Mitral valve leaflet response to ischemic mitral regurgitation: From gene expression to tissue remodeling

Abstract

AbstractAimsIschemic mitral regurgitation is frequently observed following myocardial infarction and is associated with higher mortality and poor clinical prognosis if left untreated. Accumulating evidence suggests that mitral valve leaflets actively remodel post–myocardial infarction, yet the cellular mechanisms underlying these responses and how this affects tissue function remain largely unknown. We sought to elucidate mitral valve remodeling post myocardial infarction at the tissue, cellular, and transcriptomic levels.Methods and ResultsThe mechanical behavior of ovine mitral valve leaflets pre– and 8 weeks post– myocardial infarction reveal a significant decrease in radial direction extensibility, which essentially eliminated the mechanical anisotropy typically observed in healthy mitral valves. Quantitative histology and ultrastructural assessment by transmission electron microscopy revealed altered leaflet composition and architecture at 8 weeks post–myocardial infarction. Assessment of the mitral valve interstitial cell nuclear aspect ratio, a metric of cellular deformation, revealed that they were on average rounder following myocardial infarction. RNA sequencing indicated that YAP-induced genes were elevated at 4 weeks post–myocardial infarction and genes related to extracellular matrix organization were some of the most downregulated in sheep with IMR compared to sheep without ischemic mitral regurgitation at 4 weeks post–myocardial infarction. Additionally, RNA sequencing revealed the possible recruitment of immune cells in this remodeling process due to the drastic elevation of CXCL9 and CLEC10A.ConclusionsOur multiscale assessment revealed significant mechanical and microstructural changes due to myocardial infarction. RNA sequencing provided a baseline for global gene expression changes in response to myocardial infarction with and without ischemic mitral regurgitation and suggests YAP-induced mechanotransduction, altered expression of extracellular matrix–related genes, and recruitment of immune cells as mechanisms contributing to altered mitral valve biomechanics post–myocardial infarction.