 01/22/2023] Open
Abstract
Aims Type 3 long QT syndrome (LQT3) is caused by gain-of-function mutations in the cardiac sodium channel gene (SCN5A). Previous reports on the long-term use of sodium channel blockers in LQT3 are sparse. The objective of the current study was to evaluate the long-term safety and efficacy of flecainide therapy in patients with LQT3 who carry the D1790G SCN5A mutation. Methods and results The study population comprised 30 D1790G carriers who were treated with flecainide and followed for 1-215 months (mean 145 ± 54 months, median 140 months). The mean baseline (off-drug) QTc was 522 ± 45 ms, and shortened to 469 ± 36 ms with flecainide therapy, a mean decrease of 53 ms [10.1%] (P < 0.01). A QTc longer than 500 ms was evident in 53% of carriers at baseline, and only in 13% on flecainide. All carriers while being compliant with flecainide therapy had no cardiac events during an average follow up of 83 ± 73 months. Twenty carriers stopped flecainide after an average follow up of 40 ± 42 months without symptoms. Six of them (30%) had cardiac events 1-11 months after stopping flecainide. Flecainide induced the appearance of Brugada pattern in six carriers (20%, 5 males), was stopped in three and was not associated with arrhythmia. Sinus-node dysfunction was evident in six carriers (20%) and was fully corrected by flecainide in three. Conclusions These data suggest that long-term flecainide therapy is relatively safe and effective among LQT3 patients who carry the D1790G SCN5A mutation.
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Affiliation(s)
- Ehud Chorin
- Department of Cardiology, Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Rivki Taub
- Department of Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Aron Medina
- Department of Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Nir Flint
- Department of Cardiology, Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sami Viskin
- Department of Cardiology, Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jesaia Benhorin
- Department of Cardiology, Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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40
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Wang W, Zhang S, Ni H, Garratt CJ, Boyett MR, Hancox JC, Zhang H. Mechanistic insight into spontaneous transition from cellular alternans to arrhythmia-A simulation study. PLoS Comput Biol 2018; 14:e1006594. [PMID: 30500818 PMCID: PMC6291170 DOI: 10.1371/journal.pcbi.1006594] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 12/12/2018] [Accepted: 10/23/2018] [Indexed: 02/01/2023] Open
Abstract
Cardiac electrical alternans (CEA), manifested as T-wave alternans in ECG, is a clinical biomarker for predicting cardiac arrhythmias and sudden death. However, the mechanism underlying the spontaneous transition from CEA to arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular models were used to study the transition and a potential role of INa in perpetuating such a transition. It was shown CEA evolved into either concordant or discordant action potential (AP) conduction alternans in a homogeneous one-dimensional tissue model, depending on tissue AP duration and conduction velocity (CV) restitution properties. Discordant alternans was able to cause conduction failure in the model, which was promoted by impaired sodium channel with either a reduced or increased channel current. In a two-dimensional homogeneous tissue model, a combined effect of rate- and curvature-dependent CV broke-up alternating wavefronts at localised points, facilitating a spontaneous transition from CEA to re-entry. Tissue inhomogeneity or anisotropy further promoted break-up of re-entry, leading to multiple wavelets. Similar observations have also been seen in human atrial cellular and tissue models. In conclusion, our results identify a mechanism by which CEA spontaneously evolves into re-entry without a requirement for premature ventricular complexes or pre-existing tissue heterogeneities, and demonstrated the important pro-arrhythmic role of impaired sodium channel activity. These findings are model-independent and have potential human relevance.
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Affiliation(s)
- Wei Wang
- Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, United Kingdom
| | - Shanzhuo Zhang
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Haibo Ni
- Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, United Kingdom
| | - Clifford J. Garratt
- Manchester Heart Centre, Manchester Royal Infirmary, Manchester, United Kingdom
| | - Mark R. Boyett
- Manchester Heart Centre, Manchester Royal Infirmary, Manchester, United Kingdom
| | - Jules C. Hancox
- Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, United Kingdom
- School of Physiology, Pharmacology and Neuroscience, and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, United Kingdom
| | - Henggui Zhang
- Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, United Kingdom
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
- Space Institute of Southern China, Shenzhen, China
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41
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Elston S, Kaski J, Starling L. Long QT syndrome with a functional 2:1 block and multilevel conduction disease. PROGRESS IN PEDIATRIC CARDIOLOGY 2018. [DOI: 10.1016/j.ppedcard.2018.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Brandão KO, Tabel VA, Atsma DE, Mummery CL, Davis RP. Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies. Dis Model Mech 2018; 10:1039-1059. [PMID: 28883014 PMCID: PMC5611968 DOI: 10.1242/dmm.030320] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
It is now a decade since human induced pluripotent stem cells (hiPSCs) were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies. Here, we provide an overview of the current state of the field regarding the generation of cardiomyocytes from human pluripotent stem cells and methods to assess them functionally, an essential requirement when investigating disease and therapeutic outcomes. We critically evaluate whether treatments suggested by these in vitro models could be translated to clinical practice. Finally, we consider current shortcomings of these models and propose methods by which they could be further improved.
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Affiliation(s)
- Karina O Brandão
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Viola A Tabel
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Douwe E Atsma
- Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Richard P Davis
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Abstract
BACKGROUND SCN5A encodes sodium-channel α-subunit Nav1.5. The mutations of SCN5A can lead to hereditary cardiac arrhythmias such as the long-QT syndrome type 3 and Brugada syndrome. Here we sought to identify novel mutations in a family with arrhythmia. METHODS Genomic DNA was isolated from blood of the proband, who was diagnosed with atrial flutter. Illumina Hiseq 2000 whole-exome sequencing was performed and an arrhythmia-related gene-filtering strategy was used to analyse the pathogenic genes. Sanger sequencing was applied to verify the mutation co-segregated in the family.Results and conclusionsA novel missense mutation in SCN5A (C335R) was identified, and this mutation co-segregated within the affected family members. This missense mutation was predicted to result in amplitude reduction in peak Na+ current, further leading to channel protein dysfunction. Our study expands the spectrum of SCN5A mutations and contributes to genetic counselling of families with arrhythmia.
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Digenic Heterozigosity in SCN5A and CACNA1C Explains the Variable Expressivity of the Long QT Phenotype in a Spanish Family. ACTA ACUST UNITED AC 2018; 72:324-332. [PMID: 29691127 DOI: 10.1016/j.rec.2018.03.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 03/06/2018] [Indexed: 11/20/2022]
Abstract
INTRODUCTION AND OBJECTIVES A known long QT syndrome-related mutation in Nav1.5 cardiac channels (p.R1644H) was found in 4 members of a Spanish family but only 1 of them showed prolongation of the QT interval. In the other 3 relatives, a novel missense mutation in Cav1.2 cardiac channels was found (p.S1961N). Here, we functionally analyzed p.S1961N Cav1.2 channels to elucidate whether this mutation regulates the expressivity of the long QT syndrome phenotype in this family. METHODS L-type calcium current (ICaL) recordings were performed by using the whole-cell patch-clamp technique in Chinese hamster ovary cells transiently transfected with native and/or p.S1961N Cav1.2 channels. RESULTS Expression of p.S1961N channels significantly decreased ICaL density. Using Ba as a charge carrier to suppress the Ca-dependent inactivation of Cav1.2 channels, we demonstrated that the mutation significantly accelerates the voltage-dependent inactivation of Cav1.2 channels decreasing the inactivation time constant. As a consequence, the total charge flowing through p.S1961N Cav1.2 channels significantly decreased. The effects of the p.S1961N Cav1.2 and p.R1644H Nav1.5 mutations alone or their combination on the action potential (AP) morphology were simulated using a validated model of the human ventricular AP. The p.S1961N Cav1.2 mutation shortens the AP duration and abrogates the prolongation induced by p.R1644H Nav1.5 channels. CONCLUSIONS The p.S1961N mutation in Cav1.2 channels decreased the ICaL, an effect which might shorten ventricular AP. The presence of the loss-of-function Cav1.2 mutation could functionally compensate the prolonging effects produced by the Nav1.5 gain-of-function mutation.
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Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Na v 1.5 gain-of-function mutation (G213D). Int J Cardiol 2018; 257:160-167. [DOI: 10.1016/j.ijcard.2017.11.095] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 10/24/2017] [Accepted: 11/27/2017] [Indexed: 01/14/2023]
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Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations. Int J Mol Sci 2018; 19:ijms19020634. [PMID: 29473904 PMCID: PMC5855856 DOI: 10.3390/ijms19020634] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 02/13/2018] [Accepted: 02/19/2018] [Indexed: 11/25/2022] Open
Abstract
The SCN5A gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac fast sodium current (INa). The 1795insD mutation in SCN5A causes sinus bradycardia, with a mean heart rate of 70 beats/min in mutation carriers vs. 77 beats/min in non-carriers from the same family (lowest heart rate 41 vs. 47 beats/min). To unravel the underlying mechanism, we incorporated the mutation-induced changes in INa into a recently developed comprehensive computational model of a single human sinoatrial node cell (Fabbri–Severi model). The 1795insD mutation reduced the beating rate of the model cell from 74 to 69 beats/min (from 49 to 43 beats/min in the simulated presence of 20 nmol/L acetylcholine). The mutation-induced persistent INa per se resulted in a substantial increase in beating rate. This gain-of-function effect was almost completely counteracted by the loss-of-function effect of the reduction in INa conductance. The further loss-of-function effect of the shifts in steady-state activation and inactivation resulted in an overall loss-of-function effect of the 1795insD mutation. We conclude that the experimentally identified mutation-induced changes in INa can explain the clinically observed sinus bradycardia. Furthermore, we conclude that the Fabbri–Severi model may prove a useful tool in understanding cardiac pacemaker activity in humans.
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Schwartz PJ, Crotti L. Founder populations with channelopathies and church records reveal all sorts of interesting secrets: Some are scientifically relevant. Heart Rhythm 2017; 14:1882-1883. [DOI: 10.1016/j.hrthm.2017.09.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Indexed: 11/25/2022]
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The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3. Sci Rep 2017; 7:11070. [PMID: 28894151 PMCID: PMC5593918 DOI: 10.1038/s41598-017-11210-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/21/2017] [Indexed: 01/19/2023] Open
Abstract
Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p = 0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fibrosis (both: p < 0.001). Ventricles also showed increased fibrosis with age (p < 0.001). Age and Scn5a+/ΔKPQ interacted in increasing incidences of repolarisation alternans (p = 0.02). Dobutamine increased ventricular rate (p < 0.001) and reduced both atrioventricular conduction (PR segment-p = 0.02; PR interval-p = 0.02) and incidences of repolarisation alternans (p < 0.001) in all mice. However, in Scn5a+/ΔKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present findings implicate interactions between age and Scn5a+/ΔKPQ in prolonging ventricular activation, correlating them with fibrotic change for the first time, adding activation abnormalities to established recovery abnormalities in LQTS3. These findings, together with dynamic electrophysiological responses to β-adrenergic challenge, have therapeutic implications for ageing LQTS patients.
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Vanninen SUM, Nikus K, Aalto-Setälä K. Electrocardiogram changes and atrial arrhythmias in individuals carrying sodium channel SCN5A D1275N mutation. Ann Med 2017; 49:496-503. [PMID: 28294644 DOI: 10.1080/07853890.2017.1307515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION The cardiac sodium channel SCN5A regulates atrioventricular and ventricular depolarization as well as cardiac conduction. Patients with cardiac electrical abnormalities have an increased risk of sudden cardiac death (SCD) and cardio-embolic stroke. Optimal management of cardiac disease includes the understanding of association between the causative mutations and the clinical phenotype. A 12-lead electrocardiogram (ECG) is an easy and inexpensive tool for finding risk patients. MATERIALS AND METHODS A blood sample for DNA extraction was obtained in a Finnish family with 43 members; systematic 12-lead ECG analysis was performed in 13 of the family members carrying an SCN5A D1275N mutation. Conduction defects and supraventricular arrhythmias, including atrial fibrillation/flutter, atrioventricular nodal re-entry tachycardia (AVNRT) and junctional rhythm were searched for. RESULTS Five (38%) mutation carriers had fascicular or bundle branch block, 10 had atrial arrhythmias; no ventricular arrhythmias were found. Notching of the R- and S waves - including initial QRS fragmentation - and prolonged S-wave upstroke were present in all the affected family members. Notably, four (31%) affected family members had a stroke before the age of 31 and two experienced premature death. CONCLUSIONS A 12-lead ECG can be used to predict arrhythmias in SCN5A D1275N mutation carriers. Key messages The 12-lead ECG may reveal cardiac abnormalities even before clinical symptoms occur. Specific ECG findings - initial QRS fragmentation, prolonged S-wave upstroke as well as supraventricular arrhythmias - were frequently encountered in all SCN5A D1257N mutation carriers. ECG follow-up is recommended for all SCN5A D1275N mutation carriers.
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Affiliation(s)
| | - Kjell Nikus
- a Heart Center, Tampere University Hospital , Tampere , Finland.,b Faculty of Medicine and Life Sciences , University of Tampere , Tampere , Finland
| | - Katriina Aalto-Setälä
- a Heart Center, Tampere University Hospital , Tampere , Finland.,b Faculty of Medicine and Life Sciences , University of Tampere , Tampere , Finland.,c BioMediTech, University of Tampere , Tampere , Finland
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Sacilotto L, Epifanio HB, Darrieux FCDC, Wulkan F, Oliveira TGM, Hachul DT, Pereira ADC, Scanavacca MI. Compound Heterozygous SCN5A Mutations in a Toddler - Are they Associated with a More Severe Phenotype? Arq Bras Cardiol 2017; 108:70-73. [PMID: 28146213 PMCID: PMC5245850 DOI: 10.5935/abc.20170006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 10/10/2016] [Indexed: 12/02/2022] Open
Abstract
Compound heterozygosity has been described in inherited arrhythmias, and usually
associated with a more severe phenotype. Reports of this occurrence in Brugada
syndrome patients are still rare. We report a study of genotype-phenotype
correlation after the identification of new variants by genetic testing. We
describe the case of an affected child with a combination of two different
likely pathogenic SCN5A variants, presenting sinus node
dysfunction, flutter and atrial fibrillation, prolonged HV interval, spontaneous
type 1 Brugada pattern in the prepubescent age and familiar history of sudden
death.
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Affiliation(s)
- Luciana Sacilotto
- Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | | | - Fanny Wulkan
- Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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