Congenital Aortic Valve Stenosis: Clinical Guidelines

List of Abbreviations

aPTT – activated partial thromboplastin time

ВПС – congenital heart disease

ACG – angiocardiography (retrograde left heart catheterization; panaortography)

Ao – aorta

AoV – aortic valve

LVOT – left ventricular outflow tract

LV/Ao PSG – left ventricular-aortic peak systolic gradient

BAV – bicuspid aortic valve

IMV – invasive mechanical ventilation

CAG – coronary angiography

CAS – congenital aortic stenosis

CT – computed tomography

LV – left ventricle

MV – mitral valve

MRI – magnetic resonance imaging

PDA – patent ductus arteriosus

EF – ejection fraction

AN – anulus

ECG – electrocardiography (recording of the electrocardiogram; interpretation, description, and analysis of electrocardiographic data)

Echo-CG – echocardiography

Terms and Definitions

Heart catheterization (retrograde left heart catheterization; panaortography) is an invasive procedure performed for therapeutic or diagnostic purposes in cardiovascular diseases by inserting catheters into the heart chamber or the lumen of great vessels.

Left ventricular-aortic peak systolic gradient is a Doppler echocardiographic index reflecting the pressure gradient between cavities, based on measuring blood flow velocity across the aortic valve and characterizing the degree of stenosis.

Computed tomography (CT) is a non-invasive diagnostic imaging method that provides a series of submillimeter cross-sectional axial images of human body organs and structures. It is based on measurement and complex computer processing of X-ray attenuation differences among tissues of varying density to improve differentiation between organs, as well as normal and pathological structures. Various contrast-enhancement techniques are used with iodine-containing radiopaque agents. CT angiography (contrast-enhanced cardiac computed tomography)—an intravenous bolus injection technique using an automated injector at a set flow rate and injection time—is used to visualize the cardiovascular structures. Based on the acquired data, computer post-processing with 3D reconstruction generates a three-dimensional model of the heart and vessels.

Magnetic resonance imaging (MRI) is a non-invasive method for obtaining tomographic medical images without ionizing radiation to study internal organs and tissues, based on the phenomenon of nuclear magnetic resonance and the measurement of the electromagnetic response of atomic nuclei in a strong constant magnetic field in response to excitation by a specific combination of electromagnetic waves; such nuclei are hydrogen atomic nuclei present in the human body as part of water and other substances. MR angiography (contrast-enhanced cardiac magnetic resonance imaging) is a method for imaging the vascular lumen using an MRI scanner. The method makes it possible to evaluate both anatomical and functional features of blood flow. MR angiography is based on the difference in signal between moving protons (blood) and surrounding stationary tissues, which allows obtaining vascular images without using any contrast agents – non-contrast angiography (e.g., phase-contrast MR angiography). In some cases, intravenous bolus contrast enhancement using paramagnetic contrast agents (gadobutrol**) is used.

Turner syndrome is a genetically determined form of primary gonadal agenesis or dysgenesis, classified among chromosomal diseases, accompanied by somatic development abnormalities and short stature. Associated cardiovascular malformations may include: coarctation of the aorta, patent ductus arteriosus, ventricular septal defect, aortic valve stenosis, renal artery stenosis.

Ross procedure is aortic valve replacement with a pulmonary autograft (aortic valve replacement under cardiopulmonary bypass).

Transluminal balloon valvuloplasty of the aortic valve is a percutaneous endovascular intervention aimed at relieving valve stenosis.

Level of evidence reliability – the degree of confidence that the observed effect of a medical intervention is true.

Level of убедительности рекомендаций (Class of Recommendation, CoR) – the degree of certainty in the reliability of the intervention effect and that adherence to recommendations will bring more benefit than harm in a specific clinical situation.

Echocardiography – an ultrasound method aimed at studying 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

Congenital aortic valve stenosis (CAS) — a congenital heart defect characterized by an obstruction to blood flow at the aortic valve level. Thus, the stenotic lesion is limited to the valve anulus and valve cusps.

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

There are various variants of congenital CAS due to the varying degrees of involvement of all three components of the aortic valve in the pathological process: commissures, cusps, and the aortic valve anulus. Congenital CAS can present as a unicuspid, bicuspid, tricuspid valve, or membrane. The most frequent anomaly is a congenital bicuspid aortic valve (BAV). However, in some cases, the absence of hemodynamic disorders in early childhood with BAV leads to an underestimation of the true prevalence of the pathology [1-3]. BAV arises due to deformation of the aortic valve cusps during valvulogenesis; typically, fusion of two cusps is observed, forming one smaller and one larger cusp. Variants can be very diverse: from a nearly tricuspid aortic valve with differently sized cusps to a unicuspid or dysplastic valve. BAV can lead to either aortic stenosis or regurgitation depending on the degree of commissural fusion. In many patients with BAV, the histology of the aortic walls is identical to that in Marfan syndrome: alterations in smooth muscle, extracellular matrix, elastin, and collagen [4].

1.3 Epidemiology of the Disease or Condition

The incidence of congenital CAS is 3-6% of all congenital heart defects, observed in 0.4-2% of people in the general population, and is 4 times more common in males [5,6]. Among all LVOT stenoses, CAS ranks first in frequency—about 70-83% [6-8]. The proportion of surgical interventions for congenital CAS among all congenital heart defects in Russia is 2.44% with an average mortality rate of 3.38% [9].

Congenital CAS (including bicuspid aortic valve without hemodynamic changes) is combined with PDA and aortic coarctation in 20% of cases [10-12]. Currently, a familial predisposition to the formation of aortic valve defects (especially bicuspid) has been proven [13-17]. In particular, from 12 to 38% of patients with Turner syndrome have a bicuspid aortic valve combined with such congenital heart defects as aortic coarctation and partial anomalous pulmonary venous return [18-23]. Some systemic diseases (mucopolysaccharidosis, progeria – "premature aging") can also be accompanied by the development of aortic valve stenosis due to thickening and fibrosis of the aortic cusps [24-30].

From 4 to 18% of children with congenital CAS die suddenly, which accounts for 1/5 of all children dying suddenly [7]. During the first 30 years of life, the risk of sudden death is 0.4% per year.

Mortality in congenital CAS is 23 ± 5% during the 1st year of life. It decreases to 1.2% per year over the next 20 years. Then it increases annually, and at the age of 30 to 60 years, it is 3.0, 3.5, 6.0, and 8.5% for each subsequent 10 years, respectively. Almost 60% of patients survive to 30 years and almost 60% die before 40 years.

Among the complications of the natural history of congenital CAS, infective endocarditis should be noted, which, according to some authors, affects about 0.9% of patients annually [7], and according to others, occurs with a frequency of 1.8-2.7 per 1000 person-years [11].

One of the formidable complications of existing congenital CAS against the background of poorly developed aortic wall media is dilatation, dissection, and even rupture of the ascending aorta. Such a complication develops much more frequently in CAS with a unicommissural aortic valve [31-33]. Patients with Turner syndrome and congenital CAS should also be classified as a high-risk group for developing aortic integrity disruption [34-39].

According to various authors, the development of aortic valve regurgitation can complicate the natural course of congenital CAS in 13-20% of patients older than 1 year [40,41]. Aortic regurgitation naturally developing in CAS rarely reaches a significant degree, but with the development of bacterial endocarditis, it can rapidly progress, leading to cusp destruction and severe heart failure [7].

Aortic valve calcification in congenital CAS rarely develops in patients under 15 years of age. As a rule, an increase in its frequency is noted by 20-30 years [42].

1.4 Features of Coding the Disease or Condition

Congenital anomalies [malformations] of aortic and mitral valves (Q23):

Q23.0 — Congenital stenosis of aortic valve;

Q23.1 — Congenital insufficiency of aortic valve.

1.5 Classification of the disease or condition

Current classifications of CAS are based on the morphological substrate of stenosis/angiographic picture, as well as the severity of hemodynamic disorders.

Classification of congenital aortic valve stenosis according to D. Goor and C. Lillehei (1968):

1. unicuspid valve,

2. bicuspid valve,

3. tricuspid valve (dome-shaped),

4. membrane.

A more detailed anatomical classification was proposed by R. Freedom (1985):

I. Unicuspid aortic valve

A. acommissural,

B. unicommissural,

II. Bicuspid aortic valve

III. Tricuspid aortic valve

A. anulus hypoplasia,

B. dysplasia (often combined with anulus hypoplasia),

C. inequality of cusps with or without equality of commissures.

IV. Quadricuspid aortic valve

V. Sexicuspid aortic valve

The severity of congenital aortic stenosis (CAS), according to the hemodynamic classification, is categorized as mild, moderate, or severe, depending on the valve orifice area and the peak systolic pressure gradient measured by Doppler echocardiography. However, assessing the degree of aortic valve narrowing based on the effective orifice area cannot be applied in children due to the baseline dimensions of the valve annulus differing from those in adult patients. The most acceptable hemodynamic classification for the degree of left ventricular outflow tract (LVOT) stenosis is the gradation based on the values of the maximum LV/Ao systolic pressure gradient (SPG). According to this classification, all patients can be divided into 3 clinical groups [43]:

• moderate aortic stenosis – LV/Ao SPG up to 50 mm Hg;

• severe aortic stenosis – LV/Ao SPG – 50–80 mm Hg;

• critical aortic stenosis – LV/Ao SPG > 80 mm Hg.

According to the guidelines on valvular heart disease developed in 2006 by the American College of Cardiology and the American Association of Cardiologists (ACC/AHA), the severity of aortic stenosis can be assessed by the mean LV/Ao pressure gradient (PG). Accordingly, the following are distinguished:

• mild stenosis (mean LV/Ao pressure gradient less than 25 mm Hg),

• moderate stenosis (mean LV/Ao pressure gradient – 25–40 mm Hg),

• severe stenosis (mean LV/Ao pressure gradient greater than 40 mm Hg).

  Based on severity, there are 3 grades of aortic regurgitation severity: mild, moderate, and severe [129-131].

1.6 Clinical presentation of the disease or condition

A distinctive feature of congenital CAS compared to other congenital heart defects is the potential for a sufficiently long asymptomatic period—children grow and develop age-appropriately, and the defect is detected only by discovering a murmur during routine dispensary examinations. The onset of symptoms indicates severe aortic orifice stenosis. Symptoms reported by patients' parents include increased fatigue and dyspnea (especially during physical activity), sweating, headaches and dizziness, and occasionally nosebleeds. Some patients may present with anginal pain. This patient cohort is at risk for sudden cardiac death.

A different group of patients consists of children with so-called "critical aortic stenosis" (in 70% of cases caused by a bicuspid aortic valve). The term "critical" in relation to congenital CAS denotes the severity of clinical symptoms posing a threat to the newborn's life, which implies the need for urgent intervention on the aortic valve. Clinically, critical aortic stenosis in a newborn manifests as signs of congestive heart failure and low cardiac output syndrome. This clinical situation may be aggravated by concomitant cardiac pathology in the form of mitral valve anomalies, aortic coarctation, and left ventricular fibroelastosis. Critical aortic stenosis is classified as a ductus-dependent defect, where the child's life depends on the degree of patency of the patent ductus arteriosus, which ensures blood flow not only to the descending aorta but also to the ascending aorta and coronary arteries (retrogradely). Early closure of the ductus can lead to a sharp deterioration in the newborn's condition and even death.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of CAS is verified based on the combined data of the disease history, patients' parents' complaints, clinical manifestations of the defect, as well as instrumental examination methods.

2.1 Complaints and Anamnesis

(LetC, Level of Evidence 4)

Comments: the onset of symptoms indicates severe aortic orifice stenosis. Episodes of dizziness and even loss of consciousness are associated with cerebral blood supply deficiency in severe aortic valve stenosis. The occurrence of anginal pain is due to coronary blood flow insufficiency. Sudden death in aortic stenosis most frequently occurs during or shortly after physical exertion and is associated with the onset of arrhythmias and asystole resulting from a severe deficiency in coronary blood flow [1,3-6,40].

2.2 Physical Examination

(Level of Evidence C, Grade of Recommendation 5)

(LetC, Level of Evidence 4)

Comments: patients with severe CAS may exhibit percussion-based enlargement of the cardiac borders to the left due to left ventricular hypertrophy, and palpation reveals a diffuse apex beat. In some cases, a systolic thrill is palpated at the base of the heart, transmitting to the jugular notch and along the carotid arteries.

(LetC, Level of Evidence 4)

Comments: the auscultatory picture of congenital CAS is characterized by: 1) weakening of the second heart sound (S2) or its complete disappearance due to the weakening (disappearance) of the aortic component; 2) the appearance of an early systolic ejection click at the cardiac apex, which disappears in severe CAS; 3) the presence of a harsh systolic murmur with a maximum in the second intercostal space on the right and radiation into the carotid arteries, sometimes along the left sternal border toward the cardiac apex; 4) the presence of an aortic regurgitation diastolic murmur in some patients.

2.3 Laboratory Diagnostics

In patients with CAS, laboratory diagnostics are non-specific.

• All patients with CAS are recommended to undergo a general (clinical) urinalysis and a general (clinical) blood test including total blood hemoglobin and hematocrit evaluation, red blood cell, leukocyte, and platelet counts, and erythrocyte sedimentation rate measurement as part of the initial examination, upon admission to the hospital (including for surgical treatment), during follow-up at least once a year, and in the postoperative period if necessary [1,73,74,149].

(Level of Evidence C, Grade of Recommendation 5)

Comments: performing a general (clinical) blood test for all patients with aortic valve stenosis during dispensary observation and prior to surgical treatment is important from the standpoint of detecting anemia and its timely correction. In patients with a mean corpuscular volume (MCV) of less than 80 fL, it is advisable to test serum iron, serum transferrin, serum ferritin, and total iron-binding capacity for the timely correction of iron deficiency states. In patients with an MCV greater than 100 fL, it is advisable to determine blood vitamin B12 (cyanocobalamin) and serum folic acid levels for the timely correction of B12- or folate-deficiency states. The aforementioned conditions can negatively affect the clinical and functional status and the course of the patient's disease, as well as the outcomes of surgical treatment [132,133,149].

(Level of Evidence C, Grade of Recommendation 5)

(CQR C, LCE 4)

• All newborns with CAS in critical condition are recommended to undergo testing of acid-base status and blood gases (pH, BE, pCO₂, pO₂, Lac – capillary/arterial/venous blood sample analysis) to assess the severity of metabolic disorders [49,86,132-133].

(LetC, Level of Evidence 4)

(Level of Evidence C, Grade of Recommendation 5)

Comments: if there are laboratory signs of hemostatic disorders, surgical intervention should reasonably be postponed until the causes of these disorders are identified and corrected.

• In all ASVC patients receiving thromboprophylaxis with unfractionated or low-molecular-weight heparin (antithrombotic agents; heparin group) after surgical treatment, laboratory monitoring of drug therapy (direct anticoagulants) is recommended [79,142,144,145].

(Translational Research Level B, Evidence Level 3)

Comments: when using unfractionated sodium heparin** (heparin group drugs), it is necessary to determine aPTT (optimal range in children is 60–85 sec) and blood heparin level (anti-Xa activity) (optimal range is 0.35–0.7). Until the optimal range is reached, these parameters are determined 4 hours after each infusion rate adjustment. Once the optimal range is achieved, monitoring is performed once every 12 hours (see Appendix A3). When using low-molecular-weight heparin preparations (heparin group), it is necessary to measure blood heparin level (anti-Xa activity) (optimal range is 0.5–1.0). Until the optimal range is reached, it is determined 3–4 hours after each injection; once the optimal range is achieved and the patient's clinical and laboratory status is stable, monitoring is not required [79,142,144,145].

(CQR C, LCE 5)

(Level of Evidence C, Grade of Recommendation 5)

2.4 Instrumental Diagnostics

(LetC, Level of Evidence 4)

Comments: in mild to moderately hemodynamically significant ASVC, the electrocardiogram may be unchanged. The presence of a hemodynamically significant aortic valve narrowing manifests as signs of left heart overload and hypertrophy. Additionally, ECG examination may record episodes of supraventricular arrhythmias.

(Level of Evidence C, Grade of Recommendation 5)

Comments: blood pressure measurement is necessary to determine the threshold of allowable physical exertion (in the absence of disease symptoms).

(Level of Evidence C, Grade of Recommendation 5)

Comments: the administration of antihypertensive drugs may lead to a decrease in diastolic pressure and, consequently, a reduction in coronary perfusion.

(LetC, Level of Evidence 4)

Comments: radiographic examination makes it possible to assess the cardiac configuration, the size and condition of the ascending aorta, and the pulmonary pattern. In hemodynamically mild or moderate congenital ASVC, the pulmonary pattern may be unchanged. Its enhancement of the “venous” type is a sign of marked aortic valve stenosis. Heart size in the absence of concomitant cardiac pathology (mitral valve anomaly, fibroelastosis, septal defects) may remain normal for a long time. With left ventricular enlargement, the cardiac silhouette in the direct projection acquires a characteristic configuration: there is a sharply pronounced cardiac waist, and a rounded, elevated apex forms an acute angle with the diaphragm. In oblique projections, a hypertrophied left ventricle is visualized. Enlargement of the left atrial silhouette indicates marked aortic valve stenosis. A characteristic radiological sign of congenital ASVC is post-stenotic dilatation of the ascending aorta. Signs of aortic valve calcification in early childhood are usually absent and may appear in adult patients with congenital ASVC [1,4,5,7,10,42].

(RR_C, LOC 4)

Comments: this instrumental diagnostic method is one of the primary modalities for identifying the anatomical substrate of the defect and determining the severity of hemodynamic impairment. The main views for assessing obstruction at the aortic valve (AoV) level are the parasternal long-axis view of the LV and short-axis view at the aortic valve level, the apical 5-chamber view, as well as the subcostal long-axis view of the LVOT and suprasternal long-axis view of the ascending aorta. Echocardiography is used to determine the morphology and severity of obstruction, the dimensions of the left ventricular outflow tract and AoV annulus, the ascending aorta, LV function, and associated congenital heart defects. There are numerous criteria and guidelines for assessing the severity of AoV stenosis, but they are most often applicable to adult patients. For instance, if the effective aortic valve area, which is an important component in assessing the degree of narrowing, is less than 1 cm², this indicates critical stenosis in an adult, whereas in a child under 3–5 years of age, it is normal. When determining the severity of LVOT stenosis in asymptomatic children, the systolic pressure gradient measured by echocardiography is used as a reference. The systolic pressure gradient across the LVOT may be underestimated echocardiographically in the presence of severe mitral regurgitation, volumetric hypoplasia and reduced LV myocardial contractility, tubular or multilevel LVOT involvement, or combined pathology (VSD).

Left ventricular myocardial hypertrophy is an inherent companion of obstructive LVOT diseases. Fibroelastosis is determined based on increased endocardial echogenicity. However, detecting the diffuse form of fibroelastosis using two-dimensional echocardiography is difficult. To assess left ventricular diastolic function, tissue Doppler imaging and speckle-tracking techniques must be used, which also make it possible to monitor the recovery of left ventricular functional parameters after surgical treatment [1,4,5,7,10,42,43,45,46,85].

• When assessing the severity of ASVC, it is not recommended to rely solely on the maximum LV/aorta pressure gradient value. It is recommended to also take into account the mean gradient, aortic valve area (indexed to the patient's body surface area), and left ventricular contractility [1,4,7,10,43,45].

(GPR C, EL 4)

Comments: determining the severity of ASVC based solely on the LV/aorta pressure gradient value may lead to an overestimation of stenosis severity.

(RR_C, LOC 5)

(Level of Evidence C, Grade of Recommendation 5)

Comments: this procedure is necessary to determine the level of left ventricular outflow tract (LVOT) obstruction and to assess the hemodynamic parameters of the stenosis.

Congenital CAS is characterized by: 1) thickened aortic valve leaflets (dome-shaped systolic prolapse in bicuspid valve); 2) ascending aorta dilation; 3) visualization of the contrast jet entering the ascending aorta through a centrally or eccentrically located valve orifice. Inclusion of left ventriculography in the angiocardiographic protocol allows assessment of the left ventricular cavity dimensions and the degree of hypertrophy, as well as detection of the presence/absence of intraventricular obstruction.

(Level of Evidence C, Grade of Recommendation 5)

Comments: inclusion of panaortography with coronary angiography in the angiocardiographic protocol makes it possible to assess the condition of the ascending aorta, aortic arch, and isthmus, as well as the coronary anatomy. Based on the results obtained, the surgical treatment strategy and the scope of the required intervention are subsequently determined.

• It is recommended that patients with CAS undergo contrast-enhanced cardiac computed tomography as part of the preoperative workup (or if echocardiography data are insufficient) [1,4,47,48,81].

(LetC, Level of Evidence 4)

Comments: contrast-enhanced cardiac computed tomography is necessary to clarify the morphology of the lesion, optimize surgical technique, and create 3D models for the upcoming surgery. The primary advantage of tomographic techniques in children lies in their superior spatial resolution of extracardiac structures [47,48].

• It is recommended that patients with CAS undergo contrast-enhanced cardiac magnetic resonance imaging (MRI) and/or cardiovascular magnetic resonance imaging if echocardiography and/or contrast-enhanced cardiac CT data are insufficient, or in complex combined congenital heart defects to determine the strategy and timing of surgical intervention, or during routine postoperative follow-up (if echocardiography and/or contrast-enhanced cardiac CT data are insufficient) [48].

(Level of Evidence C, Grade of Recommendation 5)

Comments: Cardiac MRI is the most accurate method for assessing cardiac function and visualizing myocardial fibrosis. Cardiac MRI is currently considered the "gold standard" imaging modality for assessing cardiac chamber function. MRI is a unique technique that allows non-invasive assessment of focal and diffuse myocardial fibrosis using contrast enhancement.

During follow-up management, the timing, frequency, and necessity of MRI are determined on an individual basis depending on annual echocardiography findings to obtain volumetric heart data, determine ventricular function and regurgitation volume (usually no more frequently than once every 3-5 years).

2.5 Other Procedures

(Level of Evidence C, Grade of Recommendation 5)

(Level of Evidence C, Grade of Recommendation 5)

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

3.1 Conservative Treatment

• In neonates with critical congenital CAS and heart failure in critical condition, an infusion of #alprostadil** is recommended (starting dose calculated as 0.003-0.03 mcg/kg/min) [82,151-152].

(Level of Evidence C, Grade of Recommendation 4)

Comments: critical congenital heart defects are defined as congenital cardiac anomalies requiring invasive intervention or leading to death within the first 30 days of life [49]. A critical condition in a neonate (cardiogenic shock, acidosis, seizures, cardiac arrest, laboratory signs of renal/hepatic failure) develops in 15.5% of patients with congenital heart disease and is caused by left-sided obstructive lesions in 90.9% of cases [49]. Approximately 40% of infants with left-sided heart defects missed at birth develop cardiogenic shock [50].

In obstructive left heart lesions and ductus-dependent systemic circulation, #alprostadil** is the first-line drug. In critical CAS, the earliest possible administration of #alprostadil** is optimal to maintain patent ductus arteriosus patency, which significantly increases the child's chances of survival and stabilizes their condition prior to an appropriate intervention—surgery or transcatheter balloon dilation of the stenosis [51-54].

• In neonates with critical congenital CAS and heart failure in critical condition, in addition to #alprostadil** infusion, it is recommended to treat with cardiotonic agents (excluding cardiac glycosides) and diuretics [49-54,82,83,91-113].

(Level of Evidence C, Grade of Recommendation 4)

Comments: #levosimendan**, which has positive inotropic and vasodilating effects, is used to treat acute heart failure in the setting of critical CAS, leading to increased myocardial contractility and a decrease in both preload and afterload (in case of hypotension, combined with inotropic support with epinephrine**). #Levosimendan** is dosed individually, usually at 0.05-0.2 mcg/kg/min. [92-93,98-102,104-106,110].

• In neonates with critical congenital CAS and heart failure in critical condition, elective tracheal intubation and controlled mechanical ventilation are recommended [49-54,119,120].

(Level of Evidence C, Grade of Recommendation 5)

• In neonates with critical congenital CAS and heart failure in critical condition, it is recommended to correct acidosis (taking into account its pathogenesis—metabolic or respiratory) to stabilize the infant's condition [49-54].

(LetC, Level of Evidence 4)

Comments: acidosis is an acid-base balance disorder characterized by an excess of acids relative to bases. Respiratory and metabolic types of acidosis are distinguished.

Respiratory acidosis is caused by an increase in blood carbon dioxide partial pressure (airway obstruction, pulmonary malformations, aspiration, atelectasis, respiratory distress syndrome, pulmonary edema, apnea, bronchopulmonary dysplasia) and depends on the degree of hypercapnia. It is characterized by the following arterial blood acid-base parameters: pH < 7.35, BE above -5 mEq/L, pCO₂ > 45 mmHg.

Metabolic acidosis is caused by the entry of excess acidic products into the blood during tissue hypoxia (ischemia), or rapid loss of buffer bases via the gastrointestinal tract and kidneys. It is characterized by the following arterial blood acid-base parameters: pH < 7.35, BE below -5 mEq/L (bicarbonate concentration < 17 mmol/L); pCO₂ < 46 mmHg.

(Level of Evidence C, Grade of Recommendation 5)

Comments: currently, there is no universally accepted medical therapy that alters the disease course or halts the progressive pathology of bicuspid aortic valve. Beta-blockers may be prescribed to delay or prevent aortic root dilation or disease progression, but improvement can be expected only in patients with Marfan syndrome or acute aortic dissection. Judicious afterload reduction in hypertensive patients, aimed at lowering systolic pressure and wall stress on the left ventricle, may slow the development of dilation and left ventricular dysfunction, but measures must be taken against the risks associated with impaired diastolic coronary perfusion. However, it is not at all obvious that afterload reduction will attenuate aortic regurgitation or reduce the need for aortic valve replacement.

• In the early postoperative period following surgical treatment of CAS in patients at high risk for thrombosis, it is recommended to administer thromboprophylaxis with low-molecular-weight or unfractionated heparin (antithrombotic agents; heparin group) [79,142,144-145].

(Translational Research Level B, Evidence Level 3)

Comments: The high-risk group for thrombosis includes patients with a history of thrombotic episodes, thrombophilia, infectious complications, heart failure, and multiorgan failure [142].

Thromboprophylaxis with heparin sodium** should be initiated with a bolus of 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, and 20 IU/kg/h in children over 1 year of age (contraindication: newborns, especially premature infants or those with low birth weight, due to the presence of benzyl alcohol in the product). Dose adjustment is made based on laboratory test results (see section 2.3, Appendix A3) [144].

Thromboprophylaxis with low-molecular-weight heparin products (heparin group) is administered as follows: #enoxaparin sodium** in children under 2 months of age – 0.75 mg/kg, in children over 2 months of age – 0.5 mg/kg twice daily; #dalteparin sodium – 150 IU/kg in children aged 1 month to 2 years, 125 IU/kg in children aged 2 to 8 years, and 100 IU/kg in children over 8 years of age, twice daily. #Fondaparinux sodium may be used in children over 1 year of age at a dose of 0.1 mg/kg twice daily. Dose adjustment is based on laboratory test results (see section 2.3) [79,142,144].

• In patients with congenital aortic valve stenosis (CAVS) following surgical correction with aortic valve replacement, lifelong thromboprophylaxis is recommended [79,87,88,142,144-145].

(RRR B, LOR 3)

Comments: in the early postoperative period, thromboprophylaxis should be carried out using unfractionated or low-molecular-weight heparin preparations (antithrombotic agents; heparin group). Subsequently, the choice of thromboprophylaxis method depends on the type of valve prosthesis. Following the implantation of a mechanical prosthesis (mechanical bileaflet aortic valve prosthesis***), the use of vitamin K antagonists is indicated (warfarin** is prescribed in children older than 3 years with an initial dose of 0.2 mg/kg per day, followed by dose adjustment under INR monitoring (first monitoring 3 days after starting warfarin**, then daily until stable target values are achieved for at least one week, after which it is checked 1–2 times a week)). The optimal INR range is 2.0–3.0 [79]. Following the implantation of a biological prosthesis (biological cardiac aortic valve prosthesis***), in the absence of risk factors for thrombosis, vitamin K antagonists are indicated for 3 months (optimal INR 2.0–3.0), and thereafter – #acetylsalicylic acid** at a dose of 1–5 mg/kg [79,144]. In high-risk thrombosis patients following the implantation of a biological prosthesis (biological cardiac aortic valve prosthesis***), long-term administration of vitamin K antagonists is indicated (optimal INR 2.0–3.0) [79].

3.2 Surgical Treatment

• In patients with severe forms of CAVS and/or combined with aortic regurgitation and marked left ventricular (LV) hypertrophy, open-heart surgery is recommended: aortic valvuloplasty under cardiopulmonary bypass or aortic valve replacement under cardiopulmonary bypass (mechanical bileaflet aortic valve prosthesis***, biological cardiac aortic valve prosthesis***, or pulmonary autograft – i.e., the Ross procedure) [1,55-58,60-64].

(LetC, Level of Evidence 4)

• In patients with severe forms of CAVS and a narrow aortic valve annulus (AVA), aortic valve replacement under cardiopulmonary bypass (mechanical bileaflet aortic valve prosthesis*** or biological cardiac aortic valve prosthesis***) utilizing annular enlargement techniques (Nicks, Manouguian procedures) is recommended [59,65-67].

(LetC, Level of Evidence 4)

Comments: open aortic valve valvulotomy, being a relatively technically straightforward valvular intervention under cardiopulmonary bypass, demonstrates quite favorable results [55,56].

Aortic valve replacement with a mechanical prosthesis (mechanical bileaflet aortic valve prosthesis***) is an effective method for treating severe aortic valve stenosis in patients when reconstructive surgery is not feasible. Research findings confirm favorable outcomes and low operative mortality [57,58]. A factor limiting prosthesis implantation in the aortic position in small children is the minimum available implantable valve size (16 mm).

The use of various aortic valve annular enlargement techniques (Nicks, Manouguian procedures) expands the applicability of this surgery and allows for the implantation of larger prostheses by increasing the annulus by 2–6 mm [59,65-68]. However, the invasiveness and extent of these interventions are limiting factors for their widespread clinical use in young children. In older children, such procedures can be performed with low surgical risk and favorable hemodynamic outcomes.

Considering the above, the most promising approach in early childhood is aortic valve replacement using a pulmonary autograft – the Ross procedure. When using this procedure: 1) there is a potential for growth of the "neo" aortic root, 2) the need for anticoagulants (antithrombotic agents) is eliminated, 3) the hemodynamic characteristics of the graft are ideal, and 4) there is no immunological reaction [58-61].

• In patients with severe forms of CAVS and impaired LV function (LV ejection fraction less than 50%), aortic valve replacement under cardiopulmonary bypass (mechanical bileaflet aortic valve prosthesis*** or biological cardiac aortic valve prosthesis***) is recommended [57-67].

(LetC, Level of Evidence 4)

• In children with severe forms of aortic regurgitation, aortic valve replacement (mechanical bileaflet aortic valve prosthesis***, biological cardiac aortic valve prosthesis***, or pulmonary autograft) is recommended if the patient is symptomatic [1,4,57,58].

(LetC, Level of Evidence 4)

• In children with severe forms of aortic regurgitation, aortic valve replacement (mechanical bileaflet aortic valve prosthesis***, biological cardiac aortic valve prosthesis***, or pulmonary autograft) is recommended if left ventricular dysfunction is persistent and progressive LV dilation is observed [1,57,58].

(LetC, Level of Evidence 4)

(LetC, Level of Evidence 4)

(Level of Evidence C, Grade of Recommendation 5)

(LetC, Level of Evidence 4)

(Level of Evidence C, Grade of Recommendation 5)

(Level of Evidence C, Grade of Recommendation 5)

(Level of Evidence C, Grade of Recommendation 5)

(Level of Evidence C, Grade of Recommendation 4)

Comments: contraindications to the Ross procedure include: 1) pulmonary valve disease; 2) presence of genetic syndromes associated with elastin and collagen deficiency (Marfan syndrome, Ehlers-Danlos syndrome); 3) systemic collagen vascular disease with immune complex formation (systemic lupus erythematosus, ankylosing spondylitis, etc.); 4) mitral valve disease requiring replacement (relative contraindication); 5) significant dilation of the aortic root compared to the pulmonary valve annulus [60-63].

3.3 Endovascular interventions

(RRR B, LOR 3)

Comments: transluminal balloon valvuloplasty of the aortic valve is a highly effective and safe surgical treatment method for AS. In some cases, it can serve as a life-saving procedure that allows stabilizing a patient in critical condition (primarily newborns and infants in the first year of life). As a rule, balloon dilation leads to a significant decrease in the peak systolic pressure gradient between the left ventricle and the aorta, and improves left ventricle function. In recent years, with the widespread clinical use of this method, mortality rates have been reduced to below 10% [69-71]. At the same time, higher mortality rates were noted in the group of patients with ductus-dependent circulation (up to 38%, compared to 5% in the group with normal circulation) [72].

(Level of Evidence C, Grade of Recommendation 4)

(Level of Evidence C, Grade of Recommendation 4)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

(Level of Evidence C, Grade of Recommendation 4)

Comment. Due to the introduction of advanced surgical and interventional methods, including perioperative intensive care, the survival rate of children with congenital heart disease has notably improved over recent decades, leading to an increase in the number of patients surviving into adulthood [154]. As patients with congenital heart disease grow older, their heart health may be additionally affected by acquired cardiovascular risk factors (e.g., arterial hypertension, obesity, diabetes) commonly seen in the general population, which increases the risk of metabolic diseases, stroke, and coronary artery disease [155,156]. It is known that the development of atherosclerotic and metabolic diseases manifesting in adulthood usually begins as early as early childhood. Childhood obesity and a sedentary lifestyle are known to be the major contributing factors [157]. This highlights the need for primary prevention; therefore, lifestyle interventions are necessary to increase the physical activity (PA) of children with congenital heart disease, as physical activity is indispensable for the physical, emotional, and psychosocial development of children [158-162].

• Children with mild AS are recommended daily physical activity defined by the WHO at > 60 minutes, without restrictions, as well as participation in all types of recreational/competitive sports with mandatory assessment of AS severity at least once a year [163-165].

(Level of Evidence C, Grade of Recommendation 5)

• Children with moderate AS are recommended daily moderate- and low-intensity physical activity, as well as participation in low- and moderate-intensity dynamic and static sports, excluding competitive sports, provided that stress testing demonstrates satisfactory exercise tolerance [163,165].

(Level of Evidence C, Grade of Recommendation 5)

• Children with severe AS are recommended to engage only in low-intensity dynamic and static sports and physical activity depending on symptoms and exercise test results, excluding competitive sports [165].

(Level of Evidence C, Grade of Recommendation 5)

(Level of Evidence C, Grade of Recommendation 5)

Comments: the following conditions may occur after AS correction:

- Residual hemodynamically significant residual left ventricular/aortic systolic pressure gradient (in valve-sparing procedures);

- Development and/or progression of aortic regurgitation (in valve-sparing procedures) [55,56];

- Development of prosthesis-related complications (endocarditis, thrombosis, systemic embolisms, paraprosthetic regurgitation or occlusion associated with pannus formation) – upon implantation of mechanical prostheses (bileaflet mechanical aortic valve prosthesis***) [57-59];

- Neo-aortic valve dilation with the development of hemodynamically significant regurgitation after the Ross procedure [1,5,58,62,64];

- Stenosis/occlusion of the neo-pulmonary trunk after the Ross procedure [1,58,62,64];

- Development of myocardial ischemia caused by occlusion/kinking of reimplanted coronary arteries [1,58,62,64];

- Development of cardiac arrhythmias, in some cases leading to sudden cardiac death [1,4,77].

(Level of Evidence C, Grade of Recommendation 5)

• Referral for sanatorium-resort treatment is recommended for children with moderate AS without hemodynamic disturbances and without prognostically significant rhythm and conduction disorders [76,153,166].

(Level of Evidence C, Grade of Recommendation 5)

Comment: climatic and balneological resorts provide comprehensive sanatorium-resort treatment including: helio-therapy (A20.30.021), climate therapy (A20.30.012), dry-air baths (A20.30.022), local (2-4 chamber) therapeutic baths (A20.30.009).

5. Prevention and Dispensary Observation

(Level of Evidence C, Grade of Recommendation 5)

(LetC, Level of Evidence 4)

(Level of Evidence C, Grade of Recommendation 5)

(Level of Evidence C, Grade of Recommendation 5)

(Level of Evidence C, Grade of Recommendation 5)

Comments: during a routine echocardiographic examination in operated patients, attention should be paid to aortic valve function and the condition of the right ventricle-to-pulmonary artery conduit (after the Ross operation), the function of the implanted prosthesis (mobility of occluders, presence of thrombotic deposits on them, peak and mean systolic pressure gradients across the prosthesis, presence of paraprosthetic fistulas) – in aortic valve replacement (including aortic valve replacement with annular enlargement); morphofunctional parameters of the ventricles; presence of a shunt across the interventricular septum when aortoventriculoplasty is performed; presence of aortic regurgitation (after interventional procedure and/or open aortic valvuloplasty); and the magnitude of the residual systolic pressure gradient between the left ventricle and the aorta. Patients with prosthetic valves implanted in the aortic position are undoubtedly candidates for repeat valve replacement surgery due to the patient "outgrowing" the prosthesis size.

Following the Ross procedure, patients are subsequently candidates for reoperations to replace the conduit implanted between the right ventricle and the pulmonary artery.

• Patients with a mechanical prosthesis implanted in the aortic position (mechanical bileaflet aortic valve prosthesis***) are recommended oral antithrombotic therapy with vitamin K antagonists (#warfarin** at an average dose of 0.09 mg/kg/day for adolescents and 0.33 mg/kg/day for infants) with subsequent dose titration under continuous monitoring of blood coagulation parameters: INR (first check 3 days after starting #warfarin**, then daily until stable target values are achieved for at least one week, after which 1–2 times a week) [1,5,7,43,57,87-90,144].

(Level of Evidence C, Grade of Recommendation 5)

Comments:When administering oral antithrombotic agents, the target INR should be 2.0 to 3.0 for low-risk patients and 2.5 to 3.5 for high-risk patients. The high-risk group includes patients with concomitant 1) atrial fibrillation, 2) decreased left ventricular systolic function, 3) a history of thromboembolic events, and 4) confirmed hypercoagulability. The patient's drug dosage must be adjusted based on body weight (as the child grows) and concurrent conditions (fever, dehydration). It is necessary to follow a diet restricting foods with high vitamin K content (mayonnaise, soybean oil, spinach, various cabbages [Chinese, Sarepta mustard cabbage, collard greens, kale, as well as sauerkraut], Brussels sprouts, broccoli, dandelion leaves, various salad greens, parsley, asparagus, bulb onions [scallion and shallot], beets, mustard, turnip, chicory, as well as grapefruit and grapefruit juice, cranberry juice, green tea, mango, fish oil, and avocado in large quantities). Medication intake affecting blood levels of #warfarin** must be monitored (the list of drugs that enhance or diminish the effect of #warfarin** is quite extensive, comprising over 182 drugs). Attention should be paid to the "Drug Interactions" section in the medication package inserts. If #warfarin** is listed there, it is mandatory to check the INR exactly 5 days after starting the drug in order to adjust the #warfarin** dose if necessary. If various elective surgical procedures (abdominal, cavitary, orthopedic, neurosurgical) are required, vitamin K antagonists must be discontinued for at least 5 days, and the patient should be switched to anticoagulant therapy with low-molecular-weight heparins (heparin group) at a therapeutic dose (administered twice daily) or, if heparin group drugs are unavailable, with #heparin sodium** at 200 IU/kg/day administered parenterally. The efficacy and safety of ongoing anticoagulant therapy with #heparin sodium** should be monitored via aPTT levels, aiming for a 1.5- to 2-fold prolongation. If emergency surgery is required, vitamin K (menadione sodium bisulfite**) can be administered subcutaneously at a dose of 0.5–2 mg, which reduces the INR to less than 2.0 within 12–24 hours. During preparation, anticoagulant therapy with low-molecular-weight heparins (heparin group) or #heparin sodium** must be administered. The duration of the interruption in vitamin K antagonist therapy is determined by the specific clinical situation. In the absence of postoperative bleeding signs (following the performed procedure), vitamin K antagonists may be prescribed and #heparin sodium** discontinued after 6–12 hours once the INR exceeds 2.0 [87-90, 144].

• Patients with congenital aortic stenosis after the Ross procedure are recommended to receive oral antithrombotic agents for 6 months, followed by a transition to intermittent courses and subsequent discontinuation under coagulogram monitoring [79,88,90].

(Level of Evidence C, Grade of Recommendation 5)

Comments: when administering antithrombotic agents, it is necessary to target INR values within the range of 2–3. As subsequent antiplatelet therapy, #acetylsalicylic acid** (off-level in children under 15 years of age) at a dose of 3–5 mg/kg/day (maximum 325 mg/day) or #clopidogrel** (off-label in children under 18 years of age) at a dose of 0.2–0.5 mg/kg/day is used [78,79,88,90].

• Patients with congenital aortic stenosis after surgical treatment are recommended to use quality of life questionnaires for patients and parents to develop individual psychological rehabilitation regimens [76].

(Level of Evidence C, Grade of Recommendation 5)

• When monitoring patients after surgical or transcatheter intervention, recommend infective endocarditis prophylaxis for 6 months [80].

(Level of Evidence C, Grade of Recommendation 5)

Comments: for any type of congenital heart defect in the correction of which synthetic materials/prostheses*** (mechanical bileaflet aortic valve prosthesis***; biological cardiac aortic valve prosthesis***; synthetic cardiovascular patch***) were used, if indicated, bacterial endocarditis prophylaxis is carried out for 6 months after surgery or lifelong if residual shunts and valve regurgitation persist. Endocarditis prophylaxis is performed during dental procedures accompanied by damage to the oral mucosa (tooth extraction, manipulation in the periapical zone of the tooth, etc.), tonsillectomy and/or adenoidectomy, cystoscopy, bladder catheterization (in the presence of infection), bronchoscopy using a rigid bronchoscope, as well as esophageal varices sclerotherapy [114-117]. The American Medical Association (1997 and 2007) recommends the following antibiotic prophylaxis regimens in children with congenital heart defects. Prophylaxis of infective endocarditis (during surgical procedures in the oral cavity and upper respiratory tract) consists of oral administration of amoxicillin** at a dose of 50 mg/kg (maximum 2.0 g) 60 minutes before the procedure. If oral administration is not possible, ampicillin** is administered intramuscularly or intravenously at the same dose 30 minutes before the procedure. In case of allergy to benzylpenicillin** or ampicillin**, #clindamycin** (off-label in children under 12 years of age) at a dose of 20 mg/kg (maximum 600 mg) orally 1 hour before the procedure, or #cephalexin** (off-label in children under 3 years of age) at a dose of 50 mg/kg (maximum 2.0 g) orally 1 hour before the procedure, or #azithromycin** capsules (off-label in children under 12 years of age) at a dose of 15 mg/kg (maximum 500 mg), or #clarithromycin** at a dose of 15 mg/kg (maximum 500 mg) 1 hour before the procedure is used [114,115,117,118,167-168].

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

1) presence of symptoms of heart failure;

2) planned surgical treatment for congenital aortic stenosis;

3) previous interventions on the aortic valve aimed at relieving stenosis;

4) correction of blood coagulation parameters if surgical manipulations/interventions are necessary in patients with mechanical heart valve prostheses implanted in the aortic position.

Indications for emergency hospitalization:

1) newborns in critical condition against the background of severe congenital aortic stenosis;

2) deterioration of the patient's functional status due to progressive symptoms of heart failure, cardiac arrhythmias;

3) development of bleeding in patients with implanted prostheses;

4) acute prosthesis dysfunction/thrombosis;

5) development of acute coronary insufficiency (after the Ross procedure);

6) development of left ventricular dysfunction;

7) infective endocarditis.

Indications for patient discharge from a medical organization:

1) absence of significant left ventricular/aortic pressure gradient across the native valve or implanted prosthetic valve;

2) absence/compensation of heart failure symptoms;

3) absence of hemodynamically significant cardiac arrhythmias;

4) established anticoagulant therapy (if prosthetic valves are implanted).

7. Additional Information

Operated or unoperated patients with congenital aortic stenosis and aortic regurgitation are at risk for aortic valve surgery (primary or repeated), since these two pathological conditions of the aortic valve are progressive diseases.

Patients with prostheses implanted in the aortic position are at risk of prosthesis-related complications in the long-term postoperative period. Prosthesis-related complications include: endocarditis, thrombosis, paravalvular regurgitation, or occlusion associated with pannus formation. Furthermore, this cohort of patients operated on in early childhood is undoubtedly a candidate for repeat valve replacement surgery due to outgrowing the prosthesis size.

Following the Ross procedure, patients are at risk for autograft dilation with progressive neo-aortic regurgitation, occlusion and/or regurgitation of the neo-pulmonary trunk, and occasionally myocardial ischemia and/or infarction associated with occlusion or kinking of the proximal coronary arteries.

In patients with congenital aortic stenosis with a significant left ventricular/aortic pressure gradient, the development of ventricular arrhythmias in adulthood and the possibility of sudden death may occur. Therefore, patients must undergo a thorough ECG examination to detect arrhythmias at early stages.

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary health care provided to children with congenital valvular aortic stenosis (ICD-10 codes: Q23.0)

Quality assessment criteria for specialized medical care provided to children with congenital valvular aortic stenosis (ICD-10 codes: Q23.0)

References

Appendix A1. Working Group Composition

1. Avramenko AA, (Samara);

2. Apkhanova TV, MD, "National Association of Experts in Sanatorium-Resort Treatment", (Moscow);

3. Arnautova IV, MD, "Association of Cardiovascular Surgeons of Russia", (Moscow);

4. Bogdanov VN, (Chelyabinsk);

5. Bokeria LA, Academician of the RAS, "Association of Cardiovascular Surgeons of Russia", (Moscow);

6. Boriskov MV, MD, (Krasnodar);

7. Borisova NA, "Russian Scientific Society of Specialists in X-ray Endovascular Diagnosis and Treatment", (Saint Petersburg);

8. Gorbatikov KV, MD, (Tyumen);

9. Gorbatykh YuN, MD, (Novosibirsk);

10. Kalashnikov S.V., Candidate of Medical Sciences, (Moscow);

11. Kim A.I., Doctor of Medical Sciences, "Association of Cardiovascular Surgeons of Russia", (Moscow);

12. Kovalyov I.A., Doctor of Medical Sciences, "Association of Pediatric Cardiologists of Russia", (Moscow);

13. Konchugova T.V., Doctor of Medical Sciences, "National Association of Experts in Spa Treatment", (Moscow);

14. Krivoshchyokov E.V., Doctor of Medical Sciences, (Tomsk);

15. Kupryashov A.A., Doctor of Medical Sciences, (Moscow);

16. Levchenko E.G., Doctor of Medical Sciences, (Moscow);

17. Movsesyan R.R., Doctor of Medical Sciences, "Association of Cardiovascular Surgeons of Russia", (Saint Petersburg);

18. Plotnikov M.V., Candidate of Medical Sciences, (Astrakhan);

19. Pursanov M.G., Doctor of Medical Sciences, (Moscow);

20. Sinelnikov Yu.S., Doctor of Medical Sciences, (Perm);

21. Trunina I.I., Doctor of Medical Sciences, "Association of Pediatric Cardiologists of Russia", (Moscow);

22. Chernogrivov A.E., Doctor of Medical Sciences, "Association of Cardiovascular Surgeons of Russia", (Moscow);

23. Shatalov K.V., Doctor of Medical Sciences, "Association of Cardiovascular Surgeons of Russia", (Moscow);

24. Yurova O.V., Doctor of Medical Sciences, "National Association of Experts in Spa Treatment", Moscow;

25. Baryshnikova I.Yu., Candidate of Medical Sciences, (Moscow), All-Russian Public Organization for the Promotion of the Development of Diagnostic Radiology and Therapy "Russian Society of Roentgenologists and Radiologists";

26. Sinitsyn V.E., Doctor of Medical Sciences, Professor, (Moscow), All-Russian Public Organization for the Promotion of the Development of Diagnostic Radiology and Therapy "Russian Society of Roentgenologists and Radiologists".

There is no conflict of interest.

All members of the Working Group have confirmed that they have no financial support or conflicts of interest to disclose.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatric cardiologist;

2. Cardiologist;

3. Cardiovascular surgeon;

4. Ultrasound diagnostics physician;

5. Pediatrician;

6. X-ray endovascular diagnostics and treatment physician;

7. Radiologist;

8. Functional diagnostics physician;

9. Neonatologist.

In the course of developing the Clinical Guidelines, a new system of scales of the Evidence Quality Level (UDD) and Evidence Strength Level (UUR) for therapeutic, rehabilitation, preventive and diagnostic interventions was used (Tables 1, 2 and 3), introduced in 2018 by the Federal State Budgetary Institution "Center for Expert Evaluation of Medical Care Quality" (TsEKKMP) of the Russian Ministry of Health.

Table 1. Scale for assessing levels of reliability of evidence (LRE) for diagnostic methods (diagnostic interventions).

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation 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 Protection of Public Health in the Russian Federation (Federal Law No. 323-FZ of November 21, 2011);

2. Procedure for providing medical care to patients with cardiovascular diseases (Order of the Russian Ministry of Health No. 918n of November 15, 2012);

3. Order of the Russian Ministry of Health No. 560n dated June 9, 2020, "On Approval of the Rules for Conducting X-ray Examinations";

4. Order of the Russian Ministry of Health No. 557n dated June 8, 2020, "On Approval of the Rules for Conducting Ultrasound Examinations".

Monitoring and dose adjustment of unfractionated heparin (heparin sodium**) [142,144].

Transthoracic echocardiography performance technique

Comprehensive echocardiography (prior to evaluation of the aortic valve) to rule out associated congenital heart disease, assess heart dimensions and contractility, and evaluate the functional competence of the valves (mitral and aortic). Measurement of the left ventricular (LV) end-diastolic dimension and quantitative assessment of LV contractility are performed in M-mode from the left parasternal long-axis view or left parasternal short-axis view at the level of the mitral valve (MV) leaflet tips, which serve as a reference point for placing the cursor perpendicular to the line of MV leaflet closure. Measurements are taken from the posterior surface of the interventricular septum to the anterior surface of the LV posterior wall. Visual assessment of the LV: from the apical four-chamber view in comparison with the right heart chambers. Left parasternal approach: evaluation of the aortic valve annulus diameter, root dimensions, and ascending aorta along the long axis. In these modes and views, the thickness of the interventricular septum and the posterolateral LV wall is measured in diastole. LV wall thickening is considered present when the relative wall thickness (the sum of the thicknesses of the interventricular septum and the posterolateral LV wall divided by the LV end-diastolic dimension) exceeds 0.42, since left ventricular outflow tract obstruction leads to increased LV afterload, which may result in concentric hypertrophy. In some cases, severe aortic valve stenosis leads to LV dilation, decreased contractility, and endocardial fibroelastosis [121,122].

Aortic valve. The goal of echocardiographic evaluation of aortic valve stenosis is a comprehensive characterization of the morphological substrate of the obstructive lesion, assessment of hemodynamic severity, and identification of associated anomalies.

In the LV short-axis view at the level of the aortic valve, abnormal leaflet structure is visualized: abnormal number of leaflets (unicuspid, bicuspid, quadricuspid), commissural fusion, leaflet thickening, annular hypoplasia, or a combination of these elements. Three-dimensional echocardiography can assist in determining valve morphology, but not in neonates due to the mismatch between the technical specifications of 3D image acquisition and high heart rate. In some cases, especially in infancy, it may be difficult to identify the true number of leaflets and commissural fusion [123].

The diameter of the fibrous ring and the dimensions of the ascending aorta are measured according to recommendations in the parasternal long-axis view of the left ventricle. It is extremely important to carefully measure the aortic valve diameter in systole with clear visualization of the hinge points of leaflet attachment in patients scheduled for transluminal balloon valvuloplasty to select the optimal balloon size [124]. The Zoom option is indicated for better visualization of the area of interest. Z-scores are used to decide on hypoplasia and dilation of the corresponding aortic segment. Post-stenotic dilation of the proximal ascending aorta occurs due to the high velocity of the turbulent and often eccentric transaortic jet.

Hemodynamic significance. The severity of aortic valve stenosis in children is assessed by measuring the peak and mean LV/Ao pressure gradients using continuous-wave Doppler.

Classification of the severity of aortic valve stenosis by Doppler analysis in patients with isolated congenital aortic stenosis and preserved LV systolic function [125,126]:

• Minimal aortic valve stenosis – Maximum peak LV/Ao gradient up to 36 mm Hg; mean gradient < 20 mm Hg; maximum flow velocity less than 3 m/s.

• Moderate aortic valve stenosis – Maximum peak LV/Ao gradient 36–64 mm Hg; mean gradient 20–40 mm Hg; maximum flow velocity 3–4 m/s.

• Severe aortic valve stenosis – Maximum peak LV/Ao gradient > 64 mm Hg, mean gradient > 40 mm Hg; maximum flow velocity greater than 4 m/s.

Color Doppler flow mapping can help localize the narrowest blood flow through the valve in case of an eccentric flow for optimal alignment of the Doppler cursor with the flow jet (divergence angle not exceeding 15°). Suprasternal visualization often provides the best alignment of the Doppler beam with the direction of flow through the aortic valve. In addition to all standard views, the right parasternal long-axis view of the left ventricle can be used to assess aortic valve flow velocity [127].

Continuous-wave Doppler is optimal for determining the maximum peak LV/Ao gradient, but pulsed-wave Doppler is extremely useful in patients with multi-level left ventricular outflow tract obstruction to determine the site of maximum narrowing.

In older children and young people with congenital aortic valve stenosis, the stenotic valve area can be calculated using the continuity equation, and adult normative values can be applied for decision-making [124]. This is especially important when combined with subvalvular aortic stenosis, where a more acute aortoseptal angle is formed.

Classification of the severity of aortic valve stenosis by effective orifice area according to the continuity equation [128]:

Mild aortic valve stenosis – > 1.5 cm² (> 0.85 cm²/m²);

Moderate aortic valve stenosis – 1.0–1.5 cm² (0.6–0.85 cm²/m²);

Severe aortic valve stenosis – < 1.0 cm² (< 0.6 cm²/m²).

The term "critical" aortic stenosis is usually applied to infants whose systemic blood flow depends on a patent ductus arteriosus. In such cases, the left ventricle may be dilated, with reduced systolic function, moderate-to-severe mitral regurgitation, and bidirectional or right-to-left shunt across the patent ductus arteriosus (detected by color Doppler or pulsed-wave Doppler) even when maximum peak LV/Ao gradients correspond to moderate aortic valve stenosis.

Postoperative echocardiography, regardless of the type of surgical intervention performed, should include a detailed evaluation of the reconstructed/prosthetic aortic valve. Specifically, this includes the maximum and mean LV/Ao gradients, assessment of valve regurgitation, detailed morphometry of the heart and great vessels, and evaluation of LV and RV systolic function.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

In congenital aortic stenosis, the stenotic lesion is limited to the annulus and leaflets of the aortic valve. This congenital heart defect ranks first in frequency among all left ventricular outflow tract obstructions.

The most common cause of congenital aortic stenosis is a bicuspid aortic valve, which in some cases exhibits familial predisposition. In the absence of significant hemodynamic abnormalities, clinical manifestations of the defect may remain silent in early childhood and present later in life, or upon an increase in the child's physical exertion (e.g., when starting sports). However, the presence of severe congenital aortic stenosis accompanied by significant hemodynamic impairment can lead to critical conditions as early as the neonatal period, thus necessitating urgent surgical intervention.

Diagnostics and diagnostic criteria for this congenital heart defect are currently well-developed and of a high standard. Therefore, congenital heart disease can be suspected and diagnosed at early stages of routine screening. Parents of children should be alert to the onset of unexplained episodes of dizziness, presyncope, and fainting in children. In such cases, consultation with a pediatric cardiologist should be sought as early as possible to prescribe appropriate diagnostic methods, formulate a diagnosis, and determine the need and urgency of referral to a cardiovascular surgeon.

The presence of pronounced hemodynamic disturbances in diagnosed congenital aortic stenosis dictates the need for surgical intervention on the valve. Currently, methods for surgical correction of congenital aortic stenosis include a wide range of procedures, from the simplest (percutaneous aortic balloon valvuloplasty, open aortic commissurotomy) to complex reconstructive interventions on the left ventricular outflow tract (various options of aortic valve replacement, including in cases of small fibrous ring size). The choice of surgical treatment is determined primarily by the clinical condition of the child, the anatomical and morphological type of the defect, as well as the capabilities of the cardiac surgery clinic and the experience of the cardiac surgeon.

Currently, good results of aortic valve interventions have been achieved with low rates of mortality and postoperative complications. An exception is the group of newborn infants with critical congenital aortic stenosis, where the aortic valve intervention is performed while the child is in a critical condition.

In the long-term follow-up after congenital heart disease surgery, children should remain under the continuous supervision of a pediatric cardiologist to assess the corrected hemodynamics of the defect and determine the need and timing for potential reoperation on the aortic valve.

Patients with mechanical valves implanted in the aortic position must be under the continuous supervision of both a pediatric cardiologist and a hematologist. Due to the lifelong need for anticoagulators, this patient cohort requires ongoing monitoring of blood coagulation parameters and is at risk for specific complications such as hemorrhage, prosthetic thrombosis, and systemic thromboembolism.

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

No.