The response of isolated ventricular cardiomyocytes to acute changes in metabolic substrates

Abstract

During a period of ischaemia, the myocardium switches predominantly from fatty acid metabolism to anaerobic glycolysis in an effort to maintain ATP levels. Increased availability of the metabolic substrates glucose and pyruvate has been found to improve recovery following ischaemia and reperfusion, while the presence of fatty acids upon reperfusion is detrimental. This study used isolated ventricular cardiomyocytes exposed to a simulated ischaemic and reperfusion protocol (metabolic inhibition and re-energisation) to investigate the effects of acute changes in specific metabolic substrates, and concentrations, prior to metabolic inhibition and/or during re-energisation at a cellular level. Perfusing isolated ventricular cardiomyocytes with an elevated concentration of glucose or fructose prior to metabolic inhibition and during re-energisation reduced a number of markers of ischaemic and re-energisation injury and thus imparted cardioprotection. Elevated glucose also affected electrical activity of the isolated ventricular cardiomyocytes by delaying action potential failure and SarcKATP channel activation. Intracellular magnesium levels were maintained with elevated glucose indicating possible sustained ATP levels, while intracellular calcium levels continued to rise throughout the protocol, suggesting the observed cardioprotection is not linked to reduced calcium overloading. Reducing pyruvate to a physiological concentration (0.5mM) only impacting on the response to metabolic inhibition, whilst elevating pyruvate to a supraphysiological concentration (10mM), only benefited those cardiomyocytes perfused under normoglycaemic conditions. Perfusion with a physiological concentration (0.5mM) of octanoate abrogated the cardioprotection 6provided by elevated glucose upon re-energisation. Metabolic preconditioning and postconditioning with elevated concentrations of metabolic substrates also improved contractile recovery. These results suggest increased availability of certain metabolic substrates are beneficial to isolated ventricular cardiomyocytes either prior to metabolic inhibition and/or the subsequent re-energisation. These observations may have clinical relevance in patients with acute coronary ischaemia. The precise mechanisms for these effects remain to be determined but are suggested to involve increased ATP availability