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

Purpose. Post-acute 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. Methods. Adults with PASC (n=35; symptoms >3 months, no significant comorbidity) and age- and sex-matched recovered controls (n=12) underwent cardiopulmonary exercising testing (CPET), echocardiogram, resting and exercise cardiac MRI and peroneal microneurography recordings of MSNA in supine and during graded head up tilt to 60º. Results. PASC participants had lower peak VO 2 indexed to lean mass (43.0±7.8 vs 52.2± 8.2ml/lean body mass kg/min, p=0.009) and whole-body mass (26.1± 7.5 v 34.9± 10.2ml/kg/min, p=0.006), lower heart rate reserve (84 ± 25 vs 98 ± 13 beats/min, p=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 P <0.0001; group x time P =0.78). Despite this, 12 of 29 PASC participants (41%) terminated the tilt protocol due to orthostatic symptoms or pre-syncope (Kaplan-Meier P =0.0178). Eight participants (27%) met POTS criteria and had lower MSNA than non-POTS participants ( P =0.045). Conclusion. 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.