Editors' ChoiceCardiology

Silencing the Sounds of Hypertrophic Cardiomyopathy

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Science Translational Medicine  06 Nov 2013:
Vol. 5, Issue 210, pp. 210ec185
DOI: 10.1126/scitranslmed.3007861

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by an asymmetric enlargement of the left ventricle, which obstructs blood flow and generates a prominent murmur on physical examination. Patients with HCM are at high risk for sudden cardiac death because the underlying myocardium is disorganized and is a substrate for fatal arrhythmias. As a consequence, HCM is the leading cause of sudden death in young adults and athletes. Although certain medications can reduce the severity and symptoms of obstruction, to date there are no interventions that can prevent the pathologic hypertrophy observed in these patients.

In humans, HCM is characterized by incomplete penetrance and genetic heterogeneity. Mutations in the contractile elements of the myocardium are known to be causal and a particular mutation (R403Q) in the MYH7 gene that produces a severe form of HCM in humans. Mice heterozygous for the same mutation in the mouse homologue (Mhy6) recapitulate human HCM; thus, the mouse model is an ideal candidate for testing therapeutic strategies. Jiang et al. used this model to target the mutated version of Myh6 with RNA interference (RNAi). Compared with control constructs, mice that were exposed to the Myh6 RNAi demonstrated allele-specific silencing of the mutated Myh6 transcripts, the absence of ventricular hypertrophy, and normal myocardial organization on histology 6 months after injection. However, exposure to the RNAi did not reverse preexisting hypertrophic changes in these mice, suggesting that this potential therapy would be more useful for preventing the development of HCM than treating existing disease.

The potential clinical applications of these findings are clear. Unaffected family members of patients with HCM could receive this type of RNAi as preventive therapy to delay or mitigate the development of HCM. In this study, the mice were exposed to the viral vectors systemically. In humans, it is possible to directly cannulate the arteries serving the hypertrophic myocardium, thus allowing for local delivery of the RNAi molecules. As our knowledge of the genetic architecture of human cardiomyopathies expands, the approach described by Jiang et al. may soon become a new addition to the cardiologists’ armamentarium for treating cardiomyopathies.

J. Jiang et al., Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy. Science 342, 111–113 (2013). [Abstract]

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