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 (EO₂) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO₂ remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO₂peak‐mild) and severely reduced (EO₂peak‐severe) EO₂ groups according to the median peak EO₂ 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 VO₂; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO₂ (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO₂ (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO₂peak‐mild exhibited greater DO₂ compared to those with EO₂peak‐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 EO₂peak‐severe group were involved in inflammatory and fibrotic processes. In the EO₂peak‐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 EO₂peak‐severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO₂peak‐mild group, there is enhanced expression of proteins involved in oxidative phosphorylation‐mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.