Effects of Exercise on Aortic Stiffness Associated with 5‐Flurouracil in Rats
Authors: Baumfalk Dryden , Hammond Stephen , Horn Andrew , Kunkel Olivia , Parr Shannon , Schadler Keri , Ade Carl , Behnke Bradley 
Published: May 2022

Background5‐fluorouracil (5‐FU) is a chemotherapy drug that is often prescribed in treatment regimens for malignancies of the gastrointestinal tract, breast, and head/neck. However, despite its clear efficacy in cancer treatment, it is also the second most common chemotherapeutic implicated in the development of short and/or long‐term cardiotoxicity that can lead to a less efficacious cancer treatment regimen. Specifically, 5‐FU is associated with increases in arterial stiffness, leading to increased risks for developing heart failure and cardiovascular disease. Exercise, both acutely and following long‐term training, has exhibited cardiovascular health benefits and protection in healthy and disease populations, including reductions in e.g., pulse wave velocity (PWV), a clinical measure of arterial stiffness. Therefore, the purpose of this study was to investigate 5‐FU induced arterial stiffness (via PWV) and evaluate the efficacy of multiple acute bouts of exercise to mitigate arterial stiffness associated with 5‐FU. Further, we utilized reverse phase protein analysis (RPPA) to investigate mechanisms associated with 5‐FU induced arterial stiffness.MethodsMale Sprague Dawley rats aged 6‐8 months (n=26) were used in this series of experiments. All animals were first acclimated to treadmill exercise, and randomized into four groups: Control (CON, n=8), 5‐FU only (5‐FU=7), exercise (EX, n=4), and 5‐FU with exercise (5‐FUEX, n=7). All animals were surgically instrumented with catheters in the external jugular vein and tail artery. Animals received a clinically relevant dose of 5‐FU with the combination of a bolus (50mg/kg), followed immediately by a 2h continuous infusion of 5‐FU (265mg/kg) through the jugular catheter. This was done to better imitate clinical drug delivery rather than i.p injections typically used in pre‐clinical models. Baseline and 2h measurements of PWV were made from the descending to lower abdominal aorta. Both exercise groups underwent four, 20–30‐minute acute bouts of moderate intensity exercise (20m/min, 5% incline) on consecutive days, 24h apart, with the last being ~10 minutes before surgical instrumentation. RPPA analysis was performed on abdominal aorta from each animal for analysis of changes in protein expression.ResultsThere were no differences in PWV between groups at either time point (p>0.05). However, a significant increase in PWV from baseline to the 2h time point was evident in the 5‐FU group alone (CON ‐1.1±4.9, 5‐FU 14.8±4.4, EX 4.6±5.7, 5‐FUEX 5.4.9±2.2%, p<0.05). Preliminary RPPA analysis indicated 1.5log2fold changes in 5‐FU animals in multiple factors, several of which have been associated with increased vascular stiffness including Steroid Receptor Co‐activator (SRC‐1) and mitogen‐activated protein kinase (MAPK1/MAPK3) that will require further investigation.ConclusionThis study suggests that 5‐FU induces aortic stiffness in rats that can be attenuated with prior acute bouts of exercise. These findings provide further efficacy of exercise therapy in cancer standards of care besides its established benefits for reducing fatigue and improving quality of life in cancer patients. Lastly, the potential to mitigate cardiovascular complications of 5‐FU therapy is clinically important as it can possibly prevent early cessation or reductions of this efficacious therapy.