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EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: Definition, characterization, and clinical implication

      Document Reviewers: Osmar A. Centurion (Paraguay), Karl-Heinz Kuck (Germany), Kristen K. Patton (USA), John L. Sapp (Canada), Martin Stiles (New Zealand), Jesper Hastrup Svendsen (Denmark), and Gaurav A. Upadhyay (USA) Review coordinator: Alena Shantsila (UK)

      Introduction and definition of atrial cardiomyopathy

      The atria provide an important contribution to cardiac function.
      • Hoit B.D.
      Left atrial size and function: role in prognosis.
      • Schotten U.
      • Verheule S.
      • Kirchhof P.
      • Goette A.
      Pathophysiological mechanisms of atrial fibrillation: a translational appraisal.
      Besides their impact on ventricular filling, they serve as a volume reservoir, host pacemaker cells and important parts of the cardiac conduction system (e.g. sinus node, AV node), and secrete natriuretic peptides like atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) that regulate fluid homeostasis. Atrial myocardium is affected by many cardiac and non-cardiac conditions
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      and is, in some respects, more sensitive than ventricular.
      • Burstein B.
      • Libby E.
      • Calderone A.
      • Nattel S.
      Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences.
      The atria are activated, besides the three specialized intermodal tracts,
      • Davies M.J.
      • Pomerance A.
      Pathology of atrial fibrillation in man.
      • Sims B.A.
      Pathogenesis of atrial arrhythmias.
      through working cardiomyocytes, so that any architectural or structural change in the atrial myocardium may cause significant electrophysiological disturbances. In addition, atrial cells (both cardiomyocytes and non-cardiomyocyte elements like fibroblasts, endothelial cells, and neurons) react briskly and extensively to pathological stimuli3 and are susceptible to a range of genetic influences.
      • Tucker N.R.
      • Ellinor P.T.
      Emerging directions in the genetics of atrial fibrillation.
      Responses include atrial cardiomyocyte hypertrophy and contractile dysfunction, arrhythmogenic changes in cardiomyocyte ion-channel and transporter function, atrial fibroblast proliferation, hyperinnervation, and thrombogenic changes.
      • Schotten U.
      • Verheule S.
      • Kirchhof P.
      • Goette A.
      Pathophysiological mechanisms of atrial fibrillation: a translational appraisal.
      Thus, atrial pathologies have a substantial impact on cardiac performance, arrhythmia occurrence, and stroke risk.
      • Hoit B.D.
      Left atrial size and function: role in prognosis.
      • Goette A.
      • Bukowska A.
      • Dobrev D.
      • Pfeiffenberger J.
      • Morawietz H.
      • Strugala D.
      • et al.
      Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles.
      Ventricular cardiomyopathies have been well classified; however, a definition and detailed analysis of ‘atrial cardiomyopathy’ is lacking from the literature. The purpose of the present consensus report, prepared by a working group with representation from the European Heart Rhythm Association (EHRA), the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and Sociedad Latino Americana de Estimulacion Cardiaca y Electrofisiologia (SOLAECE), was to define atrial cardiomyopathy, to review the relevant literature, and to consider the impact of atrial cardiomyopathies on arrhythmia management and stroke.

      Definition of atrial cardiomyopathy

      The working group proposes the following working definition of atrial cardiomyopathy: ‘Any complex of structural, architectural, contractile or electrophysiological changes affecting the atria with the potential to produce clinically-relevant manifestations’ (Table 1).
      Table 1Definition of atrial cardiomyopathy
      ‘Any complex of structural, architectural, contractile or electrophysiological changes affecting the atria with the potential to produce clinically-relevant manifestations’.
      Many diseases (like hypertension, heart failure, diabetes, and myocarditis) or conditions (like ageing and endocrine abnormalities) are known to induce or contribute to an atrial cardiomyopathy. However, the induced changes are not necessarily disease-specific and pathological changes often share many similarities.
      • Corradi D.
      Atrial fibrillation from the pathologist’s perspective.
      • Corradi D.
      • Callegari S.
      • Maestri R.
      • Benussi S.
      • Alfieri O.
      Structural remodeling in atrial fibrillation.
      The extent of pathological changes may vary over time and atrial location, causing substantial intraindividual and interindividual differences. In addition, while some pathological processes may affect the atria very selectively (e.g. atrial fibrillation-induced remodelling), most cardiomyopathies that affect the atria also involve the ventricles to a greater or lesser extent. There is no presently accepted histopathological classification of atrial pathologies. Therefore, we have proposed here a working histological/ pathopysiological classification scheme for atrial cardiomyopathies (Table 1; Figure 1). We use the acronym EHRAS (for EHRA/HRS/ APHRS/SOLAECE), defining four classes: (I) principal cardiomyocyte changes;
      • Corradi D.
      • Callegari S.
      • Benussi S.
      • Maestri R.
      • Pastori P.
      • Nascimbene S.
      • et al.
      Myocyte changes and their left atrial distribution in patients with chronic atrial fibrillation related to mitral valve disease.
      • Corradi D.
      • Callegari S.
      • Maestri R.
      • Ferrara D.
      • Mangieri D.
      • Alinovi R.
      • et al.
      Differential structural remodeling of the left-atrial posterior wall in patients affected by mitral regurgitation with or without persistent atrial fibrillation: a morphological and molecular study.
      • Ausma J.
      • Wijffels M.
      • Thone F.
      • Wouters L.
      • Allessie M.
      • Borgers M.
      Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat.
      • Frustaci A.
      • Chimenti C.
      • Bellocci F.
      • Morgante E.
      • Russo M.A.
      • Maseri A.
      Histological substrate of atrial biopsies in patients with lone atrial fibrillation.
      • Ausma J.
      • Wijffels M.
      • van Eys G.
      • Koide M.
      • Ramaekers F.
      • Allessie M.
      • et al.
      Dedifferentiation of atrial cardiomyocytes as a result of chronic atrial fibrillation.
      (II) principally fibrotic changes;
      • Corradi D.
      • Callegari S.
      • Maestri R.
      • Benussi S.
      • Alfieri O.
      Structural remodeling in atrial fibrillation.
      • Frustaci A.
      • Chimenti C.
      • Bellocci F.
      • Morgante E.
      • Russo M.A.
      • Maseri A.
      Histological substrate of atrial biopsies in patients with lone atrial fibrillation.
      • Corradi D.
      • Callegari S.
      • Benussi S.
      • Nascimbene S.
      • Pastori P.
      • Calvi S.
      • et al.
      Regional left atrial interstitial remodeling in patients with chronic atrial fibrillation undergoing mitral-valve surgery.
      (III) combined cardiomyocyte-pathology/fibrosis;
      • Corradi D.
      Atrial fibrillation from the pathologist’s perspective.
      • Corradi D.
      • Callegari S.
      • Benussi S.
      • Maestri R.
      • Pastori P.
      • Nascimbene S.
      • et al.
      Myocyte changes and their left atrial distribution in patients with chronic atrial fibrillation related to mitral valve disease.
      • Corradi D.
      • Callegari S.
      • Maestri R.
      • Ferrara D.
      • Mangieri D.
      • Alinovi R.
      • et al.
      Differential structural remodeling of the left-atrial posterior wall in patients affected by mitral regurgitation with or without persistent atrial fibrillation: a morphological and molecular study.
      (IV) primarily non-collagen infiltration (with or without cardiomyocyte changes).
      • Rocken C.
      • Peters B.
      • Juenemann G.
      • Saeger W.
      • Klein H.U.
      • Huth C.
      • et al.
      Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation.
      • Kushnir A.
      • Restaino S.W.
      • Yuzefpolskaya M.
      Giant cell arteritis as a cause of myocarditis and atrial fibrillation.
      • Camm C.F.
      • James C.A.
      • Tichnell C.
      • Murray B.
      • Bhonsale A.
      • te Riele A.S.
      • et al.
      Prevalence of atrial arrhythmias in arrhythmogenic right ventricular dysplasia/ cardiomyopathy.
      This simple classification may help to convey the primary underlying pathology in various clinical conditions. The EHRAS class may vary over time and may differ at atrial sites in certain patients. Thus, this classification is purely descriptive and in contrast to other classifications (NYHA class, CCS class etc.), there is no progression in severity from EHRAS class I to EHRAS IV (Table 2). The classification may be useful to describe pathological changes in biopsies and to correlate pathologies with results obtained from imaging technologies etc. In the future, this may help to define a tailored therapeutic approach in atrial fibrillation (AF) (Figure 1, Figure 2, Figure 3).
      Figure 1
      Figure 1Histological and pathopysiological classification of atrial cardiomyopathies (EHRA/HRS/APHRS/SOLAECE): EHRAS classification. The EHRAS class may vary over time in the cause of the disease and may differ at various atrial sites. Of note, the nature of the classification is purely descriptive. EHRAS I-IV is not intended to describe disease progression from EHRAS I to EHRAS IV.
      Table 2EHRAS classification of atrial cardiomyopathy
      EHRASHistological characterization class
      I
      • Corradi D.
      • Callegari S.
      • Benussi S.
      • Maestri R.
      • Pastori P.
      • Nascimbene S.
      • et al.
      Myocyte changes and their left atrial distribution in patients with chronic atrial fibrillation related to mitral valve disease.
      • Corradi D.
      • Callegari S.
      • Maestri R.
      • Ferrara D.
      • Mangieri D.
      • Alinovi R.
      • et al.
      Differential structural remodeling of the left-atrial posterior wall in patients affected by mitral regurgitation with or without persistent atrial fibrillation: a morphological and molecular study.
      • Ausma J.
      • Wijffels M.
      • Thone F.
      • Wouters L.
      • Allessie M.
      • Borgers M.
      Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat.
      • Frustaci A.
      • Chimenti C.
      • Bellocci F.
      • Morgante E.
      • Russo M.A.
      • Maseri A.
      Histological substrate of atrial biopsies in patients with lone atrial fibrillation.
      • Ausma J.
      • Wijffels M.
      • van Eys G.
      • Koide M.
      • Ramaekers F.
      • Allessie M.
      • et al.
      Dedifferentiation of atrial cardiomyocytes as a result of chronic atrial fibrillation.
      • Bukowska A.
      • Lendeckel U.
      • Hirte D.
      • Wolke C.
      • Striggow F.
      • Rohnert P.
      • et al.
      Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation.
      Morphological or molecular changes affecting ‘primarily’ the cardiomyocytes in terms of cell hypertrophy and myocytolysis; no significant pathological tissue fibrosis or other interstitial changes
      II
      • Goette A.
      • Bukowska A.
      • Dobrev D.
      • Pfeiffenberger J.
      • Morawietz H.
      • Strugala D.
      • et al.
      Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles.
      • Corradi D.
      • Callegari S.
      • Maestri R.
      • Ferrara D.
      • Mangieri D.
      • Alinovi R.
      • et al.
      Differential structural remodeling of the left-atrial posterior wall in patients affected by mitral regurgitation with or without persistent atrial fibrillation: a morphological and molecular study.
      • Frustaci A.
      • Chimenti C.
      • Bellocci F.
      • Morgante E.
      • Russo M.A.
      • Maseri A.
      Histological substrate of atrial biopsies in patients with lone atrial fibrillation.
      • Goette A.
      • Lendeckel U.
      • Kuchenbecker A.
      • Bukowska A.
      • Peters B.
      • Klein H.U.
      • et al.
      Cigarette smoking induces atrial fibrosis in humans via nicotine.
      • Gramley F.
      • Lorenzen J.
      • Knackstedt C.
      • Rana O.R.
      • Saygili E.
      • Frechen D.
      • et al.
      Age-related atrial fibrosis.
      • Goette A.
      • Juenemann G.
      • Peters B.
      • Klein H.U.
      • Roessner A.
      • Huth C.
      • et al.
      Determinants and consequences of atrial fibrosis in patients undergoing open heart surgery.
      Predominantly fibrotic changes; cardiomyocytes show normal appearance
      III
      • Corradi D.
      Atrial fibrillation from the pathologist’s perspective.
      • Corradi D.
      • Callegari S.
      • Benussi S.
      • Maestri R.
      • Pastori P.
      • Nascimbene S.
      • et al.
      Myocyte changes and their left atrial distribution in patients with chronic atrial fibrillation related to mitral valve disease.
      • Corradi D.
      • Callegari S.
      • Maestri R.
      • Ferrara D.
      • Mangieri D.
      • Alinovi R.
      • et al.
      Differential structural remodeling of the left-atrial posterior wall in patients affected by mitral regurgitation with or without persistent atrial fibrillation: a morphological and molecular study.
      • Anne W.
      • Willems R.
      • Roskams T.
      • Sergeant P.
      • Herijgers P.
      • Holemans P.
      • et al.
      Matrix metalloproteinases and atrial remodeling in patients with mitral valve disease and atrial fibrillation.
      • Goette A.
      • Staack T.
      • Rocken C.
      • Arndt M.
      • Geller J.C.
      • Huth C.
      • et al.
      Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation.
      Combination of cardiomyocyte changes (e.g. cell hypertrophy, myocytolysis) and fibrotic changes
      IV
      • Rocken C.
      • Peters B.
      • Juenemann G.
      • Saeger W.
      • Klein H.U.
      • Huth C.
      • et al.
      Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation.
      • Kushnir A.
      • Restaino S.W.
      • Yuzefpolskaya M.
      Giant cell arteritis as a cause of myocarditis and atrial fibrillation.
      • Camm C.F.
      • James C.A.
      • Tichnell C.
      • Murray B.
      • Bhonsale A.
      • te Riele A.S.
      • et al.
      Prevalence of atrial arrhythmias in arrhythmogenic right ventricular dysplasia/ cardiomyopathy.
      Alteration of interstitial matrix without prominent collagen fibre accumulation
      IVaAccumulation of amyloid
      IVfFatty infiltration
      IViInflammatory cells
      IVoOther interstitial alterations
      Figure 2
      Figure 2(A) EHRAS Class I (biopsy): there are severe changes affecting ‘primarily’ the cardiomyocytes in terms of cell hypertrophy and myocytolysis; fibrosis is much less evident than myocyte modifications. (B) EHRAS Class II (biopsy): cardiomyocyte alterations are relatively modest compared with severe fibrotic changes; in this case, interstitial changes are much more prevalent than myocyte ones. (C ) EHRAS Class III (biopsy): this is a combination of cardiomyocyte changes and collagen fibre deposition. (D) EHRAS Class IV (autopsy heart): primarily neutrophilic myocarditis.
      Figure 3
      Figure 3EHRAS Class IV (autopsy heart): this image shows a myocardial interstitial with some fibrosis but prominent amyloid (AL type) deposition (left-hand side, congo red staining under regular light microscope; right-hand side, congo red staining under polarized light microscope).

      Anatomical considerations and atrial muscular architecture

      Normal atrial structures

      Gross morphology

      Each atrium has a morphologically characteristic atrial body and appendage (Figure 4). In the body, there is a venous component with the orifices of the systemic or pulmonary veins (PVs) and a vestibular component that surrounds the atrial outlet.
      • Cabrera J.A.
      • Sanchez-Quintana D.
      Cardiac anatomy: what the electrophysiologist needs to know.
      The interatrial septum (IAS) separates the atrial bodies. The venous component of the left atrium (LA) is located posterosuperiorly and receives the PVs at the four corners, forming a prominent atrial dome. The LA is situated more posteriorly and superiorly than the right atrium separated by the obliquity of the plane of the IAS.
      • Ho S.Y.
      • Cabrera J.A.
      • Sanchez-Quintana D.
      Left atrial anatomy revisited.
      Figure 4
      Figure 4Schematic representations and heart dissections to show the arrangement of the myocardial strands in the superficial parts of the walls. (A) The dissection viewed from the anterior aspect display the interatrial muscle Bachmann bundle and its bifurcating branches leftward and rightward. (B) A view of the roof and posterior wall of the left and right atriums. The right pulmonary veins (PVs) passes behind the intercaval area. The subepicardial dissection shows the abrupt changes in fibre orientation and the myocardial strands (septopulmonary bundle) in the region between the left and right PVs. The red arrows show multiple muscle bridges connecting the two atria. ICV, inferior caval vein; LAA, left atrial appendage; LSPV, left superior pulmonary vein; MV, mitral valve; RAA, right atrial appendage; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein; SCV, superior caval vein; TV, tricuspid valve (see text for details).
      The LA appendage (LAA) is smaller than the right atrium appendage (RAA). Narrower and with different shapes has a distinct opening to the atrial body and overlies the left circumflex coronary artery. Its endocardial aspect is lined by a complex network of muscular ridges and membranes.
      • Sanchez-Quintana D.
      • Anderson R.H.
      • Cabrera J.A.
      • Climent V.
      • Martin R.
      • Farre J.
      • et al.
      The terminal crest: morphological features relevant to electrophysiology.
      • Cabrera J.A.
      • Ho S.Y.
      • Climent V.
      • Sanchez-Quintana D.
      The architecture of the left lateral atrial wall: a particular anatomic region with implications for ablation of atrial fibrillation.
      Different LAA morphologies have been described, and it appears that LAA morphology correlates with the risk of thrombogenesis.
      • Di Biase L.
      • Santangeli P.
      • Anselmino M.
      • Mohanty P.
      • Salvetti I.
      • Gili S.
      • et al.
      Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study.
      Bachmann’s bundle is a broad epicardial muscular band running along the anterior wall of both atria (Figure 4). The rightward arms extend superiorly towards the sinus node and inferiorly towards the right atrioventricular groove, while the leftward arms blend with deeper myofibres to pass around the neck of the LAA and reunite posteriorly to join the circumferential vestibule of the LA. The walls of LA are non-uniform in thickness (1 – 15 mm) and thicker than the right atrium.
      • Ho S.Y.
      • Anderson R.H.
      • Sanchez-Quintana D.
      Atrial structure and fibres: morphologic bases of atrial conduction.

      Normal atrial myocardium

      Atrial cardiomyocytes

      Atrial cardiomyocytes are geometrically complex cylinders that sometimes bifurcate at their ends where they connect with adjacent fibres via band-like ‘intercalated discs’. This contractile syncytium is organized in well-defined bands that establish non-uniform anisotropic propagation of the atrial impulse.
      • Corradi D.
      Atrial fibrillation from the pathologist’s perspective.
      • Corradi D.
      • Callegari S.
      • Benussi S.
      • Maestri R.
      • Pastori P.
      • Nascimbene S.
      • et al.
      Myocyte changes and their left atrial distribution in patients with chronic atrial fibrillation related to mitral valve disease.
      • Spach M.S.
      • Kootsey J.M.
      The nature of electrical propagation in cardiac muscle.
      The only clear light-microscopic morphological difference between atrial and ventricular cardiomyocytes is in size.
      • Veinot J.
      • Ghadially F.
      • Walley V.
      Light microscopy and ultrastructure of the blood vessels and heart.
      In paraffin-embedded human specimens, the cardiomyocyte transverse diameter is ×12 mm in the LAs vs. 20 – 22 mm in the ventricles.
      • Corradi D.
      • Callegari S.
      • Benussi S.
      • Maestri R.
      • Pastori P.
      • Nascimbene S.
      • et al.
      Myocyte changes and their left atrial distribution in patients with chronic atrial fibrillation related to mitral valve disease.
      • Beltrami C.A.
      • Finato N.
      • Rocco M.
      • Feruglio G.A.
      • Puricelli C.
      • Cigola E.
      • et al.
      Structural basis of end-stage failure in ischemic cardiomyopathy in humans.
      Atrial cardiomyocytes are mainly mononucleated; a minor fraction possess two or more nuclei. The nucleus is usually centrally located, with granular and/or condensed chromatin. The nuclear shape is influenced by fibre contraction, becoming more fusiform with longitudinal cell stretch.
      • Lannigan R.A.
      • Zaki S.A.
      Ultrastructure of the myocardium of the atrial appendage.
      Biochemically, atrial cardiomyocytes have greater lipid content than ventricular muscle cells.
      • Armiger L.C.
      • Seelye R.N.
      • Morrison M.A.
      • Holliss D.G.
      Comparative biochemistry and fine structure of atrial and ventricular myocardium during autolysis in vitro.
      Atrial cardiomyocytes share many characteristics with ventricular in terms of nucleus, contractile apparatus, cytoskeleton, and organelles.
      • Veinot J.
      • Ghadially F.
      • Walley V.
      Light microscopy and ultrastructure of the blood vessels and heart.
      • Lannigan R.A.
      • Zaki S.A.
      Ultrastructure of the myocardium of the atrial appendage.
      • Corradi D.
      • Maestri R.
      • Macchi E.
      • Callegari S.
      The atria: from morphology to function.
      • Kitzman D.W.
      • Edwards W.D.
      Age-related changes in the anatomy of the normal human heart.
      Unlike ventricular cardiomyocytes, atrial cardiomyocytes do not possess an extensive T-tubule network but they do have prominent sarcoplasmic reticulum (SR) elements known as Z-tubules.
      • Yamasaki Y.
      • Furuya Y.
      • Araki K.
      • Matsuura K.
      • Kobayashi M.
      • Ogata T.
      Ultra-high-resolution scanning electron microscopy of the sarcoplasmic reticulum of the rat atrial myocardial cells.
      Therefore, the atrial sarcolemma does not protrude into the cell, and voltage-operated Ca2+ channels mainly function at the cell periphery.
      • Mackenzie L.
      • Roderick H.L.
      • Berridge M.J.
      • Conway S.J.
      • Bootman M.D.
      The spatial pattern of atrial cardiomyocyte calcium signalling modulates contraction.
      Atrial cardiomyocytes display specific granules (100 – 400 nm) situated mainly in the paranuclear area adjacent to the Golgi apparatus, which contain ANP, the BNP, and related peptides.
      • Cabrera J.A.
      • Ho S.Y.
      • Climent V.
      • Sanchez-Quintana D.
      The architecture of the left lateral atrial wall: a particular anatomic region with implications for ablation of atrial fibrillation.
      • Di Biase L.
      • Santangeli P.
      • Anselmino M.
      • Mohanty P.
      • Salvetti I.
      • Gili S.
      • et al.
      Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study.

      Atrial interstitium

      Atrial interstitium consists of cellular and extracellular components (see Figure 2, Figure 3, Figure 4, Figure 5). The cellular elements include fibroblast/myofibroblasts, adipocytes, undifferentiated mesenchymal cells, and isolated inflammatory cells. The atrial wall has a significant number of medium-sized blood vessels, especially in the sub-epicardium. Mature adipose tissue is frequently found in atrial myocardium, especially the epicardium, and often permeates the layers around intramural coronary branches. The number of adipocytes is highly variable and increases with age.
      • Veinot J.
      • Ghadially F.
      • Walley V.
      Light microscopy and ultrastructure of the blood vessels and heart.
      The extracellular components consist of collagen fibres, which form most of the myocardial skeleton, proteoglycan particles, lipidic debris, spherical micro-particles, and matrix vesicles.
      • Veinot J.
      • Ghadially F.
      • Walley V.
      Light microscopy and ultrastructure of the blood vessels and heart.
      Figure 5
      Figure 5Normal histology of the left atrium and relevant pathological changes in mitral valve disease-associated atrial fibrillation. (A) Medium-power view of a normal left atrial myocardium which is composed of large bands of homogeneous cardiomyocytes. (B) In the same atrium as in (A), the Van Gieson staining show that collagen fibres (red colour) are primarily seen in the adventitial spaces of blood vessels (arrow). (C) Low-power view of a left atrium from a patient with mitral valve disease-associated atrial fibrillation. Large bands of cardiomyocytes are separated by significant amounts of pathologic fibrous tissue (arrows). (D) In the same atrium as in (C), the Van Gieson staining shows that the pathologic fibrous significantly thickens the perivascular spaces (perivascular fibrosis, arrow) and separates single or small groups of cardiomyocytes (interstitial fibrosis, arrowhead). (E) In atrial fibrillation, a variable number of cardiomyocytes undergo loss of contractile elements starting from the perinuclear area and resulting in so-called myocytolysis. These spaces may be empty (arrow) or filled with glycogen (arrowhead). (F) A higher-power view of myocytolysis with both glycogen rich (arrow) and optically empty (arrowhead) cardiomyocytes. (G) Ultrastructural view of a myolytic cardiomyocyte with significant loss of contractile elements around the nucleus (asterisk). In this empty area, there is very often accumulation of mitochondria (arrowhead) while the adjacent myofibrils display signs of abnormal contraction (arrow). (H) An LA from a patient with atrial fibrillation where the myocardial microcirculation (arrow) is slightly reduced and irregularly distributed. Stainings. (A and C) haematoxylin – eosin staining; (B and D) Van Gieson staining for collagen; (E and F) Periodic acid Schiff staining; (G) ultrastructural image; (H) immunohistochemical analysis with an anti-CD31 antibody. Original magnifications. (A, B, E, and H) ×20; (C and D) ×4; (F) ×40; (G) ×2800.
      Collagen fibers, mainly type I, are both normal and essential components (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5). Atrial fibrous tissue may be sub-divided into pure interstitial and perivascular (or adventitial). Interstitial collagen fibres represent ×5% of the atrial wall volume. The atrial myocardium is also the site of sparse postganglionic nerve endings (from the ‘intrinsic cardiac nervous system’), mostly within discrete fat pads but also among cardiomyocytes.
      • Sanchez-Quintana D.
      • Lopez-Minguez J.R.
      • Macias Y.
      • Cabrera J.A.
      • Saremi F.
      Left atrial anatomy relevant to catheter ablation.

      Atrial-specific physiological and functional considerations

      Atrial-selective electrophysiological properties

      The atria have a number of electrophysiological features that distinguish them from the ventricles and govern their arrhythmia susceptibility.

      Action potential/ion-channel properties

      Atrial cardiomyocytes have distinct action potential (AP) properties from ventricular cardiomyocytes, resulting in a large part from distinct ion-channel properties and distribution (Figure 6A).
      • Ehrlich J.R.
      • Biliczki P.
      • Hohnloser S.H.
      • Nattel S.
      Atrial-selective approaches for the treatment of atrial fibrillation.
      • Schram G.
      • Pourrier M.
      • Melnyk P.
      • Nattel S.
      Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function.
      Atrial background inward-rectifier K+ current (IK1) is smaller than that of ventricular K+ current, resulting in a less negative resting potential and more gradual slope of phase-3 repolarization. Atrial cells also have two K+-currents that are absent in ventricle cells: the ultrarapid delayed rectifier current (IKur) and the acetylcholine-regulated K+-current (IKACh). In addition, there is evidence that atrial Na+-current has different properties compared with ventricular current.
      • Burashnikov A.
      • Di Diego J.M.
      • Zygmunt A.C.
      • Belardinelli L.
      • Antzelevitch C.
      Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine.
      As well as distinctions between atrial and ventricular APs, different atrial regions may have discrete AP and ion-channel properties.
      • Schram G.
      • Pourrier M.
      • Melnyk P.
      • Nattel S.
      Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function.
      • Feng J.
      • Yue L.
      • Wang Z.
      • Nattel S.
      Ionic mechanisms of regional action potential heterogeneity in the canine right atrium.
      These cellular electrophysiological characteristics have implications for antiarrhythmic drug action and design, and may also affect the responses to atrial arrhythmias and disease.
      • Ehrlich J.R.
      • Biliczki P.
      • Hohnloser S.H.
      • Nattel S.
      Atrial-selective approaches for the treatment of atrial fibrillation.
      • Schram G.
      • Pourrier M.
      • Melnyk P.
      • Nattel S.
      Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function.
      Figure 6
      Figure 6(A) Comparison of atrial and ventricular action potential properties and underlying ionic currents. Resting potentials (2mV) are more negative (averaging 280 to 285 mV) in ventricular vs. atrial (270 to 275 mV) myocytes. (B) Connexin distribution differs between atria and ventricles, with connexin-43 only expressed in ventricular cardiomyocytes (CMs) but atrial CMs having both connexin-40 and connexin-43. (C) Ralistic reconstruction of the structure of sheep atria. The right atrium (RA), left atrium (LA), pectinate muscles (PM), Bachmann’s bundle (BB) and pulmonary veins (PV) are colour coded. From ref.
      • Butters T.D.
      • Aslanidi O.V.
      • Zhao J.
      • Smaill B.
      • Zhang H.
      A novel computational sheep atria model for the study of atrial fibrillation.
      with permission.

      Intercellular coupling properties

      The atria have a different pattern of cell-to-cell coupling protein (connexin) distribution compared with ventricular myocardium.
      • Ehrlich J.R.
      • Biliczki P.
      • Hohnloser S.H.
      • Nattel S.
      Atrial-selective approaches for the treatment of atrial fibrillation.
      Whereas working ventricular cardiomyocytes express connexin-43 exclusively, atrial cardiomyocytes have significant expression of connexin-40 (Figure 6B).
      • Ehrlich J.R.
      • Biliczki P.
      • Hohnloser S.H.
      • Nattel S.
      Atrial-selective approaches for the treatment of atrial fibrillation.
      Heterogeneities in connexin-40 distribution are common in paroxysmal AF and may play a pathophysiological role,
      • Gemel J.
      • Levy A.E.
      • Simon A.R.
      • Bennett K.B.
      • Ai X.
      • Akhter S.
      • et al.
      Connexin40 abnormalities and atrial fibrillation in the human heart.
      and gene variants affecting connexin-40 sequence and/or transcription predispose to AF occurrence.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.

      Atrial structural properties

      The atria have a very complex 3D structure (Figure 6C) not found in the ventricles. These include interatrial connections limited to Bachmann’s bundle, the septum, and the CS; pectinate muscles, the crista terminalis, and fibres surrounding the coronary sinus in the right atrium; and the PVs with complex fibre orientation around them in the LA. These structural complexities have important potential implications for atrial pathophysiology and management of atrial arrhythmias.
      • Iwasaki Y.K.
      • Nishida K.
      • Kato T.
      • Nattel S.
      Atrial fibrillation pathophysiology: implications for management.
      Extensive recent work has gone into the realistic mathematical reconstruction of such geometric complexities,
      • Butters T.D.
      • Aslanidi O.V.
      • Zhao J.
      • Smaill B.
      • Zhang H.
      A novel computational sheep atria model for the study of atrial fibrillation.
      and they have been incorporated into analytical approaches designed to implement patient-specific arrhythmia therapies.
      • McDowell K.S.
      • Zahid S.
      • Vadakkumpadan F.
      • Blauer J.
      • MacLeod R.S.
      • Trayanova N.A.
      Virtual electrophysiological study of atrial fibrillation in fibrotic remodeling.
      Cable-like strands of atrial tissue like the pectinate muscles and crista terminalis are organized such that conduction within them is primarily longitudinal, with an ‘anisotropy ratio’ (longitudinal/transverse conduction velocities) as great as 10, whereas in working ventricular muscle the ratio is typically more between 2 and 4.
      • Saffitz J.E.
      • Kanter H.L.
      • Green K.G.
      • Tolley T.K.
      • Beyer E.C.
      Tissue-specific determinants of anisotropic conduction velocity in canine atrial and ventricular myocardium.

      Autonomic ganglia

      There are autonomic ganglia on the surface of the heart that are important way-stations for cardiac autonomic control.
      • Chen P.S.
      • Chen L.S.
      • Fishbein M.C.
      • Lin S.F.
      • Nattel S.
      Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy.
      Moreover, alterations in local cardiac innervation and intracardiac autonomic reflexes play an important role in physiology and arrhythmia control. Most of the cardiac autonomic ganglia are located on the atria, and in particular in the region of the PV ostia. Thus, they are well positioned to affect atrial electrical activity in regions particularly important in AF, and their alteration by therapeutic manoeuvers like PV ablation may contribute to antiarrhythmic efficacy.
      • Iwasaki Y.K.
      • Nishida K.
      • Kato T.
      • Nattel S.
      Atrial fibrillation pathophysiology: implications for management.
      • Chen P.S.
      • Chen L.S.
      • Fishbein M.C.
      • Lin S.F.
      • Nattel S.
      Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy.
      • Lemola K.
      • Chartier D.
      • Yeh Y.H.
      • Dubuc M.
      • Cartier R.
      • Armour A.
      • et al.
      Pulmonary vein region ablation in experimental vagal atrial fibrillation: role of pulmonary veins versus autonomic ganglia.

      Left atrium mechanics

      The left atrial contribution to overall cardiovascular performance is determined by unique factors. First, left atrial function critically determines left ventricular (LV) filling. Second, chamber-specific structural, electrical and ion remodelling alter left atrial function and arrhythmia susceptibility. Third, atrial function is highly relevant for the therapeutic responses of AF. Fourth, LA volume is an important biomarker that integrates the magnitude and duration of LV diastolic dysfunction. The development of sophisticated, non-invasive indices of LA size, and function might help to clinically exploit the importance of LA function in prognosis and risk stratification.
      • Hoit B.D.
      Left atrial size and function: role in prognosis.
      • Nattel S.
      • Shiroshita-Takeshita A.
      • Cardin S.
      • Pelletier P.
      Mechanisms of atrial remodeling and clinical relevance.
      Fibre orientation of the two thin muscular layers (the fascicles of which both originate and terminate at the atrioventricular ring) introduce a complexity that challenges functional analysis. Ultrastructurally, atrial cardiomyocytes are smaller in diameter, have fewer T-tubules, and more abundant Golgi apparatus than ventricular. In addition, rates of contraction and relaxation, conduction velocity, and anisotropy differ, as does the myosin isoform composition and the expression of ion transporters, channels, and gap junctional proteins (see relevant sections).

      Functions of the left atrium

      The principal role of the LA is to modulate LV filling and cardiovascular performance by operating as a reservoir for PV return during LV systole, a conduit for PV return during early LV diastole, and as a booster pump that augments LV filling during LV diastole. There is a critical interplay between these atrial functions and ventricular systolic and diastolic performance. Thus, while LA compliance (or its inverse, stiffness), and, to a lesser extent, LA contractility and relaxation are the major determinants of reservoir function during LV systole, LV end-systolic volume and descent of the LV base during systole are important contributors. Conduit function is also governed by LA compliance and is reciprocally related to reservoir function, but because the mitral valve is open in diastole, conduit function is also closely related to LV compliance (of which relaxation is a major determinant). Atrial booster-pump function reflects the magnitude and timing of atrial contractility, but also depends on venous return (atrial preload), LV end- diastolic pressures (atrial afterload), and LV systolic reserve.

      Left atrium booster-pump function

      Left atrium booster-pump function represents the augmented LV-filling resulting from active atrial contraction (minus retrograde blood-ejection into the PVs) and has been estimated by measurements of (i) cardiac output with and without effective atrial systole, (ii) relative LV-filling using spectral Doppler of transmitral, PV, and LA-appendage flow, (iii) LA-shortening and volumetric analysis, and (iv) tissue Doppler and deformation analysis (strain and strain-rate imaging) of the LA-body.
      • Hoit B.D.
      Left atrial size and function: role in prognosis.
      Booster-pump function can also be evaluated echocardiographically by estimating the kinetic energy and force generated by LA contraction. The relative importance of the LA contribution to LV filling and cardiac output remain controversial. A load-independent index of LA contraction based on the analysis of instantaneous relation between LA pressure and volume, analogous to LV end-systolic elastance measurements, has been used as a load-independent measure of LA pump function, validated ex vivo and in the intact dog (Figure 7).
      • Hoit B.D.
      • Shao Y.
      • Gabel M.
      • Walsh R.A.
      In vivo assessment of left atrial contractile performance in normal and pathological conditions using a time-varying elastance model.
      While LA pressure – volume loops can be generated with invasive and semi-invasive means in humans,
      • Pagel P.S.
      • Kehl F.
      • Gare M.
      • Hettrick D.A.
      • Kersten J.R.
      • Warltier D.C.
      Mechanical function of the left atrium: new insights based on analysis of pressure-volume relations and Doppler echocardiography.
      these methods are cumbersome, time-consuming, and difficult to apply. Measurement of myocardial strain and strain rate, which represent the magnitude and rate of myocardial deformation, assessed using either tissue Doppler velocities (tissue Doppler imaging, TDI) or by 2D echocardiographic (2D speckle-tracking or STE) techniques (Figure 8) provide objective, non-invasive measurements of LA myocardial performance and contractility that overcome these limitations.
      • Hoit B.D.
      Left atrial size and function: role in prognosis.
      • Vieira M.J.
      • Teixeira R.
      • Goncalves L.
      • Gersh B.J.
      Left atrial mechanics: echocardiographic assessment and clinical implications.
      Figure 7
      Figure 7Left atrial pressure – volume loop. (A) Analogue recordings of left atrial pressure and dimensions in the time domain. Vertical lines indicate time of mitral valve opening (A), end of passive atrial emptying and onset of atrial diastasis (B), atrial end-diastole (C), and atrial end-systole (D). a and v represent respective venous pressure waves. (B) Left atrial pressure – volume loop from a single beat illustrating characteristic figure-of-eight configuration. Arrows indicate the direction of loop as a function of time. A loop represents active atrial contraction. V loop represents passive filling and emptying of the LA. MVO, time of mitral valve opening; MVC, approximate time of mitral valve closure; LA, left atrial end-systole; and LAd, left atrial end-diastole. Reproduced from ref.
      • Hoit B.D.
      • Shao Y.
      • Gabel M.
      • Walsh R.A.
      In vivo assessment of left atrial contractile performance in normal and pathological conditions using a time-varying elastance model.
      with permission.
      Figure 8
      Figure 8LA functions colour-coded displays of atrial functions (red, reservoir; blue, conduit; yellow, booster pump) related to events in the cardiac cycle. Displayed are pulmonary venous (PV) velocity, LA strain, LA strain rate, LA volume and pressure, and mitral spectral and tissue Doppler. Reproduced from ref.
      • Hoit B.D.
      Left atrial size and function: role in prognosis.
      with permission.

      Left atrium reservoir function

      Nearly half of the LV stroke volume and its associated energy are stored in the LA during LV systole. This energy is subsequently expended during the LV diastole. Reservoir function is governed largely by atrial compliance during ventricular systole, which is measured most rigorously by fitting atrial pressures and dimensions, taken either at the time of mitral valve opening/closure over a range of atrial pressures and volumes or during ventricular diastole, to an exponential equation.
      • Hoit B.D.
      • Walsh R.A.
      Regional atrial distensibility.
      Although this method requires atrial dimensions and pressures, the relative reservoir function can be estimated simply with PV Doppler: the proportion of LA inflow during ventricular systole provides an index of the reservoir capacity of the atrium. Reservoir function can also be estimated from LA time – volume relations as either the total ejection fraction or distensibility fraction, calculated as the maximum minus minimum LA volume, normalized to maximal or minimal LA volume, respectively.
      Although largely neglected, the LA–appendage is more compliant than the LA–body,
      • Hoit B.D.
      • Walsh R.A.
      Regional atrial distensibility.
      so the contribution of the appendage to overall LA compliance is substantial with potential negative implications for routine atrial appendectomy/ligation during mitral valve surgery.
      Left atrium strain and strain rates during LV systole predict successful sinus rhythm restoration following DC cardioversion or AF ablation, and are surrogates of atrial fibrosis and structural remodelling; coupled with an estimate of atrial pressure (e.g. transmitral E/E), strain has the potential to estimate atrial distensibility non-invasively.
      • Hoit B.D.
      Left atrial size and function: role in prognosis.
      • Kuppahally S.S.
      • Akoum N.
      • Burgon N.S.
      • Badger T.J.
      • Kholmovski E.G.
      • Vijayakumar S.
      • et al.
      Left atrial strain and strain rate in patients with paroxysmal and persistent atrial fibrillation: relationship to left atrial structural remodeling detected by delayed-enhancement MRI.

      Left atrium conduit function

      Left atrium conduit function occurs primarily during ventricular diastole and represents the trasport of blood volume that cannot be attributed to either reservoir or booster-pump functions, accounting for approximately one-third of atrial flow.
      • Hitch D.C.
      • Nolan S.P.
      Descriptive analysis of instantaneous left atrial volume—with special reference to left atrial function.
      A reciprocal relation exists between LA conduit and reservoir functions; a redistribution between these functions is an important compensatory mechanism that facilitates LV filling with myocardial ischaemia, hypertensive heart disease, and mitral stenosis (MS). Conduit function is estimated by the early diastolic transmitral flow, diastolic PV-flow, and LA strain and strain rate during early diastole.

      Atrial-selective Ca21 handling

      There are major differences in the expression and function of Ca2+-handling proteins between atria and ventricles (Figure 9).
      • Bootman M.D.
      • Higazi D.R.
      • Coombes S.
      • Roderick H.L.
      Calcium signalling during excitation-contraction coupling in mammalian atrial myocytes.
      The atria have reduced cardiomyocyte contraction and relaxation times and shorter Ca2+-transient duration.
      • Tanaami T.
      • Ishida H.
      • Seguchi H.
      • Hirota Y.
      • Kadono T.
      • Genka C.
      • et al.
      Difference in propagation of Ca2+ release in atrial and ventricular myocytes.
      • Boknik P.
      • Unkel C.
      • Kirchhefer U.
      • Kleideiter U.
      • Klein-Wiele O.
      • Knapp J.
      • et al.
      Regional expression of phospholamban in the human heart.
      • Maier L.S.
      • Barckhausen P.
      • Weisser J.
      • Aleksic I.
      • Baryalei M.
      • Pieske B.
      Ca(2+) handling in isolated human atrial myocardium.
      In atria, protein levels
      • Boknik P.
      • Unkel C.
      • Kirchhefer U.
      • Kleideiter U.
      • Klein-Wiele O.
      • Knapp J.
      • et al.
      Regional expression of phospholamban in the human heart.
      • Luss I.
      • Boknik P.
      • Jones L.R.
      • Kirchhefer U.
      • Knapp J.
      • Linck B.
      • et al.
      Expression of cardiac calcium regulatory proteins in atrium v ventricle in different species.
      and activity
      • Boknik P.
      • Unkel C.
      • Kirchhefer U.
      • Kleideiter U.
      • Klein-Wiele O.
      • Knapp J.
      • et al.
      Regional expression of phospholamban in the human heart.
      • Luss I.
      • Boknik P.
      • Jones L.R.
      • Kirchhefer U.
      • Knapp J.
      • Linck B.
      • et al.
      Expression of cardiac calcium regulatory proteins in atrium v ventricle in different species.
      of the SR Ca2+-ATPase2a (Serca2a) are two-fold higher, whereas the Serca2a-inhibitor phospholamban (PLB) is less abundant, vs. ventricles.
      • Boknik P.
      • Unkel C.
      • Kirchhefer U.
      • Kleideiter U.
      • Klein-Wiele O.
      • Knapp J.
      • et al.
      Regional expression of phospholamban in the human heart.
      • Luss I.
      • Boknik P.
      • Jones L.R.
      • Kirchhefer U.
      • Knapp J.
      • Linck B.
      • et al.
      Expression of cardiac calcium regulatory proteins in atrium v ventricle in different species.
      Atrial, but not ventricular, Serca2a is also regulated by sarcolipin (SLN) and SLN ablation increases atrial SR Ca2+-uptake and contractility.
      • Babu G.J.
      • Bhupathy P.
      • Timofeyev V.
      • Petrashevskaya N.N.
      • Reiser P.J.
      • Chiamvimonvat N.
      • et al.
      Ablation of sarcolipin enhances sarcoplasmic reticulum calcium transport and atrial contractility.
      L-type Ca2+ current
      • Li G.R.
      • Nattel S.
      Properties of human atrial ICa at physiological temperatures and relevance to action potential.
      is similar in both chambers, whereas protein levels of ryanodine receptor type-2, calsequestrin, triadin, junction and Na2+ –Ca2+ exchanger are lower in atria than in ventricles.
      • Luss I.
      • Boknik P.
      • Jones L.R.
      • Kirchhefer U.
      • Knapp J.
      • Linck B.
      • et al.
      Expression of cardiac calcium regulatory proteins in atrium v ventricle in different species.
      • Cote K.
      • Proteau S.
      • Teijeira J.
      • Rousseau E.
      Characterization of the sarcoplasmic reticulum k(+) and Ca(2+)-release channel-ryanodine receptor-in human atrial cells.
      • Wang J.
      • Schwinger R.H.
      • Frank K.
      • Muller-Ehmsen J.
      • Martin-Vasallo P.
      • Pressley T.A.
      • et al.
      Regional expression of sodium pump subunits isoforms and Na+-Ca++ exchanger in the human heart.
      In contrast to ventricular myocardium, T-tubules are less abundant in atrial cardiomyocytes.
      • Richards M.A.
      • Clarke J.D.
      • Saravanan P.
      • Voigt N.
      • Dobrev D.
      • Eisner D.A.
      • et al.
      Transverse tubules are a common feature in large mammalian atrial myocytes including human.
      In addition, atrial cardiomyocytes possess much more Ca2+-buffering mitochondria than ventricular cardiomyocytes.
      • Tanaami T.
      • Ishida H.
      • Seguchi H.
      • Hirota Y.
      • Kadono T.
      • Genka C.
      • et al.
      Difference in propagation of Ca2+ release in atrial and ventricular myocytes.
      As a consequence, the atrial Ca2+ wave starts in the myocyte periphery and then propagates to the centre of the myocyte, activating additional Ca2+-releasing sites in the SR.
      • Bootman M.D.
      • Higazi D.R.
      • Coombes S.
      • Roderick H.L.
      Calcium signalling during excitation-contraction coupling in mammalian atrial myocytes.
      Figure 9
      Figure 9Excitation – contraction coupling in atria vs. ventricles. Schematic representation of the cell structure and major Ca2+ handling proteins, along with related currents and ion transporters (A). Illustration of action potential (top), Ca2+ transient (middle) and confocal linescan image of intracellular Ca2+ wave propagation towards cell centre (bottom) in a ventricular (left) vs. atrial (right) cardiomyocyte (B). Arrows indicate differences in expression and/or function of Ca2+ handling proteins in atrial vs. ventricular cardiomyocytes. INa, Na+ current; FKPB12.6, FK506-binding protein 12.6; JPH2, Junctophilin-2; MyBP-CMyosin bindig protein C; TnI, Troponin-I; for further abbreviations, see text.

      Pathology of atrial cardiomyopathies

      Lone atrial fibrillation (atrial fibrillation without concomitant conditions)

      ‘Lone’ atrial fibrillation (LAF) is diagnosed when no apparent explanation or underlying comorbidity can be identified.
      • Kopecky S.L.
      • Gersh B.J.
      • McGoon M.D.
      • Whisnant J.P.
      • Holmes Jr, D.R.
      • Ilstrup D.M.
      • et al.
      The natural history of lone atrial fibrillation. A population-based study over three decades.
      • Fuster V.
      • Ryden L.E.
      • Cannom D.S.
      • Crijns H.J.
      • Curtis A.B.
      • Ellenbogen K.A.
      • et al.
      ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      Over the last few years, new epidemiological associations with AF have emerged and the number of true LAF cases has progressively decreased.
      • Potpara T.S.
      • Lip G.Y.
      Lone atrial fibrillation: what is known and what is to come.
      Like AF associated with comorbidities, LAF occurs more frequently in males than in females with a ratio of 3 to 4:1.
      • Potpara T.S.
      • Lip G.Y.
      Lone atrial fibrillation—an overview.
      Recent studies have shown that true cases of LAF can be diagnosed even in subjects older than 60 years, so that this age limit seems inappropriately conservative.
      • Weijs B.
      • Pisters R.
      • Nieuwlaat R.
      • Breithardt G.
      • Le Heuzey J.Y.
      • Vardas P.E.
      • et al.
      Idiopathic atrial fibrillation revisited in a large longitudinal clinical cohort.
      At the same time, it is unclear whether cases with left atrial enlargement should be excluded from the LAF category. In fact, LA enlargement might even be the consequence of the arrhythmia.
      • Sanfilippo A.J.
      • Abascal V.M.
      • Sheehan M.
      • Oertel L.B.
      • Harrigan P.
      • Hughes R.A.
      • et al.
      Atrial enlargement as a consequence of atrial fibrillation. A prospective echocardiographic study.
      ‘Lone’ atrial fibrillation is at the lower end of the thromboembolic risk spectrum, with only a 1 – 2% cumulative 15-year risk of stroke.
      • Fuster V.
      • Ryden L.E.
      • Cannom D.S.
      • Crijns H.J.
      • Curtis A.B.
      • Ellenbogen K.A.
      • et al.
      ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      However, with ageing and/or the occurrence of cardiovascular comorbidities, the risk of AF-related complications (including thromboembolic events) increases.
      • Potpara T.S.
      • Stankovic G.R.
      • Beleslin B.D.
      • Polovina M.M.
      • Marinkovic J.M.
      • Ostojic M.C.
      • et al.
      A 12-year follow-up study of patients with newly diagnosed lone atrial fibrillation: implications of arrhythmia progression on prognosis: the Belgrade Atrial Fibrillation study.
      Patients originally diagnosed with LAF may follow different clinical courses based on their left atrial volume: individuals who retain normal LA size throughout long-term follow-up show a relatively benign course, while those with LA enlargement experience adverse events like stroke, myocardial infarction, and heart failure.
      • Osranek M.
      • Bursi F.
      • Bailey K.R.
      • Grossardt B.R.
      • Brown Jr, R.D.
      • Kopecky S.L.
      • et al.
      Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: three-decade follow-up.
      The majority of LAF patients first present with paroxysmal episodes and show low progression rates into permanent AF.
      • Potpara T.S.
      • Stankovic G.R.
      • Beleslin B.D.
      • Polovina M.M.
      • Marinkovic J.M.
      • Ostojic M.C.
      • et al.
      A 12-year follow-up study of patients with newly diagnosed lone atrial fibrillation: implications of arrhythmia progression on prognosis: the Belgrade Atrial Fibrillation study.
      • Jahangir A.
      • Lee V.
      • Friedman P.A.
      • Trusty J.M.
      • Hodge D.O.
      • Kopecky S.L.
      • et al.
      Long-term progression and outcomes with aging in patients with lone atrial fibrillation: a 30-year followup study.
      Atrial fibrillation has clear genetic determinants.
      • Tucker N.R.
      • Ellinor P.T.
      Emerging directions in the genetics of atrial fibrillation.
      These include common gene variants with low predictive strength and rare gene mutationsthat have much greater penetrance.
      • Tucker N.R.
      • Ellinor P.T.
      Emerging directions in the genetics of atrial fibrillation.
      Frustaci et al.
      • Frustaci A.
      • Chimenti C.
      • Bellocci F.
      • Morgante E.
      • Russo M.A.
      • Maseri A.
      Histological substrate of atrial biopsies in patients with lone atrial fibrillation.
      explored the histological morphology of right atrial septal biopsies from patients with lone paroxysmal AF, finding chronic inflammatory infiltrates, foci of myocyte necrosis, focal replacement fibrosis, and myocyte cytoplasmic vacuoles consistent with myolysis. Of their 12 patients, 10 showed EHRAS class III changes and 2 showed EHRAS class II. Stiles et al.
      • Stiles M.K.
      • John B.
      • Wong C.X.
      • Kuklik P.
      • Brooks A.G.
      • Lau D.H.
      • et al.
      Paroxysmal lone atrial fibrillation is associated with an abnormal atrial substrate: characterizing the “second factor”.
      found bi-atrial structural change, conduction abnormalities, and sinus node dysfunction in paroxysmal LAF patients. Skalidis et al.
      • Skalidis E.I.
      • Hamilos M.I.
      • Karalis I.K.
      • Chlouverakis G.
      • Kochiadakis G.E.
      • Vardas P.E.
      Isolated atrial microvascular dysfunction in patients with lone recurrent atrial fibrillation.
      demonstrated atrial perfusion abnormalities and coronary flow reserve impairment. Much more recently, morphometric assessment of atrial biopsies from the LA posterior wall of persistent or long-lasting persistent LAF patients demonstrated cardiomyocyte hypertrophy, myolytic damage, interstitial fibrosis, and reduced connexin-43 expression vs. controls.
      • Corradi D.
      • Callegari S.
      • Manotti L.
      • Ferrara D.
      • Goldoni M.
      • Alinovi R.
      • et al.
      Persistent lone atrial fibrillation: clinicopathologic study of 19 cases.

      Isolated atrial amyloidosis

      The accumulation of insoluble, misfolded proteins is linked to an increasing number of age-related degenerative diseases.
      • Willis M.S.
      • Patterson C.
      Proteotoxicity and cardiac dysfunction.
      Amyloidosis represent the deposition of insoluble, fibrillar proteins in a cross b-sheet structure that characteristically binds dyes such as Congo red. The most common form of age-related or senile amyloidosis is limited to the atrium, a condition known as isolated atrial amyloidosis (IAA).
      • Rocken C.
      • Peters B.
      • Juenemann G.
      • Saeger W.
      • Klein H.U.
      • Huth C.
      • et al.
      Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation.
      • Steiner I.
      • Hajkova P.
      Patterns of isolated atrial amyloid: a study of 100 hearts on autopsy.
      The incidence of atrial amyloidosis increases with age, exceeding 90% in the ninth decade.
      • Steiner I.
      The prevalence of isolated atrial amyloid.
      Isolated atrial amyloidosis is also linked to structural heart disease. In atrial biopsies from 167 patients undergoing cardiac surgery, 23 of 26 amyloid-positive specimens were from patients with rheumatic heart disease (RHD), while the remaining 3 came from patients with atrial septal defects.
      • Looi L.M.
      Isolated atrial amyloidosis: a clinicopathologic study indicating increased prevalence in chronic heart disease.
      The overall incidence of 16% was greater than that was seen in control atrial autopsy specimens from trauma victims (3%). Histologically, IAA is classified as EHRAS IVa (Figure 3; Table 2). Atrial natriuretic peptide is a fibrillogenic protein that forms IAA.
      • Johansson B.
      • Wernstedt C.
      • Westermark P.
      Atrial natriuretic peptide deposited as atrial amyloid fibrils.
      Amyloid deposits are immunoreactive for ANP in most patients,
      • Rocken C.
      • Peters B.
      • Juenemann G.
      • Saeger W.
      • Klein H.U.
      • Huth C.
      • et al.
      Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation.
      while transthyretin, a transport protein implicated in systemic senile amyloidosis, was also identified in 10%
      • Burstein B.
      • Libby E.
      • Calderone A.
      • Nattel S.
      Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences.
      (NT-pro-ANP has been identified in other studies
      • Louros N.N.
      • Iconomidou V.A.
      • Tsiolaki P.L.
      • Chrysina E.D.
      • Baltatzis G.E.
      • Patsouris E.S.
      • et al.
      An N-terminal pro-atrial natriuretic peptide (NT-proANP) ‘aggregation-prone’ segment involved in isolated atrial amyloidosis.
      ). As with fibrosis, amyloidosis can cause local conduction block and P-wave duration is increased in IAA. Atrial amyloid is found more commonly in patients with AF vs. sinus rhythm (Figure 3). Both AF and IAA increased with advancing age and female sex, but the relationship between the two is independent of age and gender.
      • Leone O.
      • Boriani G.
      • Chiappini B.
      • Pacini D.
      • Cenacchi G.
      • Martin Suarez S.
      • et al.
      Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation.
      • Steiner I.
      • Hajkova P.
      • Kvasnicka J.
      • Kholova I.
      Myocardial sleeves of pulmonary veins and atrial fibrillation: a postmortem histopathological study of 100 subjects.
      Isolated atrial amyloidosis is detected in 80% of PV sleeves of elderly patients.
      • Steiner I.
      • Hajkova P.
      • Kvasnicka J.
      • Kholova I.
      Myocardial sleeves of pulmonary veins and atrial fibrillation: a postmortem histopathological study of 100 subjects.
      For organ-specific amyloidosis such as Alzheimer’s disease, there is no detectable correlation between quantity of fibrillar deposits and disease advancement.
      • Knowles T.P.
      • Vendruscolo M.
      • Dobson C.M.
      The amyloid state and its association with protein misfolding diseases.
      Rather, disease phenotype correlates most closely with accumulation of soluble, prefibrillar protein aggregates.
      • Willis M.S.
      • Patterson C.
      Proteotoxicity and cardiac dysfunction—Alzheimer’s disease of the heart?.
      Preamyloid oligomers (PAOs) are cytotoxic to cardiomyocytes.
      • McLendon P.M.
      • Robbins J.
      Desmin-related cardiomyopathy: an unfolding story.
      They do not bind Congo red and thus are not visible by standard amyloid staining methods. Using a conformation-specific antibody, PAOs often co-localizing with ANP were detected in atrial samples of 74 of 92 patients without AF undergoing cardiac surgery.
      • Sidorova T.N.
      • Mace L.C.
      • Wells K.S.
      • Yermalitskaya L.V.
      • Su P.F.
      • Shyr Y.
      • et al.
      Hypertension is associated with preamyloid oligomers in human atrium: a missing link in atrial pathophysiology?.
      The preamyloid oligomer content was independently associated with hypertension. Additional studies are needed to further confirm this association and whether PAOs are increased in AF.

      NPPA mutations

      Atrial natriuretic peptide is released from the atria in response to atrial stretch or volume expansion, and produces natriuresis, diuresis, and vasodilation.
      • Volpe M.
      • Rubattu S.
      • Burnett Jr., J.
      Natriuretic peptides in cardiovascular diseases: current use and perspectives.
      It also interacts with other endogenous systems, inhibiting the renin – angiotensin-II – aldosterone and sympathetic nervous systems, and regulates ion currents.
      • Hua R.
      • MacLeod S.L.
      • Polina I.
      • Moghtadaei M.
      • Jansen H.J.
      • Bogachev O.
      • et al.
      Effects of wild-type and mutant forms of atrial natriuretic peptide on atrial electrophysiology and arrhythmogenesis.
      • Moghtadaei M.
      • Polina I.
      • Rose R.A.
      Electrophysiological effects of natriuretic peptides in the heart are mediated by multiple receptor subtypes.
      Atrial natriuretic peptide-knockout mice develop cardiac hypertrophy and exaggerated responses to hypertrophic stress.
      • Gardner D.G.
      • Chen S.
      • Glenn D.J.
      • Grigsby C.L.
      Molecular biology of the natriuretic peptide system: implications for physiology and hypertension.
      The gene encoding the precursor protein for ANP, NPPA, encodes prepro-ANP, a 151 amino acid protein that includes a signal peptide cleaved off to form pro-ANP,
      • Vesely D.L.
      Atrial natriuretic peptide prohormone gene expression: hormones and diseases that upregulate its expression.
      which is stored in dense granules in the atria. Released pro-ANP undergoes proteolytic processing to generate N-terminal pro-ANP and ANP, 98 and 28 amino acids in length, respectively. N-terminal pro-ANP is cleaved into three hormones with biological activity similar to ANP: long-acting natriuretic hormone (LANH), vessel dilator peptide, and kaliuretic hormone.
      Genetic studies have linked abnormal ANP production to familial atrial tachyrrhythmias and atrial cardiomyopathy. In a large family with Holt – Oram syndrome, a missense mutation in T-box transcription factor 5 (TBx5) resulted in an atypical phenotype with early-onset AF and the overexpression of multiple genes, including NPPA.
      • Postma A.V.
      • van de Meerakker J.B.
      • Mathijssen I.B.
      • Barnett P.
      • Christoffels V.M.
      • Ilgun A.
      • et al.
      A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation.
      In a large family with multiple members having early-onset LAF, a 2-bp deletion was identified that abolishes the ANP stop codon, producing a mature protein containing the usual 28 amino acids plus an anomalous C-terminus of 12 additional residues.
      • Hodgson-Zingman D.M.
      • Karst M.L.
      • Zingman L.V.
      • Heublein D.M.
      • Darbar D.
      • Herron K.J.
      • et al.
      Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation.
      The mutant ANP peptide is present in affected family members at plasma concentrations 5 – 10 times higher than wild-type ANP. Studies of the electrophysiological effects of ANP have been inconsistent.96
      Additional NPPA variants (S64R and A117V) have also been linked to AF.
      • Abraham R.L.
      • Yang T.
      • Blair M.
      • Roden D.M.
      • Darbar D.
      Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.
      • Ritchie M.D.
      • Rowan S.
      • Kucera G.
      • Stubblefield T.
      • Blair M.
      • Carter S.
      • et al.
      Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation.
      The S64R variant occurs in vessel dilator peptide rather than ANP. A truncated peptide containing this mutation increased IKs several fold, an effect predicted to shorten action potential duration (APD),
      • Abraham R.L.
      • Yang T.
      • Blair M.
      • Roden D.M.
      • Darbar D.
      Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.
      but the variant has also been identified in unaffected elderly individuals without AF,
      • Perrin M.J.
      • Gollob M.H.
      The role of atrial natriuretic peptide in modulating cardiac electrophysiology.
      and its functional pathological significance remains uncertain.
      More recently, an autosomal-recessive atrial cardiomyopathy was described in patients harbouring an NPPA mutation (Arg150Gln) predicted to be damaging to protein structure.
      • Disertori M.
      • Quintarelli S.
      • Grasso M.
      • Pilotto A.
      • Narula N.
      • Favalli V.
      • et al.
      Autosomal recessive atrial dilated cardiomyopathy with standstill evolution associated with mutation of Natriuretic Peptide Precursor A.
      The phenotype is characterized by biatrial enlargement, initially associated with atrial tachyarrhythmias such as AF and atrial flutter.
      • Disertori M.
      • Mase M.
      • Marini M.
      • Mazzola S.
      • Cristoforetti A.
      • Del Greco M.
      • et al.
      Electroanatomic mapping and late gadolinium enhancement MRI in a genetic model of arrhythmogenic atrial cardiomyopathy.
      Biatrial enlargement progresses to partial and ultimately severe atrial standstill, associated with progressive decreases in atrial voltage and extensive atrial scarring. Whether atrial structural changes are primary, or secondary to atrial enlargement, is unknown. Loss of the antihypertrophic effects of ANP may cause the massive atrial enlargement seen in these patients.

      Hereditary muscular dystrophies

      A common finding in many inherited muscular dystrophies is cardiac involvement, related to myocyte degeneration with fatty or fibrotic replacement (Table 3).
      • Wallace G.Q.
      • McNally E.M.
      Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies.
      • Hermans M.C.
      • Pinto Y.M.
      • Merkies I.S.
      • de Die-Smulders C.E.
      • Crijns H.J.
      • Faber C.G.
      Hereditary muscular dystrophies and the heart.
      • Groh W.J.
      Arrhythmias in the muscular dystrophies.
      In some cases, this can be the presenting or predominant clinical manifestation. Multiple complexes and pathways are involved in the maintenance of myocyte integrity, and a defective or absent protein component can lead to progressive cell death. The large dystrophin – glycoprotein complex links the myocyte cytoskeleton to the extracellular basement membrane. For diseases of dystrophin, sarcoglycans, and other complex-related proteins, the most prominent manifestation is a dilated cardiomyopathy due to diffuse myocyte involvement, with arrhythmias and conduction abnormalities secondary to LV dysfunction.
      • Wallace G.Q.
      • McNally E.M.
      Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies.
      • Hermans M.C.
      • Pinto Y.M.
      • Merkies I.S.
      • de Die-Smulders C.E.
      • Crijns H.J.
      • Faber C.G.
      Hereditary muscular dystrophies and the heart.
      • Groh W.J.
      Arrhythmias in the muscular dystrophies.
      • Diegoli M.
      • Grasso M.
      • Favalli V.
      • Serio A.
      • Gambarin F.I.
      • Klersy C.
      • et al.
      Diagnostic work-up and risk stratification in X-linked dilated cardiomyopathies caused by dystrophin defects.
      • Townsend D.
      • Yasuda S.
      • McNally E.
      • Metzger J.M.
      Distinct pathophysiological mechanisms of cardiomyopathy in hearts lacking dystrophin or the sarcoglycan complex.
      Specific atrial involvement can lead to sinus node disease and/or atrial arrhythmias with associated thromboembolic events.
      • Finsterer J.
      • Stollberger C.
      Stroke in myopathies.
      • Finsterer J.
      • Stollberger C.
      Atrial fibrillation/flutter in myopathies.
      Myotonic dystrophy type I is the most common muscular dystrophy presenting in adults.
      • Petri H.
      • Vissing J.
      • Witting N.
      • Bundgaard H.
      • Kober L.
      Cardiac manifestations of myotonic dystrophy type 1.
      Up to 15% develop atrial arrhythmias during a 10-year follow-up.
      • Bhakta D.
      • Shen C.
      • Kron J.
      • Epstein A.E.
      • Pascuzzi R.M.
      • Groh W.J.
      Pacemaker and implantable cardioverter-defibrillator use in a US myotonic dystrophy type 1 population.
      The presence of conduction defects and atrial arrhythmias are independent risk factors for sudden death.
      • Groh W.J.
      Arrhythmias in the muscular dystrophies.
      • Groh W.J.
      • Groh M.R.
      • Saha C.
      • Kincaid J.C.
      • Simmons Z.
      • Ciafaloni E.
      • et al.
      Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1.
      In Emery-Dreifuss and Limb-Girdle type IB disease, widespread atrial fibrosis can lead to atrial standstill.
      • Wallace G.Q.
      • McNally E.M.
      Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies.
      In Emery-Dreifuss, AF and atrial flutter with slow ventricular responses and asystolic pauses can be observed, coupled with the occurrence of thromboembolism and stroke.
      • Boriani G.
      • Gallina M.
      • Merlini L.
      • Bonne G.
      • Toniolo D.
      • Amati S.
      • et al.
      Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker implant, and heart failure in Emery-Dreifuss muscular dystrophy: a long-term longitudinal study.
      In facioscapulohumeral muscular dystrophy, arrhythmias are rare, with the most common being supraventricular tachycardia.
      • Trevisan C.P.
      • Pastorello E.
      • Armani M.
      • Angelini C.
      • Nante G.
      • Tomelleri G.
      • et al.
      Facioscapulohumeral muscular dystrophy and occurrence of heart arrhythmia.
      Histologically, the tissue composition may vary substantially, including all EHRAS classes (see Table 2).
      Table 3Hereditary muscular dystrophies with cardiac involvement
      Muscular dystrophyProtein/genePrimary cardiac disease
      DuchenneDystrophinDCM
      BeckerDystrophinDCM
      Myotonic dystrophy, type 1DMPKCSD
      Emery-DreifussEmerinCSD
      Lamin A/C(DCM)
      Limb-GirdleLamin A/CCSD
      SarcoglycansCM
      others
      FacioscapulohumeralDux 4CSD (rare)
      DCM, dilated cardiomyopathy; CSD, conduction system disease; DMPK, myotonic dystrophy protein kinase.

      Atrial cardiomyopathy due to congestive heart failure

      Congestive heart failure (CHF) is a common cause (contributing condition) of AF.
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      The CHF-induced atrial phenotype is complex. A particularly important component is atrial fibrosis, which in experimental models occurs earlier in the course of CHF, and to a much greater extent, than in the ventricles, at least in part because of atrial-ventricular fibroblast – phenotype differences.
      • Burstein B.
      • Libby E.
      • Calderone A.
      • Nattel S.
      Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences.
      Congestive heart failure-related fibrosis slowly, if at all, and the AF-promoting substrate predominantly tracks fibrosis rather than other components of atrial remodelling like ion-current or connexin changes. Unlike the case for AF-induced remodelling, the atrial ion-current changes in CHF do not abbreviate APD or cause overall conduction slowing,
      • Li D.
      • Fareh S.
      • Leung T.K.
      • Nattel S.
      Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort.
      • Li D.
      • Melnyk P.
      • Feng J.
      • Wang Z.
      • Petrecca K.
      • Shrier A.
      • et al.
      Effects of experimental heart failure on atrial cellular and ionic electrophysiology.
      so they do not contribute directly to arrhythmogenesis. On the other hand, CHF atria are prone to triggered activity due to abnormal Ca2+ handling.
      • Yeh Y.H.
      • Wakili R.
      • Qi X.Y.
      • Chartier D.
      • Boknik P.
      • Kaab S.
      • et al.
      Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure.
      The principle underlying abnormality appears to be increased cellular Ca2+ load. While the underlying mechanisms are not completely clear, they likely include phospholamban hyperphosphorylation (which increases SR Ca2+ uptake) and AP prolongation (which increases Ca2+ loading by enhancing the period during which L-type Ca2+ channels are open). The final phenotypic product of the CHF-induced Ca2+-handling abnormalities is focal ectopic activity due to aberrant diastolic Ca2+-release events from the SR, similar to abnormalities seen with paroxysmal and long-standing persistent AF.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      Congestive heart failure also causes atrial hypocontractility, despite increased cytosolic Ca2+ transient, indicating reduced contractile sensitivity to intracellular Ca2+, possibly because of reduced expression of total and phosphorylated myosin-binding protein C.
      • Yeh Y.H.
      • Wakili R.
      • Qi X.Y.
      • Chartier D.
      • Boknik P.
      • Kaab S.
      • et al.
      Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure.
      This hypocontractility may be important in contributing to the increased likelihood of thromboembolic events in AF patients who also have CHF. Of the atrial changes that occur in CHF, many are also seen in the ventricle. However, the highly atrial-selective fibrosis may contribute to atrial cardiomyopathy in the absence of clear signs of disturbed ventricular function, particularly in patients with prior CHF events who later become well-compensated under therapy or after resolution of the underlying cause. Collagen depositions are prominent in CHF, leading most commonly to EHRAS Class II and III properties. However, EHRAS Class IVi and IVf may also be found in certain areas of the atria (see Table 2).

      Obstructive sleep apnoea

      Obstructive sleep apnoea (OSA) is known to impair cardiac function and predispose to AF.
      • Dimitri H.
      • Ng M.
      • Brooks A.G.
      • Kuklik P.
      • Stiles M.K.
      • Lau D.H.
      • et al.
      Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation.
      • Maeno K.
      • Kasai T.
      • Kasagi S.
      • Kawana F.
      • Ishiwata S.
      • Ohno M.
      • et al.
      Relationship between atrial conduction delay and obstructive sleep apnea.
      • Chami H.A.
      • Devereux R.B.
      • Gottdiener J.S.
      • Mehra R.
      • Roman M.J.
      • Benjamin E.J.
      • et al.
      Left ventricular morphology and systolic function in sleep-disordered breathing: the Sleep Heart Health Study.
      Obstructive sleep apnoea prolongs atrial conduction times, slows atrial conduction, reduces atrial-electrogram voltages and increases electrogram complexity.
      • Dimitri H.
      • Ng M.
      • Brooks A.G.
      • Kuklik P.
      • Stiles M.K.
      • Lau D.H.
      • et al.
      Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation.
      • Maeno K.
      • Kasai T.
      • Kasagi S.
      • Kawana F.
      • Ishiwata S.
      • Ohno M.
      • et al.
      Relationship between atrial conduction delay and obstructive sleep apnea.
      Signal-averaged P-wave duration is increased by OSA, and decreases significantly with continuous positive airway pressure treatment.
      • Maeno K.
      • Kasagi S.
      • Ueda A.
      • Kawana F.
      • Ishiwata S.
      • Ohno M.
      • et al.
      Effects of obstructive sleep apnea and its treatment on signal-averaged P-wave duration in men.
      In a rat model, repeated obstructive apnoea over a 4-week period increases AF vulnerability and slows atrial conduction by altering connexin-43 expression and inducing atrial fibrosis.
      • Iwasaki Y.K.
      • Kato T.
      • Xiong F.
      • Shi Y.F.
      • Naud P.
      • Maguy A.
      • et al.
      Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model.

      Atrial fibrillation-induced atrial remodelling

      Atrial fibrillation itself induces atrial remodelling that contributes to the maintenance, progression, and stabilization of AF.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      The high atrial rate causes cellular Ca2+ loading. This induces a decrease in ICa,L due to down-regulation of the underlying Cav1.2 subunits, and an increase in constitutively active I
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      • Yue L.
      • Feng J.
      • Gaspo R.
      • Li G.R.
      • Wang Z.
      • Nattel S.
      Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation.
      • Qi X.Y.
      • Yeh Y.H.
      • Xiao L.
      • Burstein B.
      • Maguy A.
      • Chartier D.
      • et al.
      Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current.
      MiR-328 up-regulation with consequent repression of Cav1.2-translation and Ca2+ dependent calpain activation, causing proteolytic breakdown of L-type Ca2+ channels.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      The rate-dependent up-regulation of IK1 results from a Ca2+/calcineurin/ NFAT-mediated down-regulation of the inhibitory miR-26, removing translational – inhibition of Kir2.1.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      Increased IK1 stabilizes AF by abbreviating and hyperpolarizing atrial cardiomyocyte Aps.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      Small-conductance Ca2+-activated K+ (SK) currents (ISK) also play a role in AF.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      Computational modelling shows that increased total inwardrectifier K+ current in chronic atrial fibrillation (cAF) is the major contributor to the stabilization of re-entrant circuits by shortening APD and hyperpolarizing the resting membrane potential.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      Atrial tachycardia remodelling reduces Ca2+ transient amplitude by a variety of mechanisms, contributing to atrial contractile dysfunction.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      • Lenaerts I.
      • Bito V.
      • Heinzel F.R.
      • Driesen R.B.
      • Holemans P.
      • D’Hooge J.
      • et al.
      Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation.
      Reduced atrial contractility causes atrial ‘stunning’ that may be involved in thromboembolic complications.
      Long-term atrial tachycardia remodelling causes conduction slowing in several animal models, at least partly due to INa down-regulaton.
      • Yue L.
      • Feng J.
      • Gaspo R.
      • Li G.R.
      • Wang Z.
      • Nattel S.
      Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation.
      Heterogeneously distributed gap-junction uncoupling due to connexin remodelling likely contributes to atrial conduction slowing.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      Heterogeneity in connexin-40 distribution correlates with AF stability in goats with repetitive burst-pacing-induced AF.
      • van der Velden H.M.
      • Ausma J.
      • Rook M.B.
      • Hellemons A.J.
      • van Veen T.A.
      • Allessie M.A.
      • et al.
      Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat.
      Connexin-40 expression decreases in the PVs of dogs with AF-related remodelling, possibly due to tachycardia-induced connexin-degradation by calpains.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      Long-term atrial tachycardia/AF may itself cause atrial fibrosis that contributes to long-term persistence.
      • Martins R.P.
      • Kaur K.
      • Hwang E.
      • Ramirez R.J.
      • Willis B.C.
      • Filgueiras-Rama D.
      • et al.
      Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation.
      Rapid atrial firing promotes fibroblast differentiation to collagen-secreting myofibroblasts through autocrine and paracrine mechanisms.
      • Kitzman D.W.
      • Edwards W.D.
      Age-related changes in the anatomy of the normal human heart.
      Atrial tachycardia-induced NFAT- mediated decreases in fibroblast miR-26 may also contribute to structural remodelling. Atrial fibroblasts have non-selective cation channels of the transient receptor potential (TRP) family that carry Ca2+ into the cell; the increased cell-Ca2+ then triggers increased collagen production. Since miR-26 represses TRPC3 gene expression, miR-26 reductions increase TRPC3 expression, promoting fibroblast Ca2+ entry that causes proliferation/myofibroblast differentiation.
      • Harada M.
      • Luo X.
      • Qi X.Y.
      • Tadevosyan A.
      • Maguy A.
      • Ordog B.
      • et al.
      Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation.
      TRPM7 may similarly contribute to fibrotic changes in AF.
      • Du J.
      • Xie J.
      • Zhang Z.
      • Tsujikawa H.
      • Fusco D.
      • Silverman D.
      • et al.
      TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation.
      APD shortening in cAF patients also results from increased inward-rectifier K+ currents,
      • Dobrev D.
      • Graf E.
      • Wettwer E.
      • Himmel H.M.
      • Hala O.
      • Doerfel C.
      • et al.
      Molecular basis of downregulation of G-protein-coupled inward rectifying K(+) current (I(K,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced I(K,ACh) and muscarinic receptor-mediated shortening of action potentials.
      both IK1 and a constitutive form of IK,Ach.
      • Wakili R.
      • Voigt N.
      • Kaab S.
      • Dobrev D.
      • Nattel S.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • Voigt N.
      • Nattel S.
      • Dobrev D.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      Agonist-activated IK,ACh is decreased in right atrium of AF patients because of a reduction in underlying Kir3.1 and Kir3.4 subunits,
      • Dobrev D.
      • Graf E.
      • Wettwer E.
      • Himmel H.M.
      • Hala O.
      • Doerfel C.
      • et al.
      Molecular basis of downregulation of G-protein-coupled inward rectifying K(+) current (I(K,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced I(K,ACh) and muscarinic receptor-mediated shortening of action potentials.
      whereas agonist-independent current is increased.
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