Pyruvate: Metabolic Protector of Cardiac Performance

Abstract

Abstract. Pyruvate, a metabolic product of glycolysis and an oxidizable fuel in myocardium, increases cardiac mechanical performance and energy reserves, especially when supplied at supraphysiological concentrations. The inotropic effects of pyruvate are most impressive in hearts that have been reversibly injured (stunned) by ischemia/reperfusion stress. Glucose appears to be an essential co‐substrate for pyruvate's salutary effects in stunned hearts, but other fuels including lactate, acetate, fatty acids, and ketone bodies produce little or no improvement in postischemic function over glucose alone. In contrast to pharmacological inotropism by catecholamines, metabolic inotropism by pyruvate increases cardiac energy reserves and bolsters the endogenous glutathione antioxidant system. Pyruvate enhancement of cardiac function may result from one or more of the following mechanisms: increased cytosolic ATP phosphorylation potential and Gibbs free energy of ATP hydrolysis, enhanced sarcoplasmic reticular calcium ion uptake and release, decreased cytosolic inorganic phosphate concentration, oxyradical scavenging via direct neutralization of peroxides and/or enhancement of the intracellular glutathione/NADPH antioxidant system, and/or closure of mitochondrial permeability transition pores. This review aims to summarize evidence for each of these mechanisms and to consider the potential utility of pyruvate as a therapeutic intervention for clinical management of cardiac insufficiency.

Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI

“…Pyruvate is an endogenous substance that has been proposed as a cardioprotective agent (29,30,39) during ischemic conditions. In these studies doses below 10 -18 mmol/kg were considered safe and efficacious.…”

“…Pyruvate is a substrate at a central crossroad of intermediary metabolism (29,30) leading to energy production as well as formation of lactate, alanine, and CO 2 ( Fig. 1).…”

Pyruvate-fortified resuscitation stabilizes cardiac electrical activity and energy metabolism during hypovolemia

“…Previous studies of pyruvate-enriched resuscitative fluids for treatment of hemorrhagic shock also have documented pyruvate's antioxidant capabilities [12,13,44] . Pyruvate detoxifies ROS in direct, non-enzymatic reactions [15,45] . In addition, pyruvate carboxylation generates Krebs cycle intermediates, producing citrate which, by inhibiting phosphofructokinase, diverts glucose-6-phosphate into the hexose-monophosphate pathway, the source of NADPH to maintain the endogenous antioxidant glutathione [15] .…”

“…In the cytosol, LDH maintains an equilibrium between pyruvate and lactate [13] ; in the mitochondria, pyruvate carboxylation generates oxaloacetate and, thus, Krebs cycle intermediates including citrate [15,16] . To assess pyruvate metabolism, pyruvate, lactate, and citrate were measured in left ventricular myocardium at 90 min resuscitation and 3.5 h post-resuscitation, i.e., 30 min and 4 h hindlimb reperfusion.…”

“…A non-antioxidant, lactate does not protect myocardium from oxidative stress [12][13][14] . In contrast, pyruvate is a potent physiological antioxidant [7,13,15,16] . Accordingly, fluid resuscitation with pyruvate-enriched Ringer's solution could dampen ROS formation in the myocardium, protecting CK and ameliorating cardiac electrical instability during hypovolemia and tourniquet application and release.…”