Ebstein's anomaly: clinical guidelines

List of Abbreviations

AAD - antiarrhythmic drugs

AAT - antiarrhythmic therapy

AV – atrioventricular

AV - atrioventricular groove

VKA - vitamin K antagonists

AVRT – atrioventricular reentrant tachycardia

AVN - atrioventricular node

AVNRT - atrioventricular nodal reentrant tachycardia

ACG - angiocardiography

ART - antidromic reentrant tachycardia

atrialized RV part

Ebstein anomaly

RVOT - right ventricular outflow tract

CHD - congenital heart disease

SCD — sudden cardiac death

RVOT - right ventricular outflow tract

VSD - ventricular septal defect

ASD - atrial septal defect

APVC - accessory atrioventricular connection

AP - accessory pathways

ESC - European Society of Cardiology

VT – ventricular tachycardia

CAD - coronary artery disease

CPB - cardiopulmonary bypass

CA - catheter ablation

CAG - coronarography

CT — computed tomography

CTI - cardiothoracic index

LV — left ventricle

RV - right ventricle

LA — left atrium

RA - right atrium

INR – international normalized ratio

MRI — magnetic resonance imaging

SVT - supraventricular tachycardia

CI - circulatory insufficiency

НОАК – novel oral anticoagulants

NSAIDs – nonsteroidal anti-inflammatory drugs

PDA - patent ductus arteriosus

PVRI - pulmonary vascular resistance index

PFO - patent foramen ovale

AHF - acute heart failure

RV – right ventricle

RFA - radiofrequency ablation

TG - triglycerides

TV - tricuspid valve

AFL - atrial flutter

TEC - thromboembolic complications

AF – atrial fibrillation

HDL-C - blood cholesterol, high-density lipoprotein level

LDL-C - blood cholesterol, low-density lipoprotein level

CHF – chronic heart failure

EPIS - Intracardiac electrophysiological study

ECG - electrocardiography

EchoCG – echocardiography

QRS - ventricular complex on the electrocardiogram

WPW - Wolff-Parkinson-White syndrome

NYHA – New York Heart Association

** - drug is included in the list of vital and essential drugs

*** - medical device implanted during the provision of medical care within the framework of the state program of free medical care for citizens

# - prescription of a medicinal product for indications not approved by state regulatory authorities, not mentioned in the instructions for use.

Terms and Definitions

European Society of Cardiology - the text of these clinical guidelines additionally indicates the indications for the theses in accordance with the recommendations of the European Society of Cardiology (ESC). In accordance with the international document, classes of recommendations and levels of evidence are distinguished.

Infectious endocarditis - an infectious-inflammatory cardiovascular disease caused by direct invasion by microorganisms (bacteria, fungi) of the endocardium of valve structures, surfaces of artificial materials located in the blood flow path (valve prostheses, intracardiac devices) or, less commonly, the mural endocardium with the development of polypoid- ulcerative changes in the affected heart structures with their functional insufficiency; proceeding with systemic inflammation, bacteremia, progressive heart failure, cardiogenic embolisms and immune-complex extra-cardiac lesions, infectious lesion of the endocardium of the heart valves by various pathogens.

Outcome - any possible result arising from the impact of a causal factor, preventive or therapeutic intervention, all established health status changes arising as a consequence of the intervention.

Clinical trial - any investigation conducted with human subjects to identify or confirm clinical and/or pharmacological effects of investigational products and/or to identify adverse reactions to investigational products, and/or to study their absorption, distribution, metabolism, and excretion in order to assess their safety and/or efficacy.

Conflict of interest - a situation in which a medical or pharmaceutical worker, in the exercise of their professional activities, has a personal interest in obtaining personally, or through a representative of a company, material gain or other advantage that affects or may affect the proper performance of their professional duties due to a contradiction between the personal interest of the medical or pharmaceutical worker and the interests of the patient.

Laboratory diagnostics - a set of methods aimed at analyzing the test material using various specialized equipment. Medical intervention - types of medical examinations and (or) medical manipulations performed by a medical worker and another employee entitled to carry out medical activities in relation to the patient, affecting the physical or mental state of a person and having a preventive, diagnostic, therapeutic, rehabilitative or research orientation, as well as artificial termination of pregnancy.

Supraventricular tachycardias – three or more (according to some literature sources 5 or more) consecutive heart contractions with a heart rate (HR) > 100 per minute, provided that sinus node (SN) cells, atrial myocardium, muscle sleeves of the pulmonary/vena cava veins, and/or atrioventricular (AV) junction cells participate in the self-maintenance mechanism of the arrhythmia.

Patient - an individual to whom medical care is provided or who has applied for medical care, regardless of the presence of a disease and their condition.

Working group on the development/updating of clinical guidelines - a team of specialists working together and in a coordinated manner for the purpose of developing/updating clinical guidelines, and bearing joint responsibility for the results of this work.

Wolff-Parkinson-White syndrome - defined as the presence of an overt "manifesting" accessory pathway, which leads to the development of so-called ventricular pre-excitation combined with recurrent tachycardias.

Thesis-recommendation - a provision reflecting the procedure and correctness of performing a particular medical intervention that has proven efficacy and safety.

Atrial flutter - a supraventricular tachyarrhythmia characterized by atrial activation at a rate of 250–350 per minute ("flutter waves" with the absence of an isoelectric line on the ECG) due to a macro re-entry process around a certain anatomical or functional obstacle (usually involving the tricuspid valve).

Level of evidence (LoE) - the degree of confidence that the found effect of a medical intervention is true.

Strength of recommendation (SoR) - the degree of confidence in the reliability of the intervention effect and that following the recommendations will bring more benefit than harm in a particular situation.

Atrial fibrillation - a type of supraventricular tachyarrhythmia with chaotic electrical activity of the atria at a rate of 350–700 per minute (with the absence of a P-wave on the ECG), excluding the possibility of their coordinated contraction, and, as a rule, an irregular ventricular rhythm

Echocardiography - an ultrasound imaging method aimed at studying the morphological and functional changes of the heart and its valve apparatus.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Ebstein anomaly (EA) a congenital malformation of all right heart chambers (right atrium, right ventricle, tricuspid valve. Pathology of the pulmonary valve and anomalies of cardiac conduction pathways are possible:

- Enlargement of the right atrium due to the expansion of its cavity and due to the atrialization of the right ventricle;

- Various degrees of reduction in RV size due to the displacement of the TV leaflet closing element towards the outflow tract;

- Various degrees of TV regurgitation depending on the hypoplasia of its leaflets;

- Dilatation of the true tricuspid annulus

The anatomical and pathophysiological abnormalities in Ebstein's anomaly exhibit wide individual variability—ranging from extreme forms of the defect that lead to severe heart failure in newborns and require urgent surgical correction, to incidentally detected tricuspid valve changes during routine echocardiographic examinations in elderly individuals.

Ebstein's anomaly differs from other tricuspid valve anomalies by an apical displacement of the septal leaflet of ≥ 8 mm/m² of body surface area relative to the mitral valve annulus, as measured by transthoracic echocardiography in the apical four-chamber view [1,2]

Associated cardiac anomalies

1) An atrial septal defect is present in the majority of cases.

2) Obstruction of the right ventricular outflow tract of varying severity.

3) Pulmonary stenosis or atresia

4) Patent ductus arteriosus in pulmonary atresia

5) Ventricular septal defect [3]

Arrhythmias in Ebstein's anomaly.

In patients with Ebstein's anomaly, the prevalence of supraventricular tachycardias ranges from 26% to 65% [2,4-6]

Atrial re-entry tachycardias develop in patients after surgical correction. The cause of arrhythmia development is chronic hemodynamic overload combined with the presence of postoperative scars. The most common type of atrial re-entry tachycardia is cavotricuspid isthmus (CTI)-dependent atrial flutter [7,8].

Paroxysmal atrioventricular re-entry tachycardia (AVRT) associated with the presence of accessory atrioventricular pathways occurs in 10-38% of cases [5]. In 10-45% of patients with Ebstein's anomaly, right-sided accessory pathways are present, sometimes numbering two or more [9-11].

The risk of atrial fibrillation increases with patient age and progressive changes in the atrial myocardium that predispose to arrhythmias and the formation of an arrhythmogenic substrate [12].

Ventricular arrhythmias are rare but may occur in the presence of right ventricular dysfunction [13]

Patients with Ebstein's anomaly and signs of ventricular pre-excitation on the ECG are indicated for catheter ablation in the near future due to the high probability of multiple accessory pathways and the risk of atrial tachycardias with hemodynamic instability during the arrhythmia. In patients with accessory pathways, atrial fibrillation or other supraventricular tachycardia with rapid ventricular conduction are potentially life-threatening due to the risk of transformation into ventricular fibrillation [9,14,15].

Ebstein's anomaly requires a detailed evaluation of the patient for latent forms of cardiac rhythm disturbances [5,10,11].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Familial cases of Ebstein's anomaly have been described in the literature. McIntosh N. et al. diagnosed severe Ebstein's anomaly prenatally in two sisters born to parents from Sri Lanka [16].

More detailed insights into the etiology of Ebstein's anomaly can be gained from cytogenetic studies. de Lonlay-Debeney et al. described 2 different rearrangements of the long arm of chromosome 11 in a patient with Ebstein's anomaly [17].

In a study of 44 patients with Ebstein's anomaly, standard chromosome analysis identified a number of chromosomal abnormalities in 12 patients in whom Ebstein's anomaly was part of a syndrome: in 3 of them, a 1p36 deletion combined with an Xpter-Xp22.3 duplication, an 8p23.1 deletion, and an 18q21.3-qter deletion were found [18].

Gene mutations in patients with Ebstein's anomaly were identified as heterozygous missense mutations of the NKX2.5 gene with an autosomal dominant inheritance pattern and variable penetrance. The NKX2.5 protein is a member of the evolutionarily conserved family of transcription factors, acting as a DNA-binding transcription activator. NKX2.5 regulates the expression of genes essential for heart development [19].

Additionally, heterozygous mutations of the MYH7 gene with an autosomal dominant transmission pattern and variable expressivity were discovered—three missense mutations (Tyr283Asp, Asn1918Lys, Glu1573Lys) [20, 21].

To date, it has been proven that to a certain extent, the high frequency of the defect in the intrauterine period is associated with maternal intake of lithium preparations. In women who took medications containing lithium carbonate during the first trimesters of pregnancy, the probability of having children with Ebstein's anomaly increases significantly. It is known that fetuses in whom the anomaly is detected intrauterine present with the most unfavorable anatomical variants of the defect, determining high mortality in utero or immediately after birth.

According to D. Celermajer et al. (1992), who observed the natural history, all infants with a cardiothoracic ratio (CTR) >90% died. Consequently, the authors developed an echocardiographic classification of the defect, allowing assessment of the severity of patients with Ebstein's anomaly depending on right atrial dilatation and right ventricular atrialization. As follows from the data presented by the authors, mortality in infants classified into grades 1 and 2 does not exceed 7%, whereas in grades 3-4 it is 75-100% [22].

There are reports in the literature of normal deliveries in unoperated women. In other words, patients with mild tricuspid regurgitation can remain asymptomatic for a sufficiently long time, and such patients do not require surgical treatment [2,4,8].

Adults with Ebstein's anomaly should be followed up in specialized centers with experience in treating congenital heart disease in adults, specifically Ebstein's anomaly.

1.3 Epidemiology of the Disease or Condition

According to literature data, for many years Ebstein's anomaly was considered a rather rare pathology, the frequency of which among all congenital heart defects does not exceed 1%. Ebstein's anomaly is a rare congenital malformation with an incidence ranging from 0.7 to 1% among other congenital heart defects. According to some researchers, this pathology occurs in approximately 1 in 20,000 newborns. Nevertheless, this rare anomaly represents the most frequent defect involving tricuspid valve pathology, accounting for 40% of all congenital heart defects affecting the right atrioventricular valve, with both sexes affected equally [2,4,8,23].

With the advancement of modern diagnostic capabilities, it has become clear that the data cited here regarding the true incidence of Ebstein's anomaly during different periods of cardiac formation and the postnatal period are somewhat outdated and require revision. As recent studies have shown, the intrauterine incidence of Ebstein's anomaly significantly exceeds that in the postnatal period. In postnatal pediatric cardiology practice, Ebstein's anomaly occurs in 1 out of 1,000 patients with congenital heart defects. According to G. Sharland et al. (1991) and Lang et al. (1991), the incidence of Ebstein's anomaly among prenatally diagnosed congenital heart defects is 8.5% [24, 25]. The incidence is approximately the same (7.8%) according to prenatal echocardiography data. Pronounced cardiac dysfunction in Ebstein's anomaly, leading in utero to cardiomegaly and tachycardia, is one of the most common reasons for referring patients from obstetrician-gynecologists to cardiologists. Given that cases with mild cardiomegaly are usually not diagnosed by echocardiography, the true incidence of Ebstein's anomaly in fetuses is even higher. These data indicate that the true incidence of Ebstein's anomaly is significantly higher than previously assumed [26].

1.4 Features of Coding the Disease or Condition

Congenital malformations of pulmonary and tricuspid valves (Q22): Q22.5 – Ebstein's anomaly.

I36.1 – Nonrheumatic tricuspid (valve) insufficiency.

1.5 Classification of the disease or condition

The classification of Ebstein's anomaly was proposed by A. Carpentier et al. in 1988. It is based on parameters that are important to consider when planning surgical correction of the defect (functional size of the right ventricle and condition of the anterior tricuspid leaflet) [27].

Type A. The anterior tricuspid leaflet has normal morphology, and the right ventricle size is adequate.

Type B. The anterior tricuspid leaflet has anomalous chordae, but its mobility is preserved, the right ventricle is reduced, but its size is adequate.

Type C. The anterior tricuspid leaflet has limited mobility, the right ventricle is small with a large atrialized component.

Type D. The tricuspid leaflets form a fibrous tissue "tricuspid sac" fused with the inner surface of the right ventricle. The only functional part of the right ventricle is its infundibular portion.

1.6 Clinical presentation of the disease or condition

Clinical manifestations of right-sided heart failure in Ebstein's anomaly primarily depend on the degree of tricuspid regurgitation and right ventricular atrialization. The clinical picture may also depend on associated anomalies, such as pulmonary atresia, patent ductus arteriosus, septal defects, and severe rhythm disturbances. A particularly severe patient group consists of newborns with anatomical pulmonary atresia. In these cases, surgery in the neonatal period is inevitable [28,29].

The clinical presentation of Ebstein's anomaly in a number of patients may be asymptomatic, and they lead a normal lifestyle. In some cases, they can even perform heavy physical work. At the same time, signs of heart failure may eventually appear with any form of Ebstein's anomaly. In other patients, with early cyanosis, the disease manifests in early childhood and rapidly progresses [2,4,8,23].

A constant complaint of patients with Ebstein's anomaly is dyspnea. In the vast majority of patients, dyspnea occurs only during physical exertion. About 90% of patients suffer from rapid fatigue. A pathognomonic sign of Ebstein's anomaly, in our opinion, is palpitations (80-90% of patients). With severe tricuspid valve regurgitation and a large atrial septal defect, clinical manifestations of heart failure with marked cyanosis due to right-to-left shunting at the atrial level are possible [2,4,8,23].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for establishing a diagnosis

Symptoms:

• dyspnea;

• frequent respiratory infections;

• poor weight gain;

• sweating during feeding;

• refusal to breastfeed;

• palpitations.

Anamnesis: prenatal diagnosis of congenital heart disease.

Physical examination:

• tachycardia;

• dyspnea;

• hepatomegaly;

• varying degrees of cyanosis – upon the development of heart failure or combination of Ebstein's anomaly with other congenital heart defects (functional or organic pulmonary atresia);

• systolic murmur of varying intensity (wide splitting of the first heart sound (due to later closure of the elongated anterior leaflet of the tricuspid valve), systolic murmur of tricuspid regurgitation, maximal at the point of projection of the tricuspid valve – at the base of the xiphoid process).

Laboratory tests: do not provide characteristic information for Ebstein's anomaly.

Instrumental Studies:

Chest X-ray:

• cardiomegaly of varying degree;

ECG:

• right axis deviation;

• signs of right heart overload;

• decreased voltage of QRS ventricular complexes and their deformation in right chest leads;

• when combined with WPW syndrome, a delta wave is detected on the ECG;

• other ventricular and supraventricular rhythm disturbances.

Echocardiography:

• the distinction of Ebstein's anomaly from other tricuspid valve anomalies is the degree of apical displacement of the septal leaflet $\ge$ 8 mm/m² of body surface area relative to the mitral valve annulus, measured by transthoracic echocardiography in the apical four-chamber view;

• varying degrees of tricuspid regurgitation;

• morphology of tricuspid valve leaflets, size of the functional part of the right ventricle, size of the atrialized part of the right ventricle.

2.1 Complaints and Anamnesis

ESC/ACC I C (LoE C, LoR 4)

Comments: Newborns may be admitted to clinics as an emergency immediately after birth for several reasons [4,30,31,32,33]:

1. Ebstein's anomaly with pulmonary atresia. As a rule, infants suffer from varying degrees of impaired pulmonary blood circulation with signs of cyanosis against the background of duct-dependent circulation;

2. Ebstein's anomaly in patients with functional pulmonary atresia, also with signs of cyanosis due to patent ductus arteriosus functioning.

3. Newborns with paroxysmal tachycardia.

Conventionally, all patients can be divided into three groups: 1. Asymptomatic patients who have no complaints or manifestations of circulatory failure even during physical exertion. As a rule, the closing function of the tricuspid valve in such patients is practically normal and atrialization of the right ventricle is not pronounced; Group 2: patients who show signs of right-sided circulatory failure during physical exertion (tachycardia, dyspnea, possibly cyanosis); Group 3: patients with manifestations of right-sided circulatory failure at rest (dyspnea, exercise intolerance, hepatomegaly). As a rule, such patients have severe tricuspid regurgitation. With age, patients may move from one group to another with a gradual increase in heart failure. The risk of cardiac arrhythmias also increases with age [4,8].

2.2 Physical Examination

ESC/ACC I C (LOE C, GoE 5)

Comments: Examination reveals dyspnea, enhanced jugular venous pulsation, and palpitations.

ESC/ACC I C (LoE C, LoR 5)

Comments: Auscultation reveals:

1. Wide splitting of the first heart sound (due to later closure of the elongated anterior leaflet of the tricuspid valve).

2. Systolic murmur of tricuspid regurgitation according to the Levin classification 2-3/6, maximal at the projection point of the tricuspid valve – at the base of the xiphoid process, and slightly to the left towards the apex of the heart (projection of the displaced valve).

3. Early diastolic murmur caused by oscillatory movements of the elongated anterior leaflet.

4. In the majority of patients, a blowing systolic murmur was detected.

2.3 Laboratory Diagnostics

• In all patients with Ebstein's anomaly admitted to the hospital, it is recommended to study the acid-base state and blood gases (pH, BE, pCO2, PO2, Lac - analysis of capillary/arterial/venous samples) to assess the severity of hypoxemia and the degree of metabolic disorders [4,30,31,32,34].

ESC/ACC I C (LOE C, GoE 5)

• In all patients with Ebstein's anomaly, it is recommended to perform a general (clinical) urine analysis and a complete blood count with evaluation of hemoglobin and hematocrit levels, erythrocyte, leukocyte, and platelet counts, and erythrocyte sedimentation rate during the initial examination, during follow-up at least once a year and upon admission to the hospital, as well as in the case of surgical treatment if necessary in the pre- and/or postoperative period [4,23,30,31,35].

ESC/ACC I C (LoE C LoR 5)

• In all patients, especially older ones, with Ebstein's anomaly (as part of the initial examination, upon admission to the hospital, in case of surgical treatment if necessary in the pre- and/or postoperative period, and at least once a year at a follow-up visit), to assess liver and kidney function, it is recommended to perform a general clinical blood biochemistry analysis (study of blood levels of potassium, sodium, chlorides, glucose, creatinine, total protein, albumin, urea, total bilirubin, free and conjugated bilirubin, determination of lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase activity in the blood) [30, 31,33,35,36].

ESC/ACC I C (LoE C LoR 5)

Comments: In adult patients, an additional study of total blood cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglycerides (TG) is performed to identify risk factors for concomitant atherosclerosis and, if necessary, adjust therapy in all patients with Ebstein's anomaly [30, 31,33,35,36].

Biochemical blood analysis provides information on internal organ function, metabolism, and trace element levels [112]. In patients with Ebstein's anomaly, it is necessary to monitor liver function, which suffers in the presence of significant tricuspid regurgitation (bilirubin level, aspartate aminotransferase and alanine aminotransferase activity). Patients with Ebstein's anomaly with heart failure and arrhythmias require monitoring of liver and kidney function, electrolyte balance, and thyroid status [35- 37].

• In all patients with Ebstein's anomaly admitted to the hospital for surgical treatment, it is recommended to perform a coagulogram (exploratory hemostasis study) (activated partial thromboplastin time, prothrombin time, prothrombin index, blood fibrinogen level, antithrombin III activity, and international normalized ratio (INR). Determination of ABO blood groups. Determination of the D antigen of the Rhesus system (Rh factor). Phenotyping for C, c, E, e, Cw, K, k antigens and determination of anti-erythrocyte antibodies. Determination of hepatitis B virus surface antigen (HBsAg) in the blood. Determination of antibodies to hepatitis C virus in the blood. Determination of antibodies to Treponema pallidum in the blood. Determination of IgM and IgG antibodies to human immunodeficiency virus HIV-1 in the blood, determination of IgM and IgG antibodies to human immunodeficiency virus HIV-2 in the blood to exclude association with HIV infection and hepatitis, as well as in the case of surgical treatment if necessary in the pre- and/or postoperative period [4,23,30,31-37].

ESC/ACC I C (LoE C LoR 5)

2.4 Instrumental Diagnostics

ESC/ACC I C (LoE C, LoR 4)

Comments: A highly characteristic and specific feature of classical forms of Ebstein anomaly is the low voltage of QRS complexes and their deformation in the right precordial leads. Such changes in the ventricular complexes provide a sufficiently strong basis for a preliminary diagnosis, as no other congenital heart disease exhibits such complex QRS deformations. The P wave is typically tall and peaked (the so-called "Himalayan P wave") [27]. In patients with concomitant WPW syndrome, a delta wave is detected on the ECG. Furthermore, patients with EA frequently exhibit prolongation of the PR interval, right bundle branch block, and ventricular and supraventricular arrhythmias.

ESC/ACC I C (LoE C, LoR 4)

ESC/ACC IIa C (LoE C, GoE 5)

Comments: The radiological presentation of Ebstein anomaly is typical and consists of an increased cardiothoracic ratio (CTR) and the presence of a characteristic cardiac silhouette shape. Due to the enlargement of the heart in both directions and the presence of an elongated vascular pedicle, the configuration of the cardiovascular silhouette assumes a typical globular shape or that of an "inverted chalice."

ESC/ACC I C (LoE C, GoE 5)

Comments: Echocardiography is the key diagnostic method for confirming the diagnosis of EA, as well as assessing the severity and prognosis of the disease. During the examination, valve morphology must be assessed; excessive apical displacement of the septal and posterior leaflets is the essence of this defect. The attachment of the septal leaflets is best visualized in the apical 4-chamber view. The posterior leaflet of the tricuspid valve is best visualized in a modified parasternal long-axis view. The 4-chamber view allows for the evaluation of the distal displacement of the septal leaflet. TTE reveals the following echocardiographic signs of the defect: enlargement of the right atrium; apical displacement of the tricuspid valve; fusion of the septal leaflet with the septum; and an anterior leaflet with normal attachment to the fibrous annulus, characterized by extensive amplitude of motion. Objectively, the degree of right heart chamber dilation and right ventricular dysfunction are identified. The 4-chamber view is optimal and informative for assessing the degree of enlargement of these chambers [40]. Echocardiography also visualizes the septa to detect atrial or ventricular septal defects. The function of the left ventricle and other heart valves must also be assessed.

ESC/ACC IIa C (LoE C, GoE 5)

ESC/ACC IIa C (LoE C, GoE 5)

Comments: there is a growing interest in using CT for congenital heart disease diagnosis. These methods allow determining anomaly anatomy—the magnitude of leaflet displacement, linear dimensions of cardiac structures (including right ventricular myocardial thickness); calculating cardiac chamber volumes; and assessing the ejection fraction and severity of tricuspid regurgitation. In expert laboratories, 3D measurements of RV volumes can be used, which are comparable to magnetic resonance imaging (MRI) data [49]. However, if MRI is available, it should be considered the gold standard for assessing RV volume and function [49,94,95]. CT can be used to assess RV volume and function in patients with pacemakers and other contraindications to MRI [49].

ESC/ACC IIa C (LoE C, GoE 5)

ESC/ACC IIa C (LoE C, GoE 5)

Comments: Following tricuspid valve surgery, transcatheter access to right-sided lateral accessory pathways and the slow pathway in AV nodal reciprocating tachycardia may be difficult, so it is necessary to assess arrhythmia substrates and perform catheter ablation prior to surgery [30].

ESC/RSC III C (LOC C, LOR 5)

Comments: Transvenous cardiac catheterization and angiocardiography are rarely required for preoperative hemodynamic assessment. In certain high-risk patients, performing it may be useful for risk stratification. A pathognomonic angiocardiographic sign of Ebstein anomaly is the characteristic "tri-lobed" configuration of the lower contour of the cardiac silhouette or a positive double-notch sign [4]. The first "notch," or bridge, usually corresponds to the true fibrous annulus (atrioventricular groove), and the second to the attachment site of the displaced leaflets. Thus, in classical cases, angiocardiograms contrast three cavities: the left cavity located proximal to the first "notch" corresponds to the enlarged right atrium, the central cavity located between the "notches" corresponds to the atrialized portion, and the right cavity lying distal to the second "notch" represents the functionally active right ventricle.

ESC/RSC I C (LOC C, LOR 5)

2.5 Other Procedures

• In patients with Ebstein anomaly complicated by severe (inoperable) tricuspid regurgitation, it is recommended to perform cardiopulmonary exercise testing, including assessment of peak oxygen consumption, ventilatory equivalent for carbon dioxide VE/VCO2, chronotropic response, and blood pressure response, to determine indications for heart transplantation [13,31,55,56,61].

ESC/RSC IIa C (LOC C, LOR 5) for children

ESC/ESC IIa C (LoE C, GoE 4) for adults

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

There is no conclusive evidence regarding the benefit of medications, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-blockers, or ivabradine** in patients with EA. However, when indicated (cardiac arrhythmias, CHF), the prescription of the drugs listed below should be considered.

Treatment of heart failure

Supraventricular arrhythmias are frequently the cause of heart failure in patients with EA. Atrial fibrillation and flutter with a high ventricular response rate can lead to the development of cardiomyopathy. Patients with EA tolerate arrhythmias poorly, and even if the heart rate is not high, the arrhythmia can contribute to the development or progression of heart failure. Therefore, treating arrhythmias also serves as prevention and treatment of heart failure [57]. Currently, the same groups of drugs are used to treat CHF in children as in adults [58-60]: ACE inhibitors (1A), angiotensin II receptor blockers (ARBs), beta-blockers, and aldosterone antagonists (mineralocorticoid receptor antagonists).

ESC/RSC I C (LOC C, LOR 5)

Comments: The initial single dose of Furosemide** (solution for intravenous and intramuscular administration) in children is calculated at 1 mg/kg of body weight/day, with a possible dose increase up to a maximum of 20 mg/kg/day) [110-111];

However, diuretics cannot significantly affect the reduction of cardiac output caused by right ventricular dysfunction and severe tricuspid regurgitation. Since heart failure in EA is rooted in anatomical problems, surgical correction of the defect is the primary method of treatment and prevention of heart failure in patients with EA [57].

Digoxin** should be prescribed with caution in such patients, and is preferably used when the patient has severe heart failure (NYHA functional class III-IV), low left ventricular ejection fraction (<25%), combined with a tendency toward hypotension. The optimal maintenance dose of Digoxin** for treating adult patients with CHF is considered to be 0.125-0.5 mg/day, and for children aged 3 years and older, 0.08-0.1 mg/kg/day. During long-term treatment, monitoring blood concentrations of Digoxin**, which should remain within safe limits, is necessary [62,63,112].

Due to the likelihood of ventricular arrhythmias, especially in patients with hypokalemia, strict monitoring of blood electrolytes, renal function, and ECG is required.

Treatment of supraventricular tachycardias

ESC/ESC IIb C (LoE C, GoE 5)

Comments: Long-term antiarrhythmic therapy does not show positive results in achieving freedom from arrhythmia and has many side effects in patients with CHD [42,118]. Amiodarone** is an effective agent for treating arrhythmias in moderately complex CHD (including EA) with ventricular dysfunction, but patients frequently develop side effects requiring dose reduction or discontinuation of the drug [65,118].

• Amiodarone** is not recommended for long-term treatment of rhythm disorders in adult patients with CHD, including EA [114-118].

ESC/RSC III C (LOC C, LOR 5)

• In children with EA and asymptomatic ventricular tachycardia, the disease follows a benign course, and in most cases, class I and III antiarrhythmic drugs are not recommended [59,60,66-68].

ESC/ESC III C (LoE C, GoE 5)

• Sotalol** is recommended to be used with caution in patients with EA due to the high risk of proarrhythmic effects and death [31,119-120].

ESC/ESC IIb C (LoE C, GoE 5)

ESC/ESC III C (LoE C, GoE 5)

ESC/ESC IIa C (LoE C, GoE 5)

Comments: If sinus rhythm cannot be restored or stabilized in patients with normal systemic ventricle function and no pre-excitation, pharmacological AV nodal blockade using beta-blockers or calcium channel blockers may be used to prevent rapid AV conduction. Combination therapy may be required in some patients [30,42].

Medical treatment is used as a preparatory stage for surgical treatment or to reduce heart failure symptoms and relieve the condition of patients who have contraindications to surgery.

Anticoagulant therapy in patients with EA

ESC/ESC I C (LoE C, GoE 5)

• In adult patients with EA after intracardiac repair and/or in the presence of cyanosis, it is recommended to prescribe oral anticoagulants (antithrombotic agents) in the presence of atrial fibrillation, atrial flutter, or atrial re-entry tachycardia for the prevention of thromboembolic events [76].

ESC/ESC IIa C (LoE C, GoE 5)

ESC/ESC IIa C (LoE C, GoE 5)

Management of patients after surgical correction

ESC/ESC III B (LoE C, GoE 4)

ESC/ESC I C (LoE C, GoE 5)

• All patients with EA are recommended to receive oral anticoagulant therapy using vitamin K antagonists for the first 3 months following surgical implantation of a bioprosthesis (cadaveric sterile cardiac bioprosthesis***; mitral bioprosthesis***; cardiac pulmonary valve bioprosthesis***) [81,82,83,121-124].

ESC/ESC IIa C (LoE C, GoE 4)

• In adult patients with EA and atrial fibrillation, as well as bioprostheses (cadaveric sterile cardiac bioprosthesis***; mitral bioprosthesis***; cardiac pulmonary valve bioprosthesis***), it is recommended to prescribe direct thrombin or factor Xa inhibitors after the third month of the postoperative period for the prevention of thromboembolic events [53,81,82].

ESC/ESC IIa C (LoE C, GoE 5)

Comments: Vitamin K antagonists (VKAs) are preferred when long-term anticoagulant therapy is required in patients with bioprostheses (cadaveric sterile cardiac bioprosthesis***; mitral bioprosthesis***; cardiac pulmonary valve bioprosthesis***).

ESC/ESC I B (LoE C, GoE 4)

Comments: the target INR depending on the type of mechanical prosthesis ranges from 2.5 to 3.5. There are no data demonstrating the benefit of anticoagulant therapy for more than 3 months in patients with bioprostheses (cadaveric sterile heart valve bioprosthesis***; mitral valve bioprosthesis***; cardiac pulmonary valve bioprosthesis***) except for patients with additional indications for anticoagulant therapy [53,84]. Vitamin K antagonists (VKAs) are preferred when long-term anticoagulant therapy is needed in patients with bioprostheses (cadaveric sterile heart valve bioprosthesis***; mitral valve bioprosthesis***; cardiac pulmonary valve bioprosthesis***). Despite the lack of clinical trial data, DOACs (B01A: Antithrombotic agents) may be used in patients with AF associated with a bioprosthesis (cadaveric sterile heart valve bioprosthesis***; mitral valve bioprosthesis***; cardiac pulmonary valve bioprosthesis***) after the third postoperative month [53,84]

3.2 Surgical Treatment

Catheter ablation of accessory pathways in Ebstein anomaly

ESC/HRS IIa C (LOE C, GOR 5)

• In patients with EA and signs of ventricular pre-excitation on ECG or EPS, it is recommended to perform radiofrequency ablation of arrhythmogenic zones as soon as possible due to the high risk of atrial tachycardias with hemodynamic instability [9,14,15].

ESC/ACC I C (LOE C, GOR 5)

Comments: in patients with accessory pathways, atrial fibrillation or other supraventricular tachycardia with rapid ventricular conduction are potentially life-threatening due to the risk of transformation into ventricular fibrillation [9,14,15].

ESC/HRS I B (LOE C, GOR 5)

Comments: Supraventricular tachycardia associated with the presence of accessory pathways is frequently combined with EA.

• In all adult patients with EA, it is recommended to perform catheter ablation for the treatment of AVRT and AF associated with ventricular pre-excitation syndrome [6].

ESC/HRS I B (LOE C, GOR 5)

• In patients with EA, it is recommended to perform radiofrequency ablation of arrhythmogenic zones for the treatment of supraventricular tachycardias [4,34,42,69,70,71].

ESC/HRS IIa C (LOE C, GOR 5)

Comments: radiofrequency ablation of arrhythmogenic zones is the first-line therapy, and is preferred over long-term pharmacological therapy if a targetable limited substrate is present [42].

ESC/HRS IIb C (LOE C, GOR 5)

• In children under 15 kg with EA who do not require open-heart surgery, it is not recommended to perform EPS/RFA [5,10,11].

No ESC guideline (LoE C, GoR 5)

• In patients over 15 kg with EA, it is recommended to perform EPS or EPS/RFA before open-heart surgery [5,10,11].

No ESC guideline (LoE C, GoR 5)

Indications for surgery

ESC/ESC I C (LoE C, GoE 5)

Comments: currently, an approach toward earlier surgical treatment is being considered. According to the literature, tricuspid valve repair for Ebstein anomaly is most frequently performed based on indications at the age of 4-7 years, when heart sizes allow for adequate tricuspid valve competence [87]. The optimal age for the child is 3-5 years for types B and C, prior to the development of right ventricular dysfunction. When cyanosis (right-to-left shunt across an ASD) appears during physical exertion, in severe tricuspid regurgitation and CHF, surgeries are performed earlier than this period, even in the neonatal period.

ESC/ACC IIa C (LoE C, GoE 5)

ESC/ESC I C (LoE C, GoE 5)

ESC/ESC IIa C (LoE C, GoE 5)

Comments: Indications for performing a bidirectional cavopulmonary anastomosis: 1. Right ventricular dysfunction after repair (ratio of right atrial pressure to left atrial pressure > 1.5); 2. Tricuspid valve stenosis after reconstructive surgery (mean gradient across the tricuspid valve > 9 mmHg). 3. In adult patients, if the LV end-diastolic volume index is less than 75% of normal (small, compressed, D-shaped LV).

ESC/ESC IIa C (LoE C, GoE 5)

Surgery

ESC/ESC I C (LoE C, GoE 5)

Comment: A modern method for EA correction is the reconstruction of subvalvular tricuspid valve structures and tricuspid valve repair under cardiopulmonary bypass using the "cone reconstruction" technique proposed in 2007 by da Silva and colleagues [89].

Principles of surgery:

• Tricuspid valve leaflets are detached from the fibrous and muscular attachments to the RV endocardium with the maximum possible preservation of chords for their mobile clockwise relocation.

• Before performing tricuspid valve repair, either plication or resection of the atrialized portion of the RV is performed to form a physiological size of the atrioventricular orifice.

• If necessary, during tricuspid valve repair, a neochordal apparatus can be formed using the dissection of separated tissues.

• The "cone" shape of the valve is formed by rotating the separated tissues clockwise toward the elements of the preserved septal leaflet portion. If autologous tissue is insufficient, an additional autopericardial patch or a patch made of another material can be used.

• During the repair, it is possible to use the "approximation" method for papillary muscles and valve fixation points with interrupted sutures, which additionally allows the formation of a "cone" with improved competence.

• In patients older than three years, it is optimal to perform annuloplasty (mitral and tricuspid valve annuloplasty) in the form of reinforcing the tricuspid valve neoring using a cardiovascular animal-derived patch*** or a cardiovascular synthetic patch*** fixed to the reconstructive suture, or using a mitral annuloplasty ring***.

• During the operation, associated anomalies are eliminated: septal defects, patent ductus arteriosus, pulmonary artery stenosis/atresia, and other anomalies.

• If it is not possible to preserve sufficient dimensions and pump-contractile function of the right ventricle, it is recommended (in 5-20% of cases) to perform a sesquiventricular correction using a bidirectional cavopulmonary anastomosis (creation of a cavopulmonary anastomosis).

The result of the performed correction is the creation of adequate competence of the right atrioventricular valve (a valve in the form of a "conical funnel" at the anatomically correct height), and the right heart chambers (atrium and ventricle) are reconstructed with maximum approximation to physiological dimensions [84,89].

ESC/ESC I C (LoE C, GoE 5)

Comment: Bioprostheses (cadaveric sterile cardiac valve bioprosthesis***; mitral valve bioprosthesis***; pulmonary heart valve bioprosthesis***) and mechanical prostheses (bileaflet mechanical mitral valve prosthesis***; tilting-disc cardiac valve prosthesis***) can be used for tricuspid valve replacement [3,4,35,53,88].

Mechanical prosthesis thrombosis (bileaflet mechanical mitral valve prosthesis***; tilting-disc cardiac valve prosthesis***)

ESC/RSC I C (LOC C, LOR 5)

ESC/ACC IIa C (LoE C, GoE 5)

Bioprosthesis thrombosis (cadaveric sterile cardiac valve bioprosthesis***; mitral valve bioprosthesis***; pulmonary heart valve bioprosthesis***)

ESC/RSC I C (LOC C, LOR 5)

Comments: Therapy with unfractionated #sodium heparin** should be initiated with a bolus dose of 80 IU/kg in adults and 75 IU/kg in children, followed by continuous intravenous infusion at a rate of: 28 IU/kg/h in children under 1 year of age, 20 IU/kg/h in children over 1 year of age, and 18 IU/kg/h in adults (off-label in children under 3 years of age). Dosage adjustment is made based on laboratory test results [75,125-127].

Bioprosthesis dysfunction (cadaveric sterile cardiac valve bioprosthesis***; mitral valve bioprosthesis***; pulmonary heart valve bioprosthesis***)

ESC/ACC I C (LoE C, LoR 4)

ESC/ESC IIa C (LoE C, GoE 4)

3.3 Other Treatment

Endovascular interventions in EA patients

ESC/ACC IIa C (LoE C, GoE 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

No ESC recommendation (LoE C, GoR 5)

No ESC recommendation (LoE C, GoR 5).

5. Prevention and Dispensary Observation

ESC/RSC I C (LOC C, LOR 5)

ESC/RSC I C (LOC C, LOR 5)

Comments. Asymptomatic patients with mild tricuspid regurgitation and no right ventricular dilation, dysfunction, or pulmonary hypertension can be monitored annually and should be instructed to consult a physician immediately if their symptoms change. Annual echocardiography is not mandatory unless there is clinical evidence of progressive tricuspid regurgitation. In patients with moderate tricuspid regurgitation, clinical evaluation, including echocardiography, should be performed annually or more frequently if new symptoms appear

ESC/ACC I C (LOE C, GoE 5)

Comments: it is essential not to miss the development of prosthetic dysfunction, progression of heart failure, post-pericardiotomy syndrome [91], and cardiac arrhythmias.

ESC/RSC I C (LOC C, LOR 5)

Comments: Depending on whether the patient with a corrected or uncorrected defect belongs to a particular functional class, a different frequency of follow-up and scope of required examinations are recommended:

ESC/RSC I C (LOC C, LOR 5)

Comments: The main goals of follow-up after tricuspid valve replacement are monitoring the coagulation system and INR when necessary, monitoring prosthetic function for early diagnosis of dysfunctions and detection of long-term postoperative complications, management of heart failure and cardiac arrhythmias (ECG and echocardiographic control).

ESC/RSC I C (LOC C, LOR 5)

Comments: Endocarditis prophylaxis involves the administration of systemic antibacterial drugs prior to dental procedures that involve manipulation of the gingival or periapical regions of the teeth or perforation of the oral mucosa. All EA patients must be informed about infective endocarditis prevention, which includes skin and dental hygiene, dental check-ups and sanitation at least once a year (twice a year for the high-risk group), prompt wound disinfection, and treatment of chronic bacterial infection foci [135].

ESC/RSC I C (LOC C, LOR 5)

6. Organization of Medical Care

Indications for planned hospitalization:

1) Grade 3–4 TV regurgitation; 2) NYHA Class III–IV heart failure; 3) Elective surgical intervention.

Indications for emergency hospitalization:

1) Episodes of supraventricular tachycardia resistant to antiarrhythmic drugs.

Indications for patient discharge from the hospital:

Satisfactory surgical outcome with elimination of tricuspid valve regurgitation and accessory atrioventricular pathways.

7. Additional Information

No.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Avramenko A.A., Candidate of Medical Sciences, member of the Russian Society of Cardiology, Chief freelance pediatric cardiologist. Member of the Interregional Association of Pediatric Cardiac Surgeons (Samara).

2. Bokeria L.A., MD, Prof., Academician of the Russian Academy of Sciences, President of the Association of Cardiovascular Surgeons (Moscow);

3. Podzolkov V.P., MD, Prof., Academician of the Russian Academy of Sciences, member of the Association of Cardiovascular Surgeons (Moscow);

4. Gorbachevsky S.V., MD, Prof., member of the Association of Cardiovascular Surgeons (Moscow);

5. Zelenikin M.M., MD, Prof., member of the Association of Cardiovascular Surgeons (Moscow);

6. Irtyuga O.B., Candidate of Medical Sciences, member of the Russian Society of Cardiology (Saint Petersburg);

7. Kalashnikov S.V., Candidate of Medical Sciences, member of the Association of Cardiovascular Surgeons (Moscow);

8. Kim A.I., MD, Prof., Chief freelance pediatric cardiac surgeon of the Russian Ministry of Health, President of the Interregional Association of Pediatric Cardiac Surgeons, Vice-President of the Association of Cardiovascular Surgeons (Moscow);

9. Kokshenev I.V., MD, Prof., member of the Association of Cardiovascular Surgeons (Moscow);

10. Krivoshchekov E.V., MD, Vice-President of the Interregional Association of Pediatric Cardiac Surgeons (Tomsk);

11. Movsesyan R.R., MD, Prof., Corresponding Member of the Russian Academy of Sciences, Chief freelance pediatric cardiac surgeon of St. Petersburg (Saint Petersburg);

12. Nizamov Kh.Sh., member of the Association of Cardiovascular Surgeons (Moscow);

13. Sabirov B.N., MD, member of the Association of Cardiovascular Surgeons (Moscow);

14. Stovpyuk O.F., member of the Russian Society of Cardiology (Saint Petersburg);

15. Shatalov K.V., MD, Prof., member of the Association of Cardiovascular Surgeons (Moscow);

16. Chernova A.A., MD, Prof., member of the Russian Society of Cardiology (Krasnoyarsk);

17. Nikulina S.Yu., MD, Prof. (Krasnoyarsk), member of the Russian Society of Cardiology;

18. Yanulevich O.S., Candidate of Medical Sciences, Chief freelance pediatric cardiologist (Tomsk);

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatrician;

2. Cardiologist;

3. Pediatric cardiologist;

4. Cardiovascular surgeon.

During the development of the clinical guidelines, international grading systems for the level of recommendation consensus and the level of evidence quality were used (Tables 1 and 2), as well as a new system of evidence levels and recommendation grades for therapeutic, rehabilitative, preventive, and diagnostic interventions (Tables 3, 4, and 5), introduced in 2018 by the Center for Healthcare Quality Assessment and Control of the Russian Ministry of Health. The National Guidelines were formulated based on ESC guidelines, taking into account national specifics and features of examination and treatment, as well as the availability of medical care. For this reason, the text of these clinical guidelines simultaneously utilizes two grading systems for the evidence of recommendation provisions: ESC levels of evidence with recommendation classes, and Russian evidence levels and recommendation grades. ESC recommendation classes have been added to allow assessment of the necessity of performing the recommendation provision.

Table 1. Classes of recommendations according to the European Society of Cardiology (ESC) guidelines.

Table 2. Levels of evidence reliability according to the European Society of Cardiology (ESC) guidelines.

Table 3. Scale for assessing the levels of evidence reliability (LER) for diagnostic methods (diagnostic interventions).

Table 4. Scale for assessing the levels of evidence reliability (LER) for methods of prevention, treatment, and rehabilitation (preventive, therapeutic, and rehabilitative interventions).

Table 5. Scale for assessing the levels of recommendation persuasiveness (LRP) for methods of prevention, diagnostics, treatment, and rehabilitation (preventive, diagnostic, therapeutic, and rehabilitative interventions).

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. On the Basics of Protecting the Health of Citizens in the Russian Federation (Federal Law No. 323-FZ of November 21, 2011)

2. Procedure for the Provision of Medical Care to Patients with Cardiovascular Diseases (Order of the Russian Ministry of Health No. 918n of November 15, 2012)

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

To date, it has been proven that to a certain extent, the high frequency of this malformation in the prenatal period is associated with maternal lithium intake. In women who took medications containing lithium carbonate during the first trimesters of pregnancy, the probability of having children with Ebstein's anomaly significantly increases.

After discharge from a specialized center, strictly follow the instructions specified in the discharge summary (epicrisis). Follow-up with a local cardiologist at least once every 6 months, strictly adhering to their instructions and prescriptions. Cardiologist follow-up at a specialized center at least once every 12 months. For any invasive procedures (dental, cosmetic, and other procedures involving or carrying a risk of breaching the skin and mucous membranes), antibiotic prophylaxis must be performed to prevent infective endocarditis. Planned invasive procedures must be coordinated with the patient's local cardiologist. Any changes to dosages and regimens of medications, as well as the prescription of additional or alternative drugs, must be made solely by the attending physician. If side effects from medications occur, discuss them with the attending physician as soon as possible. Excessive physical exertion should be avoided. If the following symptoms occur or rapidly progress, an immediate unscheduled cardiologist consultation is required: fatigue, dyspnea, cyanosis, edema, abdominal distension, arrhythmias, syncope, neurological deficits (loss of vision, hearing, speech, limb numbness, paresis, and paralysis, including transient ones), acute respiratory infections, fever of unknown origin.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.