The metabolic and physiologic impairments underlying long COVID associated exercise intolerance
Brooks P. Leitner, Phillip Joseph, Andres Figueroa Quast, Marı́a Jesús Ramı́rez-Expósito, Paul M. Heerdt, Jose Gomez Villalobos, Inderjit Singh
Abstract
Abstract Data from invasive CPET (iCPET) revealed long COVID patients have impaired systemic oxygen extraction (EO 2 ), suggesting impaired mitochondrial ATP production. However, it remains uncertain whether the initial severity of SARS‐CoV‐2 infection has implications on EO 2 and exercise capacity (VO 2 ) 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 EO 2 with reduced peak VO 2 (90 ± 17% predicted) relative to cardiac output (118 ± 23% predicted). Peak VO 2 [88% predicted (IQR 81% ‐ 108%) vs. 70% predicted (IQR 64% ‐ 89%); p = 0.02] and EO 2 [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 VO 2 was significantly correlated with peak venous succinate ( r = 0.68; p = 0.0008) and peak venous lactate ( r = 0.49; p = 0.0004). Peak EO 2 and consequently peak VO 2 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.