João Eduardo Izaías, Artur O. Sales, Artur O. Sales, Bruna E. Ono, Thais S. Rodrigues, Gabrielly M. P. S. Silva, Priscilla S. Pentagna, Andre L. P. Albuquerque, Flávia Neri Folchini, Fernanda M. C. Colombo, Maria C. C. Irigoyen, Amanda G. Rodrigues, Carlos Eduardo Negrão, L. Testa, Natália G. Rocha, Helena N. M. Rocha, Gabriel F. Texeira, A C Nóbrega, Natália A. S. Miyaguti, Alex A. R. Silva, Andréia M. Porcari, Antonio Viana Nascimento-Filho, Kátia De Angelis, Daniel H. Craighead, Zachary S. Clayton, Katelyn R. Ludwig, Matthew J. Rossman, Douglas R. Seals, Renata Moll‐Bernardes, Allan R. K. Sales, Allan R. K. Sales
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: ) 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.