Sympathetic Neural Overactivation, Vascular Dysfunction, and Exercise Intolerance in Long-Term Survivors of Breast Cancer Treated With Doxorubicin and Trastuzumab-Based Chemotherapy

Background: Long-term survivors of breast cancer (BC) treated with doxorubicin and trastuzumab-based chemotherapy are at increased risk of developing cardiovascular disease. However, the physiological mechanisms associated with increased cardiovascular disease risk are completely unknown. We hypothesized that long-term survivors of BC, compared with controls, exhibit sympathetic neural hyperactivity, vascular dysfunction, cardiac morphofunctional changes, exercise intolerance, and alterations in the circulating milieu. Methods: Twenty-three survivors of BC (age: 48.9±1.3 years; body mass index: 25.2±0.8 kg/m2) and 18 (age: 46.4±1.3 years; body mass index: 26.8±0.8 kg/m2) well-matched controls were studied. Muscle sympathetic nerve activity (microneurography), brachial artery flow-mediated dilation (ultrasound-Doppler), carotid-femoral pulse wave velocity (tonometry), left ventricular ejection fraction and global longitudinal strain (echocardiography), peak oxygen uptake (cardiopulmonary exercise testing), endothelial cell-derived extracellular vesicles (flow cytometry), and plasma metabolome (mass spectrometry) were assessed. Complementary experiments were conducted on human umbilical vein endothelial cells cultured with plasma samples from subjects. Results: Survivors of breast cancer were tested ⁓8 years after cancer treatment completion. Muscle sympathetic nerve activity was higher and brachial artery flow-mediated dilation and peak oxygen uptake were lower in survivors than controls. Survivors of breast cancer exhibited higher circulating endothelial cell-derived extracellular vesicles, higher reactive oxygen species bioactivity, and lower acetylcholine-evoked nitrics oxide production in plasma-treated human umbilical vein endothelial cells. Twenty-eight plasma metabolites differed in survivors versus controls. Peak oxygen uptake was inversely related to muscle sympathetic nerve activity or positively to brachial artery flow-mediated dilation. No differences in carotid-femoral pulse wave velocity, left ventricular ejection fraction, and left ventricular global longitudinal strain were observed. Conclusions: Our findings demonstrate that long-term survivors of breast cancer exhibit sympathetic overdrive, vascular dysfunction, and exercise intolerance, which may contribute to increased cardiovascular disease risk in this population.