Background: Doxorubicin, a chemotherapeutic agent, that has great efficacy in treatment of many solid tumors, bone sarcomas, and cancers of the breast, ovary, and other tumors. Unfortunately, the clinical use of this valuable anticancer drug is limited due to its life-threatening cardiotoxic effect¹. Vitamin D is recently known for its cardioprotective effects². The aim of this study: To investigate role of vitamin D on the doxorubicin-induced cardiac dysfunction. Materials and Methods: 70 female Albino-rats were divided into 4 groups: control group (C: n=21); doxorubicin-treated group (Dox: n=18): given i.p. injection of 2.5 mg/kg twice per week (cumulative dose:15 mg/kg) over 3 weeks; vitamin D-supplemented group (Vit D: n= 16): given vitamin D by oral gavage in a dose of 500 IU/kg daily, 5 days a week, also for 3 weeks; and combined Doxorubicin-treated+vitamin D-supplemented group (Dox+Vit D: n=15): rats received the same used doses for the same duration. After 3 weeks, all rats were subjected to EGG recording, determination of plasma levels of brain natriuretic peptide (BNP), cardiac troponin I (cTnI), vitamin D concentration (vit D) and total calcium level (Ca). Hearts were excised and perfused in Langendorff preparation to record intrinsic in vitro activity of the heart under basal conditions according to the technique of Langendorff. Malondialdehyde (MDA), total antioxidant capacity (TAC) and heat shock protein 20 (HSP 20) were assessed in the cardiac tissue. Also, cardiac tissue histopathological studies were performed.

Results: Dox-treated rats showed significant depression in peak tension (PT) and myocardial flow rate (MFR) together with significant prolongation in time to peak tension (TPT), half relaxation time (HRT) and contraction time (CT). These changes were accompanied by significant elevation of plasma brain naturetic peptide (BNP), cardiac troponin I (cTnI) and in cardiac tissue malondialdehyde (MDA) and a significant decrease in plasma vit D, total calcium, and cardiac tissue total antioxidant capacity (TAC) and heat shock protein20. Histopathological examination of the Dox treated rats revealed markedly distorted muscle fibers with indistinct cell borders, bright eosinophilic cytoplasm, intra-cytoplasmic vacuoles and small pyknotic nuclei or absent nuclei, together with interstitial edema & aggregates of inflammatory cells and thick irregular collagen fibers in between the muscle fibers. This functional, biochemical, and histopathological data reflects development of doxorubicin-induced cardiomyopathy.

Concomitant supplementation of vitamin D to doxorubicin treated rats resulted in significant increases in PT, MFR, plasma vitamin D, total calcium as well as cardiac TAC and HSP20; while the MDA, plasma BNP and cTnI were significantly decreased, all compared to the Dox-treated rats. These findings were associated with regaining the normal collagen fiber distribution between cardiac muscle fibers with resolution of interstitial edema.

Conclusion: Vitamin D supplementation can partially mitigate cardiac dysfunction induced by chronic doxorubicin by improving the cardiac antioxidant state and heat shock protein 20 level.