Elsevier

The Lancet

Volume 363, Issue 9424, 5 June 2004, Pages 1881-1891
The Lancet

Seminar
Hypertrophic cardiomyopathy

https://doi.org/10.1016/S0140-6736(04)16358-7Get rights and content

Summary

Hypertrophic cardiomyopathy is a common genetically transmitted disease, defined clinically by the presence of unexplained left ventricular hypertrophy. The disease has a varied clinical course and outcome; many patients have little or no discernible cardiovascular symptoms, whereas others have profound exercise limitation and recurrent arrhythmias. The overall risk of disease-related complications such as sudden death, endstage heart failure, and fatal stroke is roughly 1–2% per year, but the absolute risk in individuals varies as a function of underlying genetic abnormality, age, myocardial pathology, and other pathophysiological abnormalities such as impaired peripheral vascular responses. Genetic counselling and clinical risk stratification are relevant to all patients, but many therapeutic interventions, including septal alcohol ablation, septal myectomy, and implantable cardioverter defibrillators, are appropriate only in particular patient subsets. We review the management of patients with unexplained myocardial hypertrophy, considering the influence of underlying genetic and pathophysiological substrates on clinical decision-making.

Introduction

For the past five decades, hypertrophic cardiomyopathy has been defined by the presence of myocardial hypertrophy in the absence of haemodynamic stress that is sufficient to account for the degree of hypertrophy.1, 2 Adults with increased left ventricular thickness secondary to diseases such as amyloidosis and glycogen storage disease are usually excluded from the definition. However, exhaustive searches for all possible metabolic causes of left ventricular hypertrophy are rarely done in adults, so some patients with so-called unexplained hypertrophy may in fact have undiagnosed secondary left ventricular hypertrophy.

Hypertrophic cardiomyopathy can also be defined by a characteristic histopathogical appearance called myocyte disarray.3 Even this appearance, however, is not specific to autosomal dominant hypertrophic cardiomyopathy, since it arises in other syndromic causes of left ventricular hypertrophy such as Noonan's syndrome and Friedreich's ataxia (an autosomal recessive disorder caused by a repeating trinucleotide sequence in the gene encoding the protein frataxin),4, 5 as well as in congenital heart disease. Moreover, myocyte disarray is difficult to identify in vivo, and its extent can only be established at necropsy.

With the identification of mutations in sarcomeric protein genes in many patients with hypertrophic cardiomyopathy, a new genetic definition has emerged. However, this definition also has important limitations in clinical practice, not least that genetic analysis is not available to most clinicians. Moreover, published data from several centres indicate that mutations in sarcomeric protein genes account for only 60% of cases of the disease.6, 7, 8, 9

For the clinician, therefore, hypertrophic cardiomyopathy is still defined by the presence of left ventricular hypertrophy in the absence of a detectable cause. We review the disease in relation to diagnosis, symptomatic management, and the prevention of complications, focusing mainly on sarcomeric protein disease, but discussing, where appropriate, important disease mimics and potential diagnostic grey areas.

Section snippets

History

Although the classic appearance of asymmetrical hypertrophy of the interventricular septum was first described in 1869 by Liouville10 and Hallopeau,11 hypertrophic cardiomyopathy emerged as an accepted clinical entity only in the 1950s with the description of functional obstruction of the left ventricle by Sir Russell Brock,12 and of asymmetrical septal hypertrophy by Donald Teare.13 After these landmark papers, there was a period of intense clinical investigation in which the characteristic

Epidemiology

The few studies that have examined the prevalence of hypertrophic cardiomyopathy have used very different screening methods and diagnostic criteria.22, 23, 24, 25, 26, 27 Nevertheless, all but one recorded a prevalence of about one in 500 adults. The frequency of unexplained left ventricular hypertrophy in children remains unknown, but investigators from medical centres in the USA27 and Australia28 have reported an annual incidence of left ventricular hypertrophy (all causes) between 0·3 and

Infants and young children

Most cases of left ventricular hypertrophy in infants and young children are associated with congenital malformations and syndromes, inherited metabolic disorders, and neuromuscular diseases (panel). Familial disease is less frequent in children than in adults, with various modes of inheritance.27, 28 Autosomal dominant disorders that present in the young with left ventricular hypertrophy include Noonan's syndrome and LEOPARD's syndrome (lentigines, electrocardiogram abnormalities, ocular

Pathology

Although hypertrophic cardiomyopathy is still thought to develop during the pubertal growth spurt in most patients,49 hypertrophy can first occur after age 20 years, especially in families who have mutations in the cardiac myosin binding protein C gene.47, 50 Most patients with the disease have an asymmetric pattern of hypertrophy that affects the interventricular septum more than the posterolateral segments of the left ventricle, but concentric, apical, and other atypical distributions also

Symptoms

Most patients with hypertrophic cardiomyopathy have few symptoms, if any, and the diagnosis is made incidentally or during family screening. Chest pain during exertion and dyspnoea are the commonest symptoms, with a characteristic day-to-day variation in the activity needed to cause symptoms. Chest pain can persist at rest and is frequently caused by large meals. A few patients complain of syncope or presyncope, which can arise during exertion or at rest. Ingestion of alcohol can cause similar

Symptomatic management

The management of patients with hypertrophic cardiomyopathy is complex and can change during the course of the disease (figure 6).110, 111 Nevertheless, some basic principles of management can have an effect on quality of life and prognosis.

Prevention of sudden cardiac death

Sudden death occurs with a frequency of about 1% or less per year in adults with hypertrophic cardiomyopathy, rising to 2–4% in children and adolescents.110, 111, 140, 141, 142, 143, 144, 145, 146, 147 The mechanism of sudden death is thought to be ventricular arrhythmia in most patients, although bradyarrhythmias and thromboembolism might account for some such deaths. The underlying reasons for ventricular tachyarrhythmia include myocyte disarray and fibrosis, abnormal autonomic function, and

Genetic counselling

The management of hypertrophic cardiomyopathy should include counselling on the genetic implications of the disease and advice on related issues such as life insurance and employment. The number and variety of possible mutations means that genetic testing is not generally feasible, but careful pedigree analysis can reassure members of a family who are not at risk of inheriting the disease, and can inform discussions on the risk of complications related to the disease. Because of the autosomal

Personal perspective

Over the past half century, the view of hypertrophic cardiomyopathy has changed from a rare heart muscle disease of the young with a poor prognosis to an increasingly complex family of genetic disorders with variable clinical expression and natural history. The discovery of multiple sarcomeric protein gene mutations and genetic phenocopies has opened a new chapter in the story of the disease, suggesting not only novel disease mechanisms, but also showing just how diverse the spectrum of disease

Search strategy

We identified studies published before December, 2003, by searching the Cochrane and MEDLINE databases. Initial search terms were “hypertrophic cardiomyopathy.” We also did a hand search of references from these reports and from earlier reviews.

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