Hypertrophic cardiomyopathy: clinical guidelines

List of Abbreviations

AV – atrioventricular

AVB – atrioventricular block

AH – arterial hypertension

BP – blood pressure

ARB – angiotensin II receptor blockers

LBBB – left bundle branch block

RBBB – right bundle branch block

VUS – variant of uncertain significance (class III pathogenicity), according to pathogenicity criteria developed by the Russian Society of Medical Geneticists (RSMG) and/or ACMG

SCD – sudden cardiac death

LVOT – left ventricular outflow tract

ГКМП – hypertrophic cardiomyopathy

LVH – left ventricular hypertrophy

PG – pressure gradient

DNA – deoxyribonucleic acid

DDPM – dual-chamber implantable pacemaker (dual-chamber implantable pacemaker without rate response***; dual-chamber rate-responsive implantable pacemaker***)

ЕОК – European Society of Cardiology

VRA – ventricular rhythm abnormalities

VT – ventricular tachycardia

LVPW – left ventricular posterior wall

ACEI – angiotensin-converting enzyme inhibitors

ICD – implantable cardioverter-defibrillator (single-chamber implantable cardioverter-defibrillator***; dual-chamber implantable cardioverter-defibrillator***; triple-chamber (biventricular) implantable cardioverter-defibrillator***)

ИМ – myocardial infarction

CAG – coronary angiography

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

INR – international normalized ratio

BNP – brain natriuretic peptide

MR – mitral regurgitation

MRI – magnetic resonance imaging

NSVT – non-sustained ventricular tachycardia

OHCM – obstructive HCM

ACS – acute coronary syndrome

LGE – late gadolinium enhancement

DOACs – direct oral anticoagulants (direct thrombin inhibitors: dabigatran etexilate** or direct factor Xa inhibitors: apixaban**, rivaroxaban**, edoxaban)

SAM – systolic anterior motion

RSMG – Russian Society of Medical Geneticists

CRT – cardiac resynchronization therapy

GFR – glomerular filtration rate

SM – septal myectomy (A16.10.003.23 Morrow myectomy under cardiopulmonary bypass)

TTE – transthoracic echocardiography

SV – stroke volume

LVEF – left ventricular ejection fraction

VF – ventricular fibrillation

FC – functional class

PE – physical exertion

AF – atrial fibrillation

CKD – chronic kidney disease

Holter ECG – Holter cardiac rhythm monitoring

CHF – chronic heart failure

TEE – transesophageal echocardiography

HR – heart rate

ECG – electrocardiography

PM – pacemaker, cardiac pacing

ESA – ethanol septal ablation (06.EBJ.13.001.006 Percutaneous transluminal septal myocardial ablation)

EchoCG – echocardiography

ATTR – transthyretin amyloidosis

INOCA – ischemia with non-obstructive coronary arteries

LAMP2 – lysosome-associated membrane glycoprotein 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

ACMG – The American College of Medical Genetics and Genomics

SAM syndrome – systolic anterior motion syndrome.

EACVI – European Association of Cardiovascular Imaging

ESC – European Society of Cardiology

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

MOGE(S) – cardiomyopathy classification

NYHA – New York Heart Association

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

*** – medical device implanted when providing medical care under the state guarantee program for free medical care to citizens

# – medicinal product for medical use used inconsistently with the indications for use, contraindications, routes of administration, and doses contained in the instructions for use of the medicinal product

Terms and Definitions

Hypertrophic cardiomyopathy (HCM) is a predominantly genetically determined disease (familial and non-familial forms) characterized by left ventricular (1.5 cm or more in adults) and/or less commonly right ventricular myocardial hypertrophy, most often asymmetric due to thickening of the interventricular septum, fibrosis, and the "disarray" phenomenon, which cannot be explained solely by increased pressure load and occurs in the absence of other potentially causal systemic, syndromic, or metabolic diseases.

Obstructive hypertrophic cardiomyopathy (OHCM) is a form of HCM accompanied by impaired intracardiac hemodynamics in the form of an obstruction to systolic ejection from the left ventricle (LV) and/or right ventricle (RV), leading to an increased pressure gradient (PG) in the left and/or right ventricular outflow tract (LVOT; RVOT). HCM with mid-ventricular obstruction is also classified as an obstructive form.

HCM phenotype – LV hypertrophy with a wall thickness ≥ 1.5 cm in one or more segments, which may be caused by various factors. HCM phenotype ≠ HCM.

Subclinical stage of HCM – a stage in the development of the disease characterized by the absence of clinical symptoms typical of HCM.

Pre-hypertrophic stage of HCM – a stage in the development of the disease characterized by the absence of signs of myocardial hypertrophy detectable by imaging methods. Pre-hypertrophic stage is not equivalent to HCM genotype(+)/phenotype(-)

Genotype(+)/phenotype(-) – carriers of a high-pathogenicity genetic variant: Class V (pathogenic) or Class IV (likely pathogenic) associated with HCM.

Sudden cardiac death (SCD) – non-violent, heart disease-related death manifesting as sudden loss of consciousness within the first hour from the onset of acute symptoms.

SCD risk stratification – determination of independent predictors determining the probability of SCD risk.

Systolic anterior motion of the mitral valve leaflets – movement of the mitral valve leaflets towards the interventricular septum during systole up to contact (mitral-septal contact), contributing to LVOT obstruction. English term: systolic anterior motion syndrome (SAM syndrome).

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

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

Latent obstruction – a hemodynamic form of obstructive HCM in which the obstruction to systolic LV ejection occurs only during exertion or provocative tests.

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

Adverse remodeling – the final stage of adaptive and maladaptive changes in the affected organ. In this process, an additional phenotype—dilated or restrictive—joins the primary HCM phenotype, referred to as the "dilated stage of HCM" (dHCM) or "HCM with a restrictive phenotype" (rHCM), respectively.

Septal myectomy – surgical resection of the interventricular septum myocardium (A16.10.003.23 Morrow myectomy under cardiopulmonary bypass)

Septal reduction – surgical (A16.10.003.23 Morrow myectomy under cardiopulmonary bypass) or endovascular (ESA) intervention to reduce interventricular septal thickness.

Next-generation sequencing – (NGS, massively parallel sequencing) high-throughput technology for simultaneous sequence determination

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

Genotype-positive (G+) HCM patient – a patient in whom at least one (or more) genetic variant of high pathogenicity classes has been identified in genes responsible for HCM: Class V (pathogenic) or Class IV (likely pathogenic), according to pathogenicity criteria developed by the Russian Society of Medical Geneticists (RSMG) and/or ACMG.

Genotype-negative (G-) HCM patient – a patient in whom no genetic variants of high pathogenicity classes have been identified in genes responsible for HCM: Class V (pathogenic) or Class IV (likely pathogenic), according to pathogenicity criteria developed by RSMG and/or ACMG.

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.

HCM phenocopy – a disease phenotypically similar to HCM based on routine diagnostic methods (ECG, echocardiography), but differing in etiopathogenesis and the potential for etiopathogenetic therapy for specific nosologies.

Working Group for the Development/Updating of Clinical Guidelines – a team of specialists working together and in coordination to develop/update clinical guidelines and bearing joint responsibility for the results of this work.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hypertrophic cardiomyopathy (HCM) – a predominantly genetically determined disease (familial and non-familial forms) characterized by left ventricular (1.5 cm or more in adults) and/or less commonly right ventricular myocardial hypertrophy, most often asymmetric due to thickening of the interventricular septum, fibrosis, and the "disarray" phenomenon, which cannot be explained solely by increased pressure load and occurs in the absence of other potentially causal systemic, syndromic, or metabolic diseases.

Comment: There is no universally accepted classification of the various etiological forms of HCM.

In the AHA/ACC guidelines (2020), HCM is defined as sarcomeric HCM or genotype-negative patients with the so-called HCM phenotype (LV myocardial thickness ≥ 15 mm – HCM criterion in the proband), where LVH is not caused by another cardiac, systemic, or metabolic disease (HCM phenotype ≠ HCM). Accordingly, metabolic and multi-organ syndromes (RASopathies, mitochondrial myopathies, glycogen storage/lysosomal storage diseases, amyloidosis, sarcoidosis, hemochromatosis) do not fall under the category of HCM. These diseases are often referred to as "phenocopies" or syndromic HCM [1,2].

Under the second approach, shared by European cardiologists (ESC) and American pediatricians (the American Heart Association Council on Cardiovascular Disease in the Young), HCM encompasses a large group of diseases characterized by the HCM phenotype (LVH with wall thickness ≥ 15 mm in adults or >2 Z-scores in children), while stipulating that such a degree of LVH is not solely due to LV loading conditions.

The ESC guidelines (2014) outline 8 etiological subgroups of the disease: sarcomeric HCM, metabolic diseases, mitochondrial cardiomyopathies, neuromuscular disorders, malformation syndromes and RASopathies, infiltrative/inflammatory myocardial diseases, endocrine disorders, and drug-induced HCM [3–6].

Thus, all so-called syndromic HCM cases (a term more commonly used in pediatric patients) and "phenocopies" (a term more commonly used in adult patients) are considered as "HCM with a specific etiology".

Age at clinical manifestation–an important determinant of the prognosis andetiological classification of the HCM phenotype. For example, HCM diagnosed at the age ofunder one yearis associated with a worse prognosis and isfrequently caused by inherited metabolic disorders (glycogen storage diseases, lysosomal storage diseases) or multiorgan congenital syndromes and malformations, such as RASopathies[7–9].

Etiological causes of the HCM phenotype in children may include neuromuscular and mitochondrial diseases, which are detected much less frequently in adult patients [9–12].

The existence of two fundamentally different approaches introduces certain terminological confusion and complicates data analysis, as well as epidemiological, diagnostic, and organizational measures.

Currently, in the active Russian clinical guidelines, phenocopies and syndromic forms are not classified under the definition of HCM. A brief description of them is provided to draw physicians' attention to the need for their identification and differential diagnosis.

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

Etiology of HCM

In the 1990s, the theory of monogenic origin of HCM was put forward, that is, the assumption that a single molecular event is sufficient for the development of the disease [13].

As data accumulated, it turned out that in approximately half of the cases, the disease develops as a result of carrying pathogenic and likely pathogenic variants in genes encoding sarcomeric proteins of cardiomyocytes [1,14–17].

About 60% of patients have a positive family history—at least one relative with diagnosed cardiomyopathy—and about 40% are the first affected individuals in their family [1].

In familial cases, 70–75% of probands show an autosomal dominant inheritance pattern in their pedigree, while autosomal recessive and X-linked forms account for about 15% of cases [3].

HCM is a disease with pronounced anatomical, clinical, and genetic heterogeneity. Hypertrophic cardiomyopathy can manifest at any age. The average age of disease manifestation in adults is about 40 years [18].

The onset of HCM in childhood and adolescence, as well as in young adults, is often associated with the familial form of the disease and a more severe course [3,9,19–25].

The majority of known mutations are localized in genes encoding proteins of thick (MYH7, MYBPC3) and thin (TPM1, TNNT2, TNNI3, MYL2, MYL3, ACTC1) myofilaments of the sarcomere structure [1,3,16].

Searching for mutations in 8 genes with a proven pathogenetic role in the development of HCM makes it possible to identify causative genetic variants in 60–85% of primary patients, depending on the cohort studied [1,3,16,19–24].

Causative variants in the MYH7 and MYBPC3 genes account for about half of all cases of genotype-positive probands with HCM [1,3,27–29,16,19–24,26].

In most cases, causative variants associated with HCM represent unique substitutions described once or only in a few cases. The frequency of each such substitution among all genetic causes of HCM does not exceed 1% [11,30,31].

In some patients (5–7% of probands), the disease can develop against the background of carrying multiple (2, 3) pathogenic and likely pathogenic variants. Combinations of mutations in genes encoding sarcomeric proteins are most commonly observed. In this case, the disease is characterized by an earlier onset (often in childhood), a greater degree of interventricular septum (IVS) hypertrophy, and a higher risk of sudden cardiac death (SCD) syndrome [3,20,25,32–35].

Sudden cardiac death in HCM is also possible in the absence of significant LVH; such cases are most frequently associated with mutations in the troponin T gene (TNNT2) [29,36,37].

In addition to the aforementioned 8 sarcomeric genes, more than 40 genes encoding both sarcomeric (TTN, MYH6, ACNT2, TNNC1, etc.) and non-sarcomeric myocardial proteins (CSRP3, FHL1, PLN, FLNC, etc.) have been described to date, in which rare genetic variants putatively associated with HCM have been identified [16].

However, the level of evidence for most of these genes remains low [38]. In 2019, an international expert panel of the ClinGen consortium analyzed the evidence for the causal relationship of rare findings in 33 described genes with the development of HCM [39]. Only for 8 genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3) was the causative nature of mutations assessed as definitive, for 3 genes (CSRP3, TNNC1, JPH2) causality had a moderate level of evidence, and for the remaining genes, the evidence of their role in the pathogenesis of HCM was limited or absent [40,41].

Whole-genome sequencing revealed that 20% of HCM cases without a known mutation in a sarcomere gene are associated with pathological variants in non-coding regions or in genes not previously identified as associated with the clinical HCM phenotype. WGS-based analysis of intronic regions allows the identification of a pathogenic variant in an additional 9% of patients with familial HCM [23,42].

On the other hand, the detection of class IV and V pathogenicity variants in family members who do not meet the clinical diagnostic criteria for HCM is also a common phenomenon. This circumstance suggests that the mechanisms responsible for the phenotypic manifestations of the disease depend not only on causative mutations in sarcomeric protein genes. Pathogenesis may be largely determined by the presence of a combination of other genetic variants that either compensate for or contribute to the adverse consequences of the mutation, as well as non-genetic causes or environmental factors [23].

Observation of adult family members of the proband showed that only 10% of genotype-positive patients develop the clinical phenotype of HCM, with the vast majority of them doing so at an elderly age. Finally, one cannot ignore the well-known fact that 50% of patients with an established clinical diagnosis of HCM do not reveal mutations in genes encoding the production of contractile proteins classified as pathogenic or likely pathogenic [11,17,43].

According to imaging data, in this patient cohort, a significantly higher frequency of systolic anterior motion of the mitral valve leaflet combined with dynamic left ventricular outflow tract (LVOT) obstruction (52%) and the presence of mitral annular calcification (27%) was demonstrated [17,44].

Patients with HCM included in the EORP (EurObservational Research Program) registry have a high prevalence of cardiovascular risk factors, comparable to data in the general European population. Patients with HCM combined with hypertension and obesity were characterized by an older age, a non-familial form of HCM, a higher NYHA heart failure functional class, and a greater severity of left ventricular diastolic dysfunction [44–53].

The results of genome-wide sequencing showed that more pathogenic variants were identified in HCM patients without hypertension, whereas variants of uncertain significance were more frequently encountered in HCM patients with hypertension (64% vs 24%, P < 0.05) [54].

In some cohorts, up to 40% of patients with "classic" HCM have neither a family history of the disease nor a pathogenic sarcomere mutation. It is also unlikely that new variants of genes encoding contractile proteins or variants of other genes will be identified that would confirm a monogenic etiology for the subgroup of "non-familial HCM" [17,55].

The hypothesis of a multifactorial genesis of HCM is currently being discussed [16,17,23,55–58].

Molecular Pathogenesis of HCM

Hypertrophic cardiomyopathy is most frequently caused by mutations in genes encoding myocardial contractile proteins. The molecular basis of such HCM variants often involves impaired calcium homeostasis and increased calcium sensitivity of myofilaments. This manifests as an enhancement of sarcomere contraction force during systole and a decrease in its relaxation degree during diastole, against the background of an increased ATP demand of the cardiomyocyte, which leads to impaired intracellular signaling processes and reactivation of compensatory embryonic programs of hypertrophic growth [40,59].

At the cardiomyocyte level, these processes lead to increased synthesis of embryonic forms of sarcomeric proteins and activation of kinase signaling cascades that ensure the processes of cardiomyocyte hypertrophy proper, as well as to the enhancement of extracellular signaling systems aimed at fibroblast proliferation, fibroblast-to-myofibroblast transformation, and imbalance in the collagenolysis system [40,59,60].

At the histological level, the direct action of the "causative" genetic variant and molecular pathogenesis is reflected by disarray of cardiomyocytes and muscle fibers—the "disarray" phenomenon—as well as varying degrees of fibrosis [3,20,40,60–66].

Etiology and Pathogenesis of HCM Phenocopies

This section was added to the clinical guidelines for HCM (2023) to draw physicians' attention to the need for differential diagnosis between HCM and its phenocopies and syndromic forms that present with an HCM phenotype on imaging. An HCM phenocopy is a disease that resembles HCM in its morphofunctional phenotype according to routine diagnostic methods (ECG, echocardiography), but differs in its etiopathogenesis and the availability of etiopathogenetic therapy for specific nosologies.

It should be emphasized once again that according to the current European Society of Cardiology (ESC) classification of HCM, these forms are included within the concept of HCM. However, under the current version of the national guidelines, they are considered as a separate group and excluded from the definition of HCM [67].

The most common HCM phenocopies and their molecular pathogenesis are presented in Table 1, Appendix A3 [68,69,78,70–77].

Pathogenesis of Symptoms and Syndromes in HCM

The pathogenesis of HCM at the organ level involves a combination of several syndromes: left ventricular outflow tract (LVOT) obstruction, myocardial ischemia, left ventricular (LV) systolic and diastolic dysfunction, arrhythmias, chronic heart failure (CHF), pulmonary hypertension, formation of an LV apical aneurysm, and cardiac autonomic dysfunction.

LVOT Obstruction Syndrome

Structural, kinetic, and geometric factors contribute to LVOT obstruction [79].

1. Structural anomalies:

a. narrowing of the LVOT by a hypertrophied interventricular septum (IVS) (the reduction in the degree of LVOT obstruction following myectomy/alcohol septal ablation is due to targeting this factor);

b. systolic anterior motion (SAM) of the mitral valve (MV) leaflets;

c. reduced LV cavity;

d. papillary muscle anomalies (and other minor cardiac anomalies) (hypertrophy and dislocation, anomalous papillary muscle);

e. apical-basal muscular bundle.

2. Kinetic factors: LV hypercontractility and accelerated blood flow in the LVOT;

3. Geometric factors:

a. anterior displacement of the MV, with the MV leaflet coaptation point shifted closer to the IVS [80];

b. small aorto-mitral angle (< 120°).

The more factors present in a given patient, the more pronounced the LVOT obstruction syndrome.

SAM syndrome is caused by the following factors:

a) MV leaflet anomalies (elongation, redundancy);

b) disturbance of blood flow coordination within the LV cavity in early systole, resulting in a force acting on the MV leaflets that displaces them toward the LVOT [81,82];

c) MV chordal anomalies;

d) a lower ratio of the length of the anterior to the posterior MV leaflet (< 1.3), with the MV leaflet coaptation point shifting anteriorly closer to the LVOT [83–85].

In patients with latent obstruction, triggering factors include: an increase in LV contractility during exercise, leading to a decrease in the LV end-systolic dimension and anterior displacement of the MV; and acceleration of blood flow in the LVOT during systole, which exacerbates SAM syndrome [86].

Patients with HCM may exhibit labile obstruction, characterized by significant spontaneous fluctuations in the intraventricular gradient without an apparent cause [87].

In addition to LVOT obstruction, patients with HCM may experience mid-ventricular obstruction. Mid-ventricular obstruction develops in patients with hypertrophy of the mid-segments of the IVS and, as a rule, in combination with papillary muscle hypertrophy [88–90].

In combined hypertrophy (IVS + apical segments), a two-level obstruction may occur (mid-ventricular + at the LVOT level) [91].

Mitral Regurgitation

Mitral regurgitation (MR) can be caused by congenital MV anomalies (elongation, redundancy, altered ratio of anterior to posterior leaflet length) as well as in combination with other factors.

Factors contributing to MR:

- congenital MV anomalies (leaflet cleft);

- SAM syndrome with left ventricular outflow tract obstruction (pulling of the anterior MV leaflet into the LVOT region due to the Venturi effect, which disrupts MV leaflet coaptation);

- MV leaflet prolapse;

- abnormalities of the MV subvalvular apparatus (anterior displacement of papillary muscles, apical displacement of papillary muscles, rupture of MV chordae, etc.);

- acquired MV changes (rheumatic);

- degenerative changes of the MV leaflets with thickening, combined with mitral annular calcification and restricted mobility of the posterior MV leaflet (typically in older age groups).

The typical direction of the MR jet caused by SAM syndrome into the left atrium is posterior and lateral. However, central and anterior directions of the MR jet are also possible, meaning the jet direction cannot be used to determine its mechanism.

Increased thickness of the mitral and aortic valve leaflets, combined with MR and mild aortic regurgitation, can be observed in certain HCM phenocopies, particularly cardiac amyloidosis. This fact is important to remember when performing differential diagnosis, especially in older patients.

LV Myocardial Ischemia Syndrome

Myocardial ischemia can develop in patients with HCM in the presence of unobstructed coronary arteries. The English-language literature uses the term INOCA (ischemia and no obstructive coronary artery) [92].

Factors leading to myocardial ischemia:

a) relative coronary insufficiency (reduced coronary flow reserve in severe hypertrophy);

b) ischemia of the subendocardial myocardial layers due to compression of intramural coronary arteries;

c) perivascular fibrosis, whereby intramural coronary arteries cannot dilate during physical exertion when myocardial oxygen demand increases and greater coronary blood flow is required;

d) congenital coronary artery pathology—myocardial bridging and intramural course of major coronary branch vessels;

e) in addition to the above causes, concomitant atherosclerotic disease of epicardial coronary arteries is observed in 15–25% of patients (in the older age group).

Patients with HCM and HCM phenocopies can develop type 2 myocardial infarction (MI) (without atherothrombosis) as well as type 1 MI. Risk factors for type 2 myocardial infarction in patients with HCM are presented in Table 2, Appendix A3 [93,94,103–108,95–102].

LV Dysfunction Syndrome

LV diastolic function may be impaired even in mutation carriers at the pre-hypertrophic stage of HCM [109].

In HCM, impairments affect the two main determinants of LV diastolic filling—active relaxation and myocardial distensibility. Myocardial hypertrophy per se causes impaired active relaxation. The disarray of contractile elements and interstitial fibrosis lead to reduced LV compliance and, consequently, to increased resistance to LV filling and elevated filling pressures. In the early stages of HCM, only active relaxation of the myocardium is impaired, while left atrial pressure is not increased. As hypertrophy progresses, fibrosis develops, the degree of mitral regurgitation increases, and myocardial ischemia supervenes, diastolic abnormalities worsen, leading to elevated left atrial pressure (and correspondingly, increased LV end-diastolic pressure). Furthermore, pronounced diastolic dysfunction can lead to pulmonary hypertension in some patients (pulmonary hypertension occurs in 50% of symptomatic patients) [110–113].

LV systolic function can be assessed using both contractility parameters and volumetric indices.

Global LV systolic function, assessed by contractility parameters, is supranormal in patients with HCM, which is manifested by a high left ventricular ejection fraction (LVEF). It should be noted that the LVEF index may incorrectly characterize contractility in the presence of left ventricular hypertrophy (LVH) and a small LV. Regional LV systolic function is heterogeneous: hypertrophied LV segments are hypokinetic (decreased degree of systolic thickening and strain), while non-hypertrophied segments have normal/supranormal contractility.

A volumetric index of LV systolic function is the stroke volume (SV). In HCM with a small LV (small end-diastolic volume), SV is reduced despite a high LVEF. The capacity for an increase in SV during physical exertion is also reduced.

LV systolic function, analyzed via systolic strain, may be impaired even in carriers of the HCM mutation at the pre-hypertrophic stage.

With disease progression (adverse remodeling) in the dilated phase, a decrease in the degree of hypertrophy ("burnout") is observed, accompanied by a decline in overall LV contractility (EF < 50%) [110,112,114–118].

Right Ventricle in HCM

Structural and functional abnormalities in the right ventricle (RV) are observed in 30–44% of patients with HCM. The criterion for RV myocardial hypertrophy is considered to be an increase in RV wall thickness > 5 mm. RV myocardial thickness > 10 mm is considered extreme RV hypertrophy [119].

RV hypertrophy is isolated in rare cases, without LVH [120].

Structural RV remodeling leads to intraventricular obstruction in 15–90% of cases, which may occur at the mid-RV level or at the RV outflow tract level [121].

The criterion for the presence of LVOT obstruction is an increase in the LVOT pressure gradient ˃ 16 mm Hg at rest [122].

An increase in RVFW thickness in patients over 60 years of age with a HCM phenotype requires the exclusion of cardiac amyloidosis.

Right ventricular systolic dysfunction is manifested by a decrease in RV longitudinal strain; meanwhile, other indicators of RV systolic function (TAPSE and lateral tricuspid annular s’) are generally within normal limits.

Right ventricular diastolic dysfunction in the early stages is characterized by E/A ˂ 1, increased RV DecT (RV early filling deceleration time), and E/e’ ˃ 6.0. It has been shown that the presence of RV diastolic dysfunction is a predictor of SCD and CHF [113, 119, 121–125].

Sudden cardiac death

The pathogenesis of SCD is based on fatal rhythm disorders caused by myocardial ischemia and electrical instability. SCD is most frequently caused by VF (62.4%), bradyarrhythmias (16.5%), Torsades de pointes VT (12.7%), VT (8.3%), and asystole.

SCD affects patients with HCM at any age (even over 60 years), with a peak between 30 and 50 years of age. Unlike arrhythmogenic cardiomyopathy, in which there is a clear association between intense physical exercise and an increased risk of SCD (data from the UK Cardiomyopathy Registry), SCD in HCM in the vast majority of cases occurred at rest or during ordinary physical exertion [1, 97, 134–139, 126–133].

Syncope

Syncope can be caused by both arrhythmic and hemodynamic factors. Hemodynamic causes include situational increases in LVOT obstruction (physical exertion) causing a significant decrease in stroke volume and a drop in blood pressure, as well as a decrease in peripheral resistance due to inadequate vasodilation, including vasovagal syncope (see also Appendix B8) [140–143].

Atrial fibrillation

Factors:

a) "atrial myopathy" – left atrial function has been shown to be impaired in mutation carriers at the preclinical stage prior to the development of hypertrophy [144].

b) structural (dilation) and functional remodeling of the LA, leading to electrical instability;

c) LA interstitial fibrosis [145–152].

It is known that atrial fibrillation (AF) is a frequent symptom in HCM phenocopies; for example, the detection rate of atrial fibrillation in cardiac amyloidosis can reach 69%. The cause of left atrial enlargement is multifactorial. It should be noted that impaired left atrial contractile function in transthyretin amyloid cardiomyopathy does not depend on left atrial size [153].

Chronic heart failure

Factors:

a) reduced LV (small EDV) and, despite high LVEF, small LV SV;

b) inability to adequately increase SV during physical exertion;

c) LVOT obstruction, contributing to the reduction of SV;

d) LV systolic dysfunction during HCM progression, especially in the dilated stage (myocardial ischemia, LV dyssynchrony);

e) LV diastolic dysfunction (myocardial fibrosis, elevated LA pressure and LVEDP);

f) mitral regurgitation (contributes to increased LA pressure);

g) rhythm disorders (AF);

h) pulmonary hypertension [110, 116, 118, 149, 150, 154–157].

In 10% of patients with HCM with the "classic phenotype" at rest, B-lines are recorded on lung ultrasound, indicating pulmonary congestion. During stress echocardiography, the detection rate of B-lines increases up to 30%. In these patients, physical exertion worsens diastolic dysfunction, increases mitral regurgitation, and raises pulmonary artery pressure [158].

Formation of LV apical aneurysm

The incidence of apical aneurysm is approximately 2–3% of all HCM cases [159, 160].

Apical aneurysms in HCM can develop both in isolated apical LV hypertrophy and in morphological variants where hypertrophy develops predominantly in the mid-LV segments ("hourglass" configuration) or in mixed variants where hypertrophy develops in both the apical and mid-LV segments [161].

In mid-ventricular obstructive HCM, LV apical aneurysms are present in more than 20% of cases [89].

The development of LV apical aneurysm in HCM is due to a combination of factors causing myocardial ischemia in HCM, along with an additional factor: systolic mid-ventricular obstruction causes a sharp increase in pressure at the LV apex, leading to a decrease in coronary perfusion, especially in the subendocardial myocardial layers, and cardiomyocyte apoptosis [162, 163].

Based on size, apical aneurysms are divided into small (< 2 cm), medium (2–4 cm), and large (> 4 cm). No correlation has been found between aneurysm size and clinical outcome [161].

However, data indicate that about 20% of thromboembolic events and LV apical thrombus formation occurred in small aneurysms, whereas about 70% of SCD events occurred in patients with medium and large aneurysms [161].

Apical aneurysms are an independent predictor of potentially lethal arrhythmias, including nonsustained and sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) [164–167].

Areas of myocardial scarring adjacent to the fibrous rim of the aneurysm at the junction of viable and abnormal tissue, where re-entry circuits occur, represent the primary arrhythmogenic substrate for the emergence of malignant ventricular tachyarrhythmias regardless of aneurysm size [161].

The presence of an apical aneurysm is associated with a 4-fold increase in the risk of SCD and a 6-fold increase in the risk of thromboembolic events/LV apical thrombus formation [168].

In 2020, the presence of an apical aneurysm (regardless of size) was included for the first time in the list of established clinical risk factors for SCD in HCM [1].

Apical aneurysms can also develop in Fabry disease (up to 10% of cases), both in its typical morphological form (symmetric LVH) and in atypical forms (asymmetric and apical) [169].

Autonomic dysfunction

It has been shown that patients with HCM have impaired cardiac sympathetic innervation, and these impairments progress with the development of negative remodeling (systolic dysfunction and dilated stage) [170].

Signs of autonomic nervous system dysfunction include an inadequate blood pressure and heart rate response to exertion. It should be borne in mind that an inadequate blood pressure response to physical exertion can also be caused by purely hemodynamic reasons: insufficient stroke volume increase during exertion (small LV EDV + impaired LV diastolic filling + increased LVOT obstruction during exertion).

An inadequate blood pressure response to exertion is considered to be an increase in blood pressure of less than 20 mm Hg at peak exertion or a drop in blood pressure of more than 20 mm Hg from peak during the course of exertion [1].

Patients with HCM also exhibit an insufficient heart rate response to physical exertion (heart rate reserve – the ratio of peak heart rate to baseline during stress echocardiography). The degree of reduction in heart rate reserve does not depend on beta-blocker therapy and is an independent predictor of poor prognosis [171].

It should be noted that in the older age group of patients, the presence of autonomic dysfunction requires the exclusion of cardiac forms of amyloidosis.

Pulmonary hypertension

Histological data show that patients with obstructive HCM undergo remodeling of both pulmonary arterial and venous vessels. Vascular wall hypertrophy is noted, and the proportion of fibrous tissue increases. At the same time, the increase in pulmonary artery pressure may be slight [172].

In 20% of patients with HCM and normal pulmonary artery pressure at rest, an increase is recorded during stress echocardiography [173].

Pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg by invasive measurement) is detected in 50% of symptomatic patients with CHF with indications for septal reduction. In some patients (up to 10%), precapillary PH is diagnosed (pulmonary capillary wedge pressure ≤ 15 mm Hg, pulmonary vascular resistance > 3.0 Wood units). Patients with precapillary PH did not significantly differ in other parameters from other patients with HCM and PH. The degree of PA pressure increase is in the range of 40–60 mm Hg. After surgical myectomy, PA pressure decreases, but not to normal values [110, 174].

Pulmonary hypertension is a predictor of poor prognosis in HCM.

1.3 Epidemiology of the Disease or Condition

In HCM, there is no clear geographical, ethnic, or sex distribution pattern.

HCM is practically the only cardiovascular disease that can manifest at any age from infancy to old age (from the first days of life to 90 years and older); meanwhile, the average age of patients at diagnosis is 30–40 years.

According to epidemiological studies conducted in different parts of the world, the prevalence of HCM is 1:500 in the general population. In different age cohorts, it ranges from 1:500 to 1:200.

With the use of more sensitive imaging techniques (MRI, CT) and the broader use of genetic testing and cascade screening for first-degree relatives, the prevalence of HCM corresponds to 0.6% (1:167).

The prevalence in the general population exceeds the frequency of HCM in cardiological practice, as the majority of patients remain unidentified due to being asymptomatic. When cardiac hypertrophy is detected in older age groups with a left ventricular (LV) wall thickness of 12 mm or more, it is necessary to consider the possibility of HCM phenocopies and secondary LVH [34, 175, 176].

First and foremost, this applies to transthyretin (TTR) amyloid cardiomyopathies. Two types of TTR-CM are distinguished: native, normal "wild-type" acquired non-hereditary cardiac amyloidosis, which accounts for the majority of cases, and the hereditary type [177]. Since 2020, amyloid TTR-CM has been included in the list of rare (orphan) diseases. Amyloid TTR-CMs are frequently underdiagnosed because they mimic other causes of left ventricular hypertrophy, such as HCM, arterial hypertension, and aortic stenosis. In cohorts of patients with aortic stenosis and transcatheter aortic valve replacement, the prevalence of acquired cardiac wt-TTR amyloidosis was 16%, of which 62% of cases met the criteria for low-gradient, low-flow aortic stenosis [178].

1.4 Features of Coding the Disease or Condition

ICD-10

I42.1 – Obstructive hypertrophic cardiomyopathy.

I42.2 – Other hypertrophic cardiomyopathy.

1.5 Classification of the disease or condition

In routine clinical practice, several classification approaches are used: clinical, hemodynamic, morphological, and genetic.

Clinical variants of HCM course – see section 1.6.

Hemodynamic classification principle

Depending on the presence or absence of left ventricular outflow tract (LVOT) obstruction at rest and during exercise, the following variants of HCM are distinguished:

- non-obstructive HCM: pressure gradient in the LVOT < 30 mm Hg at rest and during exercise;

- obstructive HCM: pressure gradient in the LVOT > 30 (50) mm Hg at rest and during exercise. This includes latent obstruction, where the pressure gradient in the LVOT is < 30 at rest and > 30 (50) mm Hg during exercise (for detailed criteria of LVOT obstruction, see the "Diagnostics" section).

Morphological classification principle of HCM

1. Asymmetric form of HCM:

• Hypertrophy of the interventricular septum (IVS) (+/- right ventricular involvement);

  • Basal part of the IVS (subaortic);

  • Sigmoid IVS;

  • Hypertrophy of the entire IVS;

  • Reverse curve IVS ("reverse curve") – predominantly mid-ventricular IVS hypertrophy without involvement of the LV free wall [179–182].

• Combined (IVS + another LV or RV segment);

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

2. Apical hypertrophy (+/- mid-ventricular LV segments);

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

4. Symmetric form of HCM.

According to a multicenter registry of patients with HCM, more than 80% of patients with HCM belong to two morphological subtypes: hypertrophy of the basal part of the IVS (46%) and reverse curve IVS (38%) [181].

Concentric HCM accounts for 1% of cases, mid-ventricular obstructive HCM with apical aneurysm formation for 3%, and apical HCM for 8%.

Clinical features of the most common morphological subtypes of HCM are presented in Table 3, Appendix A3.

Classification of HCM by the degree of hypertrophy severity:

1. "Mild" (the term "mild" is used in English-language literature): maximum LV wall thickness < 18 mm;

2. Intermediate;

3. Extreme (maximum LV wall thickness ≥ 30 mm).

The MOGE(s) classification of cardiomyopathies distinguishes not only "classic" morphofunctional phenotypes (hypertrophic, dilated, restrictive, arrhythmogenic cardiomyopathy, non-compaction myocardium), but also mixed phenotypes [27, 183, 184].

Clinical and morphological classification of HCM stages

In 2012, Olivotto I et al. [185] identified 4 stages of HCM development:

Stage 1: pre-hypertrophic — a stage in the development of the disease in individuals carrying mutations that cause HCM, with no signs of myocardial hypertrophy detectable by imaging methods.

Stage 2: "classic phenotype" of HCM — a stage where the hypertrophic phenotype is fully expressed, the LV is hyperdynamic (LVEF > 65% on MRI), in the absence of extensive fibrotic changes indicating disease progression.

Stage 3: negative remodeling — a stage defined by the presence of adverse structural changes superimposed on the "classic" HCM phenotype, manifested by progressive LV fibrosis and impaired LV systolic function (LVEF ranging from 50% to 65%), with relatively preserved clinical and hemodynamic status.

Stage 4: marked dysfunction — a stage of clinical development of HCM characterized by LV systolic dysfunction (LVEF < 50%), accompanied by an extreme degree of fibrosis and remodeling, and usually associated with hemodynamic decompensation and an adverse outcome.

In these guidelines, stages 3 and 4 are combined under the term "negative remodeling".

Echocardiographic signs of the "classic phenotype" of HCM:

• asymmetric LVH;

• LV cavity size within normal limits/reduced;

• LVEF > 65%;

• LVOT obstruction;

• preserved LV diastolic function or grade 1 LV diastolic dysfunction.

1.6 Clinical presentation of the disease or condition

HCM is a disease characterized by marked heterogeneity of clinical manifestations.

Clinical presentation variants of HCM:

1. SCD — may occur with any variant of the clinical course of HCM, including without preceding symptoms (most common in young patients < 35 years old, including athletes);

2. Asymptomatic course — occurs in patients with an initially non-obstructive form of HCM (mild myocardial hypertrophy, without concomitant mitral valve anomalies). Life expectancy in these patients is similar to the general population — 75 years and older;

3. Symptomatic stable (on drug therapy) benign course:

a) in patients with an initially non-obstructive form of HCM;

b) in HOCM with a mild degree of LVOT obstruction.

4. Symptomatic complicated course of HCM manifests as:

a) atrial fibrillation — paroxysmal, persistent, or permanent (25 to 30%), associated with heart failure of varying severity and an increased risk of thromboembolic events, including stroke;

b) CHF — onset of dyspnea, weakness, fatigue, combined with presyncope and syncope, arrhythmias. Progression of CHF severity to NYHA class III–IV (NYHA) with preserved LV systolic function;

c) Angina syndrome (including atypical chest pain) or silent ischemia. Myocardial ischemia in HCM may be complicated by type 2 myocardial infarction;

d) "End-stage": further progression of congestive heart failure symptoms associated with negative remodeling and marked LV systolic and diastolic dysfunction;

e) Development of an LV apical aneurysm.

Symptoms of CHF are frequent, but its clinical profile (stage IV according to Olivotto) varies among patients. In some patients, heart failure is associated with diastolic dysfunction with a preserved EF and small LV size (rHCM) or LVOT obstruction (with or without mitral regurgitation), while in others, symptoms are caused by LV systolic dysfunction (dHCM). In this case, an additional phenotype — either dilated or restrictive — joins the main HCM phenotype, referred to as the dilated stage of HCM (dHCM) or HCM with a restrictive phenotype (rHCM), respectively. The degree of LV enlargement in the dilated stage of HCM is usually mild; moreover, the size and volume of the LV may be within normal values, but the dynamics indicate dilation (e.g., LVEDD 35 mm → 55 mm, provided correct measurement). In the dilated stage of HCM, a decrease in LV myocardial thickness may be observed — the so-called "burnout hypertrophy" phenomenon caused by cardiomyocyte loss. In HCM, it is important to acknowledge the heterogeneity of heart failure mechanisms as this affects treatment and prognosis [35,118,185,186].

The formalized approach proposed by Rowin E.J., Maron M.S. et al. for assessing variants of the clinical course suggests considering one or more syndromes in a patient: (CHF+AF), (CHF+SCD), (AF+SCD), (CHF+AF+SCD), and using the term "progressive course of symptomatic HCM" [187].

The main clinical and morphological variants of the course and outcomes of HCM are presented in Table 4, Appendix A3 [3,20,61,187–193].

General principles for formulating diagnoses in HCM

Along with the morphofunctional class, it is necessary to indicate:

• Familial form;

  - genetic variant detected – pathogenic or likely pathogenic class;

  - genetic variant not detected;

  - genetic testing was not performed.

• Non-familial form;

  - genetic variant detected, de novo mutation – pathogenic or likely pathogenic class;

  - genetic variant not detected;

  - genetic testing was not performed.

• Left ventricular hypertrophy variant (asymmetrical/symmetrical);

• Interventricular septum (IVS) morphology pattern (biconvex, basal hypertrophy, apical, etc.);

• Specify the hemodynamic variant: obstructive (including latent)/non-obstructive;

• Specify the clinical variant:

  - SCD;

  - asymptomatic course;

  - symptomatic stable (on pharmacotherapy);

  - progressive.

• Reflect the stage according to Olivotto (stages I-IV) and variants of negative remodeling in the diagnosis;

  - dilated phase of HCM (dHCM);

  - HCM with an additional restrictive phenotype;

  - presence of an apical LV aneurysm.

• It is necessary to indicate in the diagnosis the calculated risk of sudden cardiac death and the date at the time of stratification.

The SCD risk «calculator» (incorporating the European and American models) is available on the website https://professional.heart.org/en/guidelines-and-statements/hcm-risk-calculator (if contrast-enhanced MRI was performed, include LGE data)

Options for formulating the HCM diagnosis after IVS reduction:

- Post-Morrow septal myectomy from the aorta (date);

- Post-extended interventricular septal myectomy via left ventricular apex access (date) LVOT gradient;

- Post-extended interventricular septal myectomy via right ventricular access (date) LVOT gradient;

- Post-extended interventricular septal myectomy via biventricular access (date) LVOT gradient;

- Add: video-assisted / with heart mobilization; under cardiopulmonary bypass (peripheral CPB), hypothermia, and cardioplegia (date);

- Implantation of a dual-chamber endocardial cardioverter-defibrillator in DDD Vitality 2 DR pacing mode (date). Ventricular lead revision. Complete battery depletion (EOL state). CHF stage IIA, NYHA functional class II.

- Ethanol septal ablation. Post-ESA state as of (date).

Examples of diagnosis formulation

1. Primary: Non-familial HCM (genetic testing not performed), obstructive form. Olivotto stage II. Asymmetrical LV hypertrophy (maximum hypertrophy of the basal IVS, SAM syndrome. LVOT gradient = 67 mmHg). CAG: no hemodynamically significant coronary artery stenoses (date). Angina pectoris syndrome. SCD risk – 3.87% – low (date) https://professional.heart.org/en/guidelines-and-statements/hcm-risk-calculator Complications: MR grade 0-I. HFpEF (LVEF 87%), stage 1, NYHA FC II. Single and paired atrial extrasystoles. Ryan grade 4 ventricular extrasystole.

2. Primary: Mixed phenotype cardiomyopathy: non-obstructive familial HCM. Asymmetrical LV hypertrophy (combined hypertrophy of the IVS and anterior LV wall). Genetic testing was not performed. SCD risk – 3.26% – low (date) https://professional.heart.org/en/guidelines-and-statements/hcm-risk-calculator). Biventricular non-compaction cardiomyopathy. Complication: HFpEF (LVEF 76%), stage 1, NYHA FC I.

3. Primary: Familial genetic non-obstructive HCM. Olivotto stage IV, dilated phase. Asymmetrical LV hypertrophy (entire IVS). MYBPC3 genetic variant (chr11:47360209: C>T NM_000256.3:R724W), pathogenic variant according to the American College of Medical Genetics classification (ACMG 2015). Complication. AF/AFL paroxysmal form (HAS-BLED 2, EHRA II). Ryan grade 5 ventricular extrasystole. Nonsustained paroxysmal monomorphic ventricular tachycardia. High SCD risk – (7.87%) (date) https://professional.heart.org/en/guidelines-and-statements/hcm-risk-calculator, ICD implantation DF-1 (date) HFrEF (LVEF 35%), stage 1, NYHA FC IV. Ascites. Bilateral hydrothorax. Hydropericardium. Congestive hepatomegaly. Recurrent pulmonary embolism (dates). ECMO placement (date).

4. Primary: Familial non-obstructive HCM. Olivotto stage II (LVEF – 71%). Asymmetrical left ventricular hypertrophy (entire IVS). Genetic testing was not performed. Asymptomatic course. SCD risk – 2.89% low (date) https://professional.heart.org/en/guidelines-and-statements/hcm-risk-calculator. Pre-heart failure stage.

5. Primary: Familial non-obstructive HCM. Olivotto stage II. (EF 74%) Genetic variant not identified. Asymmetrical LV hypertrophy (biconvex IVS shape). SCD risk – 9.87% – high (date). https://professional.heart.org/en/guidelines-and-statements/hcm-risk-calculator. Newly diagnosed. Complication: VF, aborted SCD (date). ICD (date). Pre-heart failure stage.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for HCM

The diagnostic criterion for HCM in adults is an increased LV wall thickness in one or more segments ≥ 15 mm (determined by any imaging modality – echocardiography/MRI/CT) that is not solely explained by increased pressure load (see definition). In first-degree relatives of the proband, the diagnostic criterion for HCM is an LV wall thickness of 13–14 mm [1,3].

Diagnosis may be difficult in cases where HCM is combined with hypertension (see section «HCM and hypertension»), aortic valve stenosis, in athletes, etc. In the HCM phenotype, HCM phenocopies, primarily hereditary and non-hereditary TTR amyloidosis, must be ruled out.

The criterion for RV involvement in HCM is an increased RV wall thickness > 5 mm, while an RV myocardial thickness > 10 mm is considered extreme RVH [175,194].

The diagnostic criterion for obstructive HCM is an LVOT gradient ≥ 30 mmHg, at rest or provoked. The criterion for hemodynamically significant obstruction, requiring more intensive therapy or surgical/endovascular interventions, is a gradient ≥ 50 mmHg [1,3,195].

In HCM, besides subaortic obstruction, midventricular obstruction may occur (isolated or combined with subaortic). The criterion for midventricular obstruction is a gradient ≥ 30 mmHg at rest or provoked [1].

The criterion for RVOT obstruction is an increased RVOT gradient > 16 mmHg at rest [122].

2.1 Complaints and Anamnesis

• All patients are recommended a detailed analysis of complaints and medical history, including family history up to the 3rd generation (taking medical history and ascertaining complaints in cardiovascular and pericardial diseases) [1,3,97,196,197].

ESC/RSC IC (Level of Evidence 5, Grade of Recommendation C)

Comment: many patients are asymptomatic or have minor symptoms. In such cases, the diagnosis is made incidentally or through screening.

The issue of distinguishing true absence of symptoms from adaptation due to lifestyle changes must be resolved by performing a maximal exercise stress test and dynamically assessing CHF biomarkers.

In the advanced stage of HCM, the most frequent complaints include dyspnea, reduced exercise tolerance, various chest pain sensations of cardialgic and/or anginal character, cardiac rhythm disturbances (skipped beats, palpitations), dizziness, presyncope, and syncope.

It is important to remember that the clinical manifestation of HCM in youth and older age has significant differences.

Young age is associated with the familial form of the disease and is an important determinant of severity, the risk of adverse cardiovascular events, and a proven risk factor for SCD [25].

All risk factors for SCD, including additional «novel» ones, must be taken into account, especially in carriers of pathogenic variants, including proband relatives – genotype (+)/phenotype (-) (see corresponding sections).

When taking a family history, attention should be paid to whether relatives had indications of SCD, CHF, syncopal episodes, implanted pacemakers, stroke at a young age, and other systemic diseases.

Older age is associated with the non-familial form of the disease and comorbidities (hypertension, BMI/obesity, dyslipidemia, CAD). When taking history and assessing complaints in a cohort of patients over 60 years old, one must also remember the high frequency of detecting cardiac amyloidosis in individuals with unexplained left ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF), which ranges from 6% to 16% [156,198].

2.2 Physical Examination

• All patients are recommended a standard physical examination of the cardiovascular system, including cardiac auscultation, measurement of peripheral blood pressure – repeated if necessary, also in supine, sitting, and standing positions, pulse evaluation, heart rate measurement, and in AF, pulse deficit [1,3,199–202]

ESC/RSC IC (Level of Evidence 5, Grade of Recommendation C)

Comment: the main diagnostic sign of obstructive HCM is a harsh systolic ejection murmur heard over the entire cardiac area, with a maximum at the apex and in the fourth intercostal space to the left of the sternum. The systolic murmur is low-frequency, crescendo-decrescendo in character, heard along the left sternal border, and intensifies under the influence of factors that increase the intraventricular pressure gradient: transition to the upright position, dynamic physical exertion, tachycardia, eating, Valsalva maneuver, and administration of peripheral vasodilators.

Most patients with LVOT obstruction also have auscultatory signs of mitral regurgitation. There are usually no clinically significant abnormalities from other systems and organs in HCM [3,20,203,204].

Patients with LVOT obstruction often exhibit arterial pulse instability (significant fluctuations in heart rate in orthostasis and clinostasis, during wakefulness and sleep). This may also be due to autonomic dysfunction (see the "Pathogenesis" section).

• During a physical examination of the patient, it is recommended to thoroughly investigate symptoms not only from the cardiovascular system, but also from other organs and systems, which may indicate HCM phenocopies [68,70,208–212,71,73,75,76,183,205–207].

ESC IB (LoE 4, GoR C)

2.3 Laboratory Diagnostics

• All patients with HCM are recommended to undergo a routine laboratory workup to detect comorbid conditions, including a complete blood count and urinalysis, general clinical blood chemistry (blood cholesterol level test; blood triglycerides level test; blood potassium level test; blood sodium level test; blood glucose level test; determination of protein fractions ratio by electrophoresis; determination of alanine aminotransferase activity in blood; determination of aspartate aminotransferase activity in blood; determination of creatine kinase activity in blood; blood urea level test; blood creatinine level test; total bilirubin level test; blood uric acid level test), and calculation of the glomerular filtration rate (eGFR) [3,205,213].

ESC/RSC IC (Level of Evidence 5, Grade of Recommendation C)

Comment: routine laboratory testing helps identify comorbid conditions that can trigger or exacerbate myocardial dysfunction and the patient's condition.

Tests for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and blood troponins I, T (high-sensitivity cardiac troponin I or T) are not part of the routine laboratory workup; however, their elevated levels are associated with the severity of diastolic dysfunction, LVH, the severity of functional disorders (myocardial ischemia, progression of heart failure), and an unfavorable prognosis [3,60,61,110,188,213].

High levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) are associated with heart failure and other cardiovascular events. Despite comparable ventricular wall thickness values, plasma Nt-proBNP levels are 3–5 times higher in patients with cardiac amyloidosis. The disproportionately large increase in Nt-proBNP levels in amyloid cardiomyopathies is important to consider when performing differential diagnosis within the HCM phenotype [214,215].

• When a specific HCM phenocopies is suspected for the purpose of differential diagnosis, a specialized laboratory workup is recommended [3,75,205,206,211,212].

To rule out AL amyloidosis, indicators characterizing plasma cell dyscrasia are determined:

a) testing for immunoglobulin light chain monoclonal protein in blood by immunofixation; testing for immunoglobulin light chain monoclonal protein in urine by immunofixation

b) elevated concentration of one of the free immunoglobulin light chains (involved chain) in serum and/or urine (nephelometric method, Freelite^TM, Birmingham, UK) with an abnormal κ/λ ratio;

c) increased number of plasma cells in the myelogram (usually 5 to 10% according to bone marrow smear cytologic examination (myelogram))

ATTR amyloid cardiomyopathy is an irreversibly progressive disease with a high degree of disability due to severe cardiac involvement, peripheral and/or autonomic polyneuropathy. Mortality in patients with ATTR amyloid cardiomyopathy is usually the result of progressive heart failure. After the diagnosis of ATTR amyloid cardiomyopathy, the median survival in untreated patients is ~ 2–3.5 years.

ATTR amyloid cardiomyopathy is often underdiagnosed because it mimics other causes of LVH, primarily HCM. Patients with ATTR amyloid cardiomyopathy (hereditary and acquired) may present with both cardiac and non-cardiac manifestations and signs that, especially in combination, may indicate the presence of this disease [216]. These include: heart failure with preserved ejection fraction, intolerance to standard heart failure medications, and low voltage relative to LV mass. Non-cardiac symptoms of the disease include carpal tunnel syndrome, lumbar spinal stenosis, gastrointestinal disorders, and peripheral and autonomic nervous system dysfunction.

For transthyretin amyloid cardiomyopathy, independently of other manifestations, etiopathogenetic therapy has been developed (Tafamidis 61 mg (Vyndamax) is bioequivalent, but not interchangeable in terms of mg to tafamidis meglumine at a dose of 80 mg).

Data from the French national registry showed that 8% of patients referred for hypertrophic cardiomyopathy harbor a pathogenic mutation in the transthyretin gene [217]. R. Maurizi et al. found that the prevalence of cardiac amyloidosis among patients with an initial diagnosis of HCM is 9%, and it increases with age: from 1% at age 40–49 years to 26% in patients aged > 80 years [218].

HCM is a diagnosis of exclusion: phenocopies, secondary and specific causes of LVH and RVH must be ruled out.

In some cases, specialized laboratory testing is required when drug therapy-induced complications occur, for example, in amiodarone-induced hypothyroidism, amiodarone-induced thyrotoxicosis type 1, amiodarone-induced thyrotoxicosis type 2, mixed form of amiodarone-induced thyrotoxicosis – determination of blood levels of thyroid hormone antibodies; determination of blood levels of thyroid hormone antibodies; test for total triiodothyronine (T3) in blood; test for total thyroxine (T4) in blood serum; test for thyroid-stimulating hormone (TSH) in blood. A detailed description is provided in Section 3.1.8.1, page 71

Certain markers suggesting a specific diagnosis of an HCM phenocopy are presented in Table 5, Appendix A3 and Table 6, Appendix A3.

Medical genetic counseling and genetic testing

• Medical genetic counseling is recommended to be performed by medical geneticists or cardiologists with experience in managing this group of patients [219]. It is advisable for a medical geneticist to participate in the multidisciplinary team of specialists involved in the diagnosis and treatment of HCM [3,20,220].

ESC IC (LoE 5, GoR C)

Comment: medical genetic counseling is recommended for patients with HCM and their relatives, and should include a discussion of the benefits, risks, and limitations of genetic testing. The treatment strategy should be based both on genetic testing data and on the results of a comprehensive clinical, instrumental, and laboratory workup [25].

• Before performing genetic testing, it is recommended to consider pre-test medical genetic counseling, and after receiving genetic testing results, for correct interpretation of the results, it is recommended to conduct medical genetic counseling in centers specializing in genetic screening and follow-up of families with genetically determined heart diseases [1,41,221–223].

ESC IIaC (LoE 5, GoR C)

Comment: during medical genetic counseling, all patients should be fully informed about the purpose and significance of genetic testing, its possible results, their clinical significance, as well as general issues of etiopathogenesis and inheritance of genetically determined cardiovascular diseases.

Recommendations on genetic testing of probands

• Genetic testing for patients with a suspected genetically mediated cardiovascular disease is recommended to be performed only in conjunction with appropriate medical genetic counseling [223].

ESC IIaC (Level of Evidence 5, Grade of Recommendation C)

• Genetic testing in HCM is recommended to be performed in certified diagnostic laboratories with expert skills in assessing the pathogenicity of genetic variants associated with primary cardiomyopathies, in accordance with current guidelines [1,3,221–223].

ESC IB (Level of Evidence 5, Grade of Recommendation C)

• The panel of genes for genetic testing of probands with HCM (including cases of post-mortem DNA diagnostics) is recommended to include genes with robustly proven causative roles in HCM. Currently, these are the MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1 genes [1,3,58,222].

ESC IB (Level of Evidence 5, Grade of Recommendation C)

• In patients with HCM (including cases of post-mortem DNA diagnostics) with typical or atypical clinical presentation of HCM, or with a suspected well-defined genetic syndrome with LV hypertrophy, genetic testing for confirmatory diagnosis is recommended using a broader panel of investigated genes (ACTC1, ACTN2, ALPK3, ANKRD1, CSRP3, FHL1, FLNC, GLA, JPH2, LAMP2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYPN, NEXN, PLN, PRKAG2, PTPN11, RAF1, RIT1, SOS1, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTR, and VCL) [1,3,58,221–223].

ESC IB (Level of Evidence 5, Grade of Recommendation C)

ESC IIa C (Level of Evidence 5, Grade of Recommendation C)

Comment: genetic testing in HCM can be of a diagnostic and predictive nature.

In the former case, genetic testing is part of the diagnostic workup and is intended to help confirm the diagnosis of HCM in the presence of a mild or incomplete clinical presentation, as well as in the presence of extracardiac manifestations of the disease to rule out specific causes of the HCM phenotype (phenocopies in adults and syndromic forms in children) [3,19,20,27,224,225].

The pathogenicity of each genetic variant identified as a result of testing must be assessed in accordance with the 2015 guidelines of the American College of Medical Genetics and Genomics (ACMG), the Russian Society of Medical Genetics (RSMG) guidelines (2019), and a number of modifications and addenda developed for individual genes [220,226].

In HCM, in addition to the above sources, a mandatory document for interpreting genetic testing results is the guideline for variant interpretation in the MYH7 gene [21].

Recommendations on genetic and clinical testing of relatives

• For probands with HCM in whom variants of uncertain significance (VUS, class III pathogenicity) have been identified, it is recommended to consider performing genetic testing of affected relatives with HCM (segregation analysis) to clarify the pathogenicity class of the variant [3,20,222,223].

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

• If causative genetic variants of class IV–V pathogenicity (pathogenic and likely pathogenic) are identified in a proband with HCM, their adult relatives are recommended to consider genetic testing (cascade family screening) to detect/exclude carriage of the same genetic variants identified in the proband [3,20,21,222,223,227].

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

• If causative genetic variants of class IV–V pathogenicity (pathogenic and likely pathogenic) are identified in a proband with HCM, their minor relatives are recommended to undergo genetic testing (cascade family screening) to detect/exclude carriage of the same genetic variants that were identified in the proband, starting at the age of 10–12 years, unless the family history dictates otherwise [1,3,221–223].

ESC IIaC (LoE 5, GoR C)

• Clinical evaluation, including ECG, echocardiography, and long-term follow-up, is recommended for first-degree relatives who are found to carry the same class IV–V causative genetic variant(s) (pathogenic and likely pathogenic) as the proband [1,3,221–223,228].

ESC IB (Level of Evidence 5, Grade of Recommendation C)

• First-degree relatives who do not carry the same class IV–V causative genetic variant(s) (pathogenic and likely pathogenic) as the proband are recommended to be discharged from further follow-up, but with a recommendation to seek re-evaluation if they develop HCM symptoms or if new clinical data relevant to HCM appear [1,3,221–223].

ESC IC (Level of Evidence 5, Grade of Recommendation C)

• If genetic screening was not performed in the proband with HCM, clinical evaluation with ECG and echocardiography is recommended for first-degree relatives every 2–5 years (or every 6–12 months if diagnostically insignificant anomalies are present) [1,3,221–223,228].

ESC IIa B (Level of Evidence 5, Grade of Recommendation C)

Comment: predictive genetic screening is based on utilizing information about the specific genetic cause of the disease identified in a genotype-positive proband to determine the carrier status of the pathogenic/likely pathogenic variant in their relatives. The purpose of this screening is to determine the need for regular health checks and targeted clinical monitoring in the presence of a pathogenic variant, as well as to rule out the need for such screening in the absence of carriage of this variant.

When performing cascade screening of the proband's family members, it is recommended to combine it with a cardiovascular clinical examination (history, physical examination, ECG, and echocardiography) (see Table 7, Appendix A3).

• In families of probands with HCM who have not been found to harbor pathogenic/likely pathogenic variants (class IV–V) in genes responsible for HCM (genotype-negative), cascade family screening for diagnostic purposes is not recommended [1,3,221–223].

ESC IIIC (Level of Evidence 5, Grade of Recommendation C)

• Regular follow-up and clinical screening are not recommended for genotype-negative relatives of genotype-positive probands with HCM [1,3,221–223].

ESC IIIC (Level of Evidence 5, Grade of Recommendation C)

2.4 Instrumental Diagnostics

Electrocardiography and ECG monitoring

Standard ECG abnormalities may already be observed in carriers of HCM-associated mutations (genotype-positive/LVH-negative), i.e., at the pre-hypertrophic stage of HCM. Such signs include RV1 < RV2 > RV3, repolarization abnormalities, and pathological Q waves (in children). However, when compared with healthy individuals, these changes showed high specificity (98%) but low sensitivity (25%) [229,230].

In patients with the "classic phenotype" of HCM, the 12-lead ECG is abnormal in 75–95% of cases, including signs of LVH, pathological Q waves, and repolarization changes [182,231,232].

In some patients (about 5% of adults and up to 3% of children), the ECG may be normal. In this group, the clinical course of the disease was more favorable compared to patients who had ECG abnormalities [233].

Several patterns characteristic of the "classic phenotype" of HCM are distinguished:

1. Pathological Q waves in inferolateral leads (wherein leads with pathological Q waves show positive T waves—so-called Q/T discordance) + repolarization changes + LVH (Romhilt–Estes criteria);

2. Giant symmetrical inverted T waves in apical HCM (transient deepening of inverted T waves may indicate ischemia requiring revascularization [234]);

3. "Pseudo-STEMI" pattern (ST-segment elevation and/or tall positive T waves in 2 or more consecutive leads in the absence of LBBB) [182];

4. ST-segment depression;

5. Nonspecific ST-segment and T-wave abnormalities on the ECG [235,236].

Fragmented QRS complexes (fQRS) in patients with HCM may indicate the presence of myocardial fibrosis. Furthermore, fQRS can serve as a good candidate marker for predicting ventricular tachyarrhythmias in patients with HCM [237,238].

• Electrocardiography is recommended for all patients at initial evaluation with suspected HCM, after diagnosis during pharmacotherapy titration, following surgical and endovascular interventions, and during follow-up every 12–24 months [3,182,201,205,233,239–242].

ESC IB (Level of Evidence 3, Grade of Recommendation B)

• All patients with HCM experiencing worsening symptoms, during the adjustment of pharmacotherapy, following surgical and endovascular interventions, and during follow-up, are recommended to undergo repeat electrocardiography to detect cardiac rhythm and conduction disorders and myocardial ischemia [3,201,205,233,239–241].

ESC IB (Level of Evidence 3, Grade of Recommendation B)

• All patients with HCM, regardless of symptoms, are recommended to undergo repeat electrocardiography every 1–2 years to detect cardiac rhythm and conduction disorders and myocardial ischemia [3,201,205,233,239–241].

ESC/RCS IIaB (Level of Evidence 3, Grade of Recommendation B)

• Electrocardiography is recommended as a component of the screening algorithm in first-degree relatives of patients with HCM [3,201,205,233,239–241].

ESC IC (LoE 5, GoR C)

Ambulatory ECG monitoring (Holter ECG monitoring) in HCM

Episodes of nonsustained ventricular tachycardia are included in the sudden cardiac death (SCD) risk score. There is mounting evidence that such arrhythmias in young patients with HCM are a more valuable prognostic sign of SCD than in patients older than 35 years.

If the patient has symptoms, Holter ECG monitoring should be continued until these symptoms manifest while wearing the monitor. Some patients with infrequent symptoms may require the use of portable or implantable monitors. Therefore, patients with HCM who experience palpitations or dizziness are recommended to undergo prolonged (> 48 hours) Holter ECG monitoring.

• Holter ECG monitoring is recommended for all patients with HCM, including asymptomatic ones, to detect cardiac arrhythmias (atrial fibrillation and ventricular tachycardia) and conduction disturbances for SCD risk stratification and selection of candidates for implantable cardioverter-defibrillator (ICD)*** implantation [3,129,130,202,205,243–245].

ESC no/RCS IC (Level of Evidence 3, Grade of Recommendation B)

• Holter ECG monitoring (optimally 48–72 hours in duration) is recommended at the initial clinical evaluation, during the adjustment of antiarrhythmic therapy, after surgical and endovascular interventions, and during follow-up every 12–24 months [3,202,205,239,243,246].

ESC IIaC (Level of Evidence 2, Grade of Recommendation C)

Comment: Atrial fibrillation (AF) is the most common rhythm disorder in patients with HCM and a major predictor of heart failure-related mortality. Its prevalence in HCM is significantly higher than in individuals of a similar age in the general population, ranging from 18% to 28%. However, the true prevalence is difficult to estimate due to cases where AF may remain unnoticed. Detecting clinically silent AF, which is discovered only during prolonged Holter ECG monitoring, is crucial for assessing treatment strategy and stroke prevention, since the risk of ischemic stroke in patients with HCM and AF is 8 times higher compared to patients in sinus rhythm [1].

ESC IIaC (Level of Evidence 3, Grade of Recommendation B)

• In patients with HCM and additional AF risk factors (left atrial dilation, advanced age, heart failure NYHA class III–IV) who have no contraindications to anticoagulants, it is recommended to consider performing extended ambulatory ECG monitoring to detect asymptomatic episodes of AF during the initial evaluation, during the selection of pharmacotherapy, and during follow-up (every 12–24 months) [205].

ESC no/RCS IIb C (Level of Evidence 5, Grade of Recommendation C)

Comment: Adequate assessment of rhythm and conduction disorders is critical for SCD risk stratification; therefore, prolonged ECG monitoring is necessary in some cases. In addition to routine 24-hour ECG monitoring, options include: 48/72-hour monitoring, external loop recorder, event recorder, and implantable loop recorder. ECG diagnostics should be repeated every 12–24 months, optimally with a duration of 48 hours.

An indication for Holter ECG monitoring is the onset of patient complaints of palpitations and/or dizziness.

It must be taken into account that rhythm and conduction disorders may be caused by the ongoing therapy.

ECG features helpful in the differential diagnosis of HCM and HCM phenocopies are presented in Table 8, Appendix A3.

Echocardiography

Echocardiography in patients must be performed in accordance with domestic and international echocardiography guidelines by the AHA, ASE (American Society of Echocardiography), and EACI (European Association of Cardiovascular Imaging) [1,194,258,205,251–257].

• All patients with suspected HCM are recommended to undergo transthoracic echocardiography (TTE) with a Valsalva maneuver to detect left ventricular hypertrophy (LVH) and intraventricular obstruction during the initial evaluation [180,205,259–264].

ESC IB (Level of Evidence 4, Grade of Recommendation C)

• In all patients with HCM, measurement of the maximum diastolic left ventricular (LV) wall thickness is recommended to be performed in 2D mode in the short-axis view of the LV across all segments, from the basal levels to the apex [112,254,255,259,265–267].

ESC IC (Level of Evidence 4, Grade of Recommendation C)

• All patients with HCM are recommended a thorough assessment of LV diastolic function, including transmitral flow, pulmonary venous flow, tissue Doppler imaging, and measurement of left atrial size and volume for SCD risk stratification [109,124,180,205,268–272].

ESC IC (Level of Evidence 4, Grade of Recommendation C)

• Symptomatic patients with a maximum LV outflow tract (LVOT) gradient (at rest or provoked) < 50 mmHg are recommended to undergo stress TTE to detect provocable LVOT obstruction and stress-induced mitral regurgitation (MR) [86,125,276,277,132,180,205,262,263,273–275].

ESC IB (Level of Evidence 4, Grade of Recommendation C)

• Asymptomatic patients with a maximum LVOT pressure gradient (at rest or induced) < 50 mmHg are recommended to consider stress TTE if the presence of obstruction is relevant for lifestyle recommendations and medical therapy prescription [86,205,262,273,274].

ESC IIbC (Level of Evidence 4, Grade of Recommendation C)

• In patients with suboptimal image quality, suspected apical LV hypertrophy, apical LV aneurysm, or an atypical hypertrophy pattern, it is recommended to perform contrast-enhanced LV opacification echocardiography as an alternative to cardiac MRI [1,258].

ESC IIaC (LoE 5, GoR C)

• Intracoronary myocardial contrast echocardiography during diagnostic coronary angiography is recommended for patients scheduled for alcohol septal ablation (ASA) to identify a septal branch of the coronary artery suitable for ablation [258,278–281].

ESC IB (Level of Evidence 4, Grade of Recommendation C)

• Repeat echocardiography is recommended for patients with HCM in the event of a change in clinical status, the appearance of new cardiovascular symptoms, or to evaluate the efficacy of ongoing therapy or surgical/endovascular treatment for the timely detection of complications and cardiac remodeling dynamics [86,262,263,282].

ESC IB (Level of Evidence 4, Grade of Recommendation C)

• Echocardiography is recommended as a component of the family screening algorithm for HCM patients if at least one family member is not genotype-negative and a disease-associated gene mutation is identified [183,227].

ESC IC (Level of Evidence 5, Grade of Recommendation C)

Comment: An extended echocardiography protocol adapted for the diagnosis of HCM must be used. The list of parameters included in the transthoracic echocardiography protocol is presented in Table 9, Appendix A3.

Conditions (other than obstructive HCM) that may present with an elevated LVOT pressure gradient and systolic anterior motion (SAM) of the mitral valve are presented in Table 10, Appendix A3.

Additional echocardiographic options can be used for differential diagnosis with phenocopies and when choosing a surgical strategy in HCM, as presented in Table 11, Appendix A3.

Echocardiographic findings that help differentiate HCM from HCM phenocopies are presented in Table 2, Appendix A3 and Table 12, Appendix A3.

Recommendations for transesophageal echocardiography in HCM

• Intra-/perioperative transesophageal echocardiography (TOE) during surgical myectomy is recommended for patients to clarify the mechanism of LVOT obstruction, guide the surgical strategy, assess postsurgical complications, and detect residual LVOT obstruction [256,278,279,283–286].

ESC IC (Level of Evidence 4, Grade of Recommendation C)

ESC IIaC (Level of Evidence 4, Grade of Recommendation C)

• In patients with HCM undergoing ASA, it is recommended to perform intraoperative TOE with intracoronary myocardial contrast to correctly identify the target ablation zone [258,278–281].

ESC IIaC (Level of Evidence 4, Grade of Recommendation C)

Performing the Valsalva maneuver to diagnose latent LVOT obstruction

The Valsalva maneuver during TTE should be performed with the patient in the left lateral decubitus position. The patient should strain the anterior abdominal wall muscles, which increases intra-abdominal and intrathoracic pressure. It is advisable to monitor the strain level using a device consisting of a pressure gauge connected to a mouthpiece; the patient is asked to maintain the effort so that the pressure gauge reads 20–40 mm Hg. During the Valsalva maneuver, the peak blood flow velocity in the LVOT is recorded using continuous-wave Doppler. If the test is negative in the supine position, performing it in the sitting and standing positions is recommended.

Magnetic resonance imaging

• Cardiac MRI with contrast enhancement (in the absence of contraindications) is recommended to be performed at least once after the diagnosis of HCM is established to refine TTE data (cardiac anatomy, ventricular function), as well as to detect and assess the extent of myocardial fibrosis and rule out HCM phenocopies and other diseases [287, 288].

ESC IB (Level of Evidence 4, Grade of Recommendation C)

Comment: the need for MRI arises because TT-echocardiography may incorrectly assess myocardial thickness in certain LV segments, especially apical ones, and fail to detect small apical aneurysms.

• Cardiac MRI with contrast enhancement (in the absence of contraindications) is recommended for patients indicated for septal reduction therapy in whom TT-echocardiography fails to determine the anatomical mechanism of LVOT obstruction, to justify the choice of the septal reduction method [1, 289].

ESC no / RKS IC (LOC 5, LEV C)

ESC no/RCS IIb C (Level of Evidence 5, Grade of Recommendation C)

ESC no/RCS IIb C (Level of Evidence 5, Grade of Recommendation C)

ESC no / RKS IIbC (LOC 5, LEV C)

• In patients with suspected HCM phenocopies (cardiac amyloidosis and others, see Appendix, Tables 1/A3, 5/A3, 7/A3, 11/A3), cardiac MRI with contrast enhancement is recommended to identify specific patterns characteristic of particular phenocopies [72, 76, 208, 290–294].

ESC IIaC (LOC 4, LEV C)

Comments: in patients with suspected cardiac amyloidosis, it is recommended to use the QALE score for the initial differential diagnosis between TTR amyloidosis and AL amyloidosis during contrast-enhanced cardiac MRI [295]. The QALE score is provided in the Appendix (Table P6/G2. QALE: Score for the differential diagnosis of transthyretin amyloidosis using contrast-enhanced cardiac MRI.)

ESC IIaC (LOC 4, LEV C)

• Analysis of cardiac and vascular MRI images is recommended to be performed by specialists experienced in cardiac imaging and the evaluation of myocardial diseases [3, 78, 296–298].

ESC IC (Level of Evidence 4, Grade of Recommendation C)

ESC no/RCS IIb C (Level of Evidence 5, Grade of Recommendation C)

Comment: MRI does not have the inherent limitations of echocardiography and is the "gold standard" for assessing myocardial thickness as well as LV and RV volumes (higher measurement accuracy and reproducibility, lower operator dependency); therefore, in the absence of contraindications and if resources and expertise permit, MRI should be considered as a baseline imaging modality for patients with HCM [278, 297–300].

MRI also makes it possible to examine structural changes in the myocardium, i.e., the genesis, presence, and extent of myocardial fibrosis. The technique is based on the phenomenon of late gadolinium enhancement (LGE) in areas of myocardial fibrosis, which is the delayed washout of a Gd-containing contrast agent when scanning the heart 10–15 minutes after its intravenous administration. The presence of extensive fibrosis is a predictor of negative remodeling, the development of systolic dysfunction, and heart failure (HF), and is also classified as an additional risk factor for SCD. If myocardial fibrosis of the LV is present in an amount of ≥ 15% of the LV mass, the risk of SCD increases significantly.

MRI reveals 2 main patterns of fibrosis:

1. Markedly heterogeneous intramural fibrosis within the most thickened segments, which at the histological level reflects the direct effect of the "causative" genetic variant and molecular pathogenesis, manifesting as myocyte and muscle fiber disarray – the "disarray" phenomenon, accompanied by varying degrees of fibrosis.

2. Areas of fibrosis can be detected in the IVS in the anterior and/or posterior regions, at the junction sites of the right and left ventricular walls (the so-called "right ventricular insertion points"). It is believed that this type of fibrosis may be observed as early as the initial stages of disease and is frequently found in HCM, although it is not entirely specific to this disease. Such a contrast enhancement pattern may also occur in the "athlete's heart" or arrhythmia-induced cardiomyopathy. This is believed to be interstitial fibrosis or an intermediate phenotype of the preclinical stage, in its early phase [114,278,301].

Parameters that need to be evaluated during cardiac MRI in a patient with HCM are presented in Table 13, Appendix A3.

In mutation carriers at the pre-hypertrophic stage of HCM, MRI can detect "minor cardiac anomalies" – myocardial crypts, mitral valve anomalies, and apical displacement of the papillary muscles. At the preclinical stage, some genotype(+)/phenotype(-) patients may exhibit areas of LGE (see the diagnostic algorithm for the preclinical stage) [299,302,303].

Cardiac MRI also reveals anomalies of the mitral valve apparatus (see Table 13, Appendix A3).

In addition to its significance in the diagnosis of HCM, cardiac MRI plays a role in diagnosing HCM phenocopies. In amyloidosis, areas of LGE are predominantly identified in the intramural and subendocardial regions of the ventricles. This enhancement does not depend on myocardial blood supply zones and can be observed in all cardiac structures. Cardiac amyloidosis is also characterized by the presence of fluid in the pericardial cavity and thickening of the IVS [293,294].

In Anderson-Fabry disease, the presence of intramyocardial LGE is most commonly located in the posterolateral segment at the basal and mid-ventricular levels [304]. In athletes with LVH, LGE areas are absent (for exceptions, see the "HCM and LVH in Athletes" section) [305].

Computed Tomography/Multislice Computed Tomography

• For patients with HCM who have poor echocardiographic image quality and for whom MRI is contraindicated for evaluating myocardial thickness and ventricular chamber dimensions, it is recommended to perform ECG-synchronized cardiac CT/MSCT with cardiac contrast enhancement and evaluation of left ventricular myocardial thickness at end-diastole [1,205,278,306].

ESC IIaC (LoE 5, GoR C)

Comment: Myocardial thickness measurement during cardiac CT/MSCT should be performed at end-diastole.

In addition to anatomical data of the heart, cardiac CT also allows for the visualization of coronary arteries, assessment of their patency and anatomical features, and the presence of myocardial "muscle bridges," which plays an important role in the diagnosis of coronary artery disease, including in elderly patients with HCM. Cardiac CT/MSCT also reveals left ventricular wall diverticula and crypts – signs of HCM at an early stage of disease development.

Cardiac MSCT, which has high spatial resolution, enables accurate measurement of myocardial thickness and mass, ventricular volumes, and ejection fraction. A comparative study demonstrated high accuracy of the MSCT method, comparable to the results of cardiac MRI [307,308].

Compared to MRI, the disadvantages of MSCT are lower temporal resolution, radiation exposure to the patient during the scan, and low soft tissue contrast when assessing late enhancement, which allows only large zones of fibrosis to be evaluated [308].

Scintigraphy

ESC IIaB (LoE 3 GoR B)

Comment: myocardial scintigraphy (SPECT) can also be used for instrumental diagnosis of ischemia and to confirm the significance of epicardial coronary artery stenosis when coronary angiography shows borderline stenosis severity.

When cardiac amyloidosis is suspected, the next step is the differential diagnosis between ATTR amyloid cardiomyopathy and cardiac involvement in AL amyloidosis. Historically, endomyocardial biopsy has been the gold standard for diagnosis. Currently, a non-invasive approach using bone-seeking radiotracer myocardial scintigraphy is also available. First described by Gilmore in 2016, this approach was included in the 2019 expert consensus recommendations [311,312].

Bone scintigraphy with radiotracers can be performed using any of 3 different phosphonates, but only 99mTc-pyrophosphate (technetium pyrophosphate) is widely used in the Russian Federation. The American Society of Nuclear Cardiology (ASNC) recently issued practical guidelines for 99m-technetium pyrophosphate imaging, noting its high sensitivity and specificity in detecting ATTR amyloid cardiomyopathy and the ability to differentiate it from other types of cardiac amyloidosis without the need for biopsy.

There are two approaches to the quantitative analysis of myocardial radiotracer uptake: semiquantitative and quantitative. The semiquantitative approach involves visual comparison with bone (rib) uptake at 3 hours:

Grade 0 – no heart uptake and normal bone (rib) uptake;

Grade 1 – heart uptake present, but less than rib uptake;

Grade 2 – heart uptake equal to rib uptake;

Grade 3 – heart uptake greater than rib uptake with mild or absent rib uptake.

When cardiac amyloidosis is suspected, a myocardial uptake grade of 2 or 3 (planar scintigraphy and SPECT), combined with laboratory tests to rule out AL amyloidosis, confirms the diagnosis of ATTR-CM.

It is important to note that if any planar uptake is present, single-photon emission computed tomography should be performed to ensure that the observed uptake is located in the myocardium and not in the blood pool or adjacent bone structures.

Alternatively, the quantitative approach involves a region of interest placed over the myocardium and a similarly sized region of interest placed over the contralateral lung. The ratio of uptake in the cardiac region of interest to the contralateral lung can determine the presence of ATTR-CM:

1. A ratio greater than 1.5 indicates ATTR-CM

2. A ratio from 1.0 to 1.5 is indeterminate

3. A ratio of less than 1 does not indicate ATTR-CM

Regardless of the nuclear scintigraphy results, this study should always be combined with testing for AL amyloidosis.

Furthermore, 99mTc-pyrophosphate scintigraphy allows for precise differential diagnosis of AL and ATTR cardiac amyloidosis (provided monoclonal gammopathy of undetermined significance is excluded) [69,291].

Positron Emission Tomography

Myocardial positron emission tomography (PET) can be used for the instrumental diagnosis of ischemia and to confirm the significance of epicardial coronary artery stenosis when coronary angiography shows borderline stenosis severity [205].

PET and MRI are the preferred methods for assessing perfusion in heart failure.

PET can be used to study coronary perfusion and myocardial metabolism (radiopharmaceuticals: Fludeoxyglucose (18F) (ATC: V09IX04 Fludeoxyglucose [18F]), sodium acetate ([1-11C]), Nitrogen-13 (ATC V09GX Other diagnostic radiopharmaceuticals for the cardiovascular system), water (¹⁵O), Rubidium (82Rb) chloride (ATC V09GX04)) and to diagnose cardiac autonomic dysfunction.

In HCM, impaired neurotransmitter reuptake and decreased beta-adrenoreceptor density may be detected.

Coronary Angiography

CAG is the method of choice for diagnosing the presence and severity of obstructive epicardial coronary artery disease.

• In adult patients with HCM and aborted SCD (after successful resuscitation), patients with sustained VT, and patients with stable angina ≥ CCS class 3, invasive CAG or CT angiography is recommended to diagnose obstructive epicardial coronary artery disease [1,3,92,205,313].

ESC IC (LoE 5 GoR C)

• In patients with HCM presenting with typical chest pain (< CCS class 3 angina) who have an intermediate pre-test probability of atherosclerotic coronary artery disease based on age, gender, and atherosclerosis risk factors, CAG or CT angiography is recommended to diagnose obstructive epicardial coronary artery disease [1,3,92,205,306,314].

ESC IIa C (Level of Evidence 5, Grade of Recommendation C)

• In all patients with HCM older than 40 years, CAG or CT coronary angiography is recommended prior to septal reduction therapy, regardless of the presence of typical anginal symptoms, to diagnose obstructive epicardial coronary artery disease [3,306,315,316].

ESC IIaC (LoE 4 GoR C)

Comment: the need for CAG is dictated by clinical management requirements. In patients with HCM and INOCA, stenting may be required at a lesser degree of stenosis than conventionally accepted for CAD patients, i.e., at stenoses < 50% (see sections "Diagnosis of HCM in Specific Patient Categories" and "Pathogenesis") [92,94,100,103,317].

Invasive measurement of intracardiac pressure

ESC IB (Level of Evidence 3, Grade of Recommendation B)

• In symptomatic patients with inconclusive non-invasive cardiac imaging results, it is recommended to consider transvenous cardiac catheterization (left and right heart) to assess the severity of LVOT/RVOT obstruction and measure LV/RV filling pressures [87].

ESC IIbC (LoE 4 GoR C)

Electrophysiological Testing

• Intracardiac electrophysiological study is recommended for patients with documented persistent or recurrent supraventricular tachycardias (atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, accessory pathway-mediated tachycardia) and patients with ventricular pre-excitation syndrome to identify the ablation substrate and guide treatment [139,248,324–327].

ESC IC (Level of Evidence 4, Grade of Recommendation C)

• For selected patients with documented, symptomatic, monomorphic sustained (> 30 s) VT, it is recommended to consider performing an intracardiac electrophysiological study to identify the ablation substrate and guide treatment [139,326,328,329].

ESC IIbC (LoE 4 GoR C)

Comment: intracardiac electrophysiological study with programmed ventricular stimulation is not recommended as a routine procedure for SCD risk stratification in patients with HCM [3,128,239,328].

Stress Tests

ESC IIaB (LoE 4 GoR C)

• In symptomatic patients with HCM who have a resting maximum LVOT gradient < 30 mmHg and a Valsalva gradient < 50 mmHg, exercise TTE (stress-ECHO) is recommended to detect and quantify dynamic LVOT obstruction [1,194,274,277,332,333].

ESC IB (LoE 3 GoR B)

• In asymptomatic patients with HCM who have a resting maximum LVOT gradient < 30 mmHg and a provoked gradient < 50 mmHg during the Valsalva maneuver, TTE under load (stress echocardiography) is recommended to detect and quantify dynamic LVOT obstruction [1,194,274,277,332,333].

ESC IIa C (LoE 5 GoR C)

• In patients with HCM whose etiology of symptoms or exercise intolerance is unclear, it is recommended to consider an exercise stress test prior to septal reduction therapy [1].

ESC none / RSC IIb C (LoE 5 GoR C)

• In patients with HCM whose etiology of symptoms or exercise intolerance remains unclear during follow-up, it is recommended to consider performing an exercise stress test [1].

ESC none / RSC IIb C (LoE 5 GoR C)

Comment: types of stress tests are presented in Table 14, Appendix A3.

Questions that stress echocardiography must answer (to be included in the report):

1. Rate of LVOT gradient increase at peak exercise and during the recovery period.

2. Blood pressure response to exercise.

3. Whether LV myocardial ischemia is induced by exercise.

4. Worsening of diastolic dysfunction (E/A, E/e’).

5. Degree of change in mitral regurgitation during stress echocardiography (dynamic MR).

The most suitable method for stress echocardiography in patients with HCM is the supine bicycle ergometer, which allows echocardiographic images to be acquired at different stages of the exercise test (it is recommended to record parameters at the 50 W exercise stage, at peak exercise, and during the recovery period). The use of a treadmill and an upright bicycle ergometer does not allow echocardiographic parameters to be recorded during exercise; therefore, recordings are made immediately after its cessation and in the recovery period. It has been shown that the maximum LVOT gradient at peak exercise and immediately after its cessation are almost identical [274].

The Bruce protocol or modified Bruce protocol is used for the treadmill test. For cycle ergometry, the test stages are – 50-100-150 W.

In patients with HCM, dobutamine stress echocardiography is not recommended due to the high risk of inducing ventricular tachyarrhythmias. In addition, dobutamine can provoke an increase in the LVOT gradient in patients without HCM.

During the exercise test, ECG (continuously), blood pressure (every 2 min), and changes in clinical symptoms are recorded.

The blood pressure response to exercise is an important part of exercise testing.

An inadequate blood pressure response is considered to be:

1. Hypotensive response (blood pressure at peak exercise is lower than baseline, or if blood pressure rises slightly during the initial exercise stages and drops by more than 20 mmHg below this level at peak exercise);

2. Inadequate increase in blood pressure at peak exercise (less than 20 mmHg).

   Criteria for terminating the exercise test:

   - Attainment of submaximal heart rate;

   - Severe fatigue and dyspnea;

   - Chest pain;

   - Hypotension (decrease in blood pressure ˃20 mmHg from baseline);

   - Life-threatening ventricular tachyarrhythmias [86,194,273–277,333,334].

Cardiopulmonary exercise testing

• In symptomatic patients with HCM and LV systolic and/or diastolic dysfunction, cardiopulmonary exercise testing (CPET) with simultaneous respiratory gas analysis is recommended to determine indications for heart transplantation or mechanical circulatory support [3,318–320,322,323,335–338].

ESC IB (LoE 3 GoR B)

• In patients with HCM, regardless of symptoms, it is recommended to perform cardiopulmonary exercise testing (or standard treadmill testing, or cycle ergometry if the former is unavailable) to assess the severity and mechanism of exercise intolerance and systolic blood pressure changes [3,336,339,340].

ESC IIaB (LoE 4 GoR C)

ESC IIaC (LOC 4, LEV C)

2.5 Other Procedures

Myocardial and abdominal fat biopsy

ESC IIaC (LOC 4, LEV C)

ESC IIaB (LoE 2 GoR B)

Comment: subcutaneous adipose tissue biopsy is more informative in AL amyloidosis and hereditary TTR amyloidosis.

Endomyocardial biopsy is not required if cardiac scintigraphy shows Perugini grade 2 or 3 radiopharmaceutical uptake and AL amyloidosis has been ruled out by laboratory testing.

Endomyocardial biopsy is indicated if scintigraphy results are equivocal (Perugini grade 0 or 1 uptake), abdominal fat biopsy is negative, hematological tests are negative, and there is a high probability of ATTR amyloidosis.

2.6 Diagnosis of the disease in specific patient categories

Differential diagnosis between HCM and LVH secondary to arterial hypertension

The natural course of HCM is influenced by cardiometabolic risk factors (hypertension, obesity/overweight), the prevalence of which increases with age [345–349].

In older age groups of patients with proven HCM, the prevalence of hypertension is 70–90%. By definition, LV myocardial hypertrophy in HCM is not caused by pressure overload, but hypertension is a pressure overload; therefore, when HCM is coexistent with hypertension, modification of HCM criteria is required.

The probability of HCM in patients with hypertension increases in the presence of one or more of the following criteria:

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

2. Discrepancy between pronounced LV hypertrophy (maximum wall thickness ≥ 15 mm) and recently onset mild-to-moderate hypertension with adequate patient adherence to therapy, as well as the absence of other causes capable of inducing a similar degree of LVH.

A potential variant of the HCM criterion in concomitant hypertension is an LV myocardial thickness ≥ 20 mm; a myocardial thickness of 15–20 mm represents a "gray zone".

The choice of the HCM criterion "LV wall thickness ≥ 20 mm" in concomitant hypertension is due to evidence showing that with pressure overload (hypertension, aortic stenosis, or their combination), LV myocardial thickness generally does not exceed 20 mm (in some studies, it exceeds 20 mm in only isolated patients) [100,334,356,345,346,350–355].

If a patient's detected myocardial thickness falls in the "gray zone" (15–20 mm), a diagnosis of HCM can only be made based on a careful analysis of numerous factors: family history, duration of hypertension, level of "pressure load" (episodic blood pressure spikes or stably elevated blood pressure), patient adherence to antihypertensive therapy, presence of ECG/echocardiographic changes prior to the development of hypertension, dynamics of cardiac chamber dimensions and increased LV wall thickness on echocardiography/MRI, etc. [53].

It should also be taken into account that asymmetrical LVH may be observed in hypertension—according to some data, up to 20% (i.e., IVST/PW thickness ratio > 1.5) [352,354].

HCM and basal septal hypertrophy (sigmoid IVS with a "bulge" in the basal segment)

In elderly patients with a sigmoid IVS, a "bulge" may be detected in the basal part of the septum, which is not caused by HCM. As a rule, these patients have concomitant hypertension and/or aortic valve disease (mild aortic regurgitation and/or mild aortic stenosis) [265,266,352,353,357].

Basal septal hypertrophy can lead to an increased LVOT gradient, typically not exceeding 15–20 mmHg at rest and rising up to 35 mmHg during exercise tests [334].

The differential diagnosis algorithm for HCM and basal septal hypertrophy is presented in Table 15, Appendix A3.

HCM and type 1 and type 2 myocardial infarction

Clinically, patients with HCM and myocardial ischemia (INOCA) may develop acute coronary syndrome and myocardial infarction (MI) [92,94,106,314].

MI with non-obstructive epicardial coronary arteries (MINOCA) is a "working diagnosis" that requires clarification of the underlying cause in each individual patient.

The following pathogenetic mechanisms may be discussed in the genesis of MI in HCM:

1. Ischemia with non-obstructive coronary arteries (INOCA – Ischemia with Non-Obstructive Coronary Arteries) (see the "Pathogenesis" section);

2. Ischemia with obstructive epicardial coronary artery disease—CAD in older patients with HCM (see also Table 2, Appendix A3).

Type 1 MI can develop in HCM; its diagnosis and treatment are outlined in the relevant clinical guidelines.

To rule out/confirm obstructive epicardial coronary artery disease, patients with HCM are indicated for invasive coronary angiography or CT coronary angiography.

Simultaneously with coronary angiography, it is recommended that patients with HCM undergo left ventriculography, which reveals either an "epicardial pattern" (contractility disturbance zones within stenosed coronary arteries) or a "microvascular pattern" (contractility disturbance zones in the territories of different coronary arteries, including without stenoses) [92,94,361–363,95,103,104,106,317,358–360].

This phenomenon is referred to in Russian literature as MINOCA (myocardial infarction with non-obstructive coronary arteries) or type 2 MI. Type 2 MI (MINOCA) is an MI developing without atherothrombosis, due to a mismatch between myocardial oxygen demand and supply.

Ischemia with non-obstructive coronary arteries (INOCA) shares a common pathogenetic mechanism in both cardiomyopathies and HCM phenocopies, such as cardiac amyloidosis [72].

HCM and LVH in athletes

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

• In patients with HCM, regardless of age, sex, race, presence of LVOT obstruction, prior surgical myectomy or alcohol septal ablation, or ICD implantation***, participation in competitive sports and high-intensity exercise is not recommended (contraindicated) [3,20,137,199,244,324,364–367].

ESC III C (LoE 5 GoR C)

Comment: due to the high risk of SCD, participation in high-intensity competitive sports is contraindicated in patients with HCM.

• For the majority of patients with HCM, it is recommended to consider engaging in light- to moderate-intensity physical exercise (without systematic training and competitive participation) to improve functional status, physical rehabilitation, and quality of life [1,2].

ESC none / RSS IIb C (LoE 5 GoR C)

• For most patients with HCM, it is recommended to consider participation in low-intensity sports competitions after a comprehensive risk assessment and shared discussion with experts [1,2].

ESC none / RSS IIb C (LoE 5 GoR C)

• In carriers of class IV-V genetic variants (pathogenic/likely pathogenic) without phenotypic manifestations, it is recommended to consider participation in sports competitions of any intensity [1,2].

ESC none / RSS IIb C (LoE 5 GoR C)

• In patients with HCM, ICD implantation*** is not recommended solely for the purpose of enabling participation in sports competitions [1,2].

ESC none / RSS IIIC (LoE 5 GoR C)

Comment: for phenotype-negative carriers of class IV-V genetic variants (pathogenic/likely pathogenic), recommendations regarding the optimal level of physical activity and nature of physical exertion should be formulated following a multidisciplinary team conference (including a geneticist, cardiologist, sports medicine physician, medical psychologist, etc.) based on the identified mutation, results of regular and repeated clinical evaluations (contrast-enhanced cardiac MRI, stress tissue Doppler echocardiography), taking into account SCD risk stratification using European and American models.

It should be noted that in some cases, transthoracic echocardiography (TTE) may incorrectly assess LV wall thickness. For instance, in the study by Huurman R et al., nearly 25% of genotype(+)/phenotype(-) carriers on TTE were reclassified as genotype(+)/phenotype(+) after cardiac MRI [287]. This is of fundamental importance when making recommendations to athletes regarding eligibility for competition.

Elite athletes with LVH and an LV wall thickness of ˃ 13 mm (13–15 mm) account for only a small fraction (1.5–1.7%). As a rule, these are athletes with a large body mass. It is precisely in this group that differential diagnosis with HCM is required [244,365,367].

The most commonly used parameters for the differential diagnosis of HCM and adaptive LVH in athletes are presented in Table 16, Appendix A3.

An important differential diagnostic sign is the detection of late gadolinium enhancement (LGE) on contrast-enhanced cardiac MRI. As a rule, this indicates in favor of HCM, although the absence of LGE does not rule out the disease. However, athletes with LVH engaged in endurance sports (marathon runners, cyclists, etc.) may exhibit isolated small areas of LGE.

When analyzing athletic LVH, the following factors must also be taken into account: type of sport and training intensity, age, sex (LVH is greater in men), height, and weight of the athlete. The final conclusion regarding the diagnosis of HCM in an athlete is made based on a comprehensive assessment of as many parameters as possible.

2.7 Risk stratification and primary and secondary SCD prevention strategies

Annual cardiovascular mortality rates in adult patients with HCM are 1–2%. SCD, heart failure, and thromboembolic complications are the main causes.

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.

Cases of violent death or death resulting from poisoning, asphyxia, trauma, or any other accident are not classified as SCD.

The 10-year risk of SCD in patients with HCM without traditional risk factors is 5.9% [3,134].

• The 5-year risk of SCD is recommended to be assessed at the initial evaluation of a patient with HCM and subsequently reassessed every 1–3 years or whenever clinical status changes [3,131,139,243,368,369].

ESC I C (LoE 3 GoR B)

• The HCM Risk-SCD score is recommended as a method for estimating the 5-year risk of sudden death in patients with HCM ≥ 16 years of age without resuscitated cardiac arrest due to ventricular tachycardia/ventricular fibrillation (VT/VF) or spontaneous sustained VT causing syncope or hemodynamic compromise [3,131,133,139,241,242,261,327].

ESC IB (Level of Evidence 3, Grade of Recommendation B)

Comment: detection of life-threatening ventricular arrhythmias and bradyarrhythmias is carried out using surface resting ECG, Holter ECG monitoring, external or implantable loop recorders, as well as exercise testing [241].

Also, recent studies have shown that the detection of ECG with J-point elevation and QRS slurring/notching or the presence of a J-wave on the descending limb of the R wave ≥ 1 mm in two or more leads (usually inferolateral) excluding V1–V3 was positively associated with events such as SCD, ventricular arrhythmias, and ventricular fibrillation [370].

Regardless of the nosology, the vast majority of life-threatening ventricular arrhythmias (83.4%) are caused by myocardial electrical instability. SCD is more frequently caused by VF (62.4%), bradyarrhythmias (16.5%), Torsades de pointes VT (12.7%), and VT (8.3%).

Nonsustained VT – VT consisting of at least 3 ventricular complexes, with a rate ≥ 120 bpm and a duration of no more than 30 seconds, terminating spontaneously. VT may be monomorphic (unchanged QRS morphology in 12 leads) or polymorphic (QRS configuration changes during VT on a 12-lead ECG).

Sustained VT (monomorphic, polymorphic) – VT lasting longer than 30 seconds, often not terminating spontaneously.

Ventricular fibrillation – irregular ventricular rhythm (usually > 300 bpm) with marked variability in cycle length, morphology, and amplitude of QRS complexes.

There are two SCD risk stratification models:

1. Based on traditional risk factors (American model);

2. Based on individual risk score calculation, personalized approach (European model) – HCM Risk-SCD score.

The HCM risk assessment score in patients with HCM (European model) is presented in Table P2, Appendix G2.

The HCM SCD risk "calculator" based on the European model is available at http://doc2do.com/hcm/webHCM.html (http://doc2do.com/hcm/webHCM.html).

The HCM risk assessment score in patients with HCM (American model) is presented in Table P3, Appendix G2 (see calculator at https://professional.heart.org/en/guidelines-and-statements/hcm-risk-calculator).

The European HCM Risk-SCD prediction model has limitations:

1. Not applicable to patients older than 80 years and younger than 16 years;

2. Not applicable to patients with HCM phenocopies or athletic LVH;

3. After surgical myectomy.

Following alcohol septal ablation, the HCM Risk-SCD score (European) may be used. The ASA-SCARE Risk Score model for predicting SCD risk is currently undergoing validation [371].

A modification of the calculation formula has been introduced using factors such as maximum LV wall thickness (in the HCM Risk-SCD Calculator, it is recommended to enter no more than 35 mm) (testing of the new model is ongoing) [243].

The algorithm for primary and secondary prevention of SCD in patients with HCM is presented in Appendix B7.

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

Treatment of HCM includes medical therapy, endovascular interventions, surgical and non-surgical methods of septal reduction, mechanical circulatory support, and heart transplantation.

Recommendations for the treatment of HCM are based on data regarding the efficacy and safety of pharmacological agents derived primarily from observational studies.

Pharmacotherapy in HCM mainly improves symptoms and prevents complications (anticoagulation therapy for atrial fibrillation, amiodarone for pharmacological cardioversion and prevention of AF recurrence, treatment of ventricular arrhythmias, etc.) [180,372–374].

The only interventions in HCM believed to influence long-term prognosis are surgical myectomy and implantable cardioverter-defibrillator (ICD) placement [369,375–380].

Management of comorbidities in HCM is discussed in the relevant sections (arterial hypertension, angina pectoris, acute coronary syndrome, heart failure).

Correction of cardiovascular risk factors (dyslipidemia, diabetes mellitus, etc.) in patients with HCM is recommended in accordance with current clinical guidelines [381].

3.1 Pharmacotherapy

3.1.1 Approaches to pharmacotherapy at the hypertrophic stage of HCM in asymptomatic patients

ESC IIIC (LE 5, GRD C)

ESC IIb C (LE 4, GRD C)

Comment: whether a patient is symptomatic or asymptomatic is determined by the physician after a detailed examination.

These patients often have limited exercise tolerance, which is exacerbated by food intake.

The issue of distinguishing true absence of symptoms from lifestyle adaptation must be resolved by performing an exercise stress test and assessing dynamic changes in CHF biomarkers.

Annual re-evaluation of SCD risk is required, including ECG, Holter monitoring, and echocardiography.

The management algorithm for asymptomatic patients with HCM is presented in Appendix B1.

3.1.2 Pharmacotherapy in symptomatic patients with HCM

General principles of pharmacotherapy:

1. Treatment of patients with obstructive and non-obstructive forms of the disease has significant differences.

2. Treatment must be tailored to the unique characteristics of each individual patient.

3. Drugs traditionally used in the treatment of HCM possess negative inotropic effects and aim to relieve or alleviate the symptoms of the disease.

4. Right ventricular obstructive HCM and biventricular obstructive HCM are treated according to the same principles as LVOT obstruction.

3.1.3 Pharmacotherapy for left ventricular outflow tract obstruction

• In patients with obstructive HCM, treatment with any medications is recommended to start with minimal doses and careful titration over a sufficiently long period [1,3,20,40,64,65,382,384].

ESC IB (LE 3, GRD B)

Comment: a simplified algorithm for the diagnosis and treatment approaches for obstructive forms of HCM is presented in Appendix B2. The pharmacotherapy algorithm for obstructive HCM is presented in Appendix B3.

• In patients with LVOT obstruction (resting and provoked), beta-blockers titrated to the maximum tolerated dose are recommended as first-line therapy to reduce symptoms [1,3,20,149,382,384–387].

ESC IB (Level of Evidence 3, Grade of Recommendation B)

Comment: rules and specific features of prescribing beta-blockers are presented in Table 17, Appendix A3.

• Verapamil** titrated to the maximum tolerated dose is recommended for patients with LVOT obstruction (resting or provoked) who do not tolerate beta-blockers or have contraindications to their use [1,3,20,382,383,388,389].

ESC IB (LE 2, GRD B)

Comment: rules and specific features of prescribing verapamil** are presented in Table 18, Appendix A3.

ESC IIa C (LE 2, GRD B)

Comment: recommended starting and target doses for HCM pharmacotherapy are presented in Table 19, Appendix A3.

Patients with HCM and mid-ventricular LV obstruction are recommended high doses of beta-blockers (bisoprolol**), verapamil**, or diltiazem. The response to high doses of beta-blockers, verapamil**, or diltiazem in patients with HCM and mid-ventricular LV obstruction is often suboptimal. This cohort of patients typically presents with a symptomatic clinical course characterized by an increased risk of CHF progression and SCD. The detection rate of LV apical aneurysm ranges from 10% to 25%. The optimal management strategy for such patients should be determined by a multidisciplinary team [89–91,390–394].

The algorithm for the management and treatment of CHF in HCM is presented in Appendix B4.

• Patients with obstructive HCM and acute hypotension unresponsive to fluid administration are recommended intravenous phenylephrine** or other vasoconstrictors without inotropic activity, alone or in combination with beta-blockers [1,3,20,149,382].

ESC IC (LoE 5 GoR C)

• Patients with HCM and LVOT obstruction (resting or provoked) are not recommended the use of organic nitrates and phosphodiesterase inhibitors [1,3,20,382].

ESC IIIC (Level of Evidence 5, Grade of Recommendation C)

• Patients with HCM and LVOT obstruction (resting or provoked) are not recommended the use of dihydropyridine calcium channel blockers (selective calcium channel blockers with predominantly vascular effects) of the dihydropyridine derivative class (nifedipine**) [1,3,20,382].

ESC IIIC (LE 5, GRD C)

Comment: the main undesirable mechanism of action of organic nitrates and phosphodiesterase inhibitors is due to an increase in LVOT obstruction.

• Digoxin** is not recommended in patients with HCM and LVOT obstruction (resting and provoked) [156,395].

ESC IIIC (LE 5, GRD C)

• Verapamil** is not recommended for patients with obstructive HCM in the presence of systemic hypotension and severe dyspnea at rest [1,382,385,396].

ESC IIIC (Level of Evidence 5, Grade of Recommendation C)

3.1.4 Treatment of CHF in patients with HCM

The prevalence of CHF in patients with HCM ranges from 17% to 67% depending on the functional class [150,397,398].

CHF in patients with HCM manifests in two phenotypes: with preserved LVEF in 85–90% of cases, and with reduced LVEF in 8–10% of cases, which develops at a later stage of HCM or as a result of other comorbidities [149,154,185,186].

CHF is prevalent in the majority of patients with obstructive HCM and in 10% of patients without obstruction. Acute heart failure in HCM is rare and may be triggered by conditions such as tachyarrhythmia, myocardial infarction, acute or worsening mitral regurgitation, or comorbidities [399,400].

• In patients with HCM who develop symptoms of CHF, it is recommended to perform diagnostics in accordance with the clinical guidelines for CHF [155].

ESC IC (LoE 5 GoR C)

• In patients with HCM and CHF, regardless of LVEF, it is recommended to consider non-pharmacological recommendations (education, diet, weight loss, salt restriction, physical activity) depending on the CHF functional class in accordance with the clinical guidelines for CHF [155,156].

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

• In patients with non-obstructive HCM and CHF, it is recommended to consider prescribing medications in accordance with the clinical guidelines for CHF [1,3,150,155,156,401].

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

Comment: in the presence of congestion signs, to avoid hypovolemia, cautious use of low doses of loop or thiazide diuretics is recommended [156]. Verapamil/diltiazem are recommended in patients with CHF and preserved LVEF > 50% if beta-blockers are contraindicated, not tolerated, or ineffective [156].

• In patients with obstructive HCM and CHF, it is recommended to use non-vasodilating beta-blockers as first-line therapy to reduce clinical symptoms of CHF and decrease the gradient in the LVOT [1,3,150,155,156,387].

ESC IIa B (LE 2, GRD B)

Comment: verapamil**/diltiazem in patients with obstructive HCM and CHF with preserved LVEF > 50% may be considered as first-line therapy if beta-blockers are contraindicated, not tolerated, or ineffective [156].

• In patients with obstructive HCM and CHF in the presence of congestion signs, it is recommended to consider prescribing low doses of loop or thiazide diuretics [156].

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

Comment: conditions that lead to a decrease in circulating blood volume (hypovolemia) should be avoided to prevent an increase in the LVOT gradient.

• In patients with obstructive HCM and CHF, ACE inhibitors/ARBs and digoxin** are not recommended due to the risk of increasing the LVOT gradient [156,395].

ESC III C (LE 5, GRD C)

Comment. Spironolactone** does not improve CHF symptoms in patients with HCM [402].

Drugs recommended for the treatment of CHF with reduced, mildly reduced, and preserved LVEF [155], such as sodium-glucose cotransporter 2 inhibitors, eplerenone, sacubitril/valsartan**, ivabradine**, and omega-3 polyunsaturated fatty acids, have not been studied in obstructive HCM and CHF. The decision to prescribe these drug classes to patients with obstructive HCM and CHF can only be made by a multidisciplinary team.

Myocardial hypercontractility is a key pathophysiological mechanism in HCM and the main factor determining dynamic left ventricular outflow tract obstruction. Available pharmacological treatment options for hypertrophic cardiomyopathy are not disease-specific. Clinical trials are underway for drugs with targeted effects on the primary pathogenetic mechanism [403].

3.1.5 Treatment of angina pectoris in patients with HCM

Angina pectoris/myocardial ischemia is a frequently occurring syndrome in patients with HCM [404].

The pathogenetic mechanisms of anginal syndrome in HCM are diverse: increased myocardial oxygen demand due to greater myocardial mass and elevated filling pressure [56,405,406]; decreased regional blood flow due to epicardial coronary artery atherosclerosis [407]; coronary circulation anomalies and myocardial bridges promoting ischemia through prolonged compression and reduced blood flow in the early diastolic phase [408]; and coronary microvascular dysfunction in the absence of significant epicardial coronary artery stenoses [409–411].

The incidence of ischemia/angina associated with coronary artery atherosclerosis in patients with HCM averages 20%, and angina in non-obstructive coronary dysfunction is 51–86% [108,412].

The incidence of acute coronary syndrome (ACS) in HCM patients with non-obstructive coronary disease is comparable to that in the presence of coronary atherosclerosis [412]. Patients with HCM and ACS in the setting of non-obstructive coronary lesions exhibit a lower probability of death compared to patients with coronary atherosclerosis [412].

• The diagnosis of angina in patients with HCM is recommended to be carried out in accordance with clinical guidelines for stable angina pectoris [413].

ESC IC (LoE 5 GoR C)

Medical treatment of the anginal syndrome in patients with HCM is determined by the presence of LVOT obstruction and the pathogenetic mechanism of coronary dysfunction [414].

• In patients with non-obstructive HCM, the treatment of angina is recommended to be carried out in accordance with the clinical guidelines for stable angina pectoris [413].

ESC IC (LoE 5 GoR C)

• In patients with obstructive HCM, the use of ACE inhibitors/ARBs is not recommended due to the risk of increasing the gradient in the LVOT [395].

ESC III C (LoE 5 GoR C)

• In patients with obstructive HCM, beta-blockers are recommended as first-line drugs for relieving anginal attacks and reducing the gradient in the LVOT, regardless of the pathogenetic mechanism of coronary dysfunction [1,3,95,415,416].

ESC IIa B (LoE 2 GoR B)

• In patients with obstructive HCM, it is recommended to consider prescribing verapamil** or diltiazem to relieve anginal attacks regardless of the pathogenetic mechanism of coronary dysfunction [383,388,417,418].

ESC IIb C (LoE 2 GoR B)

Comments: rules and specific features of prescribing verapamil** are presented in Table 18, Appendix A3 and Table 19, Appendix A3.

In patients with non-obstructive HCM, verapamil** is capable of reducing myocardial ischemia, including silent ischemia, and improving left ventricular diastolic function [383].

The use of verapamil** or diltiazem for symptom relief is contraindicated (not recommended) in patients with HCM and angina in the presence of chronic heart failure with reduced ejection fraction due to a negative inotropic effect, which contributes to the development of CHF decompensation [155].

ESC/RCS IIIC (LoE 1 GoR B)

• In patients with obstructive HCM, the prescription of organic nitrates is not recommended due to the risk of increasing the gradient in the LVOT [415].

ESC IIIB (LoE 5 GoR C)

• In patients with obstructive HCM, it is recommended to consider prescribing a combination of antianginal drugs (beta-blockers, calcium channel blockers, long-acting organic nitrates, ivabradine**, nicorandil, ranolazine, trimetazidine) to relieve anginal attacks in accordance with clinical guidelines for stable ischemic heart disease and the decision of a multidisciplinary team [413].

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

3.1.6 Treatment of ACS in patients with HCM

Among patients with myocardial infarction (MI), the proportion of patients with HCM averages 0.1% [421]. Among patients with HCM, 23% develop ACS during 11 years of follow-up [412].

Patients with HCM are more likely to develop type 2 non-ST-segment elevation myocardial infarction, which has a lower in-hospital mortality rate than in patients without HCM [421,422].

The pathogenetic mechanisms of ACS in patients with HCM vary: rupture of an epicardial coronary artery atherosclerotic plaque is recorded in 20% of cases [423], while thrombosis in non-obstructive coronary dysfunction accounts for 51% of causes [412].

The pathophysiological mechanisms of coronary artery thrombosis without atherosclerotic lesions in HCM are associated with the compression of intramyocardial coronary arteries and reduced blood flow in them during the early diastolic phase, vasospasm, and endothelial dysfunction of the microvascular coronary bed [424].

• In patients with non-obstructive HCM, treatment of ACS in the presence of a coronary atherosclerotic plaque rupture according to coronary angiography is recommended to be carried out in accordance with the clinical guidelines for ST-segment elevation and non-ST-segment elevation myocardial infarction [425,426].

ESC IC (LoE 5 GoR C)

• In patients with non-obstructive HCM, it is recommended to consider treating ACS in non-obstructive coronary dysfunction in accordance with clinical guidelines for ST-segment elevation and non-ST-segment elevation myocardial infarction [425,426].

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

Comment: meta-analyses of observational studies have demonstrated that in patients with ACS and non-obstructive coronary dysfunction, the use of ACE inhibitors/ARBs, beta-blockers, statins, and dual antiplatelet therapy reduces the relative risks of major adverse cardiac events and/or death [427,428].

It is believed that the choice of antiplatelet agents and their therapeutic effect may vary depending on the pathophysiological mechanisms of MI development in non-obstructive coronary dysfunction, but determining them is extremely difficult in the diagnosis of ACS [429–431].

• In patients with obstructive HCM, regardless of the pathogenetic mechanism of thrombosis development, it is recommended to consider treating ACS in accordance with clinical guidelines for ST-segment elevation and non-ST-segment elevation myocardial infarction, with the exception of ACE inhibitors/ARBs due to the risk of increasing the LVOT gradient when using them [432].

ESC IIb C (LoE 4 GoR C)

3.1.7 Treatment of AH in patients with HCM

Arterial hypertension (AH) is recorded in 37% of HCM patients, which generally corresponds to its prevalence in the general population [46].

AH in patients with HCM does not affect the risk of death associated with HCM, but increases the risk of major adverse cardiovascular events and CHF [50].

The prognosis of patients with HCM receiving antihypertensive therapy is better, including reduced mortality [51].

• The diagnosis of AH in patients with HCM is recommended to be carried out in accordance with clinical guidelines for AH [433].

ESC I C (LoE 5 GoR C)

• In patients with HCM and AH, it is recommended to achieve target BP values in accordance with clinical guidelines for AH; no special target BP values have been established [433].

ESC I C (LoE 5 GoR C)

• Patients with HCM and AH are recommended non-pharmacological measures (education, diet, weight loss, salt restriction, physical activity) in accordance with clinical guidelines for AH [433].

ESC I C (LoE 5 GoR C)

• In patients with non-obstructive HCM, the treatment of AH is recommended in accordance with clinical guidelines for AH [433].

ESC I C (LoE 5 GoR C)

• In patients with obstructive HCM and AH, it is recommended to prescribe the maximum tolerated doses of non-vasodilating beta-blockers as first-line therapy to lower blood pressure and the gradient in the LVOT [1,3,150,386,387].

ESC IIa B (LoE 3 GoR B)

• In patients with obstructive HCM and AH, it is recommended to consider prescribing verapamil** or diltiazem if beta-blockers are contraindicated or not tolerated [1,3,150,434,435].

ESC IIb C (LoE 4 GoR C)

ESC III C (LoE 5 GoR C)

• In patients with obstructive HCM and AH, if target BP values are not achieved using maximum doses of beta-blockers or verapamil**/diltiazem, it is recommended to consider using low doses of thiazide/thiazide-like diuretics under the supervision of signs of hypovolemia [1,3,150,433].

ESC IIb C (LoE 4 GoR C)

Comment: in the presence of CKD and eGFR < 30 ml/min/1.73 m² in patients with obstructive HCM and hypertension, if target BP levels are not achieved, cautious use of low doses of loop diuretics under monitoring for signs of hypovolemia may be considered [1,3,150,433].

• In patients with obstructive HCM and hypertension, the use of ACE inhibitors/ARBs is not recommended due to the risk of increased LVOT gradient [395].

ESC III C (LoE 5 GoR C)

• In patients with obstructive HCM, the administration of dihydropyridine calcium channel blockers (“slow” calcium channel blockers with predominant vascular action, dihydropyridine calcium antagonists (nifedipine**)) is not recommended (contraindicated) due to the risk of increased LVOT gradient [415].

ESC III C (LoE 5 GoR C)

Comment: drugs recommended for the treatment of hypertension, such as spironolactone**, valsartan/sacubitril**, alpha-blockers, moxonidine**, have not been studied in obstructive HCM and hypertension in terms of BP control [433]. The decision to prescribe these drug classes may be made by a multidisciplinary team in case of resistance to ongoing antihypertensive therapy under strict monitoring of tolerability and hemodynamics.

3.1.8 Treatment of atrial fibrillation in patients with HCM

Atrial fibrillation is the most common arrhythmia in HCM, with a prevalence that depends on disease severity: 22% in the general cohort and up to 32% in the cohort of patients with indications for ICD*** and pacemaker*** / CRT-P*** implantation [40,151,246,373,399,437,438].

The incidence of de novo AF in the general HCM cohort is approximately 2% per year [151,373,399].

The objectives of pharmacotherapy in HCM complicated by AF are cardioversion, prevention of arrhythmia recurrence, and thromboembolic complications. Basic measures for the prevention of thromboembolic complications are presented in Table 23, Appendix A3.

3.1.8.1 Restoration of sinus rhythm and prevention of atrial fibrillation recurrence in patients with HCM

• To detect asymptomatic or paucisymptomattic AF paroxysms and determine the SCD risk in the cohort of HCM patients with LA size ≥ 45 mm and sinus rhythm, 48-hour Holter monitoring of cardiac rhythm is recommended every 6–12 months [1,3,129,148,152,241,373,439,440].

ESC IIa C (LoE 4, GoR C)

Comment: detection of AF using an implantable loop recorder provides a unique opportunity for early detection of asymptomatic or paucisymptomatic AF paroxysms to prevent thromboembolic complications before a stroke occurs. Predictors of AF risk in HCM include: atrial cardiomyopathy, increased LA size and volume, elevated blood NT-proBNP levels, HF stages III–IV, older age, LVOT obstruction, right heart involvement, and genetic factors.

ESC IIa C (LoE 5, GoR C)

Comment: patients with hemodynamic instability during an AF paroxysm are recommended to undergo emergency electrical cardioversion following the same rules as patients without HCM.

In hemodynamically stable patients without prior anticoagulant preparation, cardioversion can be performed only if the duration of the current paroxysm does not exceed 48 hours. In patients with asymptomatic AF paroxysms, as well as in situations where the patient cannot state the duration of the current paroxysm and is not on continuous anticoagulant therapy, it is recommended to refrain from immediate sinus rhythm restoration.

Two management strategies can be used in this situation.

First strategy: performing early cardioversion after transesophageal echocardiography (TEE) that rules out thrombi in the atrial cavities. Anticoagulant support during the sinus rhythm restoration procedure is mandatory.

Second strategy: if TEE is not feasible or thrombi are detected in the atrial cavities during TEE, delayed cardioversion should be performed after 3 weeks of anticoagulant therapy (following a control TEE, which is mandatory if thrombi were present in the atrial cavities during the initial examination).

Considering the fact that AF in patients suffering from HCM typically presents with pronounced symptoms, restoration of sinus rhythm should be considered not only for recent-onset but also for persistent AF when sinus rhythm restoration appears highly probable.

• In HCM patients after direct current electrical or pharmacological cardioversion, the administration of amiodarone** therapy is recommended for the prevention of AF recurrences [1,148,152,372,373,439,441,442].

ESC IIa B (LoE 4, GoR C)

Comment: amiodarone** is the most effective antiarrhythmic drug for the prevention of AF, and it is safe and effective in patients with HCM complicated by AF.

If amiodarone** is prescribed de novo, therapy should be initiated with loading doses (loading doses and administration rates in accordance with recommendations for the general population of patients suffering from AF) under regular heart rate monitoring and ECG monitoring of PQ and QT intervals. Daily ECG monitoring is recommended for the first three days of therapy. Prolongation of the QT interval to values exceeding 500 ms requires dose reduction or discontinuation of the drug.

The amiodarone** molecule contains two iodine atoms; therefore, amiodarone** affects thyroid hormone metabolism by inhibiting the conversion of T₃ to T₄ (blocking thyroxine 5'-deiodinase). Long-term chronic administration of amiodarone** may lead to thyroid dysfunction, including both amiodarone-induced hypothyroidism and hyperthyroidism.

Before prescribing amiodarone**, the patient should be screened for thyroid pathology (perform ultrasound examination of the thyroid and parathyroid glands and determine the level of thyroid-stimulating hormone and antibodies to thyroid peroxidase in the patient's blood). If thyroid pathology is present, the possibility of prescribing amiodarone** and/or continuing amiodarone** therapy should be discussed with an endocrinologist. During amiodarone** treatment, on a regular basis (in the absence of clinical suspicion of thyroid pathology, 3 months after initiation of therapy and thereafter at least once every 6 months), it is recommended to determine the level of thyroid-stimulating hormone, and if necessary, perform ultrasound examination of the thyroid and parathyroid glands, determine free T3 and T4 and their ratio. Amiodarone-induced hypothyroidism, as a rule, does not require discontinuation of the drug. Thyroxine treatment is recommended for all patients with manifest amiodarone-induced hypothyroidism. Subclinical forms usually do not require its administration, but the patient should be monitored with determination of thyroid hormone levels every 4-6 months. Management of patients with amiodarone-induced thyrotoxicosis depends on the type of hyperthyroidism. There are type 1 amiodarone-induced thyrotoxicosis (develops in the presence of autonomous active thyroid nodules or latent Graves' disease), type 2 amiodarone-induced thyrotoxicosis (develops as a result of destructive thyroiditis due to the cytotoxic effect of amiodarone), and a mixed form of amiodarone-induced thyrotoxicosis, characterized by a combination of both mechanisms. The onset of amiodarone-induced thyrotoxicosis in most cases requires discontinuation of the drug. In type 1 amiodarone-induced thyrotoxicosis, therapy with antithyroid drugs is indicated, while in type 2 amiodarone-induced thyrotoxicosis – glucocorticoids are indicated. Their combination is recommended for the mixed variant of amiodarone-induced thyrotoxicosis. The decision to continue or discontinue amiodarone in amiodarone-induced thyrotoxicosis should be made individually, jointly by cardiologists and endocrinologists, taking into account the benefits and risks [443–445].

Sotalol** may be used as an alternative antiarrhythmic drug in the treatment of AF in HCM patients, particularly in cases of ICD*** implantation, although clinical experience with its use is limited. At the same time, one should consider the significantly lower efficacy of sotalol** compared to amiodarone** and its more pronounced proarrhythmic effects. As with amiodarone** administration, sotalol** therapy requires regular monitoring of heart rate, PQ, and QT.

• A beta-blocker, verapamil**, or diltiazem is recommended for ventricular rate control in patients with HCM and permanent or persistent AF [1,3,128,148,152,372,373,439,441,442].

ESC IC (Level of Evidence 5, Grade of Recommendation C)

Comment: there is no evidence base confirming the efficacy of beta-blockers, verapamil**, or diltiazem in patients with HCM complicated by AF. Treatment with beta-blockers, verapamil**, or diltiazem must be carried out under the control of heart rate and AV conduction.

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

Comment: there is no evidence base confirming the efficacy of digoxin** in patients with non-obstructive HCM complicated by AF. The individual dose of digoxin** is determined by the optimal serum drug concentration (0.5–0.9 ng/mL) ensuring the best balance between efficacy and safety [152].

Initial and target doses of drugs for drug therapy of HCM are presented in Table 19, Appendix A3.

3.1.8.2 Prevention of thromboembolic events in patients with HCM and AF

• Vitamin K antagonists (warfarin**, target INR 2.0–3.0) or DOACs (dabigatran etexilate**, rivaroxaban**, or apixaban**) are recommended for all patients with HCM without contraindications who have developed persistent, permanent, or paroxysmal AF for the prevention of thromboembolic events [1,3,449,450,148,152,246,374,439,446–448].

ESC IC (Level of Evidence 2, Grade of Recommendation A)

Comment: it is necessary to keep in mind the embryotoxicity of warfarin** (see section "HCM in pregnant women").

There are fewer data on anticoagulant therapy in atrial flutter, but the risk of thromboembolism associated with it is considered to be the same as in AF.

ESC IIa B (Level of Evidence 4, Grade of Recommendation C)

Comment: A score of 3 or more on the HAS-BLED scale (not validated for patients with HCM) indicates a high risk of bleeding. In such patients, precautions must be taken with laboratory, clinical, and instrumental monitoring (coagulation panel [screening hemostasis test]; activated partial thromboplastin time; determination of the international normalized ratio [INR]). First of all, it is necessary to screen for a potential bleeding source before prescribing an oral anticoagulant. The recommended laboratory tests should be repeated as clinically indicated, but at least once a year [148,152].

HAS-BLED scale – see Table P5, Appendix G2.

Recommendations for screening for a potential bleeding source – see Table 21, Appendix A3.

Since renal pathology is associated not only with a high risk of thrombotic events but also with a high risk of bleeding, safe anticoagulant therapy requires regular monitoring of serum creatinine and calculation of creatinine clearance using the Cockcroft-Gault formula without body surface area standardization to select the optimal DOAC dose [152].

Recommended frequency of mandatory blood creatinine tests in patients – see Table 20, Appendix A3.

• If a patient with HCM complicated by AF cannot take the prescribed dose of warfarin** due to adverse reactions, inability to maintain the therapeutic level of anticoagulation (INR 2.0–3.0), or inability to monitor INR, it is recommended to use DOACs (dabigatran etexilate**, rivaroxaban**, or apixaban**) [1,3,449,450,148,152,246,374,439,446–448].

ESC IB (Level of Evidence 2, Grade of Recommendation A)

Comment: warfarin** or dabigatran etexilate** or rivaroxaban** or apixaban** should be prescribed regardless of the patient's CHA2DS2-VASc score, even after a single episode of AF. For the CHA2DS2-VASc score, see Table P4, Appendix G2.

• In all cases of HCM complicated by AF, lifelong therapy with warfarin** (INR 2.0–3.0) or DOACs (dabigatran etexilate**, rivaroxaban**, or apixaban**) is recommended, even if sinus rhythm has been restored and stably maintained [1,3,449,450,148,152,246,374,439,446–448].

ESC IC (Level of Evidence 2, Grade of Recommendation A)

• In patients with HCM complicated by AF without marked left atrial enlargement, in cases of symptoms refractory to pharmacotherapy or when antiarrhythmic drugs are contraindicated or ineffective, catheter procedures are recommended [1,3,148,152,439].

ESC IIa B (LoE 5 GoR C)

Comment: For invasive management of AF, see Section 3.2.

3.2 Surgical and interventional treatment of HCM

3.2.1 IVS reduction

In obstructive HCM, the surgical treatment method is the "gold standard".

For isolated myectomy, the average in-hospital mortality rates are less than 2%, efficacy is over 90% of patients, and the complication rate is less than 5%.

• Septal reduction is recommended for patients with obstructive HCM presenting with CHF symptoms or recurrent syncope despite optimal medical therapy [1,3,91,123,380,452,453].

ESC IB (LoE 4 GoR C)

Comment: Obstructive HCM encompasses the following forms of obstruction: LVOT gradient (at rest or maximally provoked) ≥ 50 mm Hg, including multilevel obstruction (midventricular obstruction or obstruction at the chordal level); biventricular obstruction (LVOT gradient at rest or maximally provoked ≥ 50 mm Hg; RVOT gradient > 16 mm Hg at rest). Vasovagal syncope should be ruled out in the patient (see Appendix B8).

ESC IIb B (LoE 4 GoR C)

Comment: septal reduction is performed via septal myectomy (SM) — Morrow surgical myectomy under cardiopulmonary bypass (A16.10.003.23 Morrow myectomy under cardiopulmonary bypass) with resection of the asymmetric hypertrophy zone using a transaortic approach; resection of hypertrophied muscle tissue in the obstruction zone from the infundibular part of the right ventricle; resection of muscle tissue in the hypertrophy zone in combined obstruction of the outflow tracts of both ventricles; resection of hypertrophied muscle tissue combined with plasty of the outflow tracts of both ventricles; resection of muscle tissue in the hypertrophy zone with reconstruction of the ventricular cavities; resection of muscle tissue in the hypertrophy zone combined with mitral valve repair; resection of muscle tissue in the hypertrophy zone combined with heart valve replacement; resection of muscle tissue in the hypertrophy zone combined with coronary artery bypass grafting (A16.10.031.003 Resection of muscle tissue in the hypertrophy zone in combined obstruction of the outflow tracts of both ventricles, A16.10.031.001 Resection of the asymmetric hypertrophy zone using a transaortic approach

A16.10.031.005 Resection of muscle tissue in the hypertrophy zone with reconstruction of the ventricular cavities) or alcohol septal ablation (ASA). A critical factor in achieving good outcomes for SM and ASA is the center's experience, defined as more than 50 procedures performed per year and more than 20 procedures performed by a cardiovascular or interventional radiologist/surgeon [3,123,465–471].

Septal reduction must be performed by an experienced specialist working within a multidisciplinary team of HCM experts.

Indications for septal reduction are presented in Appendix B10.

The algorithm for diagnosis and management of syncopal conditions is presented in Appendix B8.

The algorithm for selecting surgical/endovascular intervention in patients with HCM is presented in Appendix B5 (see also MRI recommendations).

The algorithm for choosing the septal reduction method in HCM is presented in Appendix B6.

A comparison of SM and ASA is presented in Appendix B11.

• In HCM patients with indications for interventricular septum (IVS) reduction who also have indications for other surgical interventions (papillary muscle anomalies worsening LVOT obstruction, mitral leaflet anomalies, severe non-SAM-associated mitral regurgitation, atrial fibrillation, multivessel coronary artery disease, or other comorbidities requiring surgical treatment), surgical myectomy is recommended to be performed in experienced centers as a preferred method over alcohol septal ablation (ASA) [1,3,380,469,470].

ESC IB (LoE 2 GoR B)

Comment: “Morrow myectomy under cardiopulmonary bypass” via a transaortic approach relieves LVOT obstruction caused by the hypertrophied IVS, but does not correct mitral valve anomalies that contribute to the increase in LVOT gradient and the development of mitral regurgitation (SAM-associated) [472].

Messmer B.J. et al. modified the Morrow procedure by extending the area of hypertrophied IVS resection in an apical direction toward the base of the anterior mitral leaflet [473].

When a two-level obstruction is identified (increased gradient in the LVOT and at the mid-LV cavity level), the myectomy may be extended to the mid-LV cavity and around the base of the papillary muscles (A16.10.031.003 Excision of muscle tissue in the hypertrophy zone for combined obstruction of both ventricular outflow tracts; A16.10.031.001 Excision of asymmetrical hypertrophy zone using a transaortic approach; A16.10.031.005 Excision of muscle tissue in the hypertrophy zone with reconstruction of ventricular cavities)

In specialized centers with the greatest experience in treating HCM patients, a transapical approach is used, aimed at reducing the pressure gradient and symptom alleviation in patients with mid-ventricular obstructive HCM. In rare cases of two-level LV obstruction, a combined transapical-transaortic approach or right ventricular and transaortic approaches are used [89,392,474–476].

In mid-ventricular obstructive HCM, in the absence of severe mitral valve anomalies, myectomy from the right ventricle can be performed via a transventricular or transatrial approach. This surgical approach has an advantage over the transaortic approach in young patients with marked IVS hypertrophy due to a lower risk of atrioventricular block [477,478].

When biventricular obstruction is detected (increased LVOT gradient > 50 mmHg and increased RVOT gradient > 16 mmHg), a combined approach may be used: transaortic approach and an approach via the right ventricle.

In specialized centers with the greatest experience in treating HCM patients, when biventricular obstruction is identified and in the absence of mitral subvalvular apparatus anomalies, myectomy can be performed from the RV via a transventricular or transatrial approach [123,466,479,480].

Anomalies of the mitral apparatus structures associated with HCM should be corrected during surgery to reduce the LVOT gradient without mitral valve replacement.

Echocardiographic criteria for the efficacy of the myectomy procedure are:

1. Anterior mitral leaflet-IVS contact (SAM-syndrome) is absent;

2. Residual LVOT gradient upon provocation should be no more than 20 mmHg;

3. Absence of severe residual mitral regurgitation < 5%.

Patient preferences (after a detailed discussion of treatment options) are important for making the final decision.

The choice of IVS reduction method should be based on a thorough patient evaluation and discussion by a multidisciplinary team of specialists.

• In HCM patients indicated for IVS reduction, primary isolated mitral valve replacement is not recommended for the purpose of relieving LVOT obstruction [1].

ESC IIIB (LoE 5 GoR C)

Comment: mitral valve replacement is associated with a worse long-term prognosis compared to its reconstruction. Mitral valve replacement in addition to myectomy significantly increases hospital mortality [481,482].

• In patients with obstructive HCM and a maximum IVS thickness < 17 mm, it is recommended to consider open cardiac surgery on the mitral valve and its subvalvular apparatus to relieve LVOT obstruction (excision of muscle tissue in the hypertrophy zone combined with mitral valve repair) [1,3,483,484].

ESC IIb C (LoE 2 GoR C)

Comment: in 2015, Ferrazzi P et al. described the results of the “shallow myectomy and secondary chordae resection” technique in patients with obstructive HCM and a relatively thin septum. The method demonstrated efficacy in reducing the LVOT gradient from 82 ± 43 mmHg to 9 ± 5 mmHg [485]. This technique proved to be reproducible and in demand, and has also rightfully gained development in the Russian Federation [469,484].

It was also demonstrated by a group of authors led by Bogachev-Prokofiev A.V. that an additional intervention on the mitral valve combined with myectomy more effectively eliminates SAM-associated mitral regurgitation [469].

The same group of authors demonstrated that mitral valve replacement compared to mitral valve repair is associated with a worse long-term prognosis and a higher rate of thromboembolic complications [468].

Veselka J et al. demonstrated that ASA in patients with an IVS ≤ 16 mm is accompanied by similar efficacy in terms of LVOT gradient reduction; a higher rate of permanent pacemaker implantations, but a better prognosis compared to patients with an IVS > 16 mm [452].

• In patients with apical and mixed forms of non-obstructive HCM with clinical symptoms of angina or dyspnea of NYHA class III–IV persisting despite optimal medical therapy, as well as heart failure with preserved LVEF and a small LV cavity size (LV EDV index < 50 mL/m², LV SV index < 30 mL/m²), it is recommended to consider LV cavity remodeling surgery (surgical myectomy) via a transapical, transaortic, or combined approach performed by experienced surgeons in specialized centers to improve disease symptoms [486–488].

ESC none/RSC IIb C (LoE 2 GoR C)

Thus, ASA can also be considered as an alternative option in patients with a “thin” septum.

Specific anesthesia for surgical and invasive procedures in HCM patients is not required.

3.2.2 Invasive treatment methods for AF in patients with HCM

• In patients with obstructive HCM who do not have indications for IVS reduction and other valve or coronary artery interventions, it is recommended to consider radiofrequency ablation of arrhythmogenic zones if atrial fibrillation cannot be prevented by antiarrhythmic therapy, or heart rate cannot be controlled by medications, or is associated with drug intolerance or adverse effects [3,128,148,373,439].

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

• In patients with obstructive HCM complicated by atrial fibrillation refractory to pharmacotherapy, it is recommended to perform the Maze procedure or its modification using radiofrequency and cryoablation during surgical myectomy for rhythm control [1].

ESC IIa B (LoE 5 GoR C)

Comment: currently, there is no evidence that the Maze procedure in patients with obstructive HCM undergoing surgical myectomy improves long-term survival [489].

Nevertheless, this intervention may contribute to the long-term maintenance of sinus rhythm in this cohort of patients [490].

If the Maze procedure is indicated, it should be performed as a concomitant procedure, following a multidisciplinary team consensus, by a surgeon experienced in performing such interventions.

Centers performing the Maze procedure (modifications III and IV) note that in HCM patients, this additional intervention during surgical myectomy is safe and effective.

Surgical treatment of atrial fibrillation in HCM patients is less successful than in patients without HCM.

Predictors of unsuccessful atrial fibrillation treatment in HCM include: severity of LV hypertrophy and diastolic dysfunction, atrial dilation, as well as the duration and type of atrial fibrillation.

The presence of concomitant organic pathology, the choice of method and scheme of surgical isolation, and the surgeon's experience determine the success of surgical treatment for atrial fibrillation in HCM patients.

Catheter ablation in HCM patients with atrial fibrillation more frequently requires repeat procedures.

HCM-dependent atrial remodeling can affect the outcome even if the procedure is initially successful.

3.2.3 Recommendations on practical aspects of implantable cardioverter-defibrillator implantation***

The algorithm for primary and secondary SCD prevention in HCM patients is presented in Appendix table B7.

The scale for assessing SCD risk in HCM patients (European model) is presented in Appendix table П2, supplement Г2.

The SCA risk assessment scale for patients with HCM (American model) is presented in Table P3, Appendix G2.

The American model allows estimating the risk of SCD in patients at low/intermediate risk.

The presence of extensive fibrosis, assessed by LGE-CMR (≥ 15% of LV mass), is a predictor of SCD risk in HCM. This parameter is not included in the European risk stratification model; however, if the patient has a low or intermediate risk of SCD (< 6%) and CMR shows a fibrosis area ≥ 15% of LV mass, this is an additional argument in favor of ICD implantation*** [131,491].

The scales are not applicable to HCM patients after septal myectomy because key calculation parameters, such as LVOT gradient and IVS thickness, are eliminated, and LV remodeling occurs, etc. Nevertheless, further SCD risk assessment after surgical treatment is required to determine indications for an ICD.

The HCM Risk-SCD model can be used to predict sudden cardiac death in patients with a history of aborted sudden cardiac arrest [368].

• In HCM patients who have survived cardiac arrest due to VT or VF, or in the presence of episodes of spontaneous sustained VT resulting in syncope or hemodynamic instability, with a life expectancy > 1 year, ICD implantation*** is recommended [3,131,138,139,325,326,492].

ESC IB (Level of Evidence 5, Grade of Recommendation C)

Comment: invasive electrophysiological testing may be performed in selected cases to verify the arrhythmia.

• In patients with HCM, the 5-year risk of sudden death is recommended to be assessed at the initial patient evaluation, as well as every 1–2 years or upon a change in clinical status [3,131,139,243,368,369].

ESC IC (Level of Evidence 4, Grade of Recommendation C)

ESC IIa B (LoE 3 GoR A)

ESC IIa B (LoE 4 GoR C)

ESC IIb B (LoE 5 GoR C)

ESC IIb B (LoE 5 GoR C)

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

3.2.4 Recommendations on the implantation of left ventricular assist devices

• In some end-stage heart failure HCM patients who are candidates for heart transplantation, it is recommended to consider implanting mechanical circulatory support devices while on the waiting list [277,319,494,495].

ESC IIb C (LoE 4 GoR C)

Comment: in global practice, 50% of heart transplant operations are performed after prior implantation of mechanical circulatory support devices [319]. However, experience with the use of mechanical circulatory support devices in patients with HCM is limited. One systematic review found that the use of such systems in patients with HCM was associated with a higher risk of perioperative and short-term mortality, right ventricular failure, infections, bleeding, stroke, renal failure, and arrhythmia compared with patients with dilated and ischemic cardiomyopathy [496]. Nevertheless, some retrospective studies showed no difference in outcomes between these cohorts [497,498].

Patients with HCM have traditionally been considered unsuitable for mechanical circulatory support device implantation due to a small left ventricular cavity and a relatively preserved ejection fraction. Several case series have demonstrated that the use of continuous-flow devices is associated with acceptable outcomes, especially in patients with larger left ventricular cavity dimensions (> 46–50 mm) [497,499].

3.2.5 Heart transplantation in patients with HCM

• In HCM patients with an LVEF < 50% and heart failure symptoms of NYHA class II–IV, or refractory ventricular arrhythmias despite optimal medical therapy, orthotopic heart transplantation is recommended if indications are present and contraindications are absent [1,156,157,192,319,321,323,494,500].

ESC IIa B (LoE 4, GoR C)

Comment: in stages 3–4 of HCM according to Olivotto, additional morphofunctional phenotypes join according to the MOGE(s) classification: dilated phenotype (dHCM); dilated stage of HCM (HCM + DCM) or restrictive phenotype (HCM with restrictive phenotype) [68].

Heart transplantation can be a life-saving treatment strategy in end-stage HCM.

The poor short-term prognosis in patients with the dilated stage of HCM suggests the expediency of earlier consideration of aggressive treatment modalities, as the "window of opportunity" may be narrow, especially in patients with a familial history of the dilated stage of HCM.

The development of LV dilation in HCM patients should be verified based on the dynamics of LV dimensions. Even "normal" LV dimensions may indicate a "dilated stage" if LV LVEDD/LVEDV are increased (subject to correct measurement).

Post-transplant survival in patients with HCM is similar to that of heart transplantation due to other causes [321,323,494].

• In HCM patients with an LVEF ≥ 50% and NYHA class III–IV heart failure symptoms caused by diastolic dysfunction resistant to medical therapy, with a high risk of adverse outcomes from septal reduction or valve repair, it is recommended to consider performing orthotopic heart transplantation in the presence of indications and absence of contraindications [1,156,157,192,319,321,323,494,500].

ESC IIb C (LoE 4 GoR C)

Comment: severe heart failure with preserved LVEF may occur in HCM with a restrictive phenotype according to the MOGE(s) classification.

The final algorithm of medical management depending on the stage of HCM and the clinical course variant is presented in Appendix B9.

3.2.6 Management of pregnancy in HCM

• During pregnancy, HCM patients are recommended to undergo maternal risk stratification using the modified WHO classification of maternal cardiovascular complications [501–505].

ESC IC (LoE 5 GoR C)

Comment: ideally, risk assessment should be performed before conception. Pregnant women with HCM are classified into WHO FC II-III according to the modified classification of maternal cardiovascular complications; however, this classification does not differentiate patients based on the presence or absence of LVOT obstruction, which is a significant drawback of this classification. Symptomatic patients with obstructive HCM and an LVOT gradient > 100 mmHg can be correlated in terms of hemodynamics and possible complications during pregnancy and childbirth with patients with severe symptomatic aortic stenosis belonging to WHO FC IV, who require surgical treatment of the underlying disease before planning pregnancy. According to Order No. 736 dated December 3, 2007: hypertrophic cardiomyopathy with severe left, right, or biventricular outflow tract obstruction and hypertrophic cardiomyopathy without left ventricular outflow tract obstruction with complex cardiac arrhythmias are indications for pregnancy termination at any gestational age.

• For HCM patients with an LVOT gradient > 50 mmHg and HCM without LVOT obstruction with complex arrhythmias, it is recommended to hold a multidisciplinary medical board regarding the feasibility of planning pregnancy and/or continuing pregnancy [506].

No ESC / RSS IC (LoE 5 GoR C)

• It is recommended that female patients with obstructive HCM or complex cardiac arrhythmias during pregnancy be examined at least once a month by a general practitioner and/or cardiologist for the timely detection of cardiovascular complications of pregnancy [501,505,507].

No ESC / RSS IC (LoE 5 GoR C)

• It is recommended that female patients with non-obstructive HCM without complex cardiac arrhythmias during pregnancy be examined at least once every 2 months by a general practitioner and/or cardiologist for the timely detection of cardiovascular complications of pregnancy [505,507].

No ESC / RSS IC (LoE 5 GoR C)

Comments: during the examination, it is mandatory to assess the appearance of new symptoms, evaluate heart rate, and assess the efficacy of ongoing therapy if administered.

• In patients with obstructive HCM, it is recommended to consider continuing beta-blocker therapy if they were taking them before pregnancy [501,503–505,508].

ESC IIa C (LE 3 LoE C)

• It is recommended to initiate beta-blocker therapy in pregnant women with HCM and symptoms of left ventricular outflow tract obstruction or cardiac arrhythmias [501,503–505,508].

ESC IIa C (LE 5 LoE C)

• During beta-blocker therapy, it is recommended to monitor the condition and growth rate of the fetus [501–505,508,509].

ESC IC (LoE 5 GoR C)

• In case of beta-blocker intolerance in a pregnant woman with HCM and symptoms of left ventricular outflow tract obstruction or cardiac arrhythmias, it is recommended to prescribe a second-line drug – verapamil** [3,501,505,510].

ESC none, RSC IC (LE 5 LoE C)

• In pregnant women with HCM who develop AF, cardioversion is recommended with optimal radiation protection [147,148,501,505,511,512].

ESC IIa C (LE 4 LoE C)

• In pregnant women with HCM and AF, anticoagulant therapy is recommended for the prevention of thromboembolic complications [148,501,503,505,508,511,512].

ESC IC (LoE 5 GoR C)

Comments: recommended anticoagulant regimens in pregnant women with HCM and AF and risks, associated with warfarin** therapy, are presented in Table 21 (Table 22, Appendix A3). The choice of drug – heparin** (low-molecular-weight, twice daily, weight-based dosage) or warfarin** – is possible from the 2nd trimester of pregnancy until weeks 36–37, maintaining a target INR of 2–3 [148].

• The administration of dabigatran etexilate**, rivaroxaban**, or apixaban** is not recommended during pregnancy [148,501,503,505,508,511].

ESC IIIC (LE 5, GRD C)

ESC IB (Level of Evidence 5, Grade of Recommendation C)

• In pregnant women with HCM without severe obstruction, who are on oral anticoagulants with a switch from warfarin** to low-molecular-weight heparin prior to delivery (INR less than 1.5) and without severe heart failure, vaginal delivery is recommended [501,503,505,509,511].

ESC IC (LoE 5 GoR C)

Comment: medical tactics for pregnancy management and delivery are presented in Appendix B12.

The choice of medical institution for the management of pregnancy and delivery is presented in Appendix B13.

Limitations in the choice of diagnostic methods in pregnant women are presented in Table 23 (Appendix A3).

In the management of pregnancy and childbirth, the interests of the mother must take precedence.

Most women with uncomplicated HCM belong to WHO maternal risk class II (WHO II) according to the modified WHO classification. Some symptomatic patients belong to WHO III; they should be monitored in specialized institutions (see table). Women with HCM complicated by heart failure and left ventricular dysfunction (dilated phase or addition of a restrictive phenotype) belong to WHO maternal risk class IV, and pregnancy is contraindicated for them. In the presence of severe symptomatic left ventricular outflow tract obstruction (also classified as WHO class IV), pregnancy may become possible after prior relief of the obstruction.

Beta-blocker therapy (metoprolol**, reserve – bisoprolol**) in pregnant women with HCM must be carried out under heart rate and blood pressure control, since excessive blood pressure reduction can lead to decreased uteroplacental blood flow and fetal growth restriction [3,20,501].

Contraception in women with asymptomatic or mildly symptomatic HCM has no special features compared to healthy individuals.

If HCM is complicated by heart failure and AF, oral contraceptives should be used with caution due to the risk of thromboembolism; their use is possible with adequate anticoagulant therapy [3,20,501,505,509].

• Implantable cardioverter-defibrillator (ICD)*** implantation for the prevention of sudden cardiac death in women at high risk of sudden cardiac death is recommended before planning pregnancy [131,139,243,282,368,505].

ESC none/RSC IIa B (LE 4 LoE C)

ESC none/RSC IIa B (LE 4 LoE C)

ESC none RSC IIa B (LE 4 LoE C)

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 prevention for HCM as a disease.

Preventive measures in patients with HCM consist in the prevention of major complications of the disease, which are presented in Table 24, Appendix A3.

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

Follow-up of patients with HCM

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

At the initial stage of drug therapy, scheduled follow-up visits to the physician are advisable at 6, 9, and 12 months (more frequently if necessary) to evaluate the tolerability, efficacy, and safety of treatment, as well as to monitor compliance with medical recommendations. In case of insufficient efficacy and poor tolerability of ongoing drug therapy, substitution of the drug with subsequent monitoring of treatment is recommended.

• All patients with HCM, including carriers of pathogenic mutations without phenotypic manifestations of the disease and patients with an asymptomatic course, are recommended to undergo dynamic monitoring (general practitioner, family physician), during which the nature and severity of clinical, morphological, and hemodynamic disorders are assessed and the treatment strategy is determined [3,20,132,385,514–517].

ESC IB (Level of Evidence 5, Grade of Recommendation C)

• In clinically stable patients, repeat transthoracic echocardiography is recommended every 1–2 years [3,20,515–517,132,159,233,246,278,282,385,514].

ESC IC (LoE 5 GoR C)

• Repeat echocardiographic studies are recommended for patients with HCM with changes in clinical status or the appearance of new cardiovascular manifestations [3,20,515–517,132,159,233,246,278,282,385,514].

ESC IB (Level of Evidence 5, Grade of Recommendation C)

• A 48-hour Holter ECG monitoring is recommended every 12–24 months in clinically stable patients, and every 6–12 months in patients with sinus rhythm and left atrial size ≥ 45 mm or upon the appearance of new palpitations [3,20,129,243,246,373,518].

ESC IC (LoE 5 GoR C)

ESC IIb C (LE 5, LoE C)

ESC IIb C (Level of Evidence 5, Grade of Recommendation C)

• A complete examination, including ECG, transthoracic echocardiography, and Holter ECG monitoring, is recommended within 1–3 months and 6–12 months after septal reduction therapy [3,228].

ESC IC (LoE 5, GoR C)

Comment: an integral part of management and follow-up in patients with HCM should be raising their educational level. Even if a physician develops an optimal treatment program for each individual patient, implementing it will be extremely difficult if treatment motivation is low. All applied treatment and prevention methods must be discussed and agreed upon with the patient. When choosing the drug administration regimen, the patient's lifestyle must be taken into account. All recommendations given to the patient must be clear, precise, and appropriate for their intellectual level.

For some patients for whom verbal recommendations are insufficient, duplicating them in writing should be considered to ensure informed patient participation in the treatment and prevention process and to increase treatment efficacy [3,20].

6. Organization of Medical Care

• For patients with an unclear diagnosis, severe symptoms, or an increased risk of disease-related complications, it is recommended to consider evaluation and treatment by a multidisciplinary team of experts in HCM management [1,3,522,20,34,43,68,186,433,520,521].

ESC IIb C (LoE C, LE 5)

• Regardless of symptom severity, it is recommended to regularly screen patients and, if possible, first-degree relatives [1,3,246,282,385,437,514,515,517,20,21,33,58,132,159,220,233].

ESC IC (LoE 5 GoR C)

• All patients with HCM are recommended to undergo evaluation and treatment at centers with a multidisciplinary team of specialists experienced in the diagnosis and management of myocardial diseases [1,3,521,522,20,34,43,53,68,186,433,520].

ESC IIaC (LE 5, LoE C)

Indications for elective hospitalization

- Clarification of the cause of LVH of unclear etiology and the need for specialized diagnostic methods (ruling out HCM phenocopies);

- Utilization of diagnostic procedures that cannot be performed or are impractical in an outpatient setting;

- Difficulties in selecting pharmacotherapy to manage syndromes (due to a combination of HCM/oHCM + hypertension, HCM + type 2 diabetes mellitus, angina pectoris syndrome);

- Initiation of beta-blockers or verapamil** should be started in an inpatient setting at low doses, with titration up to the maximum tolerated doses under the supervision of the patient's well-being and ECG monitoring;

- Refractoriness to fully optimized pharmacotherapy and the presence of indications for surgical myectomy, alcohol septal ablation, or pacemaker implantation.

Indications for emergency hospitalization:

- Progression of chronic heart failure requiring intensive care;

- Pulmonary edema;

- Stroke;

- Life-threatening cardiac rhythm and conduction disturbances requiring intensive care;

- Syncope;

- Acute coronary syndrome;

- Resuscitated SCD.

Indications for patient discharge from the hospital:

- For elective hospitalization, the indication for discharge of a patient with HCM is the improvement of clinical symptoms during ongoing pharmacotherapy, implantation of an ICD***, pacemaker***/cardiac resynchronization therapy device***, or endovascular/surgical treatment (surgical myectomy, alcohol septal ablation);

- For 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;

- Normalization of parameters (target levels of blood pressure, glycemia, lipid profile) for hypertension, type 1 or type 2 diabetes mellitus, or dyslipidemia, respectively, if the exacerbation of these conditions served as the basis for elective or emergency hospitalization of patients with HCM combined with comorbid pathology;

- For angina pectoris syndrome, the indication for discharging a patient with HCM is the achievement of a stable clinical condition on the background of pharmacotherapy and endovascular/surgical treatment (coronary artery bypass grafting);

- Establishment of the diagnosis of HCM phenocopies, and discharge/transfer of the patient to specialized departments for etiopathogenetic treatment (e.g., hematology department for 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 healthcare facilities regarding 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;

- ratio of obstructive and non-obstructive forms of HCM;

- ratio of familial and sporadic cases of the disease;

- frequency of hospitalizations due to progression of chronic heart failure, atrial fibrillation, acute coronary syndrome, and cases of SCD;

- need for ECG, echocardiography, MRI, CT, and coronary angiography to fulfill recommendations for follow-up and evaluation of the proband and first-degree relatives;

- mortality (%), complications (%) per year, at 3 years, and at 5 years;

- frequency of detection of cardiometabolic risk factors (hypertension, dyslipidemia, obesity/overweight, type 1 and type 2 diabetes mellitus) across different age groups of HCM [53];

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

7. Additional Information

Other important goals in the management of HCM include:

1. Correction of all potentially modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity);

2. Treatment of comorbid conditions in accordance with national clinical guidelines (coronary artery disease, hypertension, diabetes mellitus, chronic kidney disease).

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary health care provided to adults with hypertrophic cardiomyopathy

Quality assessment criteria for specialized medical care provided to adults with hypertrophic cardiomyopathy

References

Appendix A1. Working Group Composition

Working Group Presidium

1. Bokeria L.A., Academician of the RAS, MD, Professor (Moscow), Association of Cardiovascular Surgeons

2. Shlyakhto E.V., Academician of the RAS, MD, Professor (Saint Petersburg), Russian Society of Cardiology

3. Gabrusenko S.A., MD, Professor (Moscow), Russian Society of Cardiology

4. Gudkova A.Ya., MD (Saint Petersburg), Russian Society of Cardiology

5. Koziolova N.A., MD, Professor (Perm), Russian Society of Cardiology

Other Working Group Members

6. Alexandrova S.A., PhD (Moscow), Association of Cardiovascular Surgeons

7. Alekhin M.N., MD, Professor (Moscow), Russian Society of Cardiology

8. Afanasyev A.V., MD (Novosibirsk), Association of Cardiovascular Surgeons

9. Bogatyreva M. M-B., PhD, Associate Professor (Nazran)

10. Bogachev-Prokofiev A.V., MD (Novosibirsk), Association of Cardiovascular Surgeons

11. Bogdanov D.V., MD, Professor (Chelyabinsk), Russian Society of Cardiology

12. Berseneva M.I., PhD, Associate Professor (Moscow), Russian Society of Cardiology

13. Gordeev M.L., MD, Professor (Saint Petersburg), Association of Cardiovascular Surgeons

14. Dzemeshkevich S.L., MD, Professor (Moscow), Association of Cardiovascular Surgeons

15. Evtushenko A.V., MD (Kemerovo), Association of Cardiovascular Surgeons

16. Zaklyazminskaya E.V., MD (Moscow), Russian Society of Medical Genetics

17. Zenchenko D.I., PhD (Volgograd), Russian Society of Cardiology

18. Irtyuga O.B., MD, Associate Professor (Saint Petersburg), Russian Society of Cardiology

19. Kaplunova V.Yu., MD (Moscow), Russian Society of Cardiology

20. Kashtanov M.G., PhD (Yekaterinburg), Association of Cardiovascular Surgeons

21. Kostareva A.A., MD, Professor (Saint Petersburg), Russian Society of Cardiology, Russian Society of Medical Genetics

22. Krutikov A.N., PhD (Saint Petersburg), Russian Society of Cardiology

23. Malenkov D.A. (Moscow), Association of Cardiovascular Surgeons

24. Novikova T.N., MD, Associate Professor (Saint Petersburg), Russian Society of Cardiology

25. Rud S.D., PhD, Associate Professor (Saint Petersburg), Russian Society of Cardiology

26. Rybka M.M., MD, Professor (Moscow), Association of Cardiovascular Surgeons

27. Saidova M.A., MD, Professor (Moscow), Russian Society of Cardiology

28. Streltsova A.A. (Saint Petersburg), Russian Society of Cardiology

29. Stukalova O.V., PhD, Associate Professor (Moscow), Russian Society of Cardiology

30. Chmelevsky M.P. (Saint Petersburg), Russian Society of Cardiology

31. Shaposhnik I.I., MD, Professor (Chelyabinsk), Russian Society of Cardiology

32. Shloydo E.A., PhD (Saint Petersburg), Association of Cardiovascular Surgeons

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

Appendix A2. Methodology for Developing Clinical Guidelines

Due to the fact that the Russian Society of Cardiology (RSC) is a constituent of the European Society of Cardiology (ESC), and RSC members are also ESC members, all European guidelines are formulated with the participation of Russian experts who co-authored the guidelines. Thus, the existing ESC guidelines reflect the consensus of leading Russian and European cardiologists.

Therefore, the national guidelines were developed based on ESC recommendations, taking into account national specifics, examination and treatment features, and the availability of certain medical care. For this reason, during the development of the Russian clinical guidelines by the RSC, international recommendation classes of indications were used to assess the necessity of performing a recommendation statement and the levels of evidence for these classes (Tables 1/A2 and 2/A2).

In cases where European guidelines lacked classes and levels of evidence, but in the opinion of RSC experts these statements were extremely necessary for implementation or, conversely, strictly not recommended for use, RSC experts—based on the rules for formulating recommendation classes according to the European Society of Cardiology guidelines—assigned the classes and levels themselves. In such instances, the ESC designation is replaced with RSC classes and levels assigned by RSC experts.

In addition, a new system of levels of evidence (LE) and grades of recommendations (GR) scales for therapeutic, rehabilitative, preventive, and diagnostic interventions (Tables 3/A2, 4/A2, and 5/A2) introduced in 2018 by the Center for Healthcare Quality Assessment and Control of the Russian Ministry of Health was added. Thus, two scales were used simultaneously in the text of the clinical guidelines developed by RSC experts (Tables 1/A2, 2/A2, 3/A2, 4/A2, 5/A2).

These Guidelines were developed based on the 2016 Russian Guidelines for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy and the 2014 European Society of Cardiology Guidelines for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy, created on the basis of long-term experience and a large number of studies on various aspects of HCM diagnosis and treatment. The Guidelines outline the main aspects of pathogenesis, clinical course, diagnostic methods, and treatment principles for patients with HCM, taking into individual patient characteristics.

Target audience of these clinical guidelines

1. Cardiologist

2. General Practitioner

3. General practitioner

4. Cardiovascular surgeon

5. Functional Diagnostics Physician

6. Radiologist

7. Ultrasound Diagnostics Physician

8. Radiotherapist

9. Medical geneticist

Table 1/A2. Classes of indications according to the European Society of Cardiology (ESC) guidelines.

Table 2/A2. Levels of evidence according to the European Society of Cardiology (ESC) guidelines.

Table 3/A2. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 4/A2. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 5/A2. Scale for assessing grades of recommendations (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The clinical guideline update mechanism provides for their systematic revision – at least once every three years or upon the emergence of new information on the management tactics for patients with this disease. The decision to update is made by the Russian Ministry of Health based on proposals submitted by non-profit medical professional organizations. The formulated proposals must take into account the results of a comprehensive assessment of drugs and medical devices, as well as the results of clinical approbation of new treatment methods.

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

3. Order of the Ministry of Health of the Russian Federation No. 520n dated July 15, 2016, "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 Deadlines for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of the Information Included in Clinical Guidelines" (Registered on May 8, 2019, No. 54588)

Table 1/A3. Molecular pathogenesis of specific causes of HCM (according to ESC 2014) [3].

Table 2/A3. Risk factors for type 2 myocardial infarction in patients with HCM

Table 3/A3 Clinical features of the most common morphological subtypes of HCM (adapted from [89,181,523]).

Table 4/A3. Simplified model of clinical variants of the course of HCM

Table 5/A3. Laboratory test abnormalities suggesting certain HCM phenocopies (adapted from [3])

Table 6/A3. Clinical features and instrumental findings suggesting the diagnosis of an HCM phenocopy (adapted from [205]).

Table 7/A3. Evaluation in relatives of the proband, carriers of genotype(+)/phenotype(-) mutations in the pre-hypertrophic stage (adapted from [530])

Table 8/A3. Electrocardiographic abnormalities suggesting a specific diagnosis of HCM phenocopy or morphological variant of HCM (according to Rapezzi C et al., 2013 [208]).

Table 9/A3. Parameters of the transthoracic echocardiography protocol in a patient with HCM (adapted from [182,278])

Table 10/A3. Diseases (other than obstructive HCM) in which LVOT obstruction and SAM syndrome (MV SAM) may be recorded (adapted from [205]).

Table 11/A3. Additional options in Echocardiography

Table 12/A3. Echocardiographic features suggesting the diagnosis of HCM phenocopy (adapted from [3]).

Table 13/A3. Parameters to be assessed during cardiac MRI in a patient with HCM

Table 14/A3. Types of stress tests

Table 15/A3. Differential diagnosis scheme for HCM and basal septal hypertrophy (adapted from [531]).

Table 16/A3. Differential diagnosis of HCM and athletic LVH

Table 17/A3. Rules and specifics of prescribing beta-blockers in HCM

Table 18/A3. Rules and features of prescribing verapamil** in HCM

Table 19/A3. Initial and target doses for drug therapy of HCM

Table 20/A3. Recommended frequency of routine blood creatinine tests in patients taking anticoagulants.

Table 21/A3. Recommended laboratory tests and diagnostic examinations to screen for a potential bleeding source (before prescribing anticoagulants)

Table 22/A3. Recommended anticoagulant therapy regimens in pregnant patients with HCM and AF, and risks associated with warfarin therapy

Table 23/A3. Limitations of diagnostic methods during pregnancy

Table 24/A3. Main measures for the prevention of complications in patients with HCM

Appendix B. Physician Action Algorithms

Appendix B1. Management algorithm for asymptomatic patients with HCM

Appendix B2. Simplified algorithm for the diagnosis and treatment approaches in patients with LVOT obstruction

Appendix B3. Pharmacotherapy algorithm for obstructive HCM

Appendix B4. Clinical management algorithm for chronic heart failure in HCM

Appendix B5. Algorithm for selecting surgical/endovascular intervention in patients with HCM

Appendix B6. Algorithm for choosing the method of IVS reduction

Appendix B7. Algorithm for primary and secondary SCD prevention in patients with HCM

Appendix B8. Algorithm for the diagnosis and clinical management of syncopal episodes

Appendix B9. Clinical management algorithm depending on the stage of HCM and clinical course variant

Appendix B10. Indications for IVS reduction (SME/PCE)

Appendix B11. Comparison of SME and PCE (adapted from [395]).

Appendix B12. Management strategy for pregnancy and delivery depending on the degree of LVOT obstruction (according to [501]).

Appendix B13. Healthcare facility for management of pregnant women with HCM

Appendix C. Patient Information

General lifestyle recommendations (adapted from [3])

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

Appendix G1. Scale for predicting the probability of detecting genetic variants in HCM (adapted from [55])

Title in Russian: Scale for predicting the probability of detecting genetic variants in HCM

Original title (if any): none

Type (underline):

rating scale

index

questionnaire

other (specify):

Purpose: clinical tool for predicting the probability of detecting genetic variants in HCM

Content (template):

Appendix G2. HCM Risk-SCD. Sudden Cardiac Death Risk Prediction Model in Patients with HCM (European Model) (adapted from [236, 361])

Russian title: HCM Risk-SCD. Sudden Cardiac Death Risk Prediction Model in Patients with HCM (European Model).

Original title (if applicable): HCM Risk-SCD

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. Sudden Cardiac Death Risk Assessment Scale in Patients with HCM (American Model) (adapted from [493])

Russian title: Sudden Cardiac Death Risk Assessment Scale in Patients with HCM (American Model).

Original title (if any): none

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. CHA2DS2-VASc. Risk Assessment Scale for Thromboembolic Complications in Patients with Atrial Fibrillation / Flutter (adapted from [525])

Type (underline):

rating scale

index

questionnaire

other (specify):

Purpose: clinical tool for predicting the risk of ischemic stroke and systemic thromboembolism in atrial fibrillation

Content (template):

Key (interpretation):

Appendix G5. HAS-BLED. Bleeding Risk Assessment Scale (adapted from [449, 526])

Russian title: HAS-BLED. 1-Year Major Bleeding Risk Assessment Scale in Patients with Atrial Fibrillation / Flutter Receiving Anticoagulant Therapy With or Without Antiplatelet Agents.

Original title (if applicable): HAS-BLED

Type (underline):

rating scale

index

questionnaire

other (specify):

Purpose: clinical tool for predicting the 1-year risk of major bleeding

Content (template):

Appendix G6. QALE. Scale for differential diagnosis of transthyretin amyloidosis using cardiac contrast-enhanced MRI (adapted from [288])

Russian name: QALE

Original name (if any): QALE Score

Type (underline):

rating scale

index

questionnaire

other (specify):

Purpose: a clinical tool for the differential diagnosis of transthyretin amyloidosis and AL-amyloidosis.

Content (template):

The LGE pattern in the left ventricular walls is assessed at three levels: apical, mid-ventricular, and basal, with a specific number of points assigned based on the LGE pattern as shown in the figure
The maximum possible score for left ventricular wall assessment is 12 (4x3)
If any LGE is present in the right ventricular walls, 6 points are added to the scale
The total possible QALE score taking into account right ventricular involvement is 18 (12+6)
Additional data:
MRI semiotics	AL amyloidosis	Transthyretin amyloidosis
Indexed left ventricular mass	Moderately elevated < 100 g/m²	Significantly elevated 100 g/m²
Thickening of the interventricular and interatrial septum	Less pronounced	More pronounced
LGE	Less pronounced Often diffuse subendocardial pattern QALE < 13 points	More pronounced Often diffuse or transmural enhancement pattern QALE > 13 points
Native T1 mapping	1050-1150 ms Relatively small increase in T1 time	1050-1150 ms More pronounced increase in T1 time
Extracellular volume (ECV) value	Elevation greater than 40% Relatively small increase in ECV	Elevation greater than 40% More pronounced increase in ECV

Key (interpretation):