Cited by 16Cardiac electrophysiology and arrhythmiasAtrial Fibrillation Management and OutcomesCardiac Arrhythmias and Treatments

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions

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Klapper-Goldstein, Hadar, Murninkas, Michael, Gillis, Roni, Mulla, Wesam, Levanon, Eran, Elyagon, Sigal, Schuster, Ronen, Danan, Dor +2 more·2020·Scientific Reports

Abstract

Atrial fibrillation (AF) is a progressive arrhythmia with underlying mechanisms that are not fully elucidated, partially due to lack of reliable and affordable animal models. Here, we introduce a system for long-term assessment of AF susceptibility (substrate) in ambulatory rats implanted with miniature electrodes on the atrium. Rats were subjected to excessive aldosterone (Aldo) or solvent only (Sham). An additional group was exposed to myocardial infarction (MI). AF substrate was tested two- and four-weeks post implantation and was also compared with implanted rats early post-implantation (Base). Aldo and MI increased the AF substrate and atrial fibrosis. In the MI group only, AF duration was correlated with the level of atrial fibrosis and was inversely correlated with systolic function. Unexpectedly, Shams also developed progressive AF substrate relative to Base individuals. Further studies indicated that serum inflammatory markers (IL-6, TNF-alpha) were not elevated in the shams. In addition, we excluded anxiety\depression due to social-isolation as an AF promoting factor. Finally, enhanced biocompatibility of the atrial electrode did not inhibit the gradual development of AF substrate over a testing period of up to 8 weeks. Overall, we successfully validated the first system for long-term AF substrate testing in ambulatory rats.

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  1. [2]Chugh SS Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study Circulation 2014 129 837 847 10.1161/circulationaha.113.005119 24345399 PMC4151302 · DOI · Paper page
  2. [3]Haissaguerre M Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins N Engl J Med 1998 339 659 666 10.1056/NEJM199809033391003 9725923 · DOI
  3. [4]Brundel BJ Henning RH Kampinga HH Van Gelder IC Crijns HJ Molecular mechanisms of remodeling in human atrial fibrillation Cardiovasc Res 2002 54 315 324 10.1016/S0008-6363(02)00222-5 12062337 · DOI
  4. [5]Wakili R Voigt N Kaab S Dobrev D Nattel S Recent advances in the molecular pathophysiology of atrial fibrillation J Clin Invest 2011 121 2955 2968 10.1172/JCI46315 21804195 PMC3148739 · DOI
  5. [6]Heijman J The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis Cardiovasc Res 2016 109 467 479 10.1093/cvr/cvv275 26705366 PMC4777910 · DOI
  6. [7]Lau DH Nattel S Kalman JM Sanders P Modifiable Risk Factors and Atrial Fibrillation Circulation 2017 136 583 596 10.1161/circulationaha.116.023163 28784826 · DOI
  7. [8]Dzeshka MS Lip GY Snezhitskiy V Shantsila E Cardiac Fibrosis in Patients With Atrial Fibrillation: Mechanisms and Clinical Implications J Am Coll Cardiol 2015 66 943 959 10.1016/j.jacc.2015.06.1313 26293766 · DOI
  8. [9]Dobrev D Carlsson L Nattel S Novel molecular targets for atrial fibrillation therapy Nat Rev Drug Discov 2012 11 275 291 10.1038/nrd3682 22460122 · DOI
  9. [10]Wijesurendra RS Lone Atrial Fibrillation Is Associated With Impaired Left Ventricular Energetics That Persists Despite Successful Catheter Ablation Circulation 2016 134 1068 1081 10.1161/circulationaha.116.022931 27630135 PMC5054971 · DOI
  10. [11]Nattel S Shiroshita-Takeshita A Brundel BJ Rivard L Mechanisms of atrial fibrillation: lessons from animal models Prog Cardiovasc Dis 2005 48 9 28 10.1016/j.pcad.2005.06.002 16194689 · DOI
  11. [12]Choisy SCM Arberry LA Hancox JC James AF Increased Susceptibility to Atrial Tachyarrhythmia in Spontaneously Hypertensive Rat Hearts Hypertension 2007 49 498 505 10.1161/01.HYP.0000257123.95372.ab 17242301 · DOI
  12. [13]Kirchhof P PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression Circ Cardiovasc Genet 2011 4 123 133 10.1161/CIRCGENETICS.110.958058 21282332 · DOI
  13. [14]Shan J Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia Circ Res 2012 111 708 717 10.1161/CIRCRESAHA.112.273342 22828895 PMC3734386 · DOI
  14. [15]Riley G Syeda F Kirchhof P Fabritz L An introduction to murine models of atrial fibrillation Front Physiol 2012 3 296 22934047 PMC3429067
  15. [16]Skibsbye L Inhibition of Small Conductance Calcium-Activated Potassium (SK) Channels Prevents Arrhythmias in Rat Atria During beta-Adrenergic and Muscarinic Receptor Activation Front Physiol 2018 9 510 10.3389/fphys.2018.00510 29922167 PMC5996028 · DOI
  16. [17]Cheng C Mutation in NPPA causes atrial fibrillation by activating inflammation and cardiac fibrosis in a knock-in rat model FASEB J, fj201802455RRR 2019 10.1096/fj.201802455RRR 31034774 · DOI
  17. [18]Geng L SNX17 (Sorting Nexin 17) Mediates Atrial Fibrillation Onset Through Endocytic Trafficking of the Kv1.5 (Potassium Voltage-Gated Channel Subfamily A Member 5) Channel Circ Arrhythm Electrophysiol 2019 12 e007097 10.1161/circep.118.007097 30939909 · DOI
  18. [19]Hulsmans M A Miniaturized, Programmable Pacemaker for Long-Term Studies in the Mouse Circ Res 2018 123 1208 1219 10.1161/circresaha.118.313429 30571465 PMC6309285 · DOI
  19. [20]Etzion Y New insights into the atrial electrophysiology of rodents using a novel modality: the miniature-bipolar hook electrode Am J Physiol Heart Circ Physiol 2008 295 H1460 1469 10.1152/ajpheart.00414.2008 18660446 · DOI
  20. [21]Mor M INO-8875, a Highly-Selective A1 Adenosine Receptor Agonist: Evaluation of Chronotropic, Dromotropic and Hemodynamic Effects in Rats J Pharmacol Exp Ther 2012 10.1124/jpet.112.200873 23055540 · DOI
  21. [22]Mor M Speckle-tracking echocardiography elucidates the effect of pacing site on left ventricular synchronization in the normal and infarcted rat myocardium PLoS One 2014 9 e99191 10.1371/journal.pone.0099191 24915191 PMC4051662 · DOI
  22. [23]Mulla W Prominent differences in left ventricular performance and myocardial properties between right ventricular and left ventricular-based pacing modes in rats Sci Rep 2017 7 5931 10.1038/s41598-017-06197-w 28725029 PMC5517524 · DOI
  23. [24]Mulla W Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length Front Physiol 2018 9 897 10.3389/fphys.2018.00897 30050462 PMC6050393 · DOI
  24. [25]Mulla W Rapid Atrial Pacing Promotes Atrial Fibrillation Substrate in Unanesthetized Instrumented Rats Front Physiol 2019 10 1218 10.3389/fphys.2019.01218 31616316 PMC6763969 · DOI
  25. [26]Reil JC Aldosterone promotes atrial fibrillation Eur Heart J 2012 33 2098 2108 10.1093/eurheartj/ehr266 21816854 · DOI
  26. [27]Miyauchi Y Altered Atrial Electrical Restitution and Heterogeneous Sympathetic Hyperinnervation in Hearts With Chronic Left Ventricular Myocardial Infarction: Implications for Atrial Fibrillation Circulation 2003 108 360 366 10.1161/01.CIR.0000080327.32573.7C 12835207 · DOI
  27. [28]Bejerano T Etzion S Elyagon S Etzion Y Cohen S Nanoparticle Delivery of miRNA-21 Mimic to Cardiac Macrophages Improves Myocardial Remodeling after Myocardial Infarction Nano letters 2018 18 5885 5891 10.1021/acs.nanolett.8b02578 30141949 · DOI
  28. [29]Lammers C Spironolactone prevents aldosterone induced increased duration of atrial fibrillation in rat Cell Physiol Biochem 2012 29 833 840 10.1159/000178483 22613983 · DOI
  29. [30]Cardin S Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure Circ Arrhythm Electrophysiol 2012 5 1027 1035 10.1161/circep.112.973214 22923342 · DOI
  30. [31]Dai, H. et al. Atrial Fibrillation Promotion in a Rat Model of Rheumatoid Arthritis. J Am Heart Assoc6, 10.1161/jaha.117.007320 (2017). PMC5779041 29269354 · DOI
  31. [32]Yao C Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation Circulation 2018 138 2227 2242 10.1161/circulationaha.118.035202 29802206 PMC6252285 · DOI
  32. [33]Rygula R Anhedonia and motivational deficits in rats: impact of chronic social stress Behavioural brain research 2005 162 127 134 10.1016/j.bbr.2005.03.009 15922073 · DOI · Paper page
  33. [35]Shah Idil A Donaldson N The use of tungsten as a chronically implanted material Journal of neural engineering 2018 15 021006 10.1088/1741-2552/aaa502 29300000 · DOI
  34. [36]Everett TH Olgin JE Atrial fibrosis and the mechanisms of atrial fibrillation Heart Rhythm 2007 4 S24 27 10.1016/j.hrthm.2006.12.040 17336879 PMC1850572 · DOI
  35. [37]Budzikowski AS Aldosterone pathway in atrial fibrillation Cardiology 2011 118 238 10.1159/000329505 21734374 · DOI
  36. [38]Hung CS Aldosterone Induces Tissue Inhibitor of Metalloproteinases-1 Expression and Further Contributes to Collagen Accumulation: From Clinical to Bench Studies Hypertension 2016 67 1309 1320 10.1161/hypertensionaha.115.06768 27113051 · DOI
  37. [39]Lendeckel U Dobrev D Goette A Aldosterone-receptor antagonism as a potential therapeutic option for atrial fibrillation Br J Pharmacol 2010 159 1581 1583 10.1111/j.1476-5381.2010.00675.x 20388187 PMC2925481 · DOI
  38. [40]Zhao J Effects of spironolactone on atrial structural remodelling in a canine model of atrial fibrillation produced by prolonged atrial pacing Br J Pharmacol 2010 159 1584 1594 10.1111/j.1476-5381.2009.00551.x 20082611 PMC2925482 · DOI
  39. [41]Ito Y Effect of eplerenone on maintenance of sinus rhythm after catheter ablation in patients with long-standing persistent atrial fibrillation Am J Cardiol 2013 111 1012 1018 10.1016/j.amjcard.2012.12.020 23340033 · DOI
  40. [42]Kritis AA Gouta CP Liaretidou EI Kallaras KI Latest aspects of aldosterone actions on the heart muscle J Physiol Pharmacol 2016 67 21 30 27010892
  41. [43]Jalife J Novel upstream approaches to prevent atrial fibrillation perpetuation Cardiol Clin 2014 32 637 650 10.1016/j.ccl.2014.07.004 25443242 · DOI
  42. [44]Mummidi S Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo J Mol Cell Cardiol 2016 98 95 102 10.1016/j.yjmcc.2016.07.006 27423273 · DOI
  43. [45]Whaley-Connell A Johnson MS Sowers JR Aldosterone: role in the cardiometabolic syndrome and resistant hypertension Prog Cardiovasc Dis 2010 52 401 409 10.1016/j.pcad.2009.12.004 20226958 PMC2841057 · DOI
  44. [46]Lakin R Inhibition of soluble TNFalpha prevents adverse atrial remodeling and atrial arrhythmia susceptibility induced in mice by endurance exercise J Mol Cell Cardiol 2019 129 165 173 10.1016/j.yjmcc.2019.01.012 30796945 · DOI
  45. [47]Dobrev D Aguilar M Heijman J Guichard JB Nattel S Postoperative atrial fibrillation: mechanisms, manifestations and management Nat Rev Cardiol 2019 16 417 436 10.1038/s41569-019-0166-5 30792496 · DOI
  46. [48]Fenger-Gron M Depression, antidepressants, and the risk of non-valvular atrial fibrillation: A nationwide Danish matched cohort study European journal of preventive cardiology 2019 26 187 195 10.1177/2047487318811184 30452291 · DOI
  47. [49]Hatch AM Isolation syndrome in the rat Toxicol Appl Pharmacol 1965 7 737 745 10.1016/0041-008X(65)90132-8 4286670 · DOI
  48. [50]Thanigaimani S Progression and reversibility of stretch induced atrial remodeling: Characterization and clinical implications Prog Biophys Mol Biol 2017 130 376 386 10.1016/j.pbiomolbio.2017.07.010 28734850 · DOI

Cited by

Sorted by citations

Authors
Klapper-Goldstein, H., Murninkas, M., Gillis, R., Mulla, W., Levanon, E., Elyagon, S., Schuster, R., Danan, D., Cohen, H., & Etzion, Y.
Affiliations
Ben-Gurion University of the Negev (IL)
Corresponding author
Etzion, Yoram
Venue
Scientific Reports
Published
2020-01-17
Volume
10
Issue
1
Pages
553-553
ISSN
2045-2322 (ISSN-L)
OpenAlex
W2998874206
Cited by
16
References
2
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 2
FWCI
2.01
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Israel Science Foundation (1174/14, 1233/19)
  • Israel Heart Society
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Arrhythmias and Treatments
Keywords
atrial fibrillation, atrial fibrillation substrate, aldosterone, myocardial infarction, atrial fibrosis, atrial systolic function, inflammatory markers, social isolation
MeSH terms
Aldosterone, Animals, Atrial Fibrillation, Disease Models, Animal, Electrodes, Implanted, Fibrosis, Male, Microelectrodes, Myocardial Infarction, Tumor Necrosis Factor-alpha, Interleukin-6, Rats, Sprague-Dawley, Rats

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