Inclisiran preserves myocardial function and reduces inflammation in anthracycline trastuzumab cardiotoxicity: evidence from speckle tracking echocardiography in non-dyslipidemic models

Abstract Introduction Anthracycline and trastuzumab sequential therapy is a cornerstone in HER2-positive breast cancer treatment but is burdened by a high risk of cardiotoxicity. Inflammation is increasingly recognized as a central mediator of myocardial injury in this setting. While PCSK9 inhibitors are primarily used for lipid-lowering, emerging data suggest they may also modulate innate immune pathways. This study investigates the cardioprotective effects of inclisira, a siRNA-based PCSK9 inhibitor, in a non-dyslipidemic murine model of chemotherapy-induced cardiac dysfunction. Purpose To assess whether inclisiran confers cardioprotection against short-term doxorubicin–trastuzumab-induced cardiotoxicity through anti-inflammatory mechanisms independent of lipid-lowering, using advanced imaging and molecular profiling. Methods Female C57Bl/6 mice were randomized into control, DOXO+TRAST, inclisiran alone, and DOXO+TRAST+inclisiran groups (n = 6/group). Mice received doxorubicin (2.17 mg/kg/day, i.p., 5 days) followed by trastuzumab (2.25 mg/kg/day, i.p., 5 days), with or without inclisiran (5 mg/kg, s.c., day 1 and 6). Echocardiographic evaluation (Vevo 2100) at day 10 included EF, FS, and speckle-tracking-derived radial and longitudinal strain. Systemic biomarkers included cholesterol panel, hs-CRP, NT-proBNP, troponin T, and a comprehensive inflammatory profile: NLRP3, MyD88, IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, leukotriene B4, PGE2. Immunohistochemistry on cardiac and hepatic tissues assessed local expression of NLRP3, MyD88, IL-1β, IL-6, IL-8, and pAMPK. Results DOXO+TRAST induced marked cardiac dysfunction (↓EF, ↓FS, impaired strain; p