Research Project
9348460
Due to multiple factors, time to administration of lytic therapy or emergent percutaneous coronary intervention (PCI) in acute ST segment elevation myocardial infarction (STEMI) may be delayed, resulting in loss of additional myocardial tissue. These delays are virtually impossible to overcome in remote regions, and are associated with increased mortality. Recent small animal studies show the potential for oxygen therapeutic nanoparticles - dodecafluoropentane e m u l s i o n (DDFPe) to reduce both myocardial infarct and stroke size during prolonged myocardial ischemia. Our recent data in a murine acute STEMI m o d e l indicates that a single dose of DDFPe decreases myocardial damage by 75% in models that examine ischemia alone, and by about 30% in models with ischemia with reperfusion (I/R), along with significant reduction in apoptosis. The doses used in the I/R models were one-third the dose used in the ischemia alone model. IV DDFPe significantly decreases brain damage in an I/R stroke model. However, the efficacy of DDFPe has not been tested in a large animal model, or in models of prolonged myocardial ischemia followed by reperfusion in a clinically relevant setting mimicking atherosclerotic plaque rupture. We hypothesize that use of these nanoparticles early in the care of acute STEMI will decrease or eliminate myocardial damage from prolonged myocardial ischemia followed by reperfusion. First we will demonstrate the ability of DDFPe to reach the risk area in acute ischemia via collateral flow, and reduce the formation of mitochondrial reactive oxygen species that are the primary mediators in ischemia reperfusion injury. We will correlate DDFPe delivery with regional myocardial blood flow using neutron activated microspheres (NAM). Secondly, we will administer IV DDFPe during a prolonged four-hour period of myocardial ischemia in an atherosclerotic pig model, followed by reperfusion. DDFPe presence within the risk area will be correlated with regional myocardial blood flow in the risk area. At four weeks post infarction we will examine LV ejection fraction with magnetic resonance imaging (MRI), number of infarcted segments with delayed enhancement MRI, and actual infarct size with post-mortem Evans Blue and triphenyl tetrazolium chloride staining. DDFPe has a two-year shelf-life and has an active IND for stroke. Verification of its effectiveness in this trial would lead to IND submission for a cardioprotection trial. DDFPe could be deployed in the ambulance or upon arrival to the hospital to maintain tissue oxygenation and reduce I/R damage following percutaneous coronary revascularization. This would have profound implications in the early management of acute STEMI, as the ability of this oxygen therapeutic to reduce ischemic damage due to hypoxia could prolong the time window in which patients would be eligible for percutaneous interventions, and allow patients even in remote locations to reach definitive care. Ultimately we predict this will preserve ejection fraction and prevent heart failure and arrhythmic complications f o l l o w i n g S T E M I that still complicate current state of the art therapies.
