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Noujaim SF, Dobrev D. Non-neuronal ventricular cardiomyocyte-located nicotinergic acetylcholine receptors cause remodelling and arrhythmias. Eur Heart J 2025; 46:1247-1249. [PMID: 39842853 PMCID: PMC11959178 DOI: 10.1093/eurheartj/ehae845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2025] Open
Affiliation(s)
- Sami F Noujaim
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Dobromir Dobrev
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany
- Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Canada
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA
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Schotten U, Goette A, Verheule S. Translation of pathophysiological mechanisms of atrial fibrosis into new diagnostic and therapeutic approaches. Nat Rev Cardiol 2025; 22:225-240. [PMID: 39443702 DOI: 10.1038/s41569-024-01088-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/12/2024] [Indexed: 10/25/2024]
Abstract
Atrial fibrosis is one of the main manifestations of atrial cardiomyopathy, an array of electrical, mechanical and structural alterations associated with atrial fibrillation (AF), stroke and heart failure. Atrial fibrosis can be both a cause and a consequence of AF and, once present, it accelerates the progression of AF. The pathophysiological mechanisms leading to atrial fibrosis are diverse and include stretch-induced activation of fibroblasts, systemic inflammatory processes, activation of coagulation factors and fibrofatty infiltrations. Importantly, atrial fibrosis can occur in different forms, such as reactive and replacement fibrosis. The diversity of atrial fibrosis mechanisms and patterns depends on sex, age and comorbidity profile, hampering the development of therapeutic strategies. In addition, the presence and severity of comorbidities often change over time, potentially causing temporal changes in the mechanisms underlying atrial fibrosis development. This Review summarizes the latest knowledge on the molecular and cellular mechanisms of atrial fibrosis, its association with comorbidities and the sex-related differences. We describe how the various patterns of atrial fibrosis translate into electrophysiological mechanisms that promote AF, and critically appraise the clinical applicability and limitations of diagnostic tools to quantify atrial fibrosis. Finally, we provide an overview of the newest therapeutic interventions under development and discuss relevant knowledge gaps related to the association between clinical manifestations and pathological mechanisms of atrial fibrosis and to the translation of this knowledge to a clinical setting.
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Affiliation(s)
- Ulrich Schotten
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
- Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.
| | - Andreas Goette
- Department of Cardiology and Intensive Care Medicine, St. Vincenz Hospital, Paderborn, Germany
- Otto-von-Guericke University, Medical Faculty, Magdeburg, Germany
| | - Sander Verheule
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
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Abbas M, Gaye A. Emerging roles of noncoding RNAs in cardiovascular pathophysiology. Am J Physiol Heart Circ Physiol 2025; 328:H603-H621. [PMID: 39918596 DOI: 10.1152/ajpheart.00681.2024] [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: 10/01/2024] [Revised: 10/17/2024] [Accepted: 01/30/2025] [Indexed: 02/27/2025]
Abstract
This review comprehensively examines the diverse roles of noncoding RNAs (ncRNAs) in the pathogenesis and treatment of cardiovascular disease (CVD), focusing on microRNA (miRNA), long noncoding RNA (lncRNA), piwi-interacting RNA (piRNA), small-interfering RNA (siRNA), circular RNA (circRNA), and vesicle-associated RNAs. These ncRNAs are integral regulators of key cellular processes, including gene expression, inflammation, and fibrosis, and they hold great potential as both diagnostic biomarkers and therapeutic targets. The review highlights novel insights into how these RNA species, particularly miRNAs, lncRNAs, and piRNAs, contribute to various CVDs such as hypertension, atherosclerosis, and myocardial infarction. In addition, it explores the emerging role of extracellular vesicles (EVs) in intercellular communication and their therapeutic potential in cardiovascular health. The review underscores the need for continued research into ncRNAs and RNA-based therapies, with a focus on advancing delivery systems and expanding personalized medicine approaches to improve cardiovascular outcomes.
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Affiliation(s)
- Malak Abbas
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
| | - Amadou Gaye
- Department of Integrative Genomics and Epidemiology, School of Graduate Studies, Meharry Medical School, Nashville, Tennessee, United States
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4
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Ye X, Wu Q, Lv Q, Hou X, Yang Y, Yang C, Wang S. Smoking, Alcohol Consumption, and Atrial Fibrillation: Mendelian Randomization Study. Cardiovasc Toxicol 2025; 25:341-353. [PMID: 39987412 PMCID: PMC11885352 DOI: 10.1007/s12012-025-09964-8] [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: 08/31/2024] [Accepted: 01/15/2025] [Indexed: 02/24/2025]
Abstract
Smoking, secondhand smoke exposure, and alcohol consumption are significant risk factors that contribute to an increased global burden of cardiovascular diseases. However, the casual relationship between smoking, passive smoking, alcohol consumption, and atrial fibrillation (AF) remains uncertain. Conventional observational studies are difficult to draw conclusion on high-quality causality. To elucidate the association between smoking, secondhand smoke exposure, alcohol consumption, and AF, we conducted this two-sample Mendelian randomization (MR) analysis. Smoking encompasses current tobacco smoking, ever-smoked, and light smokers, with light smokers being defined as at least 100 smokes in lifetime, as well as secondhand smoke exposure, which is characterized by workplace had a lot of cigarette smoke from other people smoking: Often. Alcohol consumption encompasses diagnoses-secondary ICD10: Z72.1 Alcohol use and the frequency of alcohol intake. Genetic variants associated with smoking and alcohol consumption were obtained from the IEU Open GWAS project and subsequently selected as instrumental variables (IVs). The corresponding variants associated with AF were also retrieved from the IEU Open GWAS project. The primary MR method utilized was the inverse-variance weighted (IVW). To assess the robustness of our results, multiple supplementary methods were utilized, including the weighted median (WM), MR-Egger regression, MR-PRESSO, MR-Egger intercept test, and the leave-one-out method. A reverse MR analysis was also conducted to determine the potential existence of reverse causality. Genetic predictions indicate a causal relationship between active smoking (current tobacco smoking, P-val = 0.019, OR: 1.413, 95% CI = 1.058-1.888; ever smoked, P-val = 0.049, OR: 1.355, 95% CI = 1.001-1.834; light smokers, P-val = 0.001, OR: 1.444, 95% CI = 1.154-1.806) and AF. No causal association was found between secondhand smoke exposure, alcohol consumption phenotypes, and AF. Additionally, the reverse MR analysis did not reveal any evidence of reverse causality from AF to active smoking. This study provides MR evidence supporting a causal association between active smoking and AF. The significance of smoking cessation is underscored by its potential to prevent or mitigate the risk of AF. Furthermore, the impact of secondhand smoke exposure and alcohol consumption on AF, as well as the causality among these factors, warrants further investigation.
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Affiliation(s)
- Xuejiao Ye
- Department of Cardiovascular Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange, Xicheng District, Beijing, China
| | - Qian Wu
- Department of Cardiovascular Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange, Xicheng District, Beijing, China
| | - Qianyu Lv
- Department of Cardiovascular Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange, Xicheng District, Beijing, China
| | - Xinzheng Hou
- Department of Cardiovascular Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange, Xicheng District, Beijing, China
| | - Yingtian Yang
- Department of Cardiovascular Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange, Xicheng District, Beijing, China
| | - Chenyan Yang
- Department of Cardiovascular Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange, Xicheng District, Beijing, China
| | - Shihan Wang
- Department of Cardiovascular Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange, Xicheng District, Beijing, China.
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5
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Balan AI, Scridon A. MicroRNAs in atrial fibrillation - have we discovered the Holy Grail or opened a Pandora's box? Front Pharmacol 2025; 16:1535621. [PMID: 40012622 PMCID: PMC11861496 DOI: 10.3389/fphar.2025.1535621] [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: 11/27/2024] [Accepted: 01/24/2025] [Indexed: 02/28/2025] Open
Abstract
Atrial fibrillation (AF) causes a heavy socio-economic burden on healthcare systems around the globe. Identification of new preventive, diagnostic, and treatment methods is imperative. In recent years, special attention has been paid to microRNAs (miRNAs) as potential regulators of AF pathogenesis. Through post-transcriptional regulation of genes, miRNAs have been shown to play crucial roles in AF-related structural and electrical atrial remodeling. Altered expression of different miRNAs has been related to proarrhythmic changes in the duration of action potentials and atrial fibrosis. In clinical studies, miRNA changes have been associated with AF, whereas in experimental studies miRNA manipulation has emerged as a potential therapeutic approach. It would appear that, with the advent of miRNAs, we may have found the Holy Grail, and that efficient and personalized AF therapy may be one step away. Yet, the clinical relevance of miRNA evaluation and manipulation remains questionable. Studies have identified numerous miRNAs associated with AF, but none of them have shown sufficient specificity for AF. MicroRNAs are not gene-specific but regulate the expression of a myriad of genes. Cardiac and non-cardiac off-target effects may thus occur following miRNA manipulation. A Pandora's box might thus have opened with the advent of these sophisticated molecules. In this paper, we provide a critical analysis of the clinical and experimental, epidemiological and mechanistic data linking miRNAs to AF, we discuss the most promising miRNA therapeutic approaches, we emphasize a number of questions that remain to be answered, and we identify hotspots for future research.
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Affiliation(s)
| | - Alina Scridon
- Physiology Department and Center for Advanced Medical and Pharmaceutical Research, Pharmacy, Science and Technology “George Emil Palade” of Târgu Mureș, University of Medicine, Târgu Mures, Romania
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Karakasis P, Theofilis P, Vlachakis PK, Korantzopoulos P, Patoulias D, Antoniadis AP, Fragakis N. Atrial Fibrosis in Atrial Fibrillation: Mechanistic Insights, Diagnostic Challenges, and Emerging Therapeutic Targets. Int J Mol Sci 2024; 26:209. [PMID: 39796066 PMCID: PMC11720255 DOI: 10.3390/ijms26010209] [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: 11/28/2024] [Revised: 12/25/2024] [Accepted: 12/29/2024] [Indexed: 01/13/2025] Open
Abstract
Atrial fibrosis is a hallmark of atrial cardiomyopathy and plays a pivotal role in the pathogenesis of atrial fibrillation (AF), contributing to its onset and progression. The mechanisms underlying atrial fibrosis are multifaceted, involving stretch-induced fibroblast activation, oxidative stress, inflammation, and coagulation pathways. Variations in fibrosis types-reactive and replacement fibrosis-are influenced by patient-specific factors such as age, sex, and comorbidities, complicating therapeutic approaches. The heterogeneity of fibrosis leads to distinct electrophysiological abnormalities that promote AF via reentrant activity and enhanced automaticity mechanisms. Despite advancements in imaging, such as late gadolinium enhancement CMR and electroanatomical mapping, challenges in accurately quantifying fibrosis persist. Emerging therapeutic strategies include antifibrotic agents targeting the renin-angiotensin-aldosterone system, novel pathways like TGF-β signaling, and cardio-metabolic drugs like SGLT2 inhibitors and GLP-1 receptor agonists. Innovative interventions, including microRNA modulation and lipid nanoparticle-based therapies, show promise but require validation. Knowledge gaps remain in correlating clinical outcomes with fibrosis patterns and optimizing diagnostic tools. Future research should focus on precise phenotyping, integrating advanced imaging with molecular biomarkers, and conducting robust trials to evaluate antifibrotic therapies' efficacy in reducing AF burden and related complications.
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Affiliation(s)
- Paschalis Karakasis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (A.P.A.); (N.F.)
| | - Panagiotis Theofilis
- First Cardiology Department, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.)
| | - Panayotis K. Vlachakis
- First Cardiology Department, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.)
| | - Panagiotis Korantzopoulos
- First Department of Cardiology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45500 Ioannina, Greece;
| | - Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Faculty of Medicine, School of Health Sciences Aristotle, University of Thessaloniki, 54642 Thessaloniki, Greece;
| | - Antonios P. Antoniadis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (A.P.A.); (N.F.)
| | - Nikolaos Fragakis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (A.P.A.); (N.F.)
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Vermeer JR, van den Broek JL, Dekker LR. Impact of lifestyle risk factors on atrial fibrillation: Mechanisms and prevention approaches - A narrative review. INTERNATIONAL JOURNAL OF CARDIOLOGY. CARDIOVASCULAR RISK AND PREVENTION 2024; 23:200344. [PMID: 39534719 PMCID: PMC11555354 DOI: 10.1016/j.ijcrp.2024.200344] [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] [Received: 08/01/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024]
Abstract
Both the development and progression of atrial fibrillation (AF) are affected by a range of modifiable lifestyle risk factors. These key modifiable risk factors encompass obesity, hypertension, hypercholesterolemia, diabetes mellitus, smoking, chronic obstructive pulmonary disease, alcohol consumption, exercise, sedentary lifestyle and obstructive sleep apnoea. These lifestyle-dependent factors rarely exist in isolation, but rather exist together, exerting a complex influence on the development of AF. This comprehensive review elucidates the interplay and interdependency of these lifestyle factors in the arrhythmogenesis of AF, by exploring their role in AF substrate formation, modulating properties and triggering mechanisms. We emphasize the importance of targeted prevention strategies by discussing available literature on the effectiveness of treatment strategies targeting multiple risk factors. Additionally, the clinical impacts of integrated care, nurse-led care and mobile health are discussed in the context of lifestyle improvement. These management strategies have favourable applicability in both paroxysmal and persistent AF, and are also beneficial for patients receiving AF ablation. Despite the challenges accompanying lifestyle and prevention strategies, substantial benefits are apparent, such as improved quality of life and better ablation outcomes. This review further emphasizes the essential nature of awareness of appropriate lifestyle modifications as fundamental pillars in the management of individuals with AF.
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Affiliation(s)
- Jasper R. Vermeer
- Department of Cardiology, Catharina Hospital Eindhoven, the Netherlands
- Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Johannes L.P.M. van den Broek
- Department of Cardiology, Catharina Hospital Eindhoven, the Netherlands
- Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Lukas R.C. Dekker
- Department of Cardiology, Catharina Hospital Eindhoven, the Netherlands
- Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
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8
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Palarea-Albaladejo J, Bode EF, Partington C, Basili M, Mederska E, Hodgkiss-Geere H, Capewell P, Chauché C, Coultous RM, Hanks E, Dukes-McEwan J. Assessing the use of blood microRNA expression patterns for predictive diagnosis of myxomatous mitral valve disease in dogs. Front Vet Sci 2024; 11:1443847. [PMID: 39553198 PMCID: PMC11565599 DOI: 10.3389/fvets.2024.1443847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 09/30/2024] [Indexed: 11/19/2024] Open
Abstract
Background Myxomatous mitral valve disease (MMVD) is a common, acquired, and progressive canine heart disease. The presence of heart murmur and current cardiac biomarkers are useful in MMVD cases but are not sufficiently discriminatory for staging an individual patient. Objectives This study aimed to conduct a preliminary assessment of canine serum and plasma expression profiles of 15 selected miRNA markers for accurate discrimination between MMVD patients and healthy controls. Additionally, we aim to evaluate the effectiveness of this method in differentiating between pre-clinical (stage B1/B2) and clinical (stage C/D) MMVD patients. Animals Client-owned dogs (n = 123) were recruited for the study. Following sample exclusions (n = 26), healthy controls (n = 50) and MMVD cases (n = 47) were analyzed. Methods A multicenter, cross-sectional, prospective investigation was conducted. MicroRNA expression profiles were compared among dogs, and these profiles were used as input for predictive modeling. This approach aimed to distinguish between healthy controls and MMVD patients, as well as to achieve a more fine-grained differentiation between pre-clinical and clinical MMVD patients. Results Performance metrics revealed a compelling ability of the method to differentiate healthy controls from dogs with MMVD (sensitivity 0.85; specificity 0.82; and accuracy 0.83). For the discrimination between the pre-clinical (n = 29) and clinical (n = 18) MMVD cases, the results were promising (sensitivity 0.61; specificity 0.79; and accuracy 0.73). Conclusion and clinical importance The use of miRNA expression profiles in combination with customized probabilistic predictive modeling shows good scope to devise a reliable diagnostic tool to distinguish healthy controls from MMVD cases (stages B1 to D). Investigation into the ability to discriminate between the pre-clinical and clinical MMVD cases using the same method yielded promising early results, which could be further enhanced with data from an increased study population.
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Affiliation(s)
- Javier Palarea-Albaladejo
- Department of Computer Science, Applied Mathematics and Statistics, University of Girona, Girona, Spain
| | - Elizabeth F. Bode
- Department of Small Animal Clinical Science, School of Veterinary Science, Leahurst Campus, University of Liverpool, Neston, United Kingdom
| | - Catheryn Partington
- Department of Small Animal Clinical Science, School of Veterinary Science, Leahurst Campus, University of Liverpool, Neston, United Kingdom
| | - Mattia Basili
- Department of Small Animal Clinical Science, School of Veterinary Science, Leahurst Campus, University of Liverpool, Neston, United Kingdom
| | - Elzbieta Mederska
- Department of Small Animal Clinical Science, School of Veterinary Science, Leahurst Campus, University of Liverpool, Neston, United Kingdom
| | - Hannah Hodgkiss-Geere
- Department of Small Animal Clinical Science, School of Veterinary Science, Leahurst Campus, University of Liverpool, Neston, United Kingdom
| | - Paul Capewell
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Caroline Chauché
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | | | - Eve Hanks
- MI:RNA Ltd, Edinburgh, United Kingdom
| | - Joanna Dukes-McEwan
- Department of Small Animal Clinical Science, School of Veterinary Science, Leahurst Campus, University of Liverpool, Neston, United Kingdom
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Teraoka JT, Tang JJ, Delling FN, Vittinghoff E, Marcus GM. Smoking Cessation and Incident Atrial Fibrillation in a Longitudinal Cohort. JACC Clin Electrophysiol 2024; 10:2198-2206. [PMID: 39269397 DOI: 10.1016/j.jacep.2024.06.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/28/2024] [Accepted: 06/17/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND Although smoking heightens the risk of AF, it remains unknown if that risk is amenable to modification after smoking cessation. OBJECTIVES This study sought to evaluate the association between smoking cessation and atrial fibrillation (AF) risk in a large longitudinal cohort. METHODS After excluding those with prevalent AF and no history of smoking at baseline, we evaluated 146,772 UK Biobank participants with serial smoking assessments. We compared AF risk between former smokers at baseline and those who quit smoking during the study to current smokers. Incident AF was ascertained from outpatient and inpatient encounters and identified using International Classification of Diseases codes. Cox models were used to compare the risk of incident AF among current and former smokers as well as those who quit smoking during the study while controlling for age, sex, race, body mass index, education, cardiovascular comorbidities, alcohol use, and pack-years. RESULTS Among the 146,772 participants (48.3% female; age: 57.3 ± 7.9 years), 37,377 (25.5%) currently smoked; 105,429 (72.0%) were former smokers; and 3,966 (2.7%) quit smoking during the study. Over a mean 12.7 ± 2.0 years of follow-up, 11,214 (7.6%) participants developed AF. Compared to current smokers, the adjusted risk of AF was 13% lower in former smokers (HR: 0.87; 95% CI: 0.83-0.91) and 18% lower in those who quit smoking during the study (HR: 0.82; 95% CI: 0.70-0.95). CONCLUSIONS Compared to those who continue to smoke, smoking cessation was associated with a lower risk of AF.
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Affiliation(s)
- Justin T Teraoka
- Department of Medicine, Division of Cardiology, University of California-San Francisco, San Francisco, California, USA
| | - Janet J Tang
- Department of Medicine, Division of Cardiology, University of California-San Francisco, San Francisco, California, USA
| | - Francesca N Delling
- Department of Medicine, Division of Cardiology, University of California-San Francisco, San Francisco, California, USA
| | - Eric Vittinghoff
- Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, California, USA
| | - Gregory M Marcus
- Department of Medicine, Division of Cardiology, University of California-San Francisco, San Francisco, California, USA.
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Lim MW, Kalman JM. The impact of lifestyle factors on atrial fibrillation. J Mol Cell Cardiol 2024; 193:91-99. [PMID: 38838814 DOI: 10.1016/j.yjmcc.2024.05.015] [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: 12/02/2023] [Revised: 03/04/2024] [Accepted: 05/31/2024] [Indexed: 06/07/2024]
Abstract
Atrial fibrillation (AF), with its significant associated morbidity and mortality contributes to significant healthcare utilisation and expenditure. Given its progressively rising incidence, strategies to limit AF development and progression are urgently needed. Lifestyle modification is a potentially potent but underutilised weapon against the AF epidemic. The purpose of this article is to review the role of lifestyle factors as risk factors for AF, outline potential mechanisms of pathogenesis and examine the available evidence for lifestyle intervention in primary and secondary AF prevention. It will also highlight the need for investment by physicians, researchers, health services and governments in order to facilitate delivery of the comprehensive, multidisciplinary AF care that is required to manage this complex and multifactorial disease.
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Affiliation(s)
- Michael W Lim
- Department of Cardiology, The Royal Melbourne Hospital, Melbourne, Australia; Department of Medicine, The University of Melbourne, Melbourne, Australia
| | - Jonathan M Kalman
- Department of Cardiology, The Royal Melbourne Hospital, Melbourne, Australia; Department of Medicine, The University of Melbourne, Melbourne, Australia; The Baker Heart and Diabetes Research Institute, Melbourne, Australia.
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11
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Guevara A, Smith CER, Caldwell JL, Ngo L, Mott LR, Lee IJ, Tapa S, Wang Z, Wang L, Woodward WR, Ng GA, Habecker BA, Ripplinger CM. Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart. Am J Physiol Heart Circ Physiol 2024; 326:H1337-H1349. [PMID: 38551482 PMCID: PMC11381014 DOI: 10.1152/ajpheart.00749.2023] [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: 11/28/2023] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/09/2024]
Abstract
Nicotine is the primary addictive component of tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. To assess the underlying mechanisms, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days before performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the first to third thoracic vertebrae, and β-adrenergic responsiveness was additionally evaluated following norepinephrine (NE) perfusion. Baseline ex vivo heart rate (HR) and SNS stimulation threshold were higher in NIC versus CT (P = 0.004 and P = 0.003, respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC versus CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS shortened the PCL at which alternans emerged in CT but not in NIC hearts. NIC-exposed hearts tended to have slower and reduced HR responses to NE perfusion, but ventricular responses to NE were comparable between groups. Although fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content versus CT. These results suggest both sympathetic hypoinnervation of the myocardium and regional differences in β-adrenergic responsiveness with NIC. This autonomic remodeling may contribute to the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with long-term use.NEW & NOTEWORTHY Here, we show that chronic nicotine exposure was associated with increased heart rate, increased susceptibility to alternans, and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to sympathetic hypoinnervation of the myocardium and diminished β-adrenergic responsiveness of the sinoatrial node following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this proarrhythmic remodeling.
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Affiliation(s)
- Amanda Guevara
- Department of Pharmacology, University of California Davis, Davis, California, United States
| | - Charlotte E R Smith
- Department of Pharmacology, University of California Davis, Davis, California, United States
| | - Jessica L Caldwell
- Department of Pharmacology, University of California Davis, Davis, California, United States
| | - Lena Ngo
- Department of Pharmacology, University of California Davis, Davis, California, United States
| | - Lilian R Mott
- Department of Pharmacology, University of California Davis, Davis, California, United States
| | - I-Ju Lee
- Department of Pharmacology, University of California Davis, Davis, California, United States
| | - Srinivas Tapa
- Department of Pharmacology, University of California Davis, Davis, California, United States
| | - Zhen Wang
- Department of Pharmacology, University of California Davis, Davis, California, United States
- Shantou University Medical College, Shantou, People's Republic of China
| | - Lianguo Wang
- Department of Pharmacology, University of California Davis, Davis, California, United States
| | - William R Woodward
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, Oregon, United States
| | - G Andre Ng
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
- National Institute for Health and Care Research, Leicester Biomedical Research Centre, Leicester, United Kingdom
- Glenfield Hospital, Leicester, United Kingdom
| | - Beth A Habecker
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, Oregon, United States
- Department of Medicine and Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States
| | - Crystal M Ripplinger
- Department of Pharmacology, University of California Davis, Davis, California, United States
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Boen HM, Cherubin M, Franssen C, Gevaert AB, Witvrouwen I, Bosman M, Guns PJ, Heidbuchel H, Loeys B, Alaerts M, Van Craenenbroeck EM. Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2024; 6:183-199. [PMID: 38774014 PMCID: PMC11103047 DOI: 10.1016/j.jaccao.2023.12.009] [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: 07/12/2023] [Revised: 12/11/2023] [Accepted: 12/19/2023] [Indexed: 05/24/2024] Open
Abstract
Close monitoring for cardiotoxicity during anthracycline chemotherapy is crucial for early diagnosis and therapy guidance. Currently, monitoring relies on cardiac imaging and serial measurement of cardiac biomarkers like cardiac troponin and natriuretic peptides. However, these conventional biomarkers are nonspecific indicators of cardiac damage. Exploring new, more specific biomarkers with a clear link to the underlying pathomechanism of cardiotoxicity holds promise for increased specificity and sensitivity in detecting early anthracycline-induced cardiotoxicity. miRNAs (microRNAs), small single-stranded, noncoding RNA sequences involved in epigenetic regulation, influence various physiological and pathological processes by targeting expression and translation. Emerging as new biomarker candidates, circulating miRNAs exhibit resistance to degradation and offer a direct pathomechanistic link. This review comprehensively outlines their potential as early biomarkers for cardiotoxicity and their pathomechanistic link.
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Affiliation(s)
- Hanne M. Boen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Martina Cherubin
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Constantijn Franssen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Andreas B. Gevaert
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Isabel Witvrouwen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Matthias Bosman
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Pieter-Jan Guns
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Hein Heidbuchel
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Bart Loeys
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Maaike Alaerts
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Emeline M. Van Craenenbroeck
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
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Khedr AMB, Shaker OG, EL-Komy MHM, Badr AM, Erfan R. miRNA-133 and lncRNA-H19 expressions and their relation to serum levels of PKM2 and TGF-β in patients with systemic sclerosis. Noncoding RNA Res 2024; 9:253-261. [PMID: 38222070 PMCID: PMC10788181 DOI: 10.1016/j.ncrna.2023.12.003] [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: 07/28/2023] [Revised: 11/30/2023] [Accepted: 12/15/2023] [Indexed: 01/16/2024] Open
Abstract
Background and aims Systemic sclerosis (SSc) is a common autoimmune disorder involving the skin, blood vessels, and internal organs with an elusive pathophysiology. SSc is believed to be a genetically prone T-cell-mediated autoimmune disease. miRNAs and lncRNAs were thought to be involved in the etiology of several immunological diseases including SSc. This work aimed to assess the expression of miRNA-133, lncRNA-H19, PKM2, and TGF-β levels in SSc in comparison to controls and their relationship to the clinical course and severity of disease. Patients and methods Fifty patients with SSc and 40 healthy age and sex-matched controls were included in this study. miRNA-133 and H19 expression levels were detected using quantitative RT-PCR while serum levels of PKM2 and TGF-β were measured using ELISA techniques. Patients' clinical data and treatments received were extracted and correlated with proteins investigated. Results Our results showed that miRNA-133 was significantly downregulated in SSc patients in comparison to controls (Mean + SD of SSc = 0.61 ± 0.22, Mean ± SD of HC = 0.97 ± 0.007, p = 0.003). However, there was significant upregulation of the serum expressions of all other tested biomarkers in SSc patients in comparison to controls; H19 (Mean + SD of SSc = 10.37 ± 3.13, Mean ± SD of HC = 1.01 ± 0.01, p = 0.0001), PKM2 (Mean + SD of SSc = 28.0 ± 4.84, Mean ± SD of HC = 16.19 ± 1.32, p = 0.005) and TGF-β (Mean + SD of SSc = 150.8 ± 6.36, Mean ± SD of HC = 23.83 ± 0.93, p = 0.0001). We also detected several correlations between serum levels of the investigated proteins in patients with SSc. Conclusion Along with TGF-β, our results show that miRNA-133, H19, and PKM2 seem to be potential contributors to SSc pathogenesis and could be promising biomarkers in the diagnosis of SSc patients. The lncRNA-H19 correlations with TGF- β, miRNA-133, and PKM2 suggest a possible influential effect of this RNA molecule on the pathogenesis of SSc.
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Affiliation(s)
- Ahmed MB. Khedr
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Helwan University, Ain Helwan, Cairo, Egypt
| | - Olfat G. Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Amul M. Badr
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Randa Erfan
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
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14
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Improta-Caria AC, Rodrigues LF, Joaquim VHA, De Sousa RAL, Fernandes T, Oliveira EM. MicroRNAs regulating signaling pathways in cardiac fibrosis: potential role of the exercise training. Am J Physiol Heart Circ Physiol 2024; 326:H497-H510. [PMID: 38063810 PMCID: PMC11219062 DOI: 10.1152/ajpheart.00410.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 12/05/2023] [Accepted: 12/05/2023] [Indexed: 02/09/2024]
Abstract
Cardiovascular and metabolic diseases such as hypertension, type 2 diabetes, and obesity develop long-term fibrotic processes in the heart, promoting pathological cardiac remodeling, including after myocardial infarction, reparative fibrotic processes also occur. These processes are regulated by many intracellular signaling pathways that have not yet been completely elucidated, including those associated with microRNA (miRNA) expression. miRNAs are small RNA transcripts (18-25 nucleotides in length) that act as posttranscriptionally regulators of gene expression, inhibiting or degrading one or more target messenger RNAs (mRNAs), and proven to be involved in many biological processes such as cell cycle, differentiation, proliferation, migration, and apoptosis, directly affecting the pathophysiology of several diseases, including cardiac fibrosis. Exercise training can modulate the expression of miRNAs and it is known to be beneficial in various cardiovascular diseases, attenuating cardiac fibrosis processes. However, the signaling pathways modulated by the exercise associated with miRNAs in cardiac fibrosis were not fully understood. Thus, this review aims to analyze the expression of miRNAs that modulate signaling pathways in cardiac fibrosis processes that can be regulated by exercise training.
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Affiliation(s)
- Alex Cleber Improta-Caria
- Laboratory of Biochemistry and Molecular Biology of the Exercise, Physical Education and Sport School, University of São Paulo, São Paulo, Brazil
| | - Luis Felipe Rodrigues
- Laboratory of Biochemistry and Molecular Biology of the Exercise, Physical Education and Sport School, University of São Paulo, São Paulo, Brazil
| | - Victor Hugo Antonio Joaquim
- Laboratory of Biochemistry and Molecular Biology of the Exercise, Physical Education and Sport School, University of São Paulo, São Paulo, Brazil
| | | | - Tiago Fernandes
- Laboratory of Biochemistry and Molecular Biology of the Exercise, Physical Education and Sport School, University of São Paulo, São Paulo, Brazil
| | - Edilamar Menezes Oliveira
- Laboratory of Biochemistry and Molecular Biology of the Exercise, Physical Education and Sport School, University of São Paulo, São Paulo, Brazil
- Departments of Internal Medicine, Center for Regenerative Medicine, USF Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States
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15
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Leszto K, Frąk W, Kurciński S, Sinkowska J, Skwira S, Młynarska E, Rysz J, Franczyk B. Associations of Dietary and Lifestyle Components with Atrial Fibrillation. Nutrients 2024; 16:456. [PMID: 38337740 PMCID: PMC10856828 DOI: 10.3390/nu16030456] [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: 12/20/2023] [Revised: 01/27/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Atrial fibrillation (AF) is a prevalent cardiac arrhythmia that still remains a significant health concern, especially due to its consequences, including stroke and heart failure. This review explores the intricate interplay between AF, lifestyle choices, and dietary habits. It is particularly focused on findings from diverse studies about non-pharmacological methods of managing AF. Moreover, its purpose is to elucidate the implementation of lifestyle changes such as physical activity or proper diet choices in the integrated treatment strategy of patients with AF.
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Affiliation(s)
- Klaudia Leszto
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (K.L.); (J.S.); (S.S.)
| | - Weronika Frąk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (K.L.); (J.S.); (S.S.)
| | - Szymon Kurciński
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (K.L.); (J.S.); (S.S.)
| | - Julia Sinkowska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (K.L.); (J.S.); (S.S.)
| | - Sylwia Skwira
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (K.L.); (J.S.); (S.S.)
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (K.L.); (J.S.); (S.S.)
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (K.L.); (J.S.); (S.S.)
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Sato T, Sotomi Y, Hikoso S, Kitamura T, Nakatani D, Okada K, Dohi T, Sunaga A, Kida H, Matsuoka Y, Tanaka N, Watanabe T, Makino N, Egami Y, Oka T, Minamiguchi H, Miyoshi M, Okada M, Kanda T, Matsuda Y, Kawasaki M, Masuda M, Inoue K, Sakata Y. Uplift modeling to identify patients who require extensive catheter ablation procedures among patients with persistent atrial fibrillation. Sci Rep 2024; 14:2634. [PMID: 38302547 PMCID: PMC10834528 DOI: 10.1038/s41598-024-52976-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 01/25/2024] [Indexed: 02/03/2024] Open
Abstract
Identifying patients who would benefit from extensive catheter ablation along with pulmonary vein isolation (PVI) among those with persistent atrial fibrillation (AF) has been a subject of controversy. The objective of this study was to apply uplift modeling, a machine learning method for analyzing individual causal effect, to identify such patients in the EARNEST-PVI trial, a randomized trial in patients with persistent AF. We developed 16 uplift models using different machine learning algorithms, and determined that the best performing model was adaptive boosting using Qini coefficients. The optimal uplift score threshold was 0.0124. Among patients with an uplift score ≥ 0.0124, those who underwent extensive catheter ablation (PVI-plus) showed a significantly lower recurrence rate of AF compared to those who received only PVI (PVI-alone) (HR 0.40; 95% CI 0.19-0.84; P-value = 0.015). In contrast, among patients with an uplift score < 0.0124, recurrence of AF did not significantly differ between PVI-plus and PVI-alone (HR 1.17; 95% CI 0.57-2.39; P-value = 0.661). By employing uplift modeling, we could effectively identify a subset of patients with persistent AF who would benefit from PVI-plus. This model could be valuable in stratifying patients with persistent AF who need extensive catheter ablation before the procedure.
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Affiliation(s)
- Taiki Sato
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yohei Sotomi
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shungo Hikoso
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Tetsuhisa Kitamura
- Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Daisaku Nakatani
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Katsuki Okada
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Transformative System for Medical Information, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tomoharu Dohi
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Akihiro Sunaga
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hirota Kida
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuki Matsuoka
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Nobuaki Tanaka
- Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka, Japan
| | - Tetsuya Watanabe
- Division of Cardiology, Osaka General Medical Center, Osaka, Japan
- Department of Cardiovascular Medicine, Yao Municipal Hospital, Yao, Japan
| | - Nobuhiko Makino
- Cardiovascular Division, Osaka Police Hospital, Osaka, Japan
| | - Yasuyuki Egami
- Division of Cardiology, Osaka Rosai Hospital, Sakai, Japan
| | - Takafumi Oka
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
- Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka, Japan
| | - Hitoshi Minamiguchi
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
- Cardiovascular Division, Osaka Police Hospital, Osaka, Japan
| | - Miwa Miyoshi
- Department of Cardiology, Osaka Hospital, Japan Community Healthcare Organization, Osaka, Japan
| | - Masato Okada
- Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka, Japan
| | - Takashi Kanda
- Cardiovascular Division, Osaka Police Hospital, Osaka, Japan
- Cardiovascular Center, Kansai Rosai Hospital, Amagasaki, Japan
| | | | - Masato Kawasaki
- Division of Cardiology, Osaka General Medical Center, Osaka, Japan
| | - Masaharu Masuda
- Cardiovascular Center, Kansai Rosai Hospital, Amagasaki, Japan
| | - Koichi Inoue
- Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka, Japan
- Cardiovascular Division, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yasushi Sakata
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
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17
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Kwon S, Lee SR, Choi EK, Lee SW, Jung JH, Han KD, Ahn HJ, Oh S, Lip GYH. Impact of Unhealthy Lifestyles on Patients with Atrial Fibrillation at Low Risk of Stroke: A Nationwide Cohort Study. Am J Med 2024; 137:37-46.e6. [PMID: 37832755 DOI: 10.1016/j.amjmed.2023.09.012] [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: 04/25/2023] [Revised: 08/14/2023] [Accepted: 09/17/2023] [Indexed: 10/15/2023]
Abstract
BACKGROUND The impact of unhealthy lifestyles on clinical outcomes among patients with atrial fibrillation (AF) who are at low risk of stroke remains uncertain. The study objective was to evaluate the association between unhealthy lifestyles and clinical outcomes among low-risk AF patients with 0-1 non-sex risk factor of the CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke or transient ischemic attack [TIA], Vascular disease, Age 65-74 years, female Sex;) score. METHODS A total of 52,451 low-risk AF patients (mean age 51.6 ± 10.4 years) were evaluated with the National Health Insurance Service of the Republic of Korea database between 2009 and 2016. Using the survey on health habits, an unhealthy lifestyle score (ULS) was calculated by adding one point each if a respondent had a sedentary lifestyle, drinking, or smoking. The primary outcome was the composite of myocardial infarction, ischemic stroke, heart failure, and all-cause death. Multivariable Cox regression analysis was used to estimate the risk of the study outcome according to the ULS. RESULTS There was a total of 12,792 (24.4%), 24,785 (47.3%), 11,602 (22.1%), and 3272 (6.2%) low-risk AF patients with 0 to 3 points of the ULS, respectively. The median follow-up period was 4.1 (2.1-6.1) years. Compared with the healthiest-lifestyle group (ULS 0), the other groups were associated with significantly higher risks of the primary outcome, with a gradually increasing trend according to the ULS (adjusted hazard ratio [95% confidence interval] =1.17 [1.05-1.31], 1.37 [1.21-1.56], 1.82 [1.53-2.17], for the groups with ULS 1, 2, and 3, respectively). CONCLUSION Unhealthy lifestyles, including a sedentary lifestyle, drinking, and smoking, may synergistically impact poor clinical outcomes in AF patients who are deemed to be at low risk of stroke.
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Affiliation(s)
- Soonil Kwon
- Department of Internal Medicine, Seoul National University Hospital, Republic of Korea
| | - So-Ryoung Lee
- Department of Internal Medicine, Seoul National University Hospital, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Republic of Korea
| | - Eue-Keun Choi
- Department of Internal Medicine, Seoul National University Hospital, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Republic of Korea.
| | - Seung-Woo Lee
- Department of Medical Statistics, College of Medicine, The Catholic University of Korea, Seoul
| | - Jin-Hyung Jung
- Department of Medical Statistics, College of Medicine, The Catholic University of Korea, Seoul
| | - Kyung-Do Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Hyo-Jeong Ahn
- Department of Internal Medicine, Seoul National University Hospital, Republic of Korea
| | - Seil Oh
- Department of Internal Medicine, Seoul National University Hospital, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Republic of Korea
| | - Gregory Y H Lip
- Department of Internal Medicine, Seoul National University Hospital, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Republic of Korea; Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Chest & Heart Hospital, United Kingdom; Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Denmark
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18
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Guevara A, Smith CER, Caldwell JL, Ngo L, Mott LR, Lee IJ, Tapa I, Wang Z, Wang L, Woodward WR, Ng GA, Habecker BA, Ripplinger CM. Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.23.567754. [PMID: 38045290 PMCID: PMC10690259 DOI: 10.1101/2023.11.23.567754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Nicotine is the primary addictive component in tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. However, the underlying mechanisms are unclear. To address this, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days prior to performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca 2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the 1 st - 3 rd thoracic vertebrae, and β-adrenergic responsiveness was additionally evaluated as changes in heart rate (HR) following norepinephrine (NE) perfusion. Baseline ex vivo HR and SNS stimulation threshold were increased in NIC vs. CT ( P = 0.004 and P = 0.003 respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC vs. CT at baseline ( P = 0.002) and during SNS ( P = 0.0003), with similar results obtained for Ca 2+ transient alternans. SNS reduced the PCL at which alternans emerged in CT but not NIC hearts. NIC exposed hearts also tended to have slower and reduced HR responses to NE perfusion. While fibrosis was unaltered, NIC hearts had lower sympathetic nerve density ( P = 0.03) but no difference in NE content vs. CT. These results suggest both sympathetic hypo-innervation of the myocardium and diminished β-adrenergic responsiveness with NIC. This autonomic remodeling may underlie the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with continued long-term usage. NEW & NOTEWORTHY Here we show that chronic nicotine exposure was associated with increased heart rate, lower threshold for alternans and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to the sympathetic hypo-innervation of the myocardium and diminished β- adrenergic responsiveness observed following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this pro-arrhythmic remodeling.
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19
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Jones CA, Wallace MJ, Bandaru P, Woodbury ED, Mohler PJ, Wold LE. E-cigarettes and arrhythmogenesis: a comprehensive review of pre-clinical studies and their clinical implications. Cardiovasc Res 2023; 119:2157-2164. [PMID: 37517059 PMCID: PMC10578912 DOI: 10.1093/cvr/cvad113] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 06/21/2023] [Accepted: 06/29/2023] [Indexed: 08/01/2023] Open
Abstract
Electronic cigarette use has grown exponentially in recent years, and while their popularity has increased, the long-term effects on the heart are yet to be fully studied and understood. Originally designed as devices to assist with those trying to quit traditional combustible cigarette use, their popularity has attracted use by teens and adolescents who traditionally have not smoked combustible cigarettes. Acute effects on the heart have been shown to be similar to traditional combustible cigarettes, including increased heart rate and blood pressure. The main components of electronic cigarettes that contribute to these arrhythmic effects are found in the e-liquid that is aerosolized and inhaled, comprised of nicotine, flavourings, and a combination of vegetable glycerin (VG) and propylene glycol (PG). Nicotine can potentially induce both ventricular and atrial arrhythmogenesis, with both the atrial and ventricular effects resulting from the interactions of nicotine and the catecholamines they release via potassium channels. Atrial arrhythmogenesis, more specifically atrial fibrillation, can also occur due to structural alterations, which happens because of nicotine downregulating microRNAs 133 and 590, both post-transcriptional growth factor repressors. Liquid flavourings and the combination of PG and VG can possibly lead to arrhythmic events by exposing users to acrolein, an aldehyde that stimulates TRPA1 that in turn causes a change towards sympathetic activation and autonomic imbalance. The design of these electronic delivery devices is constantly changing; therefore, it has proven extremely difficult to study the long-term effects on the heart caused by electronic cigarettes but will be important to understand given their rising popularity. The arrhythmic effects of electronic cigarettes appear similar to traditional cigarettes as well; however, a comprehensive review has not been compiled and is the focus of this article.
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Affiliation(s)
- Carson A Jones
- Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, 473 W 12th Avenue, Columbus, OH 43210, USA
| | - Michael J Wallace
- Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, 473 W 12th Avenue, Columbus, OH 43210, USA
| | - Priya Bandaru
- Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, 473 W 12th Avenue, Columbus, OH 43210, USA
| | - Emerson D Woodbury
- Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, 473 W 12th Avenue, Columbus, OH 43210, USA
| | - Peter J Mohler
- Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, 473 W 12th Avenue, Columbus, OH 43210, USA
- Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Loren E Wold
- Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, 473 W 12th Avenue, Columbus, OH 43210, USA
- Division of Cardiac Surgery, Department of Surgery, Wexner Medical Center, The Ohio State University, 473 W 12th Avenue, Room 603, Columbus, OH 43210, USA
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20
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Varvil MS, dos Santos AP. A review on microRNA detection and expression studies in dogs. Front Vet Sci 2023; 10:1261085. [PMID: 37869503 PMCID: PMC10585042 DOI: 10.3389/fvets.2023.1261085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/12/2023] [Indexed: 10/24/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that function by post-transcriptional regulation of gene expression. Their stability and abundance in tissue and body fluids makes them promising potential tools for both the diagnosis and prognosis of diseases and attractive therapeutic targets in humans and dogs. Studies of miRNA expression in normal and disease processes in dogs are scarce compared to studies published on miRNA expression in human disease. In this literature review, we identified 461 peer-reviewed papers from database searches using the terms "canine," "dog," "miRNA," and "microRNA"; we screened 244 for inclusion criteria and then included a total of 148 original research peer-reviewed publications relating to specific miRNA expression in canine samples. We found an overlap of miRNA expression changes between the four groups evaluated (normal processes, non-infectious and non-inflammatory conditions, infectious and/or inflammatory conditions, and neoplasia) in 39 miRNAs, 83 miRNAs in three of the four groups, 110 miRNAs in two of the three groups, where 158 miRNAs have only been reported in one of the groups. Additionally, the mechanism of action of these overlapping miRNAs varies depending on the disease process, elucidating a need for characterization of the mechanism of action of each miRNA in each disease process being evaluated. Herein we also draw attention to the lack of standardization of miRNA evaluation, consistency within a single evaluation method, and the need for standardized methods for a direct comparison.
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Affiliation(s)
- Mara S. Varvil
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
- Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA, United States
| | - Andrea Pires dos Santos
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
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21
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Sharma AK, Singh S, Bhat M, Gill K, Zaid M, Kumar S, Shakya A, Tantray J, Jose D, Gupta R, Yangzom T, Sharma RK, Sahu SK, Rathore G, Chandolia P, Singh M, Mishra A, Raj S, Gupta A, Agarwal M, Kifayat S, Gupta A, Gupta P, Vashist A, Vaibhav P, Kathuria N, Yadav V, Singh RP, Garg A. New drug discovery of cardiac anti-arrhythmic drugs: insights in animal models. Sci Rep 2023; 13:16420. [PMID: 37775650 PMCID: PMC10541452 DOI: 10.1038/s41598-023-41942-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 09/04/2023] [Indexed: 10/01/2023] Open
Abstract
Cardiac rhythm regulated by micro-macroscopic structures of heart. Pacemaker abnormalities or disruptions in electrical conduction, lead to arrhythmic disorders may be benign, typical, threatening, ultimately fatal, occurs in clinical practice, patients on digitalis, anaesthesia or acute myocardial infarction. Both traditional and genetic animal models are: In-vitro: Isolated ventricular Myocytes, Guinea pig papillary muscles, Patch-Clamp Experiments, Porcine Atrial Myocytes, Guinea pig ventricular myocytes, Guinea pig papillary muscle: action potential and refractory period, Langendorff technique, Arrhythmia by acetylcholine or potassium. Acquired arrhythmia disorders: Transverse Aortic Constriction, Myocardial Ischemia, Complete Heart Block and AV Node Ablation, Chronic Tachypacing, Inflammation, Metabolic and Drug-Induced Arrhythmia. In-Vivo: Chemically induced arrhythmia: Aconitine antagonism, Digoxin-induced arrhythmia, Strophanthin/ouabain-induced arrhythmia, Adrenaline-induced arrhythmia, and Calcium-induced arrhythmia. Electrically induced arrhythmia: Ventricular fibrillation electrical threshold, Arrhythmia through programmed electrical stimulation, sudden coronary death in dogs, Exercise ventricular fibrillation. Genetic Arrhythmia: Channelopathies, Calcium Release Deficiency Syndrome, Long QT Syndrome, Short QT Syndrome, Brugada Syndrome. Genetic with Structural Heart Disease: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia, Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, Atrial Fibrillation, Sick Sinus Syndrome, Atrioventricular Block, Preexcitation Syndrome. Arrhythmia in Pluripotent Stem Cell Cardiomyocytes. Conclusion: Both traditional and genetic, experimental models of cardiac arrhythmias' characteristics and significance help in development of new antiarrhythmic drugs.
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Affiliation(s)
- Ashish Kumar Sharma
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India.
| | - Shivam Singh
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Mehvish Bhat
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Kartik Gill
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Mohammad Zaid
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Sachin Kumar
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Anjali Shakya
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Junaid Tantray
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Divyamol Jose
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Rashmi Gupta
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Tsering Yangzom
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Rajesh Kumar Sharma
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | | | - Gulshan Rathore
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Priyanka Chandolia
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Mithilesh Singh
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Anurag Mishra
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Shobhit Raj
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Archita Gupta
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Mohit Agarwal
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Sumaiya Kifayat
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Anamika Gupta
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Prashant Gupta
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Ankit Vashist
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Parth Vaibhav
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Nancy Kathuria
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Vipin Yadav
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Ravindra Pal Singh
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Arun Garg
- MVN University, Palwal, Haryana, India
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22
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Wu G, Wu J, Lu Q, Cheng Y, Mei W. Association between cardiovascular risk factors and atrial fibrillation. Front Cardiovasc Med 2023; 10:1110424. [PMID: 37753167 PMCID: PMC10518410 DOI: 10.3389/fcvm.2023.1110424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 08/24/2023] [Indexed: 09/28/2023] Open
Abstract
Background The most prevalent sustained arrhythmia in medical practice, atrial fibrillation (AF) is closely associated with a high risk of cardiovascular disease. Nevertheless, the risk of AF associated with cardiovascular risk factors has not been well elucidated. We pooled all published studies to provide a better depiction of the relationship among cardiovascular risk factors with AF. Methods Studies were searched in the MEDLINE, Web of Science, and EMBASE databases since initiation until January 15, 2022. Prospective cohort studies assessing the relationship a minimum of single cardiovascular risk factors to AF incidence were included if they contained adequate data for obtaining relative risks (RR) and 95% confidence intervals (CI). Random-effects models were utilized to perform independent meta-analyses on each cardiovascular risk factor. PROSPERO registry number: CRD42022310882. Results A total of 17,098,955 individuals and 738,843 incident cases were reported for data from 101 studies included in the analysis. In all, the risk of AF was 1.39 (95% CI, 1.30-1.49) for obesity, 1.27 (95% CI, 1.22-1.32) per 5 kg/m2 for increase in body mass index, 1.19 (95% CI, 1.10-1.28) for former smokers, 1.23 (95% CI, 1.09-1.38) for current smokers, 1.31 (95% CI, 1.23-1.39) for diabetes mellitus, 1.68 (95% CI, 1.51-1.87) for hypertension, and 1.12 (95% CI, 0.95-1.32) for dyslipidemia. Interpretation Adverse cardiovascular risk factors correlate with an increased risk of AF, yet dyslipidemia does not increase the risk of AF in the general population, potentially providing new insights for AF screening strategies among patients with these risk factors. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, PROSPERO identifier (CRD42022310882).
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Affiliation(s)
- Guohao Wu
- Department of General Practice, Huadu District People's Hospital, Southern Medical University, Guangzhou, China
| | - Jingguo Wu
- Department of Emergency Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qin Lu
- Department of General Practice, The First Affiliated Hospital, Sun Yat-Sen University,Guangzhou, China
| | - Yunjiu Cheng
- Department of Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University,Guangzhou, China
| | - Weiyi Mei
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University,Guangzhou, China
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23
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Parent S, Vaka R, Risha Y, Ngo C, Kanda P, Nattel S, Khan S, Courtman D, Stewart DJ, Davis DR. Prevention of atrial fibrillation after open-chest surgery with extracellular vesicle therapy. JCI Insight 2023; 8:e163297. [PMID: 37384420 PMCID: PMC10481795 DOI: 10.1172/jci.insight.163297] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 06/28/2023] [Indexed: 07/01/2023] Open
Abstract
Almost half of patients recovering from open-chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that postoperative AF is associated with increased mortality, effective measures to prevent AF after open-chest surgery are highly desirable. In this study, we tested the concept that extracellular vesicles (EVs) isolated from human atrial explant-derived cells can prevent postoperative AF. Middle-aged female and male rats were randomized to undergo sham operation or induction of sterile pericarditis followed by trans-epicardial injection of human EVs or vehicle into the atrial tissue. Pericarditis increased the probability of inducing AF while EV treatment abrogated this effect in a sex-independent manner. EV treatment reduced infiltration of inflammatory cells and production of pro-inflammatory cytokines. Atrial fibrosis and hypertrophy seen after pericarditis were markedly attenuated by EV pretreatment, an effect attributable to suppression of fibroblast proliferation by EVs. Our study demonstrates that injection of EVs at the time of open-chest surgery shows prominent antiinflammatory effects and prevents AF due to sterile pericarditis. Translation of this finding to patients might provide an effective new strategy to prevent postoperative AF by reducing atrial inflammation and fibrosis.
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Affiliation(s)
- Sandrine Parent
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ramana Vaka
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Yousef Risha
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Clarissa Ngo
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Pushpinder Kanda
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Stanley Nattel
- Research Center and Department of Medicine, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
- Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
| | - Saad Khan
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - David Courtman
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Duncan J. Stewart
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Darryl R. Davis
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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24
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Chimenti C, Magnocavallo M, Vetta G, Alfarano M, Manguso G, Ajmone F, Ballatore F, Costantino J, Ciaramella P, Severino P, Miraldi F, Lavalle C, Vizza CD. The Role of MicroRNA in the Myocarditis: a Small Actor for a Great Role. Curr Cardiol Rep 2023:10.1007/s11886-023-01888-5. [PMID: 37269474 DOI: 10.1007/s11886-023-01888-5] [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] [Accepted: 04/24/2023] [Indexed: 06/05/2023]
Abstract
PURPOSE OF REVIEW Myocarditis is an inflammation of the myocardium secondary to a variety of agents such as infectious pathogens, toxins, drugs, and autoimmune disorders. In our review, we provide an overview of miRNA biogenesis and their role in the etiology and pathogenesis of myocarditis, evaluating future directions for myocarditis management. RECENT FINDINGS Advances in genetic manipulation techniques allowed to demonstrate the important role of RNA fragments, especially microRNAs (miRNAs), in cardiovascular pathogenesis. miRNAs are small non-coding RNA molecules that regulate the post-transcriptional gene expression. Advances in molecular techniques allowed to identify miRNA's role in pathogenesis of myocarditis. miRNAs are related to viral infection, inflammation, fibrosis, and apoptosis of cardiomyocytes, making them not only promising diagnostic markers but also prognostics and therapeutic targets in myocarditis. Of course, further real-world studies will be needed to assess the diagnostic accuracy and applicability of miRNA in the myocarditis diagnosis.
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Affiliation(s)
- Cristina Chimenti
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy.
| | - Michele Magnocavallo
- Cardiology Division, Arrhythmology Unit, S. Giovanni Calibita Hospital, Isola Tiberina, Rome, Italy
| | - Giampaolo Vetta
- Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, Mesina, Italy
| | - Maria Alfarano
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Giulia Manguso
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Francesco Ajmone
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Federico Ballatore
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Jacopo Costantino
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Piera Ciaramella
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Paolo Severino
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Fabio Miraldi
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Carlo Lavalle
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
| | - Carmine Dario Vizza
- Clinical, Anestesiologic and Cardiovascular Sciences, La Sapienza University of Rome, Rome, Italy
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25
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Lage R, Cebro-Márquez M, Vilar-Sánchez ME, González-Melchor L, García-Seara J, Martínez-Sande JL, Fernández-López XA, Aragón-Herrera A, Martínez-Monzonís MA, González-Juanatey JR, Rodríguez-Mañero M, Moscoso I. Circulating miR-451a Expression May Predict Recurrence in Atrial Fibrillation Patients after Catheter Pulmonary Vein Ablation. Cells 2023; 12:cells12040638. [PMID: 36831306 PMCID: PMC9953933 DOI: 10.3390/cells12040638] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/07/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Atrial fibrillation is the most prevalent tachyarrhythmia in clinical practice, with very high cardiovascular morbidity and mortality with a high-cost impact in health systems. Currently, it is one of the main causes of stroke and subsequent heart failure and sudden death. miRNAs mediate in several processes involved in cardiovascular disease, including fibrosis and electrical and structural remodeling. Several studies suggest a key role of miRNAs in the course and maintenance of atrial fibrillation. In our study, we aimed to identify the differential expression of circulating miRNAs and their predictive value as biomarkers of recurrence in atrial fibrillation patients undergoing catheter pulmonary vein ablation. To this effect, 42 atrial fibrillation patients were recruited for catheter ablation. We measured the expression of 84 miRNAs in non-recurrent and recurrent groups (45.2%), both in plasma from peripheral and left atrium blood. Expression analysis showed that miRNA-451a is downregulated in recurrent patients. Receiver operating characteristic curve analysis showed that miR-451a in left atrium plasma could predict atrial fibrillation recurrence after pulmonary vein isolation. In addition, atrial fibrillation recurrence is positively associated with the increment of scar percentage. Our data suggest that miRNA-451a expression plays an important role in AF recurrence by controlling fibrosis and progression.
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Affiliation(s)
- Ricardo Lage
- Cardiology Group, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - María Cebro-Márquez
- Cardiology Group, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - Marta E. Vilar-Sánchez
- Cardiology Group, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Laila González-Melchor
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Javier García-Seara
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - José Luis Martínez-Sande
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - Xesús Alberte Fernández-López
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Alana Aragón-Herrera
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - María Amparo Martínez-Monzonís
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - José Ramón González-Juanatey
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - Moisés Rodríguez-Mañero
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Correspondence: (M.R.-M.); (I.M.); Tel.: +0034-88181-5409 (I.M.)
| | - Isabel Moscoso
- Cardiology Group, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- Department of Cardiology and Coronary Unit and Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research (IDIS-SERGAS), University Clinical Hospital, 15706 Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Correspondence: (M.R.-M.); (I.M.); Tel.: +0034-88181-5409 (I.M.)
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26
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Loganathan T, Doss C GP. Non-coding RNAs in human health and disease: potential function as biomarkers and therapeutic targets. Funct Integr Genomics 2023; 23:33. [PMID: 36625940 PMCID: PMC9838419 DOI: 10.1007/s10142-022-00947-4] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 01/11/2023]
Abstract
Human diseases have been a critical threat from the beginning of human history. Knowing the origin, course of action and treatment of any disease state is essential. A microscopic approach to the molecular field is a more coherent and accurate way to explore the mechanism, progression, and therapy with the introduction and evolution of technology than a macroscopic approach. Non-coding RNAs (ncRNAs) play increasingly important roles in detecting, developing, and treating all abnormalities related to physiology, pathology, genetics, epigenetics, cancer, and developmental diseases. Noncoding RNAs are becoming increasingly crucial as powerful, multipurpose regulators of all biological processes. Parallel to this, a rising amount of scientific information has revealed links between abnormal noncoding RNA expression and human disorders. Numerous non-coding transcripts with unknown functions have been found in addition to advancements in RNA-sequencing methods. Non-coding linear RNAs come in a variety of forms, including circular RNAs with a continuous closed loop (circRNA), long non-coding RNAs (lncRNA), and microRNAs (miRNA). This comprises specific information on their biogenesis, mode of action, physiological function, and significance concerning disease (such as cancer or cardiovascular diseases and others). This study review focuses on non-coding RNA as specific biomarkers and novel therapeutic targets.
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Affiliation(s)
- Tamizhini Loganathan
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore- 632014, Tamil Nadu, India
| | - George Priya Doss C
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore- 632014, Tamil Nadu, India.
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27
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Abstract
The global prevalence of atrial fibrillation (AF) has increased substantially over the past three decades and is currently approximately 60 million cases. Incident AF and its clinical consequences are largely the result of risk factors that can be modified by lifestyle changes. In this Review, we provide evidence that the lifetime risk of AF is modified not only by sex and race but also through the clinical risk factor and comorbidity burden of individual patients. We begin by summarizing the epidemiology of AF, focusing on non-modifiable and modifiable risk factors, as well as targets and strategies for the primary prevention of AF. Furthermore, we evaluate the role of modifiable risk factors in the secondary prevention of AF as well as the potential effects of risk factor interventions on the frequency and severity of subsequent AF episodes. We end the Review by proposing strategies that require evaluation as well as global policy changes that are needed for the prevention of incident AF and the management of recurrent episodes in patients already affected by AF.
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28
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Cozzolino C, Picchio V, Floris E, Pagano F, Saade W, Peruzzi M, Frati G, Chimenti I. Modified Risk Tobacco Products and Cardiovascular Repair: Still Very "Smoky". Curr Stem Cell Res Ther 2023; 18:440-444. [PMID: 35927909 DOI: 10.2174/1574888x17666220802142532] [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: 05/18/2022] [Revised: 06/01/2022] [Accepted: 06/01/2022] [Indexed: 11/22/2022]
Abstract
Smoking habits represent a cardiovascular risk factor with a tremendous impact on health. Other than damaging differentiated and functional cells of the cardiovascular system, they also negatively affect reparative mechanisms, such as those involved in cardiac fibrosis and in endothelial progenitor cell (EPC) activation. In recent years, alternative smoking devices, dubbed modified tobacco risk products (MRPs), have been introduced, but their precise impact on human health is still under evaluation. Also, they have not been characterized yet about the possible negative effects on cardiovascular reparative and regenerative cells, such as EPCs or pluripotent stem cells. In this perspective, we critically review the still scarce available data on the effects of MRPs on molecular and cellular mechanisms of cardiovascular repair and regeneration.
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Affiliation(s)
- Claudia Cozzolino
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
| | - Vittorio Picchio
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
| | - Erica Floris
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
| | - Francesca Pagano
- Institute of Biochemistry and Cell Biology, National Council of Research (IBBC-CNR), Monterotondo (RM), Italy
| | - Wael Saade
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Mariangela Peruzzi
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
- Mediterranea Cardiocentro, 80133 Napoli, Italy
| | - Giacomo Frati
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
- IRCCS NeuroMed, Pozzilli (IS), Italy
| | - Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
- Mediterranea Cardiocentro, 80133 Napoli, Italy
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29
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Qiu H, Zhang H, Han DD, Derakhshandeh R, Wang X, Goyal N, Navabzadeh M, Rao P, Wilson EE, Mohammadi L, Olgin JE, Springer ML. Increased vulnerability to atrial and ventricular arrhythmias caused by different types of inhaled tobacco or marijuana products. Heart Rhythm 2023; 20:76-86. [PMID: 36603937 PMCID: PMC10006068 DOI: 10.1016/j.hrthm.2022.09.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/01/2022] [Accepted: 09/09/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND The emergence of a plethora of new tobacco products marketed as being less harmful than smoking, such as electronic cigarettes and heated tobacco products, and the increased popularity of recreational marijuana have raised concerns about the potential cardiovascular risk associated with their use. OBJECTIVE The purpose of this study was to investigate whether the use of novel tobacco products or marijuana can cause the development of proarrhythmic substrate and eventually lead to arrhythmias. METHODS Rats were exposed to smoke from tobacco, marijuana, or cannabinoid-depleted marijuana, to aerosol from electronic cigarettes or heated tobacco products, or to clean air once per day for 8 weeks, following by assays for blood pressure, cardiac function, ex vivo electrophysiology, and histochemistry. RESULTS The rats exposed to tobacco or marijuana products exhibited progressively increased systolic blood pressure, decreased cardiac systolic function with chamber dilation, and reduced overall heart rate variability, relative to the clean air negative control group. Atrial fibrillation and ventricular tachycardia testing by ex vivo optical mapping revealed a significantly higher susceptibility to each, with a shortened effective refractory period and prolonged calcium transient duration. Histological analysis indicated that in all exposure conditions except for air, exposure to smoke or aerosol from tobacco or marijuana products caused severe fibrosis with decreased microvessel density and higher level of sympathetic nerve innervation. CONCLUSION These pathophysiological results indicate that tobacco and marijuana products can induce arrhythmogenic substrates involved in cardiac electrical, structural, and neural remodeling, facilitating the development of arrhythmias.
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Affiliation(s)
- Huiliang Qiu
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Hao Zhang
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Daniel D Han
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Ronak Derakhshandeh
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Xiaoyin Wang
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Natasha Goyal
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Mina Navabzadeh
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Poonam Rao
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Emily E Wilson
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Leila Mohammadi
- Division of Cardiology, University of California, San Francisco, San Francisco, California
| | - Jeffrey E Olgin
- Division of Cardiology, University of California, San Francisco, San Francisco, California; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California
| | - Matthew L Springer
- Division of Cardiology, University of California, San Francisco, San Francisco, California; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; Center for Tobacco Control Research and Education, University of California, San Francisco, San Francisco, California.
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Kopa-Stojak PN, Pawliczak R. Comparison of effects of tobacco cigarettes, electronic nicotine delivery systems and tobacco heating products on miRNA-mediated gene expression. A systematic review. Toxicol Mech Methods 2023; 33:18-37. [PMID: 35722939 DOI: 10.1080/15376516.2022.2089610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/16/2022] [Accepted: 06/09/2022] [Indexed: 01/05/2023]
Abstract
OBJECTIVES This work attempts to summarize current knowledge on the effects of cigarettes, electronic nicotine delivery systems and tobacco heating products on miRNA-mediated gene expression regulation and on their possible impact on smoking-related respiratory disease development. MATERIALS AND METHODS Literature search by terms combination: 'smoking', 'cigarette' 'THP', 'tobacco heating product', 'ENDS', 'electronic nicotine delivery system', 'e-cigarette', electronic cigarette' and 'miRNA-mediated gene expression' has been performed from October 2021 to February 2022. In this systematic review all relevant literature, including clinical trials, cellular and animal-based studies were included. RESULTS Cigarette smoke (CS) significantly altered transcriptome, including miRNAs expression profile. MiRNA-mediated gene expression is mentioned as one of the mechanisms associated with smoking-related respiratory disease development. Differential expression of miRNAs was reduced in aerosol from e-cigarettes (EC) and tobacco heating products (THP) when compared to CS. However, there was a significant alteration of some miRNAs expression when compared to air-controls in both EC and THP. DISCUSSION CS negatively affects transcriptome and miRNA-mediated gene expression regulation because of a huge number of hazardous substances which predispose to smoking-related diseases. Despite the reduced effect of ENDS and THP on miRNAs profile compared to CS, differences in expression of miRNAs when compared to air-control were observed, which may be harmful to never-smokers who may perceive such alternative smoking products as non-hazardous. To clearly indicate the role of ENDS and THP in the alteration of miRNA-mediated gene expression and the development of smoking-related respiratory diseases associated with this mechanism, more long-term studies should be performed in the future.
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Affiliation(s)
- Paulina Natalia Kopa-Stojak
- Department of Immunopathology, Division of Biomedical Science, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Rafał Pawliczak
- Department of Immunopathology, Division of Biomedical Science, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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31
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Bizhanov KA, Аbzaliyev KB, Baimbetov AK, Sarsenbayeva AB, Lyan E. Atrial fibrillation: Epidemiology, pathophysiology, and clinical complications (literature review). J Cardiovasc Electrophysiol 2023; 34:153-165. [PMID: 36434795 DOI: 10.1111/jce.15759] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/25/2022] [Accepted: 11/19/2022] [Indexed: 11/27/2022]
Abstract
The last three decades have been characterized by an exponential increase in knowledge and advances in the clinical management of atrial fibrillation. The purpose of the study is to provide an overview of the pathogenesis of nonvalvular atrial fibrillation and a comprehensive investigation of the epidemiological data associated with various risk factors for atrial fibrillation. The leading research methods are analysis and synthesis, comparison, observation, induction and deduction, and grouping method. Research has shown that old age, male gender, and European descent are important risk factors for developing atrial fibrillation. Other modifiable risk factors include a sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and high blood pressure predisposing to atrial fibrillation, and each has been shown to induce structural and electrical atrial remodeling. Both heart failure and myocardial infarction increase the risk of developing atrial fibrillation and vice versa creating feedback that increases mortality. The review is a comprehensive study of the epidemiological data linking nonmodifiable and modifiable risk factors for atrial fibrillation, and the pathophysiological data supporting the relationship between each risk factor and the occurrence of atrial fibrillation. This may be necessary for the practice of the treatment of the cardiac system.
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Affiliation(s)
- Kenzhebek A Bizhanov
- Department of Health Policy and Organization, Al-Farabi Kazakh National University, Almaty, Republic of Kazakhstan.,Department of Interventional Cardiology and Arrhythmology, National Scientific Center of Surgery named after A.N. Syzganov, Almaty, Republic of Kazakhstan
| | - Kuat B Аbzaliyev
- Сonsultative and Diagnostic Center, Research Institute of Cardiology and Internal Diseases, Almaty, Republic of Kazakhstan
| | - Adil K Baimbetov
- Department of Interventional Cardiology and Arrhythmology, National Scientific Center of Surgery named after A.N. Syzganov, Almaty, Republic of Kazakhstan
| | - Akmoldir B Sarsenbayeva
- Department of Interventional Cardiology and Arrhythmology, National Scientific Center of Surgery named after A.N. Syzganov, Almaty, Republic of Kazakhstan
| | - Evgeny Lyan
- Cardiovascular Center, University Clinic Schleswig-Holstein, Kiel, Germany
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Chidipi B, Chang M, Abou-Assali O, Reiser M, Tian Z, Allen-Gipson D, Noujaim SF. The Arf6/PIP5K pathway activates IKACh in cigarette smoke mediated atrial fibrillation. Cell Signal 2022; 100:110475. [PMID: 36150420 DOI: 10.1016/j.cellsig.2022.110475] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 08/29/2022] [Accepted: 09/16/2022] [Indexed: 11/29/2022]
Abstract
Cigarette smoking (CS) is a major cause of cardiovascular diseases. Smokers are at a significantly higher risk for developing atrial fibrillation (AF), a dangerous and abnormal heart rhythm. In the US, 15.5% of adults are current smokers, and it is becoming clear that CS is an independent risk factor for AF, but a detailed mechanistic understanding of how CS contributes to the molecular patho-electrophysiology of AF remains elusive. We investigated if CS related AF is in part mediated through a mechanism that depends on the cardiac acetylcholine activated inward rectifier potassium current (IKACh). We tested the hypothesis that CS increases IKACh via phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5K) and ADP ribosylation factor 6 (Arf6) signaling, leading to AF perpetuation. In vivo inducibility of AF was assessed in mice exposed to CS for 8 weeks. AF duration was increased in CS exposed mice, and TertiapinQ, an IKACh blocker prevented AF development in CS exposed mice. In HEK293 cells stably transfected with Kir3.1 and Kir3.4, the molecular correlates of IKACh, CS exposure increased the expression of the Kir3.1 and Kir3.4 proteins at the cell surface, activated Arf6 and increased the IKACh current. Inhibition of PIP5K, or of Kir3.1/Kir3.4 trafficking via Arf6 abrogated the CS effects on IKACh. Cigarette smoke modifies the atrial electrophysiological substrate, leading to arrhythmogenesis, in part, through IKACh activation via an Arf6/PIP5K dependent pathway.
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Affiliation(s)
- Bojjibabu Chidipi
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America..
| | - Mengmeng Chang
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America
| | - Obada Abou-Assali
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America
| | - Michelle Reiser
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America
| | - Zhi Tian
- Department of Pharmaceutical Science, USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States of America
| | - Diane Allen-Gipson
- Department of Pharmaceutical Science, USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States of America
| | - Sami F Noujaim
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America
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Hao H, Dai C, Han X, Li Y. A novel therapeutic strategy for alleviating atrial remodeling by targeting exosomal miRNAs in atrial fibrillation. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119365. [PMID: 36167158 DOI: 10.1016/j.bbamcr.2022.119365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 08/29/2022] [Accepted: 09/18/2022] [Indexed: 06/16/2023]
Abstract
Atrial fibrillation (AF) is one of the most frequent cardiac arrhythmias, and atrial remodeling is related to the progression of AF. Although several therapeutic approaches have been presented in recent years, the continuously increasing mortality rate suggests that more advanced strategies for treatment are urgently needed. Exosomes regulate pathological processes through intercellular communication mediated by microribonucleic acid (miRNA) in various cardiovascular diseases (CVDs). Exosomal miRNAs associated with signaling pathways have added more complexity to an already complex direct cell-to-cell interaction. Exosome delivery of miRNAs is involved in cardiac regeneration and cardiac protection. Recent studies have found that exosomes play a critical role in the diagnosis and treatment of cardiac fibrosis. By improving exosome stability and modifying surface epitopes, specific pharmaceutical agents can be supplied to improve tropism and targeting to cells and tissues in vivo. Exosomes harboring miRNAs may have clinical utility in cell-free therapeutic approaches and may serve as prognostic and diagnostic biomarkers for AF. Currently, limitations challenge pharmaceutic design, therapeutic utility and in vivo targeted delivery to patients. The aim of this article is to review the developmental features of AF associated with exosomal miRNAs and relate them to underlying mechanisms.
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Affiliation(s)
- Hongting Hao
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
| | - Chenguang Dai
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
| | - Xuejie Han
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
| | - Yue Li
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China; NHC Key Laboratory of Cell Translation, Harbin Medical University, Heilongjiang 150001, China; Key Laboratory of Hepatosplenic Surgery, Harbin Medical University, Ministry of Education, Harbin 150001, China; Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin 150001, China; Heilongjiang Key Laboratory for Metabolic Disorder & Cancer Related Cardiovascular Diseases, Harbin 150081, China; Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China.
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Ohlrogge AH, Frost L, Schnabel RB. Harmful Impact of Tobacco Smoking and Alcohol Consumption on the Atrial Myocardium. Cells 2022; 11:2576. [PMID: 36010652 PMCID: PMC9406618 DOI: 10.3390/cells11162576] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/05/2022] [Accepted: 08/11/2022] [Indexed: 11/23/2022] Open
Abstract
Tobacco smoking and alcohol consumption are widespread exposures that are legal and socially accepted in many societies. Both have been widely recognized as important risk factors for diseases in all vital organ systems including cardiovascular diseases, and with clinical manifestations that are associated with atrial dysfunction, so-called atrial cardiomyopathy, especially atrial fibrillation and stroke. The pathogenesis of atrial cardiomyopathy, atrial fibrillation, and stroke in context with smoking and alcohol consumption is complex and multifactorial, involving pathophysiological mechanisms, environmental, and societal aspects. This narrative review summarizes the current literature regarding alterations in the atrial myocardium that is associated with smoking and alcohol.
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Affiliation(s)
- Amelie H. Ohlrogge
- Department of Cardiology, University Heart and Vascular Centre Hamburg, 20246 Hamburg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - Lars Frost
- Diagnostic Centre, University Clinic for Development of Innovative Patient Pathways, Silkeborg Regional Hospital, 8600 Silkeborg, Denmark
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark
| | - Renate B. Schnabel
- Department of Cardiology, University Heart and Vascular Centre Hamburg, 20246 Hamburg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
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New Insights into the Functions of MicroRNAs in Cardiac Fibrosis: From Mechanisms to Therapeutic Strategies. Genes (Basel) 2022; 13:genes13081390. [PMID: 36011301 PMCID: PMC9407613 DOI: 10.3390/genes13081390] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/16/2022] [Accepted: 08/03/2022] [Indexed: 02/06/2023] Open
Abstract
Cardiac fibrosis is a significant global health problem associated with almost all types of heart disease. Extensive cardiac fibrosis reduces tissue compliance and contributes to adverse outcomes, such as cardiomyocyte hypertrophy, cardiomyocyte apoptosis, and even heart failure. It is mainly associated with pathological myocardial remodeling, characterized by the excessive deposition of extracellular matrix (ECM) proteins in cardiac parenchymal tissues. In recent years, a growing body of evidence demonstrated that microRNAs (miRNAs) have a crucial role in the pathological development of cardiac fibrosis. More than sixty miRNAs have been associated with the progression of cardiac fibrosis. In this review, we summarized potential miRNAs and miRNAs-related regulatory mechanisms for cardiac fibrosis and discussed the potential clinical application of miRNAs in cardiac fibrosis.
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36
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Li G, Yang J, Zhang D, Wang X, Han J, Guo X. Research Progress of Myocardial Fibrosis and Atrial Fibrillation. Front Cardiovasc Med 2022; 9:889706. [PMID: 35958428 PMCID: PMC9357935 DOI: 10.3389/fcvm.2022.889706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/10/2022] [Indexed: 12/04/2022] Open
Abstract
With the aging population and the increasing incidence of basic illnesses such as hypertension and diabetes (DM), the incidence of atrial fibrillation (AF) has increased significantly. AF is the most common arrhythmia in clinical practice, which can cause heart failure (HF) and ischemic stroke (IS), increasing disability and mortality. Current studies point out that myocardial fibrosis (MF) is one of the most critical substrates for the occurrence and maintenance of AF. Although myocardial biopsy is the gold standard for evaluating MF, it is rarely used in clinical practice because it is an invasive procedure. In addition, serological indicators and imaging methods have also been used to evaluate MF. Nevertheless, the accuracy of serological markers in evaluating MF is controversial. This review focuses on the pathogenesis of MF, serological evaluation, imaging evaluation, and anti-fibrosis treatment to discuss the existing problems and provide new ideas for MF and AF evaluation and treatment.
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Affiliation(s)
- Guangling Li
- Department of Cardiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Jing Yang
- Department of Pathology, Gansu Provincial Hospital, Lanzhou, China
| | - Demei Zhang
- Department of Cardiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Xiaomei Wang
- Department of Cardiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Jingjing Han
- Department of Cardiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Xueya Guo
- Department of Cardiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- *Correspondence: Xueya Guo,
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37
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Abstract
Cardiac arrhythmias are a significant cause of morbidity and mortality worldwide, accounting for 10% to 15% of all deaths. Although most arrhythmias are due to acquired heart disease, inherited channelopathies and cardiomyopathies disproportionately affect children and young adults. Arrhythmogenesis is complex, involving anatomic structure, ion channels and regulatory proteins, and the interplay between cells in the conduction system, cardiomyocytes, fibroblasts, and the immune system. Animal models of arrhythmia are powerful tools for studying not only molecular and cellular mechanism of arrhythmogenesis but also more complex mechanisms at the whole heart level, and for testing therapeutic interventions. This review summarizes basic and clinical arrhythmia mechanisms followed by an in-depth review of published animal models of genetic and acquired arrhythmia disorders.
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Affiliation(s)
- Daniel J Blackwell
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Jeffrey Schmeckpeper
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Bjorn C Knollmann
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
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Guo F, Tang C, Huang B, Gu L, Zhou J, Mo Z, Liu C, Liu Y. LncRNA H19 Drives Proliferation of Cardiac Fibroblasts and Collagen Production via Suppression of the miR-29a-3p/miR-29b-3p-VEGFA/TGF-β Axis. Mol Cells 2022; 45:122-133. [PMID: 34887365 PMCID: PMC8926865 DOI: 10.14348/molcells.2021.0066] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 11/27/2022] Open
Abstract
The aim of this study was to investigating whether lncRNA H19 promotes myocardial fibrosis by suppressing the miR-29a-3p/miR-29b-3p-VEGFA/TGF-β axis. Patients with atrial fibrillation (AF) and healthy volunteers were included in the study, and their biochemical parameters were collected. In addition, pcDNA3.1-H19, si-H19, and miR-29a/b-3p mimic/inhibitor were transfected into cardiac fibroblasts (CFs), and proliferation of CFs was detected by MTT assay. Expression of H19 and miR-29a/b-3p were detected using real-time quantitative polymerase chain reaction, and expression of α-smooth muscle actin (α-SMA), collagen I, collagen II, matrix metalloproteinase-2 (MMP-2), and elastin were measured by western blot analysis. The dual luciferase reporter gene assay was carried out to detect the sponging relationship between H19 and miR-29a/b-3p in CFs. Compared with healthy volunteers, the level of plasma H19 was significantly elevated in patients with AF, while miR-29a-3p and miR-29b-3p were markedly depressed (P < 0.05). Serum expression of lncRNA H19 was negatively correlated with the expression of miR-29a-3p and miR-29b-3p among patients with AF (rs = -0.337, rs = -0.236). Moreover, up-regulation of H19 expression and down-regulation of miR-29a/b-3p expression facilitated proliferation and synthesis of extracellular matrix (ECM)-related proteins. SB431542 and si-VEGFA are able to reverse the promotion of miR-29a/b-3p on proliferation of CFs and ECM-related protein synthesis. The findings of the present study suggest that H19 promoted CF proliferation and collagen synthesis by suppressing the miR-29a-3p/miR-29b-3p-VEGFA/TGF-β axis, and provide support for a potential new direction for the treatment of AF.
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Affiliation(s)
- Feng Guo
- Department of Cardiology, Shanghai Electric Power Hospital, Shanghai 200050, China
| | - Chengchun Tang
- Department of Cardiology, Zhongda Hospital Southeast University, Nanjing 210009, China
| | - Bo Huang
- Department of Cardiology, Shanghai Electric Power Hospital, Shanghai 200050, China
| | - Lifei Gu
- Department of Cardiology, Shanghai Electric Power Hospital, Shanghai 200050, China
| | - Jun Zhou
- Department of Cardiology, Shanghai Electric Power Hospital, Shanghai 200050, China
| | - Zongyang Mo
- Department of Cardiology, Shanghai Electric Power Hospital, Shanghai 200050, China
| | - Chang Liu
- Department of Cardiology, Shanghai Electric Power Hospital, Shanghai 200050, China
| | - Yuqing Liu
- Department of Emergency, Naval Characteristic Medical Center Affiliated to Shanghai, Naval Medical University, Shanghai 200433, China
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Ionescu RF, Enache RM, Cretoiu SM, Cretoiu D. The Interplay Between Gut Microbiota and miRNAs in Cardiovascular Diseases. Front Cardiovasc Med 2022; 9:856901. [PMID: 35369298 PMCID: PMC8965857 DOI: 10.3389/fcvm.2022.856901] [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: 01/17/2022] [Accepted: 02/16/2022] [Indexed: 11/16/2022] Open
Abstract
The human microbiota contains microorganisms found on the skin, mucosal surfaces and in other tissues. The major component, the gut microbiota, can be influenced by diet, genetics, and environmental factors. Any change in its composition results in pathophysiological changes that can further influence the evolution of different conditions, including cardiovascular diseases (CVDs). The microbiome is a complex ecosystem and can be considered the metagenome of the microbiota. MicroRNAs (miRNAs) are speculated to interact with the intestinal microbiota for modulating gene expressions of the host. miRNAs represent a category of small non-coding RNAs, consisting of approximately 22 nucleotides, which can regulate gene expression at post-transcriptional level, by influencing the degradation of mRNA and modifying protein amounts. miRNAs display a multitude of roles, being able to influence the pathogenesis and progression of various diseases. Circulating miRNAs are stable against degradation, due to their enclosure into extracellular vesicles (EVs). This review aims to assess the current knowledge of the possible interactions between gut microbiota, miRNAs, and CVDs. As more scientific research is conducted, it can be speculated that personalized patient care in the future may include the management of gut microbiota composition and the targeted treatment against certain expression of miRNAs.
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Affiliation(s)
| | - Robert Mihai Enache
- Department of Radiology and Medical Imaging, Fundeni Clinical Institute, Bucharest, Romania
| | - Sanda Maria Cretoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- *Correspondence: Sanda Maria Cretoiu ;
| | - Dragos Cretoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania
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Li D, Nie J, Han Y, Ni L. Epigenetic Mechanism and Therapeutic Implications of Atrial Fibrillation. Front Cardiovasc Med 2022; 8:763824. [PMID: 35127848 PMCID: PMC8815458 DOI: 10.3389/fcvm.2021.763824] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/08/2021] [Indexed: 12/28/2022] Open
Abstract
Atrial fibrillation (AF) is the most common arrhythmia attacking 1. 5–2.0% of general population worldwide. It has a significant impact on morbidity and mortality globally and its prevalence increases exponentially with age. Therapies like catheter ablation or conventional antiarrhythmic drugs have not provided effective solution to the recurrence for AF over the past decades. Over 100 genetic loci have been discovered to be associated with AF by Genome-wide association studies (GWAS) but none has led to a therapy. Recently potential involvement of epigenetics (DNA methylation, histone modification, and non-coding RNAs) in the initiation and maintenance of AF has partly emerged as proof-of-concept in the mechanism and management of AF. Here we reviewed the epigenetic features involved in AF pathophysiology and provided an update of their implications in AF therapy.
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Impact Of Smoking On Long Term Atrial Fibrillation Ablation Success. JOURNAL OF BASIC AND CLINICAL HEALTH SCIENCES 2022. [DOI: 10.30621/jbachs.1003047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Siwaponanan P, Kaewkumdee P, Phromawan W, Udompunturak S, Chomanee N, Udol K, Pattanapanyasat K, Krittayaphong R. Increased expression of six-large extracellular vesicle-derived miRNAs signature for nonvalvular atrial fibrillation. J Transl Med 2022; 20:4. [PMID: 34980172 PMCID: PMC8722074 DOI: 10.1186/s12967-021-03213-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/19/2021] [Indexed: 12/17/2022] Open
Abstract
Backgrounds Non-valvular atrial fibrillation (AF) is the most common type of cardiac arrhythmia. AF is caused by electrophysiological abnormalities and alteration of atrial tissues, which leads to the generation of abnormal electrical impulses. Extracellular vesicles (EVs) are membrane-bound vesicles released by all cell types. Large EVs (lEVs) are secreted by the outward budding of the plasma membrane during cell activation or cell stress. lEVs are thought to act as vehicles for miRNAs to modulate cardiovascular function, and to be involved in the pathophysiology of cardiovascular diseases (CVDs), including AF. This study identified lEV-miRNAs that were differentially expressed between AF patients and non-AF controls. Methods lEVs were isolated by differential centrifugation and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), flow cytometry and Western blot analysis. For the discovery phase, 12 AF patients and 12 non-AF controls were enrolled to determine lEV-miRNA profile using quantitative reverse transcription polymerase chain reaction array. The candidate miRNAs were confirmed their expression in a validation cohort using droplet digital PCR (30 AF, 30 controls). Bioinformatics analysis was used to predict their target genes and functional pathways. Results TEM, NTA and flow cytometry demonstrated that lEVs presented as cup shape vesicles with a size ranging from 100 to 1000 nm. AF patients had significantly higher levels of lEVs at the size of 101–200 nm than non-AF controls. Western blot analysis was used to confirm EV markers and showed the high level of cardiomyocyte expression (Caveolin-3) in lEVs from AF patients. Nineteen miRNAs were significantly higher (> twofold, p < 0.05) in AF patients compared to non-AF controls. Six highly expressed miRNAs (miR-106b-3p, miR-590-5p, miR-339-3p, miR-378-3p, miR-328-3p, and miR-532-3p) were selected to confirm their expression. Logistic regression analysis showed that increases in the levels of these 6 highly expressed miRNAs associated with AF. The possible functional roles of these lEV-miRNAs may involve in arrhythmogenesis, cell apoptosis, cell proliferation, oxygen hemostasis, and structural remodeling in AF. Conclusion Increased expression of six lEV-miRNAs reflects the pathophysiology of AF that may provide fundamental knowledge to develop the novel biomarkers for diagnosis or monitoring the patients with the high risk of AF. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-03213-6.
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Affiliation(s)
- Panjaree Siwaponanan
- Siriraj Center of Research Excellence for Microparticle and Exosome in Diseases, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pontawee Kaewkumdee
- Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wilasinee Phromawan
- Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Suthipol Udompunturak
- Division of Clinical Epidemiology, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nusara Chomanee
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kamol Udol
- Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kovit Pattanapanyasat
- Siriraj Center of Research Excellence for Microparticle and Exosome in Diseases, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rungroj Krittayaphong
- Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Xiao QA, He Q, Zeng J, Xia X. GDF-15, a future therapeutic target of glucolipid metabolic disorders and cardiovascular disease. Biomed Pharmacother 2021; 146:112582. [PMID: 34959119 DOI: 10.1016/j.biopha.2021.112582] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/19/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022] Open
Abstract
Growth and differentiation factor 15 (GDF-15) was discovered as a member of the transforming growth factor β (TGF-β) superfamily and the serum level of GDF-15 was significantly correlated with glucolipid metabolic disorders (GLMD) and cardiovascular diseases. In 2017, a novel identified receptor of GDF-15-glial-derived neurotrophic factor receptor alpha-like (GFRAL) was found to regulate energy homeostasis (such as obesity, diabetes and non-alcoholic fatty liver disease (NAFLD)). The function of GDF-15/GFRAL in suppressing appetite, enhancing glucose/lipid metabolism and vascular remodeling has been gradually revealed. These effects make it a potential therapeutic target for GLMD and vascular diseases. In this narrative review, we included and reviewed 121 articles by screening 524 articles from literature database. We primarily focused on the function of GDF-15 and its role in GLMD/cardiovascular diseases and discuss its potential clinical application.
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Affiliation(s)
- Qing-Ao Xiao
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang 443000, China; Third-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China
| | - Qian He
- Department of Geriatrics, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang 443000, China
| | - Jun Zeng
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang 443000, China.
| | - Xuan Xia
- Third-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China; Department of Physiology and Pathophysiology, Medical College, China Three Gorges University, Yichang 443002, China.
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Chen C, Chen Q, Cheng K, Zou T, Pang Y, Ling Y, Xu Y, Zhu W. Exosomes and Exosomal Non-coding RNAs Are Novel Promises for the Mechanism-Based Diagnosis and Treatments of Atrial Fibrillation. Front Cardiovasc Med 2021; 8:782451. [PMID: 34926627 PMCID: PMC8671698 DOI: 10.3389/fcvm.2021.782451] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 10/26/2021] [Indexed: 12/15/2022] Open
Abstract
Atrial fibrillation (AF) is the most common arrhythmia worldwide and has a significant impact on human health and substantial costs. Currently, there is a lack of accurate biomarkers for the diagnosis and prognosis of AF. Moreover, the long-term efficacy of the catheter ablation in the AF is unsatisfactory. Therefore, it is necessary to explore new biomarkers and treatment strategies for the mechanism-based AF. Exosomes are nano-sized biovesicles released by nearly all types of cells. Since the AF would be linked to the changes of the atrial cells and their microenvironment, and the AF would strictly influence the exosomal non-coding RNAs (exo-ncRNAs) expression, which makes them as attractive diagnostic and prognostic biomarkers for the AF. Simultaneously, the exo-ncRNAs have been found to play an important role in the mechanisms of the AF and have potential therapeutic prospects. Although the role of the exo-ncRNAs in the AF is being actively investigated, the evidence is still limited. Furthermore, there is a lack of consensus regarding the most appropriate approach for exosome isolation and characterization. In this article, we reviewed the new methodologies available for exosomes biogenesis, isolation, and characterization, and then discussed the mechanism of the AF and various levels and types of exosomes relevant to the AF, with the special emphasis on the exo-ncRNAs in the diagnosis, prognosis, and treatment of the mechanism-based AF.
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Affiliation(s)
| | | | | | | | | | | | | | - Wenqing Zhu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
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Zhang L, Wang X, Huang C. A narrative review of non-coding RNAs in atrial fibrillation: potential therapeutic targets and molecular mechanisms. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1486. [PMID: 34734038 PMCID: PMC8506732 DOI: 10.21037/atm-21-4483] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/16/2021] [Indexed: 11/11/2022]
Abstract
Objective This review summarizes the advances in the study of ncRNAs and atrial remodeling mechanisms to explore potential therapeutic targets and strategies for AF. Background Atrial fibrillation (AF) is one of the most common arrhythmias, and its morbidity and mortality rates are gradually increasing. Non-coding ribonucleic acid RNAs (ncRNAs) are transcribed from the genome and do not have the ability to be translated into proteins. A growing body of evidence has shown ncRNAs are extensively involved in the pathophysiological processes underlying AF. However, the precise molecular mechanisms of these associations have not been fully elucidated. Atrial remodeling plays a key role in the occurrence and development of AF, and includes electrical remodeling, structural remodeling, and autonomic nerve remodeling. Research has shown that ncRNA expression is altered in the plasma and tissues of AF patients that mediate cardiac excitation and arrhythmia, and is closely related to atrial remodeling. Methods Literatures about ncRNAs and atrial fibrillation were extensively reviewed to discuss and analyze. Conclusions The biology of ncRNAs represents a relatively new field of research and is still in an emerging stage. Recent studies have laid a foundation for understanding the molecular mechanisms of AF, future studies aimed at identifying how ncRNAs act on atrial fibrillation to provide potentially promising therapeutic targets for the treatment of atrial fibrillation.
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Affiliation(s)
- Lan Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Xi Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Congxin Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
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Kuzmin VS, Ivanova AD, Filatova TS, Pustovit KB, Kobylina AA, Atkinson AJ, Petkova M, Voronkov YI, Abramochkin DV, Dobrzynski H. Micro-RNA 133a-3p induces repolarization abnormalities in atrial myocardium and modulates ventricular electrophysiology affecting I Ca,L and Ito currents. Eur J Pharmacol 2021; 908:174369. [PMID: 34310913 DOI: 10.1016/j.ejphar.2021.174369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 07/16/2021] [Accepted: 07/21/2021] [Indexed: 01/04/2023]
Abstract
Mir-133a-3p is the most abundant myocardial microRNA. The impact of mir-133a-3p on cardiac electrophysiology is poorly explored. In this study, we investigated the effects of mir-133a-3p on the main ionic currents critical for action potential (AP) generation and electrical activity of the heart. We used conventional ECG, sharp microelectrodes and patch-clamp to clarify a role of mir-133a-3p in normal cardiac electrophysiology in rats after in vivo and in vitro transfection. Mir-133a-3p caused no changes to pacemaker APs and automaticity in the sinoatrial node. No significant changes in heart rate (HR) were observed in vivo; however, miR transfection facilitated HR increase in response to β-adrenergic stimulation. Mir-133a-3p induced repolarization abnormalities in the atrial working myocardium and the L-type calcium current (ICa,L) was significantly increased. The main repolarization currents, including the transient outward (Ito), ultra-rapid (IK,ur), and inward rectifier (IK1) remained unaffected in atrial cardiomyocytes. Mir-133a-3p affected both ICa,L and Ito in ventricular cardiomyocytes. Systemic administration of mir-133a-3p induced QT-interval prolongation. Bioinformatic analysis revealed protein phosphatase 2 (PPP2CA/B) and Kcnd3 (encoding Kv4.3 channels generating Ito) as the main miR-133a-3p targets in the heart. No changes in mRNA expression of Cacna1c (encoding Cav1.2 channels generating ICa,L) and Kcnd3 were seen in mir-133a-3p treated rats. However, the expression of Ppp2cA, encoding PPP2CA, and Kcnip2 encoding KChIP2, a Kv4.3 regulatory protein, were significantly decreased. The accumulation of mir-133a-3p in cardiac myocytes causes chamber-specific electrophysiological changes. The suppression of PPP2CA, involved in adrenergic signal transduction, and Kchip2 may indirectly mediate mir-133a-3p-induced augmentation of ICa,L and attenuation of Ito.
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Affiliation(s)
- Vladislav S Kuzmin
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia; Department of Physiology, Pirogov Russian National Research Medical University, Moscow, Russia; Laboratory of Cardiac Electrophysiology, National Medical Research Cardiological Complex (NMRCC), Institute of Experimental Cardiology, Moscow, Russia.
| | - Alexandra D Ivanova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia
| | - Tatiana S Filatova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia; Department of Physiology, Pirogov Russian National Research Medical University, Moscow, Russia; Laboratory of Cardiac Electrophysiology, National Medical Research Cardiological Complex (NMRCC), Institute of Experimental Cardiology, Moscow, Russia
| | - Ksenia B Pustovit
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia
| | - Anastasia A Kobylina
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia
| | - Andrew J Atkinson
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Maria Petkova
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Yurij I Voronkov
- State Research Center of the Russian Federation, Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, Russia
| | - Denis V Abramochkin
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia; Department of Physiology, Pirogov Russian National Research Medical University, Moscow, Russia; Laboratory of Cardiac Electrophysiology, National Medical Research Cardiological Complex (NMRCC), Institute of Experimental Cardiology, Moscow, Russia
| | - Halina Dobrzynski
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Heart Embryology and Anatomy Research Team, Department of Anatomy, Jagiellonian University Medical College, Cracow, Poland
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A Review of the Molecular Mechanisms Underlying Cardiac Fibrosis and Atrial Fibrillation. J Clin Med 2021; 10:jcm10194430. [PMID: 34640448 PMCID: PMC8509789 DOI: 10.3390/jcm10194430] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/22/2021] [Accepted: 09/24/2021] [Indexed: 01/03/2023] Open
Abstract
The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the AT2R receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.
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Zhang S, Wang N, Ma Q, Fan F, Ma X. LncRNA TUG1 acts as a competing endogenous RNA to mediate CTGF expression by sponging miR-133b in myocardial fibrosis after myocardial infarction. Cell Biol Int 2021; 45:2534-2543. [PMID: 34553456 DOI: 10.1002/cbin.11707] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 08/03/2021] [Accepted: 09/04/2021] [Indexed: 12/31/2022]
Abstract
Myocardial fibrosis (MF) is one of the basic causes of many cardiovascular diseases. Noncoding RNAs (ncRNAs), including microRNA (miRNA) and long noncoding RNA (lncRNA), have been reported to play an indispensable role in MF. The current work is focused on investigating the biological role of lncRNA taurine upregulation gene 1 (TUG1) in activating cardiac myofibroblasts as well as the underlying mechanism. The outcome revealed that after myocardial infarction TUG1 expression increased and miR-133b expression decreased in the rat model of MF. The expression level of TUG1 increased following AngII treatment in cardiac myofibroblast. TUG1 knockdown inhibited the Ang-II induced cardiac myofibroblast activation and TUG1 overexpression increased proliferation and collagen generation of cardiac myofibroblasts. Bioinformatic prediction programs predicted that TUG1 had MRE directly combined with miR-133b seed sequence, luciferase activity, and RIP experiments indicated that TUG1, acted as a sponger and interacted with miR-133b in cardiac myofibroblasts. Furthermore, a target of miR-133b was CTGF and CTGF knockdown counteracted the promotion of MF by miR-133b knockdown. Collectively, our study suggested that TUG1 mediates CTGF expression by sponging miR-133b in the activation of cardiac myofibroblasts. The current work reveals a unique role of the TUG1/miR-133b/CTGF axis in MF, thus suggesting its immense therapeutic potential in the treatment of cardiac diseases.
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Affiliation(s)
- Songlin Zhang
- Department of Structural Heart Disease, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ningbo Wang
- Department of Structural Heart Disease, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Cardiology, Sunsimiao Hospital Beijing University of Chinese Medicine, Hancheng, China
| | - Qingyan Ma
- Department of Psychiatry, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fenling Fan
- Department of Structural Heart Disease, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiancang Ma
- Department of Psychiatry, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Chiti E, Di Paolo M, Turillazzi E, Rocchi A. MicroRNAs in Hypertrophic, Arrhythmogenic and Dilated Cardiomyopathy. Diagnostics (Basel) 2021; 11:diagnostics11091720. [PMID: 34574061 PMCID: PMC8469137 DOI: 10.3390/diagnostics11091720] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/07/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of non-coding RNAs of about 20 nucleotides in length, involved in the regulation of many biochemical pathways in the human body. The level of miRNAs in tissues and circulation can be deregulated because of altered pathophysiological mechanisms; thus, they can be employed as biomarkers for different pathological conditions, such as cardiac diseases. This review summarizes published findings of these molecular biomarkers in the three most common structural cardiomyopathies: human dilated, arrhythmogenic and hypertrophic cardiomyopathy.
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Affiliation(s)
- Enrica Chiti
- Institute of Life Science, Scuola Superiore Sant’Anna, 56124 Pisa, Italy;
| | - Marco Di Paolo
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
| | - Emanuela Turillazzi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
| | - Anna Rocchi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
- Correspondence:
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Jost N, Christ T, Magyar J. New Strategies for the Treatment of Atrial Fibrillation. Pharmaceuticals (Basel) 2021; 14:ph14090926. [PMID: 34577626 PMCID: PMC8466466 DOI: 10.3390/ph14090926] [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] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 12/19/2022] Open
Abstract
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the clinical practice. It significantly contributes to the morbidity and mortality of the elderly population. Over the past 25-30 years intense effort in basic research has advanced the understanding of the relationship between the pathophysiology of AF and atrial remodelling. Nowadays it is clear that the various forms of atrial remodelling (electrical, contractile and structural) play crucial role in initiating and maintaining the persistent and permanent types of AF. Unlike in ventricular fibrillation, in AF rapid ectopic firing originating from pulmonary veins and re-entry mechanism may induce and maintain (due to atrial remodelling) this complex cardiac arrhythmia. The present review presents and discusses in detail the latest knowledge on the role of remodelling in AF. Special attention is paid to novel concepts and pharmacological targets presumably relevant to the drug treatment of atrial fibrillation.
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Affiliation(s)
- Norbert Jost
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, 6725 Szeged, Hungary
- Department of Pharmacology and Pharmacotherapy, Interdisciplinary Excellence Centre, University of Szeged, 6725 Szeged, Hungary
- ELKH-SZTE Research Group for Cardiovascular Pharmacology, Eötvös Loránd Research Network, 6725 Szeged, Hungary
- Correspondence:
| | - Torsten Christ
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
- DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - János Magyar
- Department of Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
- Department of Sport Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
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