Glutathione infusion before primary percutaneous coronary intervention: a randomised controlled pilot study

Abstract

Objective: In the setting of reperfused ST-elevation myocardial infarction (STEMI), increased production of reactive oxygen species (ROS) contributes to reperfusion injury. Among ROS, hydrogen peroxide (H₂O₂) showed toxic effects on human cardiomyocytes and may induce microcirculatory impairment. Glutathione (GSH) is a water-soluble tripeptide with a potent oxidant scavenging activity. We hypothesised that the infusion of GSH before acute reoxygenation might counteract the deleterious effects of increased H₂O₂ generation on myocardium.

Methods: Fifty consecutive patients with STEMI, scheduled to undergo primary angioplasty, were randomly assigned, before intervention, to receive an infusion of GSH (2500 mg/25 mL over 10 min), followed by drug administration at the same doses at 24, 48 and 72 hours elapsing time or placebo. Peripheral blood samples were obtained before and at the end of the procedure, as well as after 5 days. H₂O₂ production, 8-iso-prostaglandin F2α (PGF2α) formation, H₂O₂ breakdown activity (HBA) and nitric oxide (NO) bioavailability were determined. Serum cardiactroponin T (cTpT) was measured at admission and up to 5 days.

Results: Following acute reperfusion, a significant reduction of H₂O₂ production (p=0.0015) and 8-iso-PGF2α levels (p=0.0003), as well as a significant increase in HBA (p<0.0001)and NO bioavailability (p=0.035), was found in the GSH group as compared with placebo. In treated patients, attenuated production of H₂O₂ persisted up to 5 days from the index procedure (p=0.009) and these changes was linked to those of the cTpT levels (r=0.41, p=0.023).

Conclusion: The prophylactic and prolonged infusion of GSH seems to determine a rapid onset and persistent blunting of H₂O₂ generation improving myocardial cell survival. Nevertheless, a larger trial, adequately powered for evaluation of clinical endpoints, is ongoing to confirm the current finding.

Trial registration number: EUDRACT 2014-00448625; Pre-results.

Keywords: STEMI; glutathione:; hydrogen peroxide; percutaneous coronary interventions; reactive oxygen species; reperfusion injury.

Figure 1

CONSORT flow chart. GSH, glutathione; MI, myocardial infarction; PCI, percutaneous coronary intervention. CONSORT, Consolidated Standards of Reporting Trials.

Figure 2

H₂O₂ production (A), 8-iso-PGF2α formation (B), H₂O₂ breakdown activity (HBA) (C) and NO bioavailability (D) at baseline, after 2 hours (T2h) and at the 5 days (T5d) from the PCI in patients received GSH (n=25, dashed line) or placebo (n=25, continuous line). Data are expressed as mean±SEM (*P<0.05, **P<0.01, ***P<0.001). GSH, glutathione; H₂O₂, hydrogen peroxide; NO, nitric oxide; PCI, percutaneous coronary intervention; PGF2α, prostaglandin F2α.

Figure 3

cTpT levels (A) at baseline, after 6 hours (T6h), 12 hours (T12h) and at the 5 days (T5d) from the PCI in patients received GSH (n=25, dashed line) or placebo (n=25, continuous line). Data are expressed as mean±SEM (*P<0.05 vs T0, ***P<0.0001 vs T0, ^$P<0.05 between groups). Linear correlation between % Δ cTpT and % Δ H₂O₂ in GSH-treated group (B). cTpT, cardiac troponin T; H₂O₂, hydrogen peroxide; GSH, glutathione; PCI, percutaneous coronary intervention.