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Zhang ZH, Barajas-Martinez H, Duan HY, Fan GH, Jiang H, Antzelevitch C, Xia H, Hu D. Characterization of novel arrhythmogenic patterns arising secondary to heterogeneous expression and activation of Nav1.8. Front Cardiovasc Med 2025; 12:1546803. [PMID: 40182425 PMCID: PMC11965590 DOI: 10.3389/fcvm.2025.1546803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 03/07/2025] [Indexed: 04/05/2025] Open
Abstract
Background Previous studies suggested that SCN10A/Nav1.8 may influence cardiac electrophysiology and the susceptibility to cardiac arrhythmias. Notably, the expression of SCN10A is not uniform, showing variable expression in each cardiac chamber. The present study aims to explore the functional significance of Nav1.8 expression among different cell types present in the ventricular myocardium. Methods The effect of the specific Nav1.8 blocker, A-803467, on action potential was recorded from epicardial, mid-myocardial (M cells) and Purkinje tissue slices isolated from the canine left ventricle using standard microelectrode techniques and on late sodium current from Purkinje cells using patch-clamp techniques. Results A-803467 treatment did not significantly affect maximum diastolic potential, action potential amplitude or maximum rate of rise of the action potential upstroke in epicardial cells, M cells or Purkinje fibers. Action potential duration (APD) was also unaffected by A-803467 in epicardial cells. However, administration of 1,000 nmol/L A-803467 reduced APD30, APD50, and APD90 during relatively slow pacing rates of 0.2 and 0.5 Hz in M cells. In Purkinje fibers, A-803467 (100 and 1,000 nmol/L) substantially abbreviated APD50 and APD90 at slow pacing rates (0.2 and 0.5 Hz). Moreover, 100 nmol/L A-803467 significantly inhibited the development of early afterdepolarizations induced by 10 nmol/L ATX-II (7/8 vs. 2/8, p < 0.05) as well as the amplitude of late sodium current at 0.2 Hz in Purkinje cells. Conclusions The functional significance of Nav1.8 varies among different types of ventricular and conduction system cardiomyocytes. The reduction in INa,L and APD, as well as suppression of early afterdepolarizations by Nav1.8 block in Purkinje fibers suggests Nav1.8 as a potential therapeutic target for bradycardia-dependent arrhythmias.
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Affiliation(s)
- Zhong-He Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Hector Barajas-Martinez
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Department, Lankenau Institute for Medical Research, Lankenau Heart Institute, Wynnwood, PA, United States
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
| | - Hong-Yi Duan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Guo-Hua Fan
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Charles Antzelevitch
- Cardiovascular Research Department, Lankenau Institute for Medical Research, Lankenau Heart Institute, Wynnwood, PA, United States
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
| | - Hao Xia
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Dan Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
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Xue G, Yang J, Zhang Y, Yang Y, Zhang R, Li D, Tian T, Li J, Zhang X, Li C, Li X, Yang J, Shen K, Guo Y, Liu X, Yang G, Xuan L, Shan H, Lu Y, Baofeng Y, Pan Z. Binding of LncDACH1 to dystrophin impairs the membrane trafficking of Nav1.5 protein and increases ventricular arrhythmia susceptibility. eLife 2025; 12:RP89690. [PMID: 39773412 PMCID: PMC11706603 DOI: 10.7554/elife.89690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. Long noncoding RNAs (lncRNAs) are involved in the regulation of cardiac ion channels, while their influence on sodium channels remains unexplored. Our preliminary data showed that lncRNA-Dachshund homolog 1 (lncDach1) can bind to dystrophin, which drove us to investigate if lncDach1 can regulate sodium channels by interfering with dystrophin. Western blot and immunofluorescent staining showed that cardiomyocyte-specific transgenic overexpression of lncDach1 (lncDach1-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. Meanwhile, peak INa was reduced in the hearts of lncDach1-TG mice than wild-type (WT) controls. The opposite data of western blot, immunofluorescent staining and patch clamp were collected from lncDach1 cardiomyocyte conditional knockout (lncDach1-cKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in lncDach1-TG mice in vivo and ex vivo. The conservative fragment of lncDach1 inhibited membrane distribution of dystrophin and Nav1.5, and promoted the inducibility of ventricular arrhythmia. Strikingly, activation of Dystrophin transcription by dCas9-SAM system in lncDach1-TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5, and prevented the occurrence of ventricular arrhythmia. Furthermore, lncDach1 was increased in transaortic constriction (TAC) induced failing hearts, which promoted the inducibility of ventricular arrhythmia. And the expression of lncDach1 is regulated by hydroxyacyl-CoA dehydrogenase subunit beta (hadhb), which binds to lncDach1 and decreases its stability. The human homologue of lncDACH1 inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. The findings provide novel insights into the mechanism of Nav1.5 membrane targeting and the development of ventricular arrhythmias.
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Affiliation(s)
- Genlong Xue
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
- The Institute of Heart and Vascular Diseases, Department of Cardiology, and Central Laboratory, the First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Jiming Yang
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Yang Zhang
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Ying Yang
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Ruixin Zhang
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Desheng Li
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Tao Tian
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Jialiang Li
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Xiaofang Zhang
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Changzhu Li
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Xingda Li
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Jiqin Yang
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Kewei Shen
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Yang Guo
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Xuening Liu
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Guohui Yang
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Lina Xuan
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Hongli Shan
- Shanghai Frontiers Science Research Center for Druggability of Cardiovascular noncoding RNA, Institute for Frontier Medical Technology, Shanghai University of Engineering ScienceShanghaiChina
| | - Yanjie Lu
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Yang Baofeng
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical SciencesBeijingChina
| | - Zhenwei Pan
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical UniversityHarbinChina
- NHC Key Laboratory of Cell Transplantation. The First Affiliated Hospital of Harbin Medical UniversityHarbinChina
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Beaudoin CA, Kohli M, Salvage SC, Liu H, Arundel SJ, Hamaia SW, Lei M, Huang CLH, Jackson AP. Isoform-specific N-linked glycosylation of NaV channel α-subunits alters β-subunit binding sites. J Gen Physiol 2025; 157:e202413609. [PMID: 39680039 PMCID: PMC11666101 DOI: 10.1085/jgp.202413609] [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: 05/22/2024] [Revised: 09/19/2024] [Accepted: 11/25/2024] [Indexed: 12/17/2024] Open
Abstract
Voltage-gated sodium channel α-subunits (NaV1.1-1.9) initiate and propagate action potentials in neurons and myocytes. The NaV β-subunits (β1-4) have been shown to modulate α-subunit properties. Homo-oligomerization of β-subunits on neighboring or opposing plasma membranes has been suggested to facilitate cis or trans interactions, respectively. The interactions between several NaV channel isoforms and β-subunits have been determined using cryogenic electron microscopy (cryo-EM). Interestingly, the NaV cryo-EM structures reveal the presence of N-linked glycosylation sites. However, only the first glycan moieties are typically resolved at each site due to the flexibility of mature glycan trees. Thus, existing cryo-EM structures may risk de-emphasizing the structural implications of glycans on the NaV channels. Herein, molecular modeling and all-atom molecular dynamics simulations were applied to investigate the conformational landscape of N-linked glycans on NaV channel surfaces. The simulations revealed that negatively charged sialic acid residues of two glycan sites may interact with voltage-sensing domains. Notably, two NaV1.5 isoform-specific glycans extensively cover the α-subunit region that, in other NaV channel α-subunit isoforms, corresponds to the binding site for the β1- (and likely β3-) subunit immunoglobulin (Ig) domain. NaV1.8 contains a unique N-linked glycosylation site that likely prevents its interaction with the β2 and β4-subunit Ig-domain. These isoform-specific glycans may have evolved to facilitate specific functional interactions, for example, by redirecting β-subunit Ig-domains outward to permit cis or trans supraclustering within specialized cellular compartments such as the cardiomyocyte perinexal space. Further experimental work is necessary to validate these predictions.
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Affiliation(s)
| | - Manas Kohli
- Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, UK
| | - Samantha C. Salvage
- Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, UK
| | - Hengrui Liu
- Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, UK
| | - Samuel J. Arundel
- Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, UK
| | - Samir W. Hamaia
- Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, UK
| | - Ming Lei
- Department of Pharmacology, University of Oxford, Oxford, UK
| | - Christopher L.-H. Huang
- Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, UK
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Antony P. Jackson
- Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, UK
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Kaye AD, Everett ES, Lehuquet AM, Mason JW, Maitski R, Plessala MJ, Barrie S, Baptiste CJ, Mychaskiw G, Ahmadzadeh S, Shekoohi S, Varrassi G. Frontiers in Acute Pain Management: Emerging Concepts in Pain Pathways and the Role of VX-548 as a Novel NaV1.8 Inhibitor: A Narrative Review. Curr Pain Headache Rep 2024; 28:1135-1143. [PMID: 38963514 DOI: 10.1007/s11916-024-01295-7] [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] [Accepted: 06/25/2024] [Indexed: 07/05/2024]
Abstract
PURPOSE OF REVIEW Despite ongoing research into alternative postsurgical pain treatments, opioids remain widely used analgesics regardless of associated adverse effects, including dependence and overdose, as demonstrated throughout the current opioid crisis. This is likely related to a failure in proving the efficacy of alternative analgesics in clinical trials, despite strong evidence supporting the potential for effective analgesia through in vitro studies. While NaV1.7 and NaV1.8 channels have shown to be key components of pain perception, studies regarding pharmacological agents utilizing these channels as targets have largely failed to demonstrate the efficacy of these proposed analgesics when compared to current multimodal pain treatment regimens. RECENT FINDINGS However, the novel NaV1.8 channel inhibitor, VX-548 has surpassed previously studied NaV1.8 inhibitors in clinical trials and continues to hold promise of a novel efficacious analgesic to potentially be utilized in multimodal pain treatment on postsurgical patients. Additionally, NaV1.8 is encoded by the SCN10A, which has been shown to be minimally expressed in the brain, suggesting a lower likelihood of adverse effects in the CNS, including dependence and abuse. Novel pharmacologic analgesics that are efficacious without the significant side effects associated with opioids have lacked meaningful development. However, recent clinical trials have shown promising results in the safety and efficacy of the pharmacological agent VX-548. Still, more clinical trials directly comparing the efficacy of VX-548 to standard of care post-surgical drugs, including opioids like morphine and hydromorphone are needed to demonstrate the long-term viability of the agent replacing current opioids with an unfavorable side effect profile.
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Affiliation(s)
- Alan D Kaye
- Departments of Anesthesiology and Pharmacology, Toxicology, and Neurosciences, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, 71103, USA
| | - Erin S Everett
- Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA
| | - Arianna M Lehuquet
- Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA
| | - Joseph W Mason
- LSU Health Sciences Center New Orleans School of Medicine, 1901 Gravier St, New Orleans, LA, USA
| | - Rebecca Maitski
- LSU Health Sciences Center New Orleans School of Medicine, 1901 Gravier St, New Orleans, LA, USA
| | - Michael J Plessala
- LSU Health Sciences Center New Orleans School of Medicine, 1901 Gravier St, New Orleans, LA, USA
| | - Sonnah Barrie
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA
| | - Carlo Jean Baptiste
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA
| | - George Mychaskiw
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA
| | - Shahab Ahmadzadeh
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA.
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Qi B, Xie Z, Shen D, Song Y, Liu S, Wang Q, Zhou J, Ge J. Blocking Na V1.8 regulates atrial fibrillation inducibility and cardiac conduction after myocardial infarction. BMC Cardiovasc Disord 2024; 24:605. [PMID: 39472780 PMCID: PMC11520513 DOI: 10.1186/s12872-024-04261-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 10/14/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND The role of NaV1.8 impacts in atrial fibrillation susceptibility after myocardial infarction remains only partially understood. We studied the effect of blocking NaV1.8 in the cardiac ganglionated plexi (GP) on the atrial fibrillation inducibility and cardiac conduction in the myocardial infarction model. METHODS Eighteen male beagles were randomly enrolled. Left anterior descending coronary artery was ligated to created myocardial infarction model. Four weeks after surgery, NaV1.8 blocker A-803,467 (n = 9) or DMSO (n = 9, control) was injected into the four cardiac major GPs. Sinus rate, ventricular rate during atrial fibrillation, PR interval, atrial effective refractory period, atrial fibrillation duration and the cumulative window of atrial vulnerability were measured before and 60 min after A-803,467 injection. RESULTS Administration of A-803,467 significantly increased sinus rate, shortened PR interval and increased ventricular rate during atrial fibrillation compared to control. A-803,467 also significantly shortened atrial effective refractory period, prolonged atrial fibrillation duration and increased the cumulative window of atrial vulnerability. A-803,467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, which was used as the surrogate marker for GP function. Double staining of ChAT and NaV1.8 demonstrated colocalization of ChAT and NaV1.8 in canine GPs. CONCLUSIONS Blocking NaV1.8 in the cardiac GP may modulate atrial fibrillation inducibility and cardiac conduction after myocardial infarction, and the underlying mechanism may be associated with the regulation of the neural activity of the cardiac GP.
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Affiliation(s)
- Baozhen Qi
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
- Department of Cardiology, Zhongshan Hospital (Xiamen), Fudan University, 668 Jinhu Road, Xiamen, 361015, China
| | - Zhonglei Xie
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Dongli Shen
- Division of Cardiology, Department of Medicine, the Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China
| | - Yu Song
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Shaowen Liu
- Department of Cardiology, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Qibing Wang
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China.
| | - Jingmin Zhou
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
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Hang Kong AY, Tan HS, Habib AS. VX-548 in the treatment of acute pain. Pain Manag 2024; 14:477-486. [PMID: 39552600 PMCID: PMC11721852 DOI: 10.1080/17581869.2024.2421749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 11/06/2024] [Indexed: 11/19/2024] Open
Abstract
Acute pain management requires balancing analgesia with adverse effects risk. The voltage-gated sodium channel NaV1.8 plays an important role in pain physiology, and its inhibition was shown to have analgesic effects. VX-548 is a new oral NaV1.8-specific inhibitor that received United States Food and Drug Administration Fast Track and Breakthrough Therapy designations. Its efficacy was demonstrated in two Phase II trials of patients who underwent abdominoplasty and bunionectomy. These showed that VX-548, when given as an oral loading dose of 100 mg followed by 50 mg 12-hly, significantly decreased pain scores compared with placebo. Similarly, two Phase III trials of patients who underwent abdominoplasty and bunionectomy comparing VX-548 with hydrocodone bitartrate-acetaminophen and placebo reported significantly reduced pain scores compared with placebo, but no improvement compared with hydrocodone bitartrate-acetaminophen. Evidence from Phase II and III trials suggest that VX-548 is well-tolerated, with headache, nausea, constipation and dizziness being the most common adverse effects. However, the safety of prolonged VX-548 administration is uncertain; a Phase II trial of patients with diabetic neuropathy who received high-dose VX-548 over 12 weeks reported decreased creatinine clearance. Data pertaining to VX-548 safety and efficacy within the context of multimodal analgesia and pregnancy are also needed.
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Affiliation(s)
- Aaron Yik Hang Kong
- Department of Women's Anesthesia, KK Women's & Children's Hospital, 100 Bukit Timah Road, 229899, Singapore
| | - Hon Sen Tan
- Department of Women's Anesthesia, KK Women's & Children's Hospital, 100 Bukit Timah Road, 229899, Singapore
| | - Ashraf S Habib
- Department of Anesthesiology, Division of Women's Anesthesia, Duke University Medical Center Box 3094, Durham, NC27710, USA
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Hartmann N, Knierim M, Maurer W, Dybkova N, Zeman F, Hasenfuß G, Sossalla S, Streckfuss-Bömeke K. Na V1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model. Int J Mol Sci 2024; 25:6144. [PMID: 38892333 PMCID: PMC11172914 DOI: 10.3390/ijms25116144] [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: 03/03/2024] [Revised: 05/25/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
The sodium channel NaV1.8, encoded by the SCN10A gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that NaV1.8 contributes to arrhythmogenesis by inducing a persistent Na+ current (late Na+ current, INaL) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of NaV1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of SCN10A in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that INaL was significantly reduced in ventricular SCN10A-KO iPSC-CM and in control CM after a specific pharmacological inhibition of NaV1.8. In contrast, we did not find any effects on ventricular APD90. The frequency of spontaneous sarcoplasmic reticulum Ca2+ sparks and waves were reduced in SCN10A-KO iPSC-CM and control cells following the pharmacological inhibition of NaV1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in SCN10A-KO iPSC-CM and after the specific inhibition of NaV1.8 in control cells. In conclusion, we show that NaV1.8-induced INaL primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca2+ release. The inhibition or knockout of NaV1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms NaV1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy.
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Affiliation(s)
- Nico Hartmann
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
| | - Maria Knierim
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
- Clinic for Cardio-Thoracic and Vascular Surgery, University Medical Center, 37075 Göttingen, Germany
| | - Wiebke Maurer
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
| | - Nataliya Dybkova
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
| | - Florian Zeman
- Center for Clinicial Trials, University of Regensburg, 93042 Regensburg, Germany
| | - Gerd Hasenfuß
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
| | - Samuel Sossalla
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
- Medical Clinic I, Cardiology and Angiology, Giessen and Department of Cardiology at Kerckhoff Heart and Lung Center, Justus-Liebig-University, 61231 Bad Nauheim, Germany
| | - Katrin Streckfuss-Bömeke
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany
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8
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Heinle JW, Dalessio S, Janicki P, Ouyang A, Vrana KE, Ruiz-Velasco V, Coates MD. Insights into the voltage-gated sodium channel, Na V1.8, and its role in visceral pain perception. Front Pharmacol 2024; 15:1398409. [PMID: 38855747 PMCID: PMC11158627 DOI: 10.3389/fphar.2024.1398409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 04/29/2024] [Indexed: 06/11/2024] Open
Abstract
Pain is a major issue in healthcare throughout the world. It remains one of the major clinical issues of our time because it is a common sequela of numerous conditions, has a tremendous impact on individual quality of life, and is one of the top drivers of cost in medicine, due to its influence on healthcare expenditures and lost productivity in those affected by it. Patients and healthcare providers remain desperate to find new, safer and more effective analgesics. Growing evidence indicates that the voltage-gated sodium channel Nav1.8 plays a critical role in transmission of pain-related signals throughout the body. For that reason, this channel appears to have strong potential to help develop novel, more selective, safer, and efficacious analgesics. However, many questions related to the physiology, function, and clinical utility of Nav1.8 remain to be answered. In this article, we discuss the latest studies evaluating the role of Nav1.8 in pain, with a particular focus on visceral pain, as well as the steps taken thus far to evaluate its potential as an analgesic target. We also review the limitations of currently available studies related to this topic, and describe the next scientific steps that have already been undertaken, or that will need to be pursued, to fully unlock the capabilities of this potential therapeutic target.
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Affiliation(s)
- J. Westley Heinle
- Division of Gastroenterology and Hepatology, Penn State College of Medicine, Hershey, PA, United States
| | - Shannon Dalessio
- Division of Gastroenterology and Hepatology, Penn State College of Medicine, Hershey, PA, United States
| | - Piotr Janicki
- Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, PA, United States
| | - Ann Ouyang
- Division of Gastroenterology and Hepatology, Penn State College of Medicine, Hershey, PA, United States
| | - Kent E. Vrana
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, United States
| | - Victor Ruiz-Velasco
- Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, PA, United States
| | - Matthew D. Coates
- Division of Gastroenterology and Hepatology, Penn State College of Medicine, Hershey, PA, United States
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, United States
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9
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Tsuji Y, Yamazaki M, Shimojo M, Yanagisawa S, Inden Y, Murohara T. Mechanisms of torsades de pointes: an update. Front Cardiovasc Med 2024; 11:1363848. [PMID: 38504714 PMCID: PMC10948600 DOI: 10.3389/fcvm.2024.1363848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 02/19/2024] [Indexed: 03/21/2024] Open
Abstract
Torsades de Pointes (TdP) refers to a polymorphic ventricular tachycardia (VT) with undulating QRS axis that occurs in long QT syndrome (LQTS), although the term has been used to describe polymorphic ventricular tachyarrhythmias in which QT intervals are not prolonged, such as short-coupled variant of TdP currently known as short-coupled ventricular fibrillation (VF) and Brugada syndrome. Extensive works on LQTS-related TdP over more than 50 years since it was first recognized by Dessertennes who coined the French term meaning "twisting of the points", have led to current understanding of the electrophysiological mechanism that TdP is initiated by triggered activity due to early afterdepolarization (EAD) and maintained by reentry within a substrate of inhomogeneous repolarization. While a recently emerging notion that steep voltage gradients rather than EADs are crucial to generate premature ventricular contractions provides additions to the initiation mode, the research to elucidate the maintenance mechanism hasn't made much progress. The reentrant activity that produces the specific form of VT is not well characterized. We have conducted optical mapping in a rabbit model of electrical storm by electrical remodeling (QT prolongation) due to chronic complete atrioventricular block and demonstrated that a tissue-island with prolonged refractoriness due to enhanced late Na+ current (INa-L) contributes to the generation of drifting rotors in a unique manner, which may explain the ECG characteristic of TdP. Moreover, we have proposed that the neural Na+ channel NaV1.8-mediated INa-L may be a new player to form the substrate for TdP. Here we discuss TdP mechanisms by comparing the findings in electrical storm rabbits with recently published studies by others in simulation models and human and animal models of LQTS.
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Affiliation(s)
- Yukiomi Tsuji
- Departments of Cardiovascular Research and Innovation, Cardiology and Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Yamazaki
- Department of Cardiology, Nagano Hospital, Soja and Medical Device Development and Regulation Research Center and Department of Precision Engineering, The University of Tokyo, Tokyo, Japan
| | - Masafumi Shimojo
- Departments of Cardiovascular Research and Innovation, Cardiology and Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoshi Yanagisawa
- Departments of Cardiovascular Research and Innovation, Cardiology and Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuya Inden
- Departments of Cardiovascular Research and Innovation, Cardiology and Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toyoaki Murohara
- Departments of Cardiovascular Research and Innovation, Cardiology and Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan
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10
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Packer M. Foetal recapitulation of nutrient surplus signalling by O-GlcNAcylation and the failing heart. Eur J Heart Fail 2023; 25:1199-1212. [PMID: 37434410 DOI: 10.1002/ejhf.2972] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/02/2023] [Accepted: 07/09/2023] [Indexed: 07/13/2023] Open
Abstract
The development of the foetal heart is driven by increased glucose uptake and activation of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α), which drives glycolysis. In contrast, the healthy adult heart is governed by sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK), which promote fatty-acid oxidation and the substantial mitochondrial ATP production required for survival in a high-workload normoxic environment. During cardiac injury, the heart recapitulates the foetal signalling programme, which (although adaptive in the short term) is highly deleterious if sustained for long periods of time. Prolonged increases in glucose uptake in cardiomyocytes under stress leads to increased flux through the hexosamine biosynthesis pathway; its endproduct - uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) - functions as a critical nutrient surplus sensor. UDP-GlcNAc drives the post-translational protein modification known as O-GlcNAcylation, which rapidly and reversibly modifies thousands of intracellular proteins. Both O-GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas phosphorylation is regulated by hundreds of specific kinases and phosphatases, O-GlcNAcylation is regulated by only two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which adds or removes GlcNAc (N-acetylglucosamine), respectively, from target proteins. Recapitulation of foetal programming in heart failure (regardless of diabetes) is accompanied by marked increases in O-GlcNAcylation, both experimentally and clinically. Heightened O-GlcNAcylation in the heart leads to impaired calcium kinetics and contractile derangements, arrhythmias related to activation of voltage-gated sodium channels and Ca2+ /calmodulin-dependent protein kinase II, mitochondrial dysfunction, and maladaptive hypertrophy, microvascular dysfunction, fibrosis and cardiomyopathy. These deleterious effects can be prevented by suppression of O-GlcNAcylation, which can be achieved experimentally by upregulation of AMPK and SIRT1 or by pharmacological inhibition of OGT or stimulation of OGA. The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the heart are accompanied by reduced O-GlcNAcylation, and their cytoprotective effects are reportedly abrogated if their action to suppress O-GlcNAcylation is blocked. Such an action may represent one of the many mechanisms by which enhanced AMPK and SIRT1 signalling following SGLT2 inhibition leads to cardiovascular benefits. These observations, taken collectively, suggest that UDP-GlcNAc functions as a critical nutrient surplus sensor (which acting in concert with mTOR and HIF-1α) can promote the development of cardiomyopathy.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Dallas, TX, USA
- Imperial College, London, UK
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11
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Hartmann N, Knierim M, Maurer W, Dybkova N, Hasenfuß G, Sossalla S, Streckfuss-Bömeke K. Molecular and Functional Relevance of Na V1.8-Induced Atrial Arrhythmogenic Triggers in a Human SCN10A Knock-Out Stem Cell Model. Int J Mol Sci 2023; 24:10189. [PMID: 37373335 DOI: 10.3390/ijms241210189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
In heart failure and atrial fibrillation, a persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that NaV1.8 contributes to arrhythmogenesis by inducing a INaL. Genome-wide association studies indicate that mutations in the SCN10A gene (NaV1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these NaV1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the INaL and action potential duration. Ca2+ measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca2+ leak. The INaL was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of NaV1.8. No effects on atrial APD90 were detected in any groups. Both SCN10A KO and specific blockers of NaV1.8 led to decreased Ca2+ spark frequency and a significant reduction of arrhythmogenic Ca2+ waves. Our experiments demonstrate that NaV1.8 contributes to INaL formation in human atrial CMs and that NaV1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore NaV1.8 could be a new target for antiarrhythmic strategies.
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Affiliation(s)
- Nico Hartmann
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
| | - Maria Knierim
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
- Clinic for Cardio-Thoracic and Vascular Surgery, University Medical Center, 37075 Göttingen, Germany
| | - Wiebke Maurer
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
| | - Nataliya Dybkova
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
| | - Gerd Hasenfuß
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
| | - Samuel Sossalla
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
- Departments of Cardiology at Kerckhoff Heart and Lung Center, Bad Nauheim and University of Giessen, 61231 Bad Nauheim, Germany
| | - Katrin Streckfuss-Bömeke
- Clinic for Cardiology and Pneumology, University Medical Center, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen and Rhein Main, 61231 Bad Nauheim, Germany
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany
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12
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MacLeod KT. Changes in cellular Ca 2+ and Na + regulation during the progression towards heart failure. J Physiol 2023; 601:905-921. [PMID: 35946572 PMCID: PMC10952717 DOI: 10.1113/jp283082] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/02/2022] [Indexed: 11/08/2022] Open
Abstract
In adapting to disease and loss of tissue, the heart shows great phenotypic plasticity that involves changes to its structure, composition and electrophysiology. Together with parallel whole body cardiovascular adaptations, the initial decline in cardiac function resulting from the insult is compensated. However, in the long term, the heart muscle begins to fail and patients with this condition have a very poor prognosis, with many dying from disturbances of rhythm. The surviving myocytes of these hearts gain Na+ , which is positively inotropic because of alterations to Ca2+ fluxes mediated by the Na+ /Ca2+ exchange, but compromises Ca2+ -dependent energy metabolism in mitochondria. Uptake of Ca2+ into the sarcoplasmic reticulum (SR) is reduced because of diminished function of SR Ca2+ ATPases. The result of increased Ca2+ influx and reduced SR Ca2+ uptake is an increase in the diastolic cytosolic Ca2+ concentration, which promotes spontaneous SR Ca2+ release and induces delayed afterdepolarisations. Action potential duration prolongs because of increased late Na+ current and changes in expression and function of other ion channels and transporters increasing the probability of the formation of early afterdepolarisations. There is a reduction in T-tubule density and so the normal spatial arrangements required for efficient excitation-contraction coupling are compromised and lead to temporal delays in Ca2+ release from the SR. Therefore, the structural and electrophysiological responses that occur to provide compensation do so at the expense of (1) increasing the likelihood of arrhythmogenesis; (2) activating hypertrophic, apoptotic and Ca2+ signalling pathways; and (3) decreasing the efficiency of SR Ca2+ release.
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Affiliation(s)
- Kenneth T. MacLeod
- National Heart & Lung InstituteImperial Centre for Translational and Experimental MedicineImperial CollegeHammersmith HospitalLondonUK
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13
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Popa IP, Șerban DN, Mărănducă MA, Șerban IL, Tamba BI, Tudorancea I. Brugada Syndrome: From Molecular Mechanisms and Genetics to Risk Stratification. Int J Mol Sci 2023; 24:ijms24043328. [PMID: 36834739 PMCID: PMC9967917 DOI: 10.3390/ijms24043328] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 01/13/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Brugada syndrome (BrS) is a rare hereditary arrhythmia disorder, with a distinctive ECG pattern, correlated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD) in young adults. BrS is a complex entity in terms of mechanisms, genetics, diagnosis, arrhythmia risk stratification, and management. The main electrophysiological mechanism of BrS requires further research, with prevailing theories centered on aberrant repolarization, depolarization, and current-load match. Computational modelling, pre-clinical, and clinical research show that BrS molecular anomalies result in excitation wavelength (k) modifications, which eventually increase the risk of arrhythmia. Although a mutation in the SCN5A (Sodium Voltage-Gated Channel Alpha Subunit 5) gene was first reported almost two decades ago, BrS is still currently regarded as a Mendelian condition inherited in an autosomal dominant manner with incomplete penetrance, despite the recent developments in the field of genetics and the latest hypothesis of additional inheritance pathways proposing a more complex mode of inheritance. In spite of the extensive use of the next-generation sequencing (NGS) technique with high coverage, genetics remains unexplained in a number of clinically confirmed cases. Except for the SCN5A which encodes the cardiac sodium channel NaV1.5, susceptibility genes remain mostly unidentified. The predominance of cardiac transcription factor loci suggests that transcriptional regulation is essential to the Brugada syndrome's pathogenesis. It appears that BrS is a multifactorial disease, which is influenced by several loci, each of which is affected by the environment. The primary challenge in individuals with a BrS type 1 ECG is to identify those who are at risk for sudden death, researchers propose the use of a multiparametric clinical and instrumental strategy for risk stratification. The aim of this review is to summarize the latest findings addressing the genetic architecture of BrS and to provide novel perspectives into its molecular underpinnings and novel models of risk stratification.
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Affiliation(s)
- Irene Paula Popa
- Cardiology Clinic, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Dragomir N. Șerban
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Minela Aida Mărănducă
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Ionela Lăcrămioara Șerban
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Bogdan Ionel Tamba
- Department of Pharmacology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Correspondence:
| | - Ionuț Tudorancea
- Cardiology Clinic, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
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14
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Lebek S, Hegner P, Hultsch R, Rohde J, Rupprecht L, Schmid C, Sossalla S, Maier LS, Arzt M, Wagner S. Voltage-Gated Sodium Channel Na V1.8 Dysregulates Na and Ca, Leading to Arrhythmias in Patients with Sleep-Disordered Breathing. Am J Respir Crit Care Med 2022; 206:1428-1431. [PMID: 35944144 DOI: 10.1164/rccm.202205-0981le] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Simon Lebek
- University Hospital Regensburg Regensburg, Germany.,University of Texas Southwestern Medical Center Dallas, Texas
| | | | - Rosa Hultsch
- University Hospital Regensburg Regensburg, Germany
| | - Jonas Rohde
- University Hospital Regensburg Regensburg, Germany
| | | | | | - Samuel Sossalla
- University Hospital Regensburg Regensburg, Germany.,Georg-August University Göttingen Göttingen, Germany
| | | | - Michael Arzt
- University Hospital Regensburg Regensburg, Germany
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15
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Pabel S, Knierim M, Stehle T, Alebrand F, Paulus M, Sieme M, Herwig M, Barsch F, Körtl T, Pöppl A, Wenner B, Ljubojevic-Holzer S, Molina CE, Dybkova N, Camboni D, Fischer TH, Sedej S, Scherr D, Schmid C, Brochhausen C, Hasenfuß G, Maier LS, Hamdani N, Streckfuss-Bömeke K, Sossalla S. Effects of Atrial Fibrillation on the Human Ventricle. Circ Res 2022; 130:994-1010. [PMID: 35193397 PMCID: PMC8963444 DOI: 10.1161/circresaha.121.319718] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 02/08/2022] [Accepted: 02/14/2022] [Indexed: 11/16/2022]
Abstract
RATIONALE Atrial fibrillation (AF) and heart failure often coexist, but their interaction is poorly understood. Clinical data indicate that the arrhythmic component of AF may contribute to left ventricular (LV) dysfunction. OBJECTIVE This study investigates the effects and molecular mechanisms of AF on the human LV. METHODS AND RESULTS Ventricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm or rate-controlled AF was studied. LV myocardium from patients with sinus rhythm and patients with AF showed no differences in fibrosis. In functional studies, systolic Ca2+ transient amplitude of LV cardiomyocytes was reduced in patients with AF, while diastolic Ca2+ levels and Ca2+ transient kinetics were not statistically different. These results were confirmed in LV cardiomyocytes from nonfailing donors with sinus rhythm or AF. Moreover, normofrequent AF was simulated in vitro using arrhythmic or rhythmic pacing (both at 60 bpm). After 24 hours of AF-simulation, human LV cardiomyocytes from nonfailing donors showed an impaired Ca2+ transient amplitude. For a standardized investigation of AF-simulation, human iPSC-cardiomyocytes were tested. Seven days of AF-simulation caused reduced systolic Ca2+ transient amplitude and sarcoplasmic reticulum Ca2+ load likely because of an increased diastolic sarcoplasmic reticulum Ca2+ leak. Moreover, cytosolic Na+ concentration was elevated and action potential duration was prolonged after AF-simulation. We detected an increased late Na+ current as a potential trigger for the detrimentally altered Ca2+/Na+-interplay. Mechanistically, reactive oxygen species were higher in the LV of patients with AF. CaMKII (Ca2+/calmodulin-dependent protein kinase IIδc) was found to be more oxidized at Met281/282 in the LV of patients with AF leading to an increased CaMKII activity and consequent increased RyR2 phosphorylation. CaMKII inhibition and ROS scavenging ameliorated impaired systolic Ca2+ handling after AF-simulation. CONCLUSIONS AF causes distinct functional and molecular remodeling of the human LV. This translational study provides the first mechanistic characterization and the potential negative impact of AF in the absence of tachycardia on the human ventricle.
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Affiliation(s)
- Steffen Pabel
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla)
| | - Maria Knierim
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla)
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (M.K., F.A., B.W., N.D., G.H., K.S.-B., S. Sossalla)
| | - Thea Stehle
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla)
| | - Felix Alebrand
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (M.K., F.A., B.W., N.D., G.H., K.S.-B., S. Sossalla)
| | - Michael Paulus
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla)
| | - Marcel Sieme
- Institut für Forschung und Lehre (IFL), Department of Molecular and Experimental Cardiology and Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Germany (M.S., M.H., N.H.)
| | - Melissa Herwig
- Institut für Forschung und Lehre (IFL), Department of Molecular and Experimental Cardiology and Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Germany (M.S., M.H., N.H.)
| | - Friedrich Barsch
- Institute of Pathology, University Hospital Regensburg, Germany (F.B., C.B.)
| | - Thomas Körtl
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla)
| | - Arnold Pöppl
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla)
| | - Brisca Wenner
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (M.K., F.A., B.W., N.D., G.H., K.S.-B., S. Sossalla)
| | | | - Cristina E. Molina
- Institute of Experimental Cardiovascular Research, University Medical Centre Hamburg-Eppendorf, Germany (C.E.M.)
| | - Nataliya Dybkova
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (M.K., F.A., B.W., N.D., G.H., K.S.-B., S. Sossalla)
| | - Daniele Camboni
- Department of Cardiothoracic Surgery, University Hospital Regensburg, Germany (D.C., C.S.)
| | - Thomas H. Fischer
- Department of Internal Medicine I, University of Würzburg, Germany (T.H.F.)
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Austria (S.L.-H., S. Sedej, D.S.)
- Faculty of Medicine, University of Maribor, Maribor, Slovenia (S. Sedej)
- BioTechMed Graz, Graz, Austria (S. Sedej)
| | - Daniel Scherr
- Department of Cardiology, Medical University of Graz, Austria (S.L.-H., S. Sedej, D.S.)
| | - Christof Schmid
- Department of Cardiothoracic Surgery, University Hospital Regensburg, Germany (D.C., C.S.)
| | | | - Gerd Hasenfuß
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (M.K., F.A., B.W., N.D., G.H., K.S.-B., S. Sossalla)
| | - Lars S. Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla)
| | - Nazha Hamdani
- Institut für Forschung und Lehre (IFL), Department of Molecular and Experimental Cardiology and Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Germany (M.S., M.H., N.H.)
| | - Katrin Streckfuss-Bömeke
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (M.K., F.A., B.W., N.D., G.H., K.S.-B., S. Sossalla)
- Institute of Pharmacology and Toxicology, University of Würzburg, Germany (K.S.-B.)
| | - Samuel Sossalla
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla)
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany (M.K., F.A., B.W., N.D., G.H., K.S.-B., S. Sossalla)
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Horváth B, Szentandrássy N, Almássy J, Dienes C, Kovács ZM, Nánási PP, Banyasz T. Late Sodium Current of the Heart: Where Do We Stand and Where Are We Going? Pharmaceuticals (Basel) 2022; 15:ph15020231. [PMID: 35215342 PMCID: PMC8879921 DOI: 10.3390/ph15020231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023] Open
Abstract
Late sodium current has long been linked to dysrhythmia and contractile malfunction in the heart. Despite the increasing body of accumulating information on the subject, our understanding of its role in normal or pathologic states is not complete. Even though the role of late sodium current in shaping action potential under physiologic circumstances is debated, it’s unquestioned role in arrhythmogenesis keeps it in the focus of research. Transgenic mouse models and isoform-specific pharmacological tools have proved useful in understanding the mechanism of late sodium current in health and disease. This review will outline the mechanism and function of cardiac late sodium current with special focus on the recent advances of the area.
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Affiliation(s)
- Balázs Horváth
- Department of Physiology, University of Debrecen, 4032 Debrecen, Hungary; (B.H.); (N.S.); (J.A.); (C.D.); (Z.M.K.); (P.P.N.)
| | - Norbert Szentandrássy
- Department of Physiology, University of Debrecen, 4032 Debrecen, Hungary; (B.H.); (N.S.); (J.A.); (C.D.); (Z.M.K.); (P.P.N.)
- Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, 4032 Debrecen, Hungary
| | - János Almássy
- Department of Physiology, University of Debrecen, 4032 Debrecen, Hungary; (B.H.); (N.S.); (J.A.); (C.D.); (Z.M.K.); (P.P.N.)
| | - Csaba Dienes
- Department of Physiology, University of Debrecen, 4032 Debrecen, Hungary; (B.H.); (N.S.); (J.A.); (C.D.); (Z.M.K.); (P.P.N.)
| | - Zsigmond Máté Kovács
- Department of Physiology, University of Debrecen, 4032 Debrecen, Hungary; (B.H.); (N.S.); (J.A.); (C.D.); (Z.M.K.); (P.P.N.)
| | - Péter P. Nánási
- Department of Physiology, University of Debrecen, 4032 Debrecen, Hungary; (B.H.); (N.S.); (J.A.); (C.D.); (Z.M.K.); (P.P.N.)
- Department of Dental Physiology and Pharmacology, University of Debrecen, 4032 Debrecen, Hungary
| | - Tamas Banyasz
- Department of Physiology, University of Debrecen, 4032 Debrecen, Hungary; (B.H.); (N.S.); (J.A.); (C.D.); (Z.M.K.); (P.P.N.)
- Correspondence: ; Tel.: +36-(52)-255-575; Fax: +36-(52)-255-116
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Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm. Heart Rhythm 2022; 19:318-329. [PMID: 34678525 PMCID: PMC8810573 DOI: 10.1016/j.hrthm.2021.10.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND Electrical storm (ES) is a life-threatening emergency in patients at high risk of ventricular tachycardia/ventricular fibrillation (VF), but the pathophysiology and molecular basis are poorly understood. OBJECTIVE The purpose of this study was to explore the electrophysiological substrate for experimental ES. METHODS A model was created by inducing chronic complete atrioventricular block in defibrillator-implanted rabbits, which recapitulates QT prolongation, torsades des pointes (TdP), and VF episodes. RESULTS Optical mapping revealed island-like regions with action potential duration (APD) prolongation in the left ventricle, leading to increased spatial APD dispersion, in rabbits with ES (defined as ≥3 VF episodes/24 h). The maximum APD and its dispersion correlated with the total number of VF episodes in vivo. TdP was initiated by an ectopic beat that failed to enter the island and formed a reentrant wave and perpetuated by rotors whose centers swirled in the periphery of the island. Epinephrine exacerbated the island by prolonging APD and enhancing APD dispersion, which was less evident after late Na+ current blockade with 10 μM ranolazine. Nonsustained ventricular tachycardia in a non-ES rabbit heart with homogeneous APD prolongation resulted from multiple foci with an electrocardiographic morphology different from TdP driven by drifting rotors in ES rabbit hearts. The neuronal Na+-channel subunit NaV1.8 was upregulated in ES rabbit left ventricular tissues and expressed within the myocardium corresponding to the island location in optically mapped ES rabbit hearts. The NaV1.8 blocker A-803467 (10 mg/kg, intravenously) attenuated QT prolongation and suppressed epinephrine-evoked TdP. CONCLUSION A tissue island with enhanced refractoriness contributes to the generation of drifting rotors that underlies ES in this model. NaV1.8-mediated late Na+ current merits further investigation as a contributor to the substrate for ES.
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18
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Maurer W, Hartmann N, Argyriou L, Sossalla S, Streckfuss-Bömeke K. Generation of homozygous Na v1.8 knock-out iPSC lines by CRISPR Cas9 genome editing to investigate a potential new antiarrhythmic strategy. Stem Cell Res 2022; 60:102677. [PMID: 35092938 DOI: 10.1016/j.scr.2022.102677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/07/2021] [Accepted: 01/17/2022] [Indexed: 11/19/2022] Open
Abstract
The sodium channel Nav1.8, encoded by SCN10A, is reported to contribute to arrhythmogenesis by inducing the late INa and thereby enhanced persistent Na+ current. However, its exact electrophysiological role in cardiomyocytes remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) with a homozygous SCN10A knock-out from a healthy iPSC line by CRISPR Cas9 genome editing. The edited iPSCs maintained full pluripotency, genomic integrity, and spontaneous in vitro differentiation capacity. The iPSCs are able to differentiate into iPSC-cardiomyocytes, hence making it possible to investigate the role of Nav1.8 in the heart.
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Affiliation(s)
- Wiebke Maurer
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Center of Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
| | - Nico Hartmann
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Center of Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
| | - Loukas Argyriou
- Institute of Human Genetics, University Medical Center Göttingen (UMG), and DZHK (German Center of Cardiovascular Research), Partner Site Göttingen, Germany
| | - Samuel Sossalla
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Center of Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany; Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany
| | - Katrin Streckfuss-Bömeke
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Center of Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
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19
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Detrimental proarrhythmogenic interaction of Ca 2+/calmodulin-dependent protein kinase II and Na V1.8 in heart failure. Nat Commun 2021; 12:6586. [PMID: 34782600 PMCID: PMC8593192 DOI: 10.1038/s41467-021-26690-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/14/2021] [Indexed: 12/19/2022] Open
Abstract
An interplay between Ca2+/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na+ current (INaL) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform NaV1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of NaV1.8, we demonstrate that NaV1.8 contributes to INaL formation. In addition, we reveal a direct interaction between NaV1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of NaV1.8 and CaMKIIδc, we show that NaV1.8-driven INaL is CaMKIIδc-dependent and that NaV1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a NaV1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy.
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20
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Chen L, He Y, Wang X, Ge J, Li H. Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation. Clin Transl Med 2021; 11:e530. [PMID: 34709746 PMCID: PMC8516344 DOI: 10.1002/ctm2.530] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiac voltage-gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC-related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life-threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart-related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well-studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.
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Affiliation(s)
- Lulan Chen
- Department of Cardiology, Shanghai Institute of Cardiovascular DiseasesShanghai Xuhui District Central Hospital & Zhongshan‐xuhui Hospital, Zhongshan Hospital, Fudan UniversityShanghaiChina
| | - Yue He
- Department of CardiologyShanghai Xuhui District Central Hospital & Zhongshan‐xuhui HospitalShanghaiChina
| | - Xiangdong Wang
- Institute of Clinical Science, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Junbo Ge
- Department of Cardiology, Shanghai Institute of Cardiovascular DiseasesShanghai Xuhui District Central Hospital & Zhongshan‐xuhui Hospital, Zhongshan Hospital, Fudan UniversityShanghaiChina
| | - Hua Li
- Department of Cardiology, Shanghai Institute of Cardiovascular DiseasesShanghai Xuhui District Central Hospital & Zhongshan‐xuhui Hospital, Zhongshan Hospital, Fudan UniversityShanghaiChina
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21
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Pabel S, Hamdani N, Luedde M, Sossalla S. SGLT2 Inhibitors and Their Mode of Action in Heart Failure-Has the Mystery Been Unravelled? Curr Heart Fail Rep 2021; 18:315-328. [PMID: 34523061 PMCID: PMC8484236 DOI: 10.1007/s11897-021-00529-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/09/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. RECENT FINDINGS Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.
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Affiliation(s)
- Steffen Pabel
- Department of Internal Medicine II, University Medical Centre Regensburg, Regensburg, Germany
| | - Nazha Hamdani
- Department of Molecular and Experimental Cardiology and Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Mark Luedde
- Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Samuel Sossalla
- Department of Internal Medicine II, University Medical Centre Regensburg, Regensburg, Germany. .,Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
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22
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Ning S, Hua L, Ji Z, Fan D, Meng X, Li Z, Wang Q, Guo Z. Protein 4.1 family and ion channel proteins interact to regulate the process of heart failure in rats. Acta Histochem 2021; 123:151748. [PMID: 34271280 DOI: 10.1016/j.acthis.2021.151748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023]
Abstract
Heart failure (HF) is a major cause of death in cardiovascular diseases worldwide, and its molecular mechanisms and effective prevention strategies remain to be further studied. The myocardial cytoskeleton plays a pivotal role in many heart diseases. However, little is known about the function of the membrane cytoskeleton 4.1 protein family and related regulatory mechanisms in the pathogenesis of HF. In this study, we detected the localization and expression of the protein 4.1 family and ion channel proteins in a rat HF model induced by doxorubicin (DOX), and studied the interactions between them. Our results showed that compared with the control group, the HF group displayed an increased expression level of protein 4.1R and decreased levels of protein 4.1 G and 4.1 N. The Nav1.5 protein levels were significantly increased, while the SERCA2a and Cav1.2 protein levels were significantly decreased in the HF group. Furthermore, there is co-localization and interaction between protein 4.1R and Nav1.5, protein 4.1 G and SERCA2a, protein 4.1 N and Cav1.2, respectively. Taken together, the results indicated that the protein 4.1 family might be involved in the occurrence and development of HF through its interaction with ion channel proteins, suggesting that 4.1 proteins may serve as a novel therapeutic target for HF.
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Affiliation(s)
- Shuwei Ning
- Zhengzhou Key Laboratory, Zhengzhou No. 7 People's Hospital, Zhengzhou, 450016, China
| | - Lei Hua
- Zhengzhou Key Laboratory, Zhengzhou No. 7 People's Hospital, Zhengzhou, 450016, China
| | - Zhenyu Ji
- Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Dandan Fan
- Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Xiangguang Meng
- Zhengzhou Key Laboratory, Zhengzhou No. 7 People's Hospital, Zhengzhou, 450016, China
| | - Zhiying Li
- Zhengzhou Key Laboratory, Zhengzhou No. 7 People's Hospital, Zhengzhou, 450016, China
| | - Qian Wang
- Zhengzhou Key Laboratory, Zhengzhou No. 7 People's Hospital, Zhengzhou, 450016, China
| | - Zhikun Guo
- Zhengzhou Key Laboratory, Zhengzhou No. 7 People's Hospital, Zhengzhou, 450016, China; Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, China.
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23
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Couselo-Seijas M, Rodríguez-Mañero M, González-Juanatey JR, Eiras S. Updates on epicardial adipose tissue mechanisms on atrial fibrillation. Obes Rev 2021; 22:e13277. [PMID: 34002458 DOI: 10.1111/obr.13277] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/19/2021] [Indexed: 02/06/2023]
Abstract
Obesity is a well-known risk factor for atrial fibrillation (AF). Local epi-myocardial or intra-myocardial adiposity caused by aging, obesity, or cardiovascular disease (CVD) is considered to be a better predictor of the risk of AF than general adiposity. Some of the described mechanisms suggest that epicardial adipose tissue (EAT) participates in structural remodeling owing to its endocrine activity or its infiltration between cardiomyocytes. Epicardial fat also wraps up the ganglionated plexi that reach the myocardium. Although the increment of volume/thickness and activity of EAT might modify autonomic activity, autonomic system dysfunction might also change the endocrine activity of epicardial fat in a feedback response. As a result, new preventive therapeutic strategies are focused on reducing adiposity and weight loss before AF ablation or inhibiting autonomic neurotransmitter secretion on fat pads during open-heart surgery to reduce the recurrence or postoperative risk of AF. In this manuscript, we review some of the novel findings regarding the pathophysiology and associated risk factors of AF, with special emphasis on the role of EAT in the electrical, structural, and molecular mechanisms of AF initiation and maintenance. In addition, we have included a brief note provided on epicardial fat preclinical models that could be useful for identifying new therapeutic targets.
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Affiliation(s)
- Marinela Couselo-Seijas
- Translational Cardiology group, Health Research Institute, Santiago de Compostela, Spain
- University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Moisés Rodríguez-Mañero
- Translational Cardiology group, Health Research Institute, Santiago de Compostela, Spain
- CIBERCV, Madrid, Spain
- Cardiovascular Department, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - José R González-Juanatey
- University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBERCV, Madrid, Spain
- Cardiovascular Department, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
- Cardiology group, Health Research Institute, Santiago de Compostela, Spain
| | - Sonia Eiras
- Translational Cardiology group, Health Research Institute, Santiago de Compostela, Spain
- CIBERCV, Madrid, Spain
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24
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Qi B, Dai S, Song Y, Shen D, Li F, Wei L, Zhang C, Nie Z, Lin J, Cai L, Ge J. Blockade of Na V1.8 Increases the Susceptibility to Ventricular Arrhythmias During Acute Myocardial Infarction. Front Cardiovasc Med 2021; 8:708279. [PMID: 34409080 PMCID: PMC8365037 DOI: 10.3389/fcvm.2021.708279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/12/2021] [Indexed: 11/16/2022] Open
Abstract
SCN10A/NaV1.8 may be associated with a lower risk of ventricular fibrillation in the setting of acute myocardial infarction (AMI), but if and by which mechanism NaV1.8 impacts on ventricular electrophysiology is still a matter of debate. The purpose of this study was to elucidate the contribution of NaV1.8 in ganglionated plexi (GP) to ventricular arrhythmias in the AMI model. Twenty beagles were randomized to either the A-803467 group (n = 10) or the control group (n = 10). NaV1.8 blocker (A-803467, 1 μmol/0.5 mL per GP) or DMSO (0.5 mL per GP) was injected into four major GPs. Ventricular effective refractory period, APD90, ventricular fibrillation threshold, and the incidence of ventricular arrhythmias were measured 1 h after left anterior descending coronary artery occlusion. A-803467 significantly shortened ventricular effective refractory period, APD90, and ventricular fibrillation threshold compared to control. In the A-803467 group, the incidence of ventricular arrhythmias was significantly higher compared to control. A-803467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, suggesting that A-803467 could inhibit GP activity. SCN10A/NaV1.8 was readily detected in GPs, but was not validated in ventricles by quantitative RT-PCR, western blot and immunohistochemistry. While SCN10A/NaV1.8 is detectible in canine GPs but not in ventricles, blockade of NaV1.8 in GP increases the incidence of ventricular arrhythmias in AMI hearts. Our study shows for the first time an influence of SCN10A/NaV1.8 on the regulation of ventricular arrhythmogenesis via modulating GP activity in the AMI model.
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Affiliation(s)
- Baozhen Qi
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Shimo Dai
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Yu Song
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Dongli Shen
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Fuhai Li
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Lanfang Wei
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Chunyu Zhang
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Zhenning Nie
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Jiaxiong Lin
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
| | - Lidong Cai
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China
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25
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Man JCK, Bosada FM, Scholman KT, Offerhaus JA, Walsh R, van Duijvenboden K, van Eif VWW, Bezzina CR, Verkerk AO, Boukens BJ, Barnett P, Christoffels VM. Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction. Circulation 2021; 144:229-242. [PMID: 33910361 DOI: 10.1161/circulationaha.121.054083] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Genetic variants in SCN10A, encoding the neuronal voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. The cardiac function of SCN10A has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, encoding the major essential cardiac sodium channel NaV1.5. METHODS The expression of SCN10A was investigated in mouse and human hearts. With the use of CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at SCN5A-SCN10A enhancer regions and gene expression were evaluated by genome-wide association studies single-nucleotide polymorphism mapping and expression quantitative trait loci analysis. RESULTS We found that cardiomyocytes of the atria, sinoatrial node, and ventricular conduction system express a short transcript comprising the last 7 exons of the gene (Scn10a-short). Transcription occurs from an intronic enhancer-promoter complex, whereas full-length Scn10a transcript was undetectable in the human and mouse heart. Expression quantitative trait loci analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with SCN10A transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac Scn10a-short expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, whereas the expression of Scn5a, the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of Scn10a-short-encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that noncoding genetic variation modulates transcriptional regulation of Scn10a-short in cardiomyocytes that impacts NaV1.5-mediated sodium current and heart rhythm. CONCLUSIONS Genetic variants in and around SCN10A modulate enhancer function and expression of a cardiac-specific SCN10A-short transcript. We propose that noncoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility.
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Affiliation(s)
- Joyce C K Man
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Fernanda M Bosada
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Koen T Scholman
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Joost A Offerhaus
- Department of Experimental Cardiology (J.A.O., R.W., C.R.B., A.O.V., B.J.B.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Roddy Walsh
- Department of Experimental Cardiology (J.A.O., R.W., C.R.B., A.O.V., B.J.B.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Karel van Duijvenboden
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Vincent W W van Eif
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Connie R Bezzina
- Department of Experimental Cardiology (J.A.O., R.W., C.R.B., A.O.V., B.J.B.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Arie O Verkerk
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Department of Experimental Cardiology (J.A.O., R.W., C.R.B., A.O.V., B.J.B.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Bastiaan J Boukens
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Department of Experimental Cardiology (J.A.O., R.W., C.R.B., A.O.V., B.J.B.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Phil Barnett
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
| | - Vincent M Christoffels
- Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands
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26
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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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Affiliation(s)
- Ming Lei
- Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK
| | - Christopher L -H Huang
- Physiological Laboratory and Department of Biochemistry, University of Cambridge, Cambridge CB2 3EG, UK
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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Pérez-Agustín A, Pinsach-Abuin M, Pagans S. Role of Non-Coding Variants in Brugada Syndrome. Int J Mol Sci 2020; 21:E8556. [PMID: 33202810 PMCID: PMC7698069 DOI: 10.3390/ijms21228556] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 12/15/2022] Open
Abstract
Brugada syndrome (BrS) is an inherited electrical heart disease associated with a high risk of sudden cardiac death (SCD). The genetic characterization of BrS has always been challenging. Although several cardiac ion channel genes have been associated with BrS, SCN5A is the only gene that presents definitive evidence for causality to be used for clinical diagnosis of BrS. However, more than 65% of diagnosed cases cannot be explained by variants in SCN5A or other genes. Therefore, in an important number of BrS cases, the underlying mechanisms are still elusive. Common variants, mostly located in non-coding regions, have emerged as potential modulators of the disease by affecting different regulatory mechanisms, including transcription factors (TFs), three-dimensional organization of the genome, or non-coding RNAs (ncRNAs). These common variants have been hypothesized to modulate the interindividual susceptibility of the disease, which could explain incomplete penetrance of BrS observed within families. Altogether, the study of both common and rare variants in parallel is becoming increasingly important to better understand the genetic basis underlying BrS. In this review, we aim to describe the challenges of studying non-coding variants associated with disease, re-examine the studies that have linked non-coding variants with BrS, and provide further evidence for the relevance of regulatory elements in understanding this cardiac disorder.
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Affiliation(s)
- Adrian Pérez-Agustín
- Department of Medical Sciences, School of Medicine, University of Girona, 17003 Girona, Spain;
- Biomedical Research Institute of Girona, 17190 Salt, Spain;
| | | | - Sara Pagans
- Department of Medical Sciences, School of Medicine, University of Girona, 17003 Girona, Spain;
- Biomedical Research Institute of Girona, 17190 Salt, Spain;
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29
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Brown SK, Sheikh AM, Guzik TJ. Cardiovascular Research at the frontier of biomedical science. Cardiovasc Res 2020; 116:e83-e86. [PMID: 32406499 DOI: 10.1093/cvr/cvaa119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Sarah K Brown
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, Glasgow G12 8TA, UK
| | - Adam M Sheikh
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, Glasgow G12 8TA, UK
| | - Tomasz J Guzik
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, Glasgow G12 8TA, UK
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30
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Contribution of the neuronal sodium channel Na V1.8 to sodium- and calcium-dependent cellular proarrhythmia. J Mol Cell Cardiol 2020; 144:35-46. [PMID: 32418916 DOI: 10.1016/j.yjmcc.2020.05.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 04/17/2020] [Accepted: 05/05/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE In myocardial pathology such as heart failure a late sodium current (INaL) augmentation is known to be involved in conditions of arrhythmogenesis. However, the underlying mechanisms of the INaL generation are not entirely understood. By now evidence is growing that non-cardiac sodium channel isoforms could also be involved in the INaL generation. The present study investigates the contribution of the neuronal sodium channel isoform NaV1.8 to arrhythmogenesis in a clearly-defined setting of enhanced INaL by using anemone toxin II (ATX-II) in the absence of structural heart disease. METHODS Electrophysiological experiments were performed in order to measure INaL, action potential duration (APD), SR-Ca2+-leak and cellular proarrhythmic triggers in ATX-II exposed wild-type (WT) and SCN10A-/- mice cardiomyocytes. In addition, WT cardiomyocytes were stimulated with ATX-II in the presence or absence of NaV1.8 inhibitors. INCX was measured by using the whole cell patch clamp method. RESULTS In WT cardiomyocytes exposure to ATX-II augmented INaL, prolonged APD, increased SR-Ca2+-leak and induced proarrhythmic triggers such as early afterdepolarizations (EADs) and Ca2+-waves. All of them could be significantly reduced by applying NaV1.8 blockers PF-01247324 and A-803467. Both blockers had no relevant effects on cellular electrophysiology of SCN10A-/- cardiomyocytes. Moreover, in SCN10A-/--cardiomyocytes, the ATX-II-dependent increase in INaL, SR-Ca2+-leak and APD prolongation was less than in WT and comparable to the results which were obtained with WT cardiomyocytes being exposed to ATX-II and NaV1.8 inhibitors in parallel. Moreover, we found a decrease in reverse mode NCX current and reduced CaMKII-dependent RyR2-phosphorylation after application of PF-01247324 as an underlying explanation for the Na+-mediated Ca2+-dependent proarrhythmic triggers. CONCLUSION The current findings demonstrate that NaV1.8 is a significant contributor for INaL-induced arrhythmic triggers. Therefore, NaV1.8 inhibition under conditions of an enhanced INaL constitutes a promising antiarrhythmic strategy which merits further investigation.
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31
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Isaac E, Cooper SM, Jones SA, Loubani M. Do age-associated changes of voltage-gated sodium channel isoforms expressed in the mammalian heart predispose the elderly to atrial fibrillation? World J Cardiol 2020; 12:123-135. [PMID: 32431783 PMCID: PMC7215965 DOI: 10.4330/wjc.v12.i4.123] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/18/2020] [Accepted: 03/15/2020] [Indexed: 02/06/2023] Open
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. The prevalence of the disease increases with age, strongly implying an age-related process underlying the pathology. At a time when people are living longer than ever before, an exponential increase in disease prevalence is predicted worldwide. Hence unraveling the underlying mechanics of the disease is paramount for the development of innovative treatment and prevention strategies. The role of voltage-gated sodium channels is fundamental in cardiac electrophysiology and may provide novel insights into the arrhythmogenesis of AF. Nav1.5 is the predominant cardiac isoform, responsible for the action potential upstroke. Recent studies have demonstrated that Nav1.8 (an isoform predominantly expressed within the peripheral nervous system) is responsible for cellular arrhythmogenesis through the enhancement of pro-arrhythmogenic currents. Animal studies have shown a decline in Nav1.5 leading to a diminished action potential upstroke during phase 0. Furthermore, the study of human tissue demonstrates an inverse expression of sodium channel isoforms; reduction of Nav1.5 and increase of Nav1.8 in both heart failure and ventricular hypertrophy. This strongly suggests that the expression of voltage-gated sodium channels play a crucial role in the development of arrhythmias in the diseased heart. Targeting aberrant sodium currents has led to novel therapeutic approaches in tackling AF and continues to be an area of emerging research. This review will explore how voltage-gated sodium channels may predispose the elderly heart to AF through the examination of laboratory and clinical based evidence.
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Affiliation(s)
- Emmanuel Isaac
- Department of Cardiothoracic Surgery, Hull University Teaching Hospitals, Cottingham HU16 5JQ, United Kingdom
| | - Stephanie M Cooper
- Department of Biomedical Sciences, University of Hull, Hull HU6 7RX, United Kingdom
| | - Sandra A Jones
- Department of Biomedical Sciences, University of Hull, Hull HU6 7RX, United Kingdom
| | - Mahmoud Loubani
- Department of Cardiothoracic Surgery, Hull University Teaching Hospitals, Cottingham HU16 5JQ, United Kingdom
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32
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Horváth B, Hézső T, Kiss D, Kistamás K, Magyar J, Nánási PP, Bányász T. Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents. Front Pharmacol 2020; 11:413. [PMID: 32372952 PMCID: PMC7184885 DOI: 10.3389/fphar.2020.00413] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 03/18/2020] [Indexed: 12/19/2022] Open
Abstract
Based on recent findings, an increased late sodium current (INa,late) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is INa,late and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased INa,late in heart diseases, and also discusses how the upregulated INa,late can play a role in the generation of cardiac arrhythmias. The last part of the article is about INa,late inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials.
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Affiliation(s)
- Balázs Horváth
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
| | - Tamás Hézső
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Dénes Kiss
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Kornél Kistamás
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - János Magyar
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Division of Sport Physiology, University of Debrecen, Debrecen, Hungary
| | - Péter P. Nánási
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Department of Dental Physiology and Pharmacology, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary
| | - Tamás Bányász
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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33
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Pabel S, Ahmad S, Tirilomis P, Stehle T, Mustroph J, Knierim M, Dybkova N, Bengel P, Holzamer A, Hilker M, Streckfuss-Bömeke K, Hasenfuss G, Maier LS, Sossalla S. Inhibition of Na V1.8 prevents atrial arrhythmogenesis in human and mice. Basic Res Cardiol 2020; 115:20. [PMID: 32078054 PMCID: PMC7033079 DOI: 10.1007/s00395-020-0780-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 02/10/2020] [Indexed: 12/19/2022]
Abstract
Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (NaV1.8) in atrial electrophysiology. This study investigated the role and involvement of NaV1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking NaV1.8. NaV1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of NaV1.8 and NaV1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of NaV1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of NaV1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that NaV1.8 significantly contributes to late Na+ current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca2+ leak in human atrial cardiomyocytes. Selective pharmacological inhibition of NaV1.8 potently reduced late Na+ current, proarrhythmic diastolic Ca2+ release, delayed afterdepolarizations as well as spontaneous action potentials. These findings could be confirmed in murine atrial cardiomyocytes from wild-type mice and also compared to SCN10A-/- mice (genetic ablation of NaV1.8). Pharmacological NaV1.8 inhibition showed no effects in SCN10A-/- mice. Importantly, in vivo experiments in SCN10A-/- mice showed that genetic ablation of NaV1.8 protects against atrial fibrillation induction. This study demonstrates that NaV1.8 is expressed in the murine and human atria and contributes to late Na+ current generation and cellular arrhythmogenesis. Blocking NaV1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.
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Affiliation(s)
- Steffen Pabel
- Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Shakil Ahmad
- Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
| | - Petros Tirilomis
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
| | - Thea Stehle
- Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Julian Mustroph
- Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Maria Knierim
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
| | - Nataliya Dybkova
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
| | - Philipp Bengel
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
| | - Andreas Holzamer
- Department of Cardiothoracic Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Michael Hilker
- Department of Cardiothoracic Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Katrin Streckfuss-Bömeke
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
| | - Gerd Hasenfuss
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
| | - Lars S Maier
- Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Samuel Sossalla
- Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
- Clinic for Cardiology and Pneumology, Georg-August University Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany.
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany.
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Affiliation(s)
- Katja E Odening
- Department of Cardiology and Angiology I and Institute of Experimental Cardiovascular Medicine, Heart Center University of Freiburg, Medical Faculty, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
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35
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Casini S, Marchal GA, Kawasaki M, Nariswari FA, Portero V, van den Berg NWE, Guan K, Driessen AHG, Veldkamp MW, Mengarelli I, de Groot JR, Verkerk AO, Remme CA. Absence of Functional Na v1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes. Cardiovasc Drugs Ther 2019; 33:649-660. [PMID: 31916131 PMCID: PMC6994555 DOI: 10.1007/s10557-019-06925-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE Several studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/NaV1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes (CMs), focusing on the contribution of NaV1.8 to the peak and late sodium current (INa) under normal conditions in different species. METHODS The effects of the NaV1.8 blocker A-803467 were investigated through patch-clamp analysis in freshly isolated rabbit left ventricular CMs, human left atrial CMs and human-induced pluripotent stem cell-derived CMs (hiPSC-CMs). RESULTS A-803467 treatment caused a slight shortening of the action potential duration (APD) in rabbit CMs and hiPSC-CMs, while it had no effect on APD in human atrial cells. Resting membrane potential, action potential (AP) amplitude, and AP upstroke velocity were unaffected by A-803467 application. Similarly, INa density was unchanged after exposure to A-803467 and NaV1.8-based late INa was undetectable in all cell types analysed. Finally, low to absent expression levels of SCN10A were observed in human atrial tissue, rabbit ventricular tissue and hiPSC-CMs. CONCLUSION We here demonstrate the absence of functional NaV1.8 channels in non-diseased atrial and ventricular CMs. Hence, the association of SCN10A variants with cardiac electrophysiology observed in, e.g. genome wide association studies, is likely the result of indirect effects on SCN5A expression and/or NaV1.8 activity in cell types other than CMs.
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Affiliation(s)
- Simona Casini
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands.
| | - Gerard A Marchal
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | - Makiri Kawasaki
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | - Fransisca A Nariswari
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | - Vincent Portero
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | | | - Kaomei Guan
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Antoine H G Driessen
- Department of Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | - Marieke W Veldkamp
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | - Isabella Mengarelli
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | - Joris R de Groot
- Department of Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | - Arie O Verkerk
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
- Department of Medical Biology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
| | - Carol Ann Remme
- Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands
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Huo R, Hu C, Zhao L, Sun L, Wang N, Lu Y, Ye B, Deb A, Li F, Xu H. Enhancement of β-catenin/T-cell factor 4 signaling causes susceptibility to cardiac arrhythmia by suppressing Na V1.5 expression in mice. Heart Rhythm 2019; 16:1720-1728. [PMID: 31125668 PMCID: PMC7027965 DOI: 10.1016/j.hrthm.2019.05.015] [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: 03/01/2019] [Indexed: 11/21/2022]
Abstract
BACKGROUND β-Catenin/T-cell factor 4 (TCF4) signaling is enhanced in ischemic heart disease in which ventricular tachycardia (VT)/ventricular fibrillation occurs frequently. How this signaling links to arrhythmogenesis remains unclear. OBJECTIVE The purpose of this study was to investigate the role of β-catenin gain of function in the development of arrhythmia. METHODS A mouse model with a conditional deletion of CTNNB1 exon 3 resulting in cardiac exon 3-deleted and stabilized β-catenin (β-catΔE3) was used to determine the role of β-catenin gain of function in the regulation of cardiac rhythm. RESULTS Western blotting showed β-catΔE3 expression and significantly decreased NaV1.5 protein in CTNNB1 E3-/- and CTNNB1 E3+/- mouse hearts. Real-time qRT-PCR revealed significantly decreased NaV1.5 messenger RNA with no changes in Na+ channel β1 to β4 expression in these hearts. Immunofluorescence revealed accumulation of β-catΔE3 in the nuclei of CTNNB1 E3-/- cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of β-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in human ischemic hearts. Immunoprecipitation revealed that β-catΔE3 interacted with TCF4 in CTNNB1 E3-/- cardiomyocytes. Whole-cell recordings showed that Na+ currents and depolarization and amplitude of action potentials were significantly decreased in CTNNB1 E3-/- ventricular myocytes. Electrocardiographic recordings demonstrated that in mice with cardiac CTNNB1 E3-/-, the QRS complex was prolonged and VT was induced by the Na+ channel blocker flecainide. However, cardiac function, as determined by echocardiography and heart/body weight ratios, remained unchanged. CONCLUSION Enhancement of β-catenin/TCF4 signaling led to the prolongation of the QRS complex and increase in susceptibility to VT by suppression of NaV1.5 expression and Na+ channel activity in mice.
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Affiliation(s)
- Rong Huo
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Chaowei Hu
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Limei Zhao
- Department of Pathology, Center for Cardiovascular Biology and Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington
| | - Lihua Sun
- Department of Pathology, Center for Cardiovascular Biology and Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington
| | - Ning Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Yan Lu
- Department of Pathology, Center for Cardiovascular Biology and Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington; Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Bo Ye
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Arjun Deb
- Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Faqian Li
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Haodong Xu
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; Department of Pathology, Center for Cardiovascular Biology and Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington.
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Gando I, Williams N, Fishman GI, Sampson BA, Tang Y, Coetzee WA. Functional characterization of SCN10A variants in several cases of sudden unexplained death. Forensic Sci Int 2019; 301:289-298. [PMID: 31195250 DOI: 10.1016/j.forsciint.2019.05.042] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 04/03/2019] [Accepted: 05/21/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Multiple genome-wide association studies (GWAS) and targeted gene sequencing have identified common variants in SCN10A in cases of PR and QRS duration abnormalities, atrial fibrillation and Brugada syndrome. The New York City Office of Chief Medical Examiner has now also identified five SCN10A variants of uncertain significance in six separate cases within a cohort of 330 sudden unexplained death events. The gene product of SCN10A is the Nav1.8 sodium channel. The purpose of this study was to characterize effects of these variants on Nav1.8 channel function to provide better information for the reclassification of these variants. METHODS AND RESULTS Patch clamp studies were performed to assess effects of the variants on whole-cell Nav1.8 currents. We also performed RNA-seq analysis and immunofluorescence confocal microcopy to determine Nav1.8 expression in heart. We show that four of the five rare 'variants of unknown significance' (L388M, L867F, P1102S and V1518I) are associated with altered functional phenotypes. The R756W variant behaved similar to wild-type under our experimental conditions. We failed to detect Nav1.8 protein expression in immunofluorescence microscopy in rat heart. Furthermore, RNA-seq analysis failed to detect full-length SCN10A mRNA transcripts in human ventricle or mouse specialized cardiac conduction system, suggesting that the effect of Nav1.8 on cardiac function is likely to be extra-cardiac in origin. CONCLUSIONS We have demonstrated that four of five SCN10A variants of uncertain significance, identified in unexplained death, have deleterious effects on channel function. These data extend the genetic testing of SUD cases, but significantly more clinical evidence is needed to satisfy the criteria needed to associate these variants with the onset of SUD.
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Affiliation(s)
| | - Nori Williams
- Molecular Genetics Laboratory, Office of Chief Medical Examiner, New York, NY, United States
| | - Glenn I Fishman
- Neuroscience & Physiology, New York, NY, United States; Biochemistry and Molecular Pharmacology, New York, NY, United States; Medicine NYU School of Medicine, New York, NY, United States
| | - Barbara A Sampson
- Molecular Genetics Laboratory, Office of Chief Medical Examiner, New York, NY, United States
| | - Yingying Tang
- Molecular Genetics Laboratory, Office of Chief Medical Examiner, New York, NY, United States
| | - William A Coetzee
- Pediatrics, New York, NY, United States; Neuroscience & Physiology, New York, NY, United States; Biochemistry and Molecular Pharmacology, New York, NY, United States.
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Hegyi B, Bányász T, Izu LT, Belardinelli L, Bers DM, Chen-Izu Y. β-adrenergic regulation of late Na + current during cardiac action potential is mediated by both PKA and CaMKII. J Mol Cell Cardiol 2018; 123:168-179. [PMID: 30240676 DOI: 10.1016/j.yjmcc.2018.09.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/28/2018] [Accepted: 09/16/2018] [Indexed: 12/12/2022]
Abstract
Late Na+ current (INaL) significantly contributes to shaping cardiac action potentials (APs) and increased INaL is associated with cardiac arrhythmias. β-adrenergic receptor (βAR) stimulation and its downstream signaling via protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways are known to regulate INaL. However, it remains unclear how each of these pathways regulates INaL during the AP under physiological conditions. Here we performed AP-clamp experiments in rabbit ventricular myocytes to delineate the impact of each signaling pathway on INaL at different AP phases to understand the arrhythmogenic potential. During the physiological AP (2 Hz, 37 °C) we found that INaL had a basal level current independent of PKA, but partially dependent on CaMKII. βAR activation (10 nM isoproterenol, ISO) further enhanced INaL via both PKA and CaMKII pathways. However, PKA predominantly increased INaL early during the AP plateau, whereas CaMKII mainly increased INaL later in the plateau and during rapid repolarization. We also tested the role of key signaling pathways through exchange protein activated by cAMP (Epac), nitric oxide synthase (NOS) and reactive oxygen species (ROS). Direct Epac stimulation enhanced INaL similar to the βAR-induced CaMKII effect, while NOS inhibition prevented the βAR-induced CaMKII-dependent INaL enhancement. ROS generated by NADPH oxidase 2 (NOX2) also contributed to the ISO-induced INaL activation early in the AP. Taken together, our data reveal differential modulations of INaL by PKA and CaMKII signaling pathways at different AP phases. This nuanced and comprehensive view on the changes in INaL during AP deepens our understanding of the important role of INaL in reshaping the cardiac AP and arrhythmogenic potential under elevated sympathetic stimulation, which is relevant for designing therapeutic treatment of arrhythmias under pathological conditions.
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Affiliation(s)
- Bence Hegyi
- Department of Pharmacology, University of California, Davis, CA, USA.
| | - Tamás Bányász
- Department of Pharmacology, University of California, Davis, CA, USA; Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Leighton T Izu
- Department of Pharmacology, University of California, Davis, CA, USA
| | | | - Donald M Bers
- Department of Pharmacology, University of California, Davis, CA, USA
| | - Ye Chen-Izu
- Department of Pharmacology, University of California, Davis, CA, USA; Department of Biomedical Engineering, University of California, Davis, CA, USA; Department of Internal Medicine/Cardiology, University of California, Davis, CA, USA.
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