Howden EJ; Baker Heart and Diabetes Institute, Australia
Sesa-Ashton G; Foulkes SJ; Wallace I; et al

American Journal of Physiology – Heart & Circulatory Physiology.
331(6):H2028-H2038, 2026 Dec 01

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 (n = 35; symptoms
>3 mo, no significant comorbidity) and age- and sex-matched recovered
controls (n = 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 60degree. 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, P = 0.009) and whole body mass (26.1 +/-
7.5 vs. 34.9 +/- 10.2 mL/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 these findings, 12
of 29 participants with PASC (41%) terminated the tilt protocol due to
orthostatic symptoms or presyncope (Kaplan-Meier P = 0.0178). Eight
participants (27%) met postural orthostatic tachycardia syndrome (POTS)
criteria and had lower MSNA than non-POTS participants (P = 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. NEW & NOTEWORTHY
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.