Hypertrophic cardiomyopathy (HCM) is defined as unexplained LV hypertrophy associated with a non-dilated ventricular chamber in the absence of another cardiac or systemic disease that itself would be capable of producing the magnitude of hypertrophy evident in any given patient. The traditional definition requires LVH of ≥15mm to be present for a diagnosis, although theoretically, any magnitude of LVH (≥12mm) may be compatible with the disease. Furthermore, there are a sub-group of patients who carry a genetic mutation for the condition (see below) but have no LVH – the so-called “genotype-positive, phenotype-negative” patients.

Hypertrophic cardiomyopathy is the commonest cardiac genetic disorder, with a prevalence of at least 1 in 500 (0.2%) in the general population. It has an autosomal dominant mode of inheritance, meaning that the children of an affected individual each have a 50% chance of inheriting the condition, assuming that the other parent is not affected. Figure 18 below is an example of a pedigree from a family with HCM.

Although most cases of HCM are inherited, a minority may be sporadic, due to a “private” mutation occurring spontaneously (“de novo”) in an individual during development.

The genetic basis of HCM is from mutations in several genes encoding sarcomeric contractile proteins, most commonly beta-myosin heavy chain (gene MYH7) and myosin binding protein C (gene MYBPC). A gene mutation is defined as the permanent alteration of the nucleotide sequence of a gene which is not found in most individuals. Mutations can be disease-causing or innocent (non-pathogenic). The list of known HCM mutations is growing, and we now know of mutations in genes encoding other non-sarcomeric contractile proteins that can cause HCM. A summary of these genes is given in the Figure 19 below. Currently, genetic testing for mutations is routinely performed in 19 genes known to cause HCM or HCM “phenocopies” (conditions that can mimic HCM). Unfortunately, at the moment we have not discovered all the mutations that cause HCM which means that if we gene test a group of people with HCM, at best we will only find a causative gene mutation in 60% of them. Assuming they have good clinical evidence of disease, this does not mean the remaining 40% do not have HCM; it just means they have a mutation we do not yet have knowledge about. With recent advances in molecular genetics, this situation is improving rapidly.

Hypertrophic cardiomyopathy is renowned for its clinical and genetic heterogeneity; this means that within a family, members with the same mutation may have very different clinical disease expression, with some developing severe disease whilst others developing only mild disease or no disease at all (incomplete penetrance). The mechanism behind this is not fully understood, but may be due to “genetic modifiers” which can include anything from other genes to environmental factors, or even other co-existing diseases such as hypertension. Furthermore, HCM also displays variable age-related penetrance, meaning that within the same family, some members may develop disease at an early age, whereas others may not develop disease until later on in life. The clinical implications of this observation are that screening for the condition (see below) in first degree relatives of an affected individual cannot be a “one-off” event; even if no disease is found after screening, this must be repeated routinely throughout a first degree relative’s lifetime. However, genetic testing can help in this situation; if a person with HCM is found to have a positive gene mutation known to cause the disease, predictive genetic testing can be offered to their family members. If the gene test in these family members comes back negative, then further screening will not be required as we know they have not inherited the causative mutation for HCM.

The histological hallmark of HCM is cardiac muscle cell (myocyte) hypertrophy, with the myocytes exhibiting bizarre shapes and being arranged in a chaotic, disorganised pattern which is called “myocyte disarray.” Other features include scar/fibrosis and hypertrophy of the intramural arteriolar cell walls (Figure 20).

The hallmark of HCM is obviously left ventricular hypertrophy (LVH). This has classically been described as affecting the septum (asymmetric septal hypertrophy, or “ASH”). However, the LVH in HCM can affect any segment of the LV myocardium and occasionally the RV too, and may be present in a variety of different patterns. Indeed, HCM can even produce concentric LVH, which can make it challenging to distinguish HCM from hypertensive heart disease in those patients who have coexisting hypertension. The LVH in HCM usually occurs “at the expense” of the LV cavity (so-called “concentric remodelling”), resulting in some patients with HCM having a small LV chamber size. In addition, the increased stiffness of the heart (caused by LVH, fibrosis and myocyte disarray) results in diastolic dysfunction and increased intra-cardiac pressures. This can result in remodelling of the left atrium and left atrial dilatation.

A discussion and explanation of left ventricular outflow tract obstruction has already been given above in the case scenario. Although SAM of the mitral valve occurs, we now also know that some patients with HCM may exhibit structural abnormalities of the mitral valve and papillary muscles as well, including increases in the size and shape of the mitral valve, elongated mitral valve leaflets and/or redundant tissue, extra chordae tendineae or chordae tendineae with abnormal attachments, and displacement or excessive hypertrophy of the papillary muscles (none of these were seen in Adam). Apart from the mechanisms of SAM described above, these intrinsic mitral valve abnormalities may also contribute to the development of SAM.

The pathophysiology of outflow tract obstruction, SAM and mitral regurgitation in HCM have already been described and discussed in the case scenario. These may all result in breathlessness, particularly on exertion, and severe outflow tract obstruction may also result in syncope. It is important to remember that not all HCM patients will develop obstruction, as already mentioned above. Diastolic dysfunction, however, contributes to breathlessness and symptoms of heart failure and may be present even in those with non-obstructive disease.

The other mechanism of pre-syncope and syncope in HCM patients are malignant ventricular arrhythmias, namely ventricular tachycardia (VT) and ventricular fibrillation (VF), which arise due to the myocyte disarray and histopathological abnormalities described above. These abnormalities resulting in an unstable myocardial substrate, impairment of electrical impulse transmission, and development of re-entry electrical circuits. Such malignant arrhythmias can cause sudden cardiac death which, for some, may unfortunately be the first manifestation of the disease.

Palpitation in HCM may be caused not only by ventricular arrhythmias (which includes multiple ventricular ectopics in addition to VT and VF), but also supraventricular arrhythmias, particularly atrial fibrillation (AF). Indeed, AF is a cause of much morbidity and mortality in HCM due to stroke, and its presence should result in commencement of anticoagulation with Warfarin regardless of the CHA₂DS₂-VASc score usually used to risk stratify patients with AF for anticoagulation as this score is not valid in patients HCM. NOACs are not yet licensed in HCM as there in no data on their efficacy in this setting.

Finally, chest pain may occur through a number of mechanisms, but is ultimately due to myocardial ischemia. In the absence of epicardial coronary disease, the mechanisms are thought to be abnormalities of the microvasculature such as arteriolar wall hypertrophy (resulting in microvascular angina) and inadequate capillary density in the face of LVH and a greatly increased LV mass. Severe LV outflow tract obstruction may also contribute to angina in a similar fashion to aortic stenosis.

Many of the clinical features and an example in the way in which patients with HCM can present have already been discussed and described in the case scenario above. Most patients come to medical attention due to symptoms or an incidental finding of a murmur. A further proportion are identified through cascade familial screening of an affected individual with HCM. A smaller proportion are identified fortuitously, for example because of an abnormal ECG performed for another reason e.g. pre-operatively. As mentioned, a small minority present with SCD or aborted (successfully resuscitated) SCD which may be the first (and most feared) presenting symptom.

It should be remembered, of course, that the symptoms and clinical examination findings in HCM will depend both upon severity of disease and, in particular, the presence of left ventricular outflow tract obstruction. Those without outflow tract obstruction may be completely asymptomatic and in these individuals, there may be little to find on examination.

The main investigations for patients with HCM have been described above. Patients should generally have a 12-lead ECG, echocardiography, a Holter monitor and exercise test on an annual basis. A cardiac MRI scan should be performed at least once, and may be repeated if disease progression is suspected or in some cases to guide risk stratification as some authorities believe that a high burden of scar or fibrosis is a surrogate risk factor. If an inducible gradient is suspected, then exercise echocardiography is extremely useful, as we have already seen.

As with the general population, patients with HCM are susceptible to coronary artery disease and therefore chest pain of unknown cause should be investigated with a CT coronary angiogram or conventional coronary angiography. In patients with co-existing hypertension in whom LVH is present but who also have clinical features of HCM, then demonstration of LVH despite good blood pressure control on a 24-hour blood pressure monitor can help clarify this diagnostic dilemma. In some patients, a transoesophageal echocardiogram may be required, particularly to evaluate the LV outflow tract and mitral valve architecture in more detail prior to surgical myectomy (see below).

Finally, those patients with large families and young relatives may be offered genetic testing. Although it was previously thought that certain gene mutations produce more severe disease, this theory has now been discounted. Therefore gene testing is mainly useful if a positive result is found, which can then mean other family members can be offered the test to see if they carry the mutation. However, gene testing may also be useful in certain individual cases, where the diagnosis is not clear or in patients who have subtle features of disease and who pose diagnostic dilemmas. Here, a positive gene test can help confirm or clarify the diagnosis. However, because of the ~40% false-negative rate of gene testing in patients with HCM, a negative result in this situation is unfortunately not helpful in ruling out disease.