Singh I; Leitner BP; Wang Y; Zhang H; Joseph P; Lutchmansingh DD; Gulati M; Possick JD; Damsky W; Heerdt PM;
Chun HJ;

Pulmonary circulation [Pulm Circ] 2023 Apr 01; Vol. 13 (2), pp. e12220.
Date of Electronic Publication: 2023 Apr 01 (Print Publication: 2023).

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.