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

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<0.01 vs. control), elevated systemic pro-inflammatory mediators, and increased cardiac/liver expression of NLRP3, IL-6, and MyD88. Inclisiran significantly preserved cardiac function (EF, FS, radial and longitudinal strain all p<0.05 vs. DOXO+TRAST), and reduced circulating and tissue levels of inflammatory cytokines. Importantly, inclisiran activated tissue pAMPK and blunted the expression of inflammasome components in both heart and liver. Lipid levels remained unchanged, confirming non–lipid-mediated effects. Conclusion Inclisiran exerts potent cardioprotective and anti-inflammatory effects in a murine model of chemotherapy-induced cardiotoxicity, independent of lipid modulation. These findings support a novel role for PCSK9 inhibition in cardio-oncology, potentially extending therapeutic utility beyond dyslipidemia.