Hypertrophic cardiomyopathy in children: clinical guidelines

List of Abbreviations

AV — atrioventricular

AVB — atrioventricular block

AH — arterial hypertension

BP — blood pressure

ACE — angiotensin-converting enzyme

ATP — adenosine triphosphate

LBBB — left bundle branch block

RBBB — right bundle branch block

SCD — sudden cardiac death

LVOT — left ventricular outflow tract

HCM — hypertrophic cardiomyopathy

LVH — left ventricular hypertrophy

PG — pressure gradient

DNA — deoxyribonucleic acid

DDDR — dual-chamber rate-responsive implantable pacemaker***

VRA — ventricular rhythm arrhythmias

VT — ventricular tachycardia

LVPW — left ventricular posterior wall

ICD — single-chamber implantable cardioverter-defibrillator***

MINOCA — myocardial infarction with non-obstructive coronary arteries

CAG — coronarography

EDP — end-diastolic pressure

EDV — end-diastolic volume

CT/MSCT — computed tomography / multislice computed tomography

LV — left ventricle

LA — left atrium

IVS — interventricular septum

MV — mitral valve

BNP — brain natriuretic peptide

MR — mitral regurgitation

CMR — contrast-enhanced cardiac magnetic resonance imaging

NSVT — non-sustained ventricular tachycardia

OHCM — obstructive HCM

ACS — acute coronary syndrome

SAM — systolic anterior motion

RCT — randomized clinical trials

SRM — surgical resection of hypertrophied muscle tissue combined with plasty of both ventricular outflow tracts

RFA — radiofrequency ablation of arrhythmogenic zones

SAA – septal alcohol ablation

SME – surgical myectomy

TTE – transthoracic echocardiography (echocardiographic examination)

SV – stroke volume

LVEF – left ventricular ejection fraction

FC – functional class

VF – ventricular fibrillation

AF – atrial fibrillation

HMP – 24-hour ambulatory ECG monitoring

CHF – chronic heart failure

TEE – transesophageal echocardiography

HR – heart rate

ECG – electrocardiogram recording

PM – cardiac pacing

EchoCG – echocardiography

INOCA – ischemia with non-obstructive coronary arteries

LAMP2 – lysosomal-associated membrane protein 2 gene

MINOCA – myocardial infarction with non-obstructive coronary arteries

NT-proBNP – N-terminal pro-B-type natriuretic peptide

AHA – American Heart Association

ACC – American College of Cardiology

ATTR – transthyretin amyloidosis

EACVI – European Association of Cardiovascular Imaging

ESC – European Society of Cardiology

HCM Risk-SCD – sudden cardiac death risk model in hypertrophic cardiomyopathy

MOGE(S) – classification of cardiomyopathies

NYHA – New York Heart Association

Terms and Definitions

Hypertrophic cardiomyopathy (HCM) is a genetically determined myocardial disease characterized by left ventricular myocardial hypertrophy (in children, greater than two standard deviations [Z-score or Z-factor]; in adults, greater than 1.5 cm) and/or right ventricular hypertrophy, most commonly asymmetric due to predominant thickening of the interventricular septum, not attributable to increased myocardial afterload, valvular heart disease, congenital heart defects, or coronary artery anomalies.

Obstructive hypertrophic cardiomyopathy (OHCM) is a form of HCM accompanied by impaired intracardiac hemodynamics manifested as an obstruction to systolic ejection from the left ventricle (LV) and/or right ventricle (RV), leading to an increased pressure gradient (PG) across the LV outflow tract (LVOT) and/or RV outflow tract (RVOT).

Secondary LVH is a universal compensatory and adaptive reaction in response to a known hemodynamic or other factor.

Pre-hypertrophic stage of HCM is a phase in the disease development characterized by the absence of signs of myocardial hypertrophy detectable by imaging techniques.

Subclinical stage of HCM is a phase in the disease development characterized by the absence of clinical symptoms specific to HCM.

Genotype (+)/phenotype (-) – carriers of a pathological mutation associated with HCM, pre-hypertrophic and subclinical stages of HCM.

Age-dependent penetrance is an increase in the detection frequency of phenotypic features of HCM, determined by routine methods (ECG, EchoCG), among carriers of pathogenic genetic variants with advancing age.

Sudden cardiac death (SCD) is a non-violent death due to heart disease, manifested by the sudden loss of consciousness within the first hour from the onset of acute symptoms.

SCD risk stratification is the identification of independent predictors determining the probability of SCD risk in patients with a specific cardiovascular pathology. The HCM Risk-SCD score is used as a method for assessing SCD risk: low, intermediate, high.

Systolic anterior motion of the mitral valve leaflets is the systolic movement of the mitral valve leaflets toward the interventricular septum up to contact (mitral-septal contact), contributing to LVOT obstruction. The English term is systolic anterior motion syndrome (SAM syndrome).

Basal obstruction (LVOT obstruction) is an obstruction at the LVOT level to systolic ejection from the LV.

Mid-ventricular obstruction is an obstruction to systolic blood flow in the mid-cavity of the LV, at the level of the mid-LV segments.

«Classic phenotype» of HCM is a morphofunctional phenotype of HCM combining asymmetric LVH (interventricular septal hypertrophy), reduced LV cavity size, and LVOT obstruction.

Latent obstruction is a hemodynamic form of obstructive HCM in which the obstruction to systolic ejection from the LV occurs only during exertion or provocative maneuvers (orthostatic test).

Adverse remodeling is the final stage of adaptive and maladaptive changes in the affected organ. It is characterized by «mixed» morphofunctional phenotypes – hypertrophic + dilated, hypertrophic + restrictive, and, as a rule, a decrease in the degree of hypertrophy.

Extended (septal) myectomy (resection of hypertrophied muscle tissue combined with plasty of the outflow tracts of both heart ventricles) is a procedure involving resection of the interventricular septum to a greater extent than in Morrow myectomy, mobilization and resection of hypertrophied papillary muscles and hypertrophied muscular trabeculae (apico-basal muscle bundle).

Resection of the asymmetric hypertrophy zone using a transaortic approach is a surgical (SME, RME) or endovascular (SAA) intervention to reduce interventricular septal thickness.

Next-generation sequencing – decoding the structure of tens and hundreds of genes simultaneously.

Surgical myectomy is a myocardial resection procedure in the basal segments of the interventricular septum.

Level of evidence (LoE) is the degree of certainty that the observed effect of a medical intervention is beneficial.

Grade of recommendation (GoR) is the degree of certainty in the reliability of the intervention's effect and that following the recommendations will bring more benefit than harm in a specific situation.

HCM phenocopy – a disease with a known etiopathogenesis that phenotypically resembles HCM.

«Disarray» phenomenon – disorganized arrangement of cardiomyocytes and muscle fibers.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hypertrophic cardiomyopathy (HCM) is a genetically determined myocardial disease characterized by left ventricular myocardial hypertrophy (in adults – greater than 1.5 cm; in children – greater than two standard deviations [Z-score]) and/or right ventricular hypertrophy, most commonly asymmetric due to predominant thickening of the interventricular septum, not attributable to increased myocardial afterload, valvular heart disease, congenital heart defects, or coronary artery anomalies.

Comment. In the pediatric population of patients with HCM, there are specific features of etiology, pathogenesis, diagnosis, and treatment that preclude treating a child with this condition as a «small adult» by applying all the nuances of adult HCM [28,19,64,102,104,115,118,140,141,148].

The specific features of pediatric age regarding HCM include:

- a significantly higher prevalence of HCM phenocopies compared to adult patients (up to 30%);

- a higher mortality rate in children with HCM compared to the adult patient population: 10% of patients with HCM die within the first year of life, and all-cause mortality in children with HCM can reach 7% per year. Particularly high mortality is observed in children with HCM phenocopies, leading to a decrease in the prevalence of phenocopies from 30% in children to 10% in adults;

- phenotype «conversion» with age in children: extracardiac manifestations in children with HCM do not always occur in parallel with cardiac involvement (they may precede cardiac manifestations or, conversely, appear with a delay);

- treatment specifics: children exhibit specific beta-blocker metabolism characteristics, which requires more careful titration of the drug dose to achieve a therapeutic effect.

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

Etiology of HCM [8,28,44,107,111,115,118,140,141,148]

Hypertrophic cardiomyopathy is a severe, disabling disease with an unfavorable life prognosis. The vast majority of hypertrophied cardiomyopathies have a genetic etiology—this is the most common inherited cardiomyopathy. More than 20 causative genes associated with HCM development have been identified. Most genetic studies link hypertrophic cardiomyopathy to mutations in 23 genes encoding sarcomeric proteins, among which mutations in 11 genes are most frequently detected, including genes for beta-myosin, myosin-binding protein C, cardiac troponins T, C, and I, alpha-tropomyosin, and myosin light chains. The most frequently identified mutations in hypertrophic cardiomyopathy involve the MYBPC3 and MYH7 genes encoding myosin-binding protein C and the beta-myosin heavy chain protein, accounting for 20-40% and 20-45% of mutations in adult patients, respectively.

In children, the etiology of HCM is associated with syndromic, metabolic, neuromuscular, and mitochondrial diseases in approximately 30% of cases. All these cases are managed as childhood HCM until the diagnosis is refined [3,4,6,11,12,23,34,43,76,92,95,96,119,126,140,143,143]. This occurs because during initial and even repeat hospitalizations in children, it is not always possible to definitively differentiate isolated HCM from HCM phenocopies based solely on clinical manifestations and laboratory-instrumental methods. The issue is finally resolved by confirming the diagnosis using genetic testing methods, which require significant time and financial costs. Additional genetic testing is often necessary to validate the data.

Epidemiological studies show that although the causes of cardiomyopathies in children are more diverse than in adults, genes encoding sarcomeric, cytoskeletal, or desmosomal proteins remain the primary causes of cardiomyopathy at any age. Children with inborn errors of metabolism and syndromic malformations have a significantly worse prognosis regarding the development of heart failure than patients with causative mutations in sarcomeric proteins [3,4,6,11,12,23,34,43,76,92,95,96,119,126,140,143]. Pathogenic variants in the MYH7 and MYBPC3 genes account for about half of all HCM cases in adults and older children, with clinical manifestations able to appear at any age. However, the onset of clinical manifestations of HCM in childhood and adolescence is more commonly associated with the familial form of the disease and is accompanied by a more severe clinical course.

Mutations in the TNNT2 gene are associated with a high risk of sudden cardiac death syndrome, despite the absence of extreme interventricular septal wall thickening.

Cases (5–9%) have been described where HCM develops against the background of 2, 3, or more pathogenic variants. Such multiple mutations are more frequently identified in genes encoding sarcomeric proteins. The presence of combinations of pathogenic variants in sarcomeric protein genes is usually accompanied by onset in childhood, often an extreme degree of interventricular septum hypertrophy, and a high risk of sudden cardiac death syndrome.

Molecular Pathogenesis of HCM [8,43,96,107,115,118,126,140,141]

The occurrence of pathogenic variants leading to HCM in sarcomeric protein genes frequently results in impaired calcium homeostasis and increased calcium sensitivity of myofilaments, which underlies the molecular genesis of HCM. This leads to an increase in sarcomere contraction force during systole and reduces the degree of its relaxation during diastole, which is accompanied by increased ATP consumption by the cardiomyocyte and leads to the activation of compensatory embryonic hypertrophic growth programs.

At the tissue level, this leads to increased synthesis of embryonic forms of sarcomeric proteins and activates kinase signaling cascades. At the histological level, this is accompanied by cardiomyocyte hypertrophy, fibroblast proliferation, transformation of the latter into myofibroblasts, and leads to an imbalance in the collagenolysis system.

The consequence of the pathogenic genetic variant and accompanying tissue remodeling is the disorganization of cardiomyocytes and muscle fibers—the "disarray" phenomenon—and fibrosis.

The pathogenetic basis of myocardial contractility impairment in HCM is that ischemic areas of the heart muscle are unable to develop adequate contraction force during systole. Due to developing hypoxia, they begin contracting later than normally perfused segments of the heart muscle. Therefore, the detection of myocardial contraction dyssynchrony (which can be assessed only in patients with a normal QRS interval duration on the electrocardiogram, i.e., no more than 100 ms) is an early predictor of myocardial ischemia in hypertrophic cardiomyopathy.

The morphological substrate of ventricular tachycardia in patients with HCM is represented by arrhythmogenic zones against the background of dysplastic myocardial changes in the form of disrupted myofibril architectonics and a large number of necrosis and fibrosis areas.

Etiology and Molecular Pathogenesis of HCM Phenocopies [3,4,6,11,12,23,34,43,76,92,95,96,119,126,140,143]

HCM phenocopies are understood as various genetic and non-genetic diseases that are morphofunctionally similar to HCM in phenotype, but have a somewhat different etiopathogenesis.

In children, the causes of HCM phenocopies may include mutations in genes encoding non-sarcomeric proteins. The most unfavorable in terms of HCM prognosis are mutations leading to Noonan, Danon, Costello, LEOPARD syndromes, and regarding sudden cardiac death, unfavorable mutations include those in the genes for filamin-C, phospholamban, desmin, lamin A/C, SCN5A (voltage-gated sodium channel alpha subunit 5), TMEM43 (transmembrane protein 43), RBM20 (RNA-binding motif protein 20), as well as desmosomal mutations. An increased risk of arrhythmogenic events is present in children with HCM caused by mutations in desmoplakin, alpha-actin, LBD3 (LIM domain-binding protein 3), BAG3 (BCL2-associated anthanogene 3), NKX2-5 (NK2 homeobox 5), KCNQ1 and KCNH2 (voltage-gated potassium channels), TRPM4 (transient receptor potential melastatin 4), and pathogenic mutations in mitochondrial DNA. The detection rate of non-sarcomeric protein mutations in children with HCM is about 30%. Variants of HCM phenocopies are presented in Appendices P1/G1, P2/G2.

Pathogenesis of Symptoms and Syndromes of HCM [10,18,20,37,48,90,103,108,110,122,133,134,142]

The main symptoms of HCM are considered to be: left ventricular outflow tract obstruction, myocardial ischemia, left ventricular systolic and diastolic dysfunction, chronic heart failure, and arrhythmias.

Right Ventricle in HCM [110]

In addition to left ventricular hypertrophic remodeling in HCM, 30–44% of patients show signs of right ventricular involvement. The criterion for right ventricular myocardial hypertrophy is considered to be an RV wall thickness increase of > 5 mm. Extreme RV hypertrophy is a wall thickness exceeding 10 mm. Cases of isolated RV hypertrophy have been described in the literature.

Right ventricular hypertrophic remodeling can lead to intraventricular obstruction both at the level of the mid-segments and the right ventricular outflow tract [234]. The criterion for RVOT obstruction is considered to be an intraventricular pressure gradient of more than 16 mm Hg at rest.

Sudden Cardiac Death [20,79,102,103,108,134]

Sudden cardiac death is the most formidable manifestation of HCM; it frequently becomes the first and only manifestation of the disease. The main pathophysiological mechanisms of SCD are acute hemodynamic disorders (low output syndrome) and the development of life-threatening arrhythmias. Arrhythmias develop against the background of primary myocardial electrical instability with the occurrence of ventricular tachycardia and ventricular fibrillation; asystole as a result of complete atrioventricular block or sick sinus syndrome is also possible.

Myocardial ischemia and electrical instability developing in HCM contribute to the pathogenesis of fatal cardiac rhythm disorders. SCD is most frequently caused by ventricular fibrillation (62.4%), bradyarrhythmias (16.5%), Torsades de pointes ventricular tachycardia (12.7%), ventricular tachycardia (8.3%), and asystole. Sustained monomorphic ventricular tachycardia progressing to ventricular fibrillation is one of the most frequent causes of SCD in patients with HCM.

Annual mortality rates among children with HCM already in this century reached ~7%, which is comparable to SCD rates among adult patients with pronounced clinical manifestations of the disease (~6%). The minimum annual SCD rate was noted at age under 8 years—1.6%, then mortality increased, reaching a maximum at age 10 years—9.7%, from 11–13 years the indicator slightly decreased to 7%, and after 16 years it was even lower—1.7%. The maximum risk of death in girls occurs at age 10–11 years, and in boys at 15–16 years [32,35,89,93,102,104,106,123,135,150].

Based on numerous studies conducted predominantly in adults suffering from HCM, clinical features associated with a high incidence of SCD were identified and termed risk factors. According to the guidelines of the American College of Cardiology and the European Society of Cardiology, risk factors are subdivided into major and minor (additional). The major risk factors for SCD are: 1) aborted cardiac arrest episode (ventricular fibrillation) and sustained monomorphic ventricular tachycardia; 2) family history of SCD from HCM; 3) unexplained syncope; 4) extreme left ventricular wall hypertrophy (wall thickness ≥30 mm); 5) non-sustained ventricular tachycardia on Holter ECG monitoring; 6) inadequate blood pressure (BP) response to physical exertion (BP drop). Probable risk factors include: atrial fibrillation, myocardial ischemia, left ventricular outflow tract obstruction, intense physical exertion, high-risk genetic mutations, young patient age, and left atrial enlargement.

Aborted SCD (cardiac arrest) (ventricular fibrillation or spontaneous sustained ventricular tachycardia) is an absolute indication for the implantation of a single-chamber implantable cardioverter-defibrillator (single-chamber implantable cardioverter-defibrillator***) as secondary prevention of SCD in both adults and children with HCM.

Syncope [10,37]

Syncopal episodes may be the sole clinical manifestation of HCM, occurring in 26–35% of patients; they can be either recurrent or single episodes throughout life. The annual mortality rate in children with syncope is highest at 3.2%. While syncope occurring within the past 6 months is a more significant predictor of sudden cardiac death in adults, the timing of syncopal episodes is not significant in children.

The causes of syncope in patients with HCM are diverse. Causes of fainting include low cardiac output syndrome (hypovolemia) against the background of increasing left ventricular outflow tract obstruction, complete AV block, sick sinus syndrome, sustained ventricular tachycardia, atrial fibrillation, and inadequate vasodilation. A sharp increase in left ventricular obstruction and the subsequent development of low cardiac output syndrome are more characteristic of recurrent fainting situations during intense physical exertion.

In the event of sudden syncope at rest or with minimal exertion, ventricular arrhythmia must be ruled out. Syncopal episodes occurring during prolonged standing or in a hot, stuffy room accompanied by prominent autonomic symptoms, nausea, vomiting, and hyperhidrosis are more often neurocardiogenic (vasovagal) in nature.

Recurrent syncopal episodes in patients with a low risk of SCD (absence of other risk factors) and after exclusion of cardiac arrhythmias based on preliminary examination data serve as an indication for the implantation of an implantable loop recorder for long-term monitoring of the electrical activity of the cardiac conduction system (implantable cardiac monitor***) to diagnose potential concealed rhythm disorders.

A syncopal episode in children with HCM, regardless of the developmental mechanism, should be considered a major risk factor for SCD.

Cardiac arrhythmias [8,18,32,35,48,53,90,93,102,105-107,133,134,142]

Ventricular arrhythmias in patients with HCM are frequently predictors of life-threatening conditions and are described in the sections on SCD and syncope. In children with HCM phenocopies, the presence of 500 ventricular extrasystoles per day should prompt a pediatric cardiologist to perform a more detailed evaluation of the child to detect occult arrhythmias. The presence of 1000 ventricular extrasystoles per day in children with HCM phenocopies whose disease is caused by pathogenic and likely pathogenic gene mutations associated with an unfavorable risk of life-threatening cardiac arrhythmias may serve (in combination with other factors) as a basis for the implantation of a single-chamber implantable cardioverter-defibrillator*** (see Treatment section).

Atrial fibrillation

Unlike the adult HCM population, this occurs extremely rarely in children. Causes include:

- A genetically determined defect in the synthesis of a cardiomyocyte protein underlying HCM can also affect atrial cardiomyocytes, creating morphological prerequisites for myocardial electrical instability.

- Long-standing atrial myocardial remodeling combined with myocardial dysfunction causes atrial myocardial instability.

- Chronic atrial overload and wall overstretching due to pathological atrial remodeling lead to connective tissue proliferation (fibrosis).

Chronic heart failure [15,33,58,122]

Causes include:

- low left ventricular stroke volume due to a decrease in LVEDV. The persistently high LVEF does not compensate for the reduced stroke volume. During physical exertion, the decrease in stroke volume manifests clinically earlier than at rest;

- reduction in LV stroke volume due to its outflow tract obstruction;

- end-stage HCM (dilated phase) resulting in systolic LV myocardial dysfunction;

- LV myocardial fibrosis and increased LV wall thickness leading to diastolic LV myocardial dysfunction;

- mitral regurgitation leading to a decrease in effective LVEF;

- arrhythmia;

- development of venous pulmonary hypertension due to decreased LV propulsive function.

1.3 Epidemiology of the Disease or Condition

No predominant geographical, sex, or ethnic distribution of HCM is observed. The disease may manifest at any age. In children, the median age at HCM detection is 7 years.

According to epidemiological studies conducted worldwide, the prevalence of LVH as the primary phenotype of HCM is

1:500 in the general population. In various age cohorts, it varies from 1:500 to 1:200. The prevalence of HCM in the pediatric population ranges from 3 to 5 per 1,000,000, but increases to 9 per 10,000 by age 18. The annual incidence of HCM in children ranges from 0.24 to 0.47 per 100,000.

Since the disease can remain subclinical for a long time, its prevalence increases with modalities such as contrast-enhanced cardiac magnetic resonance imaging (MRI), preventive screening echocardiography, and cascade genetic screening of relatives of patients with HCM. Currently, some studies report a frequency higher than 1:200.

In children, it is very difficult to differentiate HCM phenocopies from isolated HCM because the extra-cardiac manifestations of syndromic, metabolic, neuromuscular, or mitochondrial disorders may present not in early childhood, but at a later stage. At the same time, the prognosis for children with HCM phenocopies is significantly more serious than for the isolated form. Therefore, a diagnosis of isolated HCM in a child is a diagnosis of exclusion, which is valid only when all possible phenocopies have been reliably ruled out.

In the pediatric HCM population, 25–58% of first-degree relatives of an affected child have echocardiographic signs of HCM. This must be taken into account, and cascade screening of relatives of a child with HCM should be performed for early detection of the disease in family members.

Prognosis. To date, only a limited number of studies have analyzed the long-term prognosis of HCM in young individuals based on follow-up data. Studies on survival and mortality in patients with HCM phenocopies are practically non-existent. It has been established that an unfavorable prognosis is due to two main causes: SCD and death from progressive heart failure (HF). In a large multicenter study (474 patients with isolated HCM aged 7 to 29 years; patients with HCM phenocopies were excluded), the 5-year mortality rate was 3%, and the 10-year mortality rate was 5%. Causes of death were SCD (69%), end-stage HF (10%), complications from heart transplantation (16%), and surgical myectomy (5%).

1.4 Features of Coding the Disease or Condition

I42.1 — Obstructive hypertrophic cardiomyopathy.

I42.2 — Other hypertrophic cardiomyopathy.

1.5 Classification of the disease or condition

Currently, there are several approaches to classifying HCM: clinical, morphological, hemodynamic, and genetic.

Hemodynamic classification principle

Based on the presence of LVOT obstruction gradient at rest and during exercise, the following are distinguished:

- non-obstructive HCM: LVOT pressure gradient <30 mmHg at rest and during exercise.

- obstructive HCM: LVOT pressure gradient >30 (50) mmHg at rest and during exercise.

- latent obstructive HCM: LVOT pressure gradient <30 mmHg at rest and >30 (50) mmHg during exercise.

Morphological classification principle of HCM

1. Asymmetric HCM

a. IVS hypertrophy (possible involvement of the RV):

- Basal IVS (subaortic)

- Sigmoid IVS

- Diffuse IVS hypertrophy

- Reverse curve IVS — predominantly mid-ventricular IVS hypertrophy without involvement of the LV free wall

- Combined (IVS + another LV or RV segment)

b. Apical hypertrophy (+/- mid LV segments)

c. Mid-ventricular HCM (involving mid segments of not only the IVS but also the LV free wall, hourglass-shaped LV)

d. Hypertrophy of another LV wall (lateral, posterior)

2. Symmetric HCM

According to the degree of hypertrophy severity

- Extreme (maximum LV wall thickness ≥30 mm). In the pediatric HCM population, extreme myocardial hypertrophy is defined as a thickness of 6 or more standard deviations (Z-score). Extreme myocardial hypertrophy is considered an independent risk factor for SCD. Extreme myocardial hypertrophy has greater prognostic significance as an SCD risk factor in young patients compared to adults. As a rule, hypertrophy is combined with myocardial fibrosis, which increases the likelihood of life-threatening cardiac arrhythmias.

There is also the MOGE(s) classification of cardiomyopathies (2013), which is based not only on the morphofunctional features of the CMP phenotype, but also takes genetic inheritance into account.

1.6 Clinical presentation of the disease or condition

In pediatric HCM, there can be significant variability in clinical symptoms: from an asymptomatic course to the development of severe circulatory failure [31,54,56,64,74,76,79,82,85,86,103,107,144].

Clinical presentation variants of HCM:

1. SCD can occur in any clinical variant of HCM, including in the absence of preceding symptoms. SCD in the pediatric HCM population most frequently occurs in syndromic forms of HCM, mitochondrial and metabolic HCM, as well as when HCM is associated with neuromuscular diseases, and in primary HCM with a high concentration of SCD risk factors. Children carrying gene mutations associated with an increased risk of SCD (see above) require particularly careful monitoring.

2. Asymptomatic course can be observed in patients with an initially non-obstructive form of HCM proceeding without hemodynamic disturbances and in patients with a mild degree of LVOT obstruction. Among children with an asymptomatic course of the disease, the average annual mortality rate is 1.4%, while among children with clinical manifestations of the disease, mortality rates reach their maximum at 6.6% [59,60].

3. Symptomatic benign course is more often observed in patients with adequately managed therapy for obstructive HCM, as well as in the obstructive form of HCM with a mild degree of LVOT obstruction [15,59,60,122].

4. Symptomatic complicated course of HCM is observed when the clinical picture includes atrial fibrillation (clinical manifestations of the arrhythmia itself, as well as thromboembolic complications), CHF (dyspnea, decreased exercise tolerance. Children in the first two years of life, as well as patients with metabolic forms of HCM phenocopies, Danon disease, and Pompe disease, are particularly susceptible to developing heart failure with preserved left ventricular systolic function), and angina pectoris syndrome, which can also be observed in pediatric HCM patients [3,27,53,66,96,138].

5. Symptomatic course with adverse remodeling represents the stage of myocardial function decompensation in HCM. It is accompanied by worsening symptoms of CHF against the background of pronounced systolic and diastolic myocardial dysfunction [13,15,58,122].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for HCM [8,9,54,63,83,107,115,139-141,148]

In children, the diagnostic criterion for HCM is an increase in left ventricular wall thickness of more than 2 standard deviations (Z-score).

Differential diagnosis is required with conditions such as hypertension and athletic myocardial remodeling. Differential diagnosis with HCM phenocopies in children is difficult (due to the fact that symptoms of the underlying disease may not yet manifest by the onset of HCM), but it must be performed due to the worse prognosis of HCM phenocopies in children.

The criterion for RV HCM is an increase in RV wall thickness >5 mm. An RV myocardial thickness >10 mm is considered extreme RV hypertrophy.

According to European researchers, the diagnostic criterion for obstructive HCM is a pressure gradient in the LVOT of ≥30 mmHg at rest or during exercise. A gradient of ≥50 mmHg is the criterion for hemodynamically significant obstruction [8,9,54,63,83,107,115,139-141,148].

According to American researchers, the diagnostic criterion for obstructive HCM is an LVOT pressure gradient of ≥50 mmHg at rest or during exercise.

The criterion for RVOT obstruction is an increase in the RVOT pressure gradient >16 mmHg at rest [8,107]. Degrees of obstruction are distinguished: moderate, high (pressure gradient greater than 60 mmHg).

Children with HCM may exhibit intraventricular obstruction of both the left and right ventricles. However, clear criteria for the magnitude of the pressure gradient for this form have not been established.

2.1 Complaints and Anamnesis

LoE 4 GoR C [64,82,144]

Comment: taking a family history regarding cases of SCD among relatives is very important. The definition of the term "family history of SCD in relatives" varies. In most cases, this implies SCD in first-degree relatives under 40 years of age regardless of the presence of HCM, while other researchers consider a positive family history to be the occurrence of SCD in a relative with HCM at any age. The presence of cases of SCD in the family of a child with HCM is considered an informative predictor of death. At the same time, this factor does not hold significance as a major risk factor, which may be due to the fact that in children the disease frequently arises from de novo gene mutations.

Level of Evidence 4, Grade of Recommendation C [64,82,144,145]

Level of Evidence 4, Grade of Recommendation C [64,82,144,145]

Comment: frequently in children, HCM is an incidental finding or diagnosed via screening.

In HCM, patients most commonly complain of dyspnea, decreased exercise tolerance, various cardialgic and/or anginal chest pain, cardiac rhythm disturbances (skipped beats, palpitations), dizziness, presyncope, and syncopal episodes.

When taking a family history, it is necessary to pay attention to whether relatives had cases of SCD, CHF, syncopal episodes, ICD implantation, early-onset stroke, as well as other diseases.

2.2 Physical Examination

LNC 5 LeC C

Comment: an auscultatory sign of obstructive HCM is a harsh systolic murmur heard over the entire surface of the heart, with a maximum at the apex and in the fourth intercostal space to the left of the sternum. The murmur is systolic in character, low-frequency, crescendo-decrescendo type, and is enhanced by assuming an upright posture, physical exertion, tachycardia, eating, the Valsalva maneuver, and the administration of peripheral vasodilators.

Signs of mitral regurgitation may also be auscultated.

LNC 4 LeC C

2.3 Laboratory Diagnostics

Level of Evidence 2, Grade of Recommendation B

Comment: in HCM patients with pronounced myocardial dysfunction, it is advisable to test blood levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and blood levels of troponins I and T. However, these tests are not part of the routine laboratory workup.

LE 4 GSR C

Comment: indicators suggesting a specific diagnosis of an HCM phenocopy are given in Table P1, Appendix G1.

Isolated hypertrophic cardiomyopathy (HCM) in the pediatric population is a diagnosis of exclusion. HCM phenocopies in children are significantly more common than in the adult patient population. When establishing a diagnosis of isolated HCM, a comprehensive differential diagnosis must be performed to rule out phenocopies, secondary causes, and specific causes of left and right ventricular hypertrophy. Unlike adults, children are characterized by phenotype conversion with age (the symptom complex of extracardiac pathology in children with HCM does not always develop simultaneously with the initial detection of HCM. At the early stages of syndromic, metabolic, or neuromuscular disorders, extracardiac symptoms may not yet manifest or may remain masked/subclinical/latent, only to begin dominating the clinical picture as the child grows older). Therefore, the evaluation of a child with HCM should initially be aimed at identifying syndromic and other forms. For this reason, the exclusion of phenocopies, secondary causes, and specific causes in a child with HCM should be performed not once, but repeatedly until adulthood is reached.

Genetic testing and family screening strategy [8,28,52,55,56,101,107,111,118,146]

LE 4 GSR C

LNC 5 LeC C

Comment: in patients with HCM, information about the causative genetic variant is important for sudden cardiac death risk stratification.

The necessity of genetic testing in phenotype-negative relatives to reclassify a variant of uncertain significance identified during genetic testing in the proband is still debated by researchers.

Consensus recommendations from the American College of Cardiology (ACC) / American Heart Association (AHA) dictate that family screening of first-degree relatives of probands with HCM should begin in children at 12 years of age. Earlier evaluation is appropriate only in cases of unusual growth spurts, a positive family history of sudden cardiac death (SCD), and participation in competitive sports.

The European Society of Cardiology (ESC) suggests clinical and/or genetic screening starting from 10 years of age (Class IIaC) or earlier if there is evidence of a malignant, early-onset disease course, the presence of clinical symptoms, or involvement in regular intensive physical activity (Class IIb, C). However, recent studies have demonstrated that clinical and genetic screening should not be delayed until 10 or 12 years of age due to high concordance of testing results among children of various ages, as well as the absence of differences in quality of life between genotype-positive children and their peers.

In studies of large cohorts of children, nearly 5% of screened first-degree relatives were diagnosed with HCM during initial or follow-up evaluations. HCM is diagnosed in at least one first-degree relative under 18 years of age in 8% of evaluated families. A diagnosis of HCM is more likely in the presence of a family history of childhood-onset disease.

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Recommendations for genetic testing of probands [8,28,52,55,56,101,107,111,118,146]

Level of Evidence (LE) 4, Strength of Recommendation (SR) C

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comment: genetic testing in children with borderline heart wall hypertrophy (exactly 2 Z-scores) or with borderline left ventricular hypertrophy of unclear origin should only be performed after a detailed evaluation (including cardiac magnetic resonance imaging with contrast) and a multidisciplinary team consensus.

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Comment: genetic studies in HCM may be exploratory and screening-based. Genome-wide high-coverage methods (whole-genome or whole-exome sequencing) are suitable for exploratory genetic testing. Once the results are obtained, targeted Sanger sequencing of the identified mutations must be performed in the proband and their relatives.

Assessment of the contribution of a specific genetic variant should be carried out individually and in conjunction with a geneticist.

Evaluation of the pathogenic significance of identified variants must be performed using international databases on the frequency and pathogenic role of genetic variants, such as ClinVar, gnomad, HGMD, etc.

Recommendations for genetic and clinical testing of adult relatives [8,28,52,55,56,101,107,111,118,139,146]

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Level of Evidence (LE) 5, Grade of Recommendation (GR) C

LE 5 SR C

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A "scoring model" exists for predicting the probability of detecting genetic variants in the genes most commonly associated with HCM, developed for adolescents over 16 years of age and adults; it includes patient age, female sex, presence of arterial hypertension, "reverse curve" IVS morphology, and the IVS/LVPW thickness ratio. A total score of ≤2 predicts a low probability of detecting genetic variants in the causative genes most commonly associated with HCM (Table P1, Appendix G2).

2.4 Instrumental Diagnostics

Electrocardiography and 24-hour ambulatory electrocardiographic monitoring [1,49,49,53,83,87,88,113,117,129]

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Level of Evidence (LoE) 4, Grade of Recommendation (GoR) C 

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LoE 5, GoR C

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Comment: electrocardiographic diagnostics is the most accessible and widespread method. In children with HCM, it is frequently this method that makes it possible to suspect the diagnosis. However, routine ECG is not always sufficient to detect rhythm and conduction disorders underlying SCD risk stratification, making extended ECG monitoring essential. This may include: 24-hour ECG monitoring, 48-hour and 72-hour monitoring, and the implantation of an insertable cardiac monitor for long-term recording of the electrical activity of the cardiac conduction system. Electrocardiographic recording should be repeated every 6–12 months (given the potential for rapid phenotype conversion in childhood), optimally for a duration of 24–48 hours.

An indication for unscheduled ambulatory electrocardiographic monitoring is the onset of patient complaints regarding arrhythmias, dizziness, and/or presyncopal/syncopal states.

Echocardiography [5,8,14,29,47,65,71,94,98,99,107,152]

Echocardiographic evaluation in patients with HCM is performed in accordance with the recommendations for echocardiography by the AHA, ASE (American Society of Echocardiography), and EACI (European Association of Cardiovascular Imaging) until national guidelines are issued [99].

Level of Evidence (LoE) 4, Grade of Recommendation (GoR) C 

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• In the pediatric population of HCM patients, it is recommended to perform echocardiography at least once a year, and twice a year if there is pronounced progression of parameters, regardless of changes in clinical status. When new symptoms appear, echocardiography is additionally performed promptly upon the detection of these new symptoms [5,8,14,29,47,65,71,94,98,99,152].

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Comment: it is advisable to use an extended echocardiography protocol adapted for the diagnosis of HCM. The list of parameters included in the transthoracic echocardiography protocol is presented in Table P3, Appendix G1. 

Recommendations for transesophageal echocardiography in HCM

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Performance of the Valsalva maneuver for the diagnosis of latent LVOT obstruction [27]

The Valsalva maneuver during echocardiography in older children is performed in the left lateral decubitus position. The patient strains the anterior abdominal wall muscles, which increases intra-abdominal and intrathoracic pressure. The strain level is monitored using a device consisting of a manometer connected to a mouthpiece; the patient maintains this effort so that the manometer pressure reads 20–40 mmHg. If the test is negative in the supine position, performing the test in both sitting and lying positions is recommended [8,107].

Comment: in the pediatric population of HCM patients under 12 years of age, due to the child's psychological unreadiness, performing echocardiography after physical exertion provocation (10 squats) is a viable option to detect latent LVOT obstruction. This procedure is not a classical provocative test, but it allows for suspecting or confirming latent obstruction in children with HCM.  

Magnetic resonance imaging [21,24,26,116,127,130]

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Level of Evidence (LE) 5, Grade of Recommendation (GR) C

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Comment: contrast-enhanced cardiac magnetic resonance imaging is the "gold standard" for assessing myocardial thickness and LV and RV volumes. It can provide greater measurement accuracy than echocardiography because it is not operator-dependent; therefore, it serves as a baseline imaging method for patients with HCM and allows evaluation of the myocardial structure itself, including inclusions, tissue heterogeneity, and the extent of fibrosis. Extensive myocardial fibrosis (>10%) is a predictor of adverse remodeling, the development of systolic dysfunction and heart failure, and is also considered an additional risk factor for SCD.

The value of contrast-enhanced cardiac magnetic resonance imaging is especially high in the diagnosis of HCM phenocopies. The pattern and localization of hypertrophy areas in patients with HCM phenocopies facilitate the differential diagnosis of phenocopies in children.

Computed tomography / Multislice computed tomography [99]

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Comment: the advantage of cardiac CT compared to MRI is the visualization of coronary arteries and myocardial bridging.

The disadvantages of contrast-enhanced cardiac computed tomography or ECG-synchronized spiral cardiac computed tomography are poorer soft tissue contrast and the presence of ionizing radiation.

Proton magnetic resonance spectroscopy and coronary angiography are not routinely used diagnostic methods for HCM in children.

Invasive measurement of intracardiac pressure

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Electrophysiological testing [16,50,62,75,120,131]

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Level of Evidence (LoE) 4, Grade of Recommendation (GoR) C 

Comment: invasive cardiac electrophysiology study with programmed ventricular stimulation is not among the routine diagnostic methods for patients with HCM.

Level of Reliability of Evidence 5, Level of Recommendation C

Stress tests [51,69,81,112,125]

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Comment: blood pressure response to exercise is a key part of stress testing in children with HCM. An abnormal blood pressure response is included in the SCD risk stratification score for patients with HCM. An abnormal blood pressure response is defined as a hypotensive response (blood pressure at peak exercise lower than baseline, or if it rises slightly in the early stages of exercise and falls below that level at peak exercise), as well as an inadequate rise in blood pressure at peak exercise (less than 20 mm Hg).

Cardiopulmonary exercise testing

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Myocardial biopsy [132]

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2.5 Other Procedures

Diagnosis of the disease in specific patient categories

Differential diagnosis of HCM and left ventricular hypertrophy due to arterial hypertension [2]

Stable arterial hypertension can lead to myocardial hypertrophy. However, the presence of arterial hypertension in a patient with myocardial hypertrophy does not rule out a diagnosis of HCM. In such patients, differential diagnosis between primary and secondary myocardial hypertrophy is necessary.

The probability of detecting HCM in patients with hypertension increases in the presence of the following factors:

1. positive family history of HCM or sudden cardiac death at a young age in first-degree relatives;

2. discrepancy between the duration and severity of arterial hypertension and the degree of LV hypertrophy (maximum wall thickness > 2Z).

HCM and myocardial infarction

Children with HCM and myocardial ischemia may develop acute coronary syndrome and myocardial infarction (MI) [17,41,67,80,109,152].

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Hypertrophic cardiomyopathy and LVH in athletes [136]

Recommendations for sports, physical education, and participation in athletic competitions

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Comment: participation in elite sports and competitive sports in children with HCM is associated with a high risk of SCD, and therefore these are contraindicated in patients with this nosology.

The question regarding the potential scope and nature of physical activity in sports for carriers of pathogenic and likely pathogenic gene mutations responsible for HCM, who have no clinical manifestations of the disease and no ECG or echocardiographic abnormalities, is determined by a joint decision of a multidisciplinary team of specialists, taking into account the nature of the identified mutation, the results of regular and repeated clinical examinations, and SCD risk stratification based on European and American models.

Risk stratification and strategies for primary and secondary prevention of SCD [32,35,89,93,102,104,106,123,135,150]

Annual cardiovascular mortality rates in adult patients with HCM are 1–2%. SCD, CHF, and thromboembolic events are the main causes. In the pediatric population of patients with HCM, mortality in the first year of life is 10%. According to various studies, mortality from SCD, CHF, and associated causes in children with HCM can reach up to 7% per year.

Sudden cardiac death (SCD) is death occurring unexpectedly and instantaneously due to cardiac causes (in a patient with or without heart disease) within 1 hour of the onset of the first symptoms of clinical deterioration.

The risk of SCD in patients with isolated HCM without traditional risk factors is 5.9% over 10 years. In the pediatric population of patients with HCM, the SCD prevention strategy differs from that in adults because metabolic, mitochondrial, and syndromic HCM, as well as HCM associated with neuromuscular disorders, account for about 30% of cases in children (compared to less than 10% in adults). Even a comparison of these percentages makes it clear that most patients with such forms do not survive into adulthood. They constitute the cohort most at risk for SCD, which requires a specific approach to prevention.

The strategy for preventing SCD in children with HCM consists of identifying those patients from the entire pool of HCM patients who harbor significant mutations in genes that are "unfavorable" for the development of life-threatening conditions, and applying specific indications for the implantation of a single-chamber implantable cardioverter-defibrillator*** in them. All other pediatric patients with HCM fall under risk stratification validated for sarcomeric mutations in childhood (244-249,301,310). Unfavorable mutations for SCD development in HCM include mutations in the FLNC (filamin C), PLN (phospholamban), SCN5A (sodium voltage-gated channel alpha subunit 5), TMEM43 (transmembrane protein 43), LMNA (lamin A/C), RBM20 (RNA binding motif protein 20), desmin, desmosomal genes, DSP (desplakin), LDB3 (LIM domain binding 3), BAG3 (BCL2 associated athanogene), NKX2-5 (NK2 homeobox 5), KCNQ1, KCNH2 (potassium voltage-gated channels), TRPM4 (transient receptor potential cation channel subfamily M member 4), alpha-actinin, and pathogenic mitochondrial mutations [139].

Comment: Phenotypic manifestations of cardiomyopathies with "unfavorable" mutations can vary even within the same family. The same mutation in an SCD-"unfavorable" gene can lead to a phenotype conversion not only into HCM, but also into dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or practically any other form, which requires further research in this direction. However, regardless of the cardiomyopathy phenotype, the presence of an "unfavorable" mutation leads to a significantly increased risk of SCD.

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The 5-year SCD risk assessment score developed for patients with HCM harboring sarcomeric mutations aged 16 years and older has been validated in the pediatric population of patients with HCM aged 1 to 16 years. It is also applicable only to children with HCM caused by sarcomeric protein mutations (non-syndromic HCM, non-mitochondrial, non-metabolic, not associated with neuromuscular disorders) [93,102,105].

Level of Evidence (LE) 3, Grade of Recommendation (GR) B

Level of Evidence (LE) 3, Grade of Recommendation (GR) B

It is advisable to perform SCD risk stratification in children of any age, regardless of the etiology of hypertrophic cardiomyopathy, based on the concentration of SCD risk factors in order to understand the degree of risk and optimize patient management and monitoring tactics [107,160,161].

Comment: life-threatening cardiac arrhythmias and symptomatic bradycardia can be detected during standard resting or exercise electrocardiography, 24-hour Holter monitoring, implantation of an implantable loop recorder for long-term monitoring of the cardiac conduction system's electrical activity, or during an exercise test using an ergometer. The pathogenetic basis for the development of such changes is myocardial electrical instability.

There are two models of SCD risk stratification:

1. Based on traditional risk factors (American and European models).

2. Based on the calculation of individual risk scores, a personalized approach (European model) – the HCM Risk-SCD score (children 16 years and older) and the HCM Risk-Kids Model score (children aged 1 to 16 years). The score for children aged 1 to 16 years is identical to the score for patients 16 years and older, except that it has been validated in the pediatric age group.

SCD risk "calculators" for HCM are available on the website https://qxmd.com/calculate/calculator_303/hcm-risk-scd and https://hcmriskkids.org/

The SCD risk assessment score in patients with HCM (American and European models) is presented in Appendices G3 and G4.

Comment: it should not be forgotten that, in addition to age restrictions, the European model scoring system is not applicable to patients with HCM phenocopies. Furthermore, this scale has limitations regarding the inputted left ventricular wall thickness values—up to 35 mm. With greater thickness, the results have reduced prognostic significance.

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

[7,15,16,22,30,33,42,50,57-62,66,75,84,86,96,100,114,120,121,127,128,131,137,138,147,149,151]

General principles of hypertrophic cardiomyopathy management

For the treatment of HCM in children, drug therapy, surgical treatment, the use of an implantable ventricular assist device***, and heart transplantation are used.

Data on the clinical efficacy and safety of medications used in children are based primarily on data obtained from observational studies. Randomized clinical trials are few and mostly include a small number of patients.

Pharmacotherapy in HCM and HCM phenocopies, which are often not yet differentiated during the initial examination of a child by a pediatric cardiologist, requires heightened responsibility from the physician when deciding against prescribing therapy (especially beta-blockers), since the prognosis for a child with HCM phenocopies is more serious than in isolated HCM. If there are doubts about the necessity of prescribing beta-blocker therapy, it is more correct to decide in favor of prescribing treatment rather than leaving a child with an unspecified etiology of HCM without hemodynamic cardioprotective therapy.

The issue of performing surgical myocardial resection in a child with HCM or its phenocopies is decided individually by a medical board of relevant specialists.

Approaches to drug therapy at the pre-hypertrophic stage of hypertrophic cardiomyopathy [59]

The question of the necessity of drug treatment in carriers of a pathogenic or likely pathogenic mutation associated with HCM at the pre-hypertrophic stage in children is currently only under discussion and has no definitive solution or consensus guidelines.

3.1 Conservative treatment [17,41,58,59,60,61,67,80,109,122,137,138,152]

Approaches to drug therapy at the hypertrophic stage of hypertrophic cardiomyopathy in asymptomatic patients [15,59,60,71,138]

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Level of Evidence 5, Grade of Recommendation C [13,14,15,107,108]

Comment: to make a decision regarding an asymptomatic course of HCM in a child, the physician must collect a detailed anamnesis and conduct a thorough analysis of the results of a cardiac examination, including an exercise test using a cycle ergometer and laboratory markers of myocardiocytolysis (testing blood levels of troponins I and T). A true asymptomatic course must be differentiated from adaptation due to the patient's lifestyle. The risk of SCD requires annual reassessment.

Drug therapy for symptomatic patients with hypertrophic cardiomyopathy

General principles of drug therapy [15,17,41,58,61,67,80,109,122,137,152]

Drugs for the medical treatment of HCM in children should be prescribed taking into account the individual characteristics of the child and their family's lifestyle, as the responsibility of the child and parents in maintaining medication adherence is of great importance. If poor parental compliance/supervision in administering the drug (especially beta-blockers) is suspected, preference should be given to long-acting (24-hour) beta-blockers. In children (due to their physiological characteristics), lipophilic beta-blockers are preferred over hydrophilic ones. However, the final choice of drug remains with the attending physician or multidisciplinary team of specialists. The starting dose of a beta-blocker in a child and the rate of upward titration are always selected individually, taking into account baseline blood pressure, heart rate, and the child's individual reaction to the drug.

Therapy that affects the patient's hemodynamic parameters should be initiated in a hospital setting under a physician's supervision.

The rapid growth of the child's body (tripling of body weight in the first year and a further 6-7 fold increase in weight by adulthood) requires more frequent correction of drug doses and a higher frequency of follow-up. Also, rapid weight gain leads to a greater susceptibility of the child to the development of heart failure due to a small left ventricular stroke volume against the background of impaired relaxation with extreme myocardial hypertrophy.

A child with HCM upon their first admission to the hospital (even before genetic testing and identification of the causative mutation) may require cardioprotective hemodynamic therapy and have indications for surgical treatment. How should such patients be managed if all published clinical guidelines and SCD risk calculators apply only to patients with HCM caused by sarcomeric gene mutations?

There is currently no unambiguous answer to this question, and the responsibility for deciding on the prescription or non-prescription of medical or surgical treatment lies with the multidisciplinary team that must monitor this child. If the specialists' opinions differ, and the diagnosis in a child with HCM is not clarified and therefore the prognosis is unclear, a decision should be made in favor of prescribing treatment.

The goals of drug therapy in children with HCM and HCM phenocopies are: halting the progression or reducing the rate of progression of myocardial hypertrophy; elimination or reduction of the severity of myocardial dysfunction; normalization of cardiac stroke volume; elimination or reduction of the severity of CHF; prevention of SCD, improvement of quality of life, and prolongation of patients' lifespan.

Drug therapy for left ventricular outflow tract obstruction

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Comment: it should be remembered about the side effects of beta-blockers. These include: conduction disturbances up to complete AV block, bronchospasm, peripheral vasospasm, hypoglycemia, and others. In pediatric practice, the most frequent side effect of beta-blockers is hypoglycemia, which can lead to presyncopal states during physical exertion, complicating the assessment of SCD risk in the patient. When prescribing large doses of beta-blockers, which are usually well tolerated by children, it is advisable to test blood glucose levels.

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In children with HCM and intraventricular LV obstruction receiving an adequate dose of a beta-blocker or calcium channel blocker, the response to treatment is not always predictable and optimal.

Treatment of CHF with LVEF ≥ 50% in patients with HCM

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Comment: the prescription of diuretics to children with HCM and low LV stroke volume should be carried out extremely cautiously under the control of heart rate, LV stroke volume, and LV gradient, since a decrease in circulating blood volume in these patients can lead to an increase in LVOT gradient.

In the presence of LVOT obstruction (resting or provoked) in children with HCM, organic nitrates, phosphodiesterase-5 inhibitors, calcium channel blockers, and cardiac glycosides are not prescribed.

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Treatment of CHF with LVEF < 50% in patients with HCM

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Comment: beta-blockers are the drugs of choice for reducing LVOT gradient and relieving symptoms of HCM. High doses of beta-blockers are usually well tolerated by children if titration is initiated at a low dose and performed gradually under the supervision of a specialist. The use of once-daily (24-hour) beta-blockers is preferable for maintaining consistent drug concentrations and is favored by patients due to easier management of therapy. However, in low-birth-weight children, preference is often given to medications that do not require compounding powders and are easy to dose.  

The administration of low-dose diuretics to patients with non-obstructive HCM, NYHA functional class II–IV, and LVEF <50% to reduce symptoms and lower the risk of heart failure hospitalizations is possible; however, in the absence of randomized clinical trials in HCM, their efficacy regarding hospitalizations, symptoms, and mortality is hypothesized but not proven.

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Management of angina pectoris in patients with HCM

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Comment: chest pain is a fairly common complaint in children with HCM. A differential diagnosis must be made between angina pectoris and non-cardiac chest pain, which is also a frequent complaint in pediatric practice and is caused by neuralgia, myalgia, gastrointestinal issues, chest wall deformities, scoliosis, and other causes. Ischemic cardiac pain in children with HCM most commonly results from inadequate blood supply via intramural coronary arteries to an enlarged and heavy (hypertrophied) myocardium with a high oxygen demand. A thorough history taking, 3-position ECG, stress echocardiography, and exercise testing assist in making the differential diagnosis.

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Management of arterial hypertension in children with HCM

In cases of concurrent non-obstructive HCM and arterial hypertension in children, treatment is carried out in accordance with the Clinical Guidelines for the management of arterial hypertension in children. Preference in this situation is given to the administration of beta-blockers.

Management of atrial fibrillation in children with HCM

While atrial fibrillation is the most common arrhythmia in the adult HCM population, it is very rare in children with HCM. Pharmacotherapy is administered in accordance with guidelines for the management of atrial fibrillation. Thrombotic complications of HCM are also extremely rare in the pediatric population.

3.2. Surgical and Interventional Treatment of HCM [16,22,30,42,50,57,62,66,75,84,100,114,120,121,128,131,147,149,151]

Septal Reduction

The question of surgical treatment for HCM in children is highly complex. The decision to perform cardiac myectomy and determine its extent is made on an individual basis in each case. Alcohol septal ablation is not used in children.

The effect of cardiac myectomy in children is not always long-lasting: unfortunately, cases where indications for repeat surgery arise after a short period due to rapid progression of hypertrophy are not uncommon.

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Comment: the goals of surgical treatment for HCM in children are: to increase left ventricular volume, which helps increase LV stroke volume; to remove the obstruction to left ventricular outflow by excising the hypertrophied portion of the interventricular septum protruding into the LVOT lumen, which also halts the contact between the anterior mitral valve leaflet and the interventricular septum during LV systole; to reduce the LVOT gradient to below 20 mmHg; and to correct structural anomalies of the mitral valve apparatus that contribute to hemodynamic impairment in HCM.

Consent for surgical treatment in a child with HCM is provided by the child's legal representatives. The feasibility of surgery and the selection of a specific type of cardiac myectomy for the patient are determined individually with the involvement of a multidisciplinary team.

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Comment: congenital anomalies of the mitral valve are frequently encountered in pediatric HCM patients and contribute significantly to mitral dysfunction beyond systolic anterior motion of the leaflet alone. In such cases, simple plication of the mitral valve may not achieve the desired postoperative outcome.

Guidelines for cardiac pacing in patients with obstructive HCM

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Invasive treatment methods for atrial fibrillation in patients with HCM

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Comment: radiofrequency ablation of arrhythmogenic zones in children with HCM and concomitant cardiac rhythm disorders requiring surgical correction has a lower success rate than in patients without HCM. This is due to both purely anatomical difficulties and the presence of myocardial fibrosis, myocardial ischemia, and frequently pronounced myocardial dysfunction. All of this creates additional challenges for the surgeon.

The rationale and necessity of performing the Cox-Maze procedure ("maze") or its modifications in patients with HCM and concomitant AF as part of radiofrequency ablation of arrhythmogenic zones are debated by specialists, who currently lack a consensus on this matter.

Recommendations on practical aspects of single-chamber implantable cardioverter-defibrillator implantation*** [30,66,84,100,128]

The scale for assessing the risk of sudden cardiac death in patients with HCM over 16 years of age (European model) is presented in Table P2, Appendix G2.

In children under 16 years of age in whom HCM is not caused by syndromic, mitochondrial, metabolic disorders, or neuromuscular diseases (i.e., HCM phenocopies are definitively excluded), the European model adapted and validated for the pediatric age group, similar to that for adult patients, is applicable for sudden cardiac death risk stratification.

The scale for assessing the risk of sudden cardiac death in patients with HCM (American model) is presented in Table P3, Appendix G2.

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Comment: in individual cases, invasive (intracardiac) electrophysiological study may be performed to verify the arrhythmia.

Comment: the American model is targeted at patients with HCM who have a low or intermediate risk of sudden cardiac death. Its applicability to the pediatric population of patients with HCM is ambiguous (this model has not been validated in the pediatric population).

In recent years, additional criteria have emerged whose assessment is not an unambiguous indication for the implantation of a single-chamber implantable cardioverter-defibrillator***, but is taken into account in general when making such a decision as an additional argument in favor of implantation. Such a criterion is the presence of extensive LV myocardial fibrosis assessed by late gadolinium enhancement on cardiac magnetic resonance imaging with contrast. The presence of myocardial fibrosis in the LV exceeding 15% is an additional predictor of sudden cardiac death risk in HCM and an argument in favor of implanting a single-chamber implantable cardioverter-defibrillator***.

In the pediatric population of patients with HCM carrying mutations in genes "unfavorable" for the development of life-threatening events (leading to Noonan, Danon, Costello, LEOPARD syndromes, as well as mutations in the genes for filamin-C, phospholamban, desmin, lamin A/C, SCN5A - voltage-gated sodium channel alpha subunit, TMEM43 - transmembrane protein, RBFOX20 - RNA-binding motif protein 20, and desmosomal mutations, desmoplakin mutations, alpha-actin, LBD3 - LIM domain binding 3, BAG3 - BCL2-associated athanogene, NKX2-5 - NK2 homeobox 5, KCNQ1 and KCNH2 - voltage-gated potassium channel, TRPM4 - transient receptor potential melastatin 4, and pathogenic mitochondrial mutations), additional criteria are applied for the implantation of a single-chamber implantable cardioverter-defibrillator*** [139]:

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Recommendations on the implantation of circulatory support devices

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Heart transplantation in patients with HCM

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Comment: heart transplantation or the use of mechanical circulatory support devices as a "bridge" to transplantation is often the only treatment strategy in end-stage HCM. Timely referral of the patient for heart transplantation (if feasible) is crucial, before long-standing hypoxia leads to irreversible multiorgan damage. In the pediatric population, indications for heart transplantation most frequently arise in HCM with a pronounced restrictive phenotype, in the dilated phase of HCM, and with the development of treatment-refractory heart failure against the background of myocardial dysfunction.

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4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no specific guidelines for the rehabilitation of patients with HCM. Following surgical or endovascular intervention, patients with HCM undergo the same rehabilitation measures as patients with other cardiovascular pathologies who have undergone surgical or endovascular interventions.

5. Prevention and Dispensary Observation

There is no primary prevention for HCM as a disease. A recommended repeat medical consultation (examination, counseling) by a geneticist for 1st- and 2nd-degree relatives of a proband with HCM, along with genetic testing, makes it possible to identify carriers of causative mutations, enabling couples to undergo prenatal diagnosis of the fetus for this hereditary disease before the gestational age limit for making decisions regarding the continuation of pregnancy.

Regarding the selection of an embryo free of the targeted hereditary disease during a set of procedures involving in vitro fertilization, embryo culture, and intrauterine transfer, this is currently difficult due to ethical aspects, given the preserved cognitive function of children with HCM.

Preventive measures in patients with HCM consist of preventing the main complications of the disease.

General lifestyle recommendations for patients with HCM are presented in Appendix B.

Follow-up monitoring of patients with HCM [8,107,115,140,141,148]

Patients with HCM require lifelong monitoring to detect changes in symptoms and prevent complications.

In children with HCM, the selection of therapy, prescribing beta-blockers, dose titration, and other treatments affecting hemodynamic parameters should be prescribed in a hospital setting under the supervision of specialists.

At the initial stage of drug treatment, scheduled follow-up visits to the physician are recommended to be carried out after 6, 9, and 12 months (or more frequently if necessary) to evaluate the tolerability, efficacy, and safety of treatment, as well as to monitor compliance with medical recommendations. 

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Level of Proof 5, Grade of Recommendation C

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Level of Proof 5, Grade of Recommendation C

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Comment: an integral part of the management and follow-up care for children with HCM is working with the proband's parents and the patient themselves (provided there is an age-appropriate level of understanding), aimed at increasing their awareness of the treatment strategy for the specific case of HCM. In the absence of mutual understanding regarding the necessity of continuous monitoring and uninterrupted treatment of the child, any prescribed drugs and treatment methods will not yield the expected result. Low motivation for treatment and non-compliance in adolescents can lead to adverse outcomes, up to and including death. All applied treatment and prevention methods must be discussed and agreed upon with the proband's parents. When choosing the drug administration regimen, the patient's lifestyle must be taken into account. All recommendations given to the patient must be clear, concise, and appropriate to their intellectual level.

Every effort should be made to provide all recommendations in writing to eliminate mutual misunderstanding and ensure the patient's informed participation in the treatment and prevention process.

6. Organization of Medical Care

Medical care for children with HCM is provided on an outpatient basis, during inpatient stays, and also includes rehabilitation and preventive measures.

Indications for planned inpatient admission to a medical organization

1) Clarification of the cause of left ventricular hypertrophy of unclear genesis and the need for special diagnostic methods (exclusion of HCM phenocopies).

2) Performance of diagnostic procedures that are impossible or impractical in an outpatient setting.

3) Difficulties in selecting pharmacotherapy for syndrome correction.

4) Prescription of beta-blockers, calcium channel blockers, and other medications affecting hemodynamics.

5) Refractoriness to fully administered pharmacotherapy and determination of indications for surgical treatment.

Indications for emergency inpatient admission to a medical organization

1) Progression of chronic heart failure requiring intensive care.

2) Pulmonary edema.

3) Thromboembolism.

4) Life-threatening cardiac arrhythmias and conduction disturbances requiring intensive care.

5) Syncope.

6) Acute coronary syndrome.

7) Prevented sudden cardiac death.

Indications for patient discharge from a medical organization

1) In planned hospitalization, the indication for discharge of a patient with HCM is the validation of the HCM diagnosis with the resolution of the issue regarding the absence of need for cardioprotective or other drug therapy, or the completion of the selection of such therapy in an inpatient setting, or the improvement of clinical symptoms against the background of correction of ongoing pharmacotherapy, as well as the implantation of a single-chamber cardioverter-defibrillator***, or a dual-chamber rate-responsive implantable pacemaker***, or a single-chamber implantable pacemaker***, or the performance of surgical cardiac muscle resection, or radiofrequency ablation of arrhythmogenic zones, or other endovascular/surgical treatment.

2) In emergency hospitalization, the indication for discharge of a patient with HCM is the correction of rhythm and conduction disorders, including fatal ones, the absence of complications requiring intensive care, and the stabilization of chronic heart failure.

3) In angina pectoris syndrome, the indication for discharging a patient with HCM is the achievement of stabilization of the patient's condition against the background of pharmacotherapy, endovascular/surgical treatment.

4) Establishment of the diagnosis of HCM phenocopies, discharge/transfer of the patient to specialized departments for etiopathogenetic treatment (for example, to the hematology department in AL-amyloidosis with isolated/predominant cardiac involvement).

Other organizational technologies

It is advisable to establish regional registries of patients with HCM.

When analyzing the performance of medical organizations providing care to patients with HCM, it is advisable to evaluate the following indicators:

- the ratio of HCM to HCM phenocopies, and the etiological spectrum of HCM phenocopies;

- the ratio of obstructive and non-obstructive forms of HCM; the ratio of familial and sporadic cases of the disease;

- the frequency of hospitalizations due to the progression of chronic heart failure, cardiac rhythm and conduction disorders, and cases of sudden cardiac death;

- the need for electrocardiogram recording, echocardiography, contrast-enhanced cardiac magnetic resonance imaging, contrast-enhanced cardiac computed tomography, and coronary angiography to fulfill recommendations for the follow-up and examination of the proband and first-degree relatives; - mortality (%), complications (%) per year, at 3 years, and at 5 years;

- the frequency of detection of cardiometabolic risk factors (arterial hypertension, dyslipidemia, obesity/overweight, type 1 and type 2 diabetes mellitus) in different age groups of HCM;

- the results of monitoring potentially modifiable factors: anthropometric data (BMI, waist circumference), lipid profile parameters, glycemia levels in different age groups of patients;

- additional information (including factors influencing the outcome of the disease or condition).

7. Additional Information

Other important goals in the treatment of HCM are:

- correction of all potentially modifiable risk factors (bad habits, dyslipidemia, hyperglycemia, obesity);

- treatment of comorbid conditions in accordance with national clinical guidelines (coronary artery disease, diabetes mellitus, etc.).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Working Group Presidium

1. Groznova O.S.

2. Leontyeva I.V.

3. Vasichkina E.S.

Other Working Group Members

1. Groznova O.S.

2. Leontyeva I.V.

3. Vasichkina E.S.

4. Miklashevich I.M.

5. Kovalev I.A.

6. Shcherbakova N.V.

7. Tarasova A.A.

The Working Group members confirmed the absence of financial support / conflict of interest. In case of reporting a conflict of interest, the working group member(s) was/were excluded from the discussion of sections related to the conflict of interest area.

Target audience for these clinical guidelines:

1. Pediatric Cardiologist

2. Cardiologist

3. Pediatrician

4. General Practitioner (Family Doctor)

5. Cardiovascular Surgeon

6. Functional Diagnostics Physician

Appendix A2. Methodology for Developing Clinical Guidelines

Table 1. Scale for assessing the levels of evidence (LE) 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. Order of the Ministry of Health of the Russian Federation No. 918n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Cardiovascular Diseases."

2. Order of the Russian Ministry of Health No. 159n dated March 2, 2021, "On Approval of the Standard of Medical Care for Adults with Hypertrophic Cardiomyopathy (Diagnosis, Treatment, and Dispensary Follow-up)."

3. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

4. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines, and the Requirements for Their Structure, Content, and Scientific Validity of Information Included in Clinical Guidelines."

Table 1/A3 Laboratory test abnormalities suggesting certain HCM phenocopies

Table 2/A3. Diseases most frequently accompanied by the development of HCM phenocopies

Table 3/A3. Parameters of the echocardiographic protocol in a patient with HCM

Table 4/A3. Molecular pathogenesis of HCM phenocopies

Table 5/A3. Main measures for the prevention of complications in patients with HCM

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

General lifestyle recommendations

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

Appendix G1. Scale for predicting the probability of detecting genetic variants in HCM

Russian title: Prediction scale for the likelihood of detecting genetic variants in HCM.

Original title (if applicable): none.

Source (official developer website, validation publication):

Ingles J. Non-familial hypertrophic cardiomyopathy prevalence, natural history, and clinical implications. Circ Cardiovasc. / Ingles J, Burns C, Bagnall RD et al. // Genet. 2017:10.   

Type (underline):

— rating scale

— index

— questionnaire

— other (specify):

Purpose: a clinical tool for predicting the likelihood of detecting genetic variants in HCM.

Content (template):

Appendix G2. HCM Risk-SCD and HCM Risk Kids Model. SCDS risk assessment scales for patients with HCM (European model)

Russian title: HCM Risk-SCD. SCDS risk assessment scale for patients with HCM (European model). HCM Risk-Kids Model. SCDS risk assessment scale for children with HCM (European model).

Original title (if applicable): HCM Risk-SCD, HCM Risk-Kids Model.

Source (official developer website, validation publication):

O’Mahony C. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM Risk-SCD). / O’Mahony C, Jichi F, Pavlou M et al. // Eur Heart J. 2014;35:2010–2020.

Liebregts M. Validation of the HCM Risk-SCD model in patients with hypertrophic cardiomyopathy following alcohol septal ablation / Liebregts M, Faber L, Jensen MK et al. // Europace. 2018;20(FI2):198–203.

Norrish G, Ding T, Field E, et al. Development of a novel risk prediction model for sudden cardiac death in childhood hypertrophic cardiomyopathy (HCM risk-kids). JAMA Cardiol 2019; 4: 918–927.

Calculators available at https://qxmd.com/calculate/calculator_303/hcm-risk-scd and https://hcmriskkids.org/

Type (underline):

— rating scale

— index

— questionnaire

— other (specify):

Purpose: a clinical tool for predicting the risk of SCD in patients with HCM.

Content (template):

Appendix G3. Scale for assessing the risk of SCD in patients with HCM (American model)

Russian title: SCDS risk assessment scale for patients with HCM (American model).

Original title (if applicable): none.

Source (official developer website, validation publication):

Ommen, S. R., Mital, S., Burke, M. A., Day, S. M., Deswal, A., Elliott, P., Evanovich, L. L., Hung, J., Joglar, J. A., Kantor, P., Kimmelstiel, C., Kittleson, M., Link, M. S., Maron, M. S., Martinez, M. W., Miyake, C. Y., Schaff, H. V., Semsarian, C., & Sorajja, P. (2020). 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 142(25), e558–e631. https://doi.org/10.1161/CIR.0000000000000937

Ommen, S. R., Ho, C. Y., Asif, I. M., Balaji, S., Burke, M. A., Day, S. M., Dearani, J. A., Epps, K. C., Evanovich, L., Ferrari, V. A., Joglar, J. A., Khan, S. S., Kim, J. J., Kittleson, M. M., Krittanawong, C., Martinez, M. W., Mital, S., Naidu, S. S., Saberi, S., Semsarian, C., … Peer Review Committee Members (2024). 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation, 149(23), e1239–e1311. https://doi.org/10.1161/CIR.0000000000001250

Type (underline):

— rating scale

— index

— questionnaire

— other (specify):

Purpose: a clinical tool for predicting the risk of SCD in patients with HCM.

Content (template):

Key (interpretation) for ICD*** implantation:

Appendix G4. Scale for assessing the risk of SCD in patients with HCM (European model)

Russian title: SCD risk assessment scale in patients with HCM (European model).

Original name (if any): none.

Source (official developer website, validation publication):

Authors/Task Force members, Elliott, P. M., Anastasakis, A., Borger, M. A., Borggrefe, M., Cecchi, F., Charron, P., Hagege, A. A., Lafont, A., Limongelli, G., Mahrholdt, H., McKenna, W. J., Mogensen, J., Nihoyannopoulos, P., Nistri, S., Pieper, P. G., Pieske, B., Rapezzi, C., Rutten, F. H., Tillmanns, C., … Watkins, H. (2014). 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). European heart journal, 35(39), 2733–2779. https://doi.org/10.1093/eurheartj/ehu284

Type (underline):

— rating scale

— index

— questionnaire

— other (specify):

Purpose: a clinical tool for predicting the risk of SCD in patients with HCM.

Content (template):

Key (interpretation) for ICD*** implantation: