Elsevier

The Lancet

Volume 358, Issue 9293, 10 November 2001, Pages 1627-1637
The Lancet

Review
Cardiomyopathies: from genetics to the prospect of treatment

https://doi.org/10.1016/S0140-6736(01)06657-0Get rights and content

Summary

Cardiomyopathies are defined as diseases of the myocardium associated with cardiac dysfunction ranging from lifelong symptomless forms to major health problems such as progressive heart failure, arrhythmia, thromboembolism, and sudden cardiac death. They are classified by morphological characteristics as hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), and restrictive cardiomyopathy (RCM). A familial cause has been shown in 50% of patients with HCM, 35% with DCM, and 30% with ARVC. In HCM, nine genetic loci and more than 130 mutations in ten different sarcomeric genes and in the γ2 subunit of AMP-activated protein kinase (AMPK) have been identified, suggesting impaired force production associated with inefficient use of ATP as the crucial disease mechanism. In DCM, 16 chromosomal loci with defects of several proteins also involved in the development of skeletal myopathies have been detected. These mutated cytoskeletal and nuclear transporter proteins may alter force transmission or disrupt nuclear function, resulting in cell death. Further DCM mutations have also been identified in sarcomeric genes, which indicates that different defects of the same protein can result in either HCM or DCM. In ARVC, six genetic loci and mutations in the cardiac ryanodine receptor, which controls electromechanical coupling, and in plakoglobin and desmoglobin (molecules involved in desmosomal cell-junction integrity), have been identified. Yet, no genetic linkage has been shown in RCM. Apart from disease-causing mutations, other factors, such as environment, genetic background, and the recently identified modifier genes of the renin-angiotensin, adrenergic, and endothelin systems are likely to result in the wide variety of RCM clinical presentations. Treatment options are symptomatic and are mainly focused on treatment of heart failure and prevention of thromboembolism and sudden death. Identification of patients with high risk for major arrhythmic events is important because implantable cardioverter defibrillators can prevent sudden death. Clinical and genetic risk stratification may lead to prospective trials of primary implantation of cardioverter defibrillators in people with hereditary cardiomyopathy.

Section snippets

Clinical presentation

HCM is characterised by left ventricular hypertrophy that is usually asymmetric and can affect various regions of the ventricle (panel 1). Typical histomorphological changes include myocyte hypertrophy and myofibrillar disarray. The prevalence of HCM is about 1 in 500 young adults.12 Clinical presentation of HCM ranges from lifelong symptomless forms to sudden cardiac death resulting from mechanical or electrical abnormalities in young adults.13 Likewise, onset of typical symptoms such as

Phenotype

DCM is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. DCM is also frequently associated with conduction defects. Histomorphological changes typically include extensive areas of subendocardial, focal interstitial, and perivascular fibrosis as well as hypertrophic and atrophic myofibres. The prevalence of DCM in a general population is 40–50

Arrhythmogenic right ventricular cardiomyopathy

ARVC, formerly called arrhythmogenic right ventricular dysplasia, is characterised by progressive fibrofatty replacement of right ventricular myocardium with progressive effects on the right ventricle.93 The incidence and prevalence of this disease are not documented. Clinical presentation is characterised by arrhythmias of right ventricular origin ranging from premature beats to sustained ventricular fibrillation resulting in sudden death.93 A study of sudden death in a northern Italian

Conclusion

Identification of cardiomyopathy-causing mutations has shed new light on molecular and functional mechanisms. Location of the defect within a gene affects development of clinical phenotype. Functional studies and development of transgenic models are needed to understand the pathways leading from altered gene to clinical phenotype. Given the range of phenotypes in familial cardiomyopathies, the role of modifier genes will also need to be identified. When routine identification of clusters of

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