Hypertrophic cardiomyopathy (HCM) is a genetic disease of the cardiac muscle characterized by abnormal thickening of the myocardium in the absence of hemodynamic overload conditions such as arterial hypertension or valvulopathies. The hypertrophy mainly involves the left ventricle, with particular predilection for the interventricular septum, and may result in obstruction of the left ventricular outflow tract (LVOT).
HCM is one of the leading causes of sudden cardiac death in young athletes and may manifest with variable symptoms, ranging from the absence of clinical signs to advanced heart failure. The course of the disease depends on the extent of hypertrophy, the presence of diastolic dysfunction, and the involvement of the cardiac conduction system.
Epidemiology
Hypertrophic cardiomyopathy is the most common genetic cardiomyopathy, with an estimated prevalence of about 1 in every 500 individuals. However, more recent genetic studies suggest a prevalence up to 1 in 200, as many forms remain undiagnosed.
It is an autosomal dominant disease caused by mutations in genes encoding sarcomeric proteins, especially MYH7 (beta-myosin heavy chain) and MYBPC3 (myosin-binding protein C). About 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 become more evident during 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 non-uniform thickening of the myocardium, which alters the normal architecture of the heart and impairs both diastolic function and coronary perfusion.
The main pathophysiological mechanisms include:
Asymmetric myocardial hypertrophy: the thickening mainly affects the interventricular septum, causing narrowing of the left ventricular outflow tract (LVOT) in over 70% of patients.
Microvascular abnormalities: myofibril disarray and interstitial fibrosis cause myocardial ischemia, even in the absence of coronary artery disease.
Electrical instability: myocardial fiber disarray predisposes to ventricular arrhythmias, increasing the risk of sudden cardiac death.
In patients with LVOT obstruction, the presence of an intraventricular pressure gradient may result in symptoms of low cardiac output, such as syncope, dyspnea, and chest pain. The obstruction is accentuated by physical exertion, increased sympathetic tone, and decreased preload.
Over time, disease progression may lead to myocardial fibrosis, heart failure, and, in some cases, the need for advanced therapies such as septal alcohol ablation or surgical myectomy.
Clinical Presentation
The clinical presentation of hypertrophic cardiomyopathy (HCM) is extremely variable: some patients remain asymptomatic throughout life, while others develop progressive heart failure symptoms or experience potentially fatal arrhythmias.
Main signs and symptoms
Exertional dyspnea: the most common symptom, due to diastolic dysfunction and increased atrial filling pressures.
Angina pectoris: present even without 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 left ventricular outflow tract (LVOT) obstruction or malignant arrhythmias.
Sudden cardiac death: a rare but possible event, especially in young athletes.
Symptoms tend to worsen in conditions of reduced preload (dehydration, vasodilator drugs) or increased afterload (hypertension, physical stress), which exacerbate LVOT obstruction and the consequent reduction in cardiac output.
Physical examination
On cardiac auscultation, patients with HCM may present a systolic ejection murmur, which intensifies on standing or during the Valsalva maneuver due to reduced preload that accentuates LVOT obstruction. Other clinical signs may include:
S4 sound: expression of reduced left ventricular compliance.
Laterally displaced, hyperdynamic apex beat: sign of left ventricular hypertrophy.
Biphasic carotid pulse: due to reduced ventricular compliance and double systolic peak.
Diagnosis
The diagnosis of hypertrophic cardiomyopathy is based on a combination of medical history, physical examination, and instrumental tests, with particular emphasis on echocardiography to confirm the presence of myocardial hypertrophy >15 mm in the absence of secondary causes.
Diagnostic tests
Electrocardiogram (ECG): often shows signs of left ventricular hypertrophy, deep inverted T waves in precordial leads, and sometimes ventricular arrhythmias.
Transthoracic echocardiography: the cornerstone of diagnosis, allows assessment of interventricular septal thickness, LVOT obstruction gradient, and diastolic dysfunction.
Exercise stress test: useful to assess blood pressure response, induction of arrhythmias and symptom onset under stress.
24h Holter ECG: indicated to identify ventricular arrhythmias, which increase the risk of sudden death.
Cardiac magnetic resonance (CMR): fundamental in doubtful cases or to assess myocardial fibrosis with gadolinium enhancement.
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 symmetric hypertrophy and regression with antihypertensive therapy.
Cardiac amyloidosis: often associated with ventricular wall thickening and diffuse gadolinium enhancement on CMR.
Fabry disease: to be considered in young patients with ventricular hypertrophy and skin or renal abnormalities.
Athlete's heart: characterized by symmetric and reversible hypertrophy with cessation of intense athletic activity.
Accurate diagnosis is essential to identify high-risk patients and initiate targeted treatment.
Treatment
The goal of hypertrophic cardiomyopathy (HCM) treatment is to reduce symptoms, improve quality of life, and prevent complications, especially sudden cardiac death. Therapeutic management depends on the presence of left ventricular outflow tract (LVOT) obstruction and the patient's arrhythmic risk.
Pharmacological therapy
Pharmacological therapy is the first approach in symptomatic patients, aiming to improve exercise tolerance and reduce dynamic LVOT obstruction. The most used drugs include:
Non-dihydropyridine calcium channel blockers (verapamil, diltiazem): useful in patients intolerant to beta-blockers, improve diastolic filling.
Disopyramide: antiarrhythmic agent with negative inotropic effect, used in patients with persistent symptoms and severe obstruction.
Cardiac myosin inhibitors (mavacamten): a new class of drugs approved to reduce obstruction and improve cardiac performance.
In patients with concomitant atrial fibrillation, anticoagulant therapy with DOACs or warfarin is indicated to prevent thromboembolic events.
Invasive management
In patients with severe LVOT obstruction (gradient ≥50 mmHg) and symptoms refractory to pharmacological therapy, invasive approaches are considered to reduce the obstruction:
Septal alcohol ablation: ablation with alcohol of the first septal branch to reduce interventricular septal thickness.
Surgical myectomy: surgical resection of the hypertrophic septum, indicated in young and symptomatic patients.
Implantable cardioverter-defibrillator (ICD): indicated in patients at high risk of malignant ventricular arrhythmias.
Prognosis
The prognosis of hypertrophic cardiomyopathy is extremely variable and depends on the presence of obstruction, arrhythmic risk, and therapeutic management. Long-term survival is good in well-controlled patients, with a five-year survival rate exceeding 80%.
Risk factors for sudden cardiac death
In patients with HCM, sudden cardiac death is the main cause of fatal events. Risk factors include:
Family history of sudden cardiac death: first-degree relatives with unexplained fatal events.
Unexplained syncope: especially 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 implementation of preventive strategies, such as implantable cardioverter-defibrillator (ICD) placement, which has been shown to significantly reduce mortality in high-risk subjects.
Complications
Hypertrophic cardiomyopathy (HCM) can evolve into more severe forms, with significant impact on 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 higher in patients with major risk factors, for whom implantable cardioverter-defibrillator (ICD) is indicated.
Atrial fibrillation and thromboembolism
About 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 anticoagulant therapy in patients at high thromboembolic risk.
Heart failure
Heart failure in HCM can present in two forms:
With preserved ejection fraction (HFpEF): due to impaired diastolic filling and ventricular stiffness.
With reduced ejection fraction (HFrEF): less common, occurs in advanced stage with progression toward dilated cardiomyopathy and contractile dysfunction.
Infective endocarditis
Patients with HCM and significant mitral regurgitation are at risk of infective endocarditis due to hemodynamic turbulence on the mitral valve. In these patients, antibiotic prophylaxis is indicated for high-risk invasive procedures.
Progression to restrictive cardiomyopathy
In patients with diffuse myocardial fibrosis, HCM may evolve toward a restrictive form with severe impairment of ventricular filling and increased filling pressures, similar to cardiac amyloidosis.
References
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