Elsevier

The Lancet

Volume 381, Issue 9862, 19–25 January 2013, Pages 242-255
The Lancet

Seminar
Hypertrophic cardiomyopathy

https://doi.org/10.1016/S0140-6736(12)60397-3Get rights and content

Summary

Hypertrophic cardiomyopathy is a common inherited cardiovascular disease present in one in 500 of the general population. It is caused by more than 1400 mutations in 11 or more genes encoding proteins of the cardiac sarcomere. Although hypertrophic cardiomyopathy is the most frequent cause of sudden death in young people (including trained athletes), and can lead to functional disability from heart failure and stroke, the majority of affected individuals probably remain undiagnosed and many do not experience greatly reduced life expectancy or substantial symptoms. Clinical diagnosis is based on otherwise unexplained left-ventricular hypertrophy identified by echocardiography or cardiovascular MRI. While presenting with a heterogeneous clinical profile and complex pathophysiology, effective treatment strategies are available, including implantable defibrillators to prevent sudden death, drugs and surgical myectomy (or, alternatively, alcohol septal ablation) for relief of outflow obstruction and symptoms of heart failure, and pharmacological strategies (and possibly radiofrequency ablation) to control atrial fibrillation and prevent embolic stroke. A subgroup of patients with genetic mutations but without left-ventricular hypertrophy has emerged, with unresolved natural history. Now, after more than 50 years, hypertrophic cardiomyopathy has been transformed from a rare and largely untreatable disorder to a common genetic disease with management strategies that permit realistic aspirations for restored quality of life and advanced longevity.

Introduction

Hypertrophic cardiomyopathy is a heterogeneous monogenic heart disease studied for more than 50 years and recognised to be an important cause of arrhythmic sudden death, heart failure, and atrial fibrillation (with embolic stroke).1, 2, 3, 4, 5, 6, 7, 8 In view of the growing complexity of clinical practice, international differences in strategic approaches, and advances in genetic diseases5, 8, 9, 10, 11, 12, 13 and cardiac imaging,14, 15, 16, 17 not surprisingly the diagnosis, natural history, and management of hypertrophic cardiomyopathy have become sources of uncertainty, misunderstanding,18 and debate.9, 11, 12, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 In this Seminar, we aim to put into current context the rapidly changing and diverse clinical landscape of hypertrophic cardiomyopathy to enhance our understanding of this complex genetic disease.

Section snippets

Epidemiology

Hypertrophic cardiomyopathy is a truly global disease, with cases reported in more than 50 countries on all continents3 and affecting people of both sexes29 and of various ethnic and racial origins, yet with similar causal mutations, clinical course, and phenotypic expression.3, 28, 29, 30, 31, 32, 33, 34, 35 Hypertrophic cardiomyopathy is either under-recognised or clinical diagnosis is delayed, more frequently in women29 and people of African-American origin.30

In diverse regions, including

Nomenclature

Historically, an obstacle to understanding the clinical diversity of hypertrophic cardiomyopathy has been the many names (n=75) given to this disease entity.18 Idiopathic hypertrophic subaortic stenosis or hypertrophic obstructive cardiomyopathy (popular in the UK) misleadingly infer that obstruction to left-ventricular outflow is invariable. Dynamic subaortic gradients are a highly visible feature of hypertrophic cardiomyopathy. About 70% of a hospital-based cohort will have outflow

Basic principles

Findings of genetic studies show that hypertrophic cardiomyopathy is caused by dominant mutations in 11 or more genes encoding thick and thin contractile myofilament protein components of the sarcomere or the adjacent Z-disc (figure 1).5, 9, 10, 11, 12, 13, 36 Of patients who have been genotyped successfully, about 70% have mutations in two genes, β-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3). Troponin T (TNNT2) and several other genes each account for 5% or less of cases.5,

Imaging

Suspicion of hypertrophic cardiomyopathy usually follows the onset of symptoms or a cardiac event but can also arise from recognition of a heart murmur or abnormal 12-lead electrocardiogram (ECG) during routine or preparticipation sports examinations, or in pedigree studies.55, 56 Clinical diagnosis is confirmed conventionally by imaging the hypertrophic cardiomyopathy phenotype with two-dimensional (2D) echocardiography,7, 32, 33, 41, 47 cardiovascular MRI (figure 2),14, 15, 16, 57 or both.

Natural history and clinical course

Hypertrophic cardiomyopathy is perhaps unique among cardiovascular diseases, with presentation at any age from infancy to old age.2, 4, 7, 28, 29, 30, 34, 44, 79, 80, 81, 82 A growing number of children with sarcomeric hypertrophic cardiomyopathy are being identified with phenotypic expression at a young age (<10 years, including in infancy) and adults are surviving to advanced ages (>80 years).80, 81 Many patients with hypertrophic cardiomyopathy achieve normal life expectancy with little or

Epidemiology and pathophysiology

Sudden death is the most visible, devastating, and unpredictable consequence of hypertrophic cardiomyopathy,1, 2, 4, 6, 7, 25, 34, 61, 88, 92, 93, 94, 95, 96 although it is relatively infrequent within the vast disease spectrum (about 5% in hospital-based populations).24, 34, 92 Nevertheless, hypertrophic cardiomyopathy is the most common cause of sudden death in young people, with particular predilection for children and young adults (age <30 years),6, 7, 34, 79, 83, 84, 92, 93 although risk

Presentation

Symptoms related to heart failure, which are associated with preserved left-ventricular systolic function (ie, exertional dyspnoea), can arise at virtually any age, but most frequently in middle-aged adults.2, 4, 7, 29, 47, 86, 88, 116 Evolution to severe progressive heart failure disability (ie, New York Heart Association [NYHA] functional classes III or IV) represents a relatively small but important subset of patients, comprising 10–20% of an unselected hospital-based cohort.2, 4, 7, 29, 47,

Atrial fibrillation

Atrial fibrillation is the most common sustained arrhythmia in hypertrophic cardiomyopathy, occurring in about 20% of patients, four times the proportion expected in the general population. Atrial fibrillation affects patients with hypertrophic cardiomyopathy by increasing the risk of heart-failure progression or embolic stroke (prevalence 6%, incidence 0·8% per year),90, 91 which is most substantial in patients with left-ventricular outflow obstruction.

Susceptibility to atrial fibrillation is

Search strategy and selection criteria

We did a systematic search of Medline and identified 11 370 relevant articles published in the English language from 1960 to July, 2012, which we selected to create a comprehensive balanced appraisal of hypertrophic cardiomyopathy. Most studies were observational and retrospective, but we gave greater weight to publications from the past 10 years that included large cohorts and were evidence-based, statistically powered, and of a controlled investigational design.

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