This Update examines the diagnosis, management and screening options for hypertrophic cardiomyopathy. It is by Associate Professor David Richmond, AM MBChB (Hons), MSc, FRACP, FRCP, FACC, FCSANZ.

Associate Professor David Richmond, AM MBChB (Hons), MSc, FRACP, FRCP, FACC, FCSANZ
Professor Richmond is a consultant cardiologist with a special interest in hypertrophic cardiomyopathy and bicuspid aortic valve disease with associated aortic disease, University of Sydney, NSW. 

INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a genetic disorder involving the myocardium. It is typically a primary cardiac disease, usually characterised by asymmetric left ventricular hypertrophy.

Patients with HCM may present with a range of clinical manifestations. While many individuals experience no or very few symptoms, some may be severely affected with symptoms relating to heart failure, myocardial ischaemia, or rhythm and rate disturbances.

Significantly, a proportion of patients may present for the first time with haemodynamic collapse and sudden cardiac death – a catastrophic complication of HCM.

Although HCM was previously perceived as a rare disorder, US research has shown that it occurs in 0.2% of the population, which suggests that about one in 500 people are affected.¹ Given its prevalence, HCM is becoming increasingly recognised as an important cause of cardiac morbidity – and as a leading cause of sudden cardiac death among people younger than 35 years, particularly athletes.²

The association of HCM and sudden cardiac arrest in athletes has been highlighted several times in the past decade, with competitive athletes suffering from an on-field event. Most recently, high-profile English Premier League footballer Fabrice Muamba experienced a mid-game cardiac arrest, requiring prolonged on-field resuscitation and up to 15 DC shocks to re-establish a viable cardiac rhythm.

While the cause of his cardiac arrest has not been made public to date, there is considerable speculation by experts that HCM is the likely cause. This is because HCM is the most common cause of sudden cardiac death among athletes.


Hypertrophic cardiomyopathy left ventricle

GENETICS
HCM is commonly a familial disease. It is inherited as an autosomal-dominant disorder, with no sex predilection (offspring of affected individuals have a 50% chance of inheriting the gene mutation, and there is no genetic gender preponderance for the disease, although HCM is diagnosed slightly more commonly in males). Additionally, individual members of the same family, who carry the same mutation, may express a widely differing phenotype severity. There are many known genetic mutations associated with HCM, which primarily occur within genes encoding proteins of the cardiac sarcomere, or sarcomeric-related proteins. These include cardiac beta-myosin heavy chain, cardiac myosin binding protein C, cardiac troponin I, cardiac troponin T, cardiac alpha-actin, alpha tropomyosin, myosin regulatory light chain and titin.

While a single mutation in any of these genes may lead to HCM, individuals with multiple mutations have been identified – and these people are at greater risk of developing a clinically more severe form of the disease.^3,4,5

Although more than 10 known genes have been implicated in the causation of HCM, a positive genetic mutation is found in only 50–60% of patients who are tested.

This suggests there may other unidentified mutant genes contributing to the disease.

In some cases, HCM occurs as a consequence of a de novo mutation. Although sporadic HCM is not inherited, patients with the disease are still at risk of passing the genetic mutation on to the next generation.

PATHOPHYSIOLOGY
The hallmark phenotype characteristic of HCM is asymmetric myocardial hypertrophy in the absence of an otherwise known hypertrophy stimulus, such as hypertension or aortic valve stenosis. Concentric left ventricular hypertrophy may also be seen in some individuals.

Most patients who present with clinical manifestations have wall thicknesses of 15–25mm (the normal adult left ventricular wall thickness is 7–10mm) on echocardiography. In extreme cases, wall thicknesses of greater than 40mm are seen.

Although hypertrophy can occur at any site within the left ventricle, it typically involves the interventricular septum, and this may result in an obstruction to blood flow in the left ventricular outflow tract. Apical hypertrophy is a non-obstructive variant common among certain groups.⁶

Although the most recognisable feature of HCM is hypertrophy, it is secondary to  abnormal function of the sarcomere, which causes contractile dysfunction and leads to compensatory hypertrophy. For this reason, hypertrophy of the myocardium is rare in infancy, as it develops most often in the
second decade of life, or even subsequent decades.

The most significant histopathological feature of HCM is disorganisation of  myocyte architecture, with myocyte hypertrophy and disruption to the usual alignment of the muscle cells (myocyte disarray). This is believed to occur as a consequence of the structural and functional abnormalities present within defective sarcomeric proteins. In addition, interstitial fibrosis and a thickened collagen matrix contribute to the histopathological anomalies found in HCM.

There is also pathological intimal thickening in secondary branches of the epicardial coronary arteries, notably the septal perforator arteries, which causes supply ischaemia and contributes to fibrosis and even frank infarction. In addition, a structural abnormality of the mitral valve is often present, such as elongation of the valve leaflets and abnormal positioning of the papillary muscles.

CLINCIAL PRESENTATION
Patients with symptoms attributable to HCM usually present from the second decade of life. It is from this time that the hypertrophy usually becomes manifest. However, a significant proportion of patients with HCM do not present with any symptoms of the disease, and are picked up either because of an audible murmur, an abnormal ECG, or from a family screening study.

The most common symptoms of HCM are represented in Table 1. The onset of breathlessness is mainly due to the presence of left ventricular diastolic dysfunction, and also to mitral regurgitation and left ventricular outflow obstruction. Chest pain may be due to coronary insufficiency. Pre-syncope/syncope is most importantly caused by ventricular tachyarrhythmias, but may less frequently be due to SA node or AV node dysfunction.

A small proportion of patients with HCM (less than 10%) may develop heart failure due to enlargement of the left ventricular cavity size, with wall thinning and systolic dysfunction.

Sudden death in young adults
Most patients with HCM are asymptomatic. Tragically, however, the first clinical sign of the disease in some individuals is sudden cardiac death, typically due to ventricular tachycardia or fibrillation.

The incidence of sudden cardiac death among patients with HCM is 1–4% per annum.^7,8 Younger patients are most at risk of this complication because they tend to have a much greater degree of ventricular hypertrophy earlier on in life.

In addition, HCM is a leading cause of sudden cardiac death among athletes younger than 35 years. This is likely to be secondary to fatal arrhythmias during vigorous physical exertion. However, a proportion occurs when the individual is at rest.⁹

Given the potential for dire consequences, and that sudden cardiac death is prevented by the insertion of an implantable cardioverter-defibrillator (ICD), it is advised that risk stratification for sudden cardiac death be performed at diagnosis in all patients with HCM, regardless of symptomatic or haemodynamic status.

Table 2 highlights the important factors that place patients with HCM at higher risk of sudden death. Most experts agree that ICD therapy is recommended for any patient who has any of the five major risk factors present.¹⁰

TABLE 1: Symptoms of HCM

• Fatigue
• Breathlessness, especially on exertion
• Chest pain, especially with exercise
• Palpitations, caused by arrhythmias, including ventricular or atrial premature beats, ventricular tachycardia and atrial tachyarrhythmias 
• Dizziness or pre-syncope 
• Syncope (the most serious cause being ventricular tachycardia/fibrillation)

TABLE 2: Risk stratification for sudden cardiac death in patients with HCM
Major risk factors:

• Previous cardiac arrest/ventricular tachycardia
• Family history of sudden cardiac death^11,12
• Unexplained syncope¹³
• Non-sustained ventricular tachycardia on Holter monitoring¹⁴
• Left ventricular wall thickness ≥ 30mm¹⁵

Minor risk factors

• Abnormal blood pressure response to exercise¹⁴
• Left ventricular outflow tract obstruction (≥ 30mmHg)
• Myocardial ischaemia

DIAGNOSIS
A patient may be investigated for HCM after presenting with clinical symptoms. Patients who do not present with symptoms may be investigated after a heart murmur has been heard, or an ECG has shown unexplained left ventricular hypertrophy.

Patients with HCM may have a normal cardiovascular examination. However, those with left ventricular outflow tract obstruction have characteristic findings including a sharp pulse, a double cardiac impulse, a long systolic ejection murmur and an audible fourth heart sound. The details of these are shown in Table 3.

Investigations include ECG and Echocardiography with Doppler. Table 4 shows the investigation findings that may be found in patients with HCM.

When a patient presents with left ventricular hypertrophy, it is critical to distinguish HCM from other causes. Differential diagnoses for HCM include hypertension and aortic valve stenosis, as well as infiltrative disorders of the myocardium, such as Fabry disease and other storage diseases. 

TABLE 3: Clinical findings for patients with obstructive HCM

• Pulse: Brisk upstroke (this is palpated as a ‘sharp’ pulse)
• Cardiac impulse at the apex: A double impulse is palpable
• Murmur at the apex: A long systolic ejection murmur is audible at the apex. It increases with the valsalva manoeuvre. It is due, in part, to the left ventricular outflow obstruction; and, in part, to the mitral regurgitation
• Audible fourth heart sound: This is heard at the left sternal edge and the apex

TABLE 4: Investigation findings for HCM

• ECG: The ECG is typically abnormal in HCM. Some abnormal features include increased QRS voltage and ST-T changes, pathological Q waves, left axis deviation and bundle branch block patterns. There may also be P-wave abnormalities due to left atrial or biatrial hypertrophy.
• Echocardiography with Doppler: Echocardiograph findings are consistent with a hypertrophied, reduced cavity-sized left ventricle, with maximal wall thickness of ≥ 15mm. The pattern of hypertrophy most commonly shows asymmetric septal hypertrophy. However, in the apical variant, the apex is the site of greatest hypertrophy. In obstructive cases, there will be a left ventricular outflow tract gradient and mitral regurgitation due to systolic anterior motion.

WHO SHOULD BE SCREENED?
All first-degree relatives with HCM are advised to undergo screening for the disease.

This involves referral to a cardiologist or clinic, including the Hypertrophic Cardiomyopathy Clinic & Genetic Heart Disease Clinic at Royal Prince Alfred Hospital, Sydney.

Patients will have history-taking, examination, ECG and echocardiography, and should be seen by a genetic counsellor. Patients will be informed that genetic testing can be undertaken for most of the known genetic mutations.

Genetic testing is not covered by Medicare funding at this stage.

Patients who do not have a family history, but who have evidence of unexplained hypertrophy on ECG or echocardiography, should also be screened for HCM.

Furthermore, any patient with unexplained syncope should be considered for HCM screening.

MANAGEMENT
Managing patients with HCM involves treating symptoms and preventing sudden cardiac death.

Medical treatment for patients with obstructive HCM is shown in Table 5.

Non-pharmaceutical management includes surgery to the outflow tract, catheter-based alcohol septal ablation, and dual chamber pacing. Recommendation for one of these interventions is only made if quality of life-limiting symptoms persist despite treatment with one or more medications.

All of these techniques are used to reduce or abolish the outflow tract gradient (although the pacing technique is used less often). Interestingly, by reducing the outflow obstruction, the severity of generalised left ventricular hypertrophy may improve.

For patients with non-obstructive disease, treatment is limited to those who present with heart failure and arrhythmias. A very small proportion of these patients require heart transplantation. Importantly, the transplanted heart does not develop the features of HCM.

All patients with HCM require risk stratification for sudden cardiac death and the consideration of ICD implantation. HCM patients with any of the major risk factors (see Table 2) should be referred to a specialised electro-physiology cardiologist for ICD implantation.

For those patients with only minor risk factors, clinical judgement and patient preference are important when making a decision about ICD use.

Ideally, all individuals who play competitive sports should be screened for HCM. This practice is currently being employed in Italy, where patients with HCM are excluded from competitive activities. This has led to a drop in the frequency of sudden death tragedies from HCM among athletes when compared with other countries who do not practise this routine testing.

Although routine screening for HCM is not current practice in Australia, young individuals with a diagnosis of HCM are advised not to undertake vigorous or contact sports.

The level of safe sports participation for all young HCM patients is a crucial topic, and needs to be addressed with the patient and the family at the time of diagnosis.

TABLE 5: Medical treatment of obstructive HC

• Beta blockers, e.g. metoprolol: Decreases the augmentation of heart rate and left ventricular outflow obstruction which accompany exercise
• Verapamil (non-vasodilating calcium antagonist): Improves diastolic function
• Disopyramide (Class 1a anti-arrhythmic, which is negatively inotropic): Reduces the severity of left ventricular outflow obstruction

CONCLUSION
Hypertrophic cardiomyopathy is one of the most common of the inherited cardiac conditions.

While limitation due to symptoms is an important feature of the disease, sudden cardiac death is the most serious and tragic complication.

As this is a preventable outcome of the disease (by ICD implantation), every attempt should be made to avoid it from occurring.

This includes screening of individuals who play competitive sports, and screening of all first-degree relatives of affected individuals, genetic counselling, and risk stratification for consideration of ICD implantation.

KEY POINTS

• Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death among athletes, with an incidence of 1–4% per annum.
• HCM is commonly a familial inherited autosomal-dominant disorder, but there are many known genetic mutations associated with HCM.
• The primary problem in HCM is abnormal function of the sarcomere, which causes contractile dysfunction and leads to compensatory hypertrophy, developing most often in the second decade of life.
• Sudden cardiac death is prevented by the insertion of an implantable cardioverter-defibrillator, so risk stratification for sudden cardiac death should be performed at diagnosis in all patients with HCM.            

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