The overall aim of this project is to investigate the response of ischemic myocardium to injections of angiogenic growth factors using a system that provides a substantially reduced level of invasiveness compared to alternative treatment methods. The rationale behind the proposed project is that accurate targeting and focal delivery are essential to achieve optimal therapeutic effects. Delivery of angiogenic factors will be performed using a unique dual x-ray fluoroscopy-MRI unit that permits real-time imaging during procedures. Improvements in MRI pulse sequence design and the use of recently developed MR contrast media will be pursued to evaluate the effects of angiogenic growth factors on ischemically injured myocardium. High-resolution MRI will be performed to obtain quantitative data about global and regional wall motion and blood flow at rest and stress (dobutamine and adenosine). MRI in conjunction with novel contrast media will be used to assess microvascular integrity, myocardial perfusion and viability. In vivo (physiologic and pharmacological) and ex vivo (histopathologic and quantitative analytical) studies will be performed to confirm and support MRI findings. These studies will be conducted in dogs but rapid high-resolution MR sequences suitable for use in humans will also be developed. Effects of the most widely used angiogenic growth factors, namely vascular endothelial growth factor (VEGF) for angiogenesis and fibroblast growth factor (FGF) for arteriogenesis, will be investigated in three dog models of ischemia. Since the evolution of angiogenesis and arteriogenesis differs in hypoperfused, occlusive and reperfused infarction models, dynamic vascular, cellular and morphologic changes will be longitudinally monitored and compared. This project is a collaborative effort between scientists and clinicians in the field of cardiac MRI. The potential clinical benefits of focal MRI-guided treatment are to: 1) reduce morbidity caused by open-chest surgery, 2) accomplish rapid recovery due to minimal invasiveness, 3) potentially provide treatment on an outpatient basis and 4) reduce treatment costs. The key elements of this project are: 1) development of minimally invasive MRI-guided method for focal therapies and 2) chronological evaluation of new therapies on an admixture of stunned and infarcted myocardium in coronary artery disease.
