Sympathetic neural overdrive, vascular dysfunction, and diminished exercise capacity in patients with long COVID-19: a long-term study of cardiovascular sequelae

Abstract

We have recently showed that patients with severe coronavirus disease (COVID) have neurovascular dysfunction, cardiac morphofunctional alterations, and attenuated exercise capacity. However, whether these alterations persist over time is unknown. Here, we tested the hypothesis that patients with long COVID, even 2 yr after severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, exhibit sympathetic overdrive, aortic stiffening, endothelium-dependent dysfunction, cardiac morphofunctional changes, and diminished exercise capacity. Eighteen patients with long COVID 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; electrocardiogram), E-wave/A-wave ratio (E/A ratio), left ventricular ejection fraction and global longitudinal strain (LVEF and LVGLS, respectively; echocardiography), and peak oxygen uptake (peak V̇ O2, cardiopulmonary exercise testing) were assessed ̴2 yr 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. Patients with long COVID had higher MSNA, CFPWV, and HR and lower E/A ratio, LVEF, LVGLS, and peak V̇ O2 than controls. Endothelial cell-derived EVs and carbonyls were higher in patients with long COVID than controls, whereas superoxide dismutase (SOD) was lower. No difference was observed in Ang II. Peak V̇ O2 was inversely associated with MSNA, LVGLS, and carbonyls and directly associated with BAFMD and SOD. Our findings reveal that patients with long COVID, 2 yr 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.