Atrial Fibrillation Pathogenesis: History
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Electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. 

  • atrial fibrillation
  • therapeutic implications
  • pathogenesis

1. Introduction

Cardiac senescence, largely attributed to aging, hypertension, obesity, as well as genetic predisposition, has been associated with atrial fibrillation (AF) genesis and progression [1]. AF is expected to affect 6–16 million individuals in the United States, 14 million in Europe, and 72 million in Asia by 2050 [2], imposing a surge with economic and social implications for the public health care systems.
One out of three patients with AF will develop heart failure, and 20–30% of ischemic strokes are attributed to AF, increasing morbidity and mortality [3].
Almost four centuries have elapsed since 1628 when William Harvey was probably the first to describe AF in animals [4]. Nowadays, different ablation strategies have revolutionized AF treatment. However, a ‘’ceiling’’ for more durable long-term success (strictly defined as no occurrence of AF) seems to be reached. Success rates range between 65 and 78%, requiring an in-depth understanding of mechanistic links [5].

2. Atrial Fibrillation Pathogenesis

2.1. Mechanistic Approach

Increased focal atrial triggered activity, mainly due to delayed afterdepolarizations (DADs) and micro-reentrant circuits are the main electrophysiological mechanisms in all types of AF (paroxysmal, persistent, and permanent) [6].
In 1998, Haïssaguerre M et al. suggested that pulmonary vein (PV) ectopic activity is implicated in AF pathogenesis, paving the way for pivotal ablative therapeutic modalities such as pulmonary vein isolation (PVI) [7]. Abnormal atrial repolarization (exaggerated beat-to-beat oscillations in action potential duration [APD]) and decreased atrial conduction are shown to mitigate re-entry in patients with AF [8][9].
A frequency-domain approach, utilized to explain AF initiation and maintenance, underscores that AF mechanistic links might be less chaotic than originally thought. In particular, focal impulse and rotor modulation (FIRM) mapping has already achieved a ‘’panoramic’’ bi-atrial view and suggests that a small number of stable high-frequency re-entrant sources (rotors) perpetuate AF fibrillatory waves. This spatiotemporally ordered AF substrate was successfully targeted via FIRM-guided ablation with salutary long-term effects in CONFIRM and RADAR AF trials [10][11].

2.2. Molecular Pathophysiology

2.2.1. Ionic Perturbations

The study of electric remodeling in human atria focuses, mainly, on altered calcium kinetics, impaired inwardly rectifying potassium currents, and gap junction changes.
Abnormal intracellular calcium (Ca2+) handling is critical in triggering DADs and thus increased atrial ectopic activity. In human AF models, enhanced spontaneous sarcoplasmic reticulum (SR) Ca2+ release has been attributed to ryanodine receptor (RyR2) dysregulation [12][13], Ca2+/calmodulin-dependent protein kinase-II (CaMKII) hyperactivity [14][15][16], or SPEG (striated muscle preferentially expressed protein kinase), a regulator of RyR2 phosphorylation and downregulation [17].
L-type Ca [2] current (ICa,L) attenuation leads to atrial APD shortening and seems to be implicated in AF maintenance [18][19]. An effect is at least partially driven by microRNA-21 and microRNA-328 in humans [20][21]. Early re-activation of ICa,L current can also lead to early afterdepolarizations (EADs) and AF initiation [22]. Interestingly, impaired calcium homeostasis in human cardiomyocytes leads to inositol-trisphosphate-receptor (IP3R)/CAMKII signaling, which in turn decrease ICa,L density [23].
Inwardly rectifying potassium (Kir) current (IK1) as well as acetylcholine-activated potassium current (IK,Ach) are enhanced in AF patients and shorten atrial APD [24][25]. MicroRNA-26 and microRNA-1 downregulation leads to increased Kir2.1 protein expression and establishes atrial re-entry via IK1 current activation [26][27]. Both IK1 and IK,Ach currents are critically involved in maintaining a left-to-right dominant frequency gradient in paroxysmal AF (PAF) subjects and explain AF drivers formation (rotors and focal impulses) [28].
Cardiac connexins create gap junctions, facilitating cell-to-cell electrical and molecular signaling [29]. Ultra-structural changes of atrial connexins are noticed in human AF experiments. Connexin-43 (Cx43) dysregulation is present in the atria of AF patients [30] and seems to be regulated through interplay between microRNA-613 and long noncoding RNA HOTAIR (HOX transcript antisense RNA) [31]. Connexin-40 (Cx40) is mainly found in the atrial myocardium and is associated with AF development, as shown in various genetic analyses [32][33][34]. Increased lateralization and hyperphosphorylation of either Cx43 or Cx40 are implicated in human AF pathophysiology [35][36][37].

2.2.2. Structural Changes

Atrial fibrosis is the result of increased fibroblast activity with heterogeneous patchy areas of collagen type I depositions. This favors longer AF periods, LA enlargement, distortion of intercellular electrical coupling, and perpetuation of AF fibrillatory waves [38].
Of note, delicate 3D human atria models suggested that fibrosis reduces atrial conduction velocity and stabilizes rotors and re-entrant circuits [39]. A study including patients with persistent AF, who underwent LA tissue characterization with MRI scans and concomitant high-density mapping of the LA, demonstrated increased AF rotor activity in areas of relatively low and patchy late-gadolinium enhancement (LGE) [40]. Bioinformatics’ analysis has recently revealed that LA–PV junction demonstrates distinct gene expression differences in AF patients as compared to sinus rhythm (SR) controls, favoring extracellular matrix (ECM) synthesis and chemokine up-regulation [41].
TGF-β signaling is strongly associated with these structural changes [42]. Various microRNAs and long noncoding RNAs seem to regulate cardiac fibroblast profibrogenic activity [43][44][45][46][47]. A recently discovered crosstalk between Slit2-Robo1 and TGF-β1/Smad pathways promises potential therapeutic targets against atrial fibrosis [48].
Furthermore, platelet-derived TGF-β secretion stimulates fibroblast proliferation, setting a vicious cycle of atrial fibrosis [49]. Platelet-derived growth factor (PDGF) also leads to increased cardiac fibroblast activity [50] and eventually to atrial fibrosis [51].
Mitogen-activated protein kinase 1 (MAPK1) overexpression, evident in cardiac fibroblast from AF patients, stimulates collagen deposition. An effect that can be mitigated by microRNA-450a-2-3p [52].
Angiotensin II (Ang II) is also known to induce critical ECM changes (increased collagen deposition and metalloproteinase activity) via JAK/STAT3 molecular pathway [53]. Ang II receptor type 1 (AT1) is up-regulated in the LA of subjects suffering AF [54]. Inhibition of AT1 restores intracellular calcium homeostasis and prevents arrhythmogenesis [55]. In addition, fibroblast growth factor 23 (FGF23) is involved in atrial fibrogenesis via increased oxidative stress and STAT3/SMAD3 signaling [56].
Connective tissue growth factor (CTGF) levels in human atrial fibroblasts and epicardial adipose tissue (EAT) are positively correlated with atrial fibrosis and AF arrhythmogenesis [57][58]. MicroRNA-132 and Ang II regulate CTGF levels in human atria [59][60].
Finally, atrial tissue calcitonin levels are inversely correlated with atrial arrhythmogenesis. A recent study suggested that calcitonin halts cardiac fibroblast overactivity and prevents ECM turnover [61].
Apart from generating a fibrotic substrate, cardiac fibroblasts affect cell-to-cell electrical coupling and exhibit altered electrophysiological properties in humans suffering from AF compared to SR controls [62]. This finding necessitates further evaluation, especially in the light of mechanistic data suggesting that fibroblast proliferation leads to complex fractionated atrial electrograms (CFAEs) genesis [63] and action potential propagation block in pulmonary veins [64].

2.2.3. Epicardial Adipose Tissue (EAT) and Autonomic Nervous System (ANS)

From a mechanistic point of view, the EAT in patients with persistent AF (PeAF) seems to be related to rotors capable of maintaining AF [65] and positively associated with low voltage areas, reduced conduction velocity, and CFAE [66][67].
EAT is a known cause of electrophysiological changes, such as heterogeneous atrial conduction slowing. These alterations have been attributed to Cx40 lateralization, excessive fibrosis, and heterogeneous adipose infiltration of the affected atria [68].
Interestingly, a unique molecular footprint has recently been shown in EAT from AF subjects. In particular, EAT derived extracellular vesicles (EVs) exert profibrotic/proinflammatory effects on the neighboring atrial tissue, promoting arrhythmogenesis [69]. In addition, EAT expansion seems to be positively regulated through increased atrial natriuretic peptide (ANP) levels [70].
EAT is metabolically active, and paracrine secretion of inflammatory mediators (IL-1β, among others) [71][72] is associated with atrial fibrillation in humans [73].
EAT-mediated atrial fibrosis has been linked to the PeAF subtype, and CD8+ lymphocyte infiltrates are seemingly involved [74]. Angiopoietin-like protein 2 (Angptl2), YKL-40, CTGF, activin A (TGF-β superfamily) upregulation and Omentin-1 downregulation in human EAT are also implicated in atrial fibrosis and AF development [58][75][76][77][78].
Intrinsic cardiac ANS is organized in a network of ganglionated plexi (GP), which are accommodated in EAT, mainly around PVs [79].
Various methods of cardiac ANS assessment (heart rate variability, [80][81] skin sympathetic nerve activity [82], metaiodobenzylguanidine (MIBG) scintigraphy [83]) imply that ANS instability is implicated in human AF pathogenesis.
The clinical impact of ANS modulation (GP ablation in addition to PVI in patients with PAF [84], chemical; botulinum toxin [85][86] or calcium chloride [87]; autonomic denervation in cardiac surgery patients, transcutaneous vagal nerve stimulation [88]) in managing AF further strengthens the role of autonomic remodeling in AF pathophysiology, and it is further discussed in Section 3: Therapeutic Perspectives.

2.2.4. The Role of Inflammation

Local inflammation is apparent in AF pathophysiology since human LA tissue examination has revealed an infiltrate of varying immune cells (neutrophils, proinflammatory CD68+ macrophages, CD8+ and CD3+ lymphocytes) in AF subjects [89][90][91][92].
IL-6 secretion seems to be a critical mediator in suppressing regulatory T cell function and triggering atrial fibrosis [93]. In addition, macrophage migration inhibitory factor (MIF) release, an early mediator in inflammation cascade, was previously shown to suppress I(Ca,L) current and is also associated with AF genesis [94].
Serum levels of Interleukin-2 soluble receptor and TNF-α soluble receptor are among the stronger predictors of new-onset AF, as assessed via machine learning algorithms in Multi-Ethnic Study of Atherosclerosis (MESA) [95]. This observation is in accordance with other indices of systematic inflammation (TNF-α, hs-CRP, IL-6, IL-8, and IL-18) [96][97][98][99], all of which are up-regulated in the serum of patients with AF. These findings suggest the interplay of an atrial-specific and systematic hyperinflammatory state in AF subjects. Additionally, elevated baseline hs-CRP levels independently predicted arrhythmia recurrence post-ablation and are positively associated with low LA voltage areas, rotors, and non-PV ectopic foci [100].
NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activity is also enhanced in atrial cardiomyocytes from AF patients and brings about electroanatomic remodeling [101]. Post-operative AF (POAF) patients were shown to express a higher level of the activated inflammasome in their atrial tissue, an observation linked to enhanced spontaneous SR Ca2+ release and DADs formation [102].
From a clinical perspective, recent evidence suggests that immunomodulatory agents, such as corticosteroids and colchicine, have a preventive role in POAF development [103][104][105][106] and support the fundamental role of inflammatory pathways in managing AF.

2.2.5. The Role of Proteostasis, Oxidative Stress, and Mitochondrial Bioenergetics

The role of metabolic stress is increasingly recognized in AF pathophysiology, and it is discussed below in view of impaired protein cycling, oxidative stress, and mitochondrial dysfunction.
Proteostasis is defined as the balance between protein synthesis, folding, and degradation [107]. Impaired protein homeostasis is observed in human cellular aging as well as in cardiac diseases [108]. Derailed proteostasis exhibited through heat shock proteins (HSPs) up-regulation, calpain hyperactivity, and autophagosome formation is involved in AF genesis.
HSPs are produced as a response to cellular stress and stabilize other intracellular proteins. HSP27 was previously shown to be up-regulated in the atria of PAF patients and attenuates stress-induced structural changes (myolysis) [109]. In addition, low baseline HSP27 is associated with low LA voltage areas, non-PV foci, and decreased arrhythmia free intervals in patients undergoing ablation for PAF [110]. A more recent study suggests that post-ablation rise in serum HSP27 levels are predictive of arrhythmia recurrence, while baseline levels of different HSPs are of no clinical significance, thus creating a need for further research [111].
Atrial tissue from PeAF patients demonstrates increased macroautophagy (a process of autophagosome formation and eventually lysosomal degradation of damaged proteins), which is linked to reduced I(Ca,L) current and atrial APD shortening in animal studies [112].
Calpain I (a non-lysosomal proteolytic enzyme) activity is enhanced in atrial myocytes of both PAF and PeAF patients and has been linked with APD shortening [113]. Histone deacetylase 6 (HDAC6) hyperactivity, evident in human AF atria, disrupts cytoskeleton (microtubules) and culminates in increased α-tubulin degradation by calpains [114]. Recently, HDAC6 up-regulation was proven capable of triggering atrial fibrosis and Cx lateralization in a rat AF model [115].
In PeAF patients, increased markers of DNA damage were positively associated with poly(ADP-ribose) polymerase (PADP) levels and hint an energy-deficient state. In particular, the physiologic cellular process of DNA repair sometimes leads to exaggerated PADP activity and nicotinamide adenine dinucleotide (NAD+) depletion, which in turn confers oxidative stress and progressive ATP decline [116].
Additionally, increased production of reactive oxygen species (ROS) is implicated in human AF via both local (atrial cardiomyocyte) and systematic (serum) nicotinamide-adenine dinucleotide phosphate oxidase (NOX) activity [117][118]. Low levels of DNA oxidative stress markers in serum or urine from AF patients have been associated with prolonged arrhythmia-free survival [119][120].
Finally, mitochondrial energy production is critically affected in AF patients since reduced oxidative phosphorylation and increased mitochondrial fragmentation lead to ATP depletion [121][122]. POAF patients are also known to exhibit impaired oxidative phosphorylation capacity pre-operatively [123].
Long noncoding RNAs might be involved in mitochondrial bioenergetics, regulating ATP synthase and CYP450 enzymes [124]. Mitochondrial dysfunction is postulated to induce electrical remodeling via oxidative dysfunction of RyR2 [125].
Adenosine monophosphate-regulated protein kinase (AMPK) activity demonstrates a compensatory increase as a response to AF-induced metabolic stress, restoring calcium homeostasis [126], and it is suggested to be a novel therapeutic target.
Evidently, AF pathogenesis involves overlapping cellular and molecular perturbations that hinder us from distinguishing the cause from the effect (see Fugure 1). Since gauging the critical importance of any single mechanism in different clinical AF subtypes is both impractical and unsettled, many therapeutic strategies target multiple mechanisms and seem promising, as discussed in the following section.
Figure 1. Central Illustration Legend: Six overlapping and interlinked (not shown) pathways are implicated in atrial fibrillation pathophysiology: electric remodeling, structural remodeling, autonomic instability, hyperinflammatory milieu, metabolic stress, and epicardial adipose tissue paracrine effects. The common endpoint is the initiation and maintenance of arrhythmic events. IK1—inwardly rectifying potassium current; IK,Ach—acetylcholine-activated potassium current; ANS—autonomic nervous system; Cx—connexin; TGF-β—tissue growth factor β; PDGF—platelet-derived growth factor; AngII—angiotensin II; FGF23—fibroblast growth factor 23; CTGF—connective tissue growth factor; ECM—extracellular matrix; EAT—epicardial adipose tissue; Angptl2—angiopoietin-like protein 2.

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics11091584

References

  1. Hobbelt, A.H.; Siland, J.E.; Geelhoed, B.; Van Der Harst, P.; Hillege, H.L.; Van Gelder, I.C.; Rienstra, M. Clinical, biomarker, and genetic predictors of specific types of atrial fibrillation in a community-based cohort: Data of the PREVEND study. EP Eur. 2017, 19, 226–232.
  2. Kornej, J.; Börschel, C.S.; Benjamin, E.J.; Schnabel, R.B. Epidemiology of Atrial Fibrillation in the 21st Century. Circ. Res. 2020, 127, 4–20.
  3. Hindricks, G.; Potpara, T.; Dagres, N.; Arbelo, E.; Bax, J.J.; Blomström-Lundqvist, C.; Boriani, G.; Castella, M.; Dan, G.-A.; Dilaveris, P.E.; et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 2020, 42, 373–498.
  4. Khasnis, A.; Thakur, R.K. Atrial Fibrillation: A Historical Perspective. Cardiol. Clin. 2009, 27, 1–12.
  5. Perino, A.C.; Leef, G.C.; Cluckey, A.; Yunus, F.N.; Askari, M.; Heidenreich, P.A.; Narayan, S.M.; Wang, P.J.; Turakhia, M.P. Secular trends in success rate of catheter ablation for atrial fibrillation: The SMASH-AF cohort. Am. Heart J. 2019, 208, 110–119.
  6. Burashnikov, A. Investigational Anti–Atrial Fibrillation Pharmacology and Mechanisms by Which Antiarrhythmics Terminate the Arrhythmia: Where Are We in 2020? J. Cardiovasc. Pharmacol. 2020, 76, 492–505.
  7. Haïssaguerre, M.; Jaïs, P.; Shah, D.C.; Takahashi, A.; Hocini, M.; Quiniou, G.; Garrigue, S.; Le Mouroux, A.; Le Métayer, P.; Clémenty, J. Spontaneous Initiation of Atrial Fibrillation by Ectopic Beats Originating in the Pulmonary Veins. N. Engl. J. Med. 1998, 339, 659–666.
  8. Lalani, G.G.; Schricker, A.; Gibson, M.; Rostamian, A.; Krummen, D.E.; Narayan, S.M. Atrial Conduction Slows Immediately Before the Onset of Human Atrial Fibrillation. J. Am. Coll. Cardiol. 2012, 59, 595–606.
  9. Narayan, S.M.; Franz, M.R.; Clopton, P.; Pruvot, E.J.; Krummen, D.E. Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation. Circulation 2011, 123, 2922–2930.
  10. Narayan, S.M.; Baykaner, T.; Clopton, P.; Schricker, A.; Lalani, G.G.; Krummen, D.E.; Shivkumar, K.; Miller, J.M. Ablation of Rotor and Focal Sources Reduces Late Recurrence of Atrial Fibrillation Compared with Trigger Ablation Alone. J. Am. Coll. Cardiol. 2014, 63, 1761–1768.
  11. Atienza, F.; Almendral, J.; Ormaetxe, J.M.; Moya, Á.; Martínez-Alday, J.D.; Hernández-Madrid, A.; Castellanos, E.; Arribas, F.; Arias, M.Á.; Tercedor, L.; et al. Comparison of Radiofrequency Catheter Ablation of Drivers and Circumferential Pulmonary Vein Isolation in Atrial Fibrillation. J. Am. Coll. Cardiol. 2014, 64, 2455–2467.
  12. Voigt, N.; Heijman, J.; Wang, Q.; Chiang, D.Y.; Li, N.; Karck, M.; Wehrens, X.H.T.; Nattel, S.; Dobrev, D. Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients with Paroxysmal Atrial Fibrillation. Circulation 2014, 129, 145–156.
  13. Vest, J.A.; Wehrens, X.H.T.; Reiken, S.R.; Lehnart, S.E.; Dobrev, D.; Chandra, P.; Danilo, P.; Ravens, U.; Rosen, M.R.; Marks, A.R. Defective Cardiac Ryanodine Receptor Regulation During Atrial Fibrillation. Circulation 2005, 111, 2025–2032.
  14. Voigt, N.; Li, N.; Wang, Q.; Wang, W.; Trafford, A.W.; Abu-Taha, I.; Sun, Q.; Wieland, T.; Ravens, U.; Nattel, S.; et al. Enhanced Sarcoplasmic Reticulum Ca2+ Leak and Increased Na+−Ca2+ Exchanger Function Underlie Delayed Afterdepolarizations in Patients with Chronic Atrial Fibrillation. Circulation 2012, 125, 2059–2070.
  15. Neef, S.; Dybkova, N.; Sossalla, S.; Ort, K.R.; Fluschnik, N.; Neumann, K.; Seipelt, R.; Schöndube, F.A.; Hasenfuss, G.; Maier, L.S. CaMKII-Dependent Diastolic SR Ca2+ Leak and Elevated Diastolic Ca2+ Levels in Right Atrial Myocardium of Patients with Atrial Fibrillation. Circ. Res. 2010, 106, 1134–1144.
  16. Yan, J.; Zhao, W.; Thomson, J.K.; Gao, X.; DeMarco, D.M.; Carrillo, E.; Chen, B.; Wu, X.; Ginsburg, K.S.; Bakhos, M.; et al. Stress Signaling JNK2 Crosstalk with CaMKII Underlies Enhanced Atrial Arrhythmogenesis. Circ. Res. 2018, 122, 821–835.
  17. Campbell, H.M.; Quick, A.P.; Abu-Taha, I.; Chiang, D.Y.; Kramm, C.F.; Word, T.A.; Brandenburg, S.; Hulsurkar, M.; Alsina, K.M.; Liu, H.-B.; et al. Loss of SPEG Inhibitory Phosphorylation of Ryanodine Receptor Type-2 Promotes Atrial Fibrillation. Circulation 2020, 142, 1159–1172.
  18. Herraiz-Martínez, A.; Tarifa, C.; Jiménez-Sábado, V.; Llach, A.; Godoy-Marín, H.; Colino-Lage, H.; Nolla-Colomer, C.; Casabella-Ramon, S.; Izquierdo-Castro, P.; Benítez, I.; et al. Influence of sex on intracellular calcium homoeostasis in patients with atrial fibrillation. Cardiovasc. Res. 2021.
  19. Christ, T.; Boknik, P.; Wöhrl, S.; Wettwer, E.; Graf, E.M.; Bosch, R.F.; Knaut, M.; Schmitz, W.; Ravens, U.; Dobrev, D. L-Type Ca2+ Current Downregulation in Chronic Human Atrial Fibrillation Is Associated With Increased Activity of Protein Phosphatases. Circulation 2004, 110, 2651–2657.
  20. Barana, A.; Matamoros, M.; Dolz-Gaitón, P.; Pérez-Hernández, M.; Amorós, I.; Núñez, M.; Sacristán, S.; Pedraz, Á.; Pinto, Á.; Fernández-Avilés, F.; et al. Chronic Atrial Fibrillation Increases MicroRNA-21 in Human Atrial Myocytes Decreasing L-Type Calcium Current. Circ. Arrhythmia Electrophysiol. 2014, 7, 861–868.
  21. Lu, Y.; Zhang, Y.; Wang, N.; Pan, Z.; Gao, X.; Zhang, F.; Zhang, Y.; Shan, H.; Luo, X.; Bai, Y.; et al. MicroRNA-328 Contributes to Adverse Electrical Remodeling in Atrial Fibrillation. Circulation 2010, 122, 2378–2387.
  22. Kettlewell, S.; Saxena, P.; Dempster, J.; Colman, M.A.; Myles, R.C.; Smith, G.L.; Workman, A.J. Dynamic clamping human and rabbit atrial calcium current: Narrowing I CaL window abolishes early afterdepolarizations. J. Physiol. 2019, 597, 3619–3638.
  23. Qi, X.-Y.; Vahdati Hassani, F.; Hoffmann, D.; Xiao, J.; Xiong, F.; Villeneuve, L.R.; Ljubojevic-Holzer, S.; Kamler, M.; Abu-Taha, I.; Heijman, J.; et al. Inositol Trisphosphate Receptors and Nuclear Calcium in Atrial Fibrillation. Circ. Res. 2021, 128, 619–635.
  24. Dobrev, D.; Friedrich, A.; Voigt, N.; Jost, N.; Wettwer, E.; Christ, T.; Knaut, M.; Ravens, U. The G Protein–Gated Potassium Current IK,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation. Circulation 2005, 112, 3697–3706.
  25. Biliczki, P.; Boon, R.A.; Girmatsion, Z.; Bukowska, A.; Ördög, B.; Kaess, B.M.; Hohnloser, S.H.; Goette, A.; Varró, A.; Moritz, A.; et al. Age-related regulation and region-specific distribution of ion channel subunits promoting atrial fibrillation in human left and right atria. EP Eur. 2019, 21, 1261–1269.
  26. Luo, X.; Pan, Z.; Shan, H.; Xiao, J.; Sun, X.; Wang, N.; Lin, H.; Xiao, L.; Maguy, A.; Qi, X.-Y.; et al. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J. Clin. Investig. 2013, 123, 1939–1951.
  27. Girmatsion, Z.; Biliczki, P.; Bonauer, A.; Wimmer-Greinecker, G.; Scherer, M.; Moritz, A.; Bukowska, A.; Goette, A.; Nattel, S.; Hohnloser, S.H.; et al. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm 2009, 6, 1802–1809.
  28. Voigt, N.; Trausch, A.; Knaut, M.; Matschke, K.; Varró, A.; Van Wagoner, D.R.; Nattel, S.; Ravens, U.; Dobrev, D. Left-to-Right Atrial Inward Rectifier Potassium Current Gradients in Patients with Paroxysmal Versus Chronic Atrial Fibrillation. Circ. Arrhythmia Electrophysiol. 2010, 3, 472–480.
  29. Andelova, K.; Egan Benova, T.; Szeiffova Bacova, B.; Sykora, M.; Prado, N.J.; Diez, E.R.; Hlivak, P.; Tribulova, N. Cardiac Connexin-43 Hemichannels and Pannexin1 Channels: Provocative Antiarrhythmic Targets. Int. J. Mol. Sci. 2020, 22, 260.
  30. Adam, O.; Lavall, D.; Theobald, K.; Hohl, M.; Grube, M.; Ameling, S.; Sussman, M.A.; Rosenkranz, S.; Kroemer, H.K.; Schäfers, H.-J.; et al. Rac1-Induced Connective Tissue Growth Factor Regulates Connexin 43 and N-Cadherin Expression in Atrial Fibrillation. J. Am. Coll. Cardiol. 2010, 55, 469–480.
  31. Dai, W.; Chao, X.; Li, S.; Zhou, S.; Zhong, G.; Jiang, Z. Long Noncoding RNA HOTAIR Functions as a Competitive Endogenous RNA to Regulate Connexin43 Remodeling in Atrial Fibrillation by Sponging MicroRNA-613. Cardiovasc. Ther. 2020, 2020, 5925342.
  32. Christophersen, I.E.; Holmegard, H.N.; Jabbari, J.; Haunsø, S.; Tveit, A.; Svendsen, J.H.; Olesen, M.S. Rare Variants in GJA5 Are Associated With Early-Onset Lone Atrial Fibrillation. Can. J. Cardiol. 2013, 29, 111–116.
  33. Santa Cruz, A.; Meşe, G.; Valiuniene, L.; Brink, P.R.; White, T.W.; Valiunas, V. Altered conductance and permeability of Cx40 mutations associated with atrial fibrillation. J. Gen. Physiol. 2015, 146, 387–398.
  34. Wirka, R.C.; Gore, S.; Van Wagoner, D.R.; Arking, D.E.; Lubitz, S.A.; Lunetta, K.L.; Benjamin, E.J.; Alonso, A.; Ellinor, P.T.; Barnard, J.; et al. A Common Connexin-40 Gene Promoter Variant Affects Connexin-40 Expression in Human Atria and Is Associated with Atrial Fibrillation. Circ. Arrhythmia Electrophysiol. 2011, 4, 87–93.
  35. Nao, T.; Ohkusa, T.; Hisamatsu, Y.; Inoue, N.; Matsumoto, T.; Yamada, J.; Shimizu, A.; Yoshiga, Y.; Yamagata, T.; Kobayashi, S.; et al. Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm. Am. J. Cardiol. 2003, 91, 678–683.
  36. Ghazizadeh, Z.; Kiviniemi, T.; Olafsson, S.; Plotnick, D.; Beerens, M.E.; Zhang, K.; Gillon, L.; Steinbaugh, M.J.; Barrera, V.; Sui, S.H.; et al. Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation. Circulation 2020, 141, 301–312.
  37. Dhein, S.; Rothe, S.; Busch, A.; Rojas Gomez, D.; Boldt, A.; Reutemann, A.; Seidel, T.; Salameh, A.; Pfannmüller, B.; Rastan, A.; et al. Effects of metoprolol therapy on cardiac gap junction remodelling and conduction in human chronic atrial fibrillation. Br. J. Pharmacol. 2011, 164, 607–616.
  38. Callegari, S.; Macchi, E.; Monaco, R.; Magnani, L.; Tafuni, A.; Croci, S.; Nicastro, M.; Garrapa, V.; Banchini, A.; Becchi, G.; et al. Clinicopathological Bird’s-Eye View of Left Atrial Myocardial Fibrosis in 121 Patients with Persistent Atrial Fibrillation. Circ. Arrhythmia Electrophysiol. 2020, 13, e007588.
  39. Morgan, R.; Colman, M.A.; Chubb, H.; Seemann, G.; Aslanidi, O.V. Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling. Front. Physiol. 2016, 7, 474.
  40. Nakamura, T.; Kiuchi, K.; Fukuzawa, K.; Takami, M.; Watanabe, Y.; Izawa, Y.; Suehiro, H.; Akita, T.; Takemoto, M.; Sakai, J.; et al. Late-gadolinium enhancement properties associated with atrial fibrillation rotors in patients with persistent atrial fibrillation. J. Cardiovasc. Electrophysiol. 2021, 32, 1005–1013.
  41. Zou, R.; Yang, M.; Shi, W.; Zheng, C.; Zeng, H.; Lin, X.; Zhang, D.; Yang, S.; Hua, P. Analysis of Genes Involved in Persistent Atrial Fibrillation: Comparisons of ‘Trigger’ and ‘Substrate’ Differences. Cell. Physiol. Biochem. 2018, 47, 1299–1309.
  42. Xiao, H.; Lei, H.; Qin, S.; Ma, K.; Wang, X. TGF-β1 Expression and Atrial Myocardium Fibrosis Increase in Atrial Fibrillation Secondary to Rheumatic Heart Disease. Clin. Cardiol. 2010, 33, 149–156.
  43. Su, L.; Yao, Y.; Song, W. Downregulation of miR-96 suppresses the profibrogenic functions of cardiac fibroblasts induced by angiotensin II and attenuates atrial fibrosis by upregulating KLF13. Hum. Cell 2020, 33, 337–346.
  44. Yu, R.-B.; Li, K.; Wang, G.; Gao, G.-M.; Du, J.-X. MiR-23 enhances cardiac fibroblast proliferation and suppresses fibroblast apoptosis via targeting TGF-β1 in atrial fibrillation. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 4419–4424.
  45. Xu, J.; Lei, S.; Sun, S.; Zhang, W.; Zhu, F.; Yang, H.; Xu, Q.; Zhang, B.; Li, H.; Zhu, M.; et al. MiR-324-3p Regulates Fibroblast Proliferation via Targeting TGF-β1 in Atrial Fibrillation. Int. Heart J. 2020, 61, 1270–1278.
  46. Lu, J.; Xu, F.-Q.; Guo, J.-J.; Lin, P.-L.; Meng, Z.; Hu, L.-G.; Li, J.; Li, D.; Lu, X.-H.; An, Y. Long noncoding RNA GAS5 attenuates cardiac fibroblast proliferation in atrial fibrillation via repressing ALK5. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 7605–7610.
  47. Wang, H.; Song, T.; Zhao, Y.; Zhao, J.; Wang, X.; Fu, X. Long non-coding RNA LICPAR regulates atrial fibrosis via TGF-β/Smad pathway in atrial fibrillation. Tissue Cell 2020, 67, 101440.
  48. Liu, Y.; Yin, Z.; Xu, X.; Liu, C.; Duan, X.; Song, Q.; Tuo, Y.; Wang, C.; Yang, J.; Yin, S. Crosstalk between the activated Slit2–Robo1 pathway and TGF-β1 signalling promotes cardiac fibrosis. ESC Heart Fail. 2021, 8, 447–460.
  49. Liu, Y.; Lv, H.; Tan, R.; An, X.; Niu, X.-H.; Liu, Y.-J.; Yang, X.; Yin, X.; Xia, Y.-L. Platelets Promote Ang II (Angiotensin II)-Induced Atrial Fibrillation by Releasing TGF-β1 (Transforming Growth Factor-β1) and Interacting with Fibroblasts. Hypertension 2020, 76, 1856–1867.
  50. Jiang, Z.; Zhong, G.; Wen, L.; Hong, Y.; Fang, S.; Sun, P.; Li, S.; Li, S.; Feng, G. The Role of Platelet-Derived Growth Factor-B/Platelet-Derived Growth Factor Receptor-β Signaling in Chronic Atrial Fibrillation. Cardiology 2016, 133, 242–256.
  51. Yang, D.; Yuan, J.; Liu, G.; Ling, Z.; Zeng, H.; Chen, Y.; Zhang, Y.; She, Q.; Zhou, X. Angiotensin Receptor Blockers and Statins Could Alleviate Atrial Fibrosis via Regulating Platelet-Derived Growth Factor/Rac1 /Nuclear Factor-Kappa B Axis. Int. J. Med. Sci. 2013, 10, 812–824.
  52. Liu, L.; Luo, F.; Lei, K. Exosomes Containing LINC00636 Inhibit MAPK1 through the miR-450a-2-3p Overexpression in Human Pericardial Fluid and Improve Cardiac Fibrosis in Patients with Atrial Fibrillation. Mediat. Inflamm. 2021, 2021, 9960241.
  53. Zheng, L.; Jia, X.; Zhang, C.; Wang, D.; Cao, Z.; Wang, J.; Du, X. Angiotensin II in atrial structural remodeling: The role of Ang II/JAK/STAT3 signaling pathway. Am. J. Transl. Res. 2015, 7, 1021–1031.
  54. Boldt, A.; Wetzel, U.; Weigl, J.; Garbade, J.; Lauschke, J.; Hindricks, G.; Kottkamp, H.; Gummert, J.F.; Dhein, S. Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease. J. Am. Coll. Cardiol. 2003, 42, 1785–1792.
  55. Gassanov, N.; Brandt, M.C.; Michels, G.; Lindner, M.; Er, F.; Hoppe, U.C. Angiotensin II-induced changes of calcium sparks and ionic currents in human atrial myocytes: Potential role for early remodeling in atrial fibrillation. Cell Calcium 2006, 39, 175–186.
  56. Dong, Q.; Li, S.; Wang, W.; Han, L.; Xia, Z.; Wu, Y.; Tang, Y.; Li, J.; Cheng, X. FGF23 regulates atrial fibrosis in atrial fibrillation by mediating the STAT3 and SMAD3 pathways. J. Cell. Physiol. 2019, 234, 19502–19510.
  57. Chen, J.; Guo, Y.; Chen, Q.; Cheng, X.; Xiang, G.; Chen, M.; Wu, H.; Huang, Q.; Zhu, P.; Zhang, J. TGFβ1 and HGF regulate CTGF expression in human atrial fibroblasts and are involved in atrial remodelling in patients with rheumatic heart disease. J. Cell. Mol. Med. 2019, 23, 3032–3039.
  58. Wang, Q.; Xi, W.; Yin, L.; Wang, J.; Shen, H.; Gao, Y.; Min, J.; Zhang, Y.; Wang, Z. Human Epicardial Adipose Tissue cTGF Expression is an Independent Risk Factor for Atrial Fibrillation and Highly Associated with Atrial Fibrosis. Sci. Rep. 2018, 8, 3585.
  59. Qiao, G.; Xia, D.; Cheng, Z.; Zhang, G. miR-132 in atrial fibrillation directly targets connective tissue growth factor. Mol. Med. Rep. 2017, 16, 4143–4150.
  60. Ko, W.-C.; Hong, C.-Y.; Hou, S.-M.; Lin, C.-H.; Ong, E.-T.; Lee, C.-F.; Tsai, C.-T.; Lai, L.-P. Elevated Expression of Connective Tissue Growth Factor in Human Atrial Fibrillation and Angiotensin II-Treated Cardiomyocytes. Circ. J. 2011, 75, 1592–1600.
  61. Moreira, L.M.; Takawale, A.; Hulsurkar, M.; Menassa, D.A.; Antanaviciute, A.; Lahiri, S.K.; Mehta, N.; Evans, N.; Psarros, C.; Robinson, P.; et al. Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia. Nature 2020, 587, 460–465.
  62. Jakob, D.; Klesen, A.; Darkow, E.; Kari, F.A.; Beyersdorf, F.; Kohl, P.; Ravens, U.; Peyronnet, R. Heterogeneity and Remodeling of Ion Currents in Cultured Right Atrial Fibroblasts From Patients With Sinus Rhythm or Atrial Fibrillation. Front. Physiol. 2021, 12.
  63. Ashihara, T.; Haraguchi, R.; Nakazawa, K.; Namba, T.; Ikeda, T.; Nakazawa, Y.; Ozawa, T.; Ito, M.; Horie, M.; Trayanova, N.A. The Role of Fibroblasts in Complex Fractionated Electrograms During Persistent/Permanent Atrial Fibrillation. Circ. Res. 2012, 110, 275–284.
  64. Sánchez, J.; Gomez, J.F.; Martinez-Mateu, L.; Romero, L.; Saiz, J.; Trenor, B. Heterogeneous Effects of Fibroblast-Myocyte Coupling in Different Regions of the Human Atria Under Conditions of Atrial Fibrillation. Front. Physiol. 2019, 10, 847.
  65. Nagashima, K.; Okumura, Y.; Watanabe, I.; Nakai, T.; Ohkubo, K.; Kofune, M.; Mano, H.; Sonoda, K.; Hiro, T.; Nikaido, M.; et al. Does Location of Epicardial Adipose Tissue Correspond to Endocardial High Dominant Frequency or Complex Fractionated Atrial Electrogram Sites During Atrial Fibrillation? Circ. Arrhythmia Electrophysiol. 2012, 5, 676–683.
  66. Zghaib, T.; Ipek, E.G.; Zahid, S.; Balouch, M.A.; Misra, S.; Ashikaga, H.; Berger, R.D.; Marine, J.E.; Spragg, D.D.; Zimmerman, S.L.; et al. Association of left atrial epicardial adipose tissue with electrogram bipolar voltage and fractionation: Electrophysiologic substrates for atrial fibrillation. Heart Rhythm 2016, 13, 2333–2339.
  67. Mahajan, R.; Nelson, A.; Pathak, R.K.; Middeldorp, M.E.; Wong, C.X.; Twomey, D.J.; Carbone, A.; Teo, K.; Agbaedeng, T.; Linz, D.; et al. Electroanatomical Remodeling of the Atria in Obesity. JACC Clin. Electrophysiol. 2018, 4, 1529–1540.
  68. Nalliah, C.J.; Bell, J.R.; Raaijmakers, A.J.A.; Waddell, H.M.; Wells, S.P.; Bernasochi, G.B.; Montgomery, M.K.; Binny, S.; Watts, T.; Joshi, S.B.; et al. Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality. J. Am. Coll. Cardiol. 2020, 76, 1197–1211.
  69. Shaihov-Teper, O.; Ram, E.; Ballan, N.; Brzezinski, R.Y.; Naftali-Shani, N.; Masoud, R.; Ziv, T.; Lewis, N.; Schary, Y.; Levin-Kotler, L.-P.; et al. Extracellular Vesicles From Epicardial Fat Facilitate Atrial Fibrillation. Circulation 2021, 143, 2475–2493.
  70. Suffee, N.; Moore-Morris, T.; Farahmand, P.; Rücker-Martin, C.; Dilanian, G.; Fradet, M.; Sawaki, D.; Derumeaux, G.; LePrince, P.; Clément, K.; et al. Atrial natriuretic peptide regulates adipose tissue accumulation in adult atria. Proc. Natl. Acad. Sci. USA 2017, 114, E771–E780.
  71. Liu, Q.; Zhang, F.; Yang, M.; Zhong, J. Increasing Level of Interleukin-1β in Epicardial Adipose Tissue Is Associated with Persistent Atrial Fibrillation. J. Interf. Cytokine Res. 2020, 40, 64–69.
  72. Couselo-Seijas, M.; Lopez-Canoa, J.N.; Fernandez, Á.L.; González-Melchor, L.; Seoane, L.M.; Duran-Muñoz, D.; Rozados-Luis, A.; González-Juanatey, J.R.; Rodríguez-Mañero, M.; Eiras, S. Inflammatory and lipid regulation by cholinergic activity in epicardial stromal cells from patients who underwent open-heart surgery. J. Cell. Mol. Med. 2020, 24, 10958–10969.
  73. Kusayama, T.; Furusho, H.; Kashiwagi, H.; Kato, T.; Murai, H.; Usui, S.; Kaneko, S.; Takamura, M. Inflammation of left atrial epicardial adipose tissue is associated with paroxysmal atrial fibrillation. J. Cardiol. 2016, 68, 406–411.
  74. Haemers, P.; Hamdi, H.; Guedj, K.; Suffee, N.; Farahmand, P.; Popovic, N.; Claus, P.; LePrince, P.; Nicoletti, A.; Jalife, J.; et al. Atrial fibrillation is associated with the fibrotic remodelling of adipose tissue in the subepicardium of human and sheep atria. Eur. Heart J. 2017, 38, 53–61.
  75. Kira, S.; Abe, I.; Ishii, Y.; Miyoshi, M.; Oniki, T.; Arakane, M.; Daa, T.; Teshima, Y.; Yufu, K.; Shimada, T.; et al. Role of angiopoietin-like protein 2 in atrial fibrosis induced by human epicardial adipose tissue: Analysis using an organo-culture system. Heart Rhythm 2020, 17, 1591–1601.
  76. Chen, Y.; Liu, F.; Han, F.; Lv, L.; Tang, C.; Xie, Z.; Luo, F. Omentin-1 is associated with atrial fibrillation in patients with cardiac valve disease. BMC Cardiovasc. Disord. 2020, 20, 214.
  77. Venteclef, N.; Guglielmi, V.; Balse, E.; Gaborit, B.; Cotillard, A.; Atassi, F.; Amour, J.; Leprince, P.; Dutour, A.; Clément, K.; et al. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur. Heart J. 2015, 36, 795–805.
  78. Wang, Q.; Shen, H.; Min, J.; Gao, Y.; Liu, K.; Xi, W.; Yang, J.; Yin, L.; Xu, J.; Xiao, J.; et al. YKL-40 is highly expressed in the epicardial adipose tissue of patients with atrial fibrillation and associated with atrial fibrosis. J. Transl. Med. 2018, 16, 229.
  79. Aksu, T.; Yalin, K.; Bozyel, S.; Gopinathannair, R.; Gupta, D. The anatomical basis behind the neuromodulation effects associated with pulmonary vein isolation. J. Cardiovasc. Electrophysiol. 2021, 32, 1733–1736.
  80. Pachon, J.C.; Pachon, E.I.; Pachon, C.T.C.; Santillana, T.G.; Lobo, T.J.; Pachon, J.C.; Zerpa, J.C.; Cunha, M.Z.; Higuti, C.; Ortencio, F.A.; et al. Long-Term Evaluation of the Vagal Denervation by Cardioneuroablation Using Holter and Heart Rate Variability. Circ. Arrhythmia Electrophysiol. 2020, 13, e008703.
  81. Zhu, Z.; Wang, W.; Cheng, Y.; Wang, X.; Sun, J. The predictive value of heart rate variability indices tested in early period after radiofrequency catheter ablation for the recurrence of atrial fibrillation. J. Cardiovasc. Electrophysiol. 2020, 31, 1350–1355.
  82. Kusayama, T.; Douglas, A.; Wan, J.; Doytchinova, A.; Wong, J.; Mitscher, G.; Straka, S.; Shen, C.; Everett, T.H.; Chen, P.-S. Skin sympathetic nerve activity and ventricular rate control during atrial fibrillation. Heart Rhythm 2020, 17, 544–552.
  83. Kawasaki, M.; Yamada, T.; Furukawa, Y.; Morita, T.; Tamaki, S.; Kida, H.; Sakata, Y.; Fukunami, M. Are cardiac sympathetic nerve activity and epicardial adipose tissue associated with atrial fibrillation recurrence after catheter ablation in patients without heart failure? Int. J. Cardiol. 2020, 303, 41–48.
  84. Kampaktsis, P.N.; Oikonomou, E.K.; Choi, D.Y.; Cheung, J.W. Efficacy of ganglionated plexi ablation in addition to pulmonary vein isolation for paroxysmal versus persistent atrial fibrillation: A meta-analysis of randomized controlled clinical trials. J. Interv. Card. Electrophysiol. 2017, 50, 253–260.
  85. Waldron, N.H.; Cooter, M.; Haney, J.C.; Schroder, J.N.; Gaca, J.G.; Lin, S.S.; Sigurdsson, M.I.; Fudim, M.; Podgoreanu, M.V.; Stafford-Smith, M.; et al. Temporary autonomic modulation with botulinum toxin type A to reduce atrial fibrillation after cardiac surgery. Heart Rhythm 2019, 16, 178–184.
  86. Romanov, A.; Pokushalov, E.; Ponomarev, D.; Bayramova, S.; Shabanov, V.; Losik, D.; Stenin, I.; Elesin, D.; Mikheenko, I.; Strelnikov, A.; et al. Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: Three-year follow-up of a randomized study. Heart Rhythm 2019, 16, 172–177.
  87. Wang, H.; Zhang, Y.; Xin, F.; Jiang, H.; Tao, D.; Jin, Y.; He, Y.; Wang, Q.; Po, S.S. Calcium-Induced Autonomic Denervation in Patients with Post-Operative Atrial Fibrillation. J. Am. Coll. Cardiol. 2021, 77, 57–67.
  88. Stavrakis, S.; Stoner, J.A.; Humphrey, M.B.; Morris, L.; Filiberti, A.; Reynolds, J.C.; Elkholey, K.; Javed, I.; Twidale, N.; Riha, P.; et al. TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation). JACC Clin. Electrophysiol. 2020, 6, 282–291.
  89. Wu, J.; Deng, H.; Chen, Q.; Wu, Q.; Li, X.; Jiang, S.; Wang, F.; Ye, F.; Ou, L.; Gao, H. Comprehensive Analysis of Differential Immunocyte Infiltration and Potential ceRNA Networks Involved in the Development of Atrial Fibrillation. BioMed Res. Int. 2020, 2020, 8021208.
  90. Hohmann, C.; Pfister, R.; Mollenhauer, M.; Adler, C.; Kozlowski, J.; Wodarz, A.; Drebber, U.; Wippermann, J.; Michels, G. Inflammatory cell infiltration in left atrial appendageal tissues of patients with atrial fibrillation and sinus rhythm. Sci. Rep. 2020, 10, 1685.
  91. Yamashita, T.; Sekiguchi, A.; Iwasaki, Y.; Date, T.; Sagara, K.; Tanabe, H.; Suma, H.; Sawada, H.; Aizawa, T. Recruitment of Immune Cells Across Atrial Endocardium in Human Atrial Fibrillation. Circ. J. 2010, 74, 262–270.
  92. Smorodinova, N.; Bláha, M.; Melenovský, V.; Rozsívalová, K.; Přidal, J.; Ďurišová, M.; Pirk, J.; Kautzner, J.; Kučera, T. Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm. PLoS ONE 2017, 12, e0172691.
  93. Chen, Y.; Chang, G.; Chen, X.; Li, Y.; Li, H.; Cheng, D.; Tang, Y.; Sang, H. IL-6-miR-210 Suppresses Regulatory T Cell Function and Promotes Atrial Fibrosis by Targeting Foxp3. Mol. Cells 2020, 43, 438–447.
  94. Rao, F.; Deng, C.-Y.; Wu, S.-L.; Xiao, D.-Z.; Yu, X.-Y.; Kuang, S.-J.; Lin, Q.-X.; Shan, Z.-X. Involvement of Src in L-type Ca2+ channel depression induced by macrophage migration inhibitory factor in atrial myocytes. J. Mol. Cell. Cardiol. 2009, 47, 586–594.
  95. Ambale-Venkatesh, B.; Yang, X.; Wu, C.O.; Liu, K.; Hundley, W.G.; McClelland, R.; Gomes, A.S.; Folsom, A.R.; Shea, S.; Guallar, E.; et al. Cardiovascular Event Prediction by Machine Learning. Circ. Res. 2017, 121, 1092–1101.
  96. Pan, J.; Wang, W.; Wu, X.; Kong, F.; Pan, J.; Lin, J.; Zhang, M. Inflammatory cytokines in cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation. Panminerva Med. 2018, 60, 86–91.
  97. Maida, C.D.; Vasto, S.; Di Raimondo, D.; Casuccio, A.; Vassallo, V.; Daidone, M.; Del Cuore, A.; Pacinella, G.; Cirrincione, A.; Simonetta, I.; et al. Inflammatory activation and endothelial dysfunction markers in patients with permanent atrial fibrillation: A cross-sectional study. Aging 2020, 12, 8423–8433.
  98. De Gennaro, L.; Brunetti, N.D.; Montrone, D.; De Rosa, F.; Cuculo, A.; Di Biase, M. Inflammatory activation and carbohydrate antigen-125 levels in subjects with atrial fibrillation. Eur. J. Clin. Investig. 2012, 42, 371–375.
  99. Liuba, I.; Ahlmroth, H.; Jonasson, L.; Englund, A.; Jonsson, A.; Safstrom, K.; Walfridsson, H. Source of inflammatory markers in patients with atrial fibrillation. Europace 2008, 10, 848–853.
  100. Lin, Y.-J.; Tsao, H.-M.; Chang, S.-L.; Lo, L.-W.; Tuan, T.-C.; Hu, Y.-F.; Udyavar, A.R.; Tsai, W.-C.; Chang, C.-J.; Tai, C.-T.; et al. Prognostic Implications of the High-Sensitive C-Reactive Protein in the Catheter Ablation of Atrial Fibrillation. Am. J. Cardiol. 2010, 105, 495–501.
  101. Yao, C.; Veleva, T.; Scott, L.; Cao, S.; Li, L.; Chen, G.; Jeyabal, P.; Pan, X.; Alsina, K.M.; Abu-Taha, I.; et al. Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation. Circulation 2018, 138, 2227–2242.
  102. Heijman, J.; Muna, A.P.; Veleva, T.; Molina, C.E.; Sutanto, H.; Tekook, M.; Wang, Q.; Abu-Taha, I.H.; Gorka, M.; Künzel, S.; et al. Atrial myocyte NLRP3/CaMKII nexus forms a substrate for postoperative atrial fibrillation. Circ. Res. 2020, 127, 1036–1055.
  103. Liu, C.; Wang, J.; Yiu, D.; Liu, K. The Efficacy of Glucocorticoids for the Prevention of Atrial Fibrillation, or Length of Intensive Care Unite or Hospital Stay After Cardiac Surgery: A Meta-Analysis. Cardiovasc. Ther. 2014, 32, 89–96.
  104. Liu, L.; Jing, F.-Y.; Wang, X.-W.; Li, L.-J.; Zhou, R.-Q.; Zhang, C.; Wu, Q.-C. Effects of corticosteroids on new-onset atrial fibrillation after cardiac surgery. Medicine 2021, 100, e25130.
  105. Papageorgiou, N.; Briasoulis, A.; Lazaros, G.; Imazio, M.; Tousoulis, D. Colchicine for prevention and treatment of cardiac diseases: A meta-analysis. Cardiovasc. Ther. 2017, 35, 10–18.
  106. Deftereos, S.G.; Vrachatis, D.A.; Angelidis, C.; Vrettou, A.-R.; Sarri, E.K.; Giotaki, S.G.; Varytimiadi, E.; Kossyvakis, C.; Kotsia, E.; Deftereos, G.S.; et al. The Role of Colchicine in Treating Postoperative and Post-catheter Ablation Atrial Fibrillation. Clin. Ther. 2019, 41, 21–29.
  107. Sabath, N.; Levy-Adam, F.; Younis, A.; Rozales, K.; Meller, A.; Hadar, S.; Soueid-Baumgarten, S.; Shalgi, R. Cellular proteostasis decline in human senescence. Proc. Natl. Acad. Sci. USA 2020, 117, 31902–31913.
  108. Arrieta, A.; Blackwood, E.A.; Stauffer, W.T.; Glembotski, C.C. Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart. Front. Cardiovasc. Med. 2020, 6, 193.
  109. Brundel, B.J.J.M.; Henning, R.H.; Ke, L.; van Gelder, I.C.; Crijns, H.J.G.M.; Kampinga, H.H. Heat shock protein upregulation protects against pacing-induced myolysis in HL-1 atrial myocytes and in human atrial fibrillation. J. Mol. Cell. Cardiol. 2006, 41, 555–562.
  110. Hu, Y.-F.; Yeh, H.-I.; Tsao, H.-M.; Tai, C.-T.; Lin, Y.-J.; Chang, S.-L.; Lo, L.-W.; Tuan, T.-C.; Suenari, K.; Li, C.-H.; et al. Electrophysiological Correlation and Prognostic Impact of Heat Shock Protein 27 in Atrial Fibrillation. Circ. Arrhythmia Electrophysiol. 2012, 5, 334–340.
  111. Marion, D.; Lanters, E.A.; Ramos, K.S.; Li, J.; Wiersma, M.; Baks-te Bulte, L.; JQMMuskens, A.; Boersma, E.; de Groot, N.; Brundel, B.J. Evaluating Serum Heat Shock Protein Levels as Novel Biomarkers for Atrial Fibrillation. Cells 2020, 9, 2105.
  112. Wiersma, M.; Meijering, R.A.M.; Qi, X.; Zhang, D.; Liu, T.; Hoogstra-Berends, F.; Sibon, O.C.M.; Henning, R.H.; Nattel, S.; Brundel, B.J.J.M. Endoplasmic Reticulum Stress Is Associated with Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation. J. Am. Heart Assoc. 2017, 6, e006458.
  113. Brundel, B. Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation. Cardiovasc. Res. 2002, 54, 380–389.
  114. Zhang, D.; Wu, C.-T.; Qi, X.; Meijering, R.A.M.; Hoogstra-Berends, F.; Tadevosyan, A.; Cubukcuoglu Deniz, G.; Durdu, S.; Akar, A.R.; Sibon, O.C.M.; et al. Activation of Histone Deacetylase-6 Induces Contractile Dysfunction Through Derailment of α-Tubulin Proteostasis in Experimental and Human Atrial Fibrillation. Circulation 2014, 129, 346–358.
  115. Sawa, Y.; Matsushita, N.; Sato, S.; Ishida, N.; Saito, M.; Sanbe, A.; Morino, Y.; Taira, E.; Obara, M.; Hirose, M. Chronic HDAC6 Activation Induces Atrial Fibrillation Through Atrial Electrical and Structural Remodeling in Transgenic Mice. Int. Heart J. 2021, 62, 616–626.
  116. Zhang, D.; Hu, X.; Li, J.; Liu, J.; Baks-te Bulte, L.; Wiersma, M.; Malik, N.-A.; van Marion, D.M.S.; Tolouee, M.; Hoogstra-Berends, F.; et al. DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation. Nat. Commun. 2019, 10, 1307.
  117. Kim, Y.M.; Guzik, T.J.; Zhang, Y.H.; Zhang, M.H.; Kattach, H.; Ratnatunga, C.; Pillai, R.; Channon, K.M.; Casadei, B. A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ. Res. 2005, 97, 629–636.
  118. Liu, T.; Shao, Q.; Korantzopoulos, P.; Liu, E.; Xu, G.; Li, G. Serum levels of nicotinamide-adenine dinucleotide phosphate oxidase 4 are associated with non-valvular atrial fibrillation. Biomed. Rep. 2015, 3, 864–868.
  119. Li, J.; Zhang, D.; Ramos, K.S.; Baks, L.; Wiersma, M.; Lanters, E.A.H.; Bogers, A.J.J.C.; de Groot, N.M.S.; Brundel, B.J.J.M. Blood-based 8-hydroxy-2′-deoxyguanosine level: A potential diagnostic biomarker for atrial fibrillation. Heart Rhythm 2021, 18, 271–277.
  120. Toyama, K.; Yamabe, H.; Uemura, T.; Nagayoshi, Y.; Morihisa, K.; Koyama, J.; Kanazawa, H.; Hoshiyama, T.; Ogawa, H. Analysis of oxidative stress expressed by urinary level of 8-hydroxy-2′-deoxyguanosine and biopyrrin in atrial fibrillation: Effect of sinus rhythm restoration. Int. J. Cardiol. 2013, 168, 80–85.
  121. Wiersma, M.; van Marion, D.; Wüst, R.C.; Houtkooper, R.H.; Zhang, D.; de Groot, N.; Henning, R.H.; Brundel, B.J. Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation. Cells 2019, 8, 1202.
  122. Emelyanova, L.; Ashary, Z.; Cosic, M.; Negmadjanov, U.; Ross, G.; Rizvi, F.; Olet, S.; Kress, D.; Sra, J.; Tajik, A.J.; et al. Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation. Am. J. Physiol. Circ. Physiol. 2016, 311, H54–H63.
  123. Montaigne, D.; Marechal, X.; Lefebvre, P.; Modine, T.; Fayad, G.; Dehondt, H.; Hurt, C.; Coisne, A.; Koussa, M.; Remy-Jouet, I.; et al. Mitochondrial Dysfunction as an Arrhythmogenic Substrate. J. Am. Coll. Cardiol. 2013, 62, 1466–1473.
  124. Chen, G.; Guo, H.; Song, Y.; Chang, H.; Wang, S.; Zhang, M.; Liu, C. Long non-coding RNA AK055347 is upregulated in patients with atrial fibrillation and regulates mitochondrial energy production in myocardiocytes. Mol. Med. Rep. 2016, 14, 5311–5317.
  125. Xie, W.; Santulli, G.; Reiken, S.R.; Yuan, Q.; Osborne, B.W.; Chen, B.-X.; Marks, A.R. Mitochondrial oxidative stress promotes atrial fibrillation. Sci. Rep. 2015, 5, 11427.
  126. Harada, M.; Tadevosyan, A.; Qi, X.; Xiao, J.; Liu, T.; Voigt, N.; Karck, M.; Kamler, M.; Kodama, I.; Murohara, T.; et al. Atrial Fibrillation Activates AMP-Dependent Protein Kinase and its Regulation of Cellular Calcium Handling. J. Am. Coll. Cardiol. 2015, 66, 47–58.
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