Hypertrophic cardiomyopathy: a modern view of the problem

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Introduction

Cardiomyopathy (CMP) is a significant contributor to heart failure (HF) and sudden cardiac death (SCD), particularly in young adults [1]. However, epidemiological data are lacking; as a result, determining the public health effect of these diseases and prioritizing action at the national or international level are challenging [1].

The prevalence of hypertrophic CMP (HCMP) is 1:500 in the general population [1]. According to statistics from the Heart Failure Association of the European Society of Cardiology, HCMP has a prevalence of 2–5 per 1000 in the general population [2]. HCMP occurs with similar frequency in different countries. At least 300,000 people in Russia suffer from this disease [3].

The term “cardiomyopathies” was coined by W. Bridgen in 1957. Cardiomyopathies are defined as primary myocardial lesions of undetermined etiology that cause cardiac dysfunction and are not sequelae of diseases of the coronary arteries, valve apparatus, pericardium, systemic or pulmonary hypertension, or some rare variants of cardiac conduction system lesions [4].

Probands with this pathology are common in first-line families, indicating the high inheritability of the disease (up to 65%) [5]. In HCMP, progressive CH is less common than restrictive CMP; however, its development predicts an unfavorable prognosis [6].

W.J. McKenna et al. highlighted the urgency of CMP as a problem. According to their report, CMP was present in approximately 50% of patients who died suddenly during childhood or adolescence or underwent heart transplantation [7]. SCD, with an annual incidence of 0.5%–1%, typically affects young men (between the third and fourth decades of life) with HCMP and may be the initial disease manifestation [8].

Currently, several CMP variants have been reported [2]. This literature review summarizes current information on the etiology, pathogenesis, clinical features, diagnosis, and treatment of HCMP.

Classification of cardiomyopathies

To position HCMP among other CMPs, we will refer to two classifications of CMP. In 1980, a World Health Organization task force chaired by J. Goodwin presented the first classification of CMPs based on the predominant structural and hemodynamic phenotype, 23 years after W. Bridgen proposed the term “cardiomyopathies.” This classification distinguishes three groups of CMP: dilated, hypertrophic, and restrictive CMPs [7].

The textbook by G.E. Roytberg and A.V. Strutynsky, “Internal Medicine: Cardiovascular System” [4], presents the 2006 classification of CMP developed by experts of the American Heart Association. This classification is considered the most acceptable and consistent with modern concepts of CMP etiology and pathogenesis (////////////////Table 1).

 

Table 1. Classification of cardiomyopathies (CMP, American Heart Association, 2006)

CMP groups	CMP types
Primary CMPs
Primary congenital CMPs (hereditary)	Hypertrophic CMP
	Arrhythmogenic dysplasia of the right ventricle
	Noncompact left ventricular myocardium
	Lenegre’s disease
	Congenital pathology of the ion channels – Prolonged QT syndrome – Short QT syndrome – Brugada syndrome – Idiopathic ventricular paroxysmal tachycardia (primary electrical heart disease)
Primary mixed CMPs	Dilated CMP
	Restrictive CMP
Primary acquired CMPs	Inflammatory (outcome of myocarditis)
	Stress (takotsubo CMP)
	Peripartal
	Tachycardia-induced
	CMP of children from mothers with insulin-dependent diabetes mellitus
Secondary CMPs
Infiltrative (e.g., amyloidosis)
Accumulation of CMPs (e.g., in hemochromatosis)
Toxic (e.g., alcohol and drugs)
Endocrine (diabetic CMP and CMPs in hypo- and hyperthyroidism)
CMPs in neuromuscular diseases (e.g., Duchenne muscular dystrophy and Friedreich’s ataxia))
Alimentary (e.g., vitamin B1, selenium, and carnitine deficiency)
CMPs in systemic connective tissue diseases

 

Etiology of hypertrophic cardiomyopathy

According to the American Heart Association classification (2006), the names of CMPs, such as primary acquired and secondary CMPs, reflect their causes. However, the etiology of primary congenital CMPs remains unknown and is still being investigated. Primary CMPs are hereditary diseases that occur fairly commonly, with a frequency of 0.5% in the population [9].

K.S. Kochergin-Nikitsky et al. distinguished a group of primary desminopathies, which are CMPs caused by DES mutations at locus 2q35. DES encodes the protein desmin, which serves as the main protein of the intermediate filaments of myocytes, primarily in the myocardium and skeletal muscles. Desminopathies are usually inherited in an autosomal dominant manner, accounting for 80% of all cases. Dilated and restrictive CMPs are the most common in this pathology, and HCMP is somewhat less common [9].

Over 100 genes have been reported to cause CMPs since the discovery of pathogenic variants in the myosin heavy chain 7 (MYH7) gene in HCMP [10].

Bonaventura et al. reported the eight sarcomeric genes (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, and TPM1) that are the most important and have the most convincing evidence of causing HCMP [11]. Mutations in one of the eight sarcomeric genes are present in 60% of genetically related HCMP cases [12]. According to B.J. Maron et al., affordable genetic testing has led to the identification of >11 causative genes with >2000 unique variants for individual families in patients with HCMP [13].

HCMP, caused by mutations in sarcomeric genes, is inherited in an autosomal dominant manner and exhibits a high degree of phenotypic heterogeneity [14]. In addition, up to 40% of all cases of HCMP are sporadic, which means the lack of mutations in the proband or the lack of family history [15].

Lioncino and E. Monda, et al. reported a group of HCMPs known as RASopathies. RASopathy is a multisystem disorder caused by mutations in genes related to the RAS/mitogen-activated protein kinase pathway. Compared with sarcomeric HCMP, RASopathy HCMP is associated with a higher prevalence of congestive HF and is characterized by the high prevalence and severity of left ventricular (LV) obstruction. RASopathies commonly involve biventricular issues and are often associated with congenital heart disease, particularly pulmonary artery stenosis [16].

Tadros et al. conducted a meta-analysis of three case–control studies (GWAS) and identified 14 new HCMP-associated loci [17].

Current views on hypertrophic cardiomyopathy pathogenesis

Genetic factors can cause structural and functional changes in the myocardium, leading to hemodynamic changes [4]. HCMP is characterized by the stiffening of the hypertrophied and sclerosed myocardium, which impairs the diastolic relaxation of the ventricles. Typically, systolic function is not affected in HCMP with diastolic dysfunction [4].

Relative coronary insufficiency results from the mismatch between increased myocardial mass and capillary bed, increased myocardial oxygen demand, compression of small subendocardial branches of coronary arteries, small coronary artery disease, and decreased gradient between the aorta and LV cavity [4].

According to C. Chou and M.T. Chin, no concepts can clearly explain how individual gene mutations lead to myocardial fibrosis, disruption of the cardiomyocyte structure, and asymmetric hypertrophy. The authors described the role of prolonged activation of calcium–calmodulin-dependent protein kinase II, autophagy characterized by the degradation of intracellular organelles and macromolecules in response to cellular stress, and sustained glycolysis in cardiomyocytes in this process. Intracellular changes may lead to cardiomyocyte hypertrophy, which can cause changes in the extracellular environment. These changes can promote tissue reorganization in intact cardiomyocytes, resulting in diffuse myocardial fibrosis [15].

Ventricular arrhythmias in HCMP are mainly caused by massive hypertrophy, fibrosis, and microvascular ischemia. However, functional arrhythmogenic mechanisms are likely to predominate in the early disease stages [18]. Current evidence suggests that rhythm disturbances are caused by increased late Na+ current and Ca²⁺ current via L-type calcium channels inside the cells. Furthermore, the heightened sensitivity of myofilaments to Ca²⁺ may contribute to postdepolarization and recurrent arrhythmias. In addition, reduced K⁺ currents occur during the neglected process, decreasing repolarization reserve and increasing early postdepolarizations [18].

Ranjbarvaziri et al. revealed significant dysregulation of fatty acid metabolism, decreased levels of acylcarnitines, and accumulation of free fatty acids, indicating changes in various biochemical reactions. HCMP has demonstrated signs of global energy decompensation, as evidenced by decreased levels of high-energy phosphate metabolites (adenosine triphosphate, adenosine diphosphate, and phosphocreatine) and low number of mitochondrial genes involved in the synthesis of creatine kinase and adenosine triphosphate [19].

Obstructive HCMP can cause low cardiac output due to dynamic LV outlet obstruction [4]. This obstruction is believed to be more pronounced in older patients, possibly because of frequent calcification of the mitral annulus [20].

Clinical picture of HCMP

CMP is clinically heterogeneous, and its clinical phenotype is determined by various factors, including genotype [10]. The clinical presentation of CMP can range from an asymptomatic course to SCD, which is most common in young individuals [21].

C.Y. Ho et al. reported that patients with pathogenic variants in sarcomeric genes who suffer from HCMP have higher rates of adverse events, such as HF, ventricular arrhythmias, and atrial fibrillation. Pathogenic variants in sarcomeric genes are also important predictors of adverse outcomes [22]. The most common symptoms include chest pain, shortness of breath, palpitations, fatigue, and fainting [23].

The clinical presentation in most patients is caused by diastolic dysfunction and stasis in the pulmonary circulation [24]. Chest pain syndrome resembles typical angina pectoris because it is caused by inadequate coronary blood flow with significant LV myocardial hypertrophy [24].

Syncope in HCMP can have several causes, including paroxysmal cardiac rhythm disturbances such as ventricular arrhythmias, supraventricular arrhythmias, tachyarrhythmias, and bradyarrhythmias, low ejection syndrome, which is usually associated with severe LV outlet obstruction and neurocardiogenic autonomic dysfunction [24].

Cardiac rhythm disturbances are the leading cause of SCD in patients with HCMP. In addition to pronounced subjective sensations such as palpable palpitations and interruptions in rhythm, approximately a quarter of arrhythmias are asymptomatic [24]. Furthermore, P. Teekakirikul et al. reported that the signs and symptoms of HCMP do not always correlate with the severity of myocardial hypertrophy. Thus, no significant proportion of young patients with HCMP may experience symptoms throughout their lives [25].

According to reports, HCMP symptoms may appear later in older patients than in younger ones. However, risk stratification is inversely related to age [20].

Laboratory and instrumental diagnosis of HCMP

The Ministry of Health of the Russian Federation [26] recommends standard laboratory tests for patients suspected of CMP, including clinical blood analysis, urinalysis, and biochemical blood analysis (cholesterol, triglycerides, potassium, sodium, alanine aminotransferase, aspartate aminotransferase, urea, creatinine, bilirubin, and glucose). A high NT-proBNP level indicates HF [26].

Medical and genetic counseling are recommended to identify the causative mutation [26]. According to B.J. Maron et al., genetic testing is also important in investigating next-generation family members who are at risk but usually asymptomatic (cascade genetic testing). Relatives of a proband who receive a negative genetic testing result for the same sarcomere gene mutation as the proband can be excluded from further follow-up with a high probability [13].

Patients suspected of HCMP should undergo electrocardiography (ECG) and Holter monitoring [26]. In HCMP, ECG data reveal the following [4]:

– Signs of LV hypertrophy

– Signs of left atrial overload and hypertrophy

– Abnormal Q or QS spike in leads II, III, and aVF in the case of hypertrophy of the proximal part of the interventricular septum (IVS) and in leads I and aVL in the case of hypertrophy of the lower part of the IVS and apex.

– Supraventricular and ventricular arrhythmias.

ECG should be performed annually [13]. Echocardiography is necessary to detect myocardial structure and function disorders and changes in the heart chambers and valve apparatus [27].

To diagnose HCMP, T. Ciarambino et al. suggested that the LV wall thickness should be >15 mm [27]. However, a wall thickness of 13–14 mm may also be diagnostically significant, particularly in cases with a family history of HCMP, dynamic outlet obstruction, and ECG changes [28]. In symmetric HCMP cases, LV outflow tract obstruction is typically absent [29].

Asymmetric HCMP is characterized by a ratio of IVS to posterior LV free wall thickness >1.3 [29]. It can be both nonobstructive and obstructive [30]. In idiopathic hypertrophic subaortic stenosis, the mobile distal part of the anterior mitral valve leaflet approaches the hypertrophic IVS during systole, causing dynamic obstruction of the LV outflow tract under the Bernoulli and Venturi effects. Echocardiography can detect anterior systolic displacement of the leaflet [31].

L.O. Gazun and E.V. Polukhina highlighted that Doppler echocardiography is the most informative method for assessing the degree of LV outflow tract obstruction. The degree of obstruction is determined by the pressure gradient, which does not exceed 5–6 mmHg under normal conditions. An increase of up to 30 mmHg should be considered an insignificant obstruction. An increase from 30 to 100 mmHg should be considered severe obstruction, and consultation with a cardiac surgeon is indicated when the gradient is >100 mmHg [30]. Stress echocardiography can be informative when the LV outlet gradient at rest is <30 mmHg [13].

In apex HCMP, wall thickening occurs in the apex region and a small residual cavity in the left ventricle. Dopplerography revealed accelerated return blood flow in this area [30].

In a prospective cohort study, R Karaca Özer et al. found that global longitudinal LV deformation <12.5% can distinguish HCMP from LV hypertrophy in athletes and patients with arterial hypertension with a sensitivity of 65% and specificity of 77%. According to the Kaplan–Meier 7-year survival analysis, patients with a global longitudinal strain value <12.5% had a higher risk of all-cause mortality than those with >12.5% (29% vs. 9%; p = 0.032). The LV global longitudinal strain value predicted mortality with a sensitivity of 64% and specificity of 70% for a value <12.5% (p = 0.012) [32].

The American Society of Echocardiography proposed four parameters [33] to detect diastolic dysfunction [33]:

– Maximal left atrial (LA) volume index >34 mL/m²

– Peak tricuspid regurgitation velocity (>2.8 m/s

– Mean ratio of peak early diastolic ventricular filling velocity (E) to peak atrioventricular annulus early diastolic velocity (e') >14

– Atrioventricular ring peak early diastolic velocity (e'): septal <7 cm/s, lateral <10 cm/s.

After diagnosis, patients with HCMP should undergo annual echocardiography [13]. Chest radiography is also recommended [4, 27].

HCMP typically lacks specific radiological signs. However, LA shadow enlargement may be detected in cases of volume overload caused by severe mitral regurgitation. In addition, swelling of the second arch on the left, root dilation, and signs of venous stasis in the lungs may be noticeable in cases of severe pulmonary hypertension [4, 27].

To differentiate between diagnoses, coronary angiography and ventriculography are recommended [4]. Additional options for verifying the diagnosis include cardiac magnetic resonance imaging (MRI), computed/multispiral computed tomography, scintigraphy, and positron emission tomography [26].

MRI with late gadolinium enhancement can reveal typical contrast enhancement patterns that differentiate HCMP from other conditions that mimic it, such as Anderson–Fabry disease. MRI provides detailed visualization of the IVS, mitral valve, and papillary muscles, which is useful for preoperative evaluation before IVS myomectomy [27]. B.J. Maron et al. reported that regular MRI with contrast enhancement is not mandatory for patients aged >65 years of age, although it is recommended at intervals of 3–5 years [13].

Treatment of hypertrophic cardiomyopathy

Conservative methods are initially prescribed for the treatment of HCMP. Surgical methods are only used if conservative treatment is ineffective and disease symptoms are severe [34].

First-line pharmacotherapy for symptomatic obstructive HCMP usually involves the administration of β-adrenoblockers or nondihydropyridine calcium channel blockers. These drugs have been the mainstay of treatment for decades because of their general negative inotropic and chronotropic effects, which lead to a decrease in contact between the anterior mitral valve leaflet and the IVS [35]. In patients with nonobstructive HCMP who experience HF symptoms, β-adrenoblockers or verapamil should be prescribed. These drugs can reduce and control HF symptoms; however, little evidence suggests that they can reduce SCD risk [36].

According to T.J. Gluckman, β-adrenoblockers without vasodilatory effects, such as atenolol and propranolol, are primarily used to reduce symptoms. Titrating β-adrenoblockers according to tolerability while considering a target resting heart rate of approximately 60 beats/min is recommended. These drugs are effective in reducing dyspnea during exercise and chest pain, improving diastolic filling [34].

A.M. Dybro et al. found that metoprolol reduced LV obstruction both at rest and during exercise, relieved symptoms, and improved the quality of life in patients with obstructive HCMP [37].

Currently, new drugs are being studied in addition to previously described and well-established medications.

Olivotto et al. described the results of a phase 3 randomized double-blind placebo-controlled study on the use of mavacamten, the first cardiac myosin inhibitor in its class. The study analyzed patients with HCMP, LV outlet gradient ≥50 mm Hg, and functional class II–III chronic HF. The drug demonstrated efficacy in reducing LV obstruction, improving exercise tolerance, and reducing the functional class of chronic HF compared with placebo [38].

Mavacamten is the first drug specifically designed for treating HCMP, with the potential to benefit patients with symptomatic obstruction [39]. However, this drug, despite its positive effects, does not prevent disease progression [40]. The MAVA-LTE study, which evaluates the long-term safety of mavacamten, is scheduled to be completed in November 2025 [41].

M.S. Maron et al. also reported positive results from a phase 2 clinical trial of aficamtena, another cardiac myosin inhibitor, in patients with symptomatic HCMP. The phase 3 trial of afikamtena, SEQUOIA-HCM, is currently ongoing [42]. According to C. Ferrantini et al., treatment with the late sodium current inhibitor ranolazine decreased tension predominant in the IVS in obstructive HCMP [43].

B.J. Maron et al. revealed that the effective use of an implantable cardioverter-defibrillator reduces the risk of SCD caused by fatal rhythm disturbances. The authors found that the use of an implantable cardioverter-defibrillator reduced the rate of HCMP-related mortality to 0.5% per year. An implantable cardioverter-defibrillator is generally not recommended for patients with HCMP aged ≥60 years who do not exhibit symptoms of rhythm disturbances because of the low incidence of arrhythmia-related SCD in this age group. However, there may be exceptions for individual cases, such as those involving the cardiac apex [36].

In addition to the conservative treatment of CMP, several surgical methods are available. These include myomectomy, which involves the resection of the proximal part of the IVS, mitral valve replacement, and implantation of a dual-chamber pacemaker operating in the DDD mode [4, 44].

According to B.J. Maron et al. [45], myomectomy-related mortality has significantly decreased from 6%–8% to 0.5% over the past 30 years. E.J. Rowin et al. [46] reported an improvement in HF symptoms, reduction in the functional class of chronic HF by ≥1 in ≥90% of the patients, and restoration of physical activity in 75% of the patients, regardless of age.

Some studies have reported transapical myomectomy in patients with apical HCMP. A. Nguyen et al reported a case fatality rate of 4% of patients within 30 days of surgery. At follow-up, 76% of the patients reported symptom improvement, and 3% subsequently underwent heart transplantation for the recurrence of HF symptoms. The estimated 1-, 5-, and 10-year survival rates were 96%, 87%, and 74%, respectively [47].

Alcohol ablation of the IVS is an alternative to myomectomy for patients with severe symptoms that are not candidates for surgery. However, this intervention may lead to ventricular tachyarrhythmias because of IVS scarring, which may require the use of an implantable cardioverter-defibrillator to prevent SCD [36].

Heart transplantation has been reported as a treatment option for patients with end-stage HCMP and severe symptoms of chronic HF [48]. In some cases, chronic HF caused by HCMP can progress to the terminal stage, which is characterized by diffuse fibrosis and LV remodeling, leading to severe systolic and diastolic dysfunction [41]. Heart transplantation has a 5-year survival rate of >90% [48].

Conclusions

After studying HCMP-related information, this disease requires the introduction of highly effective and modern diagnostic methods to differentiate it from other conditions. Despite the development of new drugs and surgical methods, the problem of therapy is far from being solved. Therefore, new research directions in this area remain relevant.

 

Authors’ contribution. A.N.K., supervising the work, writing the manuscript, reviewing critical content, and approving the manuscript for publication; D.Y.G., reviewing publications on the topic of the article, processing literature data, and writing the manuscript; V.I.S. and N.N.K., reviewing publications on the topic of the article and writing the manuscript.
Funding source. The study received no financial support.
Conflict of interest. The authors declare no conflict of interest for the presented article.

About the authors

Alexey N. Kalyagin

Irkutsk State Medical University; Irkutsk City Clinical Hospital No.1

Author for correspondence.
Email: akalagin@mail.ru
ORCID iD: 0000-0002-2708-3972
SPIN-code: 6737-0285

M.D., D. Sci. (Med.), Prof., Vice-rector for Medical Work and Postgraduate Education, Head of Depart., Depart. of Propedeutics of Internal Diseases

Russian Federation, Irkutsk, Russia; Irkutsk, Russia

Danil Yu. Gamayunov

Irkutsk State Medical University

Email: d.gamayunov@mail.ru
ORCID iD: 0000-0001-9348-9025
SPIN-code: 7222-6890

M.D., Resident, Depart. of Propedeutics of Internal Diseases

Russian Federation, Irkutsk, Russia

Viktor I. Silkin

Irkutsk City Clinical Hospital No.1

Email: silkin1957@inbox.ru

M.D., Anesthesiologist-Resuscitator

Russian Federation, Irkutsk, Russia

Nikolay N. Kurkov

Irkutsk City Clinical Hospital No.1

Email: kurkov.nn@yandex.ru
ORCID iD: 0000-0002-6397-1731
SPIN-code: 1859-1378

M.D., Anesthesiologist-Resuscitator

Russian Federation, Irkutsk, Russia

References

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