Sympathetic activation drives mitral valve remodeling: uncovering the non-mechanical pathways in functional mitral regurgitation

Abstract Backgrounds Structural and histological remodeling of the mitral valve (MV) play an active role in functional mitral regurgitation (FMR), primarily driven by mechanical tethering induced by left ventricular (LV) dilation and dysfunction. However, emerging evidence suggests that non-mechanical factors, may independently induce MV remodeling. Purpose To investigate whether sympathetic activation, a key neurohormonal driver, can directly cause MV remodeling in the absence of mechanical factors. Methods Sprague-Dawley rats were divided into three groups: the ISO group (subcutaneous isoproterenol for 7 days, n=12), the ischemic group (left anterior descending coronary artery ligation, n=8), and the normal control group (NC, n=6). Echocardiography was performed at baseline and every 4 weeks to assess LV remodeling. Rats with significant LV remodeling (LV end-diastolic dimension EDD increase 10%) or LV ejection fraction EF 50%) were excluded. At 12 weeks, rats were euthanized, and myocardial and MV samples were collected for histopathological analysis (HE, Masson, Movat staining), immunohistochemistry (CD31, α-SMA, TGF-β1, CD45), and metabolomics. Results In the ISO group, LVEDD remained unchanged (5. 9 ± 0. 7 vs. 6. 5 ± 1. 1 mm, P=0. 259), while LVEF mildly declined (81 ± 9 vs. 69 ± 5%, P=0. 006). The ischemic group showed significant LV dilation (5. 7 ± 0. 5 vs. 6. 9 ± 0. 8 mm, P0. 001) and reduced LVEF (87 ± 8 vs. 58 ± 13, P=0. 002). Histopathological analysis revealed myocardial necrosis and increased collagen deposition in both groups (Figure 1A). Movat staining demonstrated collagen degradation and loosening (red staining) in the MV fibrous layer and disorganized collagen fibers with increased proteoglycan (blue staining) in the spongy layer (Figure 1B). CD31 expression in endothelial cells was decreased and discontinuous (arrows) in both model groups compared to NC (Figure 1C). α-SMA, absent in NC, was present in both model groups, with higher levels in the ISO group. Similar trends were observed for TGF-β1 and CD45 (Figure 1D). Neovascularization was detected in both models (Figure 1E). Metabolomics analysis revealed more significant changes in lipid metabolites in ISO group than the ischemic group. In the ISO group, TAG (56: 4) FA20: 3 was the most upregulated, while PC, PE, and LPG were downregulated. In the ischemic group, TAG (52: 5) FA20: 4 was the most downregulated, with reductions in TAG, PC, PE, PS, LPG, LPE, and LPS (Figure 2). Conclusion This study demonstrated that ISO-induced sympathetic activation, independent of significant LV remodeling, can induce MV remodeling, including endothelial-to-mesenchymal transition, collagen fiber changes, and metabolic disturbances. These findings suggest that sympathetic activation is an independent trigger for MV remodeling, providing new insights into FMR pathophysiology and potential therapeutic targets. Figure 1 Figure 2