Skip to main content

Advertisement

SpringerLink
Log in

The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Atrial fibrillation (AF) is the most frequent arrhythmia in adults. The prevalence and incidence of AF is going to increase substantially over the next few decades. Because AF increases the risk of stroke, heart failure, dementia, and others, it severely impacts the quality of life, morbidity, and mortality. Although the pathogenesis of AF is multifaceted and complex, focal ectopic activity and reentry are considered as the fundamental proarrhythmic mechanisms underlying AF development. Over the past 2 decades, large amount of evidence points to the key role of intracellular Ca2+ dysregulation in both initiation and maintenance of AF. More recently, emerging evidence reveal that NLRP3 (NACHT, LRR, PYD domain-containing 3) inflammasome pathway contributes to the substrate of both triggered activity and reentry, ultimately promoting AF. In this article, we review the current state of knowledge on Ca2+ signaling and NLRP3 inflammasome activity in AF. We also discuss the potential crosstalk between these two quintessential contributors to AF promotion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2.
Fig. 3

Similar content being viewed by others

References

  1. Abe I, Teshima Y, Kondo H, Kaku H, Kira S, Ikebe Y, Saito S, Fukui A, Shinohara T, Yufu K, Nakagawa M, Hijiya N, Moriyama M, Shimada T, Miyamoto S, Takahashi N (2018) Association of fibrotic remodeling and cytokines/chemokines content in epicardial adipose tissue with atrial myocardial fibrosis in patients with atrial fibrillation. Heart Rhythm 15:1717–1727. https://doi.org/10.1016/j.hrthm.2018.06.025

    Article  PubMed  Google Scholar 

  2. Alsina KM, Hulsurkar M, Brandenburg S, Kownatzki-Danger D, Lenz C, Urlaub H, Abu-Taha I, Kamler M, Chiang DY, Lahiri SK, Reynolds JO, Quick AP, Scott L Jr, Word TA, Gelves MD, Heck AJR, Li N, Dobrev D, Lehnart SE, Wehrens XHT (2019) Loss of protein phosphatase 1 regulatory subunit PPP1R3A promotes atrial fibrillation. Circulation 140:681–693. https://doi.org/10.1161/CIRCULATIONAHA.119.039642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Andrade JG, Champagne J, Dubuc M, Deyell MW, Verma A, Macle L, Leong-Sit P, Novak P, Badra-Verdu M, Sapp J, Mangat I, Khoo C, Steinberg C, Bennett MT, Tang ASL, Khairy P, Investigators C-DS (2019) Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring: a randomized clinical trial. Circulation 140:1779–1788. https://doi.org/10.1161/CIRCULATIONAHA.119.042622

    Article  PubMed  Google Scholar 

  4. Antoniades C, Demosthenous M, Reilly S, Margaritis M, Zhang MH, Antonopoulos A, Marinou K, Nahar K, Jayaram R, Tousoulis D, Bakogiannis C, Sayeed R, Triantafyllou C, Koumallos N, Psarros C, Miliou A, Stefanadis C, Channon KM, Casadei B (2012) Myocardial redox state predicts in-hospital clinical outcome after cardiac surgery effects of short-term pre-operative statin treatment. J Am Coll Cardiol 59:60–70. https://doi.org/10.1016/j.jacc.2011.08.062

    Article  CAS  PubMed  Google Scholar 

  5. Babu GJ, Bhupathy P, Timofeyev V, Petrashevskaya NN, Reiser PJ, Chiamvimonvat N, Periasamy M (2007) Ablation of sarcolipin enhances sarcoplasmic reticulum calcium transport and atrial contractility. Proc Natl Acad Sci U S A 104:17867–17872. https://doi.org/10.1073/pnas.0707722104

    Article  PubMed  PubMed Central  Google Scholar 

  6. Batal O, Schoenhagen P, Shao M, Ayyad AE, Van Wagoner DR, Halliburton SS, Tchou PJ, Chung MK (2010) Left atrial epicardial adiposity and atrial fibrillation. Circ Arrhythm Electrophysiol 3:230–236. https://doi.org/10.1161/CIRCEP.110.957241

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E (2009) Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791. https://doi.org/10.4049/jimmunol.0901363

    Article  CAS  PubMed  Google Scholar 

  8. Beavers DL, Wang W, Ather S, Voigt N, Garbino A, Dixit SS, Landstrom AP, Li N, Wang Q, Olivotto I, Dobrev D, Ackerman MJ, Wehrens XHT (2013) Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization. J Am Coll Cardiol 62:2010–2019. https://doi.org/10.1016/j.jacc.2013.06.052

    Article  CAS  PubMed  Google Scholar 

  9. Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205. https://doi.org/10.1038/415198a

    Article  CAS  PubMed  Google Scholar 

  10. Bosch RF, Scherer CR, Rüb N, Wöhrl S, Steinmeyer K, Haase H, Busch AE, Seipel L, Kühlkamp V (2003) Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces ICa,Land Itoin rapid atrial pacing in rabbits. J Am Coll Cardiol 41:858–869. https://doi.org/10.1016/s0735-1097(02)02922-4

  11. Boyden PA, Dun W, Stuyvers BD (2015) What is a Ca2+ wave? Is it like an electrical wave? Arrhythmia Electrophysiol Rev 4:35–39. https://doi.org/10.15420/aer.2015.4.1.35

  12. Bracey NA, Beck PL, Muruve DA, Hirota SA, Guo J, Jabagi H, Wright JR Jr, MacDonald JA, Lees-Miller JP, Roach D, Semeniuk LM, Duff HJ (2013) The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1β. Exp Physiol 98:462–472. https://doi.org/10.1113/expphysiol.2012.068338

    Article  CAS  PubMed  Google Scholar 

  13. Brandenburg S, Kohl T, Williams GS, Gusev K, Wagner E, Rog-Zielinska EA, Hebisch E, Dura M, Didie M, Gotthardt M, Nikolaev VO, Hasenfuss G, Kohl P, Ward CW, Lederer WJ, Lehnart SE (2016) Axial tubule junctions control rapid calcium signaling in atria. J Clin Invest 126:3999–4015. https://doi.org/10.1172/JCI88241

    Article  PubMed  PubMed Central  Google Scholar 

  14. Brandenburg S, Pawlowitz J, Fakuade FE, Kownatzki-Danger D, Kohl T, Mitronova GY, Scardigli M, Neef J, Schmidt C, Wiedmann F, Pavone FS, Sacconi L, Kutschka I, Sossalla S, Moser T, Voigt N, Lehnart SE (2018) Axial Tubule Junctions Activate Atrial Ca2+ Release Across Species. Front Physiol 9:1227. https://doi.org/10.3389/fphys.2018.01227

    Article  PubMed  PubMed Central  Google Scholar 

  15. Broz P, Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 16:407–420. https://doi.org/10.1038/nri.2016.58

    Article  CAS  PubMed  Google Scholar 

  16. Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A, Gandhi C, Putnam CD, Boyle DL, Firestein GS, Horner AA, Soroosh P, Watford WT, O'Shea JJ, Kastner DL, Hoffman HM (2009) Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30:875–887. https://doi.org/10.1016/j.immuni.2009.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bukowska A, Lendeckel U, Hirte D, Wolke C, Striggow F, Rohnert P, Huth C, Klein HU, Goette A (2006) Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation. Cell Mol Life Sci 63:333–342. https://doi.org/10.1007/s00018-005-5353-3

    Article  CAS  PubMed  Google Scholar 

  18. Burashnikov A, Antzelevitch C (2006) Late-phase 3 EAD. A unique mechanism contributing to initiation of atrial fibrillation. Pacing Clin Electrophysiol 29:290–295. https://doi.org/10.1111/j.1540-8159.2006.00336.x

    Article  PubMed  PubMed Central  Google Scholar 

  19. Caballero R, de la Fuente MG, Gomez R, Barana A, Amoros I, Dolz-Gaiton P, Osuna L, Almendral J, Atienza F, Fernandez-Aviles F, Pita A, Rodriguez-Roda J, Pinto A, Tamargo J, Delpon E (2010) In humans, chronic atrial fibrillation decreases the transient outward current and ultrarapid component of the delayed rectifier current differentially on each atria and increases the slow component of the delayed rectifier current in both. J Am Coll Cardiol 55:2346–2354. https://doi.org/10.1016/j.jacc.2010.02.028

    Article  PubMed  Google Scholar 

  20. Campbell HM, Quick AP, Abu-Taha I, Chiang DY, Kramm CF, Word TA, Brandenburg S, Hulsurkar M, Alsina KM, Liu HB, Martin B, Uhlenkamp D, Moore OM, Lahiri SK, Corradini E, Kamler M, Heck AJR, Lehnart SE, Dobrev D, Wehrens XHT (2020) Loss of SPEG Inhibitory Phosphorylation of Ryanodine Receptor Type-2 Promotes Atrial Fibrillation. Circulation 142:1159–1172. https://doi.org/10.1161/CIRCULATIONAHA.120.045791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chelu MG, Sarma S, Sood S, Wang S, van Oort RJ, Skapura DG, Li N, Santonastasi M, Muller FU, Schmitz W, Schotten U, Anderson ME, Valderrabano M, Dobrev D, Wehrens XH (2009) Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. J Clin Invest 119:1940–1951. https://doi.org/10.1172/jci37059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen H, Valle G, Furlan S, Nani A, Gyorke S, Fill M, Volpe P (2013) Mechanism of calsequestrin regulation of single cardiac ryanodine receptor in normal and pathological conditions. J Gen Physiol 142:127–136. https://doi.org/10.1085/jgp.201311022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cheng H, Lederer MR, Xiao RP, Gomez AM, Zhou YY, Ziman B, Spurgeon H, Lakatta EG, Lederer WJ (1996) Excitation-contraction coupling in heart: new insights from Ca2+ sparks. Cell Calcium 20:129–140. https://doi.org/10.1016/s0143-4160(96)90102-5

    Article  CAS  PubMed  Google Scholar 

  24. Cheng T, Wang XF, Hou YT, Zhang L (2012) Correlation between atrial fibrillation, serum amyloid protein A and other inflammatory cytokines. Mol Med Rep 6:581–584. https://doi.org/10.3892/mmr.2012.934

    Article  CAS  PubMed  Google Scholar 

  25. Chiang DY, Kongchan N, Beavers DL, Alsina KM, Voigt N, Neilson JR, Jakob H, Martin JF, Dobrev D, Wehrens XH, Li N (2014) Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release. Circ Arrhythm Electrophysiol 7:1214–1222. https://doi.org/10.1161/CIRCEP.114.001973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chiang DY, Li N, Wang Q, Alsina KM, Quick AP, Reynolds JO, Wang G, Skapura D, Voigt N, Dobrev D, Wehrens XH (2014) Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation. Cardiovasc Res 103:178–187. https://doi.org/10.1093/cvr/cvu123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cho CH, Woo JS, Perez CF, Lee EH (2017) A focus on extracellular Ca2+ entry into skeletal muscle. Exp Mol Med 49:e378. https://doi.org/10.1038/emm.2017.208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Christ T, Boknik P, Wohrl S, Wettwer E, Graf EM, Bosch RF, Knaut M, Schmitz W, Ravens U, Dobrev D (2004) L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation 110:2651–2657. https://doi.org/10.1161/01.CIR.0000145659.80212.6A

    Article  CAS  PubMed  Google Scholar 

  29. Christoffels VM, Smits GJ, Kispert A, Moorman AF (2010) Development of the pacemaker tissues of the heart. Circ Res 106:240–254. https://doi.org/10.1161/CIRCRESAHA.109.205419

    Article  CAS  PubMed  Google Scholar 

  30. Clapham DE (2007) Calcium signaling. Cell 131:1047–1058. https://doi.org/10.1016/j.cell.2007.11.028

    Article  CAS  PubMed  Google Scholar 

  31. Comtois P, Kneller J, Nattel S (2005) Of circles and spirals: bridging the gap between the leading circle and spiral wave concepts of cardiac reentry. Europace 7(Suppl 2):10–20. https://doi.org/10.1016/j.eupc.2005.05.011

    Article  PubMed  Google Scholar 

  32. Dan GA, Dobrev D (2018) Antiarrhythmic drugs for atrial fibrillation: Imminent impulses are emerging. Int J Cardiol Heart Vasc 21:11–15. https://doi.org/10.1016/j.ijcha.2018.08.005

    Article  PubMed  PubMed Central  Google Scholar 

  33. De A (2011) Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys Sin 43:745–756. https://doi.org/10.1093/abbs/gmr079

    Article  CAS  PubMed  Google Scholar 

  34. De Nardo D, Latz E (2011) NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol 32:373–379. https://doi.org/10.1016/j.it.2011.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dobrev D, Nattel S (2010) New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet 375:1212–1223. https://doi.org/10.1016/S0140-6736(10)60096-7

    Article  CAS  PubMed  Google Scholar 

  36. Dobrev D, Wehrens XH (2014) Role of RyR2 phosphorylation in heart failure and arrhythmias: Controversies around ryanodine receptor phosphorylation in cardiac disease. Circ Res 114:1311–1319; discussion 1319. https://doi.org/10.1161/CIRCRESAHA.114.300568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dobrev D, Wehrens XHT (2017) Calcium-mediated cellular triggered activity in atrial fibrillation. J Physiol 595:4001–4008. https://doi.org/10.1113/JP273048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U (2005) The G protein-gated potassium current IK,Ach is constitutively active in patients with chronic atrial fibrillation. Circulation 112:3697–3706. https://doi.org/10.1161/CIRCULATIONAHA.105.575332

  39. Dobrev D, Voigt N, Wehrens XH (2011) The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc Res 89:734–743. https://doi.org/10.1093/cvr/cvq324

    Article  CAS  PubMed  Google Scholar 

  40. Dorn GW 2nd, Maack C (2013) SR and mitochondria: calcium cross-talk between kissing cousins. J Mol Cell Cardiol 55:42–49. https://doi.org/10.1016/j.yjmcc.2012.07.015

    Article  CAS  PubMed  Google Scholar 

  41. Dudley SC Jr, Hoch NE, McCann LA, Honeycutt C, Diamandopoulos L, Fukai T, Harrison DG, Dikalov SI, Langberg J (2005) Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 112:1266–1273. https://doi.org/10.1161/CIRCULATIONAHA.105.538108

    Article  CAS  PubMed  Google Scholar 

  42. Edwards AG, Grandi E, Hake JE, Patel S, Li P, Miyamoto S, Omens JH, Heller Brown J, Bers DM, McCulloch AD (2014) Nonequilibrium reactivation of Na+ current drives early afterdepolarizations in mouse ventricle. Circ Arrhythm Electrophysiol 7:1205–1213. https://doi.org/10.1161/CIRCEP.113.001666

    Article  PubMed  PubMed Central  Google Scholar 

  43. El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, Ravens U, Dobrev D (2006) Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation 114:670–680. https://doi.org/10.1161/CIRCULATIONAHA.106.636845

    Article  CAS  PubMed  Google Scholar 

  44. European Heart Rhythm A, European Cardiac Arrhythmia S, American College of C, American Heart A, Society of Thoracic S, Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, Damiano RJ Jr, Davies DW, Haines DE, Haissaguerre M, Iesaka Y, Jackman W, Jais P, Kottkamp H, Kuck KH, Lindsay BD, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Natale A, Pappone C, Prystowsky E, Raviele A, Ruskin JN, Shemin RJ (2007) HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 4:816–861. https://doi.org/10.1016/j.hrthm.2007.04.005

    Article  Google Scholar 

  45. Faggioni M, Savio-Galimberti E, Venkataraman R, Hwang HS, Kannankeril PJ, Darbar D, Knollmann BC (2014) Suppression of spontaneous ca elevations prevents atrial fibrillation in calsequestrin 2-null hearts. Circ Arrhythm Electrophysiol 7:313–320. https://doi.org/10.1161/CIRCEP.113.000994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fearnley CJ, Roderick HL, Bootman MD (2011) Calcium signaling in cardiac myocytes. Cold Spring Harb Perspect Biol 3:a004242. https://doi.org/10.1101/cshperspect.a004242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fender AC, Kleeschulte S, Stolte S, Leineweber K, Kamler M, Bode J, Li N, Dobrev D (2020) Thrombin receptor PAR4 drives canonical NLRP3 inflammasome signaling in the heart. Basic Res Cardiol 115:10. https://doi.org/10.1007/s00395-019-0771-9

    Article  PubMed  PubMed Central  Google Scholar 

  48. Fink SL, Cookson BT (2006) Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 8:1812–1825. https://doi.org/10.1111/j.1462-5822.2006.00751.x

    Article  PubMed  Google Scholar 

  49. Foskett JK, White C, Cheung K-H, Mak D-OD (2007) Inositol Trisphosphate Receptor Ca2+ Release Channels. Physiol Rev 87:593–658. https://doi.org/10.1152/physrev.00035.2006

    Article  CAS  PubMed  Google Scholar 

  50. Fujiwara K, Tanaka H, Mani H, Nakagami T, Takamatsu T (2008) Burst emergence of intracellular Ca2+ waves evokes arrhythmogenic oscillatory depolarization via the Na+ -Ca2+ exchanger: simultaneous confocal recording of membrane potential and intracellular Ca2+ in the heart. Circ Res 103:509–518. https://doi.org/10.1161/CIRCRESAHA.108.176677

  51. Gallo EM, Canté-Barrett K, Crabtree GR (2006) Lymphocyte calcium signaling from membrane to nucleus. Nat Immunol 7:25–32. https://doi.org/10.1038/ni1295

    Article  CAS  PubMed  Google Scholar 

  52. Ganesan AN, Shipp NJ, Brooks AG, Kuklik P, Lau DH, Lim HS, Sullivan T, Roberts-Thomson KC, Sanders P (2013) Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc 2:e004549. https://doi.org/10.1161/JAHA.112.004549

    Article  PubMed  PubMed Central  Google Scholar 

  53. Goette A, Kalman JM, Aguinaga L, Akar J, Cabrera JA, Chen SA, Chugh SS, Corradi D, D'Avila A, Dobrev D, Fenelon G, Gonzalez M, Hatem SN, Helm R, Hindricks G, Ho SY, Hoit B, Jalife J, Kim YH, Lip GY, Ma CS, Marcus GM, Murray K, Nogami A, Sanders P, Uribe W, Van Wagoner DR, Nattel S (2017) EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: Definition, characterization, and clinical implication. Heart Rhythm 14:e3–e40. https://doi.org/10.1016/j.hrthm.2016.05.028

    Article  PubMed  Google Scholar 

  54. Gong T, Yang Y, Jin T, Jiang W, Zhou R (2018) Orchestration of NLRP3 inflammasome activation by ion fluxes. Trends Immunol 39:393–406. https://doi.org/10.1016/j.it.2018.01.009

    Article  CAS  PubMed  Google Scholar 

  55. Goudis CA, Korantzopoulos P, Ntalas IV, Kallergis EM, Ketikoglou DG (2015) Obesity and atrial fibrillation: a comprehensive review of the pathophysiological mechanisms and links. J Cardiol 66:361–369. https://doi.org/10.1016/j.jjcc.2015.04.002

    Article  PubMed  Google Scholar 

  56. Greiser M, Kerfant BG, Williams GS, Voigt N, Harks E, Dibb KM, Giese A, Meszaros J, Verheule S, Ravens U, Allessie MA, Gammie JS, van der Velden J, Lederer WJ, Dobrev D, Schotten U (2014) Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes. J Clin Invest 124:4759–4772. https://doi.org/10.1172/JCI70102

  57. Gross O, Thomas CJ, Guarda G, Tschopp J (2011) The inflammasome: an integrated view. Immunol Rev 243:136–151. https://doi.org/10.1111/j.1600-065X.2011.01046.x

    Article  CAS  PubMed  Google Scholar 

  58. Gudmundsson H, Hund TJ, Wright PJ, Kline CF, Snyder JS, Qian L, Koval OM, Cunha SR, George M, Rainey MA, Kashef FE, Dun W, Boyden PA, Anderson ME, Band H, Mohler PJ (2010) EH domain proteins regulate cardiac membrane protein targeting. Circ Res 107:84–95. https://doi.org/10.1161/CIRCRESAHA.110.216713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gudmundsson H, Curran J, Kashef F, Snyder JS, Smith SA, Vargas-Pinto P, Bonilla IM, Weiss RM, Anderson ME, Binkley P, Felder RB, Carnes CA, Band H, Hund TJ, Mohler PJ (2012) Differential regulation of EHD3 in human and mammalian heart failure. J Mol Cell Cardiol 52:1183–1190. https://doi.org/10.1016/j.yjmcc.2012.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J (1998) Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 339:659–666. https://doi.org/10.1056/NEJM199809033391003

    Article  CAS  PubMed  Google Scholar 

  61. Hamilton NB, Kolodziejczyk K, Kougioumtzidou E, Attwell D (2016) Proton-gated Ca2+ -permeable TRP channels damage myelin in conditions mimicking ischaemia. Nature 529:523–527. https://doi.org/10.1038/nature16519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Harada M, Luo X, Qi XY, Tadevosyan A, Maguy A, Ordog B, Ledoux J, Kato T, Naud P, Voigt N, Shi Y, Kamiya K, Murohara T, Kodama I, Tardif JC, Schotten U, Van Wagoner DR, Dobrev D, Nattel S (2012) Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation 126:2051–2064. https://doi.org/10.1161/CIRCULATIONAHA.112.121830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Harada M, Luo X, Murohara T, Yang B, Dobrev D, Nattel S (2014) MicroRNA regulation and cardiac calcium signaling: role in cardiac disease and therapeutic potential. Circ Res 114:689–705. https://doi.org/10.1161/CIRCRESAHA.114.301798

    Article  CAS  PubMed  Google Scholar 

  64. Heijman J, Dewenter M, El-Armouche A, Dobrev D (2013) Function and regulation of serine/threonine phosphatases in the healthy and diseased heart. J Mol Cell Cardiol 64:90–98. https://doi.org/10.1016/j.yjmcc.2013.09.006

    Article  CAS  PubMed  Google Scholar 

  65. Heijman J, Voigt N, Nattel S, Dobrev D (2014) Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res 114:1483–1499. https://doi.org/10.1161/CIRCRESAHA.114.302226

    Article  CAS  PubMed  Google Scholar 

  66. Heijman J, Voigt N, Wehrens XH, Dobrev D (2014) Calcium dysregulation in atrial fibrillation: the role of CaMKII. Front Pharmacol 5:30. https://doi.org/10.3389/fphar.2014.00030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Heijman J, Algalarrondo V, Voigt N, Melka J, Wehrens XH, Dobrev D, Nattel S (2016) The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis. Cardiovasc Res 109:467–479. https://doi.org/10.1093/cvr/cvv275

    Article  CAS  PubMed  Google Scholar 

  68. Heijman J, Guichard JB, Dobrev D, Nattel S (2018) Translational challenges in atrial fibrillation. Circ Res 122:752–773. https://doi.org/10.1161/CIRCRESAHA.117.311081

    Article  CAS  PubMed  Google Scholar 

  69. Heijman J, Muna AP, Veleva T, Molina CE, Sutanto H, Tekook MA, Wang Q, Abu-Taha I, Gorka M, Künzel S, El-Armouche A, Reichenspurner H, Kamler M, Nikolaev VO, Ravens U, Li N, Nattel S, Wehrens XH, Dobrev D (2020) Atrial myocyte NLRP3/CaMKII nexus forms a substrate for post-operative atrial fibrillation. Circ Res 127:1036–1055. https://doi.org/10.1161/CIRCRESAHA.120.316710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Horng T (2014) Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome. Trends Immunol 35:253–261. https://doi.org/10.1016/j.it.2014.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hornung V, Latz E (2010) Critical functions of priming and lysosomal damage for NLRP3 activation. Eur J Immunol 40:620–623. https://doi.org/10.1002/eji.200940185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hove-Madsen L, Llach A, Bayes-Genis A, Roura S, Rodriguez Font E, Aris A, Cinca J (2004) Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes. Circulation 110:1358–1363. https://doi.org/10.1161/01.CIR.0000141296.59876.87

    Article  CAS  PubMed  Google Scholar 

  73. Hu YF, Chen YJ, Lin YJ, Chen SA (2015) Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 12:230–243. https://doi.org/10.1038/nrcardio.2015.2

    Article  CAS  PubMed  Google Scholar 

  74. Huang Z, Chen XJ, Qian C, Dong Q, Ding D, Wu QF, Li J, Wang HF, Li WH, Xie Q, Cheng X, Zhao N, Du YM, Liao YH (2016) Signal transducer and activator of transcription 3/MicroRNA-21 feedback loop contributes to atrial fibrillation by promoting atrial fibrosis in a rat sterile pericarditis model. Circ Arrhythm Electrophysiol 9. https://doi.org/10.1161/CIRCEP.115.003396

  75. Jones PP, Meng X, Xiao B, Cai S, Bolstad J, Wagenknecht T, Liu Z, Chen SR (2008) Localization of PKA phosphorylation site, Ser(2030), in the three-dimensional structure of cardiac ryanodine receptor. Biochem J 410:261–270. https://doi.org/10.1042/BJ20071257

    Article  CAS  PubMed  Google Scholar 

  76. Kasamatsu J, Oshiumi H, Matsumoto M, Kasahara M, Seya T (2010) Phylogenetic and expression analysis of lamprey toll-like receptors. Dev Comp Immunol 34:855–865. https://doi.org/10.1016/j.dci.2010.03.004

    Article  CAS  PubMed  Google Scholar 

  77. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671. https://doi.org/10.1038/nature15541

    Article  CAS  PubMed  Google Scholar 

  78. Kim YM, Guzik TJ, Zhang YH, Zhang MH, Kattach H, Ratnatunga C, Pillai R, Channon KM, Casadei B (2005) A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res 97:629–636. https://doi.org/10.1161/01.RES.0000183735.09871.61

    Article  CAS  PubMed  Google Scholar 

  79. Kirchhof P, Marijon E, Fabritz L, Li N, Wang W, Wang T, Schulte K, Hanstein J, Schulte JS, Vogel M, Mougenot N, Laakmann S, Fortmueller L, Eckstein J, Verheule S, Kaese S, Staab A, Grote-Wessels S, Schotten U, Moubarak G, Wehrens XH, Schmitz W, Hatem S, Muller FU (2013) Overexpression of cAMP-response element modulator causes abnormal growth and development of the atrial myocardium resulting in a substrate for sustained atrial fibrillation in mice. Int J Cardiol 166:366–374. https://doi.org/10.1016/j.ijcard.2011.10.057

    Article  PubMed  Google Scholar 

  80. Kirk MM, Izu LT, Chen-Izu Y, McCulle SL, Wier WG, Balke CW, Shorofsky SR (2003) Role of the transverse-axial tubule system in generating calcium sparks and calcium transients in rat atrial myocytes. J Physiol 547:441–451. https://doi.org/10.1113/jphysiol.2002.034355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kornej J, Borschel CS, Benjamin EJ, Schnabel RB (2020) Epidemiology of atrial fibrillation in the 21st century: novel methods and new insights. Circ Res 127:4–20. https://doi.org/10.1161/CIRCRESAHA.120.316340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kranias EG, Hajjar RJ (2012) Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome. Circ Res 110:1646–1660. https://doi.org/10.1161/CIRCRESAHA.111.259754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Landstrom AP, Dobrev D, Wehrens XHT (2017) Calcium signaling and cardiac arrhythmias. Circ Res 120:1969–1993. https://doi.org/10.1161/CIRCRESAHA.117.310083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lee SH, Chen YC, Chen YJ, Chang SL, Tai CT, Wongcharoen W, Yeh HI, Lin CI, Chen SA (2007) Tumor necrosis factor-alpha alters calcium handling and increases arrhythmogenesis of pulmonary vein cardiomyocytes. Life Sci 80:1806–1815. https://doi.org/10.1016/j.lfs.2007.02.029

    Article  CAS  PubMed  Google Scholar 

  85. Lee G-S, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJ (2012) The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492:123–127. https://doi.org/10.1038/nature11588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lenaerts I, Bito V, Heinzel FR, Driesen RB, Holemans P, D'Hooge J, Heidbuchel H, Sipido KR, Willems R (2009) Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation. Circ Res 105:876–885. https://doi.org/10.1161/CIRCRESAHA.109.206276

    Article  CAS  PubMed  Google Scholar 

  87. Li N, Brundel B (2020) Inflammasomes and proteostasis novel molecular mechanisms associated with atrial fibrillation. Circ Res 127:73–90. https://doi.org/10.1161/CIRCRESAHA.119.316364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li J, Solus J, Chen Q, Rho YH, Milne G, Stein CM, Darbar D (2010) Role of inflammation and oxidative stress in atrial fibrillation. Heart Rhythm 7:438–444. https://doi.org/10.1016/j.hrthm.2009.12.009

    Article  PubMed  Google Scholar 

  89. Li N, Wang T, Wang W, Cutler MJ, Wang Q, Voigt N, Rosenbaum DS, Dobrev D, Wehrens XH (2012) Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice. Circ Res 110:465–470. https://doi.org/10.1161/CIRCRESAHA.111.253229

    Article  CAS  PubMed  Google Scholar 

  90. Li N, Chiang DY, Wang S, Wang Q, Sun L, Voigt N, Respress JL, Ather S, Skapura DG, Jordan VK, Horrigan FT, Schmitz W, Muller FU, Valderrabano M, Nattel S, Dobrev D, Wehrens XHT (2014) Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model. Circulation 129:1276–1285. https://doi.org/10.1161/CIRCULATIONAHA.113.006611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Liang X, Xie H, Zhu PH, Hu J, Zhao Q, Wang CS, Yang C (2009) Enhanced activity of inositol-1,4,5-trisphosphate receptors in atrial myocytes of atrial fibrillation patients. Cardiology 114:180–191. https://doi.org/10.1159/000228584

    Article  CAS  PubMed  Google Scholar 

  92. Lin CC, Lin JL, Lin CS, Tsai MC, Su MJ, Lai LP, Huang SK (2004) Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation. Chest 126:1926–1932. https://doi.org/10.1378/chest.126.6.1926

    Article  CAS  PubMed  Google Scholar 

  93. Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J (2016) Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535:153–158. https://doi.org/10.1038/nature18629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu D, Zeng X, Li X, Mehta JL, Wang X (2017) Role of NLRP3 inflammasome in the pathogenesis of cardiovascular diseases. Basic Res Cardiol 113:5. https://doi.org/10.1007/s00395-017-0663-9

    Article  CAS  PubMed  Google Scholar 

  95. Liu T, Zhang L, Joo D, Sun SC (2017) NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2. https://doi.org/10.1038/sigtrans.2017.23

  96. Liu Q, Zhang D, Hu D, Zhou X, Zhou Y (2018) The role of mitochondria in NLRP3 inflammasome activation. Mol Immunol 103:115–124. https://doi.org/10.1016/j.molimm.2018.09.010

    Article  CAS  PubMed  Google Scholar 

  97. Lu Y, Zhang Y, Wang N, Pan Z, Gao X, Zhang F, Zhang Y, Shan H, Luo X, Bai Y, Sun L, Song W, Xu C, Wang Z, Yang B (2010) MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation 122:2378–2387. https://doi.org/10.1161/CIRCULATIONAHA.110.958967

    Article  CAS  PubMed  Google Scholar 

  98. Luan Y, Guo Y, Li S, Yu B, Zhu S, Li S, Li N, Tian Z, Peng C, Cheng J, Li Q, Cui J, Tian Y (2010) Interleukin-18 among atrial fibrillation patients in the absence of structural heart disease. EP Europace 12:1713–1718. https://doi.org/10.1093/europace/euq321

    Article  Google Scholar 

  99. Luo X, Pan Z, Shan H, Xiao J, Sun X, Wang N, Lin H, Xiao L, Maguy A, Qi XY, Li Y, Gao X, Dong D, Zhang Y, Bai Y, Ai J, Sun L, Lu H, Luo XY, Wang Z, Lu Y, Yang B, Nattel S (2013) MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest 123:1939–1951. https://doi.org/10.1172/JCI62185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Magupalli VG, Negro R, Tian Y, Hauenstein AV, Di Caprio G, Skillern W, Deng Q, Orning P, Alam HB, Maliga Z, Sharif H, Hu JJ, Evavold CL, Kagan JC, Schmidt FI, Fitzgerald KA, Kirchhausen T, Li Y, Wu H (2020) HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science 369:eaas8995. https://doi.org/10.1126/science.aas8995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Mahajan R, Lau DH, Brooks AG, Shipp NJ, Manavis J, Wood JP, Finnie JW, Samuel CS, Royce SG, Twomey DJ, Thanigaimani S, Kalman JM, Sanders P (2015) Electrophysiological, electroanatomical, and structural remodeling of the atria as consequences of sustained obesity. J Am Coll Cardiol 66:1–11. https://doi.org/10.1016/j.jacc.2015.04.058

    Article  CAS  PubMed  Google Scholar 

  102. Man SM, Kanneganti T-D (2015) Regulation of inflammasome activation. Immunol Rev 265:6–21. https://doi.org/10.1111/imr.12296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Menu P, Mayor A, Zhou R, Tardivel A, Ichijo H, Mori K, Tschopp J (2012) ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis 3:e261. https://doi.org/10.1038/cddis.2011.132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S (2013) Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol 14:454–460. https://doi.org/10.1038/ni.2550

    Article  CAS  PubMed  Google Scholar 

  105. Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, Horng T (2012) Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci 109:11282–11287. https://doi.org/10.1073/pnas.1117765109

    Article  PubMed  PubMed Central  Google Scholar 

  106. Nakai J, Imagawa T, Hakamat Y, Shigekawa M, Takeshima H, Numa S (1990) Primary structure and functional expression from cDNA of the cardiac ryanodine receptor/calcium release channel. FEBS Lett 271:169–177. https://doi.org/10.1016/0014-5793(90)80399-4

    Article  CAS  PubMed  Google Scholar 

  107. Nattel S (2017) Molecular and cellular mechanisms of atrial fibrosis in atrial fibrillation. JACC Clin Electrophysiol 3:425–435. https://doi.org/10.1016/j.jacep.2017.03.002

    Article  PubMed  Google Scholar 

  108. Nattel S, Heijman J, Zhou L, Dobrev D (2020) Molecular basis of atrial fibrillation pathophysiology and therapy: a translational perspective. Circ Res 127:51–72. https://doi.org/10.1161/CIRCRESAHA.120.316363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Neef S, Dybkova N, Sossalla S, Ort KR, Fluschnik N, Neumann K, Seipelt R, Schondube FA, Hasenfuss G, Maier LS (2010) CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res 106:1134–1144. https://doi.org/10.1161/CIRCRESAHA.109.203836

  110. Otsu K, Willard HF, Khanna VK, Zorzato F, Green NM, MacLennan DH (1990) Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum. J Biol Chem 265:13472–13483

  111. Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, Noseworthy PA, Rosenberg YD, Jeffries N, Mitchell LB, Flaker GC, Pokushalov E, Romanov A, Bunch TJ, Noelker G, Ardashev A, Revishvili A, Wilber DJ, Cappato R, Kuck KH, Hindricks G, Davies DW, Kowey PR, Naccarelli GV, Reiffel JA, Piccini JP, Silverstein AP, Al-Khalidi HR, Lee KL, Investigators C (2019) Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA Randomized Clinical Trial. JAMA 321:1261–1274. https://doi.org/10.1001/jama.2019.0693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pandit SV, Jalife J (2013) Rotors and the dynamics of cardiac fibrillation. Circ Res 112:849–862. https://doi.org/10.1161/CIRCRESAHA.111.300158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pogwizd SM, Bers DM (2004) Cellular basis of triggered arrhythmias in heart failure. Trends Cardiovasc Med 14:61–66. https://doi.org/10.1016/j.tcm.2003.12.002

    Article  CAS  PubMed  Google Scholar 

  114. Pott C, Philipson KD, Goldhaber JI (2005) Excitation-contraction coupling in Na+ -Ca2+ exchanger knockout mice: reduced transsarcolemmal Ca2+ flux. Circ Res 97:1288–1295. https://doi.org/10.1161/01.RES.0000196563.84231.21

  115. Purohit A, Rokita AG, Guan X, Chen B, Koval OM, Voigt N, Neef S, Sowa T, Gao Z, Luczak ED, Stefansdottir H, Behunin AC, Li N, El-Accaoui RN, Yang B, Swaminathan PD, Weiss RM, Wehrens XH, Song LS, Dobrev D, Maier LS, Anderson ME (2013) Oxidized Ca2+/calmodulin-dependent protein kinase II triggers atrial fibrillation. Circulation 128:1748–1757. https://doi.org/10.1161/CIRCULATIONAHA.113.003313

    Article  CAS  PubMed  Google Scholar 

  116. Py Bénédicte F, Kim M-S, Vakifahmetoglu-Norberg H, Yuan J (2013) Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell 49:331–338. https://doi.org/10.1016/j.molcel.2012.11.009

    Article  CAS  PubMed  Google Scholar 

  117. Qi XY, Yeh YH, Xiao L, Burstein B, Maguy A, Chartier D, Villeneuve LR, Brundel BJ, Dobrev D, Nattel S (2008) Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circ Res 103:845–854. https://doi.org/10.1161/CIRCRESAHA.108.175463

    Article  CAS  PubMed  Google Scholar 

  118. Qiao Y, Wang P, Qi J, Zhang L, Gao C (2012) TLR-induced NF-κB activation regulates NLRP3 expression in murine macrophages. FEBS Lett 586:1022–1026. https://doi.org/10.1016/j.febslet.2012.02.045

    Article  CAS  PubMed  Google Scholar 

  119. Quan C, Li M, Du Q, Chen Q, Wang H, Campbell D, Fang L, Xue B, MacKintosh C, Gao X, Ouyang K, Wang HY, Chen S (2019) SPEG controls calcium reuptake into the sarcoplasmic reticulum through regulating SERCA2a by its second kinase-domain. Circ Res 124:712–726. https://doi.org/10.1161/CIRCRESAHA.118.313916

    Article  CAS  PubMed  Google Scholar 

  120. Richards MA, Clarke JD, Saravanan P, Voigt N, Dobrev D, Eisner DA, Trafford AW, Dibb KM (2011) Transverse tubules are a common feature in large mammalian atrial myocytes including human. Am J Phys Heart Circ Phys 301:H1996–H2005. https://doi.org/10.1152/ajpheart.00284.2011

    Article  CAS  Google Scholar 

  121. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Le Heuzey JY, O'Hara G, Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL, Atrial F, Congestive Heart Failure I (2008) Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 358:2667–2677. https://doi.org/10.1056/NEJMoa0708789

    Article  CAS  PubMed  Google Scholar 

  122. Saba S, Janczewski AM, Baker LC, Shusterman V, Gursoy EC, Feldman AM, Salama G, McTiernan CF, London B (2005) Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}. Am J Phys Heart Circ Phys 289:H1456–H1467. https://doi.org/10.1152/ajpheart.00733.2004

    Article  CAS  Google Scholar 

  123. Sawaya SE, Rajawat YS, Rami TG, Szalai G, Price RL, Sivasubramanian N, Mann DL, Khoury DS (2007) Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor. Am J Phys Heart Circ Phys 292:H1561–H1567. https://doi.org/10.1152/ajpheart.00285.2006

    Article  CAS  Google Scholar 

  124. Schmidt C, Wiedmann F, Voigt N, Zhou XB, Heijman J, Lang S, Albert V, Kallenberger S, Ruhparwar A, Szabo G, Kallenbach K, Karck M, Borggrefe M, Biliczki P, Ehrlich JR, Baczko I, Lugenbiel P, Schweizer PA, Donner BC, Katus HA, Dobrev D, Thomas D (2015) Upregulation of K(2P)3.1 K+ current causes action potential shortening in patients with chronic atrial fibrillation. Circulation 132:82–92. https://doi.org/10.1161/CIRCULATIONAHA.114.012657

  125. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832. https://doi.org/10.1016/j.cell.2010.01.040

    Article  CAS  PubMed  Google Scholar 

  126. Schweikert RA, Perez Lugones A, Kanagaratnam L, Tomassoni G, Beheiry S, Bash D, Pisano E, Saliba W, Tchou PJ, Natale A (2001) A simple method of mapping atrial premature depolarizations triggering atrial fibrillation. Pacing Clin Electrophysiol 24:22–27. https://doi.org/10.1046/j.1460-9592.2001.00022.x

    Article  CAS  PubMed  Google Scholar 

  127. Scott L Jr, Li N, Dobrev D (2019) Role of inflammatory signaling in atrial fibrillation. Int J Cardiol 287:195–200. https://doi.org/10.1016/j.ijcard.2018.10.020

    Article  PubMed  Google Scholar 

  128. Shanmugam M, Molina CE, Gao S, Severac-Bastide R, Fischmeister R, Babu GJ (2011) Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation. Biochem Biophys Res Commun 410:97–101. https://doi.org/10.1016/j.bbrc.2011.05.113

  129. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–665. https://doi.org/10.1038/nature15514

    Article  CAS  PubMed  Google Scholar 

  130. Shin JN, Fattah EA, Bhattacharya A, Ko S, Eissa NT (2013) Inflammasome activation by altered proteostasis. J Biol Chem 288:35886–35895. https://doi.org/10.1074/jbc.M113.514919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Simon JN, Ziberna K, Casadei B (2016) Compromised redox homeostasis, altered nitroso-redox balance, and therapeutic possibilities in atrial fibrillation. Cardiovasc Res 109:510–518. https://doi.org/10.1093/cvr/cvw012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Sood S, Chelu MG, van Oort RJ, Skapura D, Santonastasi M, Dobrev D, Wehrens XH (2008) Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation. Heart Rhythm 5:1047–1054. https://doi.org/10.1016/j.hrthm.2008.03.030

    Article  PubMed  PubMed Central  Google Scholar 

  133. Sossalla S, Kallmeyer B, Wagner S, Mazur M, Maurer U, Toischer K, Schmitto JD, Seipelt R, Schondube FA, Hasenfuss G, Belardinelli L, Maier LS (2010) Altered Na+ currents in atrial fibrillation effects of ranolazine on arrhythmias and contractility in human atrial myocardium. J Am Coll Cardiol 55:2330–2342. https://doi.org/10.1016/j.jacc.2009.12.055

  134. Stanciu AE, Vatasescu RG, Stanciu MM, Serdarevic N, Dorobantu M (2018) The role of pro-fibrotic biomarkers in paroxysmal and persistent atrial fibrillation. Cytokine 103:63–68. https://doi.org/10.1016/j.cyto.2017.12.026

    Article  CAS  PubMed  Google Scholar 

  135. Suetomi T, Willeford A, Brand CS, Cho Y, Ross RS, Miyamoto S, Brown JH (2018) Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca2+/calmodulin-dependent protein kinase II delta signaling in cardiomyocytes are essential for adverse cardiac remodeling. Circulation 138:2530–2544. https://doi.org/10.1161/CIRCULATIONAHA.118.034621

  136. Swanson KV, Deng M, Ting JPY (2019) The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19:477–489. https://doi.org/10.1038/s41577-019-0165-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Szabo B, Sweidan R, Rajagopalan CV, Lazzara R (1994) Role of Na+:Ca2+ exchange current in Cs+-induced early afterdepolarizations in Purkinje fibers. J Cardiovasc Electrophysiol 5:933–944. https://doi.org/10.1111/j.1540-8167.1994.tb01133.x

  138. Tao H, Yang JJ, Shi KH, Li J (2016) Wnt signaling pathway in cardiac fibrosis: new insights and directions. Metab Clin Exp 65:30–40. https://doi.org/10.1016/j.metabol.2015.10.013

    Article  CAS  PubMed  Google Scholar 

  139. Terentyev D, Hamilton S (2016) Regulation of sarcoplasmic reticulum Ca2+ release by serine-threonine phosphatases in the heart. J Mol Cell Cardiol 101:156–164. https://doi.org/10.1016/j.yjmcc.2016.08.020

  140. Ting JPY, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA, Hoffman HM, Hugot J-P, Inohara N, Mackenzie A, Maltais LJ, Nunez G, Ogura Y, Otten LA, Philpott D, Reed JC, Reith W, Schreiber S, Steimle V, Ward PA (2008) The NLR gene family: a standard nomenclature. Immunity 28:285–287. https://doi.org/10.1016/j.immuni.2008.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Trafford AW, Clarke JD, Richards MA, Eisner DA, Dibb KM (2013) Calcium signalling microdomains and the t-tubular system in atrial mycoytes: potential roles in cardiac disease and arrhythmias. Cardiovasc Res 98:192–203. https://doi.org/10.1093/cvr/cvt018

    Article  CAS  PubMed  Google Scholar 

  142. Uemura N, Ohkusa T, Hamano K, Nakagome M, Hori H, Shimizu M, Matsuzaki M, Mochizuki S, Minamisawa S, Ishikawa Y (2004) Down-regulation of sarcolipin mRNA expression in chronic atrial fibrillation. Eur J Clin Investig 34:723–730. https://doi.org/10.1111/j.1365-2362.2004.01422.x

    Article  CAS  Google Scholar 

  143. van Ooijen G, van den Burg HA, Cornelissen BJ, Takken FL (2007) Structure and function of resistance proteins in solanaceous plants. Annu Rev Phytopathol 45:43–72. https://doi.org/10.1146/annurev.phyto.45.062806.094430

    Article  CAS  PubMed  Google Scholar 

  144. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17:179–188. https://doi.org/10.1038/nm.2279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Venetucci LA, Trafford AW, O'Neill SC, Eisner DA (2008) The sarcoplasmic reticulum and arrhythmogenic calcium release. Cardiovasc Res 77:285–292. https://doi.org/10.1093/cvr/cvm009

    Article  CAS  PubMed  Google Scholar 

  146. Vest JA, Wehrens XH, Reiken SR, Lehnart SE, Dobrev D, Chandra P, Danilo P, Ravens U, Rosen MR, Marks AR (2005) Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 111:2025–2032. https://doi.org/10.1161/01.CIR.0000162461.67140.4C

    Article  CAS  PubMed  Google Scholar 

  147. Voigt N, Trausch A, Knaut M, Matschke K, Varro A, Van Wagoner DR, Nattel S, Ravens U, Dobrev D (2010) Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. Circ Arrhythm Electrophysiol 3:472–480. https://doi.org/10.1161/CIRCEP.110.954636

    Article  PubMed  PubMed Central  Google Scholar 

  148. Voigt N, Li N, Wang Q, Wang W, Trafford AW, Abu-Taha I, Sun Q, Wieland T, Ravens U, Nattel S, Wehrens XH, Dobrev D (2012) Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+ -Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation 125:2059–2070. https://doi.org/10.1161/CIRCULATIONAHA.111.067306

  149. Voigt N, Heijman J, Wang Q, Chiang DY, Li N, Karck M, Wehrens XHT, Nattel S, Dobrev D (2014) Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation 129:145–156. https://doi.org/10.1161/CIRCULATIONAHA.113.006641

    Article  CAS  PubMed  Google Scholar 

  150. Wakili R, Voigt N, Kaab S, Dobrev D, Nattel S (2011) Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest 121:2955–2968. https://doi.org/10.1172/JCI46315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Waks JW, Josephson ME (2014) Mechanisms of atrial fibrillation - reentry, rotors and reality. Arrhythmia Electrophysiol Rev 3:90–100. https://doi.org/10.15420/aer.2014.3.2.90

    Article  Google Scholar 

  152. Weber K, Schilling JD (2014) Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J Biol Chem 289:9158–9171. https://doi.org/10.1074/jbc.M113.531202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wehrens XH, Lehnart SE, Reiken SR, Marks AR (2004) Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor. Circ Res 94:e61–e70. https://doi.org/10.1161/01.RES.0000125626.33738.E2

  154. Wier WG, Cannell MB, Berlin JR, Marban E, Lederer WJ (1987) Cellular and subcellular heterogeneity of [Ca2+]i in single heart cells revealed by fura-2. Science 235:325–328. https://doi.org/10.1126/science.3798114

  155. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA (1995) Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92:1954–1968. https://doi.org/10.1161/01.cir.92.7.1954

    Article  CAS  PubMed  Google Scholar 

  156. Woo SH, Cleemann L, Morad M (2005) Diversity of atrial local Ca2+ signalling: evidence from 2-D confocal imaging in Ca2+ -buffered rat atrial myocytes. J Physiol 567:905–921. https://doi.org/10.1113/jphysiol.2005.092270

  157. Wu N, Xu B, Xiang Y, Wu L, Zhang Y, Ma X, Tong S, Shu M, Song Z, Li Y, Zhong L (2013) Association of inflammatory factors with occurrence and recurrence of atrial fibrillation: a meta-analysis. Int J Cardiol 169:62–72. https://doi.org/10.1016/j.ijcard.2013.08.078

    Article  PubMed  Google Scholar 

  158. Wu Q, Liu H, Liao J, Zhao N, Tse G, Han B, Chen L, Huang Z, Du Y (2020) Colchicine prevents atrial fibrillation promotion by inhibiting IL-1beta-induced IL-6 release and atrial fibrosis in the rat sterile pericarditis model. Biomed Pharmacother 129:110384. https://doi.org/10.1016/j.biopha.2020.110384

    Article  CAS  PubMed  Google Scholar 

  159. Xie LH, Shanmugam M, Park JY, Zhao Z, Wen H, Tian B, Periasamy M, Babu GJ (2012) Ablation of sarcolipin results in atrial remodeling. Am J Physiol Cell Physiol 302:C1762–C1771. https://doi.org/10.1152/ajpcell.00425.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Xie W, Santulli G, Reiken SR, Yuan Q, Osborne BW, Chen BX, Marks AR (2015) Mitochondrial oxidative stress promotes atrial fibrillation. Sci Rep 5:11427. https://doi.org/10.1038/srep11427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Yang X, An N, Zhong C, Guan M, Jiang Y, Li X, Zhang H, Wang L, Ruan Y, Gao Y, Liu N, Shang H, Xing Y (2020) Enhanced cardiomyocyte reactive oxygen species signaling promotes ibrutinib-induced atrial fibrillation. Redox Biol 30:101432. https://doi.org/10.1016/j.redox.2020.101432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Yao C, Veleva T, Scott L Jr, Cao S, Li L, Chen G, Jeyabal P, Pan X, Alsina KM, Abu-Taha ID, Ghezelbash S, Reynolds CL, Shen YH, LeMaire SA, Schmitz W, Muller FU, El-Armouche A, Tony Eissa N, Beeton C, Nattel S, Wehrens XHT, Dobrev D, Li N (2018) Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation 138:2227–2242. https://doi.org/10.1161/CIRCULATIONAHA.118.035202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Ylikoski J, Pirvola U, Happola O, Panula P, Virtanen I (1989) Immunohistochemical demonstration of neuroactive substances in the inner ear of rat and guinea pig. Acta Otolaryngol 107:417–423. https://doi.org/10.3109/00016488909127533

    Article  CAS  PubMed  Google Scholar 

  164. Yoo S, Aistrup G, Shiferaw Y, Ng J, Mohler PJ, Hund TJ, Waugh T, Browne S, Gussak G, Gilani M, Knight BP, Passman R, Goldberger JJ, Wasserstrom JA, Arora R (2018) Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure. JCI Insight 3. https://doi.org/10.1172/jci.insight.120728

  165. Yuan Y, Zhao J, Gong Y, Wang D, Wang X, Yun F, Liu Z, Zhang S, Li W, Zhao X, Sun L, Sheng L, Pan Z, Li Y (2018) Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L-type calcium channel. Cell Death Dis 9:873. https://doi.org/10.1038/s41419-018-0860-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhang YH, Hancox JC (2009) Regulation of cardiac Na+ -Ca2+ exchanger activity by protein kinase phosphorylation--still a paradox? Cell Calcium 45:1–10. https://doi.org/10.1016/j.ceca.2008.05.005

  167. Zhang T, Miyamoto S, Brown JH (2004) Cardiomyocyte calcium and calcium/calmodulin-dependent protein kinase II: friends or foes? Recent Prog Horm Res 59:141–168. https://doi.org/10.1210/rp.59.1.141

    Article  CAS  PubMed  Google Scholar 

  168. Zhang D, Wu CT, Qi X, Meijering RA, Hoogstra-Berends F, Tadevosyan A, Cubukcuoglu Deniz G, Durdu S, Akar AR, Sibon OC, Nattel S, Henning RH, Brundel BJ (2014) Activation of histone deacetylase-6 induces contractile dysfunction through derailment of alpha-tubulin proteostasis in experimental and human atrial fibrillation. Circulation 129:346–358. https://doi.org/10.1161/CIRCULATIONAHA.113.005300

    Article  CAS  PubMed  Google Scholar 

  169. Zhang JC, Wu HL, Chen Q, Xie XT, Zou T, Zhu C, Dong Y, Xiang GJ, Ye L, Li Y, Zhu PL (2018) Calcium-mediated oscillation in membrane potentials and atrial-triggered activity in atrial cells of Casq2(R33Q/R33Q) mutation mice. Front Physiol 9:1447. https://doi.org/10.3389/fphys.2018.01447

    Article  PubMed  PubMed Central  Google Scholar 

  170. Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225. https://doi.org/10.1038/nature09663

    Article  CAS  PubMed  Google Scholar 

  171. Zhu W, Wang C, Hu J, Wan R, Yu J, Xie J, Ma J, Guo L, Ge J, Qiu Y, Chen L, Liu H, Yan X, Liu X, Ye J, He W, Shen Y, Wang C, Mohler PJ, Hong K (2018) Ankyrin-B Q1283H variant linked to arrhythmias via loss of local protein phosphatase 2A activity causes ryanodine receptor hyperphosphorylation. Circulation 138:2682–2697. https://doi.org/10.1161/CIRCULATIONAHA.118.034541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study is supported by grants from the National Institutes of Health (R01HL136389 to N.L. and D.D., R01HL147108 to N.L., and R01HL131517 and R01HL089598 to D.D.), the European Union (H2020, MAESTRIA to D.D.), the German Research Foundation (DFG, Do 769/4-1 to D.D.), and Baylor College of Medicine (CVRI pilot grant to N.L.)

Author information

Author notes

  1. Xiaolei Wang and Xiaohui Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, TX, USA

    Xiaolei Wang, Xiaohui Chen & Na Li

  2. Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany

    Dobromir Dobrev

  3. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA

    Na Li

  4. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA

    Na Li

Authors
  1. Xiaolei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaohui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dobromir Dobrev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Na Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Na Li.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is published as part of the Special Issue on “Calcium Signal Dynamics in Cardiac Myocytes and Fibroblasts: Mechanisms and Therapeutics.”

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Chen, X., Dobrev, D. et al. The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation. Pflugers Arch - Eur J Physiol 473, 389–405 (2021). https://doi.org/10.1007/s00424-021-02515-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-021-02515-4

Keywords

Search

Navigation