Elsevier

The Lancet

Volume 373, Issue 9671, 11–17 April 2009, Pages 1289-1300
The Lancet

Seminar
Arrhythmogenic right ventricular cardiomyopathy

https://doi.org/10.1016/S0140-6736(09)60256-7Get rights and content

Summary

Arrhythmogenic right ventricular cardiomyopathy is a rare inherited heart-muscle disease that is a cause of sudden death in young people and athletes. Causative mutations in genes encoding desmosomal proteins have been identified and the disease is nowadays regarded as a genetically determined myocardial dystrophy. The left ventricle is so frequently involved as to support the adoption of the broad term arrhythmogenic cardiomyopathy. Clinical diagnosis can be achieved by demonstrating function and structure changes of the right ventricle, electrocardiogram depolarisation and repolarisation abnormalities, ventricular arrhythmias, and fibrofatty replacement through endomyocardial biopsy. Although specific, the standardised diagnostic criteria lack sensitivity for early disease and their primary application remains in establishing the diagnosis in probands. However, the main clinical targets are early detection of concealed forms and risk stratification for preventive strategies, which include physical exercise restriction, antiarrhythmic drugs, and implantable cardioverter-defibrillator therapy. Cascade genetic screening of family members of gene-positive probands allows the identification of asymptomatic carriers who would require lifelong follow-up due to the age-related penetrance.

Introduction

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterised by fibrofatty replacement and ventricular arrhythmias. The first historical description of the condition was in the book De Motu Cordis et Aneurysmatibus,1 published in 1736 by Giovanni Maria Lancisi, the Pope's physician and Professor of Anatomy in Rome (figure 1). He reported a family with disease recurrence in four generations. Symptoms included palpitations, heart failure, dilatation and aneurysms of the right ventricle, and sudden death. In 1961, cases with auricularisation (strong right atrial contraction) of the right ventricle pressure curve and non-ischaemic pathology of the dilated right ventricle were published.2 However, the first comprehensive clinical description of the disease was reported in 1982 in adults with ventricular tachyarrhythmias of left bundle branch block morphology.3 The electrocardiographic features of the disease, including the characteristic epsilon wave, were first described in 1984.4 Since then, the disease has been noted to be an important cause of sudden death in young people and particularly in athletes.5

ARVC is a familial disease in at least 50% of cases and is typically transmitted as an autosomal dominant trait with variable penetrance.6 On the basis of clinical studies and data obtained from pre-participation screening for sport activity, the estimated prevalence of the disease in the general population ranges from 1 in 1000 to 1 in 5000.7, 8, 9

The condition was initially believed to be a developmental defect of the right ventricular myocardium, leading to the original term, dysplasia.3, 4, 10, 11 However, myocardial atrophy is the consequence of cell death occurring after birth, usually during childhood and is progressive with time. This process differs from Uhl's disease, a congenital heart defect in which the right ventricular myocardium does not develop during embryonic life.12 This idea has evolved into the current view of a genetically determined cardiomyopathy.13, 14

In the past 10 years, great advances have been made in the recognition and understanding of this condition, and two research grants in the USA and in Europe have greatly contributed to current knowledge.15, 16, 17

Section snippets

Pathogenesis

The replacement of the right ventricular myocardium by fibrofatty tissue is progressive, starting from the epicardium or midmyocardium and then extending to become transmural. Progression then leads to wall thinning and aneurysms, typically located at the inferior, apical, and infundibular walls (so-called triangle of dysplasia), the hallmark of ARVC.4, 13, 18 The fibrofatty replacement interferes with electrical impulse conduction, and is the key cause of epsilon waves, right bundle branch

Diagnosis

The disease affects men more frequently than women and becomes clinically overt usually from the second to the fourth decade of life.6, 60, 61 Symptoms and signs do not usually appear before puberty or beyond the age of 60 years. However, occasionally the first clinical manifestations arise even in patients older than 70 years of age.44, 62 The disease is probably often missed in the older age-group because clinicians do not take it into consideration.

The practising physician should be aware of

Treatment and prevention

Prevention of sudden death is the most important management strategy of ARVC. Retrospective analysis of clinical and pathological series identified several risk factors such as previous cardiac arrest, syncope, young age, malignant family history, participation in competitive sports, VT, severe right ventricular dysfunction, left ventricular involvement, and QRS dispersion of 40 ms or more.103, 104 However, the prognostic value of these single or combined risk factors has not been prospectively

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