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.