Sympathetic Neural Overdrive, Vascular Dysfunction and Diminished Exercise Capacity in Long COVID-19 Patients: A Long-Term Study of Cardiovascular Sequelae.

Background: We have recently showed that severe COVID patients have neurovascular dysfunction, cardiac morpho-functional alterations, and attenuated exercise capacity. However, whether these alterations persist over time is unknown. Here, we tested the hypothesis that Long COVID patients, even 2 years after SARS-COV-2 infection, exhibit sympathetic overdrive, aortic stiffening, endothelium-dependent dysfunction, cardiac morpho-functional changes, and diminished exercise capacity. Methods: Eighteen Long COVID patients and 19 well-matched controls were studied. Muscle sympathetic nerve activity (MSNA; microneurography), brachial artery flow-mediated dilation (BAFMD; ultrasound-Doppler), carotid-femoral pulse wave velocity (CFPWV; tonometry), heart rate (HR; EKG), E/A ratio, left ventricular ejection fraction and global longitudinal strain (LVEF, LVGLS; echocardiography), and peak oxygen uptake (Peak V̇O₂, cardiopulmonary exercise testing) were assessed ⁓2 years after hospital discharge. Circulating angiotensin II (Ang II, mass spectrometry), endothelial cell-derived extracellular vesicles (endothelial cell-derived EVs, flow cytometry), and oxidative stress were also evaluated. Results: Long COVID patients had higher MSNA, CFPWV, HR and lower E/A ratio, LVEF, LVGLS and Peak V̇O₂ than controls. Endothelial cell-derived EVs and carbonyls were higher in Long COVID patients than controls, whereas superoxide dismutase (SOD) was lower. No difference was observed in Ang II. Peak V̇O₂ was inversely associated with MSNA, LVGLS and carbonyls, and directly associated with BAFMD and SOD. Conclusions: Our findings reveal that Long COVID patients, 2 years after acute illness, exhibit persistent sympathetic overactivation, vascular and cardiac impairments, reduced exercise capacity, and increased endothelial cell-derived EVs and oxidative stress. As such, strategies that can resolve these persistent cardiovascular sequelae are urgently needed.