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- All Subjects: Chemotherapy
- All Subjects: obesity paradox
- Creators: Angadi, Siddhartha
Description
The anthracycline drug Doxorubicin (DOX) is a highly effective treatment for breast cancer, but its clinical utility is limited by dose-dependent cardiovascular toxicity. The toxic effects are partly attributed to DOX-induced generation of reactive oxygen species, which may impair nitric oxide-mediated vasodilation. Exercise training activates antioxidant defense mechanisms and is thus hypothesized to counteract oxidative stress when initiated prior to DOX administration. Adult 8-week old, ovariectomized female Sprague-Dawley rats were divided into 4 groups: sedentary + vehicle (Sed+Veh); Sed+DOX; exercise + veh (Ex+Veh); and Ex+DOX. Rats in the exercise groups were preconditioned with high intensity interval training consisting of 4x4 minute bouts of exercise at 85-95% of VO2peak separated by 2 minutes of active recovery performed 5 days per week. Exercise was implemented one week prior to the first injection and continued throughout the study. Animals received either DOX (4mg/kg) or veh (saline) intraperitoneal injections bi-weekly for a cumulative dose of 12 mg/kg per animal. Five days following the final injection, animals were anesthetized with isoflurane, decapitated and aortas and perivascular adipose tissue (PVAT) were removed for western blot analyses. No significant differences in aortic protein expression were detected for inducible nitric oxide synthase (iNOS) or the upstream activator of endothelial nitric oxide synthase (eNOS), Akt, across groups (p>0.05), whereas eNOS protein expression was significantly downregulated in Sed+DOX (p=0.003). In contrast, eNOS expression was not altered in Ex+DOX treated animals. Protein expression of iNOS in PVAT was upregulated with exercise in the DOX-treated groups (p=0.039). These findings suggest that exercise preconditioning may help mitigate vascular effects of DOX by preventing downregulation of eNOS in the aorta.
ContributorsO'Neill, Liam Martin (Author) / Sweazea, Karen (Thesis director) / Angadi, Siddhartha (Committee member) / Dickinson, Jared (Committee member) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
PURPOSE: Lean hypertension (HTN) is characterized by a mechanistically different HTN when compared to obese HTN. The purpose of this study is to assess whether body phenotype influences blood pressure (BP) responses following both acute and chronic exercise. METHODS: Obese (body mass index (BMI) > 30 kg/m2) and lean (BMI < 25 kg/m2) men with pre-hypertension (PHTN) (systolic BP (SBP) 120 - 139 or diastolic BP (DBP) 80 - 89 mm Hg) were asked to participate in a two-phase trial. Phase 1 assessed differences in post-exercise hypotension between groups in response to an acute exercise bout. Phase 2 consisted of a two-week aerobic exercise intervention at 65-70% of heart rate (HR) max on a cycle ergometer. Primary outcome measures were: brachial BP, central (aortic) BP, cardiac output (CO), and systemic vascular resistance (SVR) measured acutely after one exercise session and following two weeks of training. RESULTS: There were no differences between groups for baseline resting brachial BP, central BP, age, or VO2 peak (all P > 0.05). At rest, obese PHTN had greater CO compared to lean PHTN (6.3 ± 1 vs 4.7 ± 1 L/min-1, P = 0.005) and decreased SVR compared to lean PHTN (1218 ± 263 vs 1606 ± 444 Dyn.s/cm5, P = 0.003). Average 60-minute post-exercise brachial and central SBP reduced by 3 mm Hg in Lean PHTN in response to acute exercise (P < 0.005), while significantly increasing 4 mm Hg for brachial and 3 mm Hg for central SBP (P < 0.05). SVR had a significantly greater reduction following acute exercise in lean PHTN (-223 Dyn·s/cm5) compared to obese PHTN (-75 Dyn·s/cm5, P < 0.001). In lean subjects chronic training reduced brachial BP by 4 mm Hg and central BP by 3 mm Hg but training had no effect on the BP’s in obese subjects. Resting BP reduction in response to training was accompanied by reductions in SVR within lean (-169 Dyn·s/cm5, P < 0.001), while obese experienced increased SVR following training (47 Dyn·s/cm5, P < 0.001). CONCLUSION: Hemodynamic response to both acute and chronic exercise training differ between obese and lean individuals.
ContributorsZeigler, Zachary (Author) / Swan, Pamela (Thesis advisor) / Gaesser, Glenn (Committee member) / Buman, Matthew (Committee member) / Angadi, Siddhartha (Committee member) / Farouk, Mookadam (Committee member) / Arizona State University (Publisher)
Created2016
Description
Estimates indicate that in the United States 1 in 8 women will develop breast cancer in their lifetime. Improved cancer screenings, early detection, and targeted treatments have increased breast cancer survival rates. However, breast cancer patients treated with chemotherapy are at an increased risk for cardiovascular disease, functional impairments, and loss of cardiorespiratory fitness. These negative outcomes have implications for early morbidity and mortality. The purpose of this thesis was to test the hypothesis that high-intensity exercise preconditioning (exercise commenced prior to initiating chemotherapy and continued throughout treatment cycles) preserves health-related outcomes in breast cancer patients treated with anthracycline-containing chemotherapy. Here, we present a subset of preliminary data from an ongoing trial (NCT02842658) that is focused on VO2peak and skeletal muscle outcomes from the first 10 participants that have enrolled in the trial. Breast cancer patients (N=10; 50 ± 11 y; 168 ± 4 cm; 92 ± 37 kg; 32.3 ± 12.3 kg/m2) scheduled to receive anthracycline-containing chemotherapy were randomly assigned to one of two interventions: 1) exercise preconditioning, (3 days per week of supervised exercise throughout treatment) or 2) standard of care (attention-control). Pre-testing occurred 1-2 week prior to chemotherapy. The interventions were initiated 1 week prior to chemotherapy and continued throughout anthracycline treatment. Post-testing occurred 3-7 days following the last anthracycline treatment. VO2peak (L/min) was reduced by 16% in the control group (P < 0.05), whereas VO2peak was preserved in the exercise preconditioning group. Trends for greater preservation and/or improvement in the exercise preconditioning group were also observed for lean body mass and peak heart rate. Hand grip strength was not changed in either group (P > 0.05). Both groups demonstrated an increase in ultrasound-derived echogenicity measures of the vastus lateralis (P < 0.05), indicating changes in the composition of the skeletal muscle during treatment. These preliminary data highlight that exercise preconditioning may serve as a strategy to preserve cardiorespiratory fitness and perhaps lean mass during anthracycline treatment of breast cancer. There remains a need for larger, definitive clinical trials to identify strategies to prevent the array of chemotherapy-induced toxicities that are observed in breast cancer patients treated with anthracyclines.
ContributorsCasey, Kathleen (Author) / Angadi, Siddhartha (Thesis director) / Gaesser, Glenn (Committee member) / Dickinson, Jared (Committee member) / College of Health Solutions (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05