Preclinical studies use a range of species and provide a comprehensive approach to the study of drug effect and gene function in a variety of acute and chronic ischemia models. The Center has extensive experience using the ameroid constrictor porcine models and various other models of clinical angiogenesis. In fact, preclinical studies performed at the Center provided the basis for two of the largest angiogenesis trials to date (Genentech's VIVA VEGF study and Chiron's FIRST FGF-2 study). The rapid evaluation of angiogenic agents in small animal models has also enabled rapid proof of principle evaluation and mechanistic insights by using knock-out models with selective restoration of various genes. Finally, the Center's drug delivery program allows the rapid assessment and optimization of novel delivery catheters and vectors in various animal models

{short description of image} Ameroid Constrictor porcine Model: Angiography shows total occlusion of the left circumflex artery, however, with growth factor administration, both epicardial and intramyocardial collaterals are seen with almost complete reconstitution of the distal circumflex artery and absence of myocardial ischemia at rest. With stress, LCX flow remains lower than normal flow (LAD), but is significantly higher than control animals. These models are used to test the efficacy of various growth factors and gene therapy vectors in inducing functionally significant angiogenesis. Researchers at the Center have also been able to minimize the variability of the model by dedicated surgeons and interventional cardiologists, dedicated tissue and image analysis staff, and the use of multiple outcome measures including microspheres, histology, magnetic resonance imaging, echocardiographic assessment, molecular biology markers, and coronary casting studies



{short description of image} Ameroid Constrictor model: Angiography shows the metal ameroid constrictor occluding the left circumflex artery. This was a control animal with no filling of the distal vessel via collaterals and severe ischemia of the LCX distribution even at rest. Although the results for individual animals have a large variability with regards to the degree of native collateralization and ischemia induced collateralization, the use of 8-10 animals per treatment group and the use of multiple outcome measures minimizes the effect of this variability and allows a reproducible assessment the angiogenic potential of candidate genes and cytokines. In addition, as is done in clinical trials, all studies at the centers are randomized, vector-vehicle controlled, and the investigators and assessors are blinded to treatment assignment eliminating any potential bias




{short description of image} Ameroid Constrictor model with vascular casting: Polymers with different colors are used (blue for LCX, Red for LAD, White for RCA) and are injected in the coronary arteries. The polymers will then be allowed to solidify and the myocardium is digested leaving the vascular framework. In this image, arrows point to epicardial collaterals from the LAD and RCA distributions to the ischemic LCX artery. This efficacy measure is used in conjunction with all the other beforementioned measures to enable an accurate asessment of the angiogenic potential of candidate genes and molecules. Using this methods, we were able to document these epicardial collaterals (feeding collaterals, arteriogenesis) which are essentials to successful revascularization since they provide the major source of increased blood flow to the intramyocardial collaterals