Abstract 5011: Exercise prevents late Doxorubicin-induced vascular damage, decreases late-onset heart failure and fibrosis, and improved recovery from MI
Authors: Wang Fei , Kleinerman Eugenie S. 
Published: September 2020

Background Doxorubicin (Dox) is one of the most effective chemotherapy agents used to treat children and adolescent with cancer. However the use of Dox is associated with cardiac toxicities classified as acute (fibrosis and fractional shortening), early-onset (chronic dilated cardiomyopathy), and late-onset (left ventricular dysfunction and congestive heart failure). Cardiovascular disease leading to heart failure is one of the most common late effects that compromise QOL and the long-term survival of Pediatric cancer patients. We investigated whether exercise during and after Dox will prevent late-onset heart failure and allow better recovery following myocardial infarction (MI).

Methods Exercise during and after Dox and myocardial infarction (MI): 4 week old nude mice were divided into 4 groups (10 mice/group): Control (saline, no exercise); Dox alone (2.5mg/kg, 2x/week for 2 weeks); exercise (EX) alone (treadmill walking for 45 minutes @ 12m/min x5 days/week); Dox+ EX during and for 12wks after therapy. Echocardiography was performed before and at the end of the study. To investigate if exercise allows better recovery following an ischemic event, mice were subjected to MI by permanent ligation of the left anterior descending artery (LAD). Heart function post MI was monitored by echocardiography and survival rate was quantified at 6 weeks. Heart vessel morphology, vascular architecture, and deposition of fibrosis were evaluated by histology.

Results EX during and after Dox therapy prevented Dox-induced vascular damage (closed lumens, decreased pericytes), the deterioration of cardiac function (reduction of Ejection Fraction and Fractional Shortening) 12 weeks after therapy, prevented Dox-induced deposition of collagen in the left ventricular wall resulting in myocardial fibrosis, and prevented thinning of left ventricular wall post MI. Dox treated mice had an increased susceptible to MI. The survival rate of Dox treated mice was 22.2% compared to 66.7% for the Dox+Exer mice. Exercise initiated during and after therapy decreased Dox-induced late cardiac damage and improved survival rate following cardiac ischemia.

Conclusion EX has the potential to decrease Dox-induced late cardiotoxicity resulting in an increased ability to recover from an ischemic event. EX reduced the sensitivity to this physiologic event. This would be a beneficial strategy for bone sarcoma patients who have an increased incidence of late cardiotoxicity. Our data indicate that EX interventions may decrease the risk of developing cardiac disease at an early age in childhood cancer survivors.

Citation Format: Fei Wang, Eugenie S. Kleinerman. Exercise prevents late Doxorubicin-induced vascular damage, decreases late-onset heart failure and fibrosis, and improved recovery from MI [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5011.