Inherited cardiomyopathies

Symptomatic patients

Patients may present to their primary care doctor with symptoms caused by myocardial ischaemia, arrhythmia, or heart failure, which can include chest pain, syncope, dyspnoea, palpitations, or stroke. However, a pilot study of the feasibility of heart screening for sudden cardiac arrest in healthy children found that history and physical examination alone are poor predictors of disease in young people, although it is still important to take a family history.10 Initial investigation with electrocardiography, with a view to requesting cardiac imaging in the face of an abnormality, is warranted in any patient with worrying symptoms. “Red flag” symptoms (box) include palpitations and exertional dyspnoea accompanied by syncope or seizures in a young person.

After a definitive diagnosis, family doctors are often the first point of contact when patients deteriorate. Cardiomyopathies are progressive disorders and complications are a risk as patients age.4 11 12 Any worsening in symptoms of heart failure, signs of ischaemia, or unheralded syncope warrants urgent specialist re-evaluation.

Asymptomatic case finding

Electrocardiographic abnormalities suggestive of cardiomyopathy may be identified incidentally, such as during preoperative risk evaluation or personal health assessment, or as a result of population based screening programmes that are available in some countries.10

Patients may seek medical advice directly after discovering a positive family history of cardiomyopathy or premature sudden death, or the family doctor may discover a family history of cardiomyopathy on careful history taking. It is always prudent to refer first degree blood relatives of an affected individual to a specialist for cardiological or genetic evaluation (or both), as recommended by the PHG Foundation UK working group and international consensus.1 6 Because affected families may cluster in general practices, the family practitioner may be uniquely placed to discover “at risk” people. Referral of more distant relatives for evaluation depends on patterns of inheritance of the disease and is not routine practice in primary care. Because death certification may not always identify affected people who are asymptomatic and apparently undiagnosed before a sudden death, particularly those under 40 years,13 14 15 16 it is important to consider cardiomyopathy as a potential cause of death if a patient reports the sudden and unexplained death of a relative. A recent population based study from Europe found that that relatives are often not referred for evaluation of inherited cardiac conditions after a premature death in the family.7 Good communication between primary care doctors and cardiogenetic specialists, and clear patient pathways, are needed to facilitate appropriate evaluation of families and identification of family members at potential risk of inherited cardiomyopathy.

Electrocardiography

In patients clinically affected by cardiomyopathy the resting electrocardiograph is rarely normal. In gene carriers who seem to be clinically unaffected (incomplete gene expression) the electrocardiograph is usually normal.2 17 Classically, large voltage QRS complexes with ST depression and deep T wave inversion (figure; part A⇓) are seen in patients with hypertrophic cardiomyopathy, although non-specific electrocardiographic changes may also be seen and may be the only initial indication of disease. In patients with arrhythmogenic right ventricular cardiomyopathy, subtle abnormalities may be evident on electrocardiography (figure; part B) in the right precordial leads (V1-V3). These abnormalities include T wave inversion and broadening of the QRS and the “epsilon wave” (notch in the ST segment), which reflect the predilection of the disease for right ventricular muscle. Changes can be more extensive in severe arrhythmogenic right ventricular cardiomyopathy. Patients with dilated cardiomyopathy may also show non-specific abnormalities on electrocardiography (figure; part C).

Examples of electrocardiographs from patients with inherited cardiomyopathy. (A) Lateral precordial leads of a patient with hypertrophic cardiomyopathy showing Q wave (V6), ST depression, and T wave inversion associated with large voltage QRS complexes. (B) Right precordial leads of a patient with arrhythmogenic right ventricular cardiomyopathy showing epsilon wave (V2), QRS prolongation, and T wave inversion. (C) Precordial leads of a patient with dilated cardiomyopathy showing incomplete left bundle branch block and electrocardiographic left atrial enlargement

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Specialist investigations

A cardiologist will request echocardiography or magnetic resonance imaging to make a definitive diagnosis in patients with hypertrophic cardiomyopathy and dilated cardiomyopathy; these investigations can identify characteristic ventricular hypertrophy or dilation and impaired systolic function, respectively.6 9 Wide variability in gene expression in arrhythmogenic right ventricular cardiomyopathy has led experts to develop a complex diagnostic scoring system that is used to determine the likelihood of disease (http://qstatistic.com/pdg/public.php?rep=arvc_cri).2

Excluding other conditions

The cardiologist will need to exclude conditions that may mimic inherited cardiomyopathies because these will require different management strategies from the inherited conditions they resemble. Athlete’s heart (as a result of chronic exercise training) and cardiac changes secondary to hypertension and amyloid may mimic hypertrophic cardiomyopathy, and coronary artery disease and chronic alcohol excess may lead to cardiac muscle changes that mimic dilated cardiomyopathy.4 6 9

Dilated cardiomyopathies pose a particular difficulty, given that only some are inherited; the familial nature of dilated cardiomyopathy can be established only by reviewing family history, which may require investigation of blood relatives.4 9

Reducing sudden death

The risk of sudden death as a result of fatal arrhythmias can be reduced by lifestyle changes tailored to removing triggers. For example, participating in competitive sport is universally discouraged. On the basis of randomised trials, drugs such as β blockers and angiotensin converting enzyme inhibitors are commonly used to reduced the risk of death in patients with dilated cardiomyopathy, but drugs have not been shown to be useful in reducing the risk of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy or hypertrophic cardiomyopathy.5 6 18

Implantable cardioverter defibrillators are the only intervention that has been shown to reduce sudden death in most patients with an inherited cardiomyopathy. Longitudinal observational and multicentre randomised studies have shown that a previous cardiac arrest or haemodynamically compromising ventricular arrhythmia puts people with cardiomyopathy at high risk of recurrence.5 Such patients should be considered for a secondary prevention implantable defibrillator.5 Implantable defibrillators may also be offered for primary prevention to those who are at sufficiently high risk of sudden death. Risk is determined by the severity of left ventricular systolic dysfunction and conduction disease for patients with dilated cardiomyopathy, a risk scoring system for those with hypertrophic cardiomyopathy, and severity of disease and symptoms in patients with arrhythmogenic right ventricular cardiomyopathy.5 11 19

Management of progression of disease and symptoms

Symptoms of heart failure, including dyspnoea, may be reduced by achieving euvolaemia with diuretics, although we advise caution in hypertrophic cardiomyopathy because of the predominance of diastolic dysfunction. For patients with dilated cardiomyopathy, the findings of multiple large randomised controlled trials support treatment with β blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and spironolactone, in addition to cardiac resynchronisation with biventricular pacing, all of which are aimed at slowing progression of disease and reducing mortality.20 The effectiveness of these treatments in the other cardiomyopathies is less certain, although they are recommended by international guidelines for all patients with left ventricular systolic dysfunction as a result of end stage disease.20 21

In patients with hypertrophic cardiomyopathy, chest pain caused by ischaemia may be ameliorated by β blockers or verapamil. Symptoms secondary to outflow tract obstruction may be reduced by the addition of disopyramide.6 Invasive procedures such as septal alcohol ablation and surgical myomectomy may reduce the outflow tract gradient and reduce symptoms.11 22 In patients with arrhythmogenic right ventricular cardiomyopathy, symptomatic ventricular arrhythmias may be reduced by sotalol and amiodarone.18 23 Furthermore, radiofrequency ablation can be a useful adjunct in refractory arrhythmias, although recurrence as a result of progressive disease is a problem.23 24 A minority of patients with severe symptomatic disease, usually as a result of heart failure, receive heart transplants.25

Patients with hypertrophic cardiomyopathy and dilated cardiomyopathy are at increased risk of atrial fibrillation, which is important to recognise because of the concomitant thromboembolic risk.26

Diagnosis

Because genetic testing is less than 100% sensitive, it is recommended only after confirmation of the clinical diagnosis, and even then usually in a limited number of genes that cause hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy.27 Most inherited cardiomyopathies show a mendelian autosomal dominant inheritance pattern, although less common recessive forms have been described, and dilated cardiomyopathy can also be inherited in an X linked pattern.9 28 To date, more than 20 genes have been implicated in hypertrophic cardiomyopathy, detectable in 60% of families,8 whereas mutations in seven genes identify almost half of those affected by arrhythmogenic right ventricular cardiomyopathy.2 Dilated cardiomyopathy is a heterogeneous disorder, and a myriad genetic abnormalities identified account for only around 30% of familial cases.9

Cascade familial testing

Once a definite disease causing mutation is identified in an affected patient, the main diagnostic role for genetic testing is identification of carriers within a pedigree, a process known as “cascade testing.”27 Family members who carry the same genetic mutation may show different severities of disease, and this is known as variable penetrance. Hence, some patients may remain entirely asymptomatic, with little evidence of disease throughout their lives.4 However, as mutation carriers, their children remain at risk of inheriting the disorder and potentially being more severely affected. Despite an autosomal dominant inheritance pattern, the clinical picture may give the appearance of “skipped” generations in a single pedigree. Mutation analysis is useful to allow accurate identification of carriers, and it may be cost effective and reassuring because non-carriers are eliminated from clinical assessment.29

Prediction of risk

Risk prediction still depends mainly on clinical assessment for patients with cardiomyopathy. Mutational analysis may affect risk; one specific subgroup increases the risk of sudden death—mutations in the gene encoding lamin A/C (LMNA), which are associated with dilated cardiomyopathy.30 Research to assess new markers is under way.