Atrial fibrillation pathophysiology: Difference between revisions

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{{Template:Atrial fibrillation}}
{{Template:Atrial fibrillation}}


{{CMG}}
{{CMG}}; {{AE}} {{Anahita}}{{HK}}  


==Overview==
==Overview==
The primary pathologic or structural change observed in patients with atrial fibrillation is progressive [[fibrosis]] of the [[atria]]. This fibrosis is primarily due to atrial dilatation, however [[genetic]] causes and [[inflammation]] may also play a role in some individuals. There are other functional processes that contribute to the development and persistence of atrial fibrillation including [[hemodynamic]] stress (stretching of the atrium), atrial [[ischemia]], activation of the neurohormonal system, ectopic activity in the [[pulmonary vein]], multiple wavelets of electrical activity in the atrium, and [[catecholamine]] excess. The mechanism in most patients is likely to be multifactorial.
Numerous triggers such as [[Sympathetic nervous system|sympathetic]] or [[Parasympathetic nervous system|parasympathetic]] stimulation, [[Ectopic pacemaker|ectopic activity]] in [[muscle|muscular]] sleeves, [[atrial]] stretch, premature [[atrial]] beats and accessory [[Atrioventricular|AV]] ([[Atrioventricular|atrio-ventricular]]) pathways have been responsible in initiation of [[atrial fibrillation]]. Younger [[patients]] with paroxysmal [[atrial fibrillation]] may have [[Ectopic pacemaker|ectopic foci]] of electrical activity in the [[pulmonary vein]]. While the [[Pulmonary veins|pulmonary vein]] is a common source of these [[Ectopic pacemaker|ectopic foci]], there may also be foci present in the [[atrium]] itself. Unfortunately the reason why the [[Pulmonary veins|pulmonary vein]] turns to an arrhythmogenic foci is not fully understood. It seems that structure of the [[Pulmonary veins|pulmonary vein]] makes it potential for re-entry formation which can lead to [[atrial fibrillation]]. Presence of the aformentioned triggers produce re-enterant wavelets of electrical activity due to shortened [[effective refractory period]] ([[effective refractory period|ERP]]). Furthermore mechanosensitivity of [[cardiac]] [[myocytes]] is thought to play a pivotal role in initiation of [[atrial fibrillation]]. Mechanisms such as altered [[Cardiac muscle|myocyte]] stress/strain, [[catecholamine]] release secondary to [[atrium|atrial]] stretch and activation of [[G protein|G-protein coupled pathways]] have been introduced in the [[pathogenesis]] of [[atrial fibrillation]]. Dilatation of the [[atrium|atria]] can be due to structural abnormalities such as [[hypertension]], [[valvular heart disease]] and [[congestive heart failure]] that can cause a rise in the [[heart|intra-cardiac]] pressures. Once dilatation of the [[atrium|atria]] has occurred, this begins a chain of events that leads to the activation of the [[renin-angiotensin system|renin aldosterone angiotensin system]] ([[renin-angiotensin system|RAAS]]) and subsequent increase in matrix metaloproteinases and [[disintegrin]], which leads to [[atrium|atrial]] remodeling and [[fibrosis]], with loss of [[atrium|atrial]] [[muscle]] mass. In addition any [[inflammation|inflammatory state]] that affects the [[heart]] can cause [[fibrosis]] of the [[atria]]. This is typically due to [[sarcoidosis]] but may also be due to [[autoimmune disorders]] that create [[autoantibodies]] against [[myosin]] heavy chains. There are numerous evidences for presence of a relationship between [[autonomic nervous system]] and it's function and the [[Cardiac electrophysiology|atrial electrophysiology]] and [[atrial fibrillation]] development. Multiple associated [[genes]] to [[atrial fibrillation]] have been found. [[Connexin|Connexin 40]], [[potassium]] [[Voltage-gated ion channel|voltage-gated channels]], [[Atrial natriuretic peptide|natriuretic peptide]] precursor A and [[LMNA|lamin A/C]] are some of the known [[genes]] that are related to [[atrial fibrillation]] [[pathogenesis]]. The presence of [[atrial fibrillation]] often reflects the presence of an underlying [[cardiology|cardiac]] or [[respiratory disease|lung disease]]. Indeed, the proportion of [[patients]] with lone [[atrial fibrillation]] is low (approximately 12% of cases). On [[gross pathology]] [[atrium|atrial]] enlargement has been found with [[Echocardiography|echocardiographic]] evaluations as a consequence of [[atrial fibrillation]]. On [[pathology|microscopic pathology]] lateralization of [[Gap junction|gap junctional proteins]] (such as [[GJA1|connexin 43]] ([[GJA1|Cx43]]), [[GJA5|connexin 40]] ([[GJA5|Cx40]]) and [[Cadherin|N-cadherin]]) have been found. Furthermore there is an approximately 57% reduce in [[GJA1|connexin 43]] ([[GJA1|Cx43]]) in right [[atrium]] appendages and walls.


==Pathophysiology==
==Pathophysiology==


=== Triggers ===
===Pathogenesis===
Onset of atrial fibrillation is dependent upon specific triggers and tissue substrate capable of maintaining atrial fibrillation. The following triggers are know to initiate atrial fibrillation:
Onset of [[atrial fibrillation]] is dependent upon specific triggers and [[Tissue (biology)|tissue]] substrates capable of maintaining [[atrial fibrillation]]. The following triggers are know to initiate [[atrial fibrillation]]:<ref name="pmid17336878">{{cite journal |vauthors=Wit AL, Boyden PA |title=Triggered activity and atrial fibrillation |journal=Heart Rhythm |volume=4 |issue=3 Suppl |pages=S17–23 |date=March 2007 |pmid=17336878 |pmc=1855225 |doi=10.1016/j.hrthm.2006.12.021 |url=}}</ref><ref name="pmid11156892">{{cite journal| author=Allessie MA, Boyden PA, Camm AJ, Kléber AG, Lab MJ, Legato MJ | display-authors=etal| title=Pathophysiology and prevention of atrial fibrillation. | journal=Circulation | year= 2001 | volume= 103 | issue= 5 | pages= 769-77 | pmid=11156892 | doi=10.1161/01.cir.103.5.769 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11156892  }} </ref><ref name="pmid9725923">{{cite journal| author=Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G | display-authors=etal| title=Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. | journal=N Engl J Med | year= 1998 | volume= 339 | issue= 10 | pages= 659-66 | pmid=9725923 | doi=10.1056/NEJM199809033391003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9725923  }} </ref><ref name="pmid6218936">{{cite journal| author=Mary-Rabine L, Albert A, Pham TD, Hordof A, Fenoglio JJ, Malm JR | display-authors=etal| title=The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure. | journal=Circ Res | year= 1983 | volume= 52 | issue= 2 | pages= 188-99 | pmid=6218936 | doi=10.1161/01.res.52.2.188 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6218936  }} </ref>
* Sympathetic or parasympathetic stimulation
* [[Sympathetic nervous system|Sympathetic]] or [[Parasympathetic nervous system|parasympathetic]] stimulation
* Ectopic activity in muscular sleeves that extend from the left atrium into the proximal parts of pulmonary veins
* [[Ectopic pacemaker|Ectopic activity]] in [[muscle|muscular]] sleeves that extend from the [[left atrium]] into the proximal parts of [[pulmonary veins]]
* Atrial stretch
**The aforementioned regions are a mixture of [[atrium|atrial]] myocardium and [[smooth muscle]] in [[coronary sinus]] and [[Heart valve|atrioventricular valves]].
* Bradycardia
**When function normally these regions have a synchronous electrical activity, which can act as a trigger by producing delayed afterdepolarizations.
* Premature atrial beats
* [[Atrial]] stretch
* Accessory AV (atrio-ventricular) pathways
**It could be result of [[hypertension]], [[heart failure]] or [[valvular heart disease]]
**Decreased [[resting potential]] and [[action potential]] velocity due to the stretched [[atrium]]
* [[Bradycardia]]
* Premature [[atrial]] beats
* Accessory [[Atrioventricular|AV]] ([[Atrioventricular|atrio-ventricular]]) pathways


===Ectopic Foci in the Pulmonary Vein===
====Ectopic Foci in the Pulmonary Vein====
* Younger patients with paroxysmal atrial fibrillation will sometimes have ectopic foci of electrical activity in the [[pulmonary vein]] that can be ablated.  There are cells in the pulmonary vein whose electrical properties resemble those of the [[myocytes]] of the atrium.  These patients generally have high grade ectopic activity on [[Holter monitoring]]. While the pulmonary vein is a common source of these ectopic foci, there may also be foci present in the [[atrium]] itself.  While the pulmonary vein may function as a trigger, it is the heterogeneity of conduction that may sustain the atrial fibrillation
*Younger [[patients]] with paroxysmal [[atrial fibrillation]] may have [[Ectopic pacemaker|ectopic foci]] of electrical activity in the [[pulmonary vein]] that can be [[ablation|ablated]] by the [[radiofrequency]]. <ref name="pmid22083148">{{cite journal| author=Iwasaki YK, Nishida K, Kato T, Nattel S| title=Atrial fibrillation pathophysiology: implications for management. | journal=Circulation | year= 2011 | volume= 124 | issue= 20 | pages= 2264-74 | pmid=22083148 | doi=10.1161/CIRCULATIONAHA.111.019893 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22083148  }} </ref><ref name="pmid9725923">{{cite journal| author=Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G | display-authors=etal| title=Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. | journal=N Engl J Med | year= 1998 | volume= 339 | issue= 10 | pages= 659-66 | pmid=9725923 | doi=10.1056/NEJM199809033391003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9725923 }} </ref><ref name="pmid20962102">{{cite journal| author=Nishida K, Maguy A, Sakabe M, Comtois P, Inoue H, Nattel S| title=The role of pulmonary veins vs. autonomic ganglia in different experimental substrates of canine atrial fibrillation. | journal=Cardiovasc Res | year= 2011 | volume= 89 | issue= 4 | pages= 825-33 | pmid=20962102 | doi=10.1093/cvr/cvq332 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20962102  }} </ref>
*There are some [[Cell (biology)|cells]] in the [[Pulmonary veins|pulmonary vein]] whose electrical properties resemble those of the [[myocytes]] of the [[atrium]] and are responsible for the rapid discharge through the [[atrium]].<ref name="pmid9725923">{{cite journal| author=Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G | display-authors=etal| title=Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. | journal=N Engl J Med | year= 1998 | volume= 339 | issue= 10 | pages= 659-66 | pmid=9725923 | doi=10.1056/NEJM199809033391003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9725923 }} </ref> 
*These [[patients]] generally have high grade [[Ectopic pacemaker|ectopic]] activity on [[Holter monitoring]].  
*While the [[Pulmonary veins|pulmonary vein]] is a common source of these [[Ectopic pacemaker|ectopic foci]], there may also be foci present in the [[atrium]] itself.   
*While the [[Pulmonary veins|pulmonary vein]] may function as a trigger, it is the [[Heterogeneous|heterogeneity]] of conduction that may sustain the [[atrial fibrillation]].
*Methods such as [[fluoroscopy]], [[Angiogram|angiographic imaging]] and [[heart|intracardiac]] mapping have been detected [[Pulmonary veins|pulmonary vein]] as the responsible origin of this [[Cardiac arrhythmia|arrythmia]].
*Based on a study done in 1998 on 45 [[patients]] with [[atrial fibrillation]] demonstrated that in 94% of cases [[Pulmonary veins|pulmonary vein]] is the origin of abnormal electrical activity.<ref name="pmid9725923">{{cite journal| author=Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G | display-authors=etal| title=Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. | journal=N Engl J Med | year= 1998 | volume= 339 | issue= 10 | pages= 659-66 | pmid=9725923 | doi=10.1056/NEJM199809033391003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9725923  }} </ref>
*Unfortunately the reason why the [[Pulmonary veins|pulmonary vein]] turns to an arrhythmogenic foci is not fully understood. It seems that structure of the [[Pulmonary veins|pulmonary vein]] makes it potential for re-entry formation which can lead to [[atrial fibrillation]].<ref name="pmid15936621">{{cite journal| author=Po SS, Li Y, Tang D, Liu H, Geng N, Jackman WM | display-authors=etal| title=Rapid and stable re-entry within the pulmonary vein as a mechanism initiating paroxysmal atrial fibrillation. | journal=J Am Coll Cardiol | year= 2005 | volume= 45 | issue= 11 | pages= 1871-7 | pmid=15936621 | doi=10.1016/j.jacc.2005.02.070 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15936621  }} </ref>


=== Re-enterant Wavelets or Multiple Wavelets Phenomenon ===
==== Re-enterant Wavelets or Multiple Wavelets Phenomenon ====
* Presence of these triggers produce re-enterant wavelets of electrical activity due to shortened effective refractory period (ERP)
* Presence of these triggers produce re-enterant wavelets of electrical activity due to shortened [[effective refractory period]] ([[effective refractory period|ERP]]).<ref name="pmid10845084">{{cite journal| author=Nattel S, Li D, Yue L| title=Basic mechanisms of atrial fibrillation--very new insights into very old ideas. | journal=Annu Rev Physiol | year= 2000 | volume= 62 | issue=  | pages= 51-77 | pmid=10845084 | doi=10.1146/annurev.physiol.62.1.51 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10845084  }} </ref><ref name="pmid28383023">{{cite journal| author=Nattel S, Xiong F, Aguilar M| title=Demystifying rotors and their place in clinical translation of atrial fibrillation mechanisms. | journal=Nat Rev Cardiol | year= 2017 | volume= 14 | issue= 9 | pages= 509-520 | pmid=28383023 | doi=10.1038/nrcardio.2017.37 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28383023  }} </ref>
* It has been hypothesized that if there is a greater atrial mass, delayed atrial conduction times, and a shortened atrial refractory period, then this promotes the propagation of wavelets.<ref>Akyürek O, Sayin T, Dinçer I, Karaoguz R, Güldal M, Oral D. Lengthening of intraatrial conduction time in atrial fibrillation and its relation with early recurrence of atrial fibrillation. Jpn Heart J. Sep 2001;42(5):575-84.</ref>  This hypothesis is supported by the observation that prolongation of intra atrial conduction times is associated with a recurrence of atrial fibrillation.
* It has been hypothesized that if there is a greater [[atrium|atrial mass]], delayed [[atrium|atrial]] conduction times, and a shortened [[atrial]] [[Refractory period (cardiac)|refractory period]], it promotes the propagation of wavelets.<ref>Akyürek O, Sayin T, Dinçer I, Karaoguz R, Güldal M, Oral D. Lengthening of intraatrial conduction time in atrial fibrillation and its relation with early recurrence of atrial fibrillation. Jpn Heart J. Sep 2001;42(5):575-84.</ref>   
*This hypothesis is supported by the observation that prolongation of intra [[atrial]] conduction times is associated with a recurrence of [[atrial fibrillation]].


=== Molecular Pathogenesis and Role of Mechano-electric Feedback ===
==== Molecular Pathogenesis and Role of Mechano-electric Feedback ====
* Mechanosensitivity of cardiac myocytes is thought to play a pivotal role in initiation of atrial fibrillation:
* Mechanosensitivity of [[cardiac]] [[myocytes]] is thought to play a pivotal role in initiation of [[atrial fibrillation]]. The following are some of the well known factors:<ref name="Franz2000">{{cite journal|last1=Franz|first1=M|title=Mechano-electrical feedback|journal=Cardiovascular Research|volume=45|issue=2|year=2000|pages=263–266|issn=00086363|doi=10.1016/S0008-6363(99)00390-9}}</ref><ref name="SadoshimaIzumo1997">{{cite journal|last1=Sadoshima|first1=Junichi|last2=Izumo|first2=Seigo|title=THE CELLULAR AND MOLECULAR RESPONSE OF CARDIAC MYOCYTES TO MECHANICAL STRESS|journal=Annual Review of Physiology|volume=59|issue=1|year=1997|pages=551–571|issn=0066-4278|doi=10.1146/annurev.physiol.59.1.551}}</ref><ref name="Sackin1995">{{cite journal|last1=Sackin|first1=H|title=Mechanosensitive Channels|journal=Annual Review of Physiology|volume=57|issue=1|year=1995|pages=333–353|issn=0066-4278|doi=10.1146/annurev.ph.57.030195.002001}}</ref><ref name="urlpdfs.semanticscholar.org">{{cite web |url=https://pdfs.semanticscholar.org/57ac/790968975d40e81b606a9708439ed448b0cb.pdf |title=pdfs.semanticscholar.org |format= |work= |accessdate=}}</ref>
'''Altered myocyte stress/strain'''
*Altered [[Cardiac muscle|myocyte]] stress/strain
* Alteration of extacellular matrix strain of the myocytes leads to opening of specific stretch-activated channels (SAC) via cytoskeletal linkages to integrins.
**Alteration of [[extracellular matrix]] strain of the [[myocytes]] leads to opening of specific stretch-activated channels (SAC) via [[cytoskeletal]] linkages to [[integrins]].<ref name="SadoshimaIzumo1997">{{cite journal|last1=Sadoshima|first1=Junichi|last2=Izumo|first2=Seigo|title=THE CELLULAR AND MOLECULAR RESPONSE OF CARDIAC MYOCYTES TO MECHANICAL STRESS|journal=Annual Review of Physiology|volume=59|issue=1|year=1997|pages=551–571|issn=0066-4278|doi=10.1146/annurev.physiol.59.1.551}}</ref><ref name="Sackin1995">{{cite journal|last1=Sackin|first1=H|title=Mechanosensitive Channels|journal=Annual Review of Physiology|volume=57|issue=1|year=1995|pages=333–353|issn=0066-4278|doi=10.1146/annurev.ph.57.030195.002001}}</ref>
'''Catecholamine Release Secondary to Atrial Stretch'''
*[[Catecholamine]] release secondary to [[atrium|atrial]] stretch
* Stress/strain may lead to release of catecholamines leading to alpha and beta receptor activation in regions of greatest hemodynamic stress, as occurs in states of hypertension, mitral valvulitis and congestive heart failure.
**Stress/strain may lead to release of [[catecholamines]] leading to [[Alpha receptor|alpha]] and [[Beta receptors|beta receptor]] activation in regions of greatest [[Hemodynamics|hemodynamic]] stress, as occurs in states of [[hypertension]], [[Mitral valve|mitral valvulitis]] and [[congestive heart failure]].<ref name="urlpdfs.semanticscholar.org">{{cite web |url=https://pdfs.semanticscholar.org/57ac/790968975d40e81b606a9708439ed448b0cb.pdf |title=pdfs.semanticscholar.org |format= |work= |accessdate=}}</ref>
'''Actiavtion of G-protein Coupled Pathways'''
**Animal studies have shown that the [[Gap junction|gap junction protein connexin 43]] ([[Gap junction|Cx43]]) plays a key role in electrical conduction velocity in [[heart|cardiac]] [[Tissue (biology)|tissues]], and under expression of [[Gap junction|Cx43]] is linked with [[atrial fibrillation]] (especially in [[symptom|sympathetic]] [[atrial fibrillation]]).<ref name="pmid28554986">{{cite journal |vauthors=Shu C, Huang W, Zeng Z, He Y, Luo B, Liu H, Li J, Xu J |title=Connexin 43 is involved in the sympathetic atrial fibrillation in canine and canine atrial myocytes |journal=Anatol J Cardiol |volume=18 |issue=1 |pages=3–9 |date=July 2017 |pmid=28554986 |pmc=5512195 |doi=10.14744/AnatolJCardiol.2017.7602 |url=}}</ref><ref name="pmid18757477">{{cite journal |vauthors=Kontogeorgis A, Li X, Kang EY, Feig JE, Ponzio M, Kang G, Kaba RA, Wit AL, Fisher EA, Morley GE, Peters NS, Coetzee WA, Gutstein DE |title=Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=295 |issue=5 |pages=H1905–16 |date=November 2008 |pmid=18757477 |pmc=2614590 |doi=10.1152/ajpheart.590.2008 |url=}}</ref>
* Stimulation of alpha and beta receptors leads to downstream activation of G-protein coupled pathways within the cardiac myocytes.
*Activation of [[G protein|G-protein coupled pathways]]
* Beta adrenergic stimulation leads to activation of adenlyl cyclase and in turn increased cAMP production.
**Stimulation of [[Alpha receptor|alpha]] and [[beta receptors]] leads to downstream activation of [[G-protein coupled receptor|G-protein coupled]] pathways within the [[cardiac]] [[myocytes]].<ref name="pmid8884512">{{cite journal |vauthors=Satoh T, Zipes DP |title=Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation |journal=J. Cardiovasc. Electrophysiol. |volume=7 |issue=9 |pages=833–42 |date=September 1996 |pmid=8884512 |doi= |url=}}</ref><ref name="pmid10473672">{{cite journal |vauthors=Van Wagoner DR, Pond AL, Lamorgese M, Rossie SS, McCarthy PM, Nerbonne JM |title=Atrial L-type Ca2+ currents and human atrial fibrillation |journal=Circ. Res. |volume=85 |issue=5 |pages=428–36 |date=September 1999 |pmid=10473672 |doi= |url=}}</ref>
* Alpha receptor stimulation causes activation of phosphatidylinositol (PI) second messenger system that, via phospholipase C (PLC) action, synthesizes IP3 and diacylglycerol (DAG).  
**[[Beta adrenergic receptor|Beta adrenergic]] stimulation leads to activation of [[Adenylate cyclase|adenlyl cyclase]] and in turn increased [[cyclic adenosine monophosphate]] ([[cyclic adenosine monophosphate|cAMP]]) production.<ref name="pmid7877685">{{cite journal |vauthors=Krapivinsky G, Gordon EA, Wickman K, Velimirović B, Krapivinsky L, Clapham DE |title=The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins |journal=Nature |volume=374 |issue=6518 |pages=135–41 |date=March 1995 |pmid=7877685 |doi=10.1038/374135a0 |url=}}</ref>
* Protein kinases A (PKA) and C (PKC), activated by cAMP and PI pathways, respectively, produce a change in intra-cellular calcium level, via opening of L-type calcium channels and sarcoplasmic reticulum (SR) calcium release.
**[[Alpha receptor]] stimulation causes activation of [[phosphatidylinositol]] ([[phosphatidylinositol|PI]]) second messenger system that, via [[phospholipase C]] ([[phospholipase C|PLC]]) action, synthesizes [[inositol triphosphate]] ([[inositol triphosphate|IP3]]) and [[diacylglycerol]] ([[diacylglycerol|DAG]]).<ref name="urlpdfs.semanticscholar.org">{{cite web |url=https://pdfs.semanticscholar.org/d005/ae462c1ffb2997f440269fa0fc68fea6350e.pdf |title=pdfs.semanticscholar.org |format= |work= |accessdate=}}</ref>
* Moreover, protein kinase C causes mitogen-activated protein kinase (MAPK) to be activated downstream, which turns on immediate early gene (IEG) program to initiate hypertrophy and cardiac remodelling. This produces a viscous cycle that maintains an arrhythmogenic environment.
**[[Protein kinase A|Protein kinases A]] ([[Protein kinase A|PKA]]) and [[Protein kinase C|C]] ([[Protein kinase C|PKC]]), activated by [[cAMP]] and [[Phosphoinositide 3-kinase|PI]] pathways, respectively, produce a change in intra-[[Cell (biology)|cellular]] [[calcium]] level, via opening of [[L-type calcium channel|L-type calcium]] channels and [[sarcoplasmic reticulum]] ([[sarcoplasmic reticulum|SR]]) [[calcium]] release.
* The calcium influx due to opening to L-type calcium channels is a regulator of atrial excitation-contraction coupling.
**Moreover, [[protein kinase C]] causes [[mitogen-activated protein kinase]] ([[mitogen-activated protein kinase|MAPK]]) to be activated downstream, which turns on immediate early [[gene]] (IEG) program to initiate [[Hypertrophy (medical)|hypertrophy]] and [[heart|cardiac]] remodeling. This produces a vicious cycle that maintains an [[arrhythmogenic]] environment.<ref name="pmid12062330">{{cite journal |vauthors=Goette A, Lendeckel U, Klein HU |title=Signal transduction systems and atrial fibrillation |journal=Cardiovasc. Res. |volume=54 |issue=2 |pages=247–58 |date=May 2002 |pmid=12062330 |doi= |url=}}</ref>
**The [[calcium]] influx due to opening to [[L-type calcium channel|L-type calcium channels]] is a regulator of [[atrial]] excitation-contraction coupling.<ref name="pmid8635223">{{cite journal |vauthors=Matsuda N, Hagiwara N, Shoda M, Kasanuki H, Hosoda S |title=Enhancement of the L-type Ca2+ current by mechanical stimulation in single rabbit cardiac myocytes |journal=Circ. Res. |volume=78 |issue=4 |pages=650–9 |date=April 1996 |pmid=8635223 |doi= |url=}}</ref>


===Role of Dilation of the Atria/Atrial Stress===
====Role of Dilation of the Atria/Atrial Stress====
Dilatation of the atria can be due to almost any structural abnormality of the heart that can cause a rise in the intra-cardiac pressures. This includes:
*Dilatation of the [[atrium|atria]] can be due to almost any structural abnormality of the [[heart]] that can cause a rise in the [[heart|intra-cardiac]] pressures. This includes:<ref name="pmid11156892">{{cite journal| author=Allessie MA, Boyden PA, Camm AJ, Kléber AG, Lab MJ, Legato MJ | display-authors=etal| title=Pathophysiology and prevention of atrial fibrillation. | journal=Circulation | year= 2001 | volume= 103 | issue= 5 | pages= 769-77 | pmid=11156892 | doi=10.1161/01.cir.103.5.769 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11156892  }} </ref><ref name="pmid25274966">{{cite journal| author=Fornengo C, Antolini M, Frea S, Gallo C, Grosso Marra W, Morello M | display-authors=etal| title=Prediction of atrial fibrillation recurrence after cardioversion in patients with left-atrial dilation. | journal=Eur Heart J Cardiovasc Imaging | year= 2015 | volume= 16 | issue= 3 | pages= 335-41 | pmid=25274966 | doi=10.1093/ehjci/jeu193 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25274966  }} </ref><ref name="pmid23148964">{{cite journal| author=Xu Y, Sharma D, Li G, Liu Y| title=Atrial remodeling: new pathophysiological mechanism of atrial fibrillation. | journal=Med Hypotheses | year= 2013 | volume= 80 | issue= 1 | pages= 53-6 | pmid=23148964 | doi=10.1016/j.mehy.2012.10.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23148964  }} </ref>
*[[Hypertension]], most likely the most common cause of atrial dilation in the current era.
**[[Hypertension]] is the most common cause of [[atrium|atrial]] dilation in the current era.
*[[Valvular heart disease]] (such as [[mitral stenosis]], [[mitral regurgitation]], and [[tricuspid regurgitation]]).
**[[Valvular heart disease]] (such as [[mitral stenosis]], [[mitral regurgitation]], and [[tricuspid regurgitation]])
*[[Congestive heart failure]].
**[[Congestive heart failure]]
*[[Coronary Artery Bypass Graft Surgery]].
**[[Coronary Artery Bypass Graft Surgery]]
*Once dilatation of the [[atrium|atria]] has occurred, this begins a chain of events that leads to the activation of the [[renin-angiotensin system|renin aldosterone angiotensin system]] ([[renin-angiotensin system|RAAS]]) and subsequent increase in matrix metaloproteinases and [[disintegrin]], which leads to [[atrium|atrial]] remodeling and [[fibrosis]], with loss of [[atrium|atrial]] [[muscle]] mass.
*Dilation and stress may lead to decreased resting potential, [[action potential]] amplitude and duration, and occurrence of after depolarizations causing [[extrasystoles]].
*Patchy [[atrial]] [[fibrosis]] may precede the occurrence of [[atrial fibrillation]] and the magnitude of [[fibrosis]] may progress with a prolonged duration of [[atrial fibrillation]].


* Once dilatation of the atria has occurred, this begins a chain of events that leads to the activation of the [[renin-angiotensin system|renin aldosterone angiotensin system]] (RAAS) and subsequent increase in matrix metaloproteinases and [[disintegrin]], which leads to atrial remodeling and fibrosis, with loss of atrial muscle mass.
====Inflammation====
* Any [[inflammation|inflammatory state]] that affects the [[heart]] can cause [[fibrosis]] of the [[atria]]. This is typically due to [[sarcoidosis]] but may also be due to [[autoimmune disorders]] that create [[autoantibodies]] against [[myosin]] heavy chains.<ref name="pmid25746525">{{cite journal| author=Harada M, Van Wagoner DR, Nattel S| title=Role of inflammation in atrial fibrillation pathophysiology and management. | journal=Circ J | year= 2015 | volume= 79 | issue= 3 | pages= 495-502 | pmid=25746525 | doi=10.1253/circj.CJ-15-0138 | pmc=4457364 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25746525  }} </ref>
*[[Mutation]] of the [[lamin]] AC [[gene]] is also associated with [[fibrosis]] of the [[atrium|atria]] that can lead to [[atrial fibrillation]].
*The following are some of the known evidences that support the role of [[inflammation]] in [[atrial fibrillation]] development:<ref name="pmid25746525">{{cite journal| author=Harada M, Van Wagoner DR, Nattel S| title=Role of inflammation in atrial fibrillation pathophysiology and management. | journal=Circ J | year= 2015 | volume= 79 | issue= 3 | pages= 495-502 | pmid=25746525 | doi=10.1253/circj.CJ-15-0138 | pmc=4457364 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25746525  }} </ref>
**Higher level of [[inflammation|inflammatory]] [[biomarkers]] in [[heart|cardiac]] [[tissue|Tissue (biology)]] [[atrial fibrillation]], compared to the normal population
**The relieving effects of [[anti inflammatory medications]] on [[atrial fibrillation]] [[patients]]
*It seems that presence of [[inflammation]] can lead to [[pathology|pathological]] activities such as [[fibrosis]], [[Redox|oxidative stress]] and [[apoptosis]].<ref name="pmid25746525">{{cite journal| author=Harada M, Van Wagoner DR, Nattel S| title=Role of inflammation in atrial fibrillation pathophysiology and management. | journal=Circ J | year= 2015 | volume= 79 | issue= 3 | pages= 495-502 | pmid=25746525 | doi=10.1253/circj.CJ-15-0138 | pmc=4457364 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25746525  }} </ref>
*There is an association between [[inflammation]] and [[thrombogenicity]], which further explains how [[inflmmation]] can lead to [[atrial fibrillation]].<ref name="pmid25746525">{{cite journal| author=Harada M, Van Wagoner DR, Nattel S| title=Role of inflammation in atrial fibrillation pathophysiology and management. | journal=Circ J | year= 2015 | volume= 79 | issue= 3 | pages= 495-502 | pmid=25746525 | doi=10.1253/circj.CJ-15-0138 | pmc=4457364 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25746525  }} </ref>
**[[Inflammation]] is known to causes [[Endothelium|endothelial dysfunction]] plus activation of [[platelets]] and [[coagulation|coagulation pathways]], which all together increase the chance of [[thrombus]] formation.
**This relationship is also important to understand, since [[inflammation]] can increase the chance of [[thrombogenicity]] and it's related [[complications]] in a [[patient]] that has [[atrial fibrillation]].


* Dilation and stress may lead to decreased resting potential, action potential amplitude and duration, and occurrence of afterdepolarizations causing extrasystoles.
====Fibrosis of the SA Node====
* [[Fibrosis]] is not limited to the [[muscle]] mass of the [[atrium|atria]], and may occur in the [[sinoatrial node]] ([[Sinoatrial node|SA node]]) and [[atrioventricular node]] ([[atrioventricular node|AV node]]), correlating with [[sick sinus syndrome]].<ref name="pmid16908781">{{cite journal |author=Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL |title=ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society |journal=[[Circulation]] |volume=114 |issue=7 |pages=e257–354 |year=2006 |month=August |pmid=16908781 |doi=10.1161/CIRCULATIONAHA.106.177292 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=16908781 |issn=}}</ref><ref name="pmid8941126">{{cite journal |author=Elvan A, Wylie K, Zipes DP |title=Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling |journal=[[Circulation]] |volume=94 |issue=11 |pages=2953–60 |year=1996 |month=December |pmid=8941126 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=8941126 |issn=}}</ref><ref name="pmid11469431">{{cite journal |author=Manios EG, Kanoupakis EM, Mavrakis HE, Kallergis EM, Dermitzaki DN, Vardas PE |title=Sinus pacemaker function after cardioversion of chronic atrial fibrillation: is sinus node remodeling related with recurrence? |journal=[[Journal of Cardiovascular Electrophysiology]] |volume=12 |issue=7 |pages=800–6 |year=2001 |month=July |pmid=11469431 |doi= |url= |issn=}}</ref>
*Prolonged episodes of [[atrial fibrillation]] have been shown to correlate with prolongation of the [[sinoatrial node]] recovery time, suggesting that dysfunction of the [[sinoatrial node|SA node]] is progressive with prolonged episodes of [[atrial fibrillation]].<ref name="pmid16908781">{{cite journal |author=Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL |title=ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society |journal=[[Circulation]] |volume=114 |issue=7 |pages=e257–354 |year=2006 |month=August |pmid=16908781 |doi=10.1161/CIRCULATIONAHA.106.177292 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=16908781 |issn=}}</ref><ref name="pmid8941126">{{cite journal |author=Elvan A, Wylie K, Zipes DP |title=Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling |journal=[[Circulation]] |volume=94 |issue=11 |pages=2953–60 |year=1996 |month=December |pmid=8941126 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=8941126 |issn=}}</ref><ref name="pmid11469431">{{cite journal |author=Manios EG, Kanoupakis EM, Mavrakis HE, Kallergis EM, Dermitzaki DN, Vardas PE |title=Sinus pacemaker function after cardioversion of chronic atrial fibrillation: is sinus node remodeling related with recurrence? |journal=[[Journal of Cardiovascular Electrophysiology]] |volume=12 |issue=7 |pages=800–6 |year=2001 |month=July |pmid=11469431 |doi= |url= |issn=}}</ref>


===Inflammation of the Atria===
====Autonomic nervous system====
* Any inflammatory state that affects the heart can cause fibrosis of the [[atria]].  This is typically due to [[sarcoidosis]] but may also be due to [[autoimmune disorders]] that create [[autoantibodies]] against [[myosin]] heavy chains. Mutation of the [[lamin]] AC gene is also associated with [[fibrosis]] of the atria that can lead to atrial fibrillation.
*Studies have been shown that there is a relationship between [[autonomic nervous system]] and it's function and the [[Cardiac electrophysiology|atrial electrophysiology]]. Changes in [[Cardiac electrophysiology|atrial electrophysiology]] can lead to [[arrhythmia]] such as [[atrial fibrillation]].<ref name="pmid24763467">{{cite journal| author=Chen PS, Chen LS, Fishbein MC, Lin SF, Nattel S| title=Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. | journal=Circ Res | year= 2014 | volume= 114 | issue= 9 | pages= 1500-15 | pmid=24763467 | doi=10.1161/CIRCRESAHA.114.303772 | pmc=4043633 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24763467  }} </ref>
*The following evidences support the role of [[autonomic nervous system]] in [[pathogenesis]] of [[atrial fibrillation]]:<ref name="pmid10487804">{{cite journal| author=Viskin S, Golovner M, Malov N, Fish R, Alroy I, Vila Y | display-authors=etal| title=Circadian variation of symptomatic paroxysmal atrial fibrillation. Data from almost 10 000 episodes. | journal=Eur Heart J | year= 1999 | volume= 20 | issue= 19 | pages= 1429-34 | pmid=10487804 | doi=10.1053/euhj.1999.1632 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10487804  }} </ref><ref name="pmid21306960">{{cite journal| author=Leiria TL, Glavinovic T, Armour JA, Cardinal R, de Lima GG, Kus T| title=Longterm effects of cardiac mediastinal nerve cryoablation on neural inducibility of atrial fibrillation in canines. | journal=Auton Neurosci | year= 2011 | volume= 161 | issue= 1-2 | pages= 68-74 | pmid=21306960 | doi=10.1016/j.autneu.2010.12.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21306960  }} </ref><ref name="pmid18716036">{{cite journal| author=Richer LP, Vinet A, Kus T, Cardinal R, Ardell JL, Armour JA| title=Alpha-adrenoceptor blockade modifies neurally induced atrial arrhythmias. | journal=Am J Physiol Regul Integr Comp Physiol | year= 2008 | volume= 295 | issue= 4 | pages= R1175-80 | pmid=18716036 | doi=10.1152/ajpregu.00840.2007 | pmc=2576091 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18716036 }} </ref><ref name="pmid10715267">{{cite journal| author=Jayachandran JV, Sih HJ, Winkle W, Zipes DP, Hutchins GD, Olgin JE| title=Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. | journal=Circulation | year= 2000 | volume= 101 | issue= 10 | pages= 1185-91 | pmid=10715267 | doi=10.1161/01.cir.101.10.1185 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10715267  }} </ref><ref name="pmid19324302">{{cite journal| author=Nguyen BL, Fishbein MC, Chen LS, Chen PS, Masroor S| title=Histopathological substrate for chronic atrial fibrillation in humans. | journal=Heart Rhythm | year= 2009 | volume= 6 | issue= 4 | pages= 454-60 | pmid=19324302 | doi=10.1016/j.hrthm.2009.01.010 | pmc=2662134 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19324302  }} </ref>
**Presence of a [[Circadian rhythm|circadian]] related [[incidence]] in [[atrial fibrillation]] [[patients]] also can support this relationship.
**The relieving effect of factors that decrease the [[autonomic nervous system|autonomic]] outflow or innervation on [[atrial fibrillation]].
**The results of animal studies demonstrated that how increased [[Autonomic nervous system|sympathetic nerve densities]] lead to [[atrial fibrillation]] development.
**Detection of [[atrium|atrial]] [[Autonomic nervous system|sympathetic nerve densities]] in [[atrium|atrial]] [[Tissue (biology)|tissue]] of [[patients]] who had long-standing [[atrial fibrillation]].


===Stretch-induced Depolarization of Fibroblasts===
==Genetics==
* Patchy atrial fibrosis may precede the occurrence of atrial fibrillation and the magnitude of fibrosis may progress with a prolonged duration of atrial fibrillation.
Multiple associated [[genes]] to [[atrial fibrillation]] have been found. The following table is a summary of these [[genes]]:<ref name="pmid16790700">{{cite journal| author=Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q | display-authors=etal| title=Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. | journal=N Engl J Med | year= 2006 | volume= 354 | issue= 25 | pages= 2677-88 | pmid=16790700 | doi=10.1056/NEJMoa052800 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16790700  }} </ref><ref name="pmid12522251">{{cite journal| author=Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY | display-authors=etal| title=KCNQ1 gain-of-function mutation in familial atrial fibrillation. | journal=Science | year= 2003 | volume= 299 | issue= 5604 | pages= 251-4 | pmid=12522251 | doi=10.1126/science.1077771 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12522251  }} </ref><ref name="pmid18614783">{{cite journal| author=Hodgson-Zingman DM, Karst ML, Zingman LV, Heublein DM, Darbar D, Herron KJ | display-authors=etal| title=Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 2 | pages= 158-65 | pmid=18614783 | doi=10.1056/NEJMoa0706300 | pmc=2518320 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18614783  }} </ref><ref name="pmid10580070">{{cite journal| author=Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M | display-authors=etal| title=Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. | journal=N Engl J Med | year= 1999 | volume= 341 | issue= 23 | pages= 1715-24 | pmid=10580070 | doi=10.1056/NEJM199912023412302 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10580070  }} </ref><ref name="pmid12920062">{{cite journal| author=Sébillon P, Bouchier C, Bidot LD, Bonne G, Ahamed K, Charron P | display-authors=etal| title=Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. | journal=J Med Genet | year= 2003 | volume= 40 | issue= 8 | pages= 560-7 | pmid=12920062 | doi=10.1136/jmg.40.8.560 | pmc=1735561 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12920062  }} </ref><ref name="pmid16772329">{{cite journal| author=Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M | display-authors=etal| title=Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. | journal=Hum Mol Genet | year= 2006 | volume= 15 | issue= 14 | pages= 2185-91 | pmid=16772329 | doi=10.1093/hmg/ddl143 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16772329  }} </ref><ref name="pmid15368194">{{cite journal| author=Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y | display-authors=etal| title=Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. | journal=Am J Hum Genet | year= 2004 | volume= 75 | issue= 5 | pages= 899-905 | pmid=15368194 | doi=10.1086/425342 | pmc=1182120 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15368194  }} </ref><ref name="pmid15828882">{{cite journal| author=Hong K, Bjerregaard P, Gussak I, Brugada R| title=Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. | journal=J Cardiovasc Electrophysiol | year= 2005 | volume= 16 | issue= 4 | pages= 394-6 | pmid=15828882 | doi=10.1046/j.1540-8167.2005.40621.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15828882  }} </ref><ref name="pmid15922306">{{cite journal| author=Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y | display-authors=etal| title=A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. | journal=Biochem Biophys Res Commun | year= 2005 | volume= 332 | issue= 4 | pages= 1012-9 | pmid=15922306 | doi=10.1016/j.bbrc.2005.05.054 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15922306  }} </ref><ref name="pmid16818212">{{cite journal| author=Bedi M, McNamara D, London B, Schwartzman D| title=Genetic susceptibility to atrial fibrillation in patients with congestive heart failure. | journal=Heart Rhythm | year= 2006 | volume= 3 | issue= 7 | pages= 808-12 | pmid=16818212 | doi=10.1016/j.hrthm.2006.03.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16818212  }} </ref><ref name="pmid17113662">{{cite journal| author=Fatini C, Sticchi E, Gensini F, Gori AM, Marcucci R, Lenti M | display-authors=etal| title=Lone and secondary nonvalvular atrial fibrillation: role of a genetic susceptibility. | journal=Int J Cardiol | year= 2007 | volume= 120 | issue= 1 | pages= 59-65 | pmid=17113662 | doi=10.1016/j.ijcard.2006.08.079 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17113662  }} </ref><ref name="pmid19648063">{{cite journal| author=Watanabe H, Kaiser DW, Makino S, MacRae CA, Ellinor PT, Wasserman BS | display-authors=etal| title=ACE I/D polymorphism associated with abnormal atrial and atrioventricular conduction in lone atrial fibrillation and structural heart disease: implications for electrical remodeling. | journal=Heart Rhythm | year= 2009 | volume= 6 | issue= 9 | pages= 1327-32 | pmid=19648063 | doi=10.1016/j.hrthm.2009.05.014 | pmc=2740737 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19648063  }} </ref>
{| border="3"
! Gene !! Locus
|-
| [[Connexin|Connexin 40]] || [[GJA5]]
|-
| [[Potassium]] [[Voltage-gated ion channel|voltage-gated channel]] (KQT-like subfamily) || [[KvLQT1|KCNQ1]]
|-
| [[Atrial natriuretic peptide|Natriuretic peptide]] precursor A || NPPA
|-
| [[LMNA|Lamin A/C]] || [[LMNA]]
|-
| [[Potassium]] [[Voltage-gated ion channel|voltage-gated channel]] ([[Shaker gene|shaker-related subfamily]]) || [[KCNA5]]
|-
| [[Potassium]] [[Voltage-gated ion channel|voltage-gated channel]] (Isk-related family) || [[KCNE2]]
|-
| [[Potassium]] [[Voltage-gated ion channel|voltage-gated channel]] (subfamily H) || [[hERG|KCNH2]]
|-
| [[Potassium]] inwardly rectifying channel (subfamily J) || KCNJ2
|-
| [[Sodium channel]], [[Voltage-gated ion channel|voltage-gated]] (type V, α-subunit) || [[SCN5A]]
|-
| [[Angiotensin-converting enzyme|Angiotensin-converting enzyme]] || [[Angiotensin-converting enzyme|ACE]]
|-
| [[Angiotensin|Angiotensinogen]] || AGT
|}


===Fibrosis of the SA Node===
==Associated Conditions==
* Fibrosis is not limited to the muscle mass of the atria, and may occur in the [[sinus node]] ([[SA node]]) and [[atrioventricular node]] ([[AV node]]), correlating with [[sick sinus syndrome]]. Prolonged episodes of atrial fibrillation have been shown to correlate with prolongation of the sinus node recovery time,<ref name="pmid16908781">{{cite journal |author=Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL |title=ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society |journal=[[Circulation]] |volume=114 |issue=7 |pages=e257–354 |year=2006 |month=August |pmid=16908781 |doi=10.1161/CIRCULATIONAHA.106.177292 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=16908781 |issn=}}</ref><ref name="pmid8941126">{{cite journal |author=Elvan A, Wylie K, Zipes DP |title=Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling |journal=[[Circulation]] |volume=94 |issue=11 |pages=2953–60 |year=1996 |month=December |pmid=8941126 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=8941126 |issn=}}</ref><ref name="pmid11469431">{{cite journal |author=Manios EG, Kanoupakis EM, Mavrakis HE, Kallergis EM, Dermitzaki DN, Vardas PE |title=Sinus pacemaker function after cardioversion of chronic atrial fibrillation: is sinus node remodeling related with recurrence? |journal=[[Journal of Cardiovascular Electrophysiology]] |volume=12 |issue=7 |pages=800–6 |year=2001 |month=July |pmid=11469431 |doi= |url= |issn=}}</ref> suggesting that dysfunction of the [[SA node]] is progressive with prolonged episodes of atrial fibrillation.
*The presence of [[atrial fibrillation]] often reflects the presence of an underlying [[cardiology|cardiac]] or [[respiratory disease|lung disease]]. Indeed, the proportion of [[patients]] with lone [[atrial fibrillation]] is low (approximately 12% of cases). <ref name="pmid11156892">{{cite journal| author=Allessie MA, Boyden PA, Camm AJ, Kléber AG, Lab MJ, Legato MJ | display-authors=etal| title=Pathophysiology and prevention of atrial fibrillation. | journal=Circulation | year= 2001 | volume= 103 | issue= 5 | pages= 769-77 | pmid=11156892 | doi=10.1161/01.cir.103.5.769 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11156892  }} </ref><ref name="pmid3627174">{{cite journal |author=Kopecky SL, Gersh BJ, McGoon MD, ''et al'' |title=The natural history of lone atrial fibrillation. A population-based study over three decades |journal=N. Engl. J. Med. |volume=317 |issue=11 |pages=669–74 |year=1987 |month=September |pmid=3627174 |doi= |url=}}</ref><ref name="pmid8037127">{{cite journal |author=Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM |title=Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study) |journal=Am. J. Cardiol. |volume=74 |issue=3 |pages=236–41 |year=1994 |month=August |pmid=8037127 |doi= |url=}}</ref><ref name="pmid13160271">{{cite journal |author=EVANS W, SWANN P |title=Lone auricular fibrillation |journal=Br Heart J |volume=16 |issue=2 |pages=189–94 |year=1954 |month=April |pmid=13160271 |pmc=479515 |doi= |url=http://heart.bmj.com/cgi/pmidlookup?view=long&pmid=13160271}}</ref><ref name="pmid4068186">{{cite journal |author=Brand FN, Abbott RD, Kannel WB, Wolf PA |title=Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study |journal=JAMA |volume=254 |issue=24 |pages=3449–53 |year=1985 |month=December |pmid=4068186 |doi= |url=}}</ref><ref name="pmid24966695">{{cite journal| author=Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S| title=Epidemiology of atrial fibrillation: European perspective. | journal=Clin Epidemiol | year= 2014 | volume= 6 | issue=  | pages= 213-20 | pmid=24966695 | doi=10.2147/CLEP.S47385 | pmc=4064952 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24966695  }} </ref>
.
*Conditions associated with [[atrial fibrillation]] include:<ref name="pmid16908781">{{Cite pmid|16908781}}</ref><ref name="pmid24966695">{{cite journal| author=Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S| title=Epidemiology of atrial fibrillation: European perspective. | journal=Clin Epidemiol | year= 2014 | volume= 6 | issue=  | pages= 213-20 | pmid=24966695 | doi=10.2147/CLEP.S47385 | pmc=4064952 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24966695  }} </ref><ref name="pmid11156892">{{cite journal| author=Allessie MA, Boyden PA, Camm AJ, Kléber AG, Lab MJ, Legato MJ | display-authors=etal| title=Pathophysiology and prevention of atrial fibrillation. | journal=Circulation | year= 2001 | volume= 103 | issue= 5 | pages= 769-77 | pmid=11156892 | doi=10.1161/01.cir.103.5.769 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11156892  }} </ref>
**[[Hypertension]] and [[hypertensive heart disease]]
**[[Congestive heart failure]]
**[[Valvular heart disease]]
**[[Diabetes]]
**[[Obesity]]
**[[Cardiomyopathy]]
**[[Chronic (medical)|Chronic]] [[Pulmonology|pulmonary diseases]]
**[[Stroke]] and [[transient ischemic attack]] ([[TIA]])
**[[Thyroid disease]]
**[[Neuropsychiatry|Neuropsychiatric disturbances]]
 
==Gross Pathology==
On [[gross pathology]] [[atrium|atrial]] enlargement has been found with [[Echocardiography|echocardiographic]] evaluations as a consequence of [[atrial fibrillation]]. <ref name="pmid2144217">{{cite journal| author=Sanfilippo AJ, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA | display-authors=etal| title=Atrial enlargement as a consequence of atrial fibrillation. A prospective echocardiographic study. | journal=Circulation | year= 1990 | volume= 82 | issue= 3 | pages= 792-7 | pmid=2144217 | doi=10.1161/01.cir.82.3.792 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2144217  }} </ref>
 
==Microscopic Pathology==
*Based on studies done by [[electron microscope]] and quantitative immunoconfocal analysis, [[Gap junction|gap junctional proteins]] (such as [[GJA1|connexin 43]] ([[GJA1|Cx43]]),  [[GJA5|connexin 40]] ([[GJA5|Cx40]]) and [[Cadherin|N-cadherin]]) become lateralized instead of being restricted to the [[Intercalated disc|intercalated discs]].<ref name="pmid20006465">{{cite journal| author=Chimenti C, Russo MA, Carpi A, Frustaci A| title=Histological substrate of human atrial fibrillation. | journal=Biomed Pharmacother | year= 2010 | volume= 64 | issue= 3 | pages= 177-83 | pmid=20006465 | doi=10.1016/j.biopha.2009.09.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20006465  }} </ref><ref name="pmid12062341">{{cite journal| author=Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J| title=Structural correlate of atrial fibrillation in human patients. | journal=Cardiovasc Res | year= 2002 | volume= 54 | issue= 2 | pages= 361-79 | pmid=12062341 | doi=10.1016/s0008-6363(02)00273-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12062341  }} </ref>
*Furthermore there is an approximately 57% reduce in [[GJA1|connexin 43]] ([[GJA1|Cx43]]) in right [[atrium]] appendages and walls.<ref name="pmid12062341">{{cite journal| author=Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J| title=Structural correlate of atrial fibrillation in human patients. | journal=Cardiovasc Res | year= 2002 | volume= 54 | issue= 2 | pages= 361-79 | pmid=12062341 | doi=10.1016/s0008-6363(02)00273-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12062341  }} </ref><ref name="pmid9654224">{{cite journal| author=van der Velden HM, van Kempen MJ, Wijffels MC, van Zijverden M, Groenewegen WA, Allessie MA | display-authors=etal| title=Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. | journal=J Cardiovasc Electrophysiol | year= 1998 | volume= 9 | issue= 6 | pages= 596-607 | pmid=9654224 | doi=10.1111/j.1540-8167.1998.tb00940.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9654224  }} </ref>
*[[Histology|Histologic evaluation]] of [[atrial fibrillation]] showed that [[Collagen|collagen I]] is significantly higher in [[atrium]], compared to the normal population with a [[sinus rhythm]] (48% in right [[atrium]] appendages/69% in the right [[atrium]] free wall).<ref name="pmid12062341">{{cite journal| author=Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J| title=Structural correlate of atrial fibrillation in human patients. | journal=Cardiovasc Res | year= 2002 | volume= 54 | issue= 2 | pages= 361-79 | pmid=12062341 | doi=10.1016/s0008-6363(02)00273-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12062341  }} </ref>


==References==
==References==

Latest revision as of 05:31, 29 August 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anahita Deylamsalehi, M.D.[2]Syed Hassan A. Kazmi BSc, MD [3]

Overview

Numerous triggers such as sympathetic or parasympathetic stimulation, ectopic activity in muscular sleeves, atrial stretch, premature atrial beats and accessory AV (atrio-ventricular) pathways have been responsible in initiation of atrial fibrillation. Younger patients with paroxysmal atrial fibrillation may have ectopic foci of electrical activity in the pulmonary vein. While the pulmonary vein is a common source of these ectopic foci, there may also be foci present in the atrium itself. Unfortunately the reason why the pulmonary vein turns to an arrhythmogenic foci is not fully understood. It seems that structure of the pulmonary vein makes it potential for re-entry formation which can lead to atrial fibrillation. Presence of the aformentioned triggers produce re-enterant wavelets of electrical activity due to shortened effective refractory period (ERP). Furthermore mechanosensitivity of cardiac myocytes is thought to play a pivotal role in initiation of atrial fibrillation. Mechanisms such as altered myocyte stress/strain, catecholamine release secondary to atrial stretch and activation of G-protein coupled pathways have been introduced in the pathogenesis of atrial fibrillation. Dilatation of the atria can be due to structural abnormalities such as hypertension, valvular heart disease and congestive heart failure that can cause a rise in the intra-cardiac pressures. Once dilatation of the atria has occurred, this begins a chain of events that leads to the activation of the renin aldosterone angiotensin system (RAAS) and subsequent increase in matrix metaloproteinases and disintegrin, which leads to atrial remodeling and fibrosis, with loss of atrial muscle mass. In addition any inflammatory state that affects the heart can cause fibrosis of the atria. This is typically due to sarcoidosis but may also be due to autoimmune disorders that create autoantibodies against myosin heavy chains. There are numerous evidences for presence of a relationship between autonomic nervous system and it's function and the atrial electrophysiology and atrial fibrillation development. Multiple associated genes to atrial fibrillation have been found. Connexin 40, potassium voltage-gated channels, natriuretic peptide precursor A and lamin A/C are some of the known genes that are related to atrial fibrillation pathogenesis. The presence of atrial fibrillation often reflects the presence of an underlying cardiac or lung disease. Indeed, the proportion of patients with lone atrial fibrillation is low (approximately 12% of cases). On gross pathology atrial enlargement has been found with echocardiographic evaluations as a consequence of atrial fibrillation. On microscopic pathology lateralization of gap junctional proteins (such as connexin 43 (Cx43), connexin 40 (Cx40) and N-cadherin) have been found. Furthermore there is an approximately 57% reduce in connexin 43 (Cx43) in right atrium appendages and walls.

Pathophysiology

Pathogenesis

Onset of atrial fibrillation is dependent upon specific triggers and tissue substrates capable of maintaining atrial fibrillation. The following triggers are know to initiate atrial fibrillation:[1][2][3][4]

Ectopic Foci in the Pulmonary Vein

Re-enterant Wavelets or Multiple Wavelets Phenomenon

Molecular Pathogenesis and Role of Mechano-electric Feedback

Role of Dilation of the Atria/Atrial Stress

Inflammation

Fibrosis of the SA Node

Autonomic nervous system

Genetics

Multiple associated genes to atrial fibrillation have been found. The following table is a summary of these genes:[34][35][36][37][38][39][40][41][42][43][44][45]

Gene Locus
Connexin 40 GJA5
Potassium voltage-gated channel (KQT-like subfamily) KCNQ1
Natriuretic peptide precursor A NPPA
Lamin A/C LMNA
Potassium voltage-gated channel (shaker-related subfamily) KCNA5
Potassium voltage-gated channel (Isk-related family) KCNE2
Potassium voltage-gated channel (subfamily H) KCNH2
Potassium inwardly rectifying channel (subfamily J) KCNJ2
Sodium channel, voltage-gated (type V, α-subunit) SCN5A
Angiotensin-converting enzyme ACE
Angiotensinogen AGT

Associated Conditions

Gross Pathology

On gross pathology atrial enlargement has been found with echocardiographic evaluations as a consequence of atrial fibrillation. [51]

Microscopic Pathology

References

  1. ↑ Wit AL, Boyden PA (March 2007). "Triggered activity and atrial fibrillation". Heart Rhythm. 4 (3 Suppl): S17–23. doi:10.1016/j.hrthm.2006.12.021. PMC 1855225. PMID 17336878.
  2. ↑ 2.0 2.1 2.2 2.3 Allessie MA, Boyden PA, Camm AJ, Kléber AG, Lab MJ, Legato MJ; et al. (2001). "Pathophysiology and prevention of atrial fibrillation". Circulation. 103 (5): 769–77. doi:10.1161/01.cir.103.5.769. PMID 11156892.
  3. ↑ 3.0 3.1 3.2 3.3 Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G; et al. (1998). "Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins". N Engl J Med. 339 (10): 659–66. doi:10.1056/NEJM199809033391003. PMID 9725923.
  4. ↑ Mary-Rabine L, Albert A, Pham TD, Hordof A, Fenoglio JJ, Malm JR; et al. (1983). "The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure". Circ Res. 52 (2): 188–99. doi:10.1161/01.res.52.2.188. PMID 6218936.
  5. ↑ Iwasaki YK, Nishida K, Kato T, Nattel S (2011). "Atrial fibrillation pathophysiology: implications for management". Circulation. 124 (20): 2264–74. doi:10.1161/CIRCULATIONAHA.111.019893. PMID 22083148.
  6. ↑ Nishida K, Maguy A, Sakabe M, Comtois P, Inoue H, Nattel S (2011). "The role of pulmonary veins vs. autonomic ganglia in different experimental substrates of canine atrial fibrillation". Cardiovasc Res. 89 (4): 825–33. doi:10.1093/cvr/cvq332. PMID 20962102.
  7. ↑ Po SS, Li Y, Tang D, Liu H, Geng N, Jackman WM; et al. (2005). "Rapid and stable re-entry within the pulmonary vein as a mechanism initiating paroxysmal atrial fibrillation". J Am Coll Cardiol. 45 (11): 1871–7. doi:10.1016/j.jacc.2005.02.070. PMID 15936621.
  8. ↑ Nattel S, Li D, Yue L (2000). "Basic mechanisms of atrial fibrillation--very new insights into very old ideas". Annu Rev Physiol. 62: 51–77. doi:10.1146/annurev.physiol.62.1.51. PMID 10845084.
  9. ↑ Nattel S, Xiong F, Aguilar M (2017). "Demystifying rotors and their place in clinical translation of atrial fibrillation mechanisms". Nat Rev Cardiol. 14 (9): 509–520. doi:10.1038/nrcardio.2017.37. PMID 28383023.
  10. ↑ Akyürek O, Sayin T, Dinçer I, Karaoguz R, Güldal M, Oral D. Lengthening of intraatrial conduction time in atrial fibrillation and its relation with early recurrence of atrial fibrillation. Jpn Heart J. Sep 2001;42(5):575-84.
  11. ↑ Franz, M (2000). "Mechano-electrical feedback". Cardiovascular Research. 45 (2): 263–266. doi:10.1016/S0008-6363(99)00390-9. ISSN 0008-6363.
  12. ↑ 12.0 12.1 Sadoshima, Junichi; Izumo, Seigo (1997). "THE CELLULAR AND MOLECULAR RESPONSE OF CARDIAC MYOCYTES TO MECHANICAL STRESS". Annual Review of Physiology. 59 (1): 551–571. doi:10.1146/annurev.physiol.59.1.551. ISSN 0066-4278.
  13. ↑ 13.0 13.1 Sackin, H (1995). "Mechanosensitive Channels". Annual Review of Physiology. 57 (1): 333–353. doi:10.1146/annurev.ph.57.030195.002001. ISSN 0066-4278.
  14. ↑ 14.0 14.1 14.2 "pdfs.semanticscholar.org" (PDF).
  15. ↑ Shu C, Huang W, Zeng Z, He Y, Luo B, Liu H, Li J, Xu J (July 2017). "Connexin 43 is involved in the sympathetic atrial fibrillation in canine and canine atrial myocytes". Anatol J Cardiol. 18 (1): 3–9. doi:10.14744/AnatolJCardiol.2017.7602. PMC 5512195. PMID 28554986.
  16. ↑ Kontogeorgis A, Li X, Kang EY, Feig JE, Ponzio M, Kang G, Kaba RA, Wit AL, Fisher EA, Morley GE, Peters NS, Coetzee WA, Gutstein DE (November 2008). "Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents". Am. J. Physiol. Heart Circ. Physiol. 295 (5): H1905–16. doi:10.1152/ajpheart.590.2008. PMC 2614590. PMID 18757477.
  17. ↑ Satoh T, Zipes DP (September 1996). "Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation". J. Cardiovasc. Electrophysiol. 7 (9): 833–42. PMID 8884512.
  18. ↑ Van Wagoner DR, Pond AL, Lamorgese M, Rossie SS, McCarthy PM, Nerbonne JM (September 1999). "Atrial L-type Ca2+ currents and human atrial fibrillation". Circ. Res. 85 (5): 428–36. PMID 10473672.
  19. ↑ Krapivinsky G, Gordon EA, Wickman K, Velimirović B, Krapivinsky L, Clapham DE (March 1995). "The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins". Nature. 374 (6518): 135–41. doi:10.1038/374135a0. PMID 7877685.
  20. ↑ Goette A, Lendeckel U, Klein HU (May 2002). "Signal transduction systems and atrial fibrillation". Cardiovasc. Res. 54 (2): 247–58. PMID 12062330.
  21. ↑ Matsuda N, Hagiwara N, Shoda M, Kasanuki H, Hosoda S (April 1996). "Enhancement of the L-type Ca2+ current by mechanical stimulation in single rabbit cardiac myocytes". Circ. Res. 78 (4): 650–9. PMID 8635223.
  22. ↑ Fornengo C, Antolini M, Frea S, Gallo C, Grosso Marra W, Morello M; et al. (2015). "Prediction of atrial fibrillation recurrence after cardioversion in patients with left-atrial dilation". Eur Heart J Cardiovasc Imaging. 16 (3): 335–41. doi:10.1093/ehjci/jeu193. PMID 25274966.
  23. ↑ Xu Y, Sharma D, Li G, Liu Y (2013). "Atrial remodeling: new pathophysiological mechanism of atrial fibrillation". Med Hypotheses. 80 (1): 53–6. doi:10.1016/j.mehy.2012.10.009. PMID 23148964.
  24. ↑ 24.0 24.1 24.2 24.3 Harada M, Van Wagoner DR, Nattel S (2015). "Role of inflammation in atrial fibrillation pathophysiology and management". Circ J. 79 (3): 495–502. doi:10.1253/circj.CJ-15-0138. PMC 4457364. PMID 25746525.
  25. ↑ 25.0 25.1 25.2 Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL (2006). "ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society". Circulation. 114 (7): e257–354. doi:10.1161/CIRCULATIONAHA.106.177292. PMID 16908781. Unknown parameter |month= ignored (help)
  26. ↑ 26.0 26.1 Elvan A, Wylie K, Zipes DP (1996). "Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling". Circulation. 94 (11): 2953–60. PMID 8941126. Unknown parameter |month= ignored (help)
  27. ↑ 27.0 27.1 Manios EG, Kanoupakis EM, Mavrakis HE, Kallergis EM, Dermitzaki DN, Vardas PE (2001). "Sinus pacemaker function after cardioversion of chronic atrial fibrillation: is sinus node remodeling related with recurrence?". Journal of Cardiovascular Electrophysiology. 12 (7): 800–6. PMID 11469431. Unknown parameter |month= ignored (help)
  28. ↑ Chen PS, Chen LS, Fishbein MC, Lin SF, Nattel S (2014). "Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy". Circ Res. 114 (9): 1500–15. doi:10.1161/CIRCRESAHA.114.303772. PMC 4043633. PMID 24763467.
  29. ↑ Viskin S, Golovner M, Malov N, Fish R, Alroy I, Vila Y; et al. (1999). "Circadian variation of symptomatic paroxysmal atrial fibrillation. Data from almost 10 000 episodes". Eur Heart J. 20 (19): 1429–34. doi:10.1053/euhj.1999.1632. PMID 10487804.
  30. ↑ Leiria TL, Glavinovic T, Armour JA, Cardinal R, de Lima GG, Kus T (2011). "Longterm effects of cardiac mediastinal nerve cryoablation on neural inducibility of atrial fibrillation in canines". Auton Neurosci. 161 (1–2): 68–74. doi:10.1016/j.autneu.2010.12.006. PMID 21306960.
  31. ↑ Richer LP, Vinet A, Kus T, Cardinal R, Ardell JL, Armour JA (2008). "Alpha-adrenoceptor blockade modifies neurally induced atrial arrhythmias". Am J Physiol Regul Integr Comp Physiol. 295 (4): R1175–80. doi:10.1152/ajpregu.00840.2007. PMC 2576091. PMID 18716036.
  32. ↑ Jayachandran JV, Sih HJ, Winkle W, Zipes DP, Hutchins GD, Olgin JE (2000). "Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation". Circulation. 101 (10): 1185–91. doi:10.1161/01.cir.101.10.1185. PMID 10715267.
  33. ↑ Nguyen BL, Fishbein MC, Chen LS, Chen PS, Masroor S (2009). "Histopathological substrate for chronic atrial fibrillation in humans". Heart Rhythm. 6 (4): 454–60. doi:10.1016/j.hrthm.2009.01.010. PMC 2662134. PMID 19324302.
  34. ↑ Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q; et al. (2006). "Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation". N Engl J Med. 354 (25): 2677–88. doi:10.1056/NEJMoa052800. PMID 16790700.
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  40. ↑ Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y; et al. (2004). "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation". Am J Hum Genet. 75 (5): 899–905. doi:10.1086/425342. PMC 1182120. PMID 15368194.
  41. ↑ Hong K, Bjerregaard P, Gussak I, Brugada R (2005). "Short QT syndrome and atrial fibrillation caused by mutation in KCNH2". J Cardiovasc Electrophysiol. 16 (4): 394–6. doi:10.1046/j.1540-8167.2005.40621.x. PMID 15828882.
  42. ↑ Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y; et al. (2005). "A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation". Biochem Biophys Res Commun. 332 (4): 1012–9. doi:10.1016/j.bbrc.2005.05.054. PMID 15922306.
  43. ↑ Bedi M, McNamara D, London B, Schwartzman D (2006). "Genetic susceptibility to atrial fibrillation in patients with congestive heart failure". Heart Rhythm. 3 (7): 808–12. doi:10.1016/j.hrthm.2006.03.002. PMID 16818212.
  44. ↑ Fatini C, Sticchi E, Gensini F, Gori AM, Marcucci R, Lenti M; et al. (2007). "Lone and secondary nonvalvular atrial fibrillation: role of a genetic susceptibility". Int J Cardiol. 120 (1): 59–65. doi:10.1016/j.ijcard.2006.08.079. PMID 17113662.
  45. ↑ Watanabe H, Kaiser DW, Makino S, MacRae CA, Ellinor PT, Wasserman BS; et al. (2009). "ACE I/D polymorphism associated with abnormal atrial and atrioventricular conduction in lone atrial fibrillation and structural heart disease: implications for electrical remodeling". Heart Rhythm. 6 (9): 1327–32. doi:10.1016/j.hrthm.2009.05.014. PMC 2740737. PMID 19648063.
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  47. ↑ Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM (1994). "Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study)". Am. J. Cardiol. 74 (3): 236–41. PMID 8037127. Unknown parameter |month= ignored (help)
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  49. ↑ Brand FN, Abbott RD, Kannel WB, Wolf PA (1985). "Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study". JAMA. 254 (24): 3449–53. PMID 4068186. Unknown parameter |month= ignored (help)
  50. ↑ 50.0 50.1 Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S (2014). "Epidemiology of atrial fibrillation: European perspective". Clin Epidemiol. 6: 213–20. doi:10.2147/CLEP.S47385. PMC 4064952. PMID 24966695.
  51. ↑ Sanfilippo AJ, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA; et al. (1990). "Atrial enlargement as a consequence of atrial fibrillation. A prospective echocardiographic study". Circulation. 82 (3): 792–7. doi:10.1161/01.cir.82.3.792. PMID 2144217.
  52. ↑ Chimenti C, Russo MA, Carpi A, Frustaci A (2010). "Histological substrate of human atrial fibrillation". Biomed Pharmacother. 64 (3): 177–83. doi:10.1016/j.biopha.2009.09.017. PMID 20006465.
  53. ↑ 53.0 53.1 53.2 Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J (2002). "Structural correlate of atrial fibrillation in human patients". Cardiovasc Res. 54 (2): 361–79. doi:10.1016/s0008-6363(02)00273-0. PMID 12062341.
  54. ↑ van der Velden HM, van Kempen MJ, Wijffels MC, van Zijverden M, Groenewegen WA, Allessie MA; et al. (1998). "Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat". J Cardiovasc Electrophysiol. 9 (6): 596–607. doi:10.1111/j.1540-8167.1998.tb00940.x. PMID 9654224.


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