Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is characterised by left ventricular hypertrophy that is disproportionate to the haemodynamic load.¹ It results in abnormal left ventricular wall stiffness that causes impaired diastolic filling. Adults with increased left ventricular thickness secondary to diseases such as amyloidosis and glycogen storage disease are usually excluded from the definition.

The features of hypertrophic cardiomyopathy include marked, asymmetrical left ventricular hypertrophy, a non-dilated left ventricular cavity and preserved systolic function. Left ventricular outflow obstruction at rest is present in about 20% of patients.²

The diagnosis of cardiographic hypertrophy is established by the echocardiography demonstrating a hypertrophied and non-dilated left ventricle in the absence of other cardiovascular diseases capable of producing a similar degree of hypertrophy.²

• Hypertrophic cardiomyopathy is the most common familial genetic disease of the heart (1/500 to 1/1000).²
• It is also the most common cause of sudden cardiac death in young people and athletes.²
• Hypertrophic cardiomyopathy most commonly presents in the second or third decade of life, but may present at any age.
• Hypertrophic cardiomyopathy is generally inherited as an autosomal dominant trait with variable penetrance and expressivity.³
• Mutations in sarcomeric protein genes account for about 60% of cases.³
• Troponin T mutations have an increased risk of sudden death, which can occur without evidence of significant left ventricular hypertrophy.
• A minority of cases reflect a sporadic, non-familial form of the disease.³
• Hypertrophic cardiomyopathy is slightly more prevalent in males.

• The presentation is variable and includes dyspnoea (the most common presenting symptom), chest pain, palpitations and syncope.
• The presentation may be incidental on an abnormal ECG or clinical examination.
• The severity may vary between few or no symptoms and profound exercise limitation, recurrent arrhythmias or sudden death.
• Alcohol ingestion can cause dyspnoea or syncope.
• Unexplained syncope is a risk marker for sudden death.
• Examination may be normal. Abnormal clinical findings include:
  • Left ventricular outflow tract obstruction may cause a rapid upstroke and a rapid downstroke in the arterial pulse.
  • The JVP a wave may be prominent due to reduced right ventricular compliance.
  • Outflow tract obstruction may cause a systolic murmur at the left sternal edge, radiating to the aortic and mitral areas.
  • Most patients with left ventricular outflow murmurs also have mitral regurgitation.
  • Some patients have an abnormal blood pressure response during upright exercise and systolic blood pressure fails to rise by more than 20-25 mm Hg from baseline values or falls.

Other causes of left ventricular hypertrophy:

• Infants and young children:
  • Most cases are associated with congenital malformations and syndromes, inherited metabolic disorders and neuromuscular diseases.
  • Familial hypertrophic cardiomyopathy is less frequent in children than in adults.
  • Autosomal dominant disorders that present in the young with left ventricular hypertrophy include Noonan's syndrome.
  • Occasionally, some children and adolescents present with left ventricular hypertrophy several years before the development of the neurological and endocrine features of Friedreich's ataxia.
• Adults and adolescents:
  • Most adolescents and adults with hypertrophic cardiomyopathy have familial disease with an autosomal dominant pattern of inheritance.
  • Some adult patients have non-sarcomeric diseases, e.g. Anderson-Fabry's disease, mitochondrial disease.
  • Other causes of left ventricular hypertrophy include obesity, athletic training, amyloidosis and phaeochromocytoma.

Two-dimensional echocardiography demonstrates left ventricular hypertrophy and is diagnostic for hypertrophic cardiomyopathy.⁴

• Screening for metabolic causes of unexplained hypertrophy is appropriate for affected infants and children.
• ECG:
  • Findings include ST-T wave abnormalities and LV hypertrophy, right or left axis deviation, conduction abnormalities, sinus bradycardia with ectopic atrial rhythm, and atrial enlargement.⁴
  • Voltage criteria for left ventricular hypertrophy alone are non-specific and are often seen in normal young adults.
  • The commonest arrhythmias are premature ventricular complexes, non-sustained ventricular tachycardia and supraventricular tachyarrhythmias.
  • Paroxysmal or chronic atrial fibrillation develops in about 20% of adult patients and is associated with an increased risk of death due to heart failure.²
• Ambulatory electrocardiography: findings often include atrial and ventricular ectopy, sinus pauses, wandering atrial pacemaker, intermittent or variable AV block, and non-sustained atrial and/or ventricular arrhythmias.⁴
• Chest x-ray findings are variable:
  • Heart size may range from normal to markedly increased.
  • Left atrial enlargement is often seen, especially when significant mitral regurgitation is present.
• Echocardiography:
  • An unexplained maximum left ventricular wall thickness on two-dimensional echocardiography greater than 15 mm is usually sufficient to make the diagnosis in an adult.
  • Most patients have a disproportionate increase in the thickness of the interventricular septum.
  • Obstruction of the right ventricular outflow tract is rare.
  • The magnitude of obstruction is usually measured by continuous wave doppler.
• Cardiac MRI:
  • Can measure the severity and distribution of left ventricular hypertrophy, and provide information on systolic and diastolic ventricular function.
  • Can also assess myocardial tissue characteristics and so delineate myocardial infarction in patients with coronary artery disease.
• Cardiac catheterisation: may be useful to determine the degree of outflow obstruction, diastolic characteristics of the left ventricle, and the anatomy of the ventricles and coronary arteries.
• Exercise testing with simultaneous respiratory gas analysis is used to assess disease severity.
• Endomyocardial biopsy may be required to exclude other causes of increased wall thickness, e.g. amyloid.

• Genetic counselling and clinical risk assessment.
• Many interventions, including septal alcohol ablation, septal myectomy, and implantable cardioverter defibrillators, are appropriate only for certain patients.
• Heart transplantation may be necessary in patients with refractory heart failure.

Risk stratification and prevention of sudden death²

• Sudden death is the most common cause of death in hypertrophic cardiomyopathy and occurs more often in young asymptomatic or only mildly symptomatic patients.
• Implantable cardioverter defibrillator are effective in preventing sudden death in this disease. Therefore, risk stratification has a major role in patient management.
• Patients who have survived a cardiac arrest or have experienced one or more episodes of sustained ventricular tachycardia are considered at high risk and therefore candidates for a cardioverter defibrillator for secondary prevention of sudden death.
• There is more uncertainty in the selection of patients for primary prophylactic insertion of a cardioverter defibrillator:
  • Electrophysiological testing has a low prognostic accuracy in hypertrophic cardiomyopathy and does not seem to have a role in risk stratification.
  • A single strong risk factor may be an indicator of high risk in selected patients but multiple risk factors are generally considered to indicate a greater likelihood of sudden death:
    • Family history of sudden death
    • Extreme hypertrophy: extreme thickness of the left ventricular wall (30 mm) is a strong predictor of sudden death in young patients with hypertrophic cardiomyopathy
    • Unexplained syncope
    • Non-sustained ventricular tachycardia
    • Abnormal blood pressure response to exercise: hypotensive blood pressure response during upright exercise, especially in patients younger than 50 years
  • Patients with mild left ventricular hypertrophy (wall thickness < 20 mm) and no risk factor can be considered at low risk and have a mean life expectancy similar to that of the general population.

Drug treatment⁵

• Heart failure:
  • Drug treatment of heart failure has largely been based on beta-blockers, which reduce the heart rate and so prolong diastole and improve ventricular filling. Beta-blockers may also decrease the outflow gradient during effort.
  • Verapamil may be used in patients without severe outflow obstruction and is the drug of choice in patients whose main symptom is chest pain.
  • For patients with heart failure not effectively controlled with beta-blockers or verapamil, a low doses of a diuretic is usually effective in alleviating symptoms.
  • ACE inhibitors should be used with caution because outflow obstruction may be increased by reducing afterload.
  • About 5% of patients evolve towards the end stage phase of hypertrophic cardiomyopathy and have systolic dysfunction usually associated with thinning of the left ventricular wall (due to extensive fibrosis) and ventricular dilatation. These patients should receive standard treatment of heart failure, including ACE inhibitors, diuretics, beta-blockers, and digoxin, but many of these patients become candidates for heart transplantation.
• Atrial fibrillation:
  • Paroxysmal or chronic atrial fibrillation develops in about 20% of adult patients with hypertrophic cardiomyopathy and is associated with an increased risk of death due to heart failure.
  • Amiodarone is considered the most effective drug for prevention of paroxysmal atrial fibrillation.
  • Beta-blockers and/or verapamil are usually sufficient to control heart rate in patients with chronic atrial fibrillation, but ablation of the atrioventricular node and pacemaker implantation may be required.
  • Anticoagulant treatment is indicated in patients with either paroxysmal or chronic atrial fibrillation.
• The risk of infective endocarditis is low but routine antibiotic prophylaxis is recommended.⁵
• Implantable cardioverter-defibrillator: may prevent sudden death in high-risk patients (see below).

Surgical myotomy or myectomy

• 5% of patients with hypertrophic cardiomyopathy have outflow obstruction and severe symptoms unresponsive to medical therapy and are candidates for surgical myectomy or alcohol septal ablation to relieve the outflow obstruction.²
• Injection of alcohol into the proximal interventricular septum may be an alternative to surgery.⁶

Non-obstructive hypertrophic cardiomyopathy

• Angina and breathlessness may respond to beta blockers or calcium antagonists.
• Nitrates may be useful, but excessive reductions in preload must be avoided.
• Diuretics and vasodilators are indicated in patients with systolic impairment.
• Treatment of patients with restrictive disease is more difficult. Beta blockers and spironolactone, can be effective.

• The number of possible mutations means that genetic testing is not generally practical.
• Careful pedigree analysis of family members can be useful in identifying those at risk of inheriting the disease.
• It has been recommended that adult relatives are screened by clinical evaluation, ECG and echocardiogram every 5 years.⁵

• The clinical course is variable; many remain asymptomatic throughout life but others develop severe heart failure or atrial fibrillation, or die suddenly, often at a young age and in the absence of previous symptoms.²
• There may be long periods without any change in the patient's condition.
• Arrhythmias are common; paroxysmal or chronic atrial fibrillation develops in a minority of adult patients.²
• Competitive sports may increase the risk of sudden death.
• Risk of sudden death due to hypertrophic cardiomyopathy is greatest in those younger than 30 years of age.