Are you terrified of missing a patient with hypertrophic cardiomyopathy and hearing, a couple of weeks later, that he has suffered a fatal cardiac arrest?

Hypertrophic cardiomyopathy is defined as hypertrophy of the muscular tissue of the heart that cannot be explained by any other cause. It can affect both ventricles.

A retrospective study looking at the presence of echocardiographic evidence of hypertrophic cardiomyopathy in four thousand young people in America revealed a prevalence of 1 in 500 [1]. This correlates with several other studies. There have been suggestions that the actual prevalence may be higher as not all cases have clear echocardiographic features.

THE UNDERLYING DISEASE MECHANISM

In many patients, the disease has a genetic basis that affects the sarcomeres in cardiac myocytes.

Cardiac myocytes are the muscles cells of the heart. They are supported by a scaffold of fibrous tissue. So that the heart can work effectively, the myocytes need to be precisely organised in a complex, three-dimensional structure. In addition, electrical signals need to move almost instantaneously from one cell to the next. Unlike skeletal muscles cells, cardiac myocytes are branched. This gives them structural flexibility and enhances their electrical connectivity.

Cardiac myocytes contain numerous myofibrils. Myofibrils are made up of sarcomeres containing the contractile proteins, actin and myosin. Sarcomeres are the basic units of contraction. Several other proteins take part in the contractile process. These include myosin binding protein C, troponin and tropomyosin.

The genetic mutations in hypertrophic cardiomyopathy result in the production of dysfunctional contractile proteins within sarcomeres. These, in turn, cause enlargement of the myocytes. Electrical conduction is abnormal. Contraction and relaxation are impaired. The spatial configuration of myocytes is chaotic.

Over time, these cellular changes can lead to:

• areas of ventricular hypertrophy which may cause left ventricular outflow tract obstruction
• mitral valve abnormalities
• myocardial ischaemia
• myocardial fibrosis

VENTRICULAR HYPERTROPHY AND MITRAL VALVE ABNORMALITIES

There is overgrowth or hypertrophy of the ventricular muscle. The commonest pattern is hypertrophy of the basal part of the ventricular septum. The hypertrophy is usually asymmetric, and the ventricular cavity is small. The upper limit of normal ventricular septal thickness is 13 mm. A thickness of 15mm or more is considered hypertrophic. Hypertrophy sometimes affects the mid-section of the ventricular septum.

Note: because the heart is upside down, the basal septum is actually the upper part of the septum just below the aortic valve.

Apical hypertrophy is localised to the apex of the left ventricle, the lowest part of the heart.

In concentric left ventricular hypertrophy, the changes are generalised throughout the left ventricle. Concentric hypertrophy is most commonly secondary to hypertension. It can be caused by other conditions including hypertrophic cardiomyopathy.

Left ventricular septal hypertrophy can lead to left ventricular outflow tract obstruction. The left ventricular outflow tract is where the upper part of the left ventricle merges with the aorta. It is proximal to the aortic valve. It is roughly cylindrical in shape. Its posterior wall is made up of the ventricular septum, and the anterior wall is formed by the anterior leaflet of the mitral valve. If the upper part of the septum is hypertrophic it bulges into the left ventricular outflow tract. Depending on the severity of the hypertrophy and its exact position, this may cause turbulent blood flow and a degree of obstruction.

In patients with hypertrophic cardiomyopathy, the anterior leaflet of the mitral valve is often elongated. In systole, this abnormal anterior leaflet may be drawn up into the left ventricular outflow tract and can impinge on the septum. This is called systolic anterior motion of the mitral valve. It can worsen the outflow tract obstruction. Because the anterior leaflet is pulled upwards, away from the mitral valve annulus, it prevents normal valve closure resulting in mitral regurgitation.

The papillary muscles of the mitral valve may also be abnormal.

Left ventricular outflow tract obstruction is dynamic. It varies according to several different parameters.

An increase in the force of ventricular contraction will bring the hypertrophic septum and mitral valve leaflet closer together worsening any outflow obstruction. This can occur with exercise, stress, stimulants and positive ionotropic agents.

A reduction in pre-load will reduce ventricular filling. A partially filled ventricle will result in less resistance to contraction, allowing the septum and mitral valve leaflet to come together, again worsening any outflow obstruction. A reduction in preload can be caused by the Valsalva manoeuvre and dehydration due to intercurrent illness.

A reduction in after-load will also reduce resistance to contraction and have a similar effect. A reduction in after-load can be caused by vasodilators.

Because the degree of obstruction is variable, the symptoms, signs and echocardiographic findings also vary. Look out for breathlessness, chest pain, dizziness or loss of consciousness related to exercise or intercurrent illness.

Example: a twenty-year-old man with hypertrophic cardiomyopathy who is currently well, relaxed and inactive may have no clinical evidence of left ventricular outflow tract obstruction. However, if he becomes dehydrated due to severe influenza, the symptoms and signs become apparent.

MYOCARDIAL ISCHAEMIA

There are several factors thought to cause myocardial ischaemia in hypertrophic cardiomyopathy

• hypertrophic areas of muscle compress small arterial vessels
• hypertrophy of smooth muscle cells in vessel walls lead to narrowed lumens
• increased intraventricular pressure and impaired diastolic relaxation reduce coronary artery flow
• hypertrophy of myocytes causes increased oxygen demand

MYOCARDIAL FIBROSIS

Magnetic resonance imaging has revealed that myocardial fibrosis is a common consequence of many chronic cardiac conditions including hypertrophic cardiomyopathy. Contractile strain and ischaemia are thought to lead to myocyte injury and death. Fibroblasts replace damaged myocytes with fibrous tissue. We now know that myocardial fibrosis predisposes patients to the development of cardiac arrhythmias. These are thought to be due to the formation of re-entry circuits in groups of myocytes close to areas of fibrosis. Myocardial fibrosis can also lead to cardiac failure.

CARDIAC ARRYHTHMIAS

All patients should be regularly screened for cardiac arrhythmias.

Atrial fibrillation is very common. It is thought to be due to the generation of re-entry circuits secondary to fibrotic change in the atria. The risk of thromboembolism is high and, unless there are contraindications, all patients with hypertrophic cardiomyopathy and atrial fibrillation should be anticoagulated.

Similarly, ventricular tachycardia and ventricular fibrillation can occur. These may result in sudden death.

In 2022, an analysis [2] of nearly one hundred studies showed that, over the previous eleven years, the incidence of sudden death had fallen significantly to 0.32% annually: that is one death in a hundred patients every three years. It was suggested that the overall reduction in incidence was due to risk stratification and the use of defibrillators. Rates of sudden death were higher in young adults and patients from Asia.

According to the American Heart Association Guideline for the Management of Hypertrophic Cardiomyopathy [3], high risk factors for sudden death in hypertrophic cardiomyopathy include:

• previous episode of ventricular tachycardia or ventricular fibrillation
• unexplained syncope
• sudden cardiac death or sustained ventricular arrhythmia in close relative
• left ventricular wall thickness 30 mm or greater
• apical left ventricular aneurysm
• extensive ventricular fibrotic change
• ejection factor less than 50%

CARDIAC FAILURE

Heart failure is relatively common in the later stages of hypertrophic cardiomyopathy. In a study led by Melacini [4], heart failure occurred in 17% of patients. The same study demonstrated that there were three main causative mechanisms: systolic dysfunction, severe left ventricular outflow tract obstruction and diastolic dysfunction.

Left ventricular outflow tract obstruction, mitral valve regurgitation, myocardial ischaemia, impaired myocardial contractility due to fibrosis, myocardial stiffness due to fibrosis and atrial fibrillation are all important factors in the development of heart failure.

Pharmacological treatment can be tricky as several of the standard drugs used for heart failure are vasodilators and may worsen left ventricular outflow tract obstruction. Diuretics can reduce preload and may cause similar problems.

APICAL LEFT VENTRICULAR ANEURYSM

An apical left ventricular aneurysm develops in some patients with apical hypertrophy. These patients tend to have a greater burden of myocardial fibrosis. Those with large aneurysms are at high risk of sudden death from ventricular arrhythmias. Thromboembolic events are also common in this group and anticoagulation should be considered.

GENETIC MUTATIONS

The inheritance of hypertrophic cardiomyopathy is considered autosomal dominant. A number of genetic mutations have been shown to be causal. The commonest are mutations in the genes coding for two proteins found within sarcomeres, heavy myosin chains and myosin binding protein C.

Some of the recognised mutations are considered pathogenic and others are of uncertain significance. However, even with pathogenic mutations, the development of the pathological phenotype is variable. Patients with the same mutation can develop the disease at almost any age, can have different patterns of disease and different degrees of disease severity. Some patients never develop clinical disease. In a proportion of patients with hypertrophic cardiomyopathy, no mutations are found.

At present, we do not understand why expression of the abnormal genes is so varied in hypertrophic cardiomyopathy.

Screening first degree relatives of patients with hypertrophic cardiomyopathy is extremely important. Identifying undiagnosed cases may help avoid sudden deaths.

CLINICAL FEATURES

Patients are often asymptomatic in the early stages.

Left ventricular outflow tract obstruction can cause breathlessness, chest pain, dizziness and syncope. These symptoms are often related to exercise.

Arrhythmias can cause palpitations, dizziness, syncopal episodes or sudden death.

Ischaemia tends to cause angina type chest pain.

There may be a family history of hypertrophic cardiomyopathy or unexplained, sudden death.

On examination, the pulse may be normal. The hypercontractile left ventricle can cause a ‘jerky’ pulse. Ectopic beats or atrial fibrillation may be present. Left ventricular hypertrophy can cause a displaced, forceful apical impulse. Patients with outflow obstruction may have a systolic, ejection murmur, similar to the murmur of aortic stenosis. It is loudest at the left sternal edge and radiates towards the carotid arteries.

Provocation tests can be helpful. Exercise or the Valsalva manoeuvre usually make the murmur louder. Squatting will reduce it.

Some patients will have signs of mitral regurgitation. This causes a pansystolic murmur. It is usually most easily heard over the cardiac apex and radiates towards the axilla.

In advanced disease, there may be features of cardiac failure.

To carry out the Valsalva manoeuvre, the patient tries to breathe out against a closed airway. This increases intrathoracic pressure and reduces venous return to the heart. It reduces pre-load.

Squatting is thought to increase venous return by compression of large veins in the legs squeezing blood into the inferior vena cava.

INVESTIGATIONS

ELECTROCARDIOGRAM

Abnormalities are common but tend to be non-specific.

Left ventricular hypertrophy causes a deep S wave in leads V1 and V2 along with tall R waves in leads V5 and V6. There may be ST depression. T waves may be inverted and can be deep.

There may be Q waves, ST depression and T wave inversion in the lateral leads (Leads I, AVL, V5 and V6).

In apical hypertrophy, the precordial leads (V1 – V6) may have very deep, inverted T waves [5].

ECHOCARDIOGRAPHY

Echocardiography can demonstrate areas of ventricular hypertrophy, mitral valve abnormalities, left ventricular outflow tract obstruction and cardiac function.

Provocation tests may be needed to demonstrate left ventricular outflow tract obstruction. These include the Valsalva manoeuvre, exercise, dobutamine and amyl nitrate. Exercise and dobutamine increase myocardial contractility. Amyl nitrate is a vasodilator.

CARDIAC MONITORING

Cardiac monitoring is usually recommended on a regular basis to screen for arrhythmias.

CARDIAC MAGNETIC RESONANCE IMAGING

Cardiac magnetic resonance imaging can give a more detailed picture than echocardiography and may help if echocardiograph is not conclusive. It is particularly useful to look for fibrosis. It is often used prior to surgery or alcohol ablation.

CARDIAC CATHETERISATION

Cardiac catheterisation can help quantify cardiac function or any left ventricular outflow tract gradient. It may demonstrate pulmonary hypertension which occurs in some patients. It will help exclude any coincidental coronary artery disease. It is often used prior to surgery or alcohol ablation.

DIAGNOSIS.

The diagnosis is often delayed. This will be at least partly due to the variability of symptoms, signs and echocardiographic findings.

It is made by demonstrating ventricular hypertrophy with no underlying cause or a degree of hypertrophy that is out of proportion to any underlying cause.

Left ventricular hypertrophy can be caused by a number of conditions including hypertension, aortic valve stenosis and athlete’s heart. As hypertension is so common, some patients with hypertrophic cardiomyopathy will also, coincidentally, have hypertension. This can cause some diagnostic difficulty.

Genetic testing is not diagnostic in itself but can help.

Some conditions can mimic hypertrophic cardiomyopathy. These include cardiac amyloid and sarcoidosis. The following metabolic storage diseases can cause a similar picture: Danon disease, Pompe disease and Fabry disease.

TREATMENT

Patients with newly diagnosed hypertrophic cardiomyopathy should be assessed in a specialist centre by a multidisciplinary team.

EXERCISE ADVICE

Historically, patients have been advised to avoid strenuous or competitive exercise. Evidence to support this is limited. The American Heart Association recommends a tailored approach looking at each patient’s wishes and their risk of sudden death. As a general rule, mild or moderate cardiovascular exercise is thought to be beneficial for the majority of patients as long as it does not cause worrying symptoms.

PHARMACOLOGICAL TREATMENT

Positive ionotropic agents and vasodilators aggravate left ventricular outflow tract obstruction and should be avoided or used with great caution. They may be indicated in patient who develop heart failure.

There are several options for pharmacological treatment. At present they are considered helpful for symptom control, but do not reduce mortality. They are all thought to work by their negative ionotropic effects: they reduce myocardial contractility.

Beta-blockers and verapamil are recommended first line. Disopyramide is effective but can have more side-effects.

Note: the vasodilating calcium channel blockers are contraindicated.

MAVACAMTEN

This is an inhibitor of cardiac myosin function. It works by reducing myocyte contractility. It has been shown to improve left ventricular outflow tract obstruction, exercise capacity, symptoms and quality of life [6].

In some patients, it causes a severe reduction in left ventricular function and, because of this, needs to be monitored carefully.

MANAGEMENT OF ATRIAL FIBRILLATION

Atrial fibrillation is very common in hypertrophic cardiomyopathy. These patients do not tolerate atrial fibrillation well so rhythm control is better than rate control. Patients with hypertrophic cardiomyopathy and atrial fibrillation have a very high risk of thromboembolism so, ideally, they should all be anticoagulated.
Ablation, amiodarone and beta blockers are all treatment options.

MANAGEMENT OF VENTRICULAR ARRYTHMIAS

Patients at high risk of ventricular arrythmia should be offered an intracardiac defibrillator (ICD). There are some extracardiac defibrillators available now.

SURGICAL TREATMENT

Surgical treatment should only be carried out in specialist centres with plenty of experience. It is used for patients with severe, refractory symptoms or severe hypertrophy (50mm or more). There is a risk of heart block.

ALCOHOL SEPTAL ABLATION

This is the less invasive option. It depends on the presence of a suitable arterial vessel supplying the hypertrophic area. Cardiac catheterisation is required to assess this. Ethanol instillation blocks the arteriole and causes a therapeutic infarct. The hypertrophied tissue breaks down and is shed.

SEPTAL MYOMECTOMY

In septal myomectomy, surgical reduction of the hypertrophied area is carried out.

HEART TRANSPLANT

Heart transplant is a consideration for advanced disease in patients with refractory heart failure or frequent ventricular arrhythmias despite treatment.

REFERENCES

1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 1995;92(4):785-789. doi:10.1161/01.cir.92.4.785
2. Abdelfattah OM, Martinez M, Sayed A, et al. Temporal and Global Trends of the Incidence of Sudden Cardiac Death in Hypertrophic Cardiomyopathy. JACC Clin Electrophysiol. 2022;8(11):1417-1427. doi:10.1016/j.jacep.2022.07.012
3. Ommen SR, Ho CY, Asif IM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(23):e1239-e1311. doi:10.1161/CIR.0000000000001250
4. Melacini P, Basso C, Angelini A, et al. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J. 2010;31(17):2111-2123. doi:10.1093/eurheartj/ehq136
5. Yamaguchi H, Ishimura T, Nishiyama S, et al. Hypertrophic nonobstructive cardiomyopathy with giant negative T waves (apical hypertrophy): ventriculographic and echocardiographic features in 30 patients. Am J Cardiol. 1979;44(3):401-412. doi:10.1016/0002-9149(79)90388-6
6. Braunwald E, Saberi S, Abraham TP, Elliott PM, Olivotto I. Mavacamten: a first-in-class myosin inhibitor for obstructive hypertrophic cardiomyopathy. Eur Heart J. 2023;44(44):4622-4633. doi:10.1093/eurheartj/ehad637