Hypertrophic cardiomyopathy: from molecular and genetic mechanisms to clinical management

Molecular genetic research in hypertrophic cardiomyopathy (HCM) has shown t hat this heart muscle disorder, which was previously considered 'idiopathic '. is caused by a wide diversity of mutations that affect the cardiac contr actile proteins. With this information, it is now possible to explore molec ular genetic diagnosis. recalibration of clinical diagnostic tools and crit eria, and genotype-phenotype correlations. However, the biggest potential b enefit is that a detailed understanding of the disease pathway may lead to disease-modifying treatments. Demonstration of the mutations in cardiac con tractile protein genes has focused attention on alterations in contractilit y. However, no unifying abnormality of contractility is apparent; rather, t he defects point to an inefficiency of ATP usage in the sarcomere. The very recent finding of HCM-causing mutations in a regulatory subunit of AMP-act ivated protein kinase strongly supports the hypothesis that the unifying ab normality in this condition is an inability to maintain normal ATP availabi lity in the myocardium during times of stress. This conclusion should ultim ately lead to new approaches to therapy and to further consideration of the role of altered myocardial energetics in other forms of heart muscle disea se. (C) 2001 The European Society of Cardiology.