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JohannaKuusisto

Hypertrophic Cardiomyopathy

Essentials

  • Hypertrophic cardiomyopathy (HCM) is a common cause of sudden cardiac death in young people and athletes.
  • Many patients, however, remain asymptomatic or only have a few symptoms.
  • Inheritance takes usually place through autosomal dominant inheritance.
  • Consider the possibility in young patients with exertional dyspnoea, arrhythmias and/or abnormal ECG.
  • Diagnosis and risk stratification are based on a thorough clinical and ultrasound examination made by a cardiologist and on determination of the severity of the disease.
  • Cardiac MRI should be performed in all patients.
  • DNA diagnostics are essential in confirming the exact diagnosis and in investigating the relatives.
  • An implantable cardioverter defibrillator (ICD) is the most effective therapy against sudden death.

Definition

  • HCM is a disease of the myocardium characterised by the thickening of the myocardium in the absence of another disease capable of producing the magnitude of ventricular hypertrophy evident.

Prevalence

  • About 1/500 inhabitants
  • The most common genetic cardiac disorder

Aetiology

  • Most commonly HCM is caused by mutations in any of the genes that encode the protein components of the contractile elements of the myocardium, i.e. the sarcomere.
  • The diagnosis of HCM also includes thickening of the myocardial wall associated with some rare diseases, such as metabolic storage diseases (e.g. Fabry's disease) or mitochondrial myopathies, or caused by obesity, transthyretin or AL amyloidosis or sarcoidosis (ESC 2008).
  • Myocardial disorders caused by hypertension, coronary heart disease (e.g. following posterior MI) or valvular defects (aortic stenosis) are not classified as HCM.
  • Hypertension (and not HCM) remains the leading cause of ventricular hypertrophy!

Genetics and heritability

  • In about half of the cases, HCM is familial.
  • Inherited in most cases through autosomal dominant inheritance, but other types of inheritance are also possible (mitocondrial diseases, Fabry's disease through X chromosome, polygenic).
  • In about 60% of cases the underlying cause is sarcomere protein gene mutation.
  • Over 1 500 mutations are now identified in at least 23 different genes.
  • Gene mutations have also been identified in genes that, for example, regulate myocardial cellular calcium and energy metabolism.
  • According to recent research, some cases of the disease are polygenic, i.e. caused by several common gene variants. These common variants affect left ventricular thickness also in those with a sarcomere gene mutation that causes hypertrophic cardiomyopathy.
  • HCM attributable to sarcomere mutation is inherited as an autosomal dominant trait (about half of the off-spring will inherit the mutation).
  • A current European guideline recommends genetic testing for all persons with HCM in order to confirm the exact aetiology.
  • If a gene mutation causing HCM is found in a patient, his/her first-degree relatives should be investigated for that mutation.

Signs and symptoms

  • The expression of the disease does not usually occur until the growth spurt at adolescence; often the symptoms will not emerge until the patient reaches middle age. Clear cardiac symptoms in a young or middle-aged patient should always raise the suspicion of cardiomyopathy.
    • Dyspnoea on exertion characteristic symptom
    • Reduced functional capacity
    • Arrhythmias: palpitations, ectopic beats, ventricular tachycardia, paroxysmal atrial fibrillation
    • Chest pain
    • Syncope - a serious symptom often caused by ventricular tachycardia
  • Sudden cardiac death or resuscitation from ventricular fibrillation is often the first clinical manifestation of HCM
  • A family history of HCM is an important trigger to prompt the screening of asymptomatic family members.

Findings and diagnosis

  • Auscultation of the heart may reveal a loud systolic murmur reflecting left ventricular obstruction or S4 gallop.
  • The pattern of carotid pulsation may be variable.
  • Signs suggestive of heart failure are very rare.
  • Blood pressure should be measured in order to exclude hypertension.
  • Normal results in a clinical examination do not exclude HCM.
  • ECG is usually abnormal (pathological Q waves, left ventricular hypertrophy, T wave inversions, giant T waves, ST segment depression, intraventricular conduction defects, left atrial strain).
  • The heart shadow may be enlarged in the chest x-ray.
  • The diagnosis of HCM is based on two-dimensional echocardiography which can be used to demonstrate left ventricular hypertrophy (wall thickness ≥ 15 mm if there is no family history of HCM, ≥ 13 mm if HCM has been identified in close relatives or if the patient has a disease-causing gene defect).
  • The hypertrophy typically involves the interventricular septum but can also occur in any region of the left ventricular free wall - the thickness and severity of the hypertrophy varies from patient to patient.
  • Typical echocardiography findings:
    • spindle-shaped interventricular septum showing increased echodensity
    • left ventricular diastolic dysfunction as well as reduced left ventricular systolic and diastolic tissue velocity shown by tissue Doppler imaging
    • abnormal systolic motion of the mitral valve (systolic anterior motion, SAM) leading to left ventricular obstruction, observed in about one fifth.
  • The size and contractility of the left ventricle, measured by total ejection fraction, are normal in most cases (> 90% of cases).
  • Cardiac MRI (CMR) with gadolinium contrast is recommended for all patients to determine the left ventricular mass and scarring.
  • Myocardial biopsy only in special cases

Criteria for referral to specialist care

  • All patients with confirmed or suspected HCM must be referred to a cardiologist at an appropriate hospital.
  • All first degree relatives of patients with hypertrophic cardiomyopathy should be examined either by a gene test using a blood sample, or by an assessment performed at a cardiological outpatient clinic.

Prognosis and risk stratification

  • The thickening of the myocardial wall does not usually continue to progress after the age of 20-30 years, and only a small proportion (< 5%) of patients will develop left ventricular dilatation and systolic dysfunction.
  • Approximately one fifth of patients with HCM are at risk of sudden cardiac death, which is usually caused by malignant ventricular arrhythmia (ventricular tachycardia or fibrillation).
  • In the great majority of cases the disease is mild, and the patients achieve life expectancies that correspond to those of healthy individuals of the same age.
  • A clinical risk assessment must be carried out in all patients with HCM taking into account factors that increase the risk of sudden death.
  • In HCM, the efficacy of an ICD Implantable Cardioverter-Defibrillator (ICD) in the prevention of cardiac death is excellent.
    • An ICD is indicated if the patient has been resuscitated from ventricular fibrillation or has persistent ventricular tachycardia.
    • The need for an ICD should be considered if the patient has several risk factors that increase the possibility of sudden cardiac death
      • family history of sudden cardiac death
      • syncope attacks
      • ventricular wall thickening > 3 cm
      • short episodes of ventricular tachycardia on Holter recording
      • enlarged left atrium
      • blunted or hypotensive blood pressure response during a clinical exercise test
      • left ventricular dilatation and reduced ejection fraction
      • atrial fibrillation
      • increased levels of plasma brain natriuretic peptide (BNP) and/or troponin T (TnT)
      • considerable myocardial fibrosis in MRI (> 15% of the left ventricular mass)
      • cardiac failure.
    • A risk calculator is available on the internet to assist in assessing the risk of sudden death and the need for an ICD (HCM Risk-SCD calculator: see http://doc2do.com/hcm/webHCM.html).

Treatment

  • Lifestyle advice: competitive sports and extreme physical exertion are forbidden, but otherwise the patient should be encouraged to take regular exercise and adopt a healthy lifestyle.
  • In most cases, strenuous work conditions, such as night or shift work, are not suitable.
  • The patient should be screened for arterial disease risk factors, and treated appropriately, since co-existent coronary heart disease considerably increases mortality.
  • So far, there is no evidence to show that the use of medication would influence the patient's prognosis or the progress of the disease (cf. ICD therapy!).
  • Usually, asymptomatic patients do not need pharmaceutical treatment.
  • If the patient exhibits distinct symptoms, such as dyspnoea on exertion, chest pain, ventricular ectopic beats, short episodes of ventricular tachycardia, or has marked ventricular hypertrophy a beta-blocker should be prescribed.
  • Verapamil should be prescribed if beta-blockers are not suitable.
  • Atrial fibrillation
    • If possible, the aim should be to restore sinus rhythm.
    • Beta-blockers are the drugs of choice for prophylaxis
    • Amiodarone should be considered if beta-blockers are not sufficiently effective in preventing atrial fibrillation
    • Flecainide is not suitable!
    • A permanent pharmacotherapy with a direct anticoagulant should be started irrespective of the CHA2DS2-VASc score, if even one undisputed episode of atrial fibrillation has been detected.
  • Left ventricular dilatation and/or decreased ejection fraction or high proBNP: an ACE inhibitor or an angiotensin receptor blocker should be added (not for children or adolescents who are still growing).
  • Heart failure: in addition to a beta blocker and an ACE inhibitor or an angiotensin receptor blocker, diuretics are used; as a rule digitalis should be avoided
  • HCM is not a condition that continues to progress, and heart transplantation is required very rarely.
  • Heart transplantation is indicated if the patient has severe systolic heart failure refractory to pharmaceutical treatment or diastolic failure associated with marked ventricular hypertrophy.
  • Left ventricular outflow tract obstruction (gradient > 30 mmHg)
    • Present in about one fifth of patients under resting conditions, can be provoked by exercise in some patients.
    • Beta-blockers are the drugs of choice.
    • If necessary, disopyramide may be added.
    • Verapamil should be avoided.
    • If a marked outflow tract obstruction persists despite maximum pharmaceutical treatment, ventricular septal myectomy is the primary choice to be considered, and alcohol septal ablation is a secondary alternative, if the patient is elderly or has multiple diseases, or if open heart surgery is not feasible for other reasons.
    • A myosin inhibitor, mavacamten is entering the market. It affects the actin-myosin cross-bridge formation in myocardial cells.
      • The first targeted drug for hypertrophic cardiomyopathy, initially for the obstructive type. Research on the non-obstructive type is ongoing.

Monitoring and screening of family members

  • Long-term follow-up by a cardiologist at an appropriate hospital clinic.
    • The risk of atrial fibrillation and cardiac enlargement and failure increase with age, even though the thickness of the left ventricle usually does not increase after the age of 20(-30).
  • Follow-up visits every 1-2 years are usually sufficient.
  • During the visits the following should be observed: general health status, ECG, plasma brain natriuretic peptide and TnT levels, Holter monitoring and echocardiography findings.
  • A clinical exercise test should be carried out during the initial assessment and thereafter every 2-3 years.
  • A cardiac MRI should be repeated at least every 5 years, in progressive disease every 2-3 years.
  • Healthy individuals known to harbour the gene mutation (known pathogenic mutation but the patient does not exhibit diagnostic ECG or echocardiography findings) are examined every 3-5 years and if necessary more frequently (children, mild abnormalities in ECG or echocardiography).
  • Screening of family members
    • It is recommended that the off-spring, siblings and parents of a patient diagnosed with HCM undergo investigations at a cardiology clinic to exclude the disease.
    • In order to screen first-degree relatives, a blood test can be used to carry out DNA analysis in cases where the gene mutation has been identified.
    • Before DNA testing is carried out, the patient/relative must be asked for his/her consent.
    • If the gene mutation has not been identified, no benefit is to be gained from screening family members with DNA testing, and echocardiography and ECG recordings should be used instead to identify/exclude HCM.

    References

    • Authors/Task Force members., Elliott PM, Anastasakis A et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35(39):2733-79. [PubMed]