54 Sacubitril–valsartan (LCZ 696) improves longitudinal strain and ejection fraction in preclinical models treated with doxorubicin through NLRP3, MyD88, and pro-fibrotic chemokines

Abstract Aims Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril–valsartan (LCZ 696) is a combination drug, made up neprilysin inhibitor sacubitril angiotensin II receptor blocker valsartan, used for treatment heart failure patients with reduced ejection fraction. We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function inflammation preclinical models. Methods Human Foetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration doxorubicin (200 nM) alone or LCZ-696 (100 mM) 72 h. After incubation period, we performed following tests: viability, apoptosis necrosis; expression malondialdehyde 4-hydroxynonenal intracellular Ca2+. Moreover, pro-inflammatory studied also (activation NLRP3 inflammasome; TLR4/MyD88; mTORC1 Fox01/3a; NF-?B). C57Bl/6 mice untreated (Sham, n = 6) treated 10 days i.p. at 2.17 mg/kg (DOXO, 6), 60 (LCZ, combined (DOXO-LCZ, 6). Ejection fraction, radial longitudinal strain analysed through transthoracic echocardiography (Vevo 2100). Cardiac tissue inflammasome, Myd88, NF-kB, 13 chemokines (IL-1?, IL-1?, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-?, IL-18, IFN-?, TNF-?, G-CSF, GM-CSF) quantified. Results exerts cardioprotective effects, enhancing viability 48–54.6% compared only doxorubicin-treated cells (P < 0.001 all); 696 decreased NLRP3, MyD88 NF-kB cells. In study, improved significantly EF prevented reduction after doxorubicin. A tissues was seen DOXO-LCZ group DOXO 0.001). G-CSF GM-CSF indicating anti-inflammatory properties. Conclusions direct beneficial effects models, cytokine involved doxorubicin-mediated cardiotoxicity.