Sacubitril/Valsartan attenuates progression of diabetic cardiomyopathy through immunomodulation properties: an opportunity to prevent progressive disease

作者：Narainrit Karuna, Lauren Kerrigan, Kevin J. Edgar, Mark Ledwidge, Kenneth McDonald, David Grieve, Chris Watson · 发表于：Cardiovascular Diabetology · 年份：2025 · DOI：10.1186/s12933-025-02741-5 · 被引用次数：9 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiovascular Function and Risk Factors、Heart Failure Treatment and Management

Abstract Background and aims Diabetic cardiomyopathy (DbCM) is recognised as a key mediator and determinant of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Improved understanding of mechanisms underlying transition from early-stage DbCM to HFpEF will inform innovative evidence-based treatment approaches, which are urgently required to alleviate increasing disease burden. This study aimed to determine whether inhibition of neprilysin activity by Sacubitril/Valsartan in both experimental and clinical DbCM attenuates adverse remodelling through promotion of cardioprotective signalling. Methods and results Sacubitril/Valsartan effectively reduced plasma neprilysin activity in both diabetic patients with pre-clinical HFpEF from the PARABLE trial (baseline (Val n = 25; Sac/Val n = 35) and 3 months after treatment (Val n = 21/25; Sac/Val n = 33/35)) and DbCM (high-fat diet and streptozotocin) mice. Plasma neprilysin activity at baseline was correlated with worsening cardiac performance at 18 months indicated by left atrial stiffness index in patients (n = 44/60), whilst diastolic dysfunction and pathological remodelling in DbCM mice were improved by Sacubitril/Valsartan, but not Valsartan. snRNA-sequencing showed that progressive experimental DbCM is characterised by chronic low-grade inflammation, reflected by increased infiltration of pro-inflammatory monocytes (Ccr2 + Ly6c hi ) and reduction in MHC-II macrophages, which was prevented by Sacubitril...