Hypertrophic Cardiomyopathy: Etiology, Pathogenesis, Symptoms, Diagnosis, Treatment Methods

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder marked by unexplained, most often asymmetric, hypertrophy of the left ventricular (LV) wall without chamber dilation. The disease is caused by mutations in genes encoding sarcomeric proteins, leading to morphological, electrical, and hemodynamic abnormalities.

HCM is one of the most common inherited forms of cardiomyopathy, occurring in approximately 1 in 500 adults. Men are 1.5 times more likely to develop HCM than women; in women, however, the disease is usually diagnosed later in life and tends to be more severe.

Etiology

HCM results from impaired synthesis and function of sarcomeric contractile proteins. In some cases, secondary forms are identified, associated with systemic or metabolic disorders.

Furthermore, up to 60–70 % of HCM cases are linked to single-gene mutations.

Genes Associated with HCM

• The disease is inherited in an autosomal dominant pattern, meaning that a single altered gene from one parent is sufficient to cause the condition. Thus, the likelihood of developing the disease is high, but the severity and clinical manifestations may vary greatly, even within the same family.
• It should be noted that in approximately 30 % of cases, the mutation occurs de novo, without a family history.

Certain disorders may mimic the clinical features of HCM but arise from different pathogenetic mechanisms. It is critically important to distinguish these conditions from the primary (sarcomeric) form, since both treatment strategies and prognosis differ.

Forms with Secondary Hypertrophy (HCM Phenocopies)

• Даже при наличии мутации в гене саркомерного белка клиническая выраженность и течение ГКМП зависят от дополнительных факторов: 
  • Epigenetic regulators;
  • Concomitant hypertension;
  • High-intensity physical activity (especially during adolescence);
  • Sex and hormonal status (women more often develop obstructive forms, but with later onset);
  • Family history of sudden cardiac death (SCD).

Pathogenesis

• Sarcomeric dysfunction

Mutations in the relevant genes (see Etiology) lead to:

• Increased calcium sensitivity;
• Reduced contractile efficiency;
• Elevated energy demand.

Consequence: Compensatory myocardial hypertrophy develops, predominantly involving the interventricular septum, especially in the region of the left ventricular outflow tract (LVOT).

• Hypertrophy and impaired relaxation (diastolic dysfunction)

Thickening of the ventricular walls leads to:

• Reduced LV compliance;
• Impaired diastolic filling;
• Elevated diastolic pressure.

Consequence: Pulmonary congestion, manifested by dyspnea and other symptoms of heart failure with preserved ejection fraction (HFpEF).

• Significant narrowing of LVOT (obstructive form)
  • LVOT obstruction develops in 60–70 % of patients.
  • Due to the Venturi effect during systole, the anterior leaflet of the mitral valve is drawn toward the interventricular septum (systolic anterior motion, SAM phenomenon). This increases the pressure gradient and leads to mitral regurgitation (MR).

Consequence: Progressive hemodynamic overload, which worsens symptoms and increases the risk of arrhythmias.

• Microvascular ischemia

The hypertrophied myocardium requires increased oxygen supply, but:

• The capillary network cannot adequately compensate for tissue growth;
• Oxygen demand and supply are out of balance;
• Fibrosis of small-caliber vessels is frequently observed.

Consequence: Myocardial ischemia occurs despite normal coronary arteries, leading to chest pain, fibrosis, and an increased risk of arrhythmias.

• Fibrosis and electrical instability

In response to ischemia and mechanical overload of the myocardium, interstitial and focal fibrosis develops, resulting in:

• Impaired impulse conduction;
• Ventricular arrhythmias;
• Increased risk of sudden cardiovascular death (SCD).

Clinical manifestations

• Dyspnea on exertion, fatigue;
• Chest pain (angina pectoris) without coronary artery disease;
• Syncope or presyncope (especially during physical exertion);
• Ventricular arrhythmias (VA), atrial fibrillation (AF);
• SCD — particularly in younger patients and athletes with obstructive forms;
• Heart failure: The condition may develop when ejection fraction (HFpEF) is preserved or reduced (in later stages). Symptoms include edema, orthopnea, tachycardia, and reduced exercise tolerance;
• Asymptomatic course: in 25–30 % of patients, the disease is detected during family screening. A high risk of complications is not excluded.

Diagnosis of Hypertrophic Cardiomyopathy

• Echocardiography (transthoracic echocardiography, TTE) — the key method for initial diagnosis. It allows:
  • Assessment of myocardial wall thickness. Diagnosis is likely with wall thickness ≥ 15 mm in adults or ≥ 13 mm in first-degree relatives of patients with confirmed HCM;
  • Determination of hypertrophy distribution: asymmetric, concentric, apical;
  • Detection of LVOT obstruction (gradient ≥ 30 mmHg; clinically significant at ≥ 50 mmHg);
  • Identification of the SAM phenomenon (systolic anterior motion of the mitral leaflet) and MR;
  • Evaluation of LV function and diastolic dysfunction;
  • Measurement of atrial size (particularly the left atrium, due to AF risk).
• Cardiac MRI is recommended when:
  • Echocardiography does not allow precise assessment of wall thickness;
  • Apical or atypical forms of HCM are suspected;
  • Myocardial fibrosis evaluation is required.

Cardiac MRI identifies:

• The distribution and degree of hypertrophy;
• Areas of fibrosis associated with increased risk of arrhythmias and SCD;
• Differentiation from phenocopies (e.g., amyloidosis).

• ECG (echocardiogram) is nonspecific, but pathological changes are detected in more than 90 % of patients. Signs of LVH include:
  • Atypical Q waves (in leads V4–V6, I, aVL) may mimic myocardial infarction;
  • ST segment changes and inverted T wave;
  • Rhythm disturbances: AF, ventricular extrasystoles, ventricular tachycardia (VT);
  • Atrioventricular or intraventricular blocks.
• Holter monitoring. Indications:
  • Suspected arrhythmias (ventricular ectopy, VT, AF);
  • Syncope or presyncope;
  • Assessment of arrhythmia burden and indications for implantable cardioverter-defibrillator (ICD) placement
• Exercise testing (treadmill or bicycle ergometry). This modality helps:
  • Assess physical exercise tolerance;
  • Detect inducible LVOT obstruction;
  • Determine pressure gradient under stress;
  • Identify ischemic symptoms in the absence of coronary artery stenosis.
• Genetic testing. Indications:
  • Patients with confirmed HCM (especially young individuals or those with a family history of SCD);
  • Screening of first-degree relatives (children, siblings, parents);
  • Suspected phenocopies (e.g., Fabry disease, mitochondrial disorders, etc.).

The most frequently identified genes include: MYH7, MYBPC3, TNNT2, TNNI3, TPM1.

• Laboratory markers:
  • NT-proBNP / BNP — elevated in pressure overload and diastolic dysfunction;
  • Troponin T/I — may be moderately elevated in microvascular ischemia.

Treatment of Hypertrophic Cardiomyopathy

1. Lifestyle Modification:

• Avoidance of heavy physical activity and competitive sports;
• Control of blood pressure and body weight;
• Screening of first-degree relatives.

2. Medication therapy:

• β-blockers (most preferred: bisoprolol, metoprolol);
• Verapamil — for patients with contraindications to β-blockers;
• Disopyramide — as an adjunct in obstructive forms;
• Mavacamten — a novel agent with proven efficacy in reducing LVOT pressure gradient and improving symptoms (ESC 2023, AHA 2020).

3. Surgical Therapy

Indications:

• LVOT pressure gradient ≥ 50 mmHg p. at rest or following provocation;
• Severe symptoms (NYHA Class III–IV) unresponsive to β-blockers, verapamil, or disopyramide;
• Significant MR associated with SAM phenomenon;

Extended Septal Myectomy:

• This is the gold standard surgical treatment for obstructive HCM;
• The procedure is performed via mini-sternotomy or full sternotomy; in some cases, via right anterior mini-thoracotomy;
• Resection of hypertrophied interventricular septal tissue eliminates the pressure gradient;
• Mitral valve repair or resection of secondary chordae may be performed if necessary;
• Possible complications: conduction blocks, need for ICD, recurrence of gradient.

4. Alcohol septal ablation (endovascular intervention) is more often used in patients with contraindications to open surgery or high surgical risk.

• Injection of ethanol into a perforating artery → localized infarction → thinning of the septum;
• Risk of complete atrioventricular block (up to 10 %) may necessitate pacemaker implantation;
• Less predictable outcomes;
• Possibility of incomplete relief of obstruction.

5. Implantable Cardioverter-Defibrillator (ICD)

Indications:

• Prior SCD or sustained VT;
• LV wall thickness > 30 mm;
• Family history of SCD
• Unexplained syncope;
• LV ejection fraction < 50 % with progressive disease.

6. Heart transplantation may be considered in patients with end-stage, refractory heart failure despite optimal therapy.