Differential cardiopulmonary haemodynamic phenotypes in PASC-related exercise intolerance

Background: Post-acute sequelae of COVID-19 (PASC) affect a significant proportion of patients who have previously contracted SARS-CoV-2, with exertional intolerance being a prominent symptom. This study aimed to characterise the invasive haemodynamic abnormalities of PASC-related exertional intolerance using invasive cardiopulmonary exercise testing (iCPET).

Study design and intervention: 55 patients were recruited from the Yale Post-COVID-19 Recovery Program, with most experiencing mild acute illness. Supine right heart catheterisation and iCPET were performed on all participants.

Main results: The majority (75%) of PASC patients exhibited impaired peak systemic oxygen extraction (pEO₂) during iCPET in conjunction with supranormal cardiac output (CO) (i.e., PASC alone group). On average, the PASC alone group exhibited a "normal" peak exercise capacity, V'_O2 (89±18% predicted). ∼25% of patients had evidence of central cardiopulmonary pathology (i.e., 12 with resting and exercise heart failure with preserved ejection fraction (HFpEF) and two with exercise pulmonary hypertension (PH)). PASC patients with HFpEF (i.e., PASC HFpEF group) exhibited similarly impaired pEO₂ with well compensated PH (i.e., peak V'_O2 and CO >80% respectively) despite aberrant central cardiopulmonary exercise haemodynamics. PASC patients with HFpEF also exhibited increased body mass index of 39±7 kg·m^-2. To examine the relative contribution of obesity to exertional impairment in PASC HFpEF, a control group comprising obese non-PASC group (n=61) derived from a historical iCPET cohort was used. The non-PASC obese patients with preserved peak V'_O2 (>80% predicted) exhibited a normal peak pulmonary artery wedge pressure (17±14 versus 25±6 mmHg; p=0.03) with similar maximal voluntary ventilation (90±12 versus 86±10% predicted; p=0.53) compared to PASC HFpEF patients. Impaired pEO₂ was not significantly different between PASC patients who underwent supervised rehabilitation and those who did not (p=0.19).

Conclusions: This study highlights the importance of considering impaired pEO₂ in PASC patients with persistent exertional intolerance unexplained by conventional investigative testing. Results of the current study also highlight the prevalence of a distinct high output HFpEF phenotype in PASC with a primary peripheral limitation to exercise.