The Heart Valve Society

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Mitral Regurgitation from a Leaflet Perspective: Ex Vivo Modeling Reveals Early Pathogenesis
Katsuhide Maeda, Xiaoyuan Ma, Frank Hanley, R. Kirk Riemer.
Stanford University, Stanford, CA, USA.

Introduction Adult and pediatric mitral valve regurgitation (MR) is a rapidly growing burden of progressive cardiac disease. We seek to understand early changes in leaflet mechanical homeostasis that are induced by MR, and what these changes reveal about disease progression. We investigated the effects of disrupting mitral valve (MV) coaptation on the expression of genes mediating leaflet tissue homeostatic signaling. Methods A flow-culture bioreactor system was used to maintain rat mitral valves under ex vivo culture with either anterograde flow-induced cyclic coaptation (Cycling valve group; 84 BPM, 55 mmHg afterload, n = 5 experiments), or with leaflets in a sustained, unloaded open state (Open valve group n = 5). Following 3 days of culture, MV leaflets from each group were analyzed using genome-wide expression microarrays and PVR verification. Results Coaptive leaflet strain disruption for 3 only days altered the expression of >500 genes, with ~50 exhibiting markedly changed expression (>4-fold; P<0.05, Cycling Vs. Open). Several of the coaptation-regulated rat MV genes, including Igfbp3, Cd74, RT1-Da/HLA-DRA and Angpt2, have also been reported to be regulated in CAVD leaflets. Significant upstream regulatory pathways for the coaptation-disrupted rat MV genes ranked by Z-score are: Hif1-alpha > Vegf > Tnf-alpha. Conclusions Leaflet cyclic strain is critically important to sustaining their mechanical homeostasis. Disrupting MV closure markedly alters leaflet gene regulation by 72 hours, demonstrating rapid onset of changes in rat MV that are also documented in CAVD. Congruence in gene regulation among different species and valves demonstrate that disruption of coaptive strain is a common driver of valve leaflet pathophysiology that activates molecular pathways mediating responses to hypoxia and inflammation. In pathophysiological conditions such as MV stenosis or regurgitation, coaptive strain that sustains leaflet mechanical homeostasis is lacking. Our study shows that this lack of strain could accelerate the degeneration of valve leaflets, indicating a benefit of earlier intervention in MV disease.


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