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Address reprint requests and correspondence: Professor Andreas Goette, Chefarzt Medizinische Klinik II, St. Vincenz-Krankenhaus, Paderborn, Am Busdorf 2, 33098 Paderborn. Tel.: +05251/861651; fax: +05251/861652.
Departement of Cardiology and Intensive Care Medicine, St. Vincenz-Hospital Paderborn, Working Group: Molecular Electrophysiology, University Hospital Magdeburg, Germany
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Department of Cardiology, Assistance Publique–Hoˆ pitaux de Paris, Pitie´-Salpeˆtrie`re Hospital; Sorbonne University; INSERM UMR_S1166; Institute of Cardiometabolism and Nutrition-ICAN, Paris, France
Centre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia
Electrophysiology Deparment at Centros Especializados de San Vicente Fundacio´ n and Cl´ınica CES. Universidad CES, Universidad Pontificia Bolivariana (UPB), Medellin, Colombia
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Universite´ de Montre´al, Montreal Heart Institute Research Center and McGill University, Montreal, Quebec, CanadaInstitute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
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Introduction and definition of atrial cardiomyopathy
The atria provide an important contribution to cardiac function.
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
Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences.
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.
Responses include atrial cardiomyocyte hypertrophy and contractile dysfunction, arrhythmogenic changes in cardiomyocyte ion-channel and transporter function, atrial fibroblast proliferation, hyperinnervation, and thrombogenic changes.
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.
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;
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.
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.
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 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.
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.
Morphological or molecular changes affecting ‘primarily’ the cardiomyocytes in terms of cell hypertrophy and myocytolysis; no significant pathological tissue fibrosis or other interstitial changes
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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.
The extracellular components consist of collagen fibres, which form most of the myocardial skeleton, proteoglycan particles, lipidic debris, spherical micro-particles, and matrix vesicles.
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.
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).
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.
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.
These cellular electrophysiological characteristics have implications for antiarrhythmic drug action and design, and may also affect the responses to atrial arrhythmias and disease.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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,
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.
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 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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences.
). 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.
For organ-specific amyloidosis such as Alzheimer’s disease, there is no detectable correlation between quantity of fibrillar deposits and disease advancement.
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.
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.
It also interacts with other endogenous systems, inhibiting the renin – angiotensin-II – aldosterone and sympathetic nervous systems, and regulates ion currents.
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,
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.
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.
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.
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),
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.
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).
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.
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.
Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker implant, and heart failure in Emery-Dreifuss muscular dystrophy: a long-term longitudinal study.
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.
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,
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.
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.
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.
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.
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
MiR-328 up-regulation with consequent repression of Cav1.2-translation and Ca2+ dependent calpain activation, causing proteolytic breakdown of L-type Ca2+ channels.
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.
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.
Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation.
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.
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.
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.
Atrial cardiomyocytes from patients with long-standing persistent AF show spontaneous diastolic SR Ca2+ release events (SCaEs) and delayed after depolarizations (DADs).
Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation.
Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation.
Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation.
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