Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO 2 ) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO 2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO 2 peak-mild) and severely reduced (EO 2 peak-severe) EO 2 groups according to the median peak EO 2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO 2 ; 85 ± 18 vs. 131 ± 45% predicted; p  = 0.0002) with normal systemic oxygen delivery, DO 2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p  = 0.43) and reduced EO 2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p  < 0.0001). PASC patients with EO 2 peak-mild exhibited greater DO 2 compared to those with EO 2 peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p  = 0.01]. The proteins with increased expression in the EO 2 peak-severe group were involved in inflammatory and fibrotic processes. In the EO 2 peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO 2 peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO 2 peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.