Exercise Preconditioning Preserves Cardiac Function and Enhances Cardiac Recovery Following Dobutamine Stimulation in Doxorubicin‐Treated Rat Hearts

Abstract

Doxorubicin (DOX) is a chemotherapeutic drug used to treat a wide range of cancers, and its use is limited by cardiotoxicity. Exercise preconditioning has been shown to protect against DOX‐induced cardiac dysfunction when hearts are maintained under resting conditions. However, it is unclear whether this exercise‐induced protective effect is maintained when the heart is challenged during an acute exercise bout. It was hypothesized that preconditioning protects the heart against DOX cardiotoxicity when it is challenged with the β1‐adrenergic receptor agonist dobutamine (DOB), which mimics acute exercise stress.Fischer 344 rats were randomly assigned to sedentary (SED) or voluntary wheel running (WR) groups for 10 weeks. At week 11, rats were treated with either 15 mg/kg DOX or saline (SAL). Five days later, ex vivo cardiac function was assessed using an isolating working heart model at baseline, during the infusion of 7.5 μg/kg/min DOB, and during recovery.DOB infusion significantly increased left ventricular developed pressure (LVDP), maximal (dP/dtmax) and minimal (dP/dtmin) rate of left ventricular pressure development, and heart rate in all groups (p<0.05). During the recovery phase (i.e., after DOB washout) LVDP was significantly lower than baseline in all groups except for SED+DOX (baseline vs. recovery: SED+SAL: 97±2 vs. 84±5 mmHg; WR+SAL: 116±7 vs. 90±7 mmHg; SED+DOX: 83±5 vs. 76±4 mmHg; WR+DOX: 109+2 vs. 100±4 mmHg, p<0.05). SED+DOX also showed a lower baseline and recovery LVDP than WR+DOX (83±5 vs. 109±2 mmHg baseline, 76±4 vs. 100±4 mmHg recovery, p<0.05). WR+DOX showed higher dP/dtmax and lower dP/dtmin when compared to SED+DOX during DOB infusion (7311±605 vs. 5167±508 mmHg/s and ‐4059±454 vs. ‐3158±416 mmHg/s, respectively). SED+DOX dP/dtmax was significantly lower during DOB infusion and during recovery when compared to all other groups (p<0.05). During DOB and recovery, +DOX groups showed lower HR values than +SAL groups (p<0.05).These data demonstrate that exercise preconditioning preserved cardiac function after DOX exposure even when the heart is challenged, and it appeared to preserve the heart’s ability to recovery from this functional challenge. Cardioprotection seems to extend beyond rest into conditions which challenge cardiac function. These observations support the premise that exercise training can protect against cardiac dysfunction that may occur during acute exercise in cancer patients undergoing DOX treatment.