Systemic H-FABP, hs-cTnT, hs-CRP and Monocyte-to-Lymphocyte ratio were significantly reduced by sacubitril/valsartan in doxorubicin-treated preclinical models through NLRP3-mTOR-AKT pathways

Abstract Introduction The SARAH trial, presented in November 2024 at the American Heart Association Scientific Sessions, evaluated the efficacy of sacubitril/valsartan in preventing cardiotoxicity among high-risk cancer patients undergoing anthracycline-based chemotherapy. A significant reduction in the primary endpoint (incidence of ≥15% reduction in global longitudinal strain (GLS) at 6 months) was observed in the sacubitril/valsartan group compared to placebo (7.1% vs. 25.0%; hazard ratio HR 0.23;p = 0.015). Mean change in left ventricular ejection fraction (LVEF) by cardiac magnetic resonance imaging was +0.19% with sacubitril/valsartan compared to -3.47% with placebo (p = 0.011). In this study, we analyzed for the first time biochemical pathways of sacubitril/valsartan cardioprotection in pteclinical models. Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), sacubitril/valsartan at 60 mg/kg (n=6) or doxorubicin combined to sacubitril/valsartan (DOXO- sacubitril/valsartan, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Systemic levels of H-FABP, hs-cTnT, hs-CRP and Monocyte-to-Lymphocyte ratio were analyzed thorugh selective ELISA and hemocytometry methods; myocardial NLRP3, Akt and mTOR were assessed thorugh ELISA and western blot methods. Results Sacubitril/valsartan improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. Reduced systemic levels of H-FABP (-43,7%; p0.001), hs-cTnT (-63,2 %; p0.05) and hs-CRP (-44,8%;p0.001) were seen in DOXO-sacubitril/valsartan group vs DOXO, indicating significant cardioprotection. Monocyte-to-Lymphocyte ratio was 0.08 in sham, 0.37 in DOXO treated mice and 0.12 in DOXO-sacubitril/valsartan group, indicating anti-inflammatory properties. Myocardial levels of NLRP3, Akt and mTOR were significantly reduced in DOXO-sacubitril/valsartan group vs DOXO. Conclusion For the first time, new biochemical cardioprotective pathways of sacubitril/valsartan have been analyzed in models of anthracycline-induced cardiotoxicity, mediated by the NLRP3/mTOR/AkT signaling pathway. The data presented support the evidence from the SARAH trial and the use of sacubitril/valsartan in the primary prevention of CTRCD in cancer patients.