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

Hypertrophic cardiomyopathy (HCMP) is a primary myocardial disease characterized by unexplained hypertrophy of the left ventricular wall, most often asymmetric, without cavity enlargement. The disease is based on mutations in genes encoding sarcomeric proteins, leading to morphologic, electrical, and hemodynamic abnormalities.

HCMD is one of the most common inherited forms of cardiomyopathy and occurs in about 1 in 500 adults. Men are more commonly affected than women (approximate ratio 3:2), but women are usually diagnosed at a later age and have a more severe course.

Etiology

The disease is based on impaired synthesis and function of sarcomeric contractile proteins, but in some cases secondary forms associated with systemic and metabolic disorders are identified.

Up to 60-70% of cases of hypertrophic cardiomyopathy are monomutant genetic in nature.

Genes associated with the development of HCMD

• The disease is transmitted in an autosomal dominant manner, i.e. a single altered gene from one of the parents is sufficient. In this case, the probability of the disease is high, but the severity and form of manifestations can vary greatly even within the same family.
• In about 30% of cases, the mutation occurs for the first time, with no family history.

Some diseases may mimic the clinical picture of hypertrophic cardiomyopathy, but have a different pathogenetic origin. It is extremely important to distinguish them from the primary (sarcomeric) form, because the treatment and prognosis are different.

Variants with secondary hypertrophy (HCMP phenocopies)

• Even in the presence of a mutation in the sarcomeric protein gene, the clinical severity and course of HCMP depend on additional factors:
  • Epigenetic regulators;
  • Concomitant arterial hypertension;
  • High-intensity physical activity (especially during adolescence);
  • Gender and hormonal status (women are more likely to have obstructive forms, but later manifestation);
  • A family history of sudden cardiac death.

Pathogenesis

• Disorder of sarcomeric function

Mutations in genes (see etiology) lead to:

• Hypersensitivity to calcium;
• Reduced contractile efficiency;
• Increased energy requirements.

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

• Hypertrophy and impaired relaxation (diastolic dysfunction)

Wall thickening leads to:

• Decreased left ventricular distensibility;
• Disruption of its filling in diastole;
• Increased diastolic pressure.

Consequence: development of stasis in the small circle of blood circulation, which is manifested by dyspnea and other symptoms of heart failure with preserved ejection fraction.

• Severe narrowing of the LV outflow tract (obstructive form)
  • In 60-70% of patients, VTE obstruction forms.
  • Due to the Venturi effect during systole the following occurs: retraction of the anterior mitral valve leaflet to the septum (SAM-phenomenon), aggravation of the pressure gradient, development of mitral regurgitation.

The consequence: hemodynamic overload increases, which exacerbates symptoms and increases the risk of arrhythmias.

• Microvascular ischemia

Hypertrophied myocardium requires more oxygen, but:

• The capillary network does not have time to compensate for tissue growth;
• There is an imbalance between oxygen demand and delivery;
• Fibrosis of small caliber vessels is often detected.

The consequence: myocardial ischemia develops in normal coronary arteries, leading to chest pain, fibrosis and increased risk of arrhythmias.

• Fibrosis and electrical instability

In response to myocardial ischemia and mechanical overload, interstitial and focal fibrosis forms, resulting in:

• Impulse conduction disorder;
• The development of ventricular arrhythmias;
• Increased risk of sudden cardiac death (SCD).

Clinical Manifestations

• Dyspnea on exertion, fatigue;
• Chest pain (angina pectoris) without coronary artery disease;
• Syncope or pre-syncope (especially with exercise);
• Ventricular arrhythmias, atrial fibrillation;
• VSS – especially in young patients and athletes with obstructive form;
• Heart failure: may occur with preserved ejection fraction (HFpEF) or with its reduction at advanced stages. It is manifested by edema, orthopnea, tachycardia, decreased exercise tolerance;
• Asymptomatic course: in 25-30% of patients, the disease is detected by family history screening. Does not exclude a high risk of complications.

Diagnosis of hypertrophic cardiomyopathy

• Echocardiography (transthoracic echocardiography) is a key method of primary diagnosis. It allows:
  • Assess myocardial thickness. Diagnosis is likely when wall thickness is ≥15 mm in adults or ≥13 mm in first-line relatives with confirmed HCMP;
  • Determine the distribution of hypertrophy: asymmetric, concentric, apical;
  • Detect LV outflow tract obstruction (gradient ≥30 mmHg, clinically significant ≥50 mmHg);
  • Detect SAM phenomenon (systolic retraction of the mitral leaflet) and mitral regurgitation;
  • Assess LV function and the presence of diastolic dysfunction;
  • Measure atrial size (especially the left atrium – risk of FP).
• Cardiac MRI is recommended if:
  • EchoCG does not accurately assess wall thickness;
  • An apical or atypical form of HCMP is suspected;
  • Evaluation of myocardial fibrosis is required.

Reveals:

• Distribution and degree of hypertrophy;
• Areas of fibrosis – associated with increased risk of arrhythmias and VSS;
• Differentiation with phenocopies (e.g., amyloidosis).

• ECG (electrocardiography) – non-specific, but pathologic changes are found in more than 90% of patients. Signs of left ventricular hypertrophy:
  • Atypical Q teeth (in leads V4-V6, I, aVL) – may mimic myocardial infarction;
  • ST-segment changes and inversion of the T waveform;
  • Rhythm disorders: atrial fibrillation, ventricular extrasystoles, VT;
  • Atrioventricular or intraventricular block.
• Holter monitoring. Indications:
  • Suspicion of arrhythmias (VE, VT, FP);
  • Syncope or pre-syncope;
  • Assessment of the severity of rhythm disturbances and indications for ICD.
• A stress test (treadmill or cycle ergometry). Held for:
  • Assessments of exercise tolerance;
  • Detection of inducible VTE obstruction;
  • Gradient determinations against load;
  • Identification of coronary symptoms without coronary artery stenosis.
• Genetic testing. Recommended:
  • Patients with confirmed cGMP (especially those who are young or have a family history of CHD);
  • To screen first line relatives (children, siblings, parents);
  • In suspected phenocopies (Fabry disease, mitochondrial diseases, etc.).

Identifiable genes: MYH7, MYBPC3, TNNT2, TNNI3, TPM1 are the most frequent.

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

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Treatment of hypertrophic cardiomyopathy

1. Lifestyle modification:

• Exclusion of heavy physical activity and sports;
• Control of blood pressure and body weight;
• Screening of first line relatives.

2. Drug therapy:

• β-blockers (preferably: bisoprolol, metoprolol);
• Verapamil – in case of contraindications to β-blockers;
• Disopyramide – as an adjunct in the obstructive form;
• Mavacamten is a new drug with a proven effect of gradient reduction and symptom improvement (per ESC 2023 and AHA 2020).

3. Surgical Therapy

Indications:

• Left ventricular outflow tract gradient (LVOG) ≥50 mmHg. Art. at rest or on provocation;
• Severe symptoms (NYHA III-IV) not amenable to treatment with β-blockers, verapamil, or disopyramide;
• Prominent mitral regurgitation associated with SAM phenomenon.

Extended septal myectomy:

• The gold standard of surgery for obstructive cGMP;
• It is performed through a mininotomy or complete sternotomy, in some cases possibly through an anterior right minithoracotomy;
• A section of hypertrophied interventricular septum is removed, which eliminates the pressure gradient;
• If necessary, mitral valve plasty or resection of secondary chordae is performed;
• Possible complications: blockages, need for an ICD, gradient recurrence.

4. Alcohol septal ablation (endovascular intervention) is more commonly used in patients for whom open surgery is contraindicated or has too high risks.

• Ethanol injection into the perforating artery → localized infarction → decreased septal thickness;
• Risk of complete AV blockade (up to 10%) – readiness for ECS implantation is required;
• Less predictability of results;
• The possibility of incomplete relief of obstruction.

5. Cardioverter defibrillator (ICD) implantation

Indications:

• Experienced VSS or sustained VT;
• LV wall thickness >30 mm;
• VSS Family History;
• Syncope of unclear etiology;
• LWF <50% in the progressive course.

6. Cardiac transplantation in patients with terminal, refractory CH despite treatment.