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Merc MD, Kotnik U, Peterlin B, Lovrecic L. Further exploration of cardiac channelopathy and cardiomyopathy genes in stillbirth. Prenat Diagn 2024; 44:1062-1072. [PMID: 38813989 DOI: 10.1002/pd.6616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/09/2024] [Accepted: 05/20/2024] [Indexed: 05/31/2024]
Abstract
OBJECTIVE To explore genetic variation including whole genome copy number variation and sequence analysis of 98 genes associated with pediatric or adult cardiomyopathies, cardiac channelopathies, and sudden death in an unexplained intrauterine fetal death cohort. METHODS The study population included 55 stillbirth cases that remained unexplained after thorough postmortem examination, excluding maternal, fetal, and placental causes of stillbirth. Molecular karyotyping was performed in 55 cases and the trio exome sequencing approach was applied in 19 cases. RESULTS The analysis revealed six rare variants with predicted effects on protein function in six genes (CASQ2, DSC2, KCNE1, LDB3, MYH6, and SCN5A) previously reported in cases of stillbirth or severe early onset pediatric cardiac related phenotypes. When applying strict American College of Genetics and Genomics classification guidelines, these are still variants of uncertain significance. CONCLUSIONS Several potentially stillbirth-related genetic variants were detected in our cohort, adding to the growing literature on cardiac phenotype gene variation in stillbirth. However, the mechanisms of action, gene-gene interaction, and contribution of the uterine environment are still to be deciphered. In order to advance our knowledge of the genetics of unexplained fetal death, there is an evident need for international collaboration and field standardization.
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Affiliation(s)
- Maja Dolanc Merc
- Division of Gynecology and Obstetrics, Department of Perinatology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Urška Kotnik
- Clinical Institute for Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Borut Peterlin
- Clinical Institute for Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Luca Lovrecic
- Clinical Institute for Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Nakajima T, Tamura S, Kawabata-Iwakawa R, Itoh H, Hasegawa H, Kobari T, Harasawa S, Sekine A, Nishiyama M, Kurabayashi M, Imoto K, Kaneko Y, Nakatani Y, Horie M, Ishii H. Novel KCNQ1 Q234K variant, identified in patients with long QT syndrome and epileptiform activity, induces both gain- and loss-of-function of slowly activating delayed rectifier potassium currents. Front Physiol 2024; 15:1401822. [PMID: 39100276 PMCID: PMC11294085 DOI: 10.3389/fphys.2024.1401822] [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: 03/16/2024] [Accepted: 06/10/2024] [Indexed: 08/06/2024] Open
Abstract
Introduction KCNQ1 and KCNE1 form slowly activating delayed rectifier potassium currents (IKs). Loss-of-function of IKs by KCNQ1 variants causes type-1 long QT syndrome (LQTS). Also, some KCNQ1 variants are reported to cause epilepsy. Segment 4 (S4) of voltage-gated potassium channels has several positively-charged amino acids that are periodically aligned, and acts as a voltage-sensor. Intriguingly, KCNQ1 has a neutral-charge glutamine at the third position (Q3) in the S4 (Q234 position in KCNQ1), which suggests that the Q3 (Q234) may play an important role in the gating properties of IKs. We identified a novel KCNQ1 Q234K (substituted for a positively-charged lysine) variant in patients (a girl and her mother) with LQTS and epileptiform activity on electroencephalogram. The mother had been diagnosed with epilepsy. Therefore, we sought to elucidate the effects of the KCNQ1 Q234K on gating properties of IKs. Methods Wild-type (WT)-KCNQ1 and/or Q234K-KCNQ1 were transiently expressed in tsA201-cells with KCNE1 (E1) (WT + E1-channels, Q234K + E1-channels, and WT + Q234K + E1-channels), and membrane currents were recorded using whole-cell patch-clamp techniques. Results At 8-s depolarization, current density (CD) of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly larger than the WT + E1-channels (WT + E1: 701 ± 59 pA/pF; Q234K + E1: 912 ± 50 pA/pF, p < 0.01; WT + Q234K + E1: 867 ± 48 pA/pF, p < 0.05). Voltage dependence of activation (VDA) of the Q234K + E1-channels or WT + Q234K + E1-channels was slightly but significantly shifted to depolarizing potentials in comparison to the WT + E1-channels ([V1/2] WT + E1: 25.6 ± 2.6 mV; Q234K + E1: 31.8 ± 1.7 mV, p < 0.05; WT + Q234K + E1: 32.3 ± 1.9 mV, p < 0.05). Activation rate of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly delayed in comparison to the WT + E1-channels ([half activation time] WT + E1: 664 ± 37 ms; Q234K + E1: 1,417 ± 60 ms, p < 0.01; WT + Q234K + E1: 1,177 ± 71 ms, p < 0.01). At 400-ms depolarization, CD of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly decreased in comparison to the WT + E1-channels (WT + E1: 392 ± 42 pA/pF; Q234K + E1: 143 ± 12 pA/pF, p < 0.01; WT + Q234K + E1: 209 ± 24 pA/pF, p < 0.01) due to delayed activation rate and depolarizing shift of VDA. Conclusion The KCNQ1 Q234K induced IKs gain-of-function during long (8-s)-depolarization, while loss of-function during short (400-ms)-depolarization, which indicates that the variant causes LQTS, and raises a possibility that the variant may also cause epilepsy. Our data provide novel insights into the functional consequences of charge addition on the Q3 in the S4 of KCNQ1.
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Affiliation(s)
- Tadashi Nakajima
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Shuntaro Tamura
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Reika Kawabata-Iwakawa
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Japan
| | - Hideki Itoh
- Division of Patient Safety, Hiroshima University Hospital, Hiroshima, Japan
| | - Hiroshi Hasegawa
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Takashi Kobari
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Shun Harasawa
- Division of Neurology, Japanese Red Cross Maebashi Hospital, Maebashi, Japan
| | - Akiko Sekine
- Division of Neurology, Japanese Red Cross Maebashi Hospital, Maebashi, Japan
| | | | - Masahiko Kurabayashi
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Keiji Imoto
- National Institutes of Natural Sciences, Tokyo, Japan
| | - Yoshiaki Kaneko
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yosuke Nakatani
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Minoru Horie
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Ohtsu, Japan
| | - Hideki Ishii
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
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Verkerk AO, Wilders R. Human Sinoatrial Node Pacemaker Activity: Role of the Slow Component of the Delayed Rectifier K + Current, I Ks. Int J Mol Sci 2023; 24:7264. [PMID: 37108427 PMCID: PMC10138838 DOI: 10.3390/ijms24087264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
The pacemaker activity of the sinoatrial node (SAN) has been studied extensively in animal species but is virtually unexplored in humans. Here we assess the role of the slowly activating component of the delayed rectifier K+ current (IKs) in human SAN pacemaker activity and its dependence on heart rate and β-adrenergic stimulation. HEK-293 cells were transiently transfected with wild-type KCNQ1 and KCNE1 cDNA, encoding the α- and β-subunits of the IKs channel, respectively. KCNQ1/KCNE1 currents were recorded both during a traditional voltage clamp and during an action potential (AP) clamp with human SAN-like APs. Forskolin (10 µmol/L) was used to increase the intracellular cAMP level, thus mimicking β-adrenergic stimulation. The experimentally observed effects were evaluated in the Fabbri-Severi computer model of an isolated human SAN cell. Transfected HEK-293 cells displayed large IKs-like outward currents in response to depolarizing voltage clamp steps. Forskolin significantly increased the current density and significantly shifted the half-maximal activation voltage towards more negative potentials. Furthermore, forskolin significantly accelerated activation without affecting the rate of deactivation. During an AP clamp, the KCNQ1/KCNE1 current was substantial during the AP phase, but relatively small during diastolic depolarization. In the presence of forskolin, the KCNQ1/KCNE1 current during both the AP phase and diastolic depolarization increased, resulting in a clearly active KCNQ1/KCNE1 current during diastolic depolarization, particularly at shorter cycle lengths. Computer simulations demonstrated that IKs reduces the intrinsic beating rate through its slowing effect on diastolic depolarization at all levels of autonomic tone and that gain-of-function mutations in KCNQ1 may exert a marked bradycardic effect during vagal tone. In conclusion, IKs is active during human SAN pacemaker activity and has a strong dependence on heart rate and cAMP level, with a prominent role at all levels of autonomic tone.
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Affiliation(s)
- Arie O. Verkerk
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
- Department of Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Ronald Wilders
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
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Kekenes-Huskey PM, Burgess DE, Sun B, Bartos DC, Rozmus ER, Anderson CL, January CT, Eckhardt LL, Delisle BP. Mutation-Specific Differences in Kv7.1 ( KCNQ1) and Kv11.1 ( KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes. Int J Mol Sci 2022; 23:7389. [PMID: 35806392 PMCID: PMC9266926 DOI: 10.3390/ijms23137389] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 11/16/2022] Open
Abstract
The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano-Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the "benign" to a "pathogenic" binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene- and mutation-specific differences in K+ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals.
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Affiliation(s)
- Peter M. Kekenes-Huskey
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Don E. Burgess
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; (D.E.B.); (E.R.R.)
| | - Bin Sun
- Department of Pharmacology, Harbin Medical University, Harbin 150081, China;
| | | | - Ezekiel R. Rozmus
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; (D.E.B.); (E.R.R.)
| | - Corey L. Anderson
- Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (C.L.A.); (C.T.J.); (L.L.E.)
| | - Craig T. January
- Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (C.L.A.); (C.T.J.); (L.L.E.)
| | - Lee L. Eckhardt
- Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (C.L.A.); (C.T.J.); (L.L.E.)
| | - Brian P. Delisle
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; (D.E.B.); (E.R.R.)
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Santovito D, Weber C. Non-canonical features of microRNAs: paradigms emerging from cardiovascular disease. Nat Rev Cardiol 2022; 19:620-638. [PMID: 35304600 DOI: 10.1038/s41569-022-00680-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/14/2022] [Indexed: 02/08/2023]
Abstract
Research showing that microRNAs (miRNAs) are versatile regulators of gene expression has instigated tremendous interest in cardiovascular research. The overwhelming majority of studies are predicated on the dogmatic notion that miRNAs regulate the expression of specific target mRNAs by inhibiting mRNA translation or promoting mRNA decay in the RNA-induced silencing complex (RISC). These efforts mostly identified and dissected contributions of multiple regulatory networks of miRNA-target mRNAs to cardiovascular pathogenesis. However, evidence from studies in the past decade indicates that miRNAs also operate beyond this canonical paradigm, featuring non-conventional regulatory functions and cellular localizations that have a pathophysiological role in cardiovascular disease. In this Review, we highlight the functional relevance of atypical miRNA biogenesis and localization as well as RISC heterogeneity. Moreover, we delineate remarkable non-canonical examples of miRNA functionality, including direct interactions with proteins beyond the Argonaute family and their role in transcriptional regulation in the nucleus and in mitochondria. We scrutinize the relevance of non-conventional biogenesis and non-canonical functions of miRNAs in cardiovascular homeostasis and pathology, and contextualize how uncovering these non-conventional properties can expand the scope of translational research in the cardiovascular field and beyond.
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Affiliation(s)
- Donato Santovito
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU), Munich, Germany. .,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. .,Institute for Genetic and Biomedical Research (IRGB), Unit of Milan, National Research Council, Milan, Italy.
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU), Munich, Germany. .,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. .,Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. .,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
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Yang D, Deschênes I, Fu JD. Multilayer control of cardiac electrophysiology by microRNAs. J Mol Cell Cardiol 2022; 166:107-115. [PMID: 35247375 PMCID: PMC9035102 DOI: 10.1016/j.yjmcc.2022.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/22/2022] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
The electrophysiological properties of the heart include cardiac automaticity, excitation (i.e., depolarization and repolarization of action potential) of individual cardiomyocytes, and highly coordinated electrical propagation through the whole heart. An abnormality in any of these properties can cause arrhythmias. MicroRNAs (miRs) have been recognized as essential regulators of gene expression through the conventional RNA interference (RNAi) mechanism and are involved in a variety of biological events. Recent evidence has demonstrated that miRs regulate the electrophysiology of the heart through fine regulation by the conventional RNAi mechanism of the expression of ion channels, transporters, intracellular Ca2+-handling proteins, and other relevant factors. Recently, a direct interaction between miRs and ion channels has also been reported in the heart, revealing a biophysical modulation by miRs of cardiac electrophysiology. These advanced discoveries suggest that miR controls cardiac electrophysiology through two distinct mechanisms: immediate action through biophysical modulation and long-term conventional RNAi regulation. Here, we review the recent research progress and summarize the current understanding of how miR manipulates the function of ion channels to maintain the homeostasis of cardiac electrophysiology.
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Affiliation(s)
- Dandan Yang
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, 333 W. 10(th) Avenue, Columbus, OH 43210, USA
| | - Isabelle Deschênes
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, 333 W. 10(th) Avenue, Columbus, OH 43210, USA
| | - Ji-Dong Fu
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, 333 W. 10(th) Avenue, Columbus, OH 43210, USA.
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7
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Cumberland MJ, Riebel LL, Roy A, O’Shea C, Holmes AP, Denning C, Kirchhof P, Rodriguez B, Gehmlich K. Basic Research Approaches to Evaluate Cardiac Arrhythmia in Heart Failure and Beyond. Front Physiol 2022; 13:806366. [PMID: 35197863 PMCID: PMC8859441 DOI: 10.3389/fphys.2022.806366] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 01/10/2022] [Indexed: 12/20/2022] Open
Abstract
Patients with heart failure often develop cardiac arrhythmias. The mechanisms and interrelations linking heart failure and arrhythmias are not fully understood. Historically, research into arrhythmias has been performed on affected individuals or in vivo (animal) models. The latter however is constrained by interspecies variation, demands to reduce animal experiments and cost. Recent developments in in vitro induced pluripotent stem cell technology and in silico modelling have expanded the number of models available for the evaluation of heart failure and arrhythmia. An agnostic approach, combining the modalities discussed here, has the potential to improve our understanding for appraising the pathology and interactions between heart failure and arrhythmia and can provide robust and validated outcomes in a variety of research settings. This review discusses the state of the art models, methodologies and techniques used in the evaluation of heart failure and arrhythmia and will highlight the benefits of using them in combination. Special consideration is paid to assessing the pivotal role calcium handling has in the development of heart failure and arrhythmia.
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Affiliation(s)
- Max J. Cumberland
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Leto L. Riebel
- Department of Computer Science, University of Oxford, Oxford, United Kingdom
| | - Ashwin Roy
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Christopher O’Shea
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Andrew P. Holmes
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Chris Denning
- Stem Cell Biology Unit, Biodiscovery Institute, British Heart Foundation Centre for Regenerative Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Paulus Kirchhof
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Blanca Rodriguez
- Department of Computer Science, University of Oxford, Oxford, United Kingdom
| | - Katja Gehmlich
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford and British Heart Foundation Centre of Research Excellence Oxford, Oxford, United Kingdom
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Iop L, Iliceto S, Civieri G, Tona F. Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling. Cells 2021; 10:3175. [PMID: 34831398 PMCID: PMC8623957 DOI: 10.3390/cells10113175] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/03/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.
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Affiliation(s)
- Laura Iop
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padua, Via Giustiniani, 2, I-35124 Padua, Italy; (S.I.); (G.C.)
| | | | | | - Francesco Tona
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padua, Via Giustiniani, 2, I-35124 Padua, Italy; (S.I.); (G.C.)
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Yang D, Wan X, Dennis AT, Bektik E, Wang Z, Costa MG, Fagnen C, Vénien-Bryan C, Xu X, Gratz DH, Hund TJ, Mohler PJ, Laurita KR, Deschênes I, Fu JD. MicroRNA Biophysically Modulates Cardiac Action Potential by Direct Binding to Ion Channel. Circulation 2021; 143:1597-1613. [PMID: 33590773 PMCID: PMC8132313 DOI: 10.1161/circulationaha.120.050098] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND MicroRNAs (miRs) play critical roles in regulation of numerous biological events, including cardiac electrophysiology and arrhythmia, through a canonical RNA interference mechanism. It remains unknown whether endogenous miRs modulate physiologic homeostasis of the heart through noncanonical mechanisms. METHODS We focused on the predominant miR of the heart (miR1) and investigated whether miR1 could physically bind with ion channels in cardiomyocytes by electrophoretic mobility shift assay, in situ proximity ligation assay, RNA pull down, and RNA immunoprecipitation assays. The functional modulations of cellular electrophysiology were evaluated by inside-out and whole-cell patch clamp. Mutagenesis of miR1 and the ion channel was used to understand the underlying mechanism. The effect on the heart ex vivo was demonstrated through investigating arrhythmia-associated human single nucleotide polymorphisms with miR1-deficient mice. RESULTS We found that endogenous miR1 could physically bind with cardiac membrane proteins, including an inward-rectifier potassium channel Kir2.1. The miR1-Kir2.1 physical interaction was observed in mouse, guinea pig, canine, and human cardiomyocytes. miR1 quickly and significantly suppressed IK1 at sub-pmol/L concentration, which is close to endogenous miR expression level. Acute presence of miR1 depolarized resting membrane potential and prolonged final repolarization of the action potential in cardiomyocytes. We identified 3 miR1-binding residues on the C-terminus of Kir2.1. Mechanistically, miR1 binds to the pore-facing G-loop of Kir2.1 through the core sequence AAGAAG, which is outside its RNA interference seed region. This biophysical modulation is involved in the dysregulation of gain-of-function Kir2.1-M301K mutation in short QT or atrial fibrillation. We found that an arrhythmia-associated human single nucleotide polymorphism of miR1 (hSNP14A/G) specifically disrupts the biophysical modulation while retaining the RNA interference function. It is remarkable that miR1 but not hSNP14A/G relieved the hyperpolarized resting membrane potential in miR1-deficient cardiomyocytes, improved the conduction velocity, and eliminated the high inducibility of arrhythmia in miR1-deficient hearts ex vivo. CONCLUSIONS Our study reveals a novel evolutionarily conserved biophysical action of endogenous miRs in modulating cardiac electrophysiology. Our discovery of miRs' biophysical modulation provides a more comprehensive understanding of ion channel dysregulation and may provide new insights into the pathogenesis of cardiac arrhythmias.
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Affiliation(s)
- Dandan Yang
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA
| | - Xiaoping Wan
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA
| | - Adrienne T. Dennis
- Department of Medicine, Heart and Vascular Research Center, The MetroHealth System, Case Western Reserve University, Cleveland, OH 44109, USA
| | - Emre Bektik
- Department of Medicine, Heart and Vascular Research Center, The MetroHealth System, Case Western Reserve University, Cleveland, OH 44109, USA
| | - Zhihua Wang
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China
| | - Mauricio G.S. Costa
- Institute of Mineralogy, Materials Physics and Cosmochemistry, UMR 7590, Sorbonne Université, CNRS, MNHN, Paris F-75005, France
- Oswaldo Cruz Foundation, Scientific Computing Program, Vice Presidency of Education, Information and Communication, Rio de Janeiro, Brazil
| | - Charline Fagnen
- Institute of Mineralogy, Materials Physics and Cosmochemistry, UMR 7590, Sorbonne Université, CNRS, MNHN, Paris F-75005, France
| | - Catherine Vénien-Bryan
- Institute of Mineralogy, Materials Physics and Cosmochemistry, UMR 7590, Sorbonne Université, CNRS, MNHN, Paris F-75005, France
| | - Xianyao Xu
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Departments of Biomedical Engineering and Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Daniel H. Gratz
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Departments of Biomedical Engineering and Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Thomas J. Hund
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Departments of Biomedical Engineering and Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Peter J. Mohler
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA
| | - Kenneth R. Laurita
- Department of Medicine, Heart and Vascular Research Center, The MetroHealth System, Case Western Reserve University, Cleveland, OH 44109, USA
| | - Isabelle Deschênes
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA
| | - Ji-Dong Fu
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA
- Department of Medicine, Heart and Vascular Research Center, The MetroHealth System, Case Western Reserve University, Cleveland, OH 44109, USA
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10
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Jeong DU, Lim KM. Artificial neural network model for predicting changes in ion channel conductance based on cardiac action potential shapes generated via simulation. Sci Rep 2021; 11:7831. [PMID: 33837240 PMCID: PMC8035260 DOI: 10.1038/s41598-021-87578-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/30/2021] [Indexed: 11/09/2022] Open
Abstract
Many studies have revealed changes in specific protein channels due to physiological causes such as mutation and their effects on action potential duration changes. However, no studies have been conducted to predict the type of protein channel abnormalities that occur through an action potential (AP) shape. Therefore, in this study, we aim to predict the ion channel conductance that is altered from various AP shapes using a machine learning algorithm. We perform electrophysiological simulations using a single-cell model to obtain AP shapes based on variations in the ion channel conductance. In the AP simulation, we increase and decrease the conductance of each ion channel at a constant rate, resulting in 1,980 AP shapes and one standard AP shape without any changes in the ion channel conductance. Subsequently, we calculate the AP difference shapes between them and use them as the input of the machine learning model to predict the changed ion channel conductance. In this study, we demonstrate that the changed ion channel conductance can be predicted with high prediction accuracy, as reflected by an F1 score of 0.985, using only AP shapes and simple machine learning.
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Affiliation(s)
- Da Un Jeong
- IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, 39253, Republic of Korea
| | - Ki Moo Lim
- Medical IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, 39253, Republic of Korea.
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11
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Huang H, Chamness LM, Vanoye CG, Kuenze G, Meiler J, George AL, Schlebach JP, Sanders CR. Disease-linked supertrafficking of a potassium channel. J Biol Chem 2021; 296:100423. [PMID: 33600800 PMCID: PMC7988323 DOI: 10.1016/j.jbc.2021.100423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 02/04/2021] [Accepted: 02/12/2021] [Indexed: 12/21/2022] Open
Abstract
Gain-of-function (GOF) mutations in the voltage-gated potassium channel subfamily Q member 1 (KCNQ1) can induce cardiac arrhythmia. In this study, it was tested whether any of the known human GOF disease mutations in KCNQ1 act by increasing the amount of KCNQ1 that reaches the cell surface-"supertrafficking." Seven of the 15 GOF mutants tested were seen to surface traffic more efficiently than the WT channel. Among these, we found that the levels of R231C KCNQ1 in the plasma membrane were fivefold higher than the WT channel. This was shown to arise from the combined effects of enhanced efficiency of translocon-mediated membrane integration of the S4 voltage-sensor helix and from enhanced post-translational folding/trafficking related to the energetic linkage of C231 with the V129 and F166 side chains. Whole-cell electrophysiology recordings confirmed that R231C KCNQ1 in complex with the voltage-gated potassium channel-regulatory subfamily E member 1 not only exhibited constitutive conductance but also revealed that the single-channel activity of this mutant is only 20% that of WT. The GOF phenotype associated with R231C therefore reflects the effects of supertrafficking and constitutive channel activation, which together offset reduced channel activity. These investigations show that membrane protein supertrafficking can contribute to human disease.
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Affiliation(s)
- Hui Huang
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA
| | - Laura M Chamness
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | - Carlos G Vanoye
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Georg Kuenze
- Departments of Chemistry and Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Department of Bioinformatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jens Meiler
- Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA; Departments of Chemistry and Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Department of Bioinformatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alfred L George
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | | | - Charles R Sanders
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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12
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Jeong DU, Lim KM. Prediction of Cardiac Mechanical Performance From Electrical Features During Ventricular Tachyarrhythmia Simulation Using Machine Learning Algorithms. Front Physiol 2020; 11:591681. [PMID: 33329041 PMCID: PMC7732497 DOI: 10.3389/fphys.2020.591681] [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: 08/05/2020] [Accepted: 10/28/2020] [Indexed: 11/13/2022] Open
Abstract
In ventricular tachyarrhythmia, electrical instability features including action potential duration, dominant frequency, phase singularity, and filaments are associated with mechanical contractility. However, there are insufficient studies on estimated mechanical contractility based on electrical features during ventricular tachyarrhythmia using a stochastic model. In this study, we predicted cardiac mechanical performance from features of electrical instability during ventricular tachyarrhythmia simulation using machine learning algorithms, including support vector regression (SVR) and artificial neural network (ANN) models. We performed an electromechanical tachyarrhythmia simulation and extracted 12 electrical instability features and two mechanical properties, including stroke volume and the amplitude of myocardial tension (ampTens). We compared predictive performance according to kernel types of the SVR model and the number of hidden layers of the ANN model. In the SVR model, the prediction accuracies of stroke volume and ampTens were the highest when using the polynomial kernel and linear kernel, respectively. The predictive performance of the ANN model was better than that of the SVR model. The prediction accuracies were the highest when the ANN model consisted of three hidden layers. Accordingly, we propose the ANN model with three hidden layers as an optimal model for predicting cardiac mechanical contractility in ventricular tachyarrhythmia. The results of this study are expected to be used to indirectly estimate the hemodynamic response from the electrical cardiac map measured by the optical mapping system during cardiac surgery, as well as cardiac contractility under normal sinus rhythm conditions.
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Affiliation(s)
- Da Un Jeong
- Computational Medicine Lab, Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, South Korea
| | - Ki Moo Lim
- Computational Medicine Lab, Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, South Korea.,Computational Medicine Lab, Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, South Korea
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13
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Genetics and Epigenetics of Atrial Fibrillation. Int J Mol Sci 2020; 21:ijms21165717. [PMID: 32784971 PMCID: PMC7460853 DOI: 10.3390/ijms21165717] [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: 06/28/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022] Open
Abstract
Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks
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14
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Computational Study to Identify the Effects of the KCNJ2 E299V Mutation in Cardiac Pumping Capacity. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2020; 2020:7194275. [PMID: 32328155 PMCID: PMC7150720 DOI: 10.1155/2020/7194275] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/20/2020] [Accepted: 02/27/2020] [Indexed: 12/03/2022]
Abstract
The KCNJ2 gene mutations induce short QT syndrome (SQT3) by directly increasing the IK1 current. There have been many studies on the electrophysiological effects of mutations such as the KCNJ2 D172N that cause the SQT3. However, the KCNJ2 E299V mutation is distinguished from other representative gene mutations that can induce the short QT syndrome (SQT3) in that it increased IK1 current by impairing the inward rectification of K+ channels. The studies of the electromechanical effects on myocardial cells and mechanisms of E299V mutations are limited. Therefore, we investigated the electrophysiological changes and the concomitant mechanical responses according to the expression levels of the KCNJ2 E299V mutation during sinus rhythm and ventricular fibrillation. We performed excitation-contraction coupling simulations using a human ventricular model with both electrophysiological and mechanical properties. In order to observe the electromechanical changes due to the expression of KCNJ2 E299V mutation, the simulations were performed under normal condition (WT), heterogeneous mutation condition (WT/E299V), and pure mutation condition (E299V). First, a single-cell simulation was performed in three types of ventricular cells (endocardial cell, midmyocardial cell, and epicardial cell) to confirm the electrophysiological changes and arrhythmogenesis caused by the KCNJ2 E299V mutation. In three-dimensional sinus rhythm simulations, we compared electrical changes and the corresponding changes in mechanical performance caused by the expression level of E299V mutation. Then, we observed the electromechanical properties of the E299V mutation during ventricular fibrillation using the three-dimensional reentry simulation. The KCNJ2 E299V mutation accelerated the opening of the IK1 channel and increased IK1 current, resulting in a decrease in action potential duration. Accordingly, the QT interval was reduced by 48% and 60% compared to the WT condition, for the WT/E299V and E299V conditions, respectively. During sustained reentry, the wavelength was reduced due to the KCNJ2 E299V mutation. Furthermore, there was almost no ventricular contraction in both WT/E299V and E299V conditions. We concluded that in both sinus rhythm and fibrillation, the KCNJ2 E299V mutation results in very low contractility regardless of the expression level of mutation and increases the risk of cardiac arrest and cardiac death.
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15
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Abstract
Background Atrial fibrillation (AF) is a common arrhythmia seen in clinical practice. Occasionally, no common risk factors are present in patients with this arrhythmia. This suggests the potential underlying role of genetic factors associated with predisposition to developing AF. Methods and Results We conducted a comprehensive review of the literature through large online libraries, including PubMed. Many different potassium and sodium channel mutations have been discussed in their relation to AF. There have also been non–ion channel mutations that have been linked to AF. Genome‐wide association studies have helped in identifying potential links between single‐nucleotide polymorphisms and AF. Ancestry studies have also highlighted a role of genetics in AF. Blacks with a higher percentage of European ancestry are at higher risk of developing AF. The emerging field of ablatogenomics involves the use of genetic profiles in their relation to recurrence of AF after catheter ablation. Conclusions The evidence for the underlying role of genetics in AF continues to expand. Ultimately, the role of genetics in risk stratification of AF and its recurrence is of significant interest. No established risk scores that are useful in clinical practice are present to date.
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Affiliation(s)
- Julien Feghaly
- 1 Department of Internal Medicine St Louis University Hospital St Louis MO
| | - Patrick Zakka
- 2 Department of Internal Medicine Emory University Hospital Atlanta GA
| | - Barry London
- 3 Department of Cardiovascular Medicine University of Iowa Carver College of Medicine Iowa City IA
| | - Calum A MacRae
- 4 Department of Cardiovascular Medicine Brigham and Women's Hospital Boston MA
| | - Marwan M Refaat
- 5 Department of Cardiovascular Medicine American University of Beirut Medical Center Beirut Lebanon
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16
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Zhou X, Bueno-Orovio A, Schilling RJ, Kirkby C, Denning C, Rajamohan D, Burrage K, Tinker A, Rodriguez B, Harmer SC. Investigating the Complex Arrhythmic Phenotype Caused by the Gain-of-Function Mutation KCNQ1-G229D. Front Physiol 2019; 10:259. [PMID: 30967788 PMCID: PMC6430739 DOI: 10.3389/fphys.2019.00259] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/28/2019] [Indexed: 12/18/2022] Open
Abstract
The congenital long QT syndrome (LQTS) is a cardiac electrophysiological disorder that can cause sudden cardiac death. LQT1 is a subtype of LQTS caused by mutations in KCNQ1, affecting the slow delayed-rectifier potassium current (I Ks), which is essential for cardiac repolarization. Paradoxically, gain-of-function mutations in KCNQ1 have been reported to cause borderline QT prolongation, atrial fibrillation (AF), sinus bradycardia, and sudden death, however, the mechanisms are not well understood. The goal of the study is to investigate the ionic, cellular and tissue mechanisms underlying the complex phenotype of a gain-of-function mutation in KCNQ1, c.686G > A (p.G229D) using computer modeling and simulations informed by in vitro measurements. Previous studies have shown this mutation to cause AF and borderline QT prolongation. We report a clinical description of a family that carry this mutation and that a member of the family died suddenly during sleep at 21 years old. Using patch-clamp experiments, we confirm that KCNQ1-G229D causes a significant gain in channel function. We introduce the effect of the mutation in populations of atrial, ventricular and sinus node (SN) cell models to investigate mechanisms underlying phenotypic variability. In a population of human atrial and ventricular cell models and tissue, the presence of KCNQ1-G229D predominantly shortens atrial action potential duration (APD). However, in a subset of models, KCNQ1-G229D can act to prolong ventricular APD by up to 7% (19 ms) and underlie depolarization abnormalities, which could promote QT prolongation and conduction delays. Interestingly, APD prolongations were predominantly seen at slow pacing cycle lengths (CL > 1,000 ms), which suggests a greater arrhythmic risk during bradycardia, and is consistent with the observed sudden death during sleep. In a population of human SN cell models, the KCNQ1-G229D mutation results in slow/abnormal sinus rhythm, and we identify that a stronger L-type calcium current enables the SN to be more robust to the mutation. In conclusion, our computational modeling experiments provide novel mechanistic explanations for the observed borderline QT prolongation, and predict that KCNQ1-G229D could underlie SN dysfunction and conduction delays. The mechanisms revealed in the study can potentially inform management and treatment of KCNQ1 gain-of-function mutation carriers.
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Affiliation(s)
- Xin Zhou
- Department of Computer Science, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
| | - Alfonso Bueno-Orovio
- Department of Computer Science, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
| | | | | | - Chris Denning
- Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Divya Rajamohan
- Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Kevin Burrage
- Department of Computer Science, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
- Australian Research Council Centre of Excellence for Mathematical and Statistical Frontiers, Queensland University of Technology, Brisbane, QLD, Australia
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Andrew Tinker
- The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Blanca Rodriguez
- Department of Computer Science, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
| | - Stephen C. Harmer
- The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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17
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Yuniarti AR, Setianto F, Marcellinus A, Hwang HJ, Choi SW, Trayanova N, Lim KM. Effect of KCNQ1 G229D mutation on cardiac pumping efficacy and reentrant dynamics in ventricles: Computational study. INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING 2018; 34:e2970. [PMID: 29488358 PMCID: PMC6556218 DOI: 10.1002/cnm.2970] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 02/09/2018] [Accepted: 02/12/2018] [Indexed: 05/12/2023]
Abstract
There is growing interest in genetic arrhythmia since mutations in gene which encodes the ion channel underlie numerous arrhythmias. Hasegawa et al reported that G229D mutation in KCNQ1 underlies atrial fibrillation due to significant shortening of action potential duration (APD) in atrial cells. Here, we predicted whether KCNQ1 G229D mutation affects ventricular fibrillation generation, although it shortens APD slightly compared with the atrial cell. We analyzed the effects of G229D mutation on electrical and mechanical ventricle behaviors (not considered in previous studies). We compared action potential shapes under wild-type and mutant conditions. Electrical wave propagations through ventricles were analyzed during sinus rhythm and reentrant conditions. IKs enhancement due to G229D mutation shortened the APD in the ventricular cells (6%, 0.3%, and 8% for endo, M, and epi-cells, respectively). The shortened APD contributed to 7% shortening of QT intervals, 29% shortening of wavelengths, 20% decrease in intraventricular pressure, and increase in end-systolic volume 17%, end-diastolic volume 7%, and end-diastolic pressure 11%, which further resulted in reduction in stroke volume as well as cardiac output (28%), ejection fraction 33% stroke work 44%, and ATP consumption 28%. In short, using computational model of the ventricle, we predicted that G229D mutation decreased cardiac pumping efficacy and increased the vulnerability of ventricular fibrillation.
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Affiliation(s)
- Ana Rahma Yuniarti
- Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, South Korea
| | - Febrian Setianto
- Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, South Korea
| | - Aroli Marcellinus
- Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, South Korea
| | - Han Jeong Hwang
- Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, South Korea
| | - Seong Wook Choi
- Department of Mechanical & Biomedical Engineering, Kangwon National University, Chuncheon, South Korea
| | - Natalia Trayanova
- Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Ki Moo Lim
- Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, South Korea
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18
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Mah DY, Shakti D, Gauvreau K, Colan SD, Alexander ME, Abrams DJ, Brown DW. Relation of Left Atrial Size to Atrial Fibrillation in Patients Aged ≤22 Years. Am J Cardiol 2017; 119:52-56. [PMID: 27780555 DOI: 10.1016/j.amjcard.2016.09.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 09/13/2016] [Accepted: 09/13/2016] [Indexed: 11/26/2022]
Abstract
Left atrial (LA) dilation has been shown to be associated with atrial fibrillation (AF) in the adult population, with some studies indicating that larger LAs are more prone to AF recurrence. The relation of LA size to AF in the pediatric and young adult population has not been investigated. In this study, all pediatric patients (aged ≤22 years) who presented to Boston Children's Hospital from January 2002 to December 2012 with AF were reviewed. Patients with significant congenital heart disease, cardiomyopathies, proven channelopathies, previous cardiac surgery, end-stage renal disease, or severe lung disease/cystic fibrosis were excluded. LA measurements were taken using the echocardiogram performed at the initial presentation. In total, 48 patients with AF were identified. The median age at presentation was 17.1 years (range 3.7 to 22.9 years); 38 patients (79%) were men. Eleven patients (23%) had at least 1 recurrence of their AF. There was no difference in body mass index, prevalence of systemic hypertension, alcohol, stimulant, or illicit drug use between those who had an isolated episode of AF and those who had a recurrence. There was no significant difference in LA dimension Z-scores between groups, with only 2 patients (1 isolated AF, 1 recurrent AF) having Z-scores >2. In conclusion, AF in the young without underlying heart disease is not associated with LA dilation.
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19
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Zulfa I, Shim EB, Song KS, Lim KM. Computational simulations of the effects of the G229D KCNQ1 mutation on human atrial fibrillation. J Physiol Sci 2016; 66:407-15. [PMID: 26922794 PMCID: PMC10717180 DOI: 10.1007/s12576-016-0438-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 02/08/2016] [Indexed: 10/22/2022]
Abstract
Atrial fibrillation (AF) is related to mutations at the genetic level. This includes mutations in genes that encode KCNQ1, a subunit of the I Ks channel. Here, we investigate the mechanism of gain-of-function in I Ks towards the occurrence of AF. We used the Courtemanche-Ramirez-Nattel (CRN) human atrial cell model (Am J Physiol Heart Circ Physiol 275:H301-H321, 1998) and applied the modification proposed by Hasegawa et al. (Heart Rhythm 11:67-75, 2014) to fit the behavior of I Ks due to the G229D mutation in KCNQ1 under a heterozygous mutant form. This was incorporated into two-(2D) and three-dimensional (3D) tissue models, where the mutation sustained a reentrant wave. However, under the wild-type condition, the reentrant wave terminated before the end of our simulations (in 2D, the spiral wave terminated before 10 s, while in 3D, the spiral wave terminated before 13 s). Sustained reentry under the mutation conditions also resulted in a spiral wave breakup in the 3D model, which was sustained until the end of the simulation (20 s), indicating AF.
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Affiliation(s)
- Indana Zulfa
- Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Yangho-dong, Gumi, Gyeongbuk, 730-701, Republic of Korea
| | - Eun Bo Shim
- Department of Mechanical and Biomedical Engineering, Kangwon National University, Chuncheon, Republic of Korea
| | - Kwang-Soup Song
- Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Yangho-dong, Gumi, Gyeongbuk, 730-701, Republic of Korea
| | - Ki Moo Lim
- Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Yangho-dong, Gumi, Gyeongbuk, 730-701, Republic of Korea.
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20
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Abstract
Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this article, we will review their molecular identities and biophysical properties. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia.
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Affiliation(s)
- Lei Chen
- Department of Pharmacology, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA
| | - Kevin J Sampson
- Department of Pharmacology, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA
| | - Robert S Kass
- Department of Pharmacology, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA.
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21
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Franco D, Lozano-Velasco E, Aranega A. Gene regulatory networks in atrial fibrillation. World J Med Genet 2016; 6:1-16. [DOI: 10.5496/wjmg.v6.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 12/15/2015] [Accepted: 02/17/2016] [Indexed: 02/06/2023] Open
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmogenic syndrome in humans. With an estimate incidence of 1%-2% in the general population, AF raises up to almost 10%-12% in 80+ years. Thus, AF represents nowadays a highly prevalent medical problem generating a large economic burden. At the electrophysiological level, distinct mechanisms have been elucidated. Yet, despite its prevalence, the genetic and molecular culprits of this pandemic cardiac electrophysiological abnormality have remained largely obscure. Molecular genetics of AF familiar cases have demonstrated that single nucleotide mutations in distinct genes encoding for ion channels underlie the onset of AF, albeit such alterations only explain a minor subset of patients with AF. In recent years, analyses by means of genome-wide association studies have unraveled a more complex picture of the etiology of AF, pointing out to distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Furthermore a new layer of regulatory mechanisms have emerged, i.e., post-transcriptional regulation mediated by non-coding RNA, which have been demonstrated to exert pivotal roles in cardiac electrophysiology. In this manuscript, we aim to provide a comprehensive review of the genetic regulatory networks that if impaired exert electrophysiological abnormalities that contribute to the onset, and subsequently, on self-perpetuation of AF.
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22
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Pellman J, Sheikh F. Atrial fibrillation: mechanisms, therapeutics, and future directions. Compr Physiol 2016; 5:649-65. [PMID: 25880508 DOI: 10.1002/cphy.c140047] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, affecting 1% to 2% of the general population. It is characterized by rapid and disorganized atrial activation leading to impaired atrial function, which can be diagnosed on an EKG by lack of a P-wave and irregular QRS complexes. AF is associated with increased morbidity and mortality and is a risk factor for embolic stroke and worsening heart failure. Current research on AF support and explore the hypothesis that initiation and maintenance of AF require pathophysiological remodeling of the atria, either specifically as in lone AF or secondary to other heart disease as in heart failure-associated AF. Remodeling in AF can be grouped into three categories that include: (i) electrical remodeling, which includes modulation of L-type Ca(2+) current, various K(+) currents and gap junction function; (ii) structural remodeling, which includes changes in tissues properties, size, and ultrastructure; and (iii) autonomic remodeling, including altered sympathovagal activity and hyperinnervation. Electrical, structural, and autonomic remodeling all contribute to creating an AF-prone substrate which is able to produce AF-associated electrical phenomena including a rapidly firing focus, complex multiple reentrant circuit or rotors. Although various remodeling events occur in AF, current AF therapies focus on ventricular rate and rhythm control strategies using pharmacotherapy and surgical interventions. Recent progress in the field has started to focus on the underlying substrate that drives and maintains AF (termed upstream therapies); however, much work is needed in this area. Here, we review current knowledge of AF mechanisms, therapies, and new areas of investigation.
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Affiliation(s)
- Jason Pellman
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
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23
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Palatinus JA, Das S. Your Father and Grandfather's Atrial Fibrillation: A Review of the Genetics of the Most Common Pathologic Cardiac Dysrhythmia. Curr Genomics 2015; 16:75-81. [PMID: 26085805 PMCID: PMC4467307 DOI: 10.2174/1389202916666150108222031] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 12/24/2014] [Accepted: 01/06/2015] [Indexed: 12/19/2022] Open
Abstract
Atrial fibrillation (AF) remains the most common pathologic dysrhythmia in humans with a prevalence of 1-2% of the total population and as high as 10% of the elderly. AF is an independent risk marker for cardiovascular mortality and morbidity, and given the increasing age of the population, represents an increasing burden of disease. Although age and hypertension are known risk factors for development of AF, the study of families with early onset AF revealed mutations in genes coding for ion channels and other proteins involved in electrotonic coupling as likely culprits for the pathology in select cases. Recent investigations using Genome-Wide Association Studies have revealed several single nucleotide polymorphisms (SNPs) that appear to be associated with AF and have highlighted new genes in the proximity of the SNPs that may potentially contribute to the development of the dysrhythmia. Here we review the genetics of AF and discuss how application of GWAS and next generation sequencing have advanced our knowledge of AF and further investigations may yield novel therapeutic targets for the disease.
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Affiliation(s)
- Joseph A Palatinus
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Saumya Das
- Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA
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24
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Christophersen IE, Ellinor PT. Genetics of atrial fibrillation: from families to genomes. J Hum Genet 2015; 61:61-70. [DOI: 10.1038/jhg.2015.44] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 03/27/2015] [Accepted: 04/07/2015] [Indexed: 12/19/2022]
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25
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Abstract
Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity. As the population ages and the prevalence of AF continues to rise, the socioeconomic consequences of AF will become increasingly burdensome. Although there are well-defined clinical risk factors for AF, a significant heritable component is also recognized. To identify the molecular basis for the heritability of AF, investigators have used a combination of classical Mendelian genetics, candidate gene screening, and genome-wide association studies. However, these avenues have, as yet, failed to define the majority of the heritability of AF. The goal of this review is to describe the results from both candidate gene and genome-wide studies, as well as to outline potential future avenues for creating a more complete understanding of AF genetics. Ultimately, a more comprehensive view of the genetic underpinnings for AF will lead to the identification of novel molecular pathways and improved risk prediction of this complex arrhythmia.
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Affiliation(s)
- Nathan R Tucker
- From the Cardiovascular Research Center, Massachusetts General Hospital, Boston
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