Disease Pathways and Novel Therapeutic Targets in Hypertrophic Cardiomyopathy

As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still c...

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Bibliographic Details
Published in:Circulation research 2011-06, Vol.109 (1), p.86-96
Main Authors: Ashrafian, Houman, McKenna, William J, Watkins, Hugh
Format: Article
Language:English
Subjects:
Actin Cytoskeleton - physiology
Animals
Biological and medical sciences
Calcium - metabolism
Cardiology. Vascular system
Cardiomyopathy, Hypertrophic - drug therapy
Cardiomyopathy, Hypertrophic - etiology
Cardiomyopathy, Hypertrophic - genetics
Energy Metabolism
Fundamental and applied biological sciences. Psychology
Heart
Humans
Medical sciences
Mutation
Myocarditis. Cardiomyopathies
Myocardium - metabolism
Signal Transduction
Vertebrates: cardiovascular system
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Summary:As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is principally a disease of the sarcomere. At the biophysical level, myofilament mutations generally enhance Ca sensitivity, maximal force production, and ATPase activity. These defects ultimately appear to converge on energy deficiency and altered Ca handling as major common paths leading to the anatomic (hypertrophy, myofiber disarray, and fibrosis) and functional features (pathological signaling and diastolic dysfunction) characteristic of HCM. In this review, we provide an account of the consequences of HCM mutations and describe how specifically targeting these molecular features has already yielded early promise for novel therapies for HCM. Although substantial efforts are still required to understand the molecular link between HCM mutations and their clinical consequences, HCM endures as an exemplar of how novel insights derived from molecular characterization of Mendelian disorders can inform the understanding of biological processes and translate into rational therapies.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.111.242974