Pyruvate-fortified cardioplegia suppresses oxidative stress and enhances phosphorylation potential of arrested myocardium

Abstract

Cardioplegic arrest for bypass surgery imposes global ischemia on the myocardium, which generates oxyradicals and depletes myocardial high-energy phosphates. The glycolytic metabolite pyruvate, but not its reduced congener lactate, increases phosphorylation potential and detoxifies oxyradicals in ischemic and postischemic myocardium. This study tested the hypothesis that pyruvate mitigates oxidative stress and preserves the energy state in cardioplegically arrested myocardium. In situ swine hearts were arrested for 60 min with a 4:1 mixture of blood and crystalloid cardioplegia solution containing 188 mM glucose alone (control) or with additional 23.8 mM lactate or 23.8 mM pyruvate and then reperfused for 3 min with cardioplegia-free blood. Glutathione (GSH), glutathione disulfide (GSSG), and energy metabolites [phosphocreatine (PCr), creatine (Cr), P(i)] were measured in myocardium, which was snap frozen at 45 min arrest and 3 min reperfusion to determine antioxidant GSH redox state (GSH/GSSG) and PCr phosphorylation potential {[PCr]/([Cr][P(i)])}. Coronary sinus 8-isoprostane indexed oxidative stress. Pyruvate cardioplegia lowered 8-isoprostane release approximately 40% during arrest versus control and lactate cardioplegia. Lactate and pyruvate cardioplegia dampened (P < 0.05 vs. control) the surge of 8-isoprostane release following reperfusion. Pyruvate doubled GSH/GSSG versus lactate cardioplegia during arrest, but GSH/GSSG fell in all three groups after reperfusion. Myocardial [PCr]/([Cr][P(i)]) was maintained in all three groups during arrest. Pyruvate cardioplegia doubled [PCr]/([Cr][P(i)]) versus control and lactate cardioplegia after reperfusion. Pyruvate cardioplegia mitigates oxidative stress during cardioplegic arrest and enhances myocardial energy state on reperfusion.

Superior cardiac function via anaplerotic pyruvate in the immature swine heart after cardiopulmonary bypass and reperfusion

“…Thus, the impact on free radical formation and release should have been minimized. Under aerobic or reperfusion conditions similar to those existing during pyruvate supplementation in our study, pyruvate is know to elevate or maintain cytosolic ATP phosphorylation potential in part through the modulation of the mitochondrial NADH-to-NAD ratio (15,16). Pyruvate can also enhance carbon substrate delivery to the TCA cycle during aerobic conditions, either through the formation of acetyl-CoA or pyruvate carboxylase.…”

Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass

“…Recent studies in this model (14,15) demonstrated that pyruvate-enriched cardioplegia acutely increased myocardial pyruvate and ATP contents, PCr phosphorylation potential, i.e., indicator of the redox state of the myocardium's antioxidant systems (32), was increased greater than or equal to twofold (P Ͻ 0.05) 4 h after pyruvate treatment vs. sham and control cardioplegia-treated myocardium (Fig. 2D).…”

“…A cannula was inserted into the aortic root for cardioplegia infusion. Crystalloid cardioplegia (pH 7.6) contained 104 mM NaCl, 135 mM NaHCO 3, 91 mM KCl, 6 mM CaCl2, 188 mM glucose, 68 U/l insulin, and 676 mg/l lidocaine (14). Pyruvate cardioplegia was prepared by equimolar substitution of 24 mM sodium pyruvate for NaCl.…”

“…Next, transmural samples were quickly excised and snap-frozen for analyses of myocardial mRNA and proteins. Pyruvate, ATP, phosphocreatine (PCr), creatine (Cr), inorganic phosphate (Pi), glutathione (GSH), and glutathione disulfide (GSSG) were extracted and colorimetrically assayed, as previously described (10,14 (14,35). Myocardial water content was determined by weighing tissue samples (ϳ200 mg) before and after dessication to constant mass in an oven.…”

“…In a small, randomized trial in patients undergoing coronary artery revascularization on cardiopulmonary bypass (CPB), the use of pyruvate-fortified vs. conventional cardioplegia attenuated myocardial injury, hastened recovery of cardiac function, and shortened hospitalization (27). In a swine CPB model, cardioplegic arrest and reperfusion provoked oxidative stress, inactivated myocar-dial enzymes, and produced cardiac edema, but pyruvate cardioplegia prevented these detrimental acute effects (14,15). However, pyruvate-enriched cardioplegia is rapidly cleared when the heart is reperfused with whole blood (35), so it seems unlikely that pyruvate's direct metabolic properties could explain its persistent, favorable cardiac effects in the clinical trial (27).…”