The metabolic and physiologic impairments underlying long COVID associated exercise intolerance

Abstract

Data from invasive CPET (iCPET) revealed long COVID patients have impaired systemic oxygen extraction (EO₂), suggesting impaired mitochondrial ATP production. However, it remains uncertain whether the initial severity of SARS-CoV-2 infection has implications on EO₂ and exercise capacity (VO₂) nor has there been assessment of anerobic ATP generation in long COVID patients. iCPET was performed on 47 long COVID patients (i.e., full cohort; n = 8 with severe SARS-CoV-2 infection). In a subset of patients (i.e., metabolomic cohort; n = 26) metabolomics on venous and arterial blood samples during iCPET was performed. In the full cohort, long COVID patients exhibited reduced peak EO₂ with reduced peak VO₂ (90 ± 17% predicted) relative to cardiac output (118 ± 23% predicted). Peak VO₂ [88% predicted (IQR 81% - 108%) vs. 70% predicted (IQR 64% - 89%); p = 0.02] and EO₂ [0.59(IQR 0.53-0.62) vs. 0.53(IQR 0.50-0.48); p = 0.01) were lower in severe versus mild infection. In the metabolomic cohort, 12 metabolites were significantly consumed, and 41 metabolites were significantly released (p-values < 0.05). Quantitative metabolomics demonstrated significant increases in inosine and succinate arteriovenous gradients during exercise. Peak VO₂ was significantly correlated with peak venous succinate (r = 0.68; p = 0.0008) and peak venous lactate (r = 0.49; p = 0.0004). Peak EO₂ and consequently peak VO₂ impact long COVID patients in a severity dependent manner. Exercise intolerance associated with long COVID is defined by impaired aerobic and anaerobic energy production. Peak venous succinate may serve as a potential biomarker in long COVID.

Keywords: PASC; invasive CPET; long COVID; metabolomic.

Figure 1

Study design overview. Data set included the full cohort (n = 47) that examined the cardio‐pulmonary physiological perturbance observed in long COVID patients and a metabolomic cohort that examined metabolic profile (n = 26) of long COVID patients with unexplained exertional intolerance. VO2 – aerobic exercise capacity; RER – respiratory exchange ratio; HR – heart rate.

Figure 2

Fold change from resting oxygen extraction (EO2) as a function of increasing exercise intensity as measured by metabolic equivalents (METs). METs = VO2/Rest VO2. Mann Whitney U Tests were used for comparisons between groups. Data presented as median and interquartile range.

Figure 3

Global metabolomics reflects contribution of numerous metabolic pathways for peak exercise. Metabolites differentially expressed when measured as arteriovenous peak – arteriovenous rest, with hierarchical clustering by similarity (n = 26). Differential expression analysis was performed between rest and peak exercise for all patients, with benjamani‐hochberg corrections for multiple comparisons. Padj = adjusted p‐value.