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Subati T, Kim K, Yang Z, Murphy MB, Van Amburg JC, Christopher IL, Dougherty OP, Woodall KK, Smart CD, Johnson JE, Fogo AB, Amarnath V, Agrawal V, Barnett JV, Saffitz JE, Murray KT. Oxidative Stress Causes Mitochondrial and Electrophysiologic Dysfunction to Promote Atrial Fibrillation in Pitx2+/-Mice. Circ Arrhythm Electrophysiol 2025:e013199. [PMID: 39989351 DOI: 10.1161/circep.124.013199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 01/30/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND The strongest genetic risk factors for atrial fibrillation (AF) are DNA variants on chromosome 4q25 near the transcription factor gene PITX2. Mice deficient in Pitx2 (Pitx2+/-) have increased AF susceptibility, although the molecular mechanism(s) remains controversial. Pitx2 encodes a transcription factor that activates an antioxidant response to promote cardiac repair. Increased reactive oxygen species causing oxidation of polyunsaturated fatty acids generates reactive lipid dicarbonyl moieties that adduct to proteins and other macromolecules to promote cellular injury. We tested the hypothesis that oxidative stress, and specifically isolevuglandins, the most reactive lipid dicarbonyls identified, are increased in the setting of Pitx2 deficiency to promote proarrhythmic remodeling and AF. METHODS Pitx2+/- and Pitx2+/+ wild-type littermate control mice were treated orally with vehicle, the lipid dicarbonyl scavenger 2-hydroxybenzylamine, or an inactive control compound at weaning, until study at age 16 to 18 weeks. RESULTS Pitx2+/- mice demonstrated increased P wave duration indicative of slowed atrial conduction, as well as increased inducible AF burden and sustained AF, compared with wild type, and these abnormalities were prevented by 2-hydroxybenzylamine. Both reactive oxygen species and isolevuglandin protein adducts were elevated in Pitx2+/- atria with reduced expression of reactive oxygen species-protective genes. High-resolution respirometry demonstrated impaired mitochondrial function in Pitx2+/- atria, with disruption of mitochondrial integrity and cell-cell junctions with connexin lateralization, as well as decreased mitochondrial biogenesis gene expression. Proarrhythmic ionic current remodeling in Pitx2+/- atrial myocytes included elevated resting membrane potential, abbreviated action potential duration, and reduced maximum phase 0 upstroke velocity compared with wild type. Most of these abnormalities were ameliorated or prevented by 2-hydroxybenzylamine. CONCLUSIONS These results demonstrate a critical role for lipid dicarbonyl mediators of oxidative stress in the proarrhythmic remodeling and AF susceptibility that occurs with Pitx2 deficiency, implying the possibility of genotype-specific therapy to prevent AF.
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Affiliation(s)
- Tuerdi Subati
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Kyungsoo Kim
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Zhenjiang Yang
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Matthew B Murphy
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Joseph C Van Amburg
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Isis L Christopher
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Owen P Dougherty
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Kaylen K Woodall
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Charles D Smart
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Joyce E Johnson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt Univ School of Medicine, Nashville, TN. (J.E.J., A.B.F.)
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt Univ School of Medicine, Nashville, TN. (J.E.J., A.B.F.)
| | - Venkataraman Amarnath
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Vineet Agrawal
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
| | - Joey V Barnett
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
| | - Jeffrey E Saffitz
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA (J.E.S.)
| | - Katherine T Murray
- Department of Medicine, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, V. Agrawal, J.V.B., K.T.M.)
- Department of Pharmacology, Vanderbilt Univ School of Medicine, Nashville, TN. (T.S., K.K., Z.Y., M.B.M., J.C.V.A., I.L.C., O.P.D., K.K.W., C.D.S., V. Amarnath, J.V.B., K.T.M.)
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Yan Z, Pu X, Chang X, Liu Z, Liu R. Genetic basis and causal relationship between atrial fibrillation and sinus node dysfunction: Evidence from comprehensive genetic analysis. Int J Cardiol 2025; 418:132609. [PMID: 39389108 DOI: 10.1016/j.ijcard.2024.132609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/16/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Atrial fibrillation (AF) and sinus node dysfunction (SND) are commonly observed together clinically. However, little is known about the genetic background and causal relationship between the two. METHODS Firstly, we investigated the global and local genetic correlations between AF and SND using LDSC and HESS. Then, we identified shared "Novel SNPs" between AF and SND through two complementary cross-trait meta-analyses and mapped the "pleiotropic genes" behind these SNPs, validated by colocalization analysis. Additionally, we explored the degree of genetic enrichment of SNPs in specific tissues using LDSC-SEG and MAGMA, and identified potential functional genes in tissues using summary data-based Mendelian randomization (SMR). Finally, two-sample Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) were used to explore the causal relationship between AF and SND. RESULTS Both global and local genetic correlation analyses revealed a high positive genetic correlation between AF and SND. HESS identified 9 shared loci, with chr4(q25-q26) and chr11(p11.12-q11) being prominent. Cross-trait meta-analysis and colocalization analysis identified ENPEP and PITX2 as novel pleiotropic genes. MAGMA revealed genetic enrichment of SNPs for AF and SND in the "Heart Left Ventricle" and "Heart Atrial Appendage" tissues, with CEP68 and BEST3 identified as potential functional genes through SMR. MR analysis indicated that AF increases the risk of SND, even after adjusting for confounding factors. CONCLUSION This study provides genetic evidence for the increased risk of SND associated with AF, identifying multiple shared risk loci and enriched tissues, and discovering 2 novel pleiotropic genes and 2 new functional genes.
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Affiliation(s)
- Zhaoqi Yan
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiangyi Pu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Heriot-Watt University, Edinburgh, United Kingdom
| | - Xing Chang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiming Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ruxiu Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Schulze-Bahr E. [Cardiogenetics in Germany- a view and review]. Herzschrittmacherther Elektrophysiol 2024; 35:127-137. [PMID: 38418599 PMCID: PMC10924006 DOI: 10.1007/s00399-024-01008-y] [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: 02/06/2024] [Indexed: 03/01/2024]
Abstract
The development of the cardiogenetics field in Germany has been increasing since the mid-1990s with many national contributions, some of them were really important and groundbreaking. The starting point was and still is the patient and his family, e.g. with a familial form of arrhythmia or cardiomyopathy, the clarification of the genetic cause and the personalized treatment of those being affected. The scientific, always translationally oriented interest in identifying a causative gene and uncovering the underlying pathomechanisms has led to notable contributions for Brugada syndrome, short QT syndrome and cardiac conduction disorders or sinus node dysfunction, but also in DCM or ARVC. What is important, however, is always the way back (bench > bed side): implementation of national and international recommendations for cardiogenetic diagnostics in daily cardiological routine and the personalized care and therapy of those being affected.
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Affiliation(s)
- E Schulze-Bahr
- Institut für Genetik von Herzerkrankungen (IfGH), Spezialambulanz für Patienten mit genetischen Herzerkrankungen, Universitätsklinikum Münster (UKM), Domagkstr. 3, 48145, Münster, Deutschland.
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Kim K, Blackwell DJ, Yuen SL, Thorpe MP, Johnston JN, Cornea RL, Knollmann BC. The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency. J Mol Cell Cardiol 2023; 180:1-9. [PMID: 37080450 PMCID: PMC10330243 DOI: 10.1016/j.yjmcc.2023.04.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/25/2023] [Accepted: 04/17/2023] [Indexed: 04/22/2023]
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and morbidity. The strongest genetic risk factors for AF in humans are variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 gene PITX2. Although mice deficient in Pitx2 (Pitx2+/-) have increased AF susceptibility, the mechanism remains controversial. Recent evidence has implicated hyperactivation of the cardiac ryanodine receptor (RyR2) in Pitx2 deficiency, which may be associated with AF susceptibility. We investigated pacing-induced AF susceptibility and spontaneous Ca2+ release events in Pitx2 haploinsufficient (+/-) mice and isolated atrial myocytes to test the hypothesis that hyperactivity of RyR2 increases susceptibility to AF, which can be prevented by a potent and selective RyR2 channel inhibitor, ent-verticilide. Compared with littermate wild-type Pitx2+/+, the frequency of Ca2+ sparks and spontaneous Ca2+ release events increased in permeabilized and intact atrial myocytes from Pitx2+/- mice. Atrial burst pacing consistently increased the incidence and duration of AF in Pitx2+/- mice. The RyR2 inhibitor ent-verticilide significantly reduced the frequency of spontaneous Ca2+ release in intact atrial myocytes and attenuated AF susceptibility with reduced AF incidence and duration. Our data demonstrate that RyR2 hyperactivity enhances SR Ca2+ leak and AF inducibility in Pitx2+/- mice via abnormal Ca2+ handling. Therapeutic targeting of hyperactive RyR2 in AF using ent-verticilide may be a viable mechanism-based approach to treat atrial arrhythmias caused by Pitx2 deficiency.
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Affiliation(s)
- Kyungsoo Kim
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Daniel J Blackwell
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Samantha L Yuen
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Madelaine P Thorpe
- Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA
| | - Jeffrey N Johnston
- Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA
| | - Razvan L Cornea
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Björn C Knollmann
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
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Christensen MA, Bonde A, Sillesen M. Genetic risk factors for postoperative atrial fibrillation-a nationwide genome-wide association study (GWAS). Front Cardiovasc Med 2023; 10:1040757. [PMID: 37404734 PMCID: PMC10315824 DOI: 10.3389/fcvm.2023.1040757] [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: 09/09/2022] [Accepted: 05/29/2023] [Indexed: 07/06/2023] Open
Abstract
Background Atrial fibrillation (AF) is a major cause of morbidity with a high prevalence among the elderly and has an established genetic disposition. Surgery is a well-known risk factor for AF; however, it is currently not recognized how much common genetic variants influence the postoperative risk. The purpose of this study was to identify Single Nucleotide Polymorphisms associated with postoperative AF. Methods The UK Biobank was utilized to conduct a Genome-Wide Association Study (GWAS) to identify variants associated with AF after surgery. An initial discovery GWAS was performed in patients that had undergone surgery with subsequent replication in a unique non-surgical cohort. In the surgical cohort, cases were defined as newly diagnosed AF within 30 days after surgery. The threshold for significance was set at 5 × 10-8. Results After quality control, 144,196 surgical patients with 254,068 SNPs were left for analysis. Two variants (rs17042171 (p = 4.86 × 10-15) and rs17042081 (p = 7.12 × 10-15)) near the PITX2-gene reached statistical significance. These variants were replicated in the non-surgical cohort (1.39 × 10-101 and 1.27 × 10-93, respectively). Several other loci were significantly associated with AF in the non-surgical cohort. Conclusion In this GWAS-analysis of a large national biobank, we identified 2 variants that were significantly associated with postoperative AF. These variants were subsequently replicated in a unique non-surgical cohort. These findings bring new insight in the genetics of postoperative AF and may help identify at-risk patients and guide management.
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Affiliation(s)
- Mathias A. Christensen
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshosptialet, Denmark
- Center for Surgical Translational and Artificial Intelligence Research (CSTAR), Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Alexander Bonde
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshosptialet, Denmark
- Center for Surgical Translational and Artificial Intelligence Research (CSTAR), Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Martin Sillesen
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshosptialet, Denmark
- Center for Surgical Translational and Artificial Intelligence Research (CSTAR), Copenhagen University Hospital, Rigshospitalet, Denmark
- Institute of Clinical Medicine, University of Copenhagen Medical School, Copenhagen, Denmark
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Zhang Y, Gao F, Gong H, Fu Y, Liu B, Qin X, Zheng Q. Intermittent fasting attenuates obesity-related atrial fibrillation via SIRT3-mediated insulin resistance mitigation. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166638. [PMID: 36657499 DOI: 10.1016/j.bbadis.2023.166638] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 12/21/2022] [Accepted: 01/04/2023] [Indexed: 01/18/2023]
Abstract
OBJECTIVE Atrial fibrillation (AF) is the most common tachyarrhythmia in urgent need of therapeutic optimization. Obesity engenders AF, and its pathogenesis is closely intertwined with insulin resistance (IR), but mechanism-based management is still underinvestigated. Intermittent fasting (IF) is a novel lifestyle intervention that mitigates IR, a potential AF driver, yet whether IF can prevent obesity-related AF remains elusive. Here, we aimed to evaluate the impacts of short-term IF on AF and to uncover the underlying mechanism. METHODS We subjected obese mice (high-fat diet for 8-week) to IF (alternative-day fasting for another 5-week) for AF vulnerability and substrate formation assessment, and similarly treated neonatal atrial cardiomyocytes (NRCMs) and fibroblasts (NRCFs) (palmitate, 200 μM) with IF (alternative-day short-term starvation for 8-day) for mechanism investigation. RESULTS Obese mice were prone to AF and atrial remodeling. IF reduced AF inducibility, duration, and reversed atrial remodeling including channel disturbance, left atrial dilation, cardiac hypertrophy and fibrosis in obese mice independent of weight loss. Mechanistically, IF up-regulated the SIRT3 protein level both in vivo and in vitro, and pharmacologic inhibition (3-(1H-1,2,3-Triazol-4-yl) pyridine, 50 μM) and genetic suppression of SIRT3 could attenuate the IF-mediated benefits against hypertrophy and fibrosis. Furthermore, IF activated AMPK and Akt signaling, two positive downstream targets of SIRT3, and inactivated HIF1α signaling, a negative downstream target of SIRT3 in both obese mice atria and palmitate-treated cells, while inhibition of SIRT3 reversed these effects. CONCLUSION IF prevents obesity-related AF via SIRT3-mediated IR mitigation, thus representing a feasible lifestyle intervention to improve AF management.
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Affiliation(s)
- Yudi Zhang
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Feng Gao
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Haoyu Gong
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Yuping Fu
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Binghua Liu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xinghua Qin
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
| | - Qiangsun Zheng
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
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van Kampen SJ, Han SJ, van Ham WB, Kyriakopoulou E, Stouthart EW, Goversen B, Monshouwer-Kloots J, Perini I, de Ruiter H, van der Kraak P, Vink A, van Laake LW, Groeneweg JA, de Boer TP, Tsui H, Boogerd CJ, van Veen TAB, van Rooij E. PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy. Stem Cell Reports 2023; 18:749-764. [PMID: 36868229 PMCID: PMC10031305 DOI: 10.1016/j.stemcr.2023.01.015] [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: 08/29/2022] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 03/05/2023] Open
Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.
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Affiliation(s)
- Sebastiaan J van Kampen
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Su Ji Han
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Willem B van Ham
- Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Eirini Kyriakopoulou
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Elizabeth W Stouthart
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Birgit Goversen
- Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical Center, the Netherlands
| | - Jantine Monshouwer-Kloots
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Ilaria Perini
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Hesther de Ruiter
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Petra van der Kraak
- Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Aryan Vink
- Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Linda W van Laake
- Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Judith A Groeneweg
- Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Teun P de Boer
- Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Hoyee Tsui
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Cornelis J Boogerd
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Toon A B van Veen
- Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Eva van Rooij
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
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8
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Shan L, Chen J, Sun Y, Pan Y, Wang C, Wang Y, Zhang Y. Advances of Liquid Biopsy for Diagnosis of Atrial Fibrillation and Its Recurrence After Ablation in Clinical Application. Methods Mol Biol 2023; 2695:351-365. [PMID: 37450131 DOI: 10.1007/978-1-0716-3346-5_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Atrial fibrillation (AF) is a common arrhythmia disease with high morbidity in clinical practice and leads to stroke, heart failure, peripheral embolism, and other severe complications. With aging of the society, AF has become one of the biggest public health challenges. Effective treatments including antiarrhythmic drugs, electrical cardioversion, and ablation (with or without catheters) can alleviate the symptoms of AF. Ablation is the most effective method for the treatment of persistent AF, but cannot cure all patients. Recurrence of AF is a realistic and unavoidable problem. For early predicting and warning of AF and its recurrence, liquid biopsy for accurate molecular analysis of biofluids is a new strategy with potential value and easy sampling and can detect genetic and epigenetic polymorphisms, especially microRNAs. In this review, liquid biopsy is constructed as a new powerful way for diagnosing AF and predicting its recurrence, contributing to the treatment of AF.
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Affiliation(s)
- Lingtong Shan
- Department of Thoracic Surgery, Sheyang County People's Hospital, Yancheng, Jiangsu, People's Republic of China
| | - Jiapeng Chen
- Xinglin College, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Yangyang Sun
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Yilin Pan
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Chong Wang
- Department of Cardiovascular Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuliang Wang
- Department of Immunology, Nanjing Medical University, Nanjing, China.
| | - Yangyang Zhang
- Department of Cardiovascular Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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9
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Kato Y, Takahashi S. Atrial Cardiopathy and Cryptogenic Stroke. Front Neurol 2022; 13:839398. [PMID: 35273560 PMCID: PMC8901724 DOI: 10.3389/fneur.2022.839398] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022] Open
Abstract
Recent advances in pathophysiology suggest that a pathological atrial substrate can cause embolic stroke even in patients without atrial fibrillation (AF). This pathological condition is called “atrial cardiopathy”, which indicates atrial structural and functional disorders that can precede AF. The objective of this narrative review was to provide a current overview of atrial cardiopathy and cryptogenic stroke. We searched the PubMed database and summarized the recent findings of the identified studies, including the pathogenesis of atrial cardiopathy, biomarkers of atrial cardiopathy, relationship between atrial cardiopathy and cryptogenic stroke, and therapeutic interventions for atrial cardiopathy. Abnormal atrial substrate (atrial cardiopathy) that leads to AF can result in embolic stroke before developing AF, and may explain the source of cryptogenic stroke in some patients. Although there are several potential biomarkers indicative of atrial cardiopathy, P-wave terminal force in lead V1 (>5,000 μV* ms), N-terminal pro-brain natriuretic peptide (>250 pg/ml), and left atrial enlargement are currently promising biomarkers for the diagnosis of atrial cardiopathy. Because the optimal combination and thresholds of biomarkers for diagnosing atrial cardiopathy remain uncertain, atrial cardiopathy represents a spectrum disorder. The concept of atrial cardiopathy appears to be most valuable as a starting point for therapeutic intervention to prevent stroke. Validation of the diagnosis of atrial cardiopathy and whether it can be used as a new therapeutic target for direct oral anticoagulants are currently being covered in the ARCADIA trial.
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Affiliation(s)
- Yuji Kato
- Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Shinichi Takahashi
- Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, Hidaka, Japan
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10
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Fang Y, Li Q, Li X, Luo GH, Kuang SJ, Luo XS, Li QQ, Yang H, Liu Y, Deng CY, Xue YM, Wu SL, Rao F. Piezo1 Participated in Decreased L-Type Calcium Current Induced by High Hydrostatic Pressure via. CaM/Src/Pitx2 Activation in Atrial Myocytes. Front Cardiovasc Med 2022; 9:842885. [PMID: 35252406 PMCID: PMC8891577 DOI: 10.3389/fcvm.2022.842885] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/18/2022] [Indexed: 01/25/2023] Open
Abstract
Hypertension is a major cardiovascular risk factor for atrial fibrillation (AF) worldwide. However, the role of mechanical stress caused by hypertension on downregulating the L-type calcium current (ICa,L), which is vital for AF occurrence, remains unclear. Therefore, the aim of the present study was to investigate the role of Piezo1, a mechanically activated ion channel, in the decrease of ICa,L in response to high hydrostatic pressure (HHP, one of the principal mechanical stresses) at 40 mmHg, and to elucidate the underlying pathways. Experiments were conducted using left atrial appendages from patients with AF, spontaneously hypertensive rats (SHRs) treated with valsartan (Val) at 30 mg/kg/day and atrium-derived HL-1 cells exposed to HHP. The protein expression levels of Piezo1, Calmodulin (CaM), and Src increased, while that of the L-type calcium channel a1c subunit protein (Cav1.2) decreased in the left atrial tissue of AF patients and SHRs. SHRs were more vulnerable to AF, with decreased ICa,L and shortened action potential duration, which were ameliorated by Val treatment. Validation of these results in HL-1 cells in the context of HHP also demonstrated that Piezo1 is required for the decrease of ICa,L by regulating Ca2+ transient and activating CaM/Src pathway to increase the expression of paired like homeodomain-2 (Pitx2) in atrial myocytes. Together, these data demonstrate that HHP stimulation increases AF susceptibility through Piezo1 activation, which is required for the decrease of ICa,Lvia. the CaM/Src/Pitx2 pathway in atrial myocytes.
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Affiliation(s)
- Yuan Fang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Qian Li
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xin Li
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Guan-Hao Luo
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Su-Juan Kuang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xue-Shan Luo
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Qiao-Qiao Li
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hui Yang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yang Liu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chun-Yu Deng
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yu-Mei Xue
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- *Correspondence: Yu-Mei Xue
| | - Shu-Lin Wu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shu-Lin Wu
| | - Fang Rao
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Fang Rao
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11
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Erhard N, Metzner A, Fink T. Late arrhythmia recurrence after atrial fibrillation ablation: incidence, mechanisms and clinical implications. Herzschrittmacherther Elektrophysiol 2022; 33:71-76. [PMID: 35006336 PMCID: PMC8873127 DOI: 10.1007/s00399-021-00836-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/15/2021] [Indexed: 11/24/2022]
Abstract
Background and objectives Catheter ablation of atrial fibrillation (AF) has become a well-established and widely used therapy, with pulmonary vein isolation (PVI) being the key modality of ablation. However, arrhythmia recurrences after PVI are common, with a relevant number of patients undergoing repeat ablation. Arrhythmia recurrence after PVI may vary regarding time point and mode of recurrence. While early arrhythmia recurrences of AF after PVI are mostly found to be the product of electrical reconnection of the pulmonary veins, the exact mechanisms of very late arrhythmia recurrence, occurring later than 12 months after successful PVI, remain unclear. This review provides an overview on the current evidence on time point and mechanisms of arrhythmia recurrence after PVI focussing on late arrhythmia recurrence. Recent findings The incidence of late arrhythmia recurrence after PVI can lie at a rate of up to 30% according to long-term follow-up studies. Mechanisms of recurrence include electrical reconnection of previously isolated pulmonary veins and development of atrial fibrosis. The use of cryoballoon ablation is likely to be more effective in reducing late arrhythmia recurrences compared to radiofrequency ablation. Novel scores such as the MB-LATER score or the APPLE score may become useful tools in predicting arrhythmia recurrence after PVI. Results and conclusion Late arrhythmia recurrence after PVI is common and leads to a relevant impairment of long-term success. Relevant data are currently limited and exact mechanisms of arrhythmia recurrence remain unclear. Further studies are needed to elucidate pathogenetic mechanisms of late arrhythmia recurrence after PVI in order to improve treatment strategies.
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Affiliation(s)
- Nico Erhard
- Department of Electrophysiology, German Heart Centre Munich, Lazarettstr. 36, 80636, Munich, Germany.
| | - Andreas Metzner
- Department of Cardiac Electrophysiology, University Heart Center, University Hospital Hamburg Eppendorf, Hamburg, Germany
| | - Thomas Fink
- Clinic for Electrophysiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany
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12
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García-Padilla C, Domínguez JN, Lodde V, Munk R, Abdelmohsen K, Gorospe M, Jiménez-Sábado V, Ginel A, Hove-Madsen L, Aránega AE, Franco D. Identification of atrial-enriched lncRNA Walras linked to cardiomyocyte cytoarchitecture and atrial fibrillation. FASEB J 2022; 36:e22051. [PMID: 34861058 PMCID: PMC8684585 DOI: 10.1096/fj.202100844rr] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 01/03/2023]
Abstract
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in humans. Genetic and genomic analyses have recently demonstrated that the homeobox transcription factor Pitx2 plays a fundamental role regulating expression of distinct growth factors, microRNAs and ion channels leading to morphological and molecular alterations that promote the onset of AF. Here we address the plausible contribution of long non-coding (lnc)RNAs within the Pitx2>Wnt>miRNA signaling pathway. In silico analyses of annotated lncRNAs in the vicinity of the Pitx2, Wnt8 and Wnt11 chromosomal loci identified five novel lncRNAs with differential expression during cardiac development. Importantly, three of them, Walaa, Walras, and Wallrd, are evolutionarily conserved in humans and displayed preferential atrial expression during embryogenesis. In addition, Walrad displayed moderate expression during embryogenesis but was more abundant in the right atrium. Walaa, Walras and Wallrd were distinctly regulated by Pitx2, Wnt8, and Wnt11, and Wallrd was severely elevated in conditional atrium-specific Pitx2-deficient mice. Furthermore, pro-arrhythmogenic and pro-hypertrophic substrate administration to primary cardiomyocyte cell cultures consistently modulate expression of these lncRNAs, supporting distinct modulatory roles of the AF cardiovascular risk factors in the regulation of these lncRNAs. Walras affinity pulldown assays revealed its association with distinct cytoplasmic and nuclear proteins previously involved in cardiac pathophysiology, while loss-of-function assays further support a pivotal role of this lncRNA in cytoskeletal organization. We propose that lncRNAs Walaa, Walras and Wallrd, distinctly regulated by Pitx2>Wnt>miRNA signaling and pro-arrhythmogenic and pro-hypertrophic factors, are implicated in atrial arrhythmogenesis, and Walras additionally in cardiomyocyte cytoarchitecture.
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Affiliation(s)
- Carlos García-Padilla
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Jorge N. Domínguez
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Valeria Lodde
- Laboratory of Genetics and Genomics, National Institute on Aging IRP, National Institutes of Health, Baltimore, Maryland, USA,Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Rachel Munk
- Laboratory of Genetics and Genomics, National Institute on Aging IRP, National Institutes of Health, Baltimore, Maryland, USA
| | - Kotb Abdelmohsen
- Laboratory of Genetics and Genomics, National Institute on Aging IRP, National Institutes of Health, Baltimore, Maryland, USA
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging IRP, National Institutes of Health, Baltimore, Maryland, USA
| | | | - Antonino Ginel
- Department Cardiac Surgery, Hospital de Sant Pau, Barcelona, Spain,Biomedical Research Institute IIB Sant Pau, Barcelona, Spain
| | - Leif Hove-Madsen
- CIBERCV, Barcelona, Spain,Biomedical Research Institute IIB Sant Pau, Barcelona, Spain,Biomedical Research Institute Barcelona (IIBB-CSIC), Barcelona, Spain
| | - Amelia E. Aránega
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
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13
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Fu T, Chen M, Xu L, Gong J, Zheng J, Zhang F, Ji N. Association of the MYH6 Gene Polymorphism with the Risk of Atrial Fibrillation and Warfarin Anticoagulation Therapy. Genet Test Mol Biomarkers 2021; 25:590-599. [PMID: 34515533 DOI: 10.1089/gtmb.2021.0025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Objective: To study the associations of single nucleotide polymorphisms (SNP) of the myosin heavy chain 6 (MYH6) gene with the risk of atrial fibrillation (AF) and warfarin anticoagulation therapy. Methods: Sanger sequencing was employed to analyze the genotypes of the MYH6 gene's rs28730771, rs365990, and rs2277473 loci in 243 AF patients and 243 non-AF patients (control group) selected according to the age and sex of AF patients at a 1:1 ratio. A multiple logistic regression analysis was used to analyze the risk factors in AF. SHEsis was adopted to analyze the association between rs28730771, rs365990, rs2277473 haplotypes and susceptibility to AF. The average weekly doses of warfarin administered to AF patients with different genotypes were compared. Results: The T allele at rs28730771 of the MYH6 gene (odds ratio [OR] = 2.82, 95% confidence interval [CI]: 1.73-4.59, p < 0.01), the G allele at rs365990 (OR = 1.65, 95% CI: 1.22-2.24, p < 0.01) and the T allele at rs2277473 (OR = 1.91, 95% CI: 1.25-2.91, p < 0.01) were significantly associated with an elevated risk of AF. The results of a logistic regression analysis demonstrated that hypertension, smoking, drinking, family history of stroke, as well as the genotypes at the rs28730771, rs365990, and rs2277473 loci were all risk factors in AF (p < 0.05). The CAG haplotype for the three SNPs was associated with a reduced risk of AF susceptibility (OR = 0.61, 95% CI: 0.46-0.81, p < 0.01), and the CGG haplotype was related to an increased risk of AF (OR = 1.49, 95% CI: 1.07-2.06, p = 0.02). The doses of warfarin used in AF patients with different genotypes at the MYH6 rs28730771, rs365990, and rs2277473 loci were significantly different (p < 0.05). Conclusion: The three SNPs (rs28730771, rs365990, and rs2277473) of the MYH6 gene loci were significantly associated with the risk of AF susceptibility and the dose of warfarin anticoagulant therapy.
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Affiliation(s)
- Ting Fu
- Department of Cardiology, Yiwu Central Hospital, Yiwu, China
| | - Mengyan Chen
- Department of Cardiology, Yiwu Central Hospital, Yiwu, China
| | - Lei Xu
- Department of Cardiology, Yiwu Central Hospital, Yiwu, China
| | - Jianping Gong
- Department of Cardiology, Yiwu Central Hospital, Yiwu, China
| | - Juanqing Zheng
- Department of Cardiology, Yiwu Central Hospital, Yiwu, China
| | - Fen Zhang
- Department of Cardiology, Jinhua People's Hospital, Jinhua, China
| | - Ningning Ji
- Department of Cardiology, Yiwu Central Hospital, Yiwu, China
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14
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Detection of Subclinical Paroxysmal Atrial Fibrillation and Its Correlation with Candidate Genes in Patients with Cryptogenic Ischemic Stroke and TIA. ACTA MEDICA MARTINIANA 2021. [DOI: 10.2478/acm-2021-0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Introduction: Cardioembolic etiology is assumed to be the most frequent cause of cryptogenic strokes. The detection of subclinical paroxysmal atrial fibrillation (AF) is important in the correct choice of preventive treatment. The aim of this prospective study was to detect the incidence of AF in patients with a cryptogenic stroke or transient ischemic attack (TIA) and to evaluate the association between the presence of AF and selected single-nucleotide polymorphisms (SNP).
Methods: Patients with a cryptogenic stroke/ TIA (n=100) and a control group (n=15) of volunteers without significant cardiovascular disease were included in the study during the period of 2014 to 2019. To detect AF they underwent 12 months of ECG monitoring using an implanted loop recorder (ILR). Genotyping for SNPs rs10033464, rs2200733, rs225132, and rs2106261 was performed by a high resolution melting analysis.
Results: We found AF to be present in 24 (24%) patients with a cryptogenic stroke/TIA, versus no subjects in the control group. The SNPs rs2106261, rs2200733, rs225132, and rs10033464 were not found to be associated with AF in our study (p=0.240; 1.000; 0.887; 0.589). However, a weak trend for a higher frequency of rs2106261 risk allele A homozygotes was observed in the patients with AF compared to the patients without AF (0.416 vs. 0.263, p=0.073). Homozygotes for allele A of rs2106261 were also present in a significantly higher frequency in AF patients compared to the controls (0.416 vs. 0.133, p = 0.012).
Conclusion: In our study paroxysmal AF was a probable etiological factor in 24% of patients with cryptogenic ischemic stroke / TIA during the 12 months of monitoring. The homozygous allele A of rs2106261 was identified to be the possible genetic risk factor of AF, but this should be verified in larger cohorts.
The study has been registered at www.clinicaltrials.gov, identifier NCT02216370.
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15
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Ching SC, Wen LJ, Ismail NIM, Looi I, Kooi CW, Peng LS, Mui LS, Tamibmaniam J, Muninathan P, Hooi OB, Ali SMM, Hassan MRA, Mohamad MS, Griffiths LR, Wei LK. SLC17A3 rs9379800 and Ischemic Stroke Susceptibility at the Northern Region of Malaysia. J Stroke Cerebrovasc Dis 2021; 30:105908. [PMID: 34384670 DOI: 10.1016/j.jstrokecerebrovasdis.2021.105908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/24/2021] [Accepted: 05/19/2021] [Indexed: 10/20/2022] Open
Abstract
OBJECTIVES The relationships of Paired Like Homeodomain 2 (PITX2), Ninjurin 2 (NINJ2), TWIST-Related Protein 1 (TWIST1), Ras Interacting Protein 1 (Rasip1), Solute Carrier Family 17 Member 3 (SLC17A3), Methylmalonyl Co-A Mutase (MUT) and Fer3 Like BHLH Transcription Factor (FERD3L) polymorphisms and gene expression with ischemic stroke have yet to be determined in Malaysia. Hence, this study aimed to explore the associations of single nucleotide polymorphisms (SNPs) and gene expression with ischemic stroke risk among population who resided at the Northern region of Malaysia. MATERIALS AND METHODS Study subjects including 216 ischemic stroke patients and 203 healthy controls were recruited upon obtaining ethical clearance. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assays. Gene expression levels were quantified by real-time polymerase chain reaction assays. Statistical and genetic analyses were conducted with SPSS version 22.2, PLINK version 1.07 and multifactor dimensionality reduction software. RESULTS Study subjects with G allele, CG or GG genotypes of SLC17A3 rs9379800 demonstrated increased risk of ischemic stroke with the odds ratios ranging from 1.76-fold to 3.14-fold (p<0.05). When stratified study subjects according to the ethnicity, SLC17A3 rs9379800 G allele and CG genotype contributed to 2.14- and 2.96-fold of ischemic stroke risk among Malay population significantly, in the multivariate analysis (p<0.05). However, no significant associations were observed for PITX2, NINJ2, TWIST1, Rasip1, and MUT polymorphisms with ischemic stroke risk in the multivariate analysis for the pooled cases and controls as well as when stratified them according to the ethnicity. Lower mRNA expression levels of Rasip1, SLC17A3, MUT and FERD3L were observed among cases (p<0.05). After FDR adjustment, the mRNA level of SLC17A3 remained significantly associated with ischemic stroke among Malay population (q=0.034). CONCLUSION In conclusion, this study suggests that SLC17A3 rs9379800 polymorphism and its gene expression contribute to significant ischemic stroke risk among Malaysian population, particularly the Malay who resided at the Northern Region of the country. Our findings can provide useful information for the future diagnosis, management and treatment of ischemic stroke patients.
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Affiliation(s)
- Shu Chai Ching
- Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Lim Jing Wen
- Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Nor Ismaliza Mohd Ismail
- Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Irene Looi
- Clinical Research Centre, Seberang Jaya Hospital, Ministry of Health, Penang, Malaysia
| | - Cheah Wee Kooi
- Clinical Research Centre, Taiping Hospital, Jalan Tamingsari, Taiping, Perak, Malaysia
| | - Long Soo Peng
- Clinical Research Centre, Seberang Jaya Hospital, Ministry of Health, Penang, Malaysia
| | - Lee Soon Mui
- Clinical Research Centre, Seberang Jaya Hospital, Ministry of Health, Penang, Malaysia
| | | | - Prema Muninathan
- Clinical Research Centre, Taiping Hospital, Jalan Tamingsari, Taiping, Perak, Malaysia
| | - Ong Beng Hooi
- Clinical Research Centre, Hospital Sultanah Bahiyah, Kedah, Malaysia
| | | | | | - Mohd Saberi Mohamad
- Department of Genetics and Genomics, College of Medical and Health Sciences, United Arab Emirates University, United Arab Emirates
| | - Lyn R Griffiths
- Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD, Australia
| | - Loo Keat Wei
- Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, 31900 Kampar, Perak, Malaysia.
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16
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Gharanei M, Shafaattalab S, Sangha S, Gunawan M, Laksman Z, Hove-Madsen L, Tibbits GF. Atrial-specific hiPSC-derived cardiomyocytes in drug discovery and disease modeling. Methods 2021; 203:364-377. [PMID: 34144175 DOI: 10.1016/j.ymeth.2021.06.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/08/2021] [Accepted: 06/12/2021] [Indexed: 12/19/2022] Open
Abstract
The discovery and application of human-induced pluripotent stem cells (hiPSCs) have been instrumental in the investigation of the pathophysiology of cardiovascular diseases. Patient-specific hiPSCs can now be generated, genome-edited, and subsequently differentiated into various cell types and used for regenerative medicine, disease modeling, drug testing, toxicity screening, and 3D tissue generation. Modulation of the retinoic acid signaling pathway has been shown to direct cardiomyocyte differentiation towards an atrial lineage. A variety of studies have successfully differentiated patient-specific atrial cardiac myocytes (hiPSC-aCM) and atrial engineered heart tissue (aEHT) that express atrial specific genes (e.g., sarcolipin and ANP) and exhibit atrial electrophysiological and contractility profiles. Identification of protocols to differentiate atrial cells from patients with atrial fibrillation and other inherited diseases or creating disease models using genetic mutation studies has shed light on the mechanisms of atrial-specific diseases and identified the efficacy of atrial-selective pharmacological compounds. hiPSC-aCMs and aEHTs can be used in drug discovery and drug screening studies to investigate the efficacy of atrial selective drugs on atrial fibrillation models. Furthermore, hiPSC-aCMs can be effective tools in studying the mechanism, pathophysiology and treatment options of atrial fibrillation and its genetic underpinnings. The main limitation of using hiPSC-CMs is their immature phenotype compared to adult CMs. A wide range of approaches and protocols are used by various laboratories to optimize and enhance CM maturation, including electrical stimulation, culture time, biophysical cues and changes in metabolic factors.
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Affiliation(s)
- Mayel Gharanei
- Molecular Cardiac Physiology Group, Departments of Biomedical Physiology and Kinesiology and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada; hiPSC-CM Research Team, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia V5Z 4H4, Canada
| | - Sanam Shafaattalab
- Molecular Cardiac Physiology Group, Departments of Biomedical Physiology and Kinesiology and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada; hiPSC-CM Research Team, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia V5Z 4H4, Canada
| | - Sarabjit Sangha
- Molecular Cardiac Physiology Group, Departments of Biomedical Physiology and Kinesiology and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada; hiPSC-CM Research Team, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia V5Z 4H4, Canada
| | - Marvin Gunawan
- Molecular Cardiac Physiology Group, Departments of Biomedical Physiology and Kinesiology and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada; hiPSC-CM Research Team, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia V5Z 4H4, Canada
| | - Zachary Laksman
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
| | - Leif Hove-Madsen
- Cardiac Rhythm and Contraction Group, IIBB-CSIC, CIBERCV, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Glen F Tibbits
- Molecular Cardiac Physiology Group, Departments of Biomedical Physiology and Kinesiology and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada; hiPSC-CM Research Team, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia V5Z 4H4, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
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Phneh KY, Chong ETJ, Lee PC. Role of single nucleotide polymorphisms in susceptibility of stroke: A systemic review. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Kany S, Reissmann B, Metzner A, Kirchhof P, Darbar D, Schnabel RB. Genetics of atrial fibrillation-practical applications for clinical management: if not now, when and how? Cardiovasc Res 2021; 117:1718-1731. [PMID: 33982075 PMCID: PMC8208749 DOI: 10.1093/cvr/cvab153] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Indexed: 12/12/2022] Open
Abstract
The prevalence and economic burden of atrial fibrillation (AF) are predicted to more than double over the next few decades. In addition to anticoagulation and treatment of concomitant cardiovascular conditions, early and standardized rhythm control therapy reduces cardiovascular outcomes as compared with a rate control approach, favouring the restoration, and maintenance of sinus rhythm safely. Current therapies for rhythm control of AF include antiarrhythmic drugs (AADs) and catheter ablation (CA). However, response in an individual patient is highly variable with some remaining free of AF for long periods on antiarrhythmic therapy, while others require repeat AF ablation within weeks. The limited success of rhythm control therapy for AF is in part related to incomplete understanding of the pathophysiological mechanisms and our inability to predict responses in individual patients. Thus, a major knowledge gap is predicting which patients with AF are likely to respond to rhythm control approach. Over the last decade, tremendous progress has been made in defining the genetic architecture of AF with the identification of rare mutations in cardiac ion channels, signalling molecules, and myocardial structural proteins associated with familial (early-onset) AF. Conversely, genome-wide association studies have identified common variants at over 100 genetic loci and the development of polygenic risk scores has identified high-risk individuals. Although retrospective studies suggest that response to AADs and CA is modulated in part by common genetic variation, the development of a comprehensive clinical and genetic risk score may enable the translation of genetic data to the bedside care of AF patients. Given the economic impact of the AF epidemic, even small changes in therapeutic efficacy may lead to substantial improvements for patients and health care systems.
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Affiliation(s)
- Shinwan Kany
- Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg Eppendorf, Martinistraße 52, 20251 Hamburg, Hamburg, Germany.,German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Martinistraße 52, 20251 Hamburg, Hamburg, Germany
| | - Bruno Reissmann
- Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg Eppendorf, Martinistraße 52, 20251 Hamburg, Hamburg, Germany
| | - Andreas Metzner
- Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg Eppendorf, Martinistraße 52, 20251 Hamburg, Hamburg, Germany
| | - Paulus Kirchhof
- Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg Eppendorf, Martinistraße 52, 20251 Hamburg, Hamburg, Germany.,German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Martinistraße 52, 20251 Hamburg, Hamburg, Germany.,The Institute of Cardiovascular Sciences, University of Birmingham, Edgbaston Birmingham B15 2TT, UK
| | - Dawood Darbar
- Division of Cardiology, Departments of Medicine, University of Illinois at Chicago and Jesse Brown Veterans Administration, 840 South Wood Street, Suite 928 M/C 715, Chicago, IL 60612, USA
| | - Renate B Schnabel
- Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg Eppendorf, Martinistraße 52, 20251 Hamburg, Hamburg, Germany.,German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Martinistraße 52, 20251 Hamburg, Hamburg, Germany
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19
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Lkhagva B, Lin Y, Chen Y, Cheng W, Higa S, Kao Y, Chen Y. ZFHX3 knockdown dysregulates mitochondrial adaptations to tachypacing in atrial myocytes through enhanced oxidative stress and calcium overload. Acta Physiol (Oxf) 2021; 231:e13604. [PMID: 33332716 DOI: 10.1111/apha.13604] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 12/06/2020] [Accepted: 12/11/2020] [Indexed: 01/02/2023]
Abstract
AIM To investigate the role of zinc finger homeobox 3 gene (ZFHX3) in tachypacing-induced mitochondrial dysfunction and explore its molecular mechanisms and potential as a therapeutic target in atrial fibrillation (AF). METHODS Through a bioluminescent assay, a patch clamp, confocal fluorescence and fluorescence microscopy, microplate enzyme activity assays and Western blotting, we studied ATP and ADP production, mitochondrial electron transfer chain complex activities, ATP-sensitive potassium channels (IKATP ), mitochondrial oxidative stress, Ca2+ content, and protein expression in control and ZFHX3 knockdown (KD) HL-1 cells subjected to 1 and 5-Hz pacing for 24 hours. RESULTS Compared with 1-Hz pacing, 5-Hz pacing increased ATP and ADP production, IKATP , phosphorylated adenosine monophosphate-activated protein kinase and inositol 1,4,5-triphosphate (IP3 ) receptor (IP3 R) protein expression. Tachypacing induced mitochondrial oxidative stress and Ca2+ overload in both cell types. Furthermore, under 1- and 5-Hz pacing, ZFHX3 KD cells showed higher IKATP , ATP and ADP production, mitochondrial oxidative stress and Ca2+ content than control cells. Under 5-Hz pacing, 2-aminoethoxydiphenyl borate (2-APB; 3 μmol/L, an IP3 R inhibitor) and MitoTEMPO (10 µmol/L, a mitochondria-targeted antioxidant) reduced ADP and increased ATP production in both cell types; however, only 2-APB significantly reduced mitochondrial Ca2+ overload in control cells. Under 5-Hz pacing, mitochondrial oxidative stress was significantly reduced by both MitoTEMPO and 2-APB and only by 2-APB in control and ZFHX3 KD cells respectively. CONCLUSION ZFHX3 KD cells modulate mitochondrial adaptations to tachypacing in HL-1 cardiomyocytes through Ca2+ overload, oxidative stress and metabolic disorder. Targeting IP3 R signalling or oxidative stress could reduce AF.
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Affiliation(s)
- Baigalmaa Lkhagva
- Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan
| | - Yung‐Kuo Lin
- Division of Cardiology Department of Internal Medicine School of Medicine College of Medicine Taipei Medical University Taipei Taiwan
| | - Yao‐Chang Chen
- Department of Biomedical Engineering National Defense Medical Center Taipei Taiwan
| | - Wan‐Li Cheng
- Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan
| | - Satoshi Higa
- Cardiac Electrophysiology and Pacing Laboratory Division of Cardiovascular Medicine Makiminato Central Hospital Okinawa Japan
| | - Yu‐Hsun Kao
- Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan
- Department of Medical Education and Research Wan‐Fang Hospital Taipei Medical University Taipei Taiwan
| | - Yi‐Jen Chen
- Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan
- Cardiovascular Research CenterWan‐Fang HospitalTaipei Medical University Taipei Taiwan
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20
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Liu T, Huang H, Liu X, Yang Y, Mei X, Feng L. Personalized warfarin treatment based on the PITX2 single nucleotide polymorphism rs6843082. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:2831-2839. [PMID: 33284871 PMCID: PMC7716133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 09/01/2020] [Indexed: 06/12/2023]
Abstract
OBJECTIVE To explore the effect of PITX2 gene rs6843082 single nucleotide polymorphism on the efficacy and adverse reactions of warfarin in patients with atrial fibrillation and hypertension, and to provide a theoretical basis for individualized warfarin treatment. METHODS Data on 97 patients with atrial fibrillation and hypertension treated in our hospital were collected from September, 2018 to December, 2019. PCR and SNP genotyping techniques were used to measure the genotype at the rs6843082 locus (pituitary homeobox 2, PITX2) using DNA from the peripheral blood cells of all patients. We compared the efficacy of warfarin and the incidence of adverse reactions in patients of different genotypes. RESULTS (1) Among 97 subjects, 58 cases (59.79%), 32 cases (32.99%) and 7 cases (7.22%) of PITX2 (rs6843082) genotypes GG, GA and AA were identified respectively. The G and A allele frequencies were 76.29% and 23.71%, respectively. (2) After all patients took warfarin to achieve the standard, the GA group and AA group's time to achieve the standard was significantly longer than that of the GG group (P<0.05). The difference was not statistically significant among groups (P>0.05). Compared with the GG group, the maintenance dose of the AA group was increased (P<0.05). (3) Compared with the GG and the GA group, the probability of bleeding events was higher in the AA group (P<0.05). (4) There was no difference in left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) group among GG, GA and AA groups (P>0.05). Compared with the GG group, left ventricular ejection fraction (LVEF) of the AA group was significantly reduced (P<0.05). (5) The mortality rates of the GG, GA, and AA groups were 15.51%, 12.50% and 22.57%, respectively, at the end of 120 d follow-up. CONCLUSION Our findings show that rs6843082 SNP leads to the warfarin dose response differences that were observed in patients with atrial fibrillation and hypertension. Genotyping patients for rs6843082 before initiating warfarin treatment may optimize the treatment response and reduce bleeding incidence.
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Affiliation(s)
- Tianhua Liu
- Department of Cardiology, Shidong Hospital Shanghai 200000, China
| | - Hongman Huang
- Department of Cardiology, Shidong Hospital Shanghai 200000, China
| | - Xinbing Liu
- Department of Cardiology, Shidong Hospital Shanghai 200000, China
| | - Yuya Yang
- Department of Cardiology, Shidong Hospital Shanghai 200000, China
| | - Xiang Mei
- Department of Cardiology, Shidong Hospital Shanghai 200000, China
| | - Liuliu Feng
- Department of Cardiology, Shidong Hospital Shanghai 200000, China
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Tidbury N, Preston J, Ding WY, Rivera-Caravaca JM, Marín F, Lip GYH. Utilizing biomarkers associated with cardiovascular events in atrial fibrillation: informing a precision medicine response. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1804864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Nicola Tidbury
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK
| | - Joshua Preston
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK
| | - Wern Yew Ding
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK
| | - José Miguel Rivera-Caravaca
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK
- Department of Cardiology, Hospital Clínico Universitario Virgen De La Arrixaca, University of Murcia, Instituto Murciano De Investigación Biosanitaria (Imib-arrixaca), CIBERCV, Murcia, Spain
| | - Francisco Marín
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK
- Department of Cardiology, Hospital Clínico Universitario Virgen De La Arrixaca, University of Murcia, Instituto Murciano De Investigación Biosanitaria (Imib-arrixaca), CIBERCV, Murcia, Spain
| | - Gregory Y. H. Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK
- Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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Xu C, Zhang R, Xia Y, Xiong L, Yang W, Wang P. Annotation of susceptibility SNPs associated with atrial fibrillation. Aging (Albany NY) 2020; 12:16981-16998. [PMID: 32902410 PMCID: PMC7521544 DOI: 10.18632/aging.103615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 06/18/2020] [Indexed: 01/24/2023]
Abstract
OBJECTIVE Genome-wide association studies (GWAS) and the candidate gene based association studies have identified a panel of variants associated with atrial fibrillation (AF), however, most of the identified single nucleotide polymorphisms (SNPs) were found located within intergenic or intronic genomic regions, and whether the positive SNPs have a real biological function is unknown, and the real disease causing gene need to be studied. RESULTS The current results of the genetic studies including common variants identified by GWAS (338 index SNPs) and candidate gene based association studies (40 SNPs) were summarized. CONCLUSION Our study suggests the relationship between genetic variants and possible targeted genes, and provides insight into potential genetic pathways underlying AF incidence and development. The results may provide an encyclopedia of AF susceptibility SNPs and shed light on the functional mechanisms of AF variants identified through genetic studies. METHODS We summarized AF susceptibility SNPs identified by GWAS and candidate gene based association studies, and give a comprehensive functional annotation of all these AF susceptibility loci. by genomic annotation, microRNA binding prediction, promoter activity analysis, enhancer activity analysis, transcription factors binding activity prediction, expression quantitative trait loci (eQTL) analysis, long-range transcriptional regulatory function analysis, gene ontology and pathway enrichment analysis.
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Affiliation(s)
- Chengqi Xu
- College of Life Science and Technology, Center for Human Genome Research and Cardio-X Institute, Huazhong University of Science and Technology, Wuhan 430074, P. R. China
| | - Rongfeng Zhang
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, P. R. China
| | - Yunlong Xia
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, P. R. China
| | - Liang Xiong
- Department of Clinical Laboratory, Liyuan Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, P. R. China
| | - Wei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun 130041, P. R. China
| | - Pengyun Wang
- Department of Clinical Laboratory, Liyuan Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, P. R. China
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23
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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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Clinical and Genetic Contributors to New-Onset Atrial Fibrillation in Critically Ill Adults. Crit Care Med 2020; 48:22-30. [PMID: 31599812 DOI: 10.1097/ccm.0000000000004034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES New-onset atrial fibrillation during critical illness is an independent risk factor for mortality. The ability to identify patients at high risk for new-onset atrial fibrillation is limited. We hypothesized that genetic susceptibility contributes to risk of new-onset atrial fibrillation in the ICU. DESIGN Retrospective sub-study of a prospective observational cohort study. SETTING Medical and general surgical ICUs in a tertiary academic medical center. PATIENTS One-thousand three-hundred sixty-nine critically ill patients admitted to the ICU for at least 2 days with no known history of atrial fibrillation who had DNA available for genotyping. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We genotyped 21 single-nucleotide polymorphisms associated with atrial fibrillation in ambulatory studies using a Sequenom platform (San Diego, CA). We collected demographics, medical history, and development of new-onset atrial fibrillation during the first four days of ICU admission. New-onset atrial fibrillation occurred in 98 patients (7.2%) and was associated with age, male sex, coronary artery disease, and vasopressor use. Single-nucleotide polymorphisms associated with new-onset atrial fibrillation were rs3853445 (near PITX2, p = 0.0002), rs6838973 (near PITX2, p = 0.01), and rs12415501 (in NEURL, p = 0.03) on univariate testing. When controlling for clinical factors, rs3853445 (odds ratio, 0.47; 95% CI, 0.30-0.73; p = 0.001) and rs12415501 (odds ratio, 1.72; 95% CI, 1.27-2.59; p = 0.01) remained significantly associated with new-onset atrial fibrillation. The addition of genetic variables to clinical factors improved new-onset atrial fibrillation discrimination in a multivariable logistic regression model (C-statistic 0.82 vs 0.78; p = 0.0009). CONCLUSIONS We identified several single-nucleotide polymorphisms associated with new-onset atrial fibrillation in a large cohort of critically ill ICU patients, suggesting there is genetic susceptibility underlying this common clinical condition. This finding may provide new targets for future mechanistic studies and additional insight into the application of genomic information to identify patients at elevated risk for a common and important condition in the ICU.
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van Ouwerkerk AF, Hall AW, Kadow ZA, Lazarevic S, Reyat JS, Tucker NR, Nadadur RD, Bosada FM, Bianchi V, Ellinor PT, Fabritz L, Martin J, de Laat W, Kirchhof P, Moskowitz I, Christoffels VM. Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation. Circ Res 2020; 127:34-50. [PMID: 32717170 PMCID: PMC8315291 DOI: 10.1161/circresaha.120.316574] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (AF), the most common arrhythmia. Many of the top AF-associated loci harbor key cardiac transcription factors, including PITX2, TBX5, PRRX1, and ZFHX3. Moreover, the vast majority of the AF-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. In this review, we discuss a transcriptional regulatory network model for AF defined by effector genes in Genome-wide association studies loci. We describe the current state of the field regarding the identification and function of AF-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. We illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact AF risk. Last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.
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Affiliation(s)
- Antoinette F. van Ouwerkerk
- Department of Medical Biology, Amsterdam University Medical Centers, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Amelia W. Hall
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Zachary A. Kadow
- Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
- Medical Scientist Training Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Sonja Lazarevic
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA
| | - Jasmeet S. Reyat
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
| | - Nathan R. Tucker
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Masonic Medical Research Institute, Utica, NY, USA
| | - Rangarajan D. Nadadur
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA
| | - Fernanda M. Bosada
- Department of Medical Biology, Amsterdam University Medical Centers, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Valerio Bianchi
- Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Patrick T. Ellinor
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Larissa Fabritz
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
- SWBH and UHB NHS Trusts, Birmingham, UK
| | - Jim Martin
- Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
- Texas Heart Institute, Houston, Texas, 77030
| | - Wouter de Laat
- Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Paulus Kirchhof
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
- SWBH and UHB NHS Trusts, Birmingham, UK
- University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Ivan Moskowitz
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA
| | - Vincent M. Christoffels
- Department of Medical Biology, Amsterdam University Medical Centers, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
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Correa A, Haider SW, Aronow WS. Precision medicine in cardiac electrophysiology: where we are and where we need to go. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1754127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Ashish Correa
- Department of Cardiology, Mount Sinai Morningside (formerly Mount St. Luke’s), Icahn School of Medicine, New York, NY, USA
| | - Syed Waqas Haider
- Department of Cardiology, Mount Sinai Morningside (formerly Mount St. Luke’s), Icahn School of Medicine, New York, NY, USA
| | - Wilbert S. Aronow
- Department of Cardiology, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
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Khan MS, Yamashita K, Sharma V, Ranjan R, Dosdall DJ. RNAs and Gene Expression Predicting Postoperative Atrial Fibrillation in Cardiac Surgery Patients Undergoing Coronary Artery Bypass Grafting. J Clin Med 2020; 9:jcm9041139. [PMID: 32316120 PMCID: PMC7231013 DOI: 10.3390/jcm9041139] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/14/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
Postoperative atrial fibrillation (POAF) is linked with increased morbidity, mortality rate and financial liability. About 20–50% of patients experience POAF after coronary artery bypass graft (CABG) surgery. Numerous review articles and meta-analyses have investigated links between patient clinical risk factors, demographic conditions, and pre-, peri- and post-operative biomarkers to forecast POAF incidence in CABG patients. This narrative review, for the first time, summarize the role of micro-RNAs, circular-RNAs and other gene expressions that have shown experimental evidence to accurately predict the POAF incidence in cardiac surgery patients after CABG. We envisage that identifying specific genomic markers for predicting POAF might be a significant step for the prevention and effective management of this type of post-operative complication and may provide critical perspective into arrhythmogenic substrate responsible for POAF.
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Affiliation(s)
- Muhammad Shuja Khan
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112, USA; (M.S.K.); (K.Y.); (R.R.)
| | - Kennosuke Yamashita
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112, USA; (M.S.K.); (K.Y.); (R.R.)
- Division of Cardiovascular Medicine, The University of Utah-Health, Salt Lake City, UT 84132, USA
| | - Vikas Sharma
- Division of Cardiothoracic Surgery, The University of Utah-Health, Salt Lake City, UT 84132, USA;
| | - Ravi Ranjan
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112, USA; (M.S.K.); (K.Y.); (R.R.)
- Division of Cardiovascular Medicine, The University of Utah-Health, Salt Lake City, UT 84132, USA
- Department of Biomedical Engineering, The University of Utah, Salt Lake City, UT 84112, USA
| | - Derek James Dosdall
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112, USA; (M.S.K.); (K.Y.); (R.R.)
- Division of Cardiovascular Medicine, The University of Utah-Health, Salt Lake City, UT 84132, USA
- Division of Cardiothoracic Surgery, The University of Utah-Health, Salt Lake City, UT 84132, USA;
- Department of Biomedical Engineering, The University of Utah, Salt Lake City, UT 84112, USA
- Correspondence: ; Tel.: +1-801-587-2036
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Bai J, Lu Y, Lo A, Zhao J, Zhang H. PITX2 upregulation increases the risk of chronic atrial fibrillation in a dose-dependent manner by modulating IKs and ICaL -insights from human atrial modelling. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:191. [PMID: 32309338 PMCID: PMC7154416 DOI: 10.21037/atm.2020.01.90] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Functional analysis has shown that the paired-like homeodomain transcription factor 2 (PITX2) overexpression associated with atrial fibrillation (AF) leads to the slow delayed rectifier K+ current (IKs) increase and the L-type Ca2+ current (ICaL) reduction observed in isolated right atrial myocytes from chronic AF (CAF) patients. Through multiscale computational models, this study aimed to investigate the functional impact of the PITX2 overexpression on atrial electrical activity. Methods The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial action potentials (APs) was updated to incorporate experimental data on alterations in IKs and ICaL due to the PITX2 overexpression. These cell models for sinus rhythm (SR) and CAF were then incorporated into homogeneous multicellular one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) tissue models. The proarrhythmic effects of the PITX2 overexpression were quantified with ion current profiles, AP morphology, AP duration (APD) restitution, conduction velocity restitution (CVR), wavelength (WL), vulnerable window (VW) for unidirectional conduction block, and minimal substrate size required to induce re-entry. Dynamic behaviors of spiral waves were characterized by measuring lifespan (LS), tip patterns and dominant frequencies. Results The IKs increase and the ICaL decrease arising from the PITX2 overexpression abbreviated APD and flattened APD restitution (APDR) curves in single cells. It reduced WL and increased CV at high excitation rates at the 1D tissue level. Although it had no effects on VW for initiating spiral waves, it decreased the minimal substrate size necessary to sustain re-entry. It also stabilized and accelerated spiral waves in 2D and 3D tissue models. Conclusions Electrical remodeling (IKs and ICaL) due to the PITX2 overexpression increases susceptibility to AF due to increased tissue vulnerability, abbreviated APD, shortened WL and altered CV, which, in combination, facilitate initiation and maintenance of spiral waves.
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Affiliation(s)
- Jieyun Bai
- Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yaosheng Lu
- Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou 510632, China
| | - Andy Lo
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Jichao Zhao
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Henggui Zhang
- Biological Physics Group, School of Physics & Astronomy, University of Manchester, Manchester, UK
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Okubo Y, Nakano Y, Ochi H, Onohara Y, Tokuyama T, Motoda C, Amioka M, Hironobe N, Okamura S, Ikeuchi Y, Miyauchi S, Chayama K, Kihara Y. Predicting atrial fibrillation using a combination of genetic risk score and clinical risk factors. Heart Rhythm 2020; 17:699-705. [PMID: 31931171 DOI: 10.1016/j.hrthm.2020.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 01/02/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Atrial fibrillation (AF) has a genetic basis, and environmental factors can modify its actual pathogenesis. OBJECTIVE The purpose of this study was to construct a combined risk assessment method including both genetic and clinical factors in the Japanese population. METHODS We screened a cohort of 540 AF patients and 520 non-AF controls for single nucleotide polymorphisms (SNPs) previously associated with AF by genome-wide association studies. The most strongly associated SNPs after propensity score analysis were then used to calculate a weighted genetic risk score (WGRS). We also enrolled 1018 non-AF Japanese subjects as a validation cohort and monitored AF emergence over several years. Finally, we constructed a logistic model for AF prediction combining WGRS and clinical risk factors. RESULTS We identified 5 SNPs (in PRRX1, ZFHX3, PITX2, HAND2, and NEURL1) associated with AF after Bonferroni correction. There was a 4.92-fold difference in AF risk between the highest and lowest WGRS calculated using these 5 SNPs (P = 2.32 × 10-10). Receiver operating characteristic analysis of WGRS yielded an area under the curve (AUC) of 0.73 for the screening cohort and 0.72 for the validation cohort. The predictive logistic model constructed using a combination of WGRS and AF clinical risk factors (age, body mass index, sex, and hypertension) demonstrated better discrimination of AF than WGRS alone (AUC = 0.84; sensitivity 75.4%; specificity 80.2%). CONCLUSION This novel predictive model of combined AF-associated SNPs and known clinical risk factors can accurately stratify AF risk in the Japanese population.
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Affiliation(s)
- Yousaku Okubo
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Yukiko Nakano
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
| | - Hidenori Ochi
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Department of Health Management, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Yuko Onohara
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Takehito Tokuyama
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Chikaaki Motoda
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Michitaka Amioka
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Naoya Hironobe
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Sho Okamura
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Yoshihiro Ikeuchi
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Syunsuke Miyauchi
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasuki Kihara
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
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Ghazizadeh Z, Kiviniemi T, Olafsson S, Plotnick D, Beerens ME, Zhang K, Gillon L, Steinbaugh MJ, Barrera V, Sui SH, Werdich AA, Kapur S, Eranti A, Gunn J, Jalkanen J, Airaksinen J, Kleber AG, Hollmén M, MacRae CA. Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation. Circulation 2019; 141:301-312. [PMID: 31735076 DOI: 10.1161/circulationaha.119.044268] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models. METHODS Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell-derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non-cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations. RESULTS There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)-related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models. CONCLUSIONS These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.
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Affiliation(s)
- Zaniar Ghazizadeh
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Tuomas Kiviniemi
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Heart Center, Turku University Hospital (T.K., A.E., J.G., J.A.), Harvard T.H
- University of Turku, Finland (T.K., A.E., J.G., J.A.). Harvard T.H
| | - Sigurast Olafsson
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - David Plotnick
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Manu E Beerens
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Kun Zhang
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Leah Gillon
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | | | - Victor Barrera
- Chan School of Public Health, Boston, MA (M.J.S., V.B., S.H.S.)
| | - Shannan Ho Sui
- Chan School of Public Health, Boston, MA (M.J.S., V.B., S.H.S.)
| | - Andreas A Werdich
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Sunil Kapur
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Antti Eranti
- Heart Center, Turku University Hospital (T.K., A.E., J.G., J.A.), Harvard T.H
- University of Turku, Finland (T.K., A.E., J.G., J.A.). Harvard T.H
| | - Jarmo Gunn
- Heart Center, Turku University Hospital (T.K., A.E., J.G., J.A.), Harvard T.H
- University of Turku, Finland (T.K., A.E., J.G., J.A.). Harvard T.H
| | - Juho Jalkanen
- Medicity Research Laboratories (J.J., M.H.), Harvard T.H
| | - Juhani Airaksinen
- Heart Center, Turku University Hospital (T.K., A.E., J.G., J.A.), Harvard T.H
- University of Turku, Finland (T.K., A.E., J.G., J.A.). Harvard T.H
| | - Andre G Kleber
- Department of Pathology, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA (A.G.K.)
| | - Maija Hollmén
- Medicity Research Laboratories (J.J., M.H.), Harvard T.H
| | - Calum A MacRae
- Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Genetics and Network Medicine Divisions (C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Harvard Stem Cell Institute, Boston, MA (C.A.M.)
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31
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Fan SM, Fann A, Nah G, Pletcher MJ, Olgin JE, Marcus GM. Characteristics of Atrial Fibrillation Patients with a Family History of Atrial Fibrillation. J Atr Fibrillation 2019; 12:2198. [PMID: 31687072 DOI: 10.4022/jafib.2198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 12/14/2018] [Accepted: 02/26/2019] [Indexed: 11/10/2022]
Abstract
Background Family history has been shown to be associated with increased risk of atrial fibrillation (AF). However, the specific AF characteristics that travel with a family history have not yet been elucidated. The purpose of this study was to determine whether a family history of AF is associated with specific patient characteristics in a worldwide, remote cohort. Methods From the Health eHeart Study, an internet-based prospective cohort, we performed a cross-sectional analysis of AF participants who reported their family history and completed questionnaires regarding their medical conditions and AF symptoms. We assessed demographics, cardiovascular comorbidities, and AF symptom characteristics in AF participants with and without a family history of AF. Results In multivariable analysis of 5,884 participants with AF (mean age 59.9 ± 14.5, 59% male, 92% white), female sex (odds ratio [OR]=1.35, 95% CI, 1.17-1.54, p<0.0001) and birth in the U.S. (OR=2.54, 95% CI, 2.12-3.05, p<0.0001) were independently associated with having a family history of AF. Having a family history of AF was also more commonly associated with symptoms of shortness of breath (OR=1.40, 95% CI, 1.07-1.82, p=0.014), chest pain, pressure, or discomfort (OR=1.95, 95% CI, 1.22-3.13, p=0.0052), and feeling generally "off" about oneself (OR=1.84, 95% CI, 1.27-2.67, p=0.0013). Conclusions Patients with a family history of AF are more likely to be female, be US-born, and experience symptoms of AF, suggesting underlying mechanistic differences between those with and without family history of AF.
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Affiliation(s)
- Shannon M Fan
- Division of Cardiology, Department of Medicine, University of California, San Francisco, California
| | - Amy Fann
- Division of Cardiology, Department of Medicine, University of California, San Francisco, California
| | - Gregory Nah
- Division of Cardiology, Department of Medicine, University of California, San Francisco, California
| | - Mark J Pletcher
- Department of Epidemiology and Biostatistics, University of California, San Francisco, California
| | - Jeffrey E Olgin
- Division of Cardiology, Department of Medicine, University of California, San Francisco, California
| | - Gregory M Marcus
- Division of Cardiology, Department of Medicine, University of California, San Francisco, California
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32
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Kao YH, Chung CC, Cheng WL, Lkhagva B, Chen YJ. Pitx2c inhibition increases atrial fibroblast activity: Implications in atrial arrhythmogenesis. Eur J Clin Invest 2019; 49:e13160. [PMID: 31378929 DOI: 10.1111/eci.13160] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 07/31/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND A Pitx2c deficiency increases the risk of atrial fibrillation (AF). Atrial structural remodelling with fibrosis blocks electrical conduction and leads to arrhythmogenesis. A Pitx2c deficiency enhances profibrotic transforming growth factor (TGF)-β expression and calcium dysregulation, suggesting that Pitx2c may play a role in atrial fibrosis. The purposes of this study were to evaluate whether a Pitx2c deficiency modulates cardiac fibroblast activity and study the underlying mechanisms. MATERIALS AND METHODS A migration assay, proliferation analysis, Western blot analysis and calcium fluorescence imaging were conducted in Pitx2c-knockdown human atrial fibroblasts (HAFs) using short hairpin (sh)RNA or small interfering (si)RNA. RESULTS Compared to control HAFs, Pitx2c-knockdown HAFs had a greater migration but a similar proliferative ability. Pitx2c-knockdown HAFs had a higher calcium influx with enhanced phosphorylation of calmodulin kinase II (CaMKII), α-smooth muscle actin and matrix metalloproteinase-2. In the presence of a CaMKII inhibitor (KN-93, 0.5 μmol/L), control and Pitx2c-knockdown HAFs exhibited similar migratory abilities. CONCLUSION These findings suggest that downregulation of Pitx2c may regulate atrial fibrosis through modulating calcium homeostasis, which may contribute to its role in anti-atrial fibrosis, and Pitx2c downregulation may change the atrial electrophysiology and AF occurrence through modulating fibroblast activity.
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Affiliation(s)
- Yu-Hsun Kao
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Medical Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Chih Chung
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Wan-Li Cheng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Baigalmaa Lkhagva
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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33
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Kalstø SM, Siland JE, Rienstra M, Christophersen IE. Atrial Fibrillation Genetics Update: Toward Clinical Implementation. Front Cardiovasc Med 2019; 6:127. [PMID: 31552271 PMCID: PMC6743416 DOI: 10.3389/fcvm.2019.00127] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/12/2019] [Indexed: 12/16/2022] Open
Abstract
Atrial fibrillation (AF) is the most common heart rhythm disorder worldwide and may have serious cardiovascular health consequences. AF is associated with increased risk of stroke, dementia, heart failure, and death. There are several known robust, clinical risk predictors for AF, such as male sex, increasing age, and hypertension; however, during the last couple of decades, a substantive genetic component has also been established. Over the last 10 years, the discovery of novel AF-related genetic variants has accelerated, increasing our understanding of mechanisms behind AF. Current studies are focusing on mapping the polygenic structure of AF, improving risk prediction, therapeutic development, and patient-specific management. Nevertheless, it is still difficult for clinicians to interpret the role of genetics in AF prediction and management. Here, we provide an overview of relevant topics within the genetics of AF and attempt to provide some guidance on how to interpret genetic advances and their implementation into clinical decision-making.
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Affiliation(s)
- Silje Madeleine Kalstø
- Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud, Norway
| | - Joylene Elisabeth Siland
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Michiel Rienstra
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Ingrid E Christophersen
- Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud, Norway.,The Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
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Cruz D, Pinto R, Freitas-Silva M, Nunes JP, Medeiros R. GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications. Pharmacogenomics 2019; 20:765-780. [PMID: 31368859 DOI: 10.2217/pgs-2019-0054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.
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Affiliation(s)
- Diana Cruz
- Molecular Oncology & Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr António Bernardino de Almeida, 4200-4072 Porto, Portugal.,FMUP, Faculty of Medicine, Porto University, Alameda Prof Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Ricardo Pinto
- Molecular Oncology & Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr António Bernardino de Almeida, 4200-4072 Porto, Portugal
| | - Margarida Freitas-Silva
- FMUP, Faculty of Medicine, Porto University, Alameda Prof Hernâni Monteiro, 4200-319 Porto, Portugal.,Department of Medicine, Centro Hospitalar São João, Porto, Portugal
| | - José Pedro Nunes
- FMUP, Faculty of Medicine, Porto University, Alameda Prof Hernâni Monteiro, 4200-319 Porto, Portugal.,Department of Medicine, Centro Hospitalar São João, Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology & Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr António Bernardino de Almeida, 4200-4072 Porto, Portugal.,FMUP, Faculty of Medicine, Porto University, Alameda Prof Hernâni Monteiro, 4200-319 Porto, Portugal.,Research Department, Portuguese League Against Cancer (NRNorte), Estrada Interior da Circunvalação, 6657, 4200-172 Porto, Portugal.,CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Praça 9 de Abril, 349, 4249-004 Porto, Portugal
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35
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Sapelnikov OV, Kulikov AA, Favorova OO, Matveeva NA, Cherkashin DI, Nikolaeva OA, Akchurin RS. Genetic, Epigenetic and Transcription Factors in Atrial Fibrillation. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2019. [DOI: 10.20996/1819-6446-2019-15-3-407-415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Atrial fibrillation (AF) is one of the most common arrhythmia that occurs in patients with cardiovascular diseases. Congenital forms of AF are quite rare. Many studies have shown that genetic, epigenetic and transcription factors may play an important role in the development and the progression of AF. In our review, studies have been conducted on the identification of mutations in ionic and non-ionic channels, possibly associated with AF. These mutations were found only in isolated groups of patients with AF, and in general, monogenic forms of AF are a rare subtype of the disease. Genomic association studies have helped to identify potential links between single nucleotide polymorphisms and AF. The risk of AF in the general population is likely to be determined by the interaction between environmental factors and many alleles. In recent years, the emergence of a genome-wide associative studies has significantly expanded the understanding of the genetic basis for the inheritance of AF and has led to the emergence of new evidence of the important role of genetic factors in the development of AF, in the risk stratification of AF and the recurrence of AF. Epigenetic factors are also important in AF. Epigenetic therapy aimed at treating a disease through exposure to epigenome is currently under development. A newly emerged area of ablatogenomics includes the use of genetic profiles that allow assessing the likelihood of recurrence of AF after catheter ablation. The results of genetic studies in AF show that, in addition to their role in the appearance of congenital heart pathologies, transcription factors play an important role in the pathogenesis of AF.
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Affiliation(s)
| | | | - O. O. Favorova
- National Medical Research Center of Cardiology
Pirogov Russian National Research Medical University
| | - N. A. Matveeva
- National Medical Research Center of Cardiology
Pirogov Russian National Research Medical University
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Lozano-Velasco E, Garcia-Padilla C, Aránega AE, Franco D. Genetics of Atrial Fibrilation: In Search of Novel Therapeutic Targets. Cardiovasc Hematol Disord Drug Targets 2019; 19:183-194. [PMID: 30727926 DOI: 10.2174/1871529x19666190206150349] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 01/16/2019] [Accepted: 01/23/2019] [Indexed: 06/09/2023]
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmogenic disease in humans, ranging from 2% in the general population and rising up to 10-12% in 80+ years. Genetic analyses of AF familiar cases have identified a series of point mutations in distinct ion channels, supporting a causative link. However, these genetic defects only explain a minority of AF patients. Genomewide association studies identified single nucleotide polymorphisms (SNPs), close to PITX2 on 4q25 chromosome, that are highly associated to AF. Subsequent GWAS studies have identified several new loci, involving additional transcription and growth factors. Furthermore, these risk 4q25 SNPs serve as surrogate biomarkers to identify AF recurrence in distinct surgical and pharmacological interventions. Experimental studies have demonstrated an intricate signalling pathway supporting a key role of the homeobox transcription factor PITX2 as a transcriptional regulator. Furthermore, cardiovascular risk factors such as hyperthyroidism, hypertension and redox homeostasis have been identified to modulate PITX2 driven gene regulatory networks. We provide herein a state-of-the-art review of the genetic bases of atrial fibrillation, our current understanding of the genetic regulatory networks involved in AF and its plausible usage for searching novel therapeutic targets.
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Affiliation(s)
- Estefanía Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Carlos Garcia-Padilla
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Amelia E Aránega
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
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37
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Bai J, Gladding PA, Stiles MK, Fedorov VV, Zhao J. Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells. Sci Rep 2018; 8:15642. [PMID: 30353147 PMCID: PMC6199257 DOI: 10.1038/s41598-018-33958-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 09/24/2018] [Indexed: 12/16/2022] Open
Abstract
Transcription factors TBX5 and PITX2 involve in the regulation of gene expression of ion channels and are closely associated with atrial fibrillation (AF), the most common cardiac arrhythmia in developed countries. The exact cellular and molecular mechanisms underlying the increased susceptibility to AF in patients with TBX5/PITX2 insufficiency remain unclear. In this study, we have developed and validated a novel human left atrial cellular model (TPA) based on the ten Tusscher-Panfilov ventricular cell model to systematically investigate how electrical remodeling induced by TBX5/PITX2 insufficiency leads to AF. Using our TPA model, we have demonstrated that spontaneous diastolic depolarization observed in atrial myocytes with TBX5-deletion can be explained by altered intracellular calcium handling and suppression of inward-rectifier potassium current (IK1). Additionally, our computer simulation results shed new light on the novel cellular mechanism underlying AF by indicating that the imbalance between suppressed outward current IK1 and increased inward sodium-calcium exchanger current (INCX) resulted from SR calcium leak leads to spontaneous depolarizations. Furthermore, our simulation results suggest that these arrhythmogenic triggers can be potentially suppressed by inhibiting sarcoplasmic reticulum (SR) calcium leak and reversing remodeled IK1. More importantly, this study has clinically significant implications on the drugs used for maintaining SR calcium homeostasis, whereby drugs such as dantrolene may confer significant improvement for the treatment of AF patients with TBX5/PITX2 insufficiency.
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Affiliation(s)
- Jieyun Bai
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand.
- School of Computer Science and Technology, Harbin Institute Technology, Harbin, China.
| | - Patrick A Gladding
- Department of Cardiology, Waitemata District Health Board, Auckland, New Zealand
| | | | - Vadim V Fedorov
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, United States of America
| | - Jichao Zhao
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand.
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Naylor J, Churilov L, Johnstone B, Guo R, Xiong Y, Koome M, Chen Z, Thevathasan A, Chen Z, Liu X, Kwan P, Campbell BCV. The Association Between Atrial Fibrillation and Poststroke Seizures is Influenced by Ethnicity and Environmental Factors. J Stroke Cerebrovasc Dis 2018; 27:2755-2760. [PMID: 30037649 DOI: 10.1016/j.jstrokecerebrovasdis.2018.05.044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 05/28/2018] [Indexed: 12/31/2022] Open
Abstract
GOAL Epilepsy is a major complication of stroke. There have been suggestions that patients with cardioembolic stroke are at a greater risk of developing seizures than other stroke subtypes. However, the incidence of atrial fibrillation (AF) and cardioembolic stroke varies considerably across countries, generally higher in Western populations than in Asian populations. This study assessed whether ethnicity affects the association between AF and poststroke seizure (PSS) development. We hypothesized that Royal Melbourne Hospital ([RMH] Melbourne) patients will have significantly higher incidence of AF-related PSS than in the Jinling Hospital (Nanjing) population. MATERIALS AND METHODS This was a retrospective, multicenter cohort study including patients with anterior circulation ischemic stroke admitted between 2008 and 2015. Occurrences of PSS were ascertained by reviewing medical records or telephone follow-up. To test the hypothesis of an interaction between ethnicity and AF for PSS occurrence, a logistic regression model with AF and ethnicity together with an ethnicity-by-AF interaction term was used. FINDINGS Of 782 patients followed-up for seizure development at RMH, 247 (31.6%) patients had AF, of whom 10 (4%) developed PSS. Of 1185 patients followed-up and included at JH, 54 (4.8%) patients with AF, of whom 4 (7.4%) developed PSS. At RMH, no significant association was found between AF and PSS; odds ratio .75, 95% confidence interval .4-1.6, (P = .4). At JH, there was a significant association between AF and increased PSS: OR 4.0, 95% CI 1.3-12.1, (P = .01), P for interaction = .03. CONCLUSION Further understanding of genetic risks and environmental differences across ethnic populations and the role in PSS is required.
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Affiliation(s)
- Jillian Naylor
- Melbourne Brain Centre, Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Parkville, Australia.
| | - Leonid Churilov
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia
| | - Benjamin Johnstone
- Melbourne Brain Centre, Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Parkville, Australia
| | - Ruibing Guo
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yunyun Xiong
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Miriam Koome
- Melbourne Brain Centre, Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Parkville, Australia
| | - Ziyi Chen
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Arthur Thevathasan
- Melbourne Brain Centre, Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Parkville, Australia
| | - Ziyuan Chen
- Melbourne Brain Centre, Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Parkville, Australia
| | - Xinfeng Liu
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Patrick Kwan
- Melbourne Brain Centre, Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Parkville, Australia
| | - Bruce C V Campbell
- Melbourne Brain Centre, Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Parkville, Australia
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40
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Rani U, Praveen Kumar KS, Munisamaiah M, Rajesh D, Balakrishna S. Atrial fibrillation associated genetic variation near PITX2 gene increases the risk of preeclampsia. Pregnancy Hypertens 2018; 13:214-217. [PMID: 30177054 DOI: 10.1016/j.preghy.2018.06.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 06/20/2018] [Accepted: 06/30/2018] [Indexed: 11/24/2022]
Abstract
OBJECTIVES SNP rs2200733 located near PITX2 gene is associated with the risk of atrial fibrillation. Preeclamptic women are at increased risk of developing cardiovascular disease like atrial fibrillation. Whether this translates into an association between SNP rs2200733 and preeclampsia is not known. Therefore, we determined the association of SNP rs2200733 (C/T) with the risk of preeclampsia. STUDY DESIGN A hospital based prospective case-control study involving 585 pregnant women of whom 285 were preeclamptic and 300 were normotensive. SNP rs2200733 was genotyped by PCR-RFLP method. MAIN OUTCOME MEASURES Statistical significance of the difference in the minor allele frequency between case and control groups was determined by Fisher's exact test. RESULTS Minor allele frequency was 21.4% among preeclamptic pregnant women and 13.7% among normotensive pregnant women (P = 0.00064; odds ratio = 1.72 (0.95 CI: 1.23-2.41). The measures of association were heterogeneous when compared after categorisation of the preeclamptic group into clinical sub-groups. The association was not significant with the eclampsia sub-group (P = 0.39) but relatively higher with the sub-group not superimposed by eclampsia (P = 0.0000048; odds ratio = 2.10 [0.95CI: 1.50-2.92]). Furthermore, the association was relatively higher with the sub-group involving intrauterine growth retardation and intrauterine death (P = 0.00017; odds ratio = 2.89 (0.95CI: 1.65-4.94)]. CONCLUSIONS Minor allele of SNP rs2200733 is associated with the risk of preeclampsia. SNP rs220073 may represent a common risk factor that predispose women to develop both preeclampsia during pregnancy and cardiovascular disease later on.
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Affiliation(s)
- Usha Rani
- Department of Cell Biology and Molecular Genetics, Sri Devaraj Urs Academy of Higher Education and Research, Kolar, Karnataka 563103, India
| | - K S Praveen Kumar
- Department of Cell Biology and Molecular Genetics, Sri Devaraj Urs Academy of Higher Education and Research, Kolar, Karnataka 563103, India
| | - Munikrishna Munisamaiah
- Department of Obstetrics and Gynaecology, Sri Devaraj Urs Medical College, Kolar, Karnataka 563103, India
| | - Deepa Rajesh
- Department of Cell Biology and Molecular Genetics, Sri Devaraj Urs Academy of Higher Education and Research, Kolar, Karnataka 563103, India.
| | - Sharath Balakrishna
- Department of Cell Biology and Molecular Genetics, Sri Devaraj Urs Academy of Higher Education and Research, Kolar, Karnataka 563103, India.
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Rattanawong P, Chenbhanich J, Vutthikraivit W, Chongsathidkiet P. A Chromosome 4q25 Variant is Associated with Atrial Fibrillation Recurrence After Catheter Ablation: A Systematic Review and Meta-Analysis. J Atr Fibrillation 2018; 10:1666. [PMID: 29988284 DOI: 10.4022/jafib.1666] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 09/19/2017] [Accepted: 03/02/2018] [Indexed: 12/30/2022]
Abstract
Background Recent studies suggested that variants on chromosome loci 4q25, 1q21, and 16q22 were associated with atrial fibrillation recurrence after catheter ablation. In this study, we performed a systematic review and meta-analysis to explore the association between variants on chromosome loci 4q25, 1q21, and 16q22 and atrial fibrillation recurrence after catheter ablation. Methods We comprehensively searched the databases of MEDLINE and EMBASE from inception to January 2017. Included studies were published prospective or retrospective cohort and case control studies that compared the risk of atrial fibrillation recurrence after catheter ablation in AF patients with chromosome 4q25, 1q21, and 16q22 variants versus no variants. Single-nucleotide polymorphism rs1906617, rs2106261, rs7193343, rs2200733, rs10033464, rs13376333, and rs6843082 were included in this analysis. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate the risk ratios and 95% confidence intervals. Results Seven studies from January 2010 to June 2017 involving 3,322 atrial fibrillation patients were included in this meta-analysis. According to the pooled analysis, there was a strong independent association between chromosome 4q25 variant (rs2200733) and the risk of atrial fibrillation recurrence after catheter ablation (risk ratio 1.45 [95% confidence interval 1.15-1.83], P = 0.002). No association was found in other variants. Conclusion Our meta-analysis demonstrates a statistically significant increased risk of atrial fibrillation recurrence after catheter ablation in 4q25 variant (only in rs2200733) but not in 1q21 or 16q22 variants.
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Affiliation(s)
- Pattara Rattanawong
- University of Hawaii Internal Medicine Residency Program, Honolulu, HI, USA.,University of Hawaii Internal Medicine Residency Program, Honolulu, HI, USA
| | - Jirat Chenbhanich
- Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Kinney N, Larsen TR, Kim DM, Varghese RT, Poelzing S, Garner HR, AlMahameed ST. Whole-exome sequencing reveals microsatellite DNA markers for response to dofetilide initiation in patients with persistent atrial fibrillation: A pilot study. Clin Cardiol 2018; 41:849-854. [PMID: 29671888 DOI: 10.1002/clc.22969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 04/08/2018] [Accepted: 04/16/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Dofetilide is a class III antiarrhythmic drug effective for the treatment of atrial fibrillation (AF). Dofetilide initiation (DI) associates with corrected QT interval (QTc) prolongation. Significant QTc prolongation during DI mandates dose adjustment or discontinuation of the drug. Microsatellite DNA are novel genetic markers associated with congenital and acquired health conditions. HYPOTHESIS DNA microsatellite polymorphism may associate with QTc response to dofetilide initiation in patients with persistent AF. METHODS We performed whole-exome sequencing in a cohort of patients with persistent AF undergoing DI. Electrocardiographic variables and clinical data were assessed. We defined patients as eligible for DI when no significant QTc prolongation (>20% compared with baseline) was seen with a 500-μg dose. We defined patients as ineligible for DI when significant QTc prolongation was seen during DI with 500 μg. We investigated polymorphisms for 11 919 DNA microsatellite loci in relation to QTc response to DI. RESULTS During the study, 14 consecutive patients with persistent AF presenting for DI were enrolled. Whole-exome sequencing revealed 14 different microsatellite loci in the 2 groups. All genes or proximal genes that harbor these loci are known to have expression in the human heart. Two genes, MYH6 and TRAK2, are known to have expression in the atria. TRAK2 is known to interact with KCNJ2, the inward-rectifier potassium channel 1. CONCLUSIONS Microsatellite DNA polymorphisms seem to associate with QTc response to DI therapy in patients with persistent AF who are deemed otherwise eligible for dofetilide therapy.
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Affiliation(s)
- Nick Kinney
- Edward Via College of Osteopathic Medicine, Blacksburg, Virginia
| | - Timothy R Larsen
- Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, Virginia
| | - David M Kim
- Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, Virginia
| | - Robin T Varghese
- Edward Via College of Osteopathic Medicine, Blacksburg, Virginia
| | - Steven Poelzing
- Virginia Tech Carilion Research Institute, and the Center for Heart and Regenerative Medicine, Virginia Polytechnic University, Roanoke, Virginia
| | - Harold R Garner
- Edward Via College of Osteopathic Medicine, Blacksburg, Virginia
- Gibbs Cancer Center and Research Institute, Spartanburg, South Carolina
| | - Soufian T AlMahameed
- Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, Virginia
- MetroHealth Medical Center and Case Western Reserve University, Cleveland, Ohio
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43
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Kalinderi K, Fragakis N, Sotiriadou M, Oriol DI, Katritsis D, Letsas K, Korantzopoulos P, Karamanolis A, Pagourelias E, Antoniadis AP, Dalampyras P, Mavroudi M, Kyriakou P, Papadopoulos C, Skeberis V, Vassilikos V, Fidani L. PRRX1 Rs3903239 polymorphism and atrial fibrillation in a Greek population. Hellenic J Cardiol 2018; 59:298-299. [PMID: 29355724 DOI: 10.1016/j.hjc.2018.01.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 01/04/2018] [Accepted: 01/12/2018] [Indexed: 12/27/2022] Open
Affiliation(s)
- Kallirhoe Kalinderi
- Department of General Biology, Medical School, Aristotle University of Thessaloniki, Greece
| | - Nikolaos Fragakis
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Melani Sotiriadou
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Dols-Icardo Oriol
- Department of Neurology, Memory Unit and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Center for Networked Biomedical Research into Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | | | - Konstantinos Letsas
- Second Department of Cardiology, Evangelismos General Hospital, Athens, Greece
| | | | - Athanasios Karamanolis
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Efstathios Pagourelias
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Antonios P Antoniadis
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Panagiotis Dalampyras
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Melaxrini Mavroudi
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Panagiota Kyriakou
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Christodoulos Papadopoulos
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Vassileios Skeberis
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Vassileios Vassilikos
- Third Cardiology Department, Hippokrateion Hospital, Aristotle University Medical School, Thessaloniki, Greece
| | - Liana Fidani
- Department of General Biology, Medical School, Aristotle University of Thessaloniki, Greece.
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Jabbari R, Jabbari J, Glinge C, Risgaard B, Sattler S, Winkel BG, Terkelsen CJ, Tilsted HH, Jensen LO, Hougaard M, Haunsø S, Engstrøm T, Albert CM, Tfelt-Hansen J. Association of common genetic variants related to atrial fibrillation and the risk of ventricular fibrillation in the setting of first ST-elevation myocardial infarction. BMC MEDICAL GENETICS 2017; 18:138. [PMID: 29162046 PMCID: PMC5699191 DOI: 10.1186/s12881-017-0497-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 11/09/2017] [Indexed: 01/09/2023]
Abstract
Background Cohort studies have revealed an increased risk for ventricular fibrillation (VF) and sudden cardiac death (SCD) in patients with atrial fibrillation (AF). In this study, we hypothesized that single nucleotide polymorphisms (SNP) previously associated with AF may be associated with the risk of VF caused by first ST-segment elevation myocardial infarction (STEMI). Methods We investigated association of 24 AF-associated SNPs with VF in the prospectively assembled case–control study among first STEMI-patients of Danish ancestry. Results We included 257 cases (STEMI with VF) and 537 controls (STEMI without VF). The median age at index infarction was 60 years for the cases and 61 years for the controls (p = 0.100). Compared to the control group, the case group was more likely to be male (86% vs. 75%, p = 0.001), have a history of AF (7% vs. 2%, p = 0.006) or hypercholesterolemia (39% vs. 31%, p = 0.023), and a family history of sudden death (40% vs. 25%, p < 0.001). All 24 selected SNPs have previously been associated with AF. None of the 24 SNPs were associated with the risk of VF after adjustment for age and sex under additive genetic model of inheritance in the logistic regression model. Conclusion In this study, we found that the 24 AF-associated SNPs may not be involved in increasing the risk of VF. Larger VF cohorts and use of new next generation sequencing and epigenetic may in future identify additional AF and VF risk loci and improve our understanding of genetic pathways behind the two arrhythmias.
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Affiliation(s)
- Reza Jabbari
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark.
| | - Javad Jabbari
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark
| | - Charlotte Glinge
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark
| | - Bjarke Risgaard
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark
| | - Stefan Sattler
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark
| | - Bo Gregers Winkel
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark
| | - Christian Juhl Terkelsen
- Department of Cardiology, Aarhus University Hospital, Skejby, Nørrebrogade, 44, 8000, Aarhus C, Denmark
| | - Hans-Henrik Tilsted
- Department of Cardiology, Aalborg University Hospital, Hobrovej 18-22, 9100, Aalborg, Denmark
| | - Lisette Okkels Jensen
- Department of Cardiology, Odense University Hospital, Søndre Blvd. 29, 5000, Odense C, Denmark
| | - Mikkel Hougaard
- Department of Cardiology, Odense University Hospital, Søndre Blvd. 29, 5000, Odense C, Denmark
| | - Stig Haunsø
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark.,Laboratory of Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Juliane Mariesvej 20, 2100, Copenhagen Ø, Denmark
| | - Thomas Engstrøm
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark.,Department of Cardiology, University of Lund, Lund, Sweden
| | - Christine M Albert
- Center for Arrhythmia Prevention, Division of Preventive Medicine, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Jacob Tfelt-Hansen
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark
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Multiple Roles of Pitx2 in Cardiac Development and Disease. J Cardiovasc Dev Dis 2017; 4:jcdd4040016. [PMID: 29367545 PMCID: PMC5753117 DOI: 10.3390/jcdd4040016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 10/02/2017] [Accepted: 10/03/2017] [Indexed: 12/14/2022] Open
Abstract
Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases.
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Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. Sci Rep 2017; 7:11303. [PMID: 28900195 PMCID: PMC5595875 DOI: 10.1038/s41598-017-09396-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/26/2017] [Indexed: 12/19/2022] Open
Abstract
It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10−5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10−8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
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Bapat A, Anderson CD, Ellinor PT, Lubitz SA. Genomic basis of atrial fibrillation. Heart 2017; 104:201-206. [PMID: 28893835 DOI: 10.1136/heartjnl-2016-311027] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 08/03/2017] [Accepted: 08/11/2017] [Indexed: 01/24/2023] Open
Abstract
Atrial fibrillation (AF) is a prevalent arrhythmia associated with substantial morbidity, mortality and costs. Available management strategies generally have limited efficacy and are associated with potential adverse effects. In part, the limited efficacy of approaches to managing AF reflect an incomplete understanding of the biological mechanisms underlying the arrhythmia, and only a partial understanding of how best to individualise management. Over the last several decades, a greater understanding of genome biology has led to recognition of a widespread genetic susceptibility to AF. Through genome-wide association studies, at least 30 genetic loci have been identified in association with AF, most of which implicate mechanisms not previously appreciated to be involved in the development of AF. We now recognise that AF is a polygenic condition, yet a great deal of work lies ahead to better understand the precise mechanisms by which genomic variation causes AF. Understanding the genetic basis of AF could provide a better understanding of AF mechanisms and cardiovascular biology, inform the management of patients through risk-guided approaches and facilitate the development of novel therapeutics.
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Affiliation(s)
- Aneesh Bapat
- Cardiology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Christopher D Anderson
- Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.,Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Patrick T Ellinor
- Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.,Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
| | - Steven A Lubitz
- Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.,Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
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Syeda F, Kirchhof P, Fabritz L. PITX2-dependent gene regulation in atrial fibrillation and rhythm control. J Physiol 2017; 595:4019-4026. [PMID: 28217939 PMCID: PMC5471504 DOI: 10.1113/jp273123] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 01/17/2017] [Indexed: 01/15/2023] Open
Abstract
Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. There are several major mechanisms that cause AF in patients, including a genetic predisposition to develop AF. Genome-wide association studies have identified genetic variants associated with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription factor PITX2. The effect of these common gene variants on cardiac PITX2 mRNA is currently under study. PITX2 protein regulates right-left differentiation of the embryonic heart, thorax and aorta. PITX2 is expressed in the adult left atrium, but much less so in other heart chambers. Pitx2 deficiency results in electrical and structural remodelling, and impaired repair of the heart in murine models, all of which may influence AF through divergent mechanisms. PITX2 levels and single nucleotide polymorphisms on chromosome 4q25 may also be a predictor of the effectiveness of anti-arrhythmic drug therapy.
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Affiliation(s)
- Fahima Syeda
- Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK
| | - Paulus Kirchhof
- Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK
- Department of CardiologyUHB NHS TrustBirminghamUK
- Department of CardiologySWBTBirminghamUK
| | - Larissa Fabritz
- Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK
- Department of CardiologyUHB NHS TrustBirminghamUK
- Department of Cardiovascular Medicine, Division of RhythmologyUniversity Hospital MünsterMünsterGermany
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Why are South Asians seemingly protected against the development of atrial fibrillation? A review of current evidence. Trends Cardiovasc Med 2017; 27:249-257. [DOI: 10.1016/j.tcm.2016.11.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 11/20/2016] [Accepted: 11/21/2016] [Indexed: 01/09/2023]
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Ebana Y, Ozaki K, Liu L, Hachiya H, Hirao K, Isobe M, Kubo M, Tanaka T, Furukawa T. Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25. J Cardiol 2017; 70:366-373. [PMID: 28087289 DOI: 10.1016/j.jjcc.2016.11.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 10/31/2016] [Accepted: 11/16/2016] [Indexed: 01/16/2023]
Abstract
BACKGROUND Chromosome 4q25 has been repeatedly identified as atrial fibrillation (AF)-sensitive locus in multiple genome-wide association studies (GWAS) and is considered to hold some clues to AF pathogenesis. We aimed to investigate the clinical utilities in Japanese and to unveil the function of the 4q25 locus in affecting transcription of adjacent genes. METHODS We conducted AF GWAS in Japanese population (1382 AF cases and 1478 controls) and the replication panel (1666 AF cases and 1229 controls) with detailed clinical information which showed the acceleration of AF onset. Stepwise investigations with linkage disequilibrium analysis, histone code patterns, and reporter assay in the 4q25 locus were performed. RESULTS The AF GWAS confirmed a significant association of rs4611994 and rs1906617 in chromosome 4q25 with AF. In the clinical analysis, AF onset of the individuals with risk allele accelerated 2.5 years compared with those with protective allele (p=0.00012). Next, in the functional analysis, three single nucleotide polymorphisms (SNPs) in the variant group selected by linkage disequilibrium analysis were identified as candidates for the cis-regulatory element toward adjacent genes in chromatin immunoprecipitation assay. Among them, rs4611994 and rs72900144 regions showed higher effects on the transcriptional activity of luciferase gene in the risk alleles than those in the protective alleles (p<0.0001, p<0.005, respectively). CONCLUSIONS AF GWAS in Japanese confirmed the association with 4q25 locus and indicated that its SNP affected the acceleration of AF onset. The candidate regions of the causative SNPs, rs4611994 and rs72900144, could alter the adjacent gene expression level.
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Affiliation(s)
- Yusuke Ebana
- Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kouichi Ozaki
- Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Lian Liu
- Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hitoshi Hachiya
- Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kenzo Hirao
- Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mitsuaki Isobe
- Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Michiaki Kubo
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Toshihiro Tanaka
- Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Human Genetics and Disease Diversity, Graduate School of Medicine and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsushi Furukawa
- Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
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