Journal of the American Osteopathic Association
Statement of Significance: Cardiovascular disease is the leading cause of morbidity and mortality in long-term cancer survivors. Chemotherapy with doxorubicin and other anthracyclines is the most common cause of cardiac toxicity in treated cancer patients. These agents are used to manage both hematologic and solid-tumor malignancies. Cardiac manifestations often develop months to years after initial exposure, causing cardiomyopathy and heart failure. Osteopathic medicine approaches disease in a holistic manner attempting to prevent major complications earlier in the disease course. Preventing or reducing chemotherapy-induced cardiotoxicity would greatly improve the outlook for these patients and their overall wellbeing.
Methods: Smad3+/+ wild type (WT), Smad3+/-, and Smad3-/- mice were treated with 4 weekly doses of doxorubicin, 5 mg/kg each, for a total dose of 20 mg/kg. Control groups of mice were treated with saline. The mice were killed 1 to 9 weeks after the completion of therapy and their hearts harvested in order to perform histological, immunohistochemical, and functional analyses. This allowed us to compare the effects of doxorubicin in mice with and without the SMAD3 gene.
Data Analysis: We used transthoracic echocardiography to measure cardiac function in Wild Type and Smad3 deficient mice. We then conducted a cardiac vessel analysis using immunohistochemistry. Parameters measured were vascular area, capillary and arteriolar density, and cardiac fibrosis. We also measured the weights of hearts to look for changes between wild type and Smad3 deficient mice.
Results: Using transthoracic echocardiography, we detected depressed cardiac function in doxorubicin treated WT mice but not in Smad3-deficient mice. Specifically, ejection fraction and radial strain were increased in doxorubicin treated Smad3 deficient mice compared with WT mice while the cardiac function was decreased in WT mice but unchanged in Smad3 deficient mice. Cardiac vessel analysis indicated a trend of increasing vascular area in doxorubicin-treated mice vs saline-treated mice. There were no differences in capillary and arteriolar density, heart weight, and cardiac fibrosis area between saline- and doxorubicin-treated hearts.
Conclusion: Doxorubicin-induced contractile and vascular defects were attenuated in Smad3-deficient mice, highlighting the importance of the TGFβ pathway in the development of cardiomyopathy. The inhibition of TGFβ/Smad3 pathway is a feasible approach to alleviate doxorubicin-induced cardiotoxicity in treated cancer patients. Preventing chemotherapy-induced cardiotoxicity would vastly improve the outlook for patients treated with anthracyclines. This research fits into the osteopathic approach to patient care by focusing on a disease pathway at a point before symptoms arise when it is too late for prevention.
Campbell K, Dorfman E, Yang J, Cobb MS, Girgis M, Hauptman J, Tao S, Vincent R, Buddhadeb D, Konorev EA. Cardiac Damage by Doxorubicin Is Mitigated in Smad3 Deficient Mice. Journal of the American Osteopathic Association. 2019; 119(12). doi: 10.7556/jaoa.2019.128.