Orthostatic and exercise intolerance in postacute sequelae of COVID-19 occur with intact sympathetic neural control and preserved cardiac reserve

Postacute sequelae of COVID-19 syndrome (PASC) is widely attributed to dysautonomia, although sympathetic outflow has rarely been measured directly. We tested whether exercise and orthostatic intolerance in PASC reflect impaired cardiac reserve or abnormal muscle sympathetic nerve activity (MSNA) and its reflex control. Adults with PASC ( = 35; symptoms >3 mo, no significant comorbidity) and age- and sex-matched recovered controls ( = 12) underwent cardiopulmonary exercise testing (CPET), echocardiogram, resting and exercise cardiac MRI, and peroneal microneurography recordings of MSNA in supine position and during graded head-up tilt to 60°. Participants with PASC had lower peak oxygen uptake ([Formula: see text]) indexed to lean mass (43.0 ± 7.8 vs. 52.2 ± 8.2 mL/lean body mass kg/min, = 0.009) and whole body mass (26.1 ± 7.5 vs. 34.9 ± 10.2 mL/kg/min, = 0.006), lower heart rate reserve (84 ± 25 vs. 98 ± 13 beats/min, = 0.019), and impaired ventilatory efficiency. Cardiac structure and biventricular contractile reserve were normal. Supine MSNA burst frequency, burst incidence, sympathetic baroreflex gain, and neurovascular transduction did not differ between groups, and MSNA and mean arterial pressure increased similarly during tilt (time < 0.0001; group × time = 0.78). Despite these findings, 12 of 29 participants with PASC (41%) terminated the tilt protocol due to orthostatic symptoms or presyncope (Kaplan-Meier = 0.0178). Eight participants (27%) met postural orthostatic tachycardia syndrome (POTS) criteria and had lower MSNA than non-POTS participants ( = 0.045). Orthostatic intolerance occurred despite normal recruitment of MSNA and maintained arterial pressure and exercise intolerance despite preserved contractile reserve. Symptoms are therefore unlikely to originate in the efferent sympathetic limb or myocardium and more likely reflect afferent reflex dysregulation or impaired cerebral perfusion. Muscle sympathetic nerve activity (MSNA), sympathetic baroreflex gain, and neurovascular transduction were intact in people with postacute sequelae of COVID-19 syndrome (PASC), and MSNA was recruited normally during head-up tilt. However, 41% of participants could not complete the tilt. Biventricular contractile reserve was likewise preserved. Symptoms that track neither sympathetic outflow nor systemic pressure localize the disturbance upstream, to afferent reflex control, or downstream to the cerebral circulation.