Key result
Mitral valve tenting area and cells undergoing endothelial-to-mesenchymal transition were significantly associated with mitral regurgitation severity (R2 = 0.58).
Why the study?
Although animal studies linked EndMT to MV remodeling after MI, little was known about how MV tissue responds to ischemic heart changes in humans.
Observational (n=17)
Yes
Human mitral valves from patients with ischemic mitral regurgitation exhibit endothelial-to-mesenchymal transition and distinct proteomic changes that correlate with regurgitation severity and maladaptive fibrotic remodeling.
EndMT markers and proteomic shifts correlate with MR severity in human IMR; extends animal data, identifies candidate proteins, and leaves therapeutic targeting open.
Background: Following myocardial infarction, mitral regurgitation (MR) is a common complication. Previous animal studies demonstrated the association of endothelial-to-mesenchymal transition (EndMT) with mitral valve (MV) remodeling. Nevertheless, little is known about how MV tissue responds to ischemic heart changes in humans. Methods: MVs were obtained by the Cardiothoracic Surgical Trials Network from 17 patients with ischemic mitral regurgitation (IMR). Echo-doppler imaging assessed MV function at time of resection. Cryosections of MVs were analyzed using a multi-faceted histology and immunofluorescence examination of cell populations. MVs were further analyzed using unbiased label-free proteomics. Echo-Doppler imaging, histo-cytometry measures and proteomic analysis were then integrated. Results: MVs from patients with greater MR exhibited proteomic changes associated with proteolysis-, inflammatory- and oxidative stress-related processes compared to MVs with less MR. Cryosections of MVs from patients with IMR displayed activated valvular interstitial cells (aVICs) and double positive CD31+ αSMA+ cells, a hallmark of EndMT. Univariable and multivariable association with echocardiography measures revealed a positive correlation of MR severity with both cellular and geometric changes (e.g., aVICs, EndMT, leaflet thickness, leaflet tenting). Finally, proteomic changes associated with EndMT showed gene-ontology enrichment in vesicle-, inflammatory- and oxidative stress-related processes. This discovery approach indicated new candidate proteins associated with EndMT regulation in IMR. Conclusion: We describe an atypical cellular composition and distinctive proteome of human MVs from patients with IMR, which highlighted new candidate proteins implicated in EndMT-related processes, associated with maladaptive MV fibrotic remodeling.
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Lupieri et al. (2021) conducted an observational in Ischemic mitral regurgitation (n=17). Severe ischemic mitral regurgitation vs. Moderately severe ischemic mitral regurgitation was evaluated on Proteomic, cellular, and geometric changes associated with mitral regurgitation severity. Mitral valve tenting area and cells undergoing endothelial-to-mesenchymal transition were significantly associated with mitral regurgitation severity (R2 = 0.58).
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