(P30-028-24) The Effect of Linoleic Acid on Heart Structure and Function in Mice Administered Anthracycline Chemotherapy

Objectives: Anthracycline chemotherapy (AC) has toxic effects in non-tumor, mitochondrial rich tissues including cardiac muscle by inhibiting topoisomerase IIb and impairing the cell cycle. In addition, AC binds to cardiolipin (CL), the signature phospholipid of the inner mitochondrial membrane. Linoleic acid (LA), the preferred fatty acyl side chain in CL, maximizes ATP synthesis. In heart failure, oleic acid (OA) replaces LA on CL. Therefore, we will test our hypotheses that increasing LA in the diet in mice undergoing chemotherapy will preserve cardiac structure and function through CL remodeling.

Methods: Ovariectomized, female (n=36, C57Bl/6J) mice will be inoculated with mammary E0771 cells. After 3 weeks of growth, tumors will be resected and mice will be divided into four groups: DBS + lard (LD) diet, DBS + high-linoleic safflower oil (SO) diet, chemo + LD, chemo + SO. Chemotherapy regimen will include 2 tail vein injections of 9 mg/kg anthracycline, 90 mg/kg cyclophosphamide 2 weeks apart. Before necropsy, echocardiograms (ECGs) will be performed on mice to measure left ventricular function. At necropsy, hearts will be evaluated for differences in histology, myosin heavy chain (MHC) isoform separation using SDS-PAGE, and mitochondrial lipidome and oxidative phosphorylation.

Results: We anticipate that AC will reduce fractional shortening and LA will attenuate this. Cardiac tissue of mice on the LA-rich diet will have a higher proportion of LA-rich tetralinoleoyl cardiolipin and higher oxidative phosphorylation. Histological analysis will reveal fibrosis and ultrastructural alterations caused by AC and will be reduced in the LA group. AC will cause an isoform shift, decreasing MHCα and increasing MHCβ, which will be attenuated by the LA-rich diet.

Conclusions: LA-rich diet (vs. control diet) will attenuate damage to cardiac muscle caused by AC treatment.

Funding Sources: Ohio Agricultural Research and Development Center