Abstract 18204: Ex Vivo Flow Culture Modeling of Aortic Insufficiency Reveals Additive Effects of Impaired Coaptation and Accelerated Flow on Leaflet Gene Expression

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Abstract

Introduction: Aortic valve insufficiency (AI) is one of the more common valve disorders. It has a variety of causes and is known to get progressively worse once the insufficiency starts. The mechanisms of AI disease progression are debated, but leaflet damage in these patients is common, and suggests that leaflet changes contribute to disease progression.

Methods: We used an ex vivo flow culture bioreactor to assess the separate effects of flow shear and coaptive stretch on rat aortic valve (AV) leaflet gene expression after seven days of culture. We asked if expression was different in valves cultured under two conditions: Intact valves prevented from closing (Open, no coaptation and no flow; n=3) and valves made incompetent by splitting a leaflet tip (AI, flow-induced cycling with impaired coaptation, N=2). After 7 days of culture, leaflets were harvested, flash frozen, and purified RNA was used to interrogate rat whole-transcriptome RTA1.0 microarrays to evaluate transcript expression relative to condition.

Results: Open condition AV exhibited a decreased expression of multiple endothelial and non-endothelial genes compared with normally cycling AV (Figure). When expression in AI valves was compared with Open condition, we observed a marked decrease in expression of these same genes.

Conclusions: Impaired coaptation decreases leaflet expression of multiple genes. The accelerated flow shear of AI also decreases the expression of the same genes, in an additive manner to Open condition. These results demonstrate for the first time that AV leaflets respond rapidly to conditions that disrupt their complete closure, and that accelerated flow through the incompetent valve further intensifies these changes. Interventions to correct conditions of disrupted valve function are best started as soon as possible.

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