Atrial cardiomyopathy — a new concept with a long history

Atrial cardiomyopathy (ACM) is a relatively common but clinically underestimated disorder, which is characterized by an increased atrial size and dysfunction. Previously, ACM was considered a primary disorder, but in 2016 this concept was revised by European Heart Rhythm Association (EHRA) working group with inclusion of secondary atrial remodeling. The EHRA document details aspects of atrial anatomy and pathophysiology, proposes definitions of ACM, histological classification, outlines the molecular mechanisms of atrial arrhythmia and the problems of personalized treatment and optimization of indications for catheter ablation. Practical application of the proposed ACM classification system, the clinical significance of novel ACM concept and the potential role of this information for a practitioner are presented in this article. Two clinical cases of ACM with “primary” (familial form of ACM due to NPPA gene mutation with primary defect in atrial structure and function) and “secon-dary” atrial remodeling (ACM caused by a long-term supraventricular tachyarrhythmias due to SCN1B gene mutation). and none. mutations in the sodium channel protein type 5 subunit alpha ( SCN5A ) and connexin-40 ( GJA5 ) genes. Mutations in potassium channel subunits ( KCNQ1 , KCNH2 , KCND3 , and KCNE5 ) and loss-of-function mutation in the SCN5A gene have been identified in patients with AF. Gain-of-function mutations in the KCNJ8 gene are associated with AF and early repolarization

In recent years, the structural and electromechanical atrial abnormalities as markers of unfavorable clinical prognosis in various groups of patients with cardiovascular diseases has been actively studied. The issues of atrial cardiomyopathy are today the subject of scholarly discussion. However, the fact that atrial cardiomyopathy (ACM) is a fairly common, but still clinically underestimated pathology, is beyond doubt by most researchers.
The first report of a familial fibrotic ACM (FACM) was provided by Williams D, et al. (1972) during long-term follow-up of family members with atrial ectopic beats and atrioventricular (AV) block, when three out of five brothers and sisters had progressive symptoms of chrono-, dromo-and inotropic atrial dysfunction [1]. Later, many researchers reported on histopathological changes in the atria (inflammation, interstitial or focal fibrosis) that were observed in patients with atrial fibrillation (AF) in the absence of structural causes of arrhythmia, such as valvular heart disease or heart failure (HF) [2,3]. Kottkamp H, et al. (2012) for the first time defined FACM as an independent and progressive ACM with atrial fibrotic lesion, which cannot be caused by age, heart disease, or the presence of atrial fibrillation [4]. The authors suggested that a specific form of FACM is a common pathological manifestation of all AF types, but is caused by a primary process in atrial myocytes, regardless of arrhythmia. In 2016, experts of the European Heart Rhythm Association (EHRA), the Heart Rhythm Society (HRS), the Asia-Pacific Heart Rhythm Society (APHRS) and the Latin American Society of Cardiac Pacing and Electrophysiology (SOLAECE) proposed new definitions of ACM as any complex of structural, contractile or electrophysiological abnormalities affecting the atria and contributing to the clinically significant manifestations [5]. This definition resembles the concept of arrhythmogenic atrial remodeling, defined as any change in the structure or function of the atria that contributes to atrial arrhythmias [6]. However, a new element of ACM definitions reflects a potentially important position -the adverse consequences of atrial electromechanical disturbances may be completely independent of atrial arrhythmias. This is a very important aspect, emphasizing the fact that the risk of cerebral thromboembolic events (CTEs) in the presence of ACM may not depend on the onset/ development of AF. The second difference is that the terminological subtext of atrial remodeling includes the assumption that the atria were normal before they were exposed to any external influences. Thus, ACM can be caused by primary processes in the atria -structural, electrical and functional disorders characteristic of some genetic diseases (for example, due to MYL4 or NPPА gene mutations) [7,8]), as well as secondary arrhythmogenic changes caused by isolated AF and other risk factors for AF causing structural myocardial remodeling [9,10].

ACM -orphan or common disorder?
It is known that many diseases (hypertension valvular heart disease, heart failure, diabetes, myocarditis) or conditions (aging, smoking, obesity, metabolic disorders) cause or contribute to the development of ACM [11]. However, changes in the atria caused by these diseases are not specific for ACM -the localization, prevalence and degree of pathological atrial remodeling depend on the duration and severity of disease, on the modification of many other concomitant factors that cause significant individual differences. The progression of the remodeling substrate depends on many factors that influence the cardiomyocyte reaction in response to electrical, mechanical, hemodynamic, and metabolic stress. Some components of atrial remodeling are reversible (adaptive), while others are permanent (maladaptive). The progression of atrial injury due to underlying heart disease is a major pathogenic factor. Recent studies have demonstrated the effectiveness of AF prevention by successful management of such modifiable risk factors as obstructive sleep apnea syndrome, obesity, hypertension (HTN), hyperglycemia and dyslipidemia [12][13][14][15]. Elimination of these abnormalities contributed to the prevention of further atrial damage, and conversely, additional risk factors was associated with recurrence and persistence of AF with progression of the pathological substrate, which supports the Wijffels-Allessie postulate that AF begets AF [16].
However, in addition to the fact that some pathological processes can affect the atria very selectively (for example, AF-related remodeling), there are other less specific mechanisms that cause changes not only in the atria, but also in the ventricles to a greater or lesser extent (primary cardiomyopathies, HTN, muscular dystrophies (MD), amyloidosis, myocarditis) [17].
Thus, ACM is associated with a variety of causes that contribute to pathological atrial remodeling. The most common causes are isolated AF, HF, HTN, myocarditis, valvular heart disease, diabetes, obesity, amyloidosis, hereditary MD. The main etiological, clinical and morphometric features of atrial remodeling leading to electromechanical dysfunction and ACM are presented in Table 1 [5].
In 2016, experts of the EHRA/HRS/APHRS/ SOLAECE working group developed a consensus document with a detailed presentation of atrial anatomy, physiology and pathology, definitions with histological classification of ACM, molecular mechanisms affecting the development of arrhyth-mias, imaging and mapping methods, where they also identified problematic issues of personalized treatment and optimization of indications for cathe ter ablation. The authors proposed a histological (pathophysiological) classification using the EHRAS abbreviation (E -EHRA, HR -HRS, A -APHRS, S -SOLEACE) to define 4 classes of ACM [1]: I -primarily cardiomyocyte-dependent; II -primarily fibroblast-dependent; III -mixed cardiomyocyte-fibroblast-dependent; IV -primarily non-collagen deposits ( Table 2) [5].
This simple classification reflects the dominant morphological pathology in various clinical and pathophysiological situations. These EHRAS classes correspond to their histopathological characteristics. However, at least two problems limit the application of this classification in clinical practice. First, the system is based on histological interpretation, requiring analysis of atrial tissue samples for verification, which in most cases is technically impossible. Second, there is significant overlap between EHRAS classes within almost every etiological category of ACM (Table 1). For example, the histopathological characterization of valvular heart disease can have features of all four classes; pathomorphological signs of HTN, diabetes and MD will overlap within three classes. Only atrial amyloidosis will be in one class (class IV). While class I is often seen in patients with hereditary AF and diabetes, class II is characteristic of atrial remodeling with aging and smoking (Table 1). In patients with HF, the remodeling type corresponds to class III or II, while class IV is often observed in isolated atrial lesions [5].

Clinical application of a novel concept with a long history
At first glance, the ACM classification seems to be not suitable for a practitioner, since for most patients it is impossible to unambiguously determine the EHRAS class without histopathological assessment. But even if the patient's phenotype is unambiguously assigned to a certain I or IV class, it is not fully clear what to do in the future and how to use this information correctly.
However, considering all of the listed ACM classes have one common feature (electromechanical atrial dysfunction caused by structural, mechanical and electrical remodeling) and these changes most often lead to AF [5][6][7], which is associated with an increased risk of thromboembolic events (TEE), decompensated HF and mortality due to stroke [11,[13][14][15][16][17][18][19][20], it is quite expected that the analysis of ACM etiology, assessment of atrial hemodynamic parameters (speckle tracking, tissue Doppler imaging), macroscopic determination of atrial fibrosis degree using contract-enhanced magnetic resonance imaging (MRI) and the identification of patient procoagulant status will have important prognostic and therapeutic value. Figure 1 shows the main thromboembolic risk factors that are used for risk stratification in patients with AF before oral anticoagulant (OAC) therapy.
Today, the CHA 2 DS 2 -VASc score is widely used in practice, including predictors (HF, HTN, age from 65 to 74 years, age 75 years and older, female sex, diabetes, prior stroke or transient ischemic attack, TEE, vascular diseases), which determine the decision to use OAC therapy in accordance with generally accepted guidelines [20,21]. It is known that all these predictors of TEE are also independent risk factors and the main causes of ACM. Logically, clinicians do not make clinical decisions about prescribing OAC therapy on the basis of AF as such, but rather taking into account concomitant conditions and diseases associated, including with ACM. This hypothesis is supported by the results of studies showing the absence of absolute synchronization of episodes of AF and stroke [21][22][23][24][25]. The authors' conclusions that ACM is an independent risk factor for cerebral TEE contradict the classical scenario of stroke due to embolization by thrombi from the left atrial (LA) appendage. The ASSERT study revealed that AF were observed within 30 days before stroke in only 8% of patients, and in 16% of patients with cerebral TEE, paroxysmal AF developed after cerebrovascular accident, while in 49%, subclinical episodes of AF were not observed [24,25]. The absence of a temporal relationship between the AF and cerebral TEE was also demonstrated in the IMPACT study [26]. One of the possible explanations for this phenomenon is the structural mechanisms of atrial remodeling with inotropic and endothelial atrial dysfunction, which increases the risk of stroke even without AF. The well-known diseases with a predominant atrial lesion (cardiac amyloidosis and Fabry disease) associated with an increased risk of TEE, including stroke, which are caused by serious atrial contractile dysfunction, confirm the direct association between ACM and cerebral TEE [27]. Mutations in the MYL4 gene also cause ACM with severe atrial contractile dysfunction [7][8][9] and a high risk of stroke [8]. ACM with an autosomal recessive inheritance has been well stu died in patients with a homozygous NPPA gene mutation (p.Arg150Gln), leading to structural damage to atrial natriuretic peptide (ANP) [28]. The phenotype is characterized by significant biatrial dilatation, supraventricular arrhythmias with progressive loss of sinus and atrial electrical activity with stable normal left ventricular (LV) contractile function. These patients often require pacemaker implantation and long-term anticoagulant therapy due to the high risk  of TEE. Dilation and structural changes (fibrosis) of the atria are associated with the loss of ANP antihypertrophic effect [28].
The study of the potential causes of ACM, a better understanding of the pathogenesis and interrelationships of arrhythmogenic conditions with the atrial anatomy, structure and function may already be in demand today for predicting unfavorable outcomes and preventing cerebral TEE in patients with AF. For this, it is necessary to develop clinical tools for conducting the research, which will determine the practical and predictive value of ACM concept. The search for clinical tools and tactics for ACM treatment is presented below on two case reports: 1) a case of familial ACM due to mutation in the NPPA gene, causing a "primary" genetic defect in the atrial structure and function, and 2) a case of "secondary" atrial remodeling, associated with a long-term arrhythmic factor -supraventricular (SV) tachyarrhythmia, including AF associated with a SCN1B gene mutation.

Case report 1
Female patient, born in 1993, first consulted a cardiologist in 2019 with complaints of heart palpitations and shortness of breath with brisk walking. Cardiac examination was initiated by a gynecologist as a search for disorders of the patient's reproductive system.
As a result of electrocardiography (ECG), the following data were obtained: sinus rhythm with a heart rate (HR) of 73 bpm and first-degree AV Morphological changes in cardiomyocytes (hypertrophy, myocytolysis); without fibrosis and interstitial changes.
Mostly fibrotic changes; cardiomyocytes are not changed.
Alteration of interstitial matrix without prominent collagen fibre accumulation: IVa -accumulation of amyloid IVf -fatty infiltration IVi -inflammatory cells IVo -other interstitial alterations.
LA RA Figure 2. Representative fragments of ECG, HM, pre-and post-contrast MRI, x-ray signs of biatrial cardiomegaly in proband (case 1): A) abnormal ECG: wide and biphasic P wave with signs of interatrial block and biatrial dilatation, fragmentated QRS; B) speckle-tracking echocardiography of LA; C) signs of a significant decrease in peak atrial longitudinal strain (9,8%); D) X-ray signs of biatrial cardiomegaly; E) MRI movie in a 4-chamber view along the long axis in late diastolic phase with signs of pronounced biatrial dilatation; F) accumulation of contrast agent in the walls of both atria and interatrial septum during the delayed phase of MRI scanning (zones of atrial fibrosis are indicated by arrows); G) increased integral area of terminal P wave activity to 0,168 mm*s (negative component of the P wave ʃP-V1=1,4 mm×0,12 s=0,168 mm*s); H) increased duration of the abnormal P wave to 160 ms in III; biphasic P-waves in I, II, III, aVL; duration of 100 ms between two peaks of the biphasic P wave in aVL; I) six-axis system (I -0 ○ , II -+60 ○ , aVF -+90 ○ , aVR --150 ○ , aVL --30 ○ ), representing the normal P wave axis (0-75 ○ ); the abnormal P wave axis on the ECG of the proband is equal to +80 ○ ; K) HM fragment with an episode of unstable atrial tachycardia and postectopic depression of the sinus node function with escaping/replacing ectopic atrial rhythm. Thus, the patient showed signs of pronounced structural atrial remodeling (significant LA and RA dilatation and fibrosis), electromechanical atrial dysfunction with Bayes syndrome [29] (third-degree interatrial block and supraventricular arrhythmia): the duration of the P wave was 160 ms (normal to 120 ms); biphasic P wave, visualized in all leads, with a maximum duration of 100 ms between two P peaks in aVL (Figure 2 H); the duration of the terminal negative phase of the P wave in V1 was 120 ms (0,12 s), the amplitude -1,4 mm. The integral area of terminal P wave activity was 0,168 mm*s: the ne gative component of the P wave ʃP -V1 =1,4 mm×0,12 s=0,168 mm*s (Figure 2 G), which is a significant deviation, indicating LA dilatation. Normally, the integral area of the negative P wave does not exceed 0,04 mm*s. P-wave axis was +80 ○ as shown in Figure 2 I and, normally the angle of the P axis varies from 0 ○ to 75 ○ .
In the patient's blood plasma, an increase in the level of myocardial stress biomarker NT-proBNP (N-terminal pro-brain natriuretic peptide) up to 326 pg/ml and a decrease in the level of pro atrial natriuretic peptide -0,67 nmol/ml.
Taking into account the presence of electromechanical dysfunction of significantly dilated atria with signs of ACM (differential diagnosis with restrictive cardiomyopathy) and burdened heredity (recurrent cerebral TEE in the mother from 45 years of age and development of heart failure with AF and fatal stroke at the age of 49), family cascade screening and genetic testing was performed.
Genotyping of proband (II:1) and family members available for examination was carried out in accordance with the Declaration of Helsinki. The patients signed written informed consent. Sequence analysis of 174 genes of the target panel (NGS) in the patient revealed two variants of unknown clinical significance were identified and confirmed by Sanger sequencing: c.G448A (rs762850913) in the 2 nd exon of the teletonin gene (TCAP) and c.G455A tree, the results of Sequence analysis of the 2 nd exon of the TCAP gene, the 3 rd exon of NPPA gene in members of the proband's family and the clinical diagnosis in the MOGE (S) classification are shown in Figure 3 F. The NPPA gene encodes the synthesis of atrial natriuretic peptide (ANP), which plays a key role in maintaining homeostasis by regulating the natriuresis, diuresis and vasodilation. Along with the regulation of intravascular volume and vascular tone, it takes part in modifying the ion channels and helps prevent atrial electrical remodeling [28]. ANP also participates in the development and onset of pregnancy, promoting trophoblast invasion and remodeling of the uterine spiral artery. NPPA gene mutations, leading to a decrease in the ANP level, disrupt all of these mechanisms. In vivo models (knockout mice) with long-term exposure to low ANP levels resulted in damage to myocytes with the development of extensive fibrotic areas and significant atrial dilatation [30].
In the presented case, the proband had severe manifestations of NPPA mutation -atrial cardiomyopathy with severe dilatation and biatrial fibrosis, SV arrhythmia and reproductive dysfunction (without anatomical, hormonal, immunological, endocrine and other causes). Taking into account the genetic status, low systolic function of significantly dilated atria, endothelial atrial dysfunction with prothrombotic changes (increased von Willebrand factor level) and increased HF signs (mild contractile and severe LV diastolic dysfunction, CHA 2 DS 2 -VASc score of 2), the patient was prescribed OACs together with HF therapy.

Case report 2
Male patient, born in 1965, without concomitant hypertension, coronary artery disease, diabetes and obesity, without a history of bad habits. From the age of 30, the patient had asymptomatic SV arrhythmias (moderate sinus bradycardia with escape atrial and junctional beats, SV premature beats) and grade 2 mitral valve prolapse. Symptomatic arrhythmias in the form of paroxysmal AF appeared at the age of 53, and in 2019 the patient sought medical help with complaints of rapidly developing resistance to the "pill-in-the-pocket" strategy with the use of class 1C antiarrhythmic agents and to parenteral antiarrhythmic drugs with the need for repeated electrical cardioversion. Examination of the patient for the first time (at the age of 54) revealed signs of LA dilatation with impaired atrial systolic dynamics and electrical (Bayes syndrome) criteria for LA remodeling, characteristic of ACM.
The ECG admission showed a sinus rhythm with a heart rate of 82 bpm, first-degree AV block (PQ interval, 240 ms), signs of LA dilation with thirddegree interatrial (Figure 4 A) and the biphasic P wave duration in I, II, III, aVF >195 ms, left axis deviation, terminal negative P wave integral in V1 was 0,144 mm*s (Р negative amplitude --1,2 mm, duration -0,11 s).
Holter monitoring revealed episodes of firstdegree AV block and transient right bundle branch block, episodes of stable and unstable junctional rhythm against the background of moderate chronotropic sinus node dysfunction, multifocal atrial ectopic activity (ectopic index -30-45% per day) -isolated, coupled, and group SV premature beats with episodes of atrial Galavardin's tachycardia (Figure 4 B) and unstable paroxysmal AF (Figure 4 C).
Echocardiography revealed signs of significant LA dilatation ( According to selective angiography, atherosclerotic coronary lesions and right coronary artery hypoplasia were not found. Given the low efficiency of non-invasive interventions to control the rhythm and the presence of structural and electromechanical signs of ACM, endocardial pulmonary vein radiofrequency ablation (RFA) was considered. Before RFA, a transesophageal echocardiography was performed: there were no signs of LA appendage thrombi, but there  was a pronounced (grade 3) spontaneous contrasting; LA appendage area was 7,8 cm 2 , peak blood f low velocity -0,47 m/s. Frequency and rhythm control following a successful invasive procedure was achieved with a prophylactic dose of a betablocker. Taking into account the CHA 2 DS 2 -VASc score of 2 and increased von Willebrand factor, a history of varicose veins and recurrent lower limb venous thromboembolism, the patient underwent endovenous laser coagulation of great saphenous vein branches and was prescribed prophylactic OAC therapy.
Due to presence of familial ACM with arrhythmia (positive family history: in maternal grandmother, sinus node dysfunction with implantation of pacemaker, AF, LA dilation and dysfunction, arrhythmias and fatal stroke in a grandmother at the age of 50), a family cascade screening and genetic testing were performed.
Genotype test of proband (II: 1) and family members available for examination was carried out in accordance with the Declaration of Helsinki. All patients signed written informed consent. Sequence analysis of 174 genes of the target panel (NGS) in the patient revealed c.C35A variant (p.A12E, NM_001037) in the first exon of the SCN1B gene. An identical mutation was found in the mother of the proband. The SCN1B gene encodes the sodium channel beta-1 subunit. Mutations in this gene are associated with cardiac arrhythmias (AF that were observed in the family of proband.
Thus, in clinical practice, it is extremely important to take into account the possible etiological factors of ACM, since the causes of ACM can have clear diagnostic, prognostic and therapeutic consequences. For example, mutations in the MYL4 and NPPA genes lead to specific ACMrapidly progressive, with chrono-, dromo-and inotropic atrial dysfunction, with a high risk of AF, cerebral TEE and the need for OAC therapy or pacing [6][7][8][9]28].
Comparative characteristics of atrial electromechanical dysfunction, parameters of LV diastolic and contractile function, laboratory biomarkers in family members of proband with EHRAS class III ACM (NPPA mutation carriers) and a patient with EHRAS class I ACM (SCNB1 mutation carrier) are presented in Table 3. Table 3 Comparative characteristics of echocardiographic, The main clinical and prognostic factors of ACM in the presented clinical observations (Table 3) are specified by the severity of mechanical and electrical atrial dysfunction, their structural remodeling (fibrosis), procoagulation status, and atrial endothelial dysfunction. Thus, a more severe ACM phenotype with an early manifestation of the disease was observed in the 1 st case with primary atrial remodeling caused by NPPA gene mutation. The following were used as a non-invasive clinical tool for assessing ACM: echocardiography with LA function analysis (determination of E/e`, atrial volume indexes, assessment of atrial tissue using speckle tracking echocardiography with determination of peak systolic strain and strain rate), 12-lead surface ECG with analysis of atrial electrical dysfunction markers and MRI (assessment of fibrosis), which have important diagnostic and predictive value for assessing the risk of developing SV arrhythmias, including AF.

ECG and laboratory biomarkers in patients with EHRAS type I and III ACM
Atrial endothelial dysfunction with coagulation system activation and increased synthesis of prothrombotic tissue factors in the LA endocardium (plasminogen activator inhibitor (PAI) 1, von Wil-lebrand factor (vWF), adhesion molecules (ICAM, VCAM, selectins) and changes in the tumor necrosis factor receptor superfamily such as CD40/CD154, which control interactions between platelets, leukocytes and endothelial cells [31,32]) are important additional risk factors for ACM-related cerebral TEE.
Thus, Figure 5 shows the main diagnostic elements that can be used in research and practice for verification, classification, treatment and prediction of ACM complications.
As practice shows, a strategically important clinical task in choosing treatment tactics and in determining the prognosis is the etiological verification of ACM. Thus, mutations in the MYL4 or NPPA genes determine severe, rapidly progressive types of ACM with a high risk of AF, HF and cerebral TEE [6][7][8][9]28]; it is also important to take into account/control the toxicity of certain drugs and their adverse effects ( Table 1). Treatment of obesity, endocrine disorders (diabetes, hypo-and hyperthyroidism) and infiltrative disorders (amyloidosis) is an equally important factor contributing to an improvement in the ACM prognosis. The beneficial effects of weight loss in  obesity and modification of other AF risk factors have been demonstrated in the randomized trials REVERSE-AF and HUNT [33,34]. Thus, the individual prognosis of a patient with AF is influenced, on the one hand, by the risk factors for TEE, and on the other hand, by factors that cause or maintain an abnormal heart rhythm ( Figure 5). The main reason for the progression of AF from paroxysmal to permanent or longstanding persistent is usually the arrhythmia itself. In addition to focal triggers, which are often located at the pulmonary vein orifices, multiple-loop reentry and electrical dissociation between the epicardial and endocardial layers influence the onset and maintenance of AF [35,36]. The common of these mechanisms is that they depend on electrical and structural atrial changes that are observed in ACM.
Thus, an important clinical, highly sensitive tool for assessing atrial dysfunction is ECG (PQ interval prolongation [37], an increased P wave duration, increased terminal negative P wave in V1, and an abnormal P-wave axis [38]), and also the low voltage in endocardial mapping [39]. Echocardiography is a highly specific method for assessing the atrial structure and function: transmitral spectral and tissue Doppler with E/e` determination, atrial volume indexes, 3D speckle tracking assessment of fibrous tissue with determination of peak systolic strain and strain rate [40]. Non-invasive quantification of atrial fibrosis, which plays an important role in the pathophysiology of AF and is closely associated with recurrent AF, can be performed with contrastenhanced MRI [41,42]. In addition to the technique for assessing delayed contrast accumulation to detect replacement fibrosis, pre-and post-contrast T1 mapping can be used to quantify diffuse interstitial fibrosis. Typically, these techniques are widely used for ventricular imaging, while the assessment of thin-walled atria is somewhat limited by technical problems. However, a multicenter study revealed that quantitative MRI assessment of atrial fibrosis can play a key role in the selection of patients for catheter ablation of AF [43][44][45]. Thus, the risk of recurrent AF increased by 15% in stage I fibrosis (<10% of the atrial wall) and up to 69% in stage IV fibrosis (≥30% of the atrial wall) [43].

Discussion
To conduct studies that determine the practical and prognostic value of the ACM concept, highly sensitive and specific clinical tools are in demand today for the early diagnosis of atrial electromechanical dysfunction and the determination of clear prognostic risk factors for cardiovascular events.
If ACM is a significant risk factor for stroke, irrespective of AF, how to identify patients at increased risk of TEE (without history of AF) for OAC therapy? In the study by Wolsk E, et al. (2015), the CHA 2 DS 2 -VASc score was defined as an independent risk factor for TEE in the absence of any history of AF in patients with heart failure [46]. Similar results in assessing the predictive value of the CHA 2 DS 2 -VASc scale were demonstrated by the studies of Belen E, et al. (2016) when assessing spontaneous LA contrasting in patients with rheumatic mitral stenosis and without AF history, who had a high risk of LA thrombus formation and TEE, despite sinus rhythm [47]. It is known that patients with mechanical valve prostheses and significant mitral stenosis are not adequately protected by a direct OAC and require anticoagulant therapy with warfarin [22]. Could there be other groups of patients who should be given warfarin to prevent TEE when specific signs of ACM are detected? [48]. Is it possible to identify patients who require more aggressive approaches to TEE prevention, such as the combination of an antiplatelet agent with OAC or the use of LA appendage occluders? The study, analysis and potential of using ACM-specific characteristics for assessing the high risk of TEE and OAC therapy in patients with sinus rhythm should be carried out in prospective randomized multicenter studies.
A combined assessment of etiological factors and signs associated with ACM can be useful information in the selection of initial drug therapy, while analysis of fibrosis severity, LA electrical characteristics and function can be critical in choosing invasive interventions. Thus, electromechanical and structural (fibrosis) markers of ACM have demonstrated prognostic value in assessing the risk of AF recurrence after catheter RFA in a number of studies [49][50][51].
Could these predictors be used to predict outcomes in patients for whom RFA would not be warranted and thereby eliminating the risk of unnecessary procedures? Can the characteristic features of ACM be used to select the optimal catheter ablation technique for a particular patient?
In accordance with current guidelines, RFA is recommended as a second-line treatment for antiarrhythmic drug intolerance or ineffectiveness. As a firstline treatment, indications are limited to paro xysmal AF only. According to these guidelines, RFA is generally considered by clinicians after a longer period of conservative therapy for AF. The development of tools and methods for the identification of ACM markers can allow avoiding the discrepancy between the optimal period for RFA and its time in accordance with a substrate-oriented diagnosis and treatment of AF.

Conclusion
Thus, further randomized prospective studies are required for a comprehensive and individua-lized approach to treatment, including optimal OAC therapy, ablation (taking into account the type and severity of ACM), and, possibly, genetics-based approaches in the future.
Conceptual reevaluation and classification of ACM are important for predicting and persona lizing treatment strategies, taking into account etiology, morphology, pathogenesis, geno-and phenotype. Although the genetic determinants of ACM are poorly understood today, significant efforts have been made in the last decade to identify the genetic causes of AF, which is both a complication of ACM and its common cause. Study of the genetic basis of primary defects in the atrial structure and function, as well as the genetic contribution of other cardiac pathology and concomitant diseases, adverse environmental and lifestyle factors that lead to secondary atrial remodeling, improvement of invasive and non-invasive technologies for visualization of atrial remodeling will contribute to the creation of new risk stratification approaches for complications such as AF, heart failure and TEE.
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