Targeting valvular heart disease

The prevalence of valvular heart disease, in particular stenotic aortic disease, increases with age and reaches 13% in individuals over the age of 75 years. Despite this the aetiology and molecular mechanisms remain unclear, although several lines of evidence have suggested that its pathogenesis shares similarities to atherosclerotic disease, namely infiltration of inflammatory cells and accumulation of oxidised lowdensity lipoprotein within the valve, extracellular matrix remodeling and calcification. Based on these mechanisms, statins appeared to be ideal candidates to delay the progression of disease but despite initial promise from retrospective cohort data, prospective randomized controlled trials have not supported their use.

In this study the authors examine the role of periostin, a transforming growth factor beta inducible protein that is known to be involved in cardiac valve maturation during development. Using tissue from human valves with degenerative and rheumatic disease, they demonstrate that periostin is significantly overexpressed in these tissues in comparison with normal valve tissue and that when periostin was added to valvular cells in culture it promoted angiogenesis – a hallmark of vascular disease. Using a mouse model to explore this novel pathway further the authors then demonstrate that a high fat diet in wild-type mice was able to induce a phenotypic change with thickening of the aortic valve, which has been described previously, and is similar to early aortic valve disease in humans. However, when using this same diet in periostin knockout animals, although similar levels of obesity and hypercholesterolaemia were found, the mice did not develop valve disease, suggesting a pivotal role for periostin in this process.

Further work to elucidate the molecular pathogenesis of valvular disease will lead to attractive targets for drugs to attenuate progression of the disease, and periostin or one of its downstream targets may well in the future be an excellent candidate. The challenge of translating these findings into real clinical gains remains substantial but presents hope for rationally designed and targeted treatments in the future.

Conclusions
These data strongly support the hypothesis that periostin plays a causal role in valve disease. Although at an early experimental stage, further development and independent validation of these findings is important as there is currently a paucity of viable medical treatment strategies to prevent the progression of early-stage stenotic valve disease.

• Hakuno D, Kimura N, Yoshioka M, et al. Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents. J Clin Invest 2010;120:2292e306.

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