Grant: Operating Grant

A reduction in blood flow to the heart (termed cardiac ischemia) or an imbalance between oxygen supply and oxygen demand (workload) causes anginal pain and depresses the normal contractile activity of the heart. Severe reductions in blood flow may cause a heart attack (termed myocardial infarction). Following a heart attack, the heart cells can be saved from dying by the speedy restoration of blood flow (termed reperfusion). Although restoration of blood flow is beneficial and prevents heart cells from dying, there may be a delay before the heart is able to pump normally. There has been a major research effort aimed at enhancing the recovery contractile function, and we have determined that one of the factors that contribute to poor recovery is a high rate of acid production within heart cells that causes excessive and deleterious accumulation of calcium ions that worsen mechanical function and promote cardiac cell death. We have already discovered some drug targets in the pathways of glucose metabolism that reduce acid production inside of heart cells, and that this limits calcium accumulation and improves recovery of heart mechanical function. Using our novel experimental system in which we can measure glucose metabolism, intracellular calcium levels and mechanical function in hearts under carefully controlled conditions of energy supply and demand, we plan additional and detailed studies on the pharmacological regulation of new, as yet unexplored, targets that we hypothesize will regulate glucose metabolism and calcium accumulation. We anticipate that these approaches will be beneficial and will facilitate an improved return of normal pumping activity, as well as reduce irreversible injury and cell death (infarction). We expect our planned investigation will help identify new drug strategies that will ultimately translate into clinical practice to enhance recovery of the heart from potentially lethal reductions in blood flow.