Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy.

Abstract:

: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(2+) sensitivity, maximal force production, and ATPase activity. These defects ultimately appear to converge on energy deficiency and altered Ca(2+) 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.

journal_name

Circ Res

journal_title

Circulation research

authors

Ashrafian H,McKenna WJ,Watkins H

doi

10.1161/CIRCRESAHA.111.242974

subject

Has Abstract

pub_date

2011-06-24 00:00:00

pages

86-96

issue

1

eissn

0009-7330

issn

1524-4571

pii

109/1/86

journal_volume

109

pub_type

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