HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart muscle characterized by abnormal myocardial thickening in the absence of hemodynamic overload conditions such as arterial hypertension or valvular disease. Hypertrophy predominantly affects the left ventricle, particularly the interventricular septum, and may cause left ventricular outflow tract (LVOT) obstruction.

HCM is one of the leading causes of sudden cardiac death in young athletes and presents with variable symptoms, ranging from asymptomatic cases to advanced heart failure. The disease progression depends on the extent of hypertrophy, the presence of diastolic dysfunction, and the involvement of the cardiac electrical system.

Epidemiology

Hypertrophic cardiomyopathy is the most common genetic cardiomyopathy, with an estimated prevalence of approximately 1 case per 500 individuals. However, recent genetic studies suggest a prevalence of up to 1 in 200, as many cases remain undiagnosed.

HCM is an autosomal dominant disorder caused by mutations in genes encoding sarcomeric proteins, particularly MYH7 (beta-myosin heavy chain) and MYBPC3 (myosin-binding protein C). Around 60% of cases have an identifiable genetic basis, while the remaining 40% are idiopathic or sporadic.

The disease can manifest at any age, but symptoms typically become more evident in adolescence or early adulthood. In young athletes, HCM is the leading cause of sudden cardiac death due to malignant ventricular arrhythmias, often triggered by intense physical exertion.

Pathophysiology

Hypertrophic cardiomyopathy is characterized by heterogeneous myocardial thickening, which alters the normal architecture of the heart and impairs both diastolic function and coronary perfusion.

The main pathophysiological mechanisms include:

• Asymmetric myocardial hypertrophy: thickening primarily affects the interventricular septum, leading to narrowing of the left ventricular outflow tract (LVOT) in over 70% of patients.
• Diastolic dysfunction: hypertrophy reduces ventricular compliance, impeding diastolic filling and increasing atrial filling pressures.
• Microvascular abnormalities: myofibrillar disarray and interstitial fibrosis cause myocardial ischemia, even in the absence of coronary artery disease.
• Electrical instability: myocardial fiber disorganization predisposes to ventricular arrhythmias, increasing the risk of sudden cardiac death.

In patients with LVOT obstruction, the presence of an intraventricular pressure gradient can lead to symptoms of low cardiac output, such as syncope, dyspnea, and chest pain. Obstruction is exacerbated by physical exertion, increased sympathetic tone, and decreased preload.

Over time, disease progression may result in myocardial fibrosis, heart failure, and, in some cases, the need for advanced therapeutic interventions, such as septal alcohol ablation or surgical myectomy.

Clinical Presentation

The clinical presentation of hypertrophic cardiomyopathy (HCM) is highly variable: some patients remain asymptomatic throughout life, while others develop progressive heart failure symptoms or experience potentially fatal arrhythmias.

Key Signs and Symptoms

• Exertional dyspnea: the most common symptom, due to diastolic dysfunction and increased atrial filling pressures.
• Angina pectoris: occurs even in the absence of coronary artery disease, caused by microvascular ischemia and increased myocardial oxygen demand.
• Palpitations: often associated with atrial arrhythmias (atrial fibrillation) or ventricular arrhythmias.
• Syncope or presyncope: related to LVOT obstruction or malignant arrhythmias.
• Sudden cardiac death: a rare but possible event, particularly in young athletes.

Symptoms tend to worsen in conditions of reduced preload (dehydration, vasodilator medications) or increased afterload (hypertension, physical stress), which exacerbate LVOT obstruction and the subsequent reduction in cardiac output.

Physical Examination

On cardiac auscultation, patients with HCM may present a harsh systolic ejection murmur, which intensifies with standing or the Valsalva maneuver due to reduced preload, increasing LVOT obstruction. Other clinical findings include:

• S4 heart sound: indicative of reduced left ventricular compliance.
• Hyperdynamic and laterally displaced apical impulse: a sign of left ventricular hypertrophy.
• Bifid carotid pulse: due to reduced ventricular compliance and a double systolic peak.

Diagnosis

The diagnosis of hypertrophic cardiomyopathy is based on a combination of medical history, physical examination, and instrumental tests, with a key role played by echocardiography in confirming the presence of myocardial hypertrophy >15 mm in the absence of secondary causes.

Diagnostic Tests

• Electrocardiogram (ECG): often shows left ventricular hypertrophy, deep T-wave inversions in precordial leads, and sometimes ventricular arrhythmias.
• Transthoracic echocardiography: the key diagnostic test, allows assessment of interventricular septal thickness, LVOT gradient, and diastolic dysfunction.
• Exercise stress test: useful for assessing blood pressure response, arrhythmia induction, and symptom onset during stress.
• 24-hour Holter ECG: indicated to detect ventricular arrhythmias, which increase the risk of sudden death.
• Cardiac magnetic resonance imaging (CMR): essential in uncertain cases or to evaluate myocardial fibrosis using gadolinium contrast.
• Genetic testing: recommended for patients with a positive family history to identify sarcomeric gene mutations.

Differential Diagnosis

It is essential to exclude other conditions that can cause left ventricular hypertrophy, such as:

• Hypertensive cardiomyopathy: characterized by more symmetrical hypertrophy that regresses with antihypertensive treatment.
• Cardiac amyloidosis: often associated with diffuse gadolinium enhancement on CMR.
• Fabry disease: to be considered in young patients with hypertrophy and cutaneous or renal involvement.
• Athlete’s heart: characterized by symmetric and reversible hypertrophy upon cessation of intense sports activity.

Accurate diagnosis is crucial to identifying high-risk patients and initiating targeted management strategies.

Treatment

The goal of treating hypertrophic cardiomyopathy (HCM) is to reduce symptoms, improve quality of life, and prevent complications, particularly sudden cardiac death. The therapeutic approach depends on the presence of left ventricular outflow tract (LVOT) obstruction and the patient’s arrhythmic risk.

Pharmacological Therapy

Pharmacological therapy is the first-line treatment for symptomatic patients, aiming to improve exercise tolerance and reduce dynamic obstruction of the LVOT. The most commonly used medications include:

• Beta-blockers (bisoprolol, metoprolol, carvedilol): decrease heart rate, improve diastolic perfusion, and reduce symptoms.
• Non-dihydropyridine calcium channel blockers (verapamil, diltiazem): useful in patients intolerant to beta-blockers, improving diastolic filling.
• Disopyramide: an antiarrhythmic agent with negative inotropic effects, used in patients with persistent symptoms and severe obstruction.
• Cardiac myosin inhibitors (mavacamten): a newly approved drug class that reduces obstruction and improves cardiac performance.

In patients with concomitant atrial fibrillation, anticoagulation therapy with DOACs or warfarin is recommended to prevent thromboembolic events.

Invasive Management

For patients with severe LVOT obstruction (gradient ≥50 mmHg) and symptoms refractory to pharmacological therapy, invasive procedures may be considered to reduce obstruction:

• Septal alcohol ablation: selective alcohol injection into the first septal branch to reduce interventricular septal thickness.
• Surgical myectomy: resection of the hypertrophic septum, indicated for symptomatic young patients.
• Implantable cardioverter-defibrillator (ICD): indicated in patients at high risk of malignant ventricular arrhythmias.

Prognosis

The prognosis of hypertrophic cardiomyopathy varies significantly and depends on the presence of obstruction, arrhythmic risk, and treatment strategies. Long-term survival is good in well-managed patients, with a 5-year survival rate exceeding 80%.

Risk Factors for Sudden Cardiac Death

In patients with HCM, sudden cardiac death (SCD) is the leading cause of fatal events. The major risk factors include:

• Family history of sudden cardiac death: first-degree relatives with unexplained fatal events.
• Unexplained syncope: particularly in young patients with HCM.
• Presence of non-sustained ventricular tachycardia (NSVT): documented on Holter ECG.
• Septal thickness ≥30 mm: associated with a high risk of arrhythmic events.
• Abnormal blood pressure response to exercise: inability to increase systolic blood pressure.

Early identification of high-risk patients allows for the implementation of preventive strategies, such as the implantation of an automatic implantable defibrillator (ICD), which has been shown to significantly reduce mortality in high-risk individuals.

Complications

Hypertrophic cardiomyopathy (HCM) can progress to more severe forms, significantly impacting quality of life and prognosis. The main complications include:

Sudden Cardiac Death (SCD)

Sudden cardiac death is one of the most feared complications of HCM, especially in young athletes. It is caused by sustained ventricular tachycardia or ventricular fibrillation. The risk is highest in patients with multiple risk factors, for whom an automatic implantable defibrillator (ICD) is recommended.

Atrial Fibrillation and Thromboembolism

Approximately 20-25% of patients with HCM develop atrial fibrillation due to increased left atrial pressure and progressive atrial fibrosis. This condition increases the risk of ischemic stroke and requires management with anticoagulant therapy in high-risk patients.

Heart Failure

Heart failure in HCM can manifest in two forms:

• With preserved ejection fraction (HFpEF): due to impaired diastolic filling and increased ventricular stiffness.
• With reduced ejection fraction (HFrEF): less common, occurring in the advanced stage with progression to dilated cardiomyopathy and contractile dysfunction.

Infective Endocarditis

Patients with HCM and significant mitral regurgitation are at risk of infective endocarditis due to hemodynamic turbulence over the mitral valve. In these patients, antibiotic prophylaxis is indicated before high-risk invasive procedures.

Progression to Restrictive Cardiomyopathy

In patients with diffuse myocardial fibrosis, HCM can evolve into a restrictive form with severe impairment of ventricular filling and increased filling pressures, resembling cardiac amyloidosis.

References
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