Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application.

Abstract

Cardiac contractile function is adenosine-5'-triphosphate (ATP)-intensive, and the myocardium's high demand for oxygen and energy substrates leaves it acutely vulnerable to interruptions in its blood supply. The myriad cardioprotective properties of the natural intermediary metabolite pyruvate make it a potentially powerful intervention against the complex injury cascade ignited by myocardial ischemia-reperfusion. A readily oxidized metabolic substrate, pyruvate augments myocardial free energy of ATP hydrolysis to a greater extent than the physiological fuels glucose, lactate and fatty acids, particularly when it is provided at supra-physiological plasma concentrations. Pyruvate also exerts antioxidant effects by detoxifying reactive oxygen and nitrogen intermediates, and by increasing nicotinamide adenine dinucleotide phosphate reduced form (NADPH) production to maintain glutathione redox state. These enhancements of free energy and antioxidant defenses combine to augment sarcoplasmic reticular Ca2+ release and re-uptake central to cardiac mechanical performance and to restore β-adrenergic signaling of ischemically stunned myocardium. By minimizing Ca2+ mismanagement and oxidative stress, pyruvate suppresses inflammation in post-ischemic myocardium. Thus, pyruvate administration stabilized cardiac performance, augmented free energy of ATP hydrolysis and glutathione redox systems, and/or quelled inflammation in a porcine model of cardiopulmonary bypass, a canine model of cardiac arrest-resuscitation, and a caprine model of hypovolemia and hindlimb ischemia-reperfusion. Pyruvate's myriad benefits in preclinical models provide the mechanistic framework for its clinical application as metabolic support for myocardium at risk. Phase one trials have demonstrated pyruvate's safety and efficacy for intravenous resuscitation for septic shock, intracoronary infusion for heart failure and as a component of cardioplegia for cardiopulmonary bypass. The favorable outcomes of these trials, which argue for expanded, phase three investigations of pyruvate therapy, mirror findings in isolated, perfused hearts, underscoring the pivotal role of preclinical research in identifying clinical interventions for cardiovascular diseases. Impact statement This article reviews pyruvate's cardioprotective properties as an energy-yielding metabolic fuel, antioxidant and anti-inflammatory agent in mammalian myocardium. Preclinical research has shown these properties make pyruvate a powerful intervention to curb the complex injury cascade ignited by ischemia and reperfusion. In ischemically stunned isolated hearts and in large mammal models of cardiopulmonary bypass, cardiac arrest-resuscitation and hypovolemia, intracoronary pyruvate supports recovery of myocardial contractile function, intracellular Ca2+ homeostasis and free energy of ATP hydrolysis, and its antioxidant actions restore β-adrenergic signaling and suppress inflammation. The first clinical trials of pyruvate for cardiopulmonary bypass, fluid resuscitation and intracoronary intervention for congestive heart failure have been reported. Receiver operating characteristic analyses show remarkable concordance between pyruvate's beneficial functional and metabolic effects in isolated, perfused hearts and in patients recovering from cardiopulmonary bypass in which they received pyruvate- vs. L-lactate-fortified cardioplegia. This research exemplifies the translation of mechanism-oriented preclinical studies to clinical application and outcomes.