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Luo Y, Ma W, Kang Q, Pan H, Shi L, Ma J, Song J, Gong D, Kang K, Jin X. Atrial APD prolongation caused by the upregulation of RAGE and subsequent I NaL increase in diabetic patients. Acta Biochim Biophys Sin (Shanghai) 2025. [PMID: 40109091 DOI: 10.3724/abbs.2025018] [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: 03/22/2025] Open
Abstract
Diabetes mellitus (DM) is a risk factor for the development of atrial fibrillation (AF). The action potential duration (APD) has been demonstrated to be prolonged in the atrium of diabetic mice. In contrast, the APD is generally shortened in AF patients. It is unclear what change occurs in the atrial APD of diabetic patients. In this study, we explore the APD change of atrial myocytes from diabetic patients and the underlying molecular mechanisms. The whole-cell patch-clamp technique is used to detect single-cell electrical activity in diabetic and nondiabetic human samples. The results show that both APD 50 and APD 90, the APD at 50% and 90% repolarization, are increased in diabetic patients compared with those in nondiabetic controls. The density of late sodium current ( I NaL) in the atrial myocytes of diabetic patients is greater than that in the myocytes of nondiabetic patients. The expression of receptor for advanced glycation end products (RAGE) is increased in the atria of diabetic patients. In cultured HL-1 cells, high glucose (HG) treatment increases I NaL, and the expression of RAGE prolongs APD. The siRNA-mediated knockdown of RAGE reduces the I NaL and shortens the APD. The APD is prolonged in the atria of diabetic patients because of the upregulation of RAGE and the subsequent increase in I NaL. Our findings provide novel insights into atrial electrical remodeling in diabetic patients.
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Affiliation(s)
- Yingchun Luo
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Wenbo Ma
- Department of State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Qi Kang
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Han Pan
- Department of State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Ling Shi
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Jiudong Ma
- Department of State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Jiahui Song
- Department of State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Dongmei Gong
- Department of State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Kai Kang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Xuexin Jin
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
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Liu HH, Yang F, Zhang L, Zhang XL, Zhao N, Zhang ZY, Zhou JB, Wei TP, Qian LL, Ding LG, Wang RX. Decreased PLK2 promotes atrial fibrillation in diabetic mice through Nrf2/HO-1 pathway. Acta Diabetol 2025:10.1007/s00592-025-02480-9. [PMID: 40080197 DOI: 10.1007/s00592-025-02480-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 02/23/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is associated with an increased incidence of atrial fibrillation (AF). However, the exact mechanisms involved have not yet been fully elucidated. Dysregulation of cardiac potassium channels can trigger AF. This study aimed to investigate the mechanisms of abnormal expression of atrial potassium channel proteins Kv1.5, Kv4.2, and Kv4.3 in type 2 diabetic mice. METHODS The db/db mice and their control littermates were set as the T2DM group and the control (Con) group. Acetylcholine-calcium chloride was injected via the tail veins to induce AF. HL-1 cells were cultured with normal or high-glucose medium and treated with or without Dimethyl Fumarate (DMF) or hemin in vitro. The expression and cellular localization of proteins were evaluated by western blotting and immunofluorescence. RESULTS The results showed that high glucose impaired the expression of Kv1.5, Kv4.2 and Kv4.3 proteins both in vivo and in vitro, in parallel with a significant down-regulation of polo-like kinase 2 (PLK2), nuclear factor erythroid 2-related factor 2 (Nrf2), p-Nrf2 and heme oxygenase-1 (HO-1) proteins. Moreover, immunofluorescence revealed that both high glucose and PLK2 knockdown could result in reduced Nrf2 and p-Nrf2 expression and subsequent nuclear translocation. While overexpression of PLK2, treatment with DMF, an agonist of Nrf2, or hemin, an inducer of HO-1, could restore the reduction of Kv1.5, Kv4.2 and Kv4.3 proteins caused by high glucose. CONCLUSION Diabetes reduces the expression of Kv1.5, Kv4.2 and Kv4.3 proteins in atrial cells through inhibition of PLK2/Nrf2/HO-1 pathway, thereby leading to the increased susceptibility to AF in T2DM.
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Affiliation(s)
- Huan-Huan Liu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Fan Yang
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Lei Zhang
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Xiao-Lu Zhang
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Ning Zhao
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Zhen-Ye Zhang
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Jia-Bin Zhou
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Tian-Peng Wei
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Ling-Ling Qian
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China.
| | - Li-Gang Ding
- Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
| | - Ru-Xing Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China.
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Zhou Y, Ye T, Yu F, Song Z, Wang L, Zhang C, Yang B, Yang J, Wang X. Inhibition of P2X7 receptor mitigates atrial fibrillation susceptibility in isoproterenol-induced rats. Biochem Biophys Res Commun 2025; 749:151340. [PMID: 39855041 DOI: 10.1016/j.bbrc.2025.151340] [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: 08/20/2024] [Revised: 01/07/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND Atrial fibrillation (AF) is a common cardiac arrhythmia that is characterized by atrial electrical remodeling. The P2X7 receptor (P2X7R), an ATP-gated ion channel, has been implicated in cardiovascular pathologies; however, its role in atrial electrical remodeling remains unclear. This study investigated whether inhibition of P2X7R could mitigate isoproterenol (ISO)-induced atrial electrical remodeling in rats and explored the underlying mechanisms. METHODS Two gene expression profiles related to AF (GSE79768 and GSE10598) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using GEO2R. Mendelian randomization (MR) investigated the causal relationship between P2X7R expression and AF. Enrichment analysis was also conducted. An animal model was established via intraperitoneal injection of ISO for 2 weeks. The rats were divided into three groups: control (CTL), ISO, and ISO + Brilliant Blue G (BBG). Cardiac electrophysiological parameters were assessed using programmed electrical stimulation. Myocardial fibrosis and hypertrophy were evaluated using Sirius Red and Wheat Germ Agglutinin staining, respectively. P2X7R abundance was assessed using immunofluorescence, and relevant proteins were detected by Western blotting. RESULTS GEO2R and MR analyses indicated a correlation between P2X7R expression and AF. Rats in the ISO group exhibited increased P2X7R levels, abnormal cardiac electrophysiology, altered ion channel protein expression, myocardial hypertrophy, and fibrosis. Enrichment analysis indicated that oxidative stress responses might be involved, and Western blotting showed significantly elevated levels of NOX, CaMKII, and associated proteins. BBG (P2X7R inhibitor) treatment mitigated these effects. CONCLUSIONS P2X7R was associated with AF, and inhibition of P2X7R curbed electrical and structural remodeling in ISO-induced AF, potentially via the NOX/CaMKII pathway.
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Affiliation(s)
- Yunping Zhou
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China
| | - Tianxin Ye
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China
| | - Fangcong Yu
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China
| | - Zhuonan Song
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China
| | - Longbo Wang
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China
| | - Cui Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China
| | - Bo Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China
| | - Jinxiu Yang
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China.
| | - Xingxiang Wang
- Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China.
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Yue ZJ, Li XR, Shi Z, Li XW. Myocardial ferroptosis may exacerbate the progression of atrial fibrillation through isolevuglandins. Eur J Med Res 2025; 30:93. [PMID: 39940048 PMCID: PMC11823066 DOI: 10.1186/s40001-025-02302-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 01/16/2025] [Indexed: 02/14/2025] Open
Abstract
Atrial fibrillation (AF) poses a serious health threat to human health and causes various adverse effects. It is currently the most common type of arrhythmia in adults. Long-term AF induces a series of heart-remodeling events, including mainly cardiac structural remodeling and electrical remodeling, which further exacerbates AF. The oxidative stress has been shown to play a role in inducing myocardial remodeling and the progression of AF. Recent studies have shown that ferroptosis occurs in the myocardium of patients with AF, which exacerbates oxidative stress and may constitute a new mechanism for the progression of AF. However, it is unknown to us how ferroptosis is involved in the initiation and maintenance of AF, so the purpose of this review is to elucidate the possible underlying mechanism of ferroptosis exacerbating AF. We reviewed the latest studies on myocardial ferroptosis and AF and speculate that the lipid peroxidation products isolevuglandins (IsoLGs), which are produced during myocardial ferroptosis, may be involved in the progression of AF through two pathways: (1) IsoLGs inhibit the degradation of myocardial collagen, worsening myocardial fibrosis; and (2) IsoLGs promote the occurrence of amyloidosis in the myocardium and increase the risk of AF. Consequently, we aim to prevent the progression of atrial fibrillation by either suppressing the production of IsoLGs or enhancing their clearance process to inhibit ferroptosis in the myocardium, improving the prognosis of patients with AF.
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Affiliation(s)
- Zhi-Jie Yue
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Long Cheng Street 99, Taiyuan, 030032, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xin-Ru Li
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Long Cheng Street 99, Taiyuan, 030032, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhan Shi
- Department of Cardiology, Affiliated Hospital of Army Medical University NCO School, Zhong Shan Road 450, Shijiazhuang, 050047, Hebei, China.
| | - Xue-Wen Li
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Long Cheng Street 99, Taiyuan, 030032, China.
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Choi J, Lee SR, Choi EK, Lee KY, Ahn HJ, Kwon S, Han KD, Oh S, Lip GYH. Effect of physical activity on incident atrial fibrillation in individuals with varying duration of diabetes: a nationwide population study. Cardiovasc Diabetol 2024; 23:115. [PMID: 38555442 PMCID: PMC10981812 DOI: 10.1186/s12933-024-02194-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 03/10/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Diabetes mellitus (DM) duration affects incident atrial fibrillation (AF) risk; the effect of physical activity on mitigating AF risk related to varying DM duration remains unknown. We assessed the effect of physical activity on incident AF in patients with DM with respect to known DM duration. METHODS Patients with type 2 DM who underwent the Korean National Health Insurance Service health examination in 2015-2016 were grouped by DM duration: new onset and < 5, 5-9, and ≥ 10 years. Physical activity was classified into four levels: 0, < 500, 500-999, 1,000-1,499, and ≥ 1,500 metabolic equivalent task (MET)-min/week, with the primary outcome being new-onset AF. RESULTS The study enrolled 2,392,486 patients (aged 59.3 ± 12.0 years, 39.8% female) with an average follow-up of 3.9 ± 0.8 years and mean DM duration of 5.3 ± 5.1 years. Greater physical activity was associated with a lower AF risk. Lowering of incident AF risk varied with different amounts of physical activity in relation to known DM duration. Among patients with new-onset DM, DM duration < 5 years and 5-9 years and 1,000-1,499 MET-min/week exhibited the lowest AF risk. Physical activity ≥ 1,500 MET-min/week was associated with the lowest incident AF risk in patients with DM duration ≥ 10 years (by 15%), followed DM duration of 5-9 years (12%) and < 5 years (9%) (p-for-interaction = 0.002). CONCLUSIONS Longer DM duration was associated with a high risk of incident AF, while increased physical activity generally reduced AF risk. Engaging in > 1,500 MET-min/week was associated with the greatest AF risk reduction in patients with longer DM duration, highlighting the potential benefits of higher activity levels for AF prevention.
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Affiliation(s)
- JungMin Choi
- Division of cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - So-Ryoung Lee
- Division of cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Eue-Keun Choi
- Division of cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
| | - Kyung-Yeon Lee
- Division of cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyo-Jeong Ahn
- Division of cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Soonil Kwon
- Division of cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyung-Do Han
- Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Seil Oh
- Division of cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Gregory Y H Lip
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Liverpool Center for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Chest & Heart Hospital, Liverpool, UK
- Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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Kang J, Mun D, Chun Y, Park D, Kim H, Yun N, Joung B. Engineered small extracellular vesicle-mediated NOX4 siRNA delivery for targeted therapy of cardiac hypertrophy. J Extracell Vesicles 2023; 12:e12371. [PMID: 37795828 PMCID: PMC10552075 DOI: 10.1002/jev2.12371] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 09/18/2023] [Accepted: 09/27/2023] [Indexed: 10/06/2023] Open
Abstract
Small-interfering RNA (siRNA) therapy is considered a powerful therapeutic strategy for treating cardiac hypertrophy, an important risk factor for subsequent cardiac morbidity and mortality. However, the lack of safe and efficient in vivo delivery of siRNAs is a major challenge for broadening its clinical applications. Small extracellular vesicles (sEVs) are a promising delivery system for siRNAs but have limited cell/tissue-specific targeting ability. In this study, a new generation of heart-targeting sEVs (CEVs) has been developed by conjugating cardiac-targeting peptide (CTP) to human peripheral blood-derived sEVs (PB-EVs), using a simple, rapid and scalable method based on bio-orthogonal copper-free click chemistry. The experimental results show that CEVs have typical sEVs properties and excellent heart-targeting ability. Furthermore, to treat cardiac hypertrophy, CEVs are loaded with NADPH Oxidase 4 (NOX4) siRNA (siNOX4). Consequently, CEVs@siNOX4 treatment enhances the in vitro anti-hypertrophic effects by CEVs with siRNA protection and heart-targeting ability. In addition, the intravenous injection of CEVs@siNOX4 into angiotensin II (Ang II)-treated mice significantly improves cardiac function and reduces fibrosis and cardiomyocyte cross-sectional area, with limited side effects. In conclusion, the utilization of CEVs represents an efficient strategy for heart-targeted delivery of therapeutic siRNAs and holds great promise for the treatment of cardiac hypertrophy.
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Affiliation(s)
- Ji‐Young Kang
- Division of Cardiology, Department of Internal MedicineYonsei University College of MedicineSeodaemun‐guSeoulRepublic of Korea
| | - Dasom Mun
- Division of Cardiology, Department of Internal MedicineYonsei University College of MedicineSeodaemun‐guSeoulRepublic of Korea
| | - Yumin Chun
- Division of Cardiology, Department of Internal MedicineYonsei University College of MedicineSeodaemun‐guSeoulRepublic of Korea
| | - Da‐Seul Park
- Division of Cardiology, Department of Internal MedicineYonsei University College of MedicineSeodaemun‐guSeoulRepublic of Korea
| | - Hyoeun Kim
- Department of Biochemistry and Molecular BiologyYonsei University College of MedicineSeodaemun‐guSeoulRepublic of Korea
| | - Nuri Yun
- GNTPharma Science and Technology Center for Health, Giheung‐guYongin‐siIncheonRepublic of Korea
| | - Boyoung Joung
- Division of Cardiology, Department of Internal MedicineYonsei University College of MedicineSeodaemun‐guSeoulRepublic of Korea
- Graduate School of Medical Science, Brain Korea 21 ProjectYonsei University College of MedicineSeodaemun‐guSeoulRepublic of Korea
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Sun DK, Zhang N, Liu Y, Qiu JC, Tse G, Li GP, Roever L, Liu T. Dysglycemia and arrhythmias. World J Diabetes 2023; 14:1163-1177. [PMID: 37664481 PMCID: PMC10473954 DOI: 10.4239/wjd.v14.i8.1163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/19/2023] [Accepted: 07/05/2023] [Indexed: 08/11/2023] Open
Abstract
Disorders in glucose metabolism can be divided into three separate but interrelated domains, namely hyperglycemia, hypoglycemia, and glycemic variability. Intensive glycemic control in patients with diabetes might increase the risk of hypoglycemic incidents and glucose fluctuations. These three dysglycemic states occur not only amongst patients with diabetes, but are frequently present in other clinical settings, such as during critically ill. A growing body of evidence has focused on the relationships between these dysglycemic domains with cardiac arrhythmias, including supraventricular arrhythmias (primarily atrial fibrillation), ventricular arrhythmias (malignant ventricular arrhythmias and QT interval prolongation), and bradyarrhythmias (bradycardia and heart block). Different mechanisms by which these dysglycemic states might provoke cardiac arr-hythmias have been identified in experimental studies. A customized glycemic control strategy to minimize the risk of hyperglycemia, hypoglycemia and glucose variability is of the utmost importance in order to mitigate the risk of cardiac arrhythmias.
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Affiliation(s)
- Dong-Kun Sun
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Nan Zhang
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Ying Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Jiu-Chun Qiu
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Gary Tse
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
- Kent and Medway Medical School, Kent CT2 7NT, Canterbury, United Kingdom
- School of Nursing and Health Studies, Metropolitan University, Hong Kong 999077, China
| | - Guang-Ping Li
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Leonardo Roever
- Department of Clinical Research, Federal University of Uberlândia, Uberlândia, 38400384, MG, Brazil
| | - Tong Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
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8
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Zheng D, Wu Q, Zeng P, Li S, Cai Y, Chen S, Luo X, Kuang S, Rao F, Lai Y, Zhou M, Wu F, Yang H, Deng C. Advanced glycation end products induce senescence of atrial myocytes and increase susceptibility of atrial fibrillation in diabetic mice. Aging Cell 2022; 21:e13734. [PMID: 36278684 PMCID: PMC9741501 DOI: 10.1111/acel.13734] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 09/07/2022] [Accepted: 10/02/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is a common chronic metabolic disease caused by significant accumulation of advanced glycation end products (AGEs). Atrial fibrillation (AF) is a common cardiovascular complication of DM. Here, we aim to clarify the role and mechanism of atrial myocyte senescence in the susceptibility of AF in diabetes. Rapid transesophageal atrial pacing was used to monitor the susceptibility of mice to AF. Whole-cell patch-clamp was employed to record the action potential (AP) and ion channels in single HL-1 cell and mouse atrial myocytes. More importantly, anti-RAGE antibody and RAGE-siRNA AAV9 were used to investigate the relationship among diabetes, aging, and AF. The results showed that elevated levels of p16 and retinoblastoma (Rb) protein in the atrium were associated with increased susceptibility to AF in diabetic mice. Mechanistically, AGEs increased p16/Rb protein expression and the number of SA-β-gal-positive cells, prolonged the action potential duration (APD), reduced protein levels of Cav1.2, Kv1.5, and current density of ICa,L , IKur in HL-1 cells. Anti-RAGE antibody or RAGE-siRNA AAV9 reversed these effects in vitro and in vivo, respectively. Furthermore, downregulating p16 or Rb by siRNA prevented AGEs-mediated reduction of Cav1.2 and Kv1.5 proteins expression. In conclusion, AGEs accelerated atrial electrical remodeling and cellular senescence, contributing to increased AF susceptibility by activating the p16/Rb pathway. Inhibition of RAGE or the p16/Rb pathway may be a potential therapeutic target for AF in diabetes.
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Affiliation(s)
- Dan‐Lin Zheng
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina
| | - Qing‐Rui Wu
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,School of MedicineSouth China University of TechnologyGuangzhouChina
| | - Peng Zeng
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,School of MedicineSouth China University of TechnologyGuangzhouChina
| | - Sui‐Min Li
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina
| | - Yong‐Jiang Cai
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouChina
| | - Shu‐Zhen Chen
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina
| | - Xue‐Shan Luo
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,School of MedicineSouth China University of TechnologyGuangzhouChina
| | - Su‐Juan Kuang
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina
| | - Fang Rao
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina
| | - Ying‐Yu Lai
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouChina
| | - Meng‐Yuan Zhou
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina
| | - Fei‐Long Wu
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina
| | - Hui Yang
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina
| | - Chun‐Yu Deng
- Guangdong Provincial Key Laboratory of Clinical PharmacologyResearch Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,Department of Cardiology, Guangdong Cardiovascular InstituteGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouChina,School of MedicineSouth China University of TechnologyGuangzhouChina,School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouChina
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9
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Use of P wave indices to evaluate efficacy of catheter ablation and atrial fibrillation recurrence: a systematic review and meta-analysis. J Interv Card Electrophysiol 2022; 65:827-840. [PMID: 35488962 DOI: 10.1007/s10840-022-01147-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND To investigate the changes of P wave indices in atrial fibrillation (AF) patients after catheter ablation and the association between P wave indices and AF recurrence. METHODS PubMed, Embase, and Cochrane Database were searched through September 15th 2021 for studies on the association between P wave indices and AF with catheter ablation. Heterogeneity was estimated using the I2 statistic, the random effects model was used to calculate the pooled results, and summary receiver operating characteristic curve (SROC) was used to evaluate the predictive value. RESULTS Among included fourteen studies with 1674 AF patients, we found significantly decreased P wave dispersion (Pdis) (mean difference [MD]: - 6.5 ms, 95% confidence interval [95% CI]: - 11.81 to - 1.18, P = 0.02) after cryoballoon ablation (CBA) or radiofrequency ablation (RFA), and maximum P wave (Pmax) (MD: - 8.57 ms, 95% CI: - 17.03 to - 0.10, P = 0.05) after RFA only, but increased minimum P wave (Pmin) (MD: 3.43 ms, 95% CI: 1.07 to 5.79, P < 0.01) after CBA only. Pdis measured before ablation was remarkably higher (MD: 5.79 ms, 95% CI: 2.23 to 9.36, P < 0.01) in patients with recurrence than without; meanwhile, Pmax was higher measured both before and after ablation (MD: 6.49 ms, 95% CI: 2.30 to 10.69, P < 0.01 and MD: 11.2 ms, 95% CI: 2.88 to 19.52, P < 0.01). Furthermore, SROC analysis showed acceptable predictive efficiencies of Pdis (AUC = 0.776) and Pmax (AUC = 0.759) for AF recurrence. CONCLUSION Pdis was significantly decreased after AF catheter ablation. Higher Pdis and Pmax may have predictive values for AF recurrence.
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10
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Zhan X, Cheng L, Huo N, Yu L, Liu C, Liu T, Li G, Fu H. Sodium-glucose cotransporter-2 inhibitor alleviated atrial remodeling in STZ-induced diabetic rats by targeting TLR4 pathway. Front Cardiovasc Med 2022; 9:908037. [PMID: 36148071 PMCID: PMC9485554 DOI: 10.3389/fcvm.2022.908037] [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: 03/30/2022] [Accepted: 08/05/2022] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The mechanism of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) reducing the incidence of atrial fibrillation remains unclear. We hypothesize that sodium-glucose cotransporter-2 inhibitor alleviated atrial remodeling in STZ-induced diabetic rats by targeting TLR4 pathway. METHODS A total of 42 rats were randomly assigned into three groups: control group (CON group); diabetes group (DM group): diabetes mellitus rats were established by 65 mg/kg streptozotocin (STZ) intraperitoneal injection; and diabetes + dapagliflozin group (DM + DAPA group): diabetic rats were given DAPA gavage administration (DAPA 2mg/kg/d for 4 weeks by gavage administration), 14 rats in each group. Epicardial multiple-lead recording and intracardiac electrophysiology studies were performed to investigate the electrical remodeling in the heart and the atrial fibrillation inducibility in each group. Western blot analysis and real-time PCR were used to determine the protein and mRNA expression of toll-like receptor 4 (TLR4), interleukin receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor-kappa B (NF-κB), and type I collagen (collagen I). RESULTS Compared with rats in CON group, rats in DM group showed marked myocardial fibrosis, ectopic pacing excitement, reduced conduction velocity, decreased cardiac function. TLR4/IRAK1/TRAF6/NF-κB, collagen I proteins expressions and incidence of atrial fibrillation (27.3%) were increased in DM group. Parts of these changes were reversed by treatment of DAPA. Incidence of atrial fibrillation was decreased in DM + DAPA group (2.8%). CONCLUSIONS SGLT-2i dapagliflozin may prevent diabetic rats' atrial remodeling and reduce the inducibility of atrial fibrillation partly by targeting TLR4/IRAK1/TRAF6/NF-κB inflammatory pathway.
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Affiliation(s)
| | | | | | | | | | | | | | - Huaying Fu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
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11
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Gao Q, Liu P, Lv T, Yang Y, Zhang P. Utility of speckle-tracking echocardiography for predicting atrial fibrillation following ischemic stroke: a systematic review and meta-analysis. THE INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING 2022; 38:1771-1780. [PMID: 37726516 DOI: 10.1007/s10554-022-02570-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/12/2022] [Indexed: 11/05/2022]
Abstract
Undiagnosed atrial fibrillation (AF) is one of the main sources of cryptogenic stroke. And strain indices measured by speckle-tracking echocardiography are associated with atrial remodeling supposed to be the substrate of AF. Therefore, there is a strong need for evaluating the utility of speckle-tracking echocardiography to predict the likelihood of AF in patients with cryptogenic stroke. PubMed, Embase and Cochrane Database were searched for studies. The random-effects model was used to calculate the pooled results, and summary receiver operating characteristic curve (SROC) analysis was performed to show the overall predictive value. There were 1483 patients with cryptogenic stroke from 8 studies. Meta-analysis showed that strain indices including global longitudinal strain (GLS) (mean difference [SMD]: - 0.22, 95% confidence interval [95% CI] - 0.40 to - 0.04), left atrial reservoir strain (εR), (SMD: - 0.87, 95% CI - 1.26 to - 0.48, conduit strain (εCD) (SMD: - 0.56, 95% CI - 0.81 to - 0.30), contractile strain (εCT) (SMD: - 1.00, 95% CI - 1.39 to - 0.61), and left atrial reservoir strain rate (SRe) (SMD: - 0.54, 95% CI - 0.80 to - 0.28) measured at the period of cryptogenic stroke was significantly decreased in patients with AF occurrence compared to without. SROC analysis suggested an acceptable predictive efficiency of εR for AF occurrence (AUC = 0.799). For patients after cryptogenic stroke, GLS, εR, εCD, εCT and SRe were significantly decreased in AF occurrence compared with non-occurrence. But there was no value in left atrial reservoir strain rate (SRs) and contractile strain rate (SRa) for predicting AF.
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Affiliation(s)
- Qinggele Gao
- School of Clinical Medicine, Tsinghua University, Beijing, 100084, China
| | - Peng Liu
- School of Clinical Medicine, Tsinghua University, Beijing, 100084, China
| | - Tingting Lv
- Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, China
| | - Ying Yang
- School of Clinical Medicine, Tsinghua University, Beijing, 100084, China
| | - Ping Zhang
- School of Clinical Medicine, Tsinghua University, Beijing, 100084, China.
- Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, China.
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12
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Karamichalakis N, Kolovos V, Paraskevaidis I, Tsougos E. A New Hope: Sodium-Glucose Cotransporter-2 Inhibition to Prevent Atrial Fibrillation. J Cardiovasc Dev Dis 2022; 9:jcdd9080236. [PMID: 35893226 PMCID: PMC9331782 DOI: 10.3390/jcdd9080236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/17/2022] [Accepted: 07/22/2022] [Indexed: 11/16/2022] Open
Abstract
Atrial arrhythmias are common in patients with diabetes mellitus (DM), and despite recent advances in pharmaceutical and invasive treatments, atrial fibrillation (AF) and atrial flutter (AFl) are still associated with substantial mortality and morbidity. Clinical trial data imply a protective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on the occurrence of AF and AFl. This review summarizes the state of knowledge regarding DM-mediated mechanisms responsible for AF genesis and recurrence but also discusses the recent data from experimental studies, published trials and metanalyses.
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13
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Gallego M, Zayas-Arrabal J, Alquiza A, Apellaniz B, Casis O. Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes. Front Pharmacol 2021; 12:687256. [PMID: 34305599 PMCID: PMC8295895 DOI: 10.3389/fphar.2021.687256] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/15/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetes is a chronic metabolic disease characterized by hyperglycemia in the absence of treatment. Among the diabetes-associated complications, cardiovascular disease is the major cause of mortality and morbidity in diabetic patients. Diabetes causes a complex myocardial dysfunction, referred as diabetic cardiomyopathy, which even in the absence of other cardiac risk factors results in abnormal diastolic and systolic function. Besides mechanical abnormalities, altered electrical function is another major feature of the diabetic myocardium. Both type 1 and type 2 diabetic patients often show cardiac electrical remodeling, mainly a prolonged ventricular repolarization visible in the electrocardiogram as a lengthening of the QT interval duration. The underlying mechanisms at the cellular level involve alterations on the expression and activity of several cardiac ion channels and their associated regulatory proteins. Consequent changes in sodium, calcium and potassium currents collectively lead to a delay in repolarization that can increase the risk of developing life-threatening ventricular arrhythmias and sudden death. QT duration correlates strongly with the risk of developing torsade de pointes, a form of ventricular tachycardia that can degenerate into ventricular fibrillation. Therefore, QT prolongation is a qualitative marker of proarrhythmic risk, and analysis of ventricular repolarization is therefore required for the approval of new drugs. To that end, the Thorough QT/QTc analysis evaluates QT interval prolongation to assess potential proarrhythmic effects. In addition, since diabetic patients have a higher risk to die from cardiovascular causes than individuals without diabetes, cardiovascular safety of the new antidiabetic drugs must be carefully evaluated in type 2 diabetic patients. These cardiovascular outcome trials reveal that some glucose-lowering drugs actually reduce cardiovascular risk. The mechanism of cardioprotection might involve a reduction of the risk of developing arrhythmia.
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Affiliation(s)
- Mónica Gallego
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Julián Zayas-Arrabal
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Amaia Alquiza
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Beatriz Apellaniz
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Oscar Casis
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
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14
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Hou Q, Feng L, Yang J, Liu Y, You L, Wang L, Zhang Y, Liu Q, Zhao Y, Xie R. The immediate trends in atrial electrical remodeling for paroxysmal atrial fibrillation across different modes of catheter ablation. Clin Cardiol 2021; 44:938-945. [PMID: 34061373 PMCID: PMC8259153 DOI: 10.1002/clc.23617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/13/2021] [Accepted: 04/20/2021] [Indexed: 11/30/2022] Open
Abstract
Background Catheter ablation has emerged as a major strategy for paroxysmal atrial fibrillation (PAF). Atrial electrical remodeling (AER) plays a critical role in the recurrence of PAF after ablation. Hypothesis To characterize the immediate trends of AER during ablations in patients with PAF, and assess the relationship between immediate trends and recurrence. Methods We performed this prospective observational study of 135 patients to investigate AER following three ablation modes: radiofrequency ablation (RFA), cryoablation (CA) and 3D mapping‐guided cryoablation (3D‐CA). The atrial effective refractory period (AERP) and atrial conduction time (ACT) were measured via electrophysiology before and immediately after ablation, and P‐wave indices were measured via electrocardiography before and within 24 h after ablation. Follow‐up visits were conducted for at least 1 year or until relapse. Results Different approaches of ablation caused a fairly significant increase in the shortest P‐wave duration and AERP in both the proximal coronary sinus (PCS) and distal coronary sinus (DCS) but caused a shortened P‐wave dispersion. No different effect was found at the AERP among the three modes. Compared to patients who received CA, among patients who received RFA, a significant reduction in total ACT and right ACT was seen. Statistically, there was a weakly positive association between changes in total ACT and early recurrence. Conclusions Injury during ablation for PAF was associated with an increase in the AERP but not in the ACT. Total ACT and right ACT were shorter after RFA than after CA. The increase in total ACT were slightly predictive of early recurrence.
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Affiliation(s)
- Qian Hou
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Liang Feng
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jing Yang
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yue Liu
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ling You
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lianxia Wang
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yan Zhang
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qian Liu
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuliang Zhao
- Department of Otorhinolaryngology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ruiqin Xie
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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15
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Aguilar M, Rose RA, Takawale A, Nattel S, Reilly S. New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation. Cardiovasc Res 2021; 117:1645-1661. [PMID: 33723575 PMCID: PMC8208746 DOI: 10.1093/cvr/cvab080] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/25/2021] [Accepted: 03/11/2021] [Indexed: 12/20/2022] Open
Abstract
Hormones are potent endo-, para-, and autocrine endogenous regulators of the function of multiple organs, including the heart. Endocrine dysfunction promotes a number of cardiovascular diseases, including atrial fibrillation (AF). While the heart is a target for endocrine regulation, it is also an active endocrine organ itself, secreting a number of important bioactive hormones that convey significant endocrine effects, but also through para-/autocrine actions, actively participate in cardiac self-regulation. The hormones regulating heart-function work in concert to support myocardial performance. AF is a serious clinical problem associated with increased morbidity and mortality, mainly due to stroke and heart failure. Current therapies for AF remain inadequate. AF is characterized by altered atrial function and structure, including electrical and profibrotic remodelling in the atria and ventricles, which facilitates AF progression and hampers its treatment. Although features of this remodelling are well-established and its mechanisms are partly understood, important pathways pertinent to AF arrhythmogenesis are still unidentified. The discovery of these missing pathways has the potential to lead to therapeutic breakthroughs. Endocrine dysfunction is well-recognized to lead to AF. In this review, we discuss endocrine and cardiocrine signalling systems that directly, or as a consequence of an underlying cardiac pathology, contribute to AF pathogenesis. More specifically, we consider the roles of products from the hypothalamic-pituitary axis, the adrenal glands, adipose tissue, the renin–angiotensin system, atrial cardiomyocytes, and the thyroid gland in controlling atrial electrical and structural properties. The influence of endocrine/paracrine dysfunction on AF risk and mechanisms is evaluated and discussed. We focus on the most recent findings and reflect on the potential of translating them into clinical application.
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Affiliation(s)
- Martin Aguilar
- Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, QC, Canada.,Department of Pharmacology and Physiology/Institute of Biomedical Engineering, Université de Montréal, Montréal, QC, Canada
| | - Robert A Rose
- Department of Cardiac Sciences, Department of Physiology and Pharmacology, Libin Cardiovascular Institute, Cumming School of Medicine, Health Research Innovation Center, University of Calgary, AB, Canada
| | - Abhijit Takawale
- Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, QC, Canada.,Department of Pharmacology and Physiology/Institute of Biomedical Engineering, Université de Montréal, Montréal, QC, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
| | - Stanley Nattel
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.,Faculty of Medicine, Department of Pharmacology and Physiology, and Research Centre, Montreal Heart Institute and University of Montreal, Montreal, QC, Canada.,Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Germany.,IHU LIRYC and Fondation Bordeaux Université, Bordeaux, France
| | - Svetlana Reilly
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK
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16
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Lee TW, Lee TI, Lin YK, Chen YC, Kao YH, Chen YJ. Effect of antidiabetic drugs on the risk of atrial fibrillation: mechanistic insights from clinical evidence and translational studies. Cell Mol Life Sci 2021; 78:923-934. [PMID: 32965513 PMCID: PMC11072414 DOI: 10.1007/s00018-020-03648-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 08/18/2020] [Accepted: 09/12/2020] [Indexed: 12/13/2022]
Abstract
Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF), which is the most common sustained arrhythmia and is associated with substantial morbidity and mortality. Advanced glycation end product and its receptor activation, cardiac energy dysmetabolism, structural and electrical remodeling, and autonomic dysfunction are implicated in AF pathophysiology in diabetic hearts. Antidiabetic drugs have been demonstrated to possess therapeutic potential for AF. However, clinical investigations of AF in patients with DM have been scant and inconclusive. This article provides a comprehensive review of research findings on the association between DM and AF and critically analyzes the effect of different pharmacological classes of antidiabetic drugs on AF.
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Affiliation(s)
- Ting-Wei Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ting-I Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Department of General Medicine, School of 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
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yao-Chang Chen
- Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan
| | - 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 Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
- Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan.
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17
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Li T, Li G, Guo X, Li Z, Yang J, Sun Y. The influence of diabetes and prediabetes on left heart remodeling: A population-based study. J Diabetes Complications 2021; 35:107771. [PMID: 33144026 DOI: 10.1016/j.jdiacomp.2020.107771] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/06/2020] [Accepted: 10/08/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND Diabetes was regarded as an independent risk factor for abnormal left heart remodeling. However, there was lacking population-based data on the relationship of glucose status with left ventricular hypertrophy (LVH) or left atrial enlargement (LAE). This study intended to clarify the influence of diabetes and prediabetes on the prevalence and incidence of LVH and LAE based on a northeast rural population of China. METHODS We analyzed clinical, laboratory and echocardiographic data of a total of 2824 participants aged over 35 years from a population-based prospective cohort NCRCHS study with 2 years of follow-up, which was carried out in rural areas of northeast China. All measurements were performed according to standardized protocols. RESULTS There were 2179 controls, 342 subjects with prediabetes and 303 ones with diabetes. The baseline distribution of LAD, IVSd, LVIDd, LVIDs, LVMI, E wave, A wave, E/A, E/e', diastolic dysfunction, LVEDV, LVESV and SV was significantly different among three groups (all Ptrend<0.05). After the adjustment for age, gender, BMI, waist circumference, heart rate, hypertension and dyslipidemia, glucose status remained associated with LVIDd and E/e' (all P < 0.05). At baseline, diabetes was independently related to the prevalence of LVH (OR = 1.53; 95%CI = 1.12-2.10; P < 0.01) and LAE (OR = 1.71; 95%CI = 1.19-2.43; P < 0.01) in the overall population, and the same significant results were also found in gender specific subgroups. During the 2-year follow-up, Cox regression models revealed that baseline diabetes had an independent association with the incidence of LAE in the total subjects (HR = 1.83; 95%CI = 1.10-3.06; P = 0.02) and females (HR = 1.90; 95%CI = 1.05-3.46; P = 0.04) after adjusting the potential confounders. CONCLUSION Diabetes, but not prediabetes, is an independent predictor for the prevalence of LVH and LAE, and for the new-onset LAE, it should be considered in the assessment of diabetes and cardiac structural remodeling.
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Affiliation(s)
- Tan Li
- Department of Cardiovascular Ultrasound, the First Hospital of China Medical University, Shenyang 110001, China.
| | - Guangxiao Li
- Department of Medical Record Management Center, the First Hospital of China Medical University, Shenyang 110001, China.
| | - Xiaofan Guo
- Department of Cardiology, the First Hospital of China Medical University, Shenyang 110001, China.
| | - Zhao Li
- Department of Cardiology, the First Hospital of China Medical University, Shenyang 110001, China.
| | - Jun Yang
- Department of Cardiovascular Ultrasound, the First Hospital of China Medical University, Shenyang 110001, China.
| | - Yingxian Sun
- Department of Cardiology, the First Hospital of China Medical University, Shenyang 110001, China.
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18
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Ozturk N, Uslu S, Ozdemir S. Diabetes-induced changes in cardiac voltage-gated ion channels. World J Diabetes 2021; 12:1-18. [PMID: 33520105 PMCID: PMC7807254 DOI: 10.4239/wjd.v12.i1.1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 11/05/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus affects the heart through various mechanisms such as microvascular defects, metabolic abnormalities, autonomic dysfunction and incompatible immune response. Furthermore, it can also cause functional and structural changes in the myocardium by a disease known as diabetic cardiomyopathy (DCM) in the absence of coronary artery disease. As DCM progresses it causes electrical remodeling of the heart, left ventricular dysfunction and heart failure. Electrophysiological changes in the diabetic heart contribute significantly to the incidence of arrhythmias and sudden cardiac death in diabetes mellitus patients. In recent studies, significant changes in repolarizing K+ currents, Na+ currents and L-type Ca2+ currents along with impaired Ca2+ homeostasis and defective contractile function have been identified in the diabetic heart. In addition, insulin levels and other trophic factors change significantly to maintain the ionic channel expression in diabetic patients. There are many diagnostic tools and management options for DCM, but it is difficult to detect its development and to effectively prevent its progress. In this review, diabetes-associated alterations in voltage-sensitive cardiac ion channels are comprehensively assessed to understand their potential role in the pathophysiology and pathogenesis of DCM.
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Affiliation(s)
- Nihal Ozturk
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Serkan Uslu
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Semir Ozdemir
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
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19
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Yu R, Xi H, Wang P, Xu D, Lu J, Xu F, An L, Zhao X, Bai R. Catheter ablation of atrial fibrillation after pericardiectomy: multi-center experience in China. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:580. [PMID: 32566607 PMCID: PMC7290548 DOI: 10.21037/atm.2020.04.49] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background To study the effectiveness and safety of atrial fibrillation (AF) catheter ablation after pericardiectomy. Methods Data of 24 consecutive AF patients after pericardiectomy underwent catheter ablation from five centers were collected and analyzed retrospectively. All patients were followed up at 1, 3, and 12 months after catheter ablation. Results of a repeated blood test, electrocardiogram, and echocardiography during follow-up were also collected. Adverse events such as recurrence of AF, heart failure, stroke/transient ischemic attack (TIA) and minor, and major bleeding were recorded. All patients underwent brain magnetic resonance imaging (MRI) at the end of 12 months follow-up. Results Patients were young (20-73 years old, 48.1±11.0). Fifteen (62.5%) patients were male. CHA2DS2-VASc score (0-3, 0.21±0.41) was low in these 24 patients. Among these patients, 11 (45.8%) were paroxysmal AF, 8 (33.3%) were persistent AF, and 5 (20.8%) were long-lasting persistent AF. Left atrium diameter over 45 mm was detected in 17 (70.8%) patients. All patients underwent catheter ablation successfully. No peri-ablation procedure-related complication happened. Oral anticoagulant therapy was stopped 3 months after the final ablation. Anti-arrhythmia drugs were continued for all patients after ablation. For 12 months follow-up, AF recurred in 10 (41.7%) patients 3-7 months after the first ablation. MRI detected silent cerebral infarction (SCI) in 2 (8.3%) patients. No other adverse events occurred during follow-up. Conclusions It is safe for AF patients to undergo catheter ablation after pericardiectomy, but the rate of recurrence of AF is high.
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Affiliation(s)
- Ronghui Yu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.,National Clinical Research Center for Cardiovascular Diseases, Beijing 100029, China
| | - Hui Xi
- Department of Cardiology, Peking University International Hospital, Beijing 102206, China
| | - Peize Wang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.,National Clinical Research Center for Cardiovascular Diseases, Beijing 100029, China
| | - Dongling Xu
- Department of Cardiology, The Second Hospital of Shandong University, Jinan 250033, China
| | - Jun Lu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Fengqiang Xu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Lei An
- Department of Cardiology, Langfang People Hospital, Langfang 250033, China
| | - Xin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.,National Clinical Research Center for Cardiovascular Diseases, Beijing 100029, China
| | - Rong Bai
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.,National Clinical Research Center for Cardiovascular Diseases, Beijing 100029, China
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Jansen HJ, Bohne LJ, Gillis AM, Rose RA. Atrial remodeling and atrial fibrillation in acquired forms of cardiovascular disease. Heart Rhythm O2 2020; 1:147-159. [PMID: 34113869 PMCID: PMC8183954 DOI: 10.1016/j.hroo.2020.05.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Atrial fibrillation (AF) is prevalent in common conditions and acquired forms of heart disease, including diabetes mellitus (DM), hypertension, cardiac hypertrophy, and heart failure. AF is also prevalent in aging. Although acquired heart disease is common in aging individuals, age is also an independent risk factor for AF. Importantly, not all individuals age at the same rate. Rather, individuals of the same chronological age can vary in health status from fit to frail. Frailty can be quantified using a frailty index, which can be used to assess heterogeneity in individuals of the same chronological age. AF is thought to occur in association with electrical remodeling due to changes in ion channel expression or function as well as structural remodeling due to fibrosis, myocyte hypertrophy, or adiposity. These forms of remodeling can lead to triggered activity and electrical re-entry, which are fundamental mechanisms of AF initiation and maintenance. Nevertheless, the underlying determinants of electrical and structural remodeling are distinct in different conditions and disease states. In this focused review, we consider the factors leading to atrial electrical and structural remodeling in human patients and animal models of acquired cardiovascular disease or associated risk factors. Our goal is to identify similarities and differences in the cellular and molecular bases for atrial electrical and structural remodeling in conditions including DM, hypertension, hypertrophy, heart failure, aging, and frailty.
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Affiliation(s)
- Hailey J Jansen
- Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Loryn J Bohne
- Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Anne M Gillis
- Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Robert A Rose
- Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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