Pyridostigmine did not significantly improve peak VO2 compared to placebo in the overall cohort of Long-COVID patients with RV preload dysfunction (median change +39 mL vs -140 mL, p=0.35).
RCT (n=32)
double-blind
randomized
No
Does pyridostigmine improve peak VO2 in Long-COVID patients with RV preload dysfunction?
Pyridostigmine did not significantly improve peak VO2 in the overall cohort of Long-COVID patients with RV preload dysfunction, but showed a borderline benefit in those with normal pulmonary artery compliance.
Absolute Event Rate: 39% vs -140%
p-value: p=0.35
Abstract Rationale Long-COVID, characterized by symptoms ≥12 weeks post-SARS-CoV-2 infection, presents with exercise intolerance and fatigue. Exercise intolerance may involve right ventricular (RV) preload failure, characterized by abnormally low right atrial pressure (RAP), identified via invasive cardiopulmonary exercise testing (iCPET). Pyridostigmine, an acetylcholinesterase inhibitor, may enhance sympathetic transmission and venoconstriction, improving venous return and RV preload. Though beneficial in chronic fatigue syndrome, pyridostigmine’s role in Long-COVID remains unknown. Methods We conducted a prospective, double-blind, randomized, placebo-controlled trial at the Federal University of Sao Paulo, Brazil (REBEC: RBR-7kyk2wy), enrolling Long-COVID patients with RV preload dysfunction (peak RAP ≤7 mmHg by iCPET). Participants received placebo or pyridostigmine with dose escalation to 360 mg/day over 6-10 weeks. Follow-up iCPET assessed pyridostigmine’s effect on exercise intolerance. Subgroup analysis excluded patients with pulmonary arterial compliance (PAC) ≥8.6 ml/mmHg to eliminate those with predominant pulmonary vascular autonomic dysfunction. Results 289 patients were screened (2023-2025) identifying 32 patients with RV preload dysfunction (72% women; age 51±10 years; BMI 31.1±5.9 kg/m2). No baseline differences were found between groups (n = 18 pyridostigmine; n = 14 placebo) in demographics, resting or peak exercise hemodynamics . Baseline peak RAP was 3.2±2.2 mmHg vs. 3.4±2.2 mmHg and baseline peak VO2 was 1,253±406 mL vs. 1,401±435 mL for pyridostigmine vs. placebo (p 0.05). In the overall cohort, post-treatment peak VO2 change did not differ significantly between pyridostigmine and placebo (median IQ range: +39 −138 to + 117 mL vs. −140 −137 to + 62 mL, respectively; p = 0.35). However, when restricting the analysis to patients with baseline pulmonary artery compliance 8.6 mL/mmHg, analysis of covariance revealed a borderline between-group difference (F = 4.9, p = 0.049) after adjusting for baseline resting VO2. In this subgroup, peak VO2 demonstrated a trend toward improvement with pyridostigmine (median IQ range: +60 +29 to + 165 mL) compared with placebo (−16 −88 to + 83 mL), with a mean treatment effect of + 103 mL (95% CI: −0.5 to + 205 mL; p = 0.051) favoring the pyridostigmine group. Conclusions Pyridostigmine demonstrated a borderline beneficial effect on peak VO2 in Long-COVID patients with RV preload dysfunction and normal PAC, suggesting that pathophysiologic heterogeneity may identify treatment-responsive subgroups. These preliminary findings support further investigation of hemodynamic phenotyping-guided pharmacological strategies in post-viral cardiopulmonary syndromes, though larger randomized trials are needed to confirm efficacy. This is the first Latin American randomized clinical trial on Long COVID. This abstract is funded by: CNPq Brazil
Duarte et al. (Fri,) conducted a rct in Long-COVID with RV preload dysfunction (n=32). Pyridostigmine vs. Placebo was evaluated on post-treatment peak VO2 change (p=0.35). Pyridostigmine did not significantly improve peak VO2 compared to placebo in the overall cohort of Long-COVID patients with RV preload dysfunction (median change +39 mL vs -140 mL, p=0.35).