Cardiomyopathies: from genetics to the prospect of treatment

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, a nd sudden cardiac death. They are classified by morphological characteristi cs as hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular ( ARVC), and restrictive cardiomyopathy (RCM). A familial cause has been show n in 50% of patients with HCM, 35% with DCM, and 30% with ARVC. In HCM, nin e genetic loci and more than 130 mutations in ten different sarcomeric gene s and in the gamma2 subunit of AMP-activated protein kinase (AMPK) have bee n identified, suggesting impaired force production associated with ineffici ent use of ATP as the crucial disease mechanism. In DCM, 16 chromosomal loc i with defects of several proteins also involved in the development of skel etal myopathies have been detected. These mutated cytoskeletal and nuclear transporter proteins may alter force transmission or disrupt nuclear functi on, resulting in cell death. Further DCM mutations have also been identifie d in sarcomeric genes, which indicates that different defects of the same p rotein can result in either HCM or DCM. In ARVC, six genetic loci and mutat ions in the cardiac ryanodine receptor, which controls electromechanical co upling, and in plakoglobin and desmoglobin (molecules involved in desmosoma l cell-junction integrity), have been identified. Yet, no genetic linkage h as been shown in RCM. Apart from disease-causing mutations, other factors, such as environment, genetic background, and the recently identified modifi er genes of the renin-angiotensin, adrenergic, and endothelin systems are l ikely to result in the wide variety of RCM clinical presentations. Treatmen t options are symptomatic and are mainly focused on treatment of heart fail ure and prevention of thromboembolism and sudden death. Identification of p atients with high risk for major arrhythmic events is important because imp lantable cardioverter defibrillators can prevent sudden death. Clinical and genetic risk stratification may lead to prospective trials of primary impl antation of cardioverter defibrillators in people with hereditary cardiomyo pathy.