Cardioprotective effects of exercise training on doxorubicin-induced cardiomyopathy: a systematic review with meta-analysis of preclinical studies

Abstract

Doxorubicin (DOX)-induced cardiotoxicity in chemotherapy is a major treatment drawback. Clinical trials on the cardioprotective effects of exercise in cancer patients have not yet been published. Thus, we conducted a systematic review and meta-analysis of preclinical studies for to assess the efficacy of exercise training on DOX-induced cardiomyopathy. We included studies with animal models of DOX-induced cardiomyopathy and exercise training from PubMed, Web of Sciences and Scopus databases. The outcome was the mean difference (MD) in fractional shortening (FS, %) assessed by echocardiography between sedentary and trained DOX-treated animals. Trained DOX-treated animals improved 7.40% (95% CI 5.75-9.05, p < 0.001) in FS vs. sedentary animals. Subgroup analyses revealed a superior effect of exercise training execution prior to DOX exposure (MD = 8.20, 95% CI 6.27-10.13, p = 0.010). The assessment of cardiac function up to 10 days after DOX exposure and completion of exercise protocol was also associated with superior effect size in FS (MD = 7.89, 95% CI 6.11-9.67, p = 0.020) vs. an echocardiography after over 4 weeks. Modality and duration of exercise, gender and cumulative DOX dose did were not individually associated with changes on FS. Exercise training is a cardioprotective approach in rodent models of DOX-induced cardiomyopathy. Exercise prior to DOX exposure exerts greater effect sizes on FS preservation.

Figure 1

Flow chart of the study selection procedure.

Figure 2

Study quality graph based on Cochrane Collaboration criteria.

Figure 3

Overall effects of exercise training in fractional shortening of cardiac function of experimental models of doxorubicin-induced cardiomyopathy. Hydock et al., 2008 treadmill group (a) at day 5 and (b) at day 10, (c) wheel running group at day 5 and (d) at day 10; Hydock et al., 2011 (a) treadmill group, (b) wheel running group; Hydock et al., 2012 (a) 15 mg/kg and (b) 20 mg/kg cumulative dose of DOX; Jensen et al., 2013 treadmill group (a) at day 1, (b) at day 3, (c) at day 5, (d) at day 7 and (e) at day 9, wheel running group (f) at day 1, (g) at day 3, (h) at day 5, (i) at day 7 and (j) at day 9; Lien et al., 2015 treadmill group receiving (a) 10 mg/kg and (b) 15 mg/kg cumulative dose of DOX, wheel running group receiving (c) 10 mg/kg and (d) 15 mg/kg cumulative dose of DOX; Parry et al., 2015 wheel running group (a) at day 1, (b) at day 3 and (c) at day 5; Wang et al., 2018 mice (a) C57BL/6 and (b) Athymic Swiss Nude.

Figure 4

Effects of the timing of exercise protocol in relation to doxorubicin exposure (before vs. concomitantly and/or after) on fractional shortening of animals with doxorubicin-induced cardiomyopathy.

Figure 5

Sensitivity analysis of changes in fractional shortening (FS) based on clinical predictors of exercise training success. Unpaired Student’s T test, p < 0.05.