Myocardial infarction (MI) occurs in ~900,000 Americans annually accounting for a mortality of 7-18%.While percutaneous coronary intervention (PCI) is invariably successful in restoring epicardial patency,significant microvascular obstruction (MVO) resulting in the "no-reflow phenomenon" (NRF) occurs frequentlywhich significantly impacts mortality and the development of CHF. Current devices are only partially effective inmitigating MVO and NRF following PCI for MI. Adenosine attenuates many of the mechanisms responsible for MVO and NRF. Seminal studies in ourlaboratory demonstrated that intravenous adenosine resulted in striking vascular and myocardial protectionand this was subsequently confirmed in large clinical trials. Adenosine's full potential is compromised due to itsultra-short half-life. Since the guidewire is the first PCI device deployed into the coronary vascular bed, wedeveloped a simple, two-step procedure to make a pentameric form of adenosine (PA) that can be coated ontoguidewires (Adenowire) and allows for continuous and sustained elution of adenosine into the coronarycirculation during PCI. We validated the structure of PA with NMR, its stability by calorimetry and confirmed itssafety with biocompatibility tests. We also demonstrated that PA released adenosine in vitro over 60 mins.Porcine studies demonstrated that pharmacologically active amounts of adenosine are released as verified bya significant and sustained increase in coronary blood flow following wire insertion. Since our initial submissionof this grant proposal we have developed strong relationships with industry leading guidewire and coatingcompanies resulting in the production of a viable commercial product. The goal of this Phase II application is to advance this novel technology to the clinical arena. We willutilize a LDLR knockout swine model which manifests hypercholesterolemia and human-like atheroscleroticlesions. Two important mechanisms of MVO will be tested: 1) efficacy of Adenowire to reverse potent smoothmuscle vasoconstrictors; and 2) effect of Adenowire to ameliorate cellular obstruction by endothelial cells andformed elements thereby attenuating NRF following regional ischemia and reperfusion. The data obtained from these studies will be invaluable in advancing this highly novel guidewire deviceto clinical trials. The concept is transformative and has a high likelihood of success since it will deliver highconcentrations of adenosine directly at the target site throughout the PCI procedure. If clinical trials confirmthat Adenowire is effective in preventing MVO and NRF it would represent a major advance in treatment of MIpatients. This would have important societal and economic benefits for MI patients treated with PCI in the USeach year.
Public Health Relevance Statement: Project Narrative Microvascular obstruction remains a significant barrier to optimize outcomes following PCI for myocardial infarction (MI), the leading cause of death in the US. We have developed a novel pentameric form of adenosine that can be coated onto guidewires (Adenowire) and allows for continuous elution of adenosine, a potent cardioprotective agent, throughout the procedure. The overall goal of this project is to advance development of Adenowire to clinical trials to improve outcomes in MI patients.
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