Despite recent improvements in treatment, coronary artery disease remains the number one cause of mortality in the United States. The Cardiology Branch sees more and more patients who can no longer be helped by surgery or drugs in current use. Although there is as yet no direct evidence of angiogenesis (new blood vessel growth) occurring in the human heart, our attempt has been to try to understand and to enhance this process. We have followed the lead of cancer researchers who have purified and cloned a family of proteins which cause angiogenesis in vivo and cause migration and mitosis of endothelial cells and fibroblasts in vitro. They have also found that heparin (which is used to prevent blood clotting in heart patients) enhances angiogenesis caused by tumors but is not angiogenic by itself. A non-anticoagulant fraction of heparin has the same effects. We devised a model of ischemia in the rat, in which we have shown that treatment with heparin or a non-anticoagulant fragment of heparin prior to coronary ligation results in a smaller myocardial infarction and lower mortality. Heparin has multiple actions, but our evidence to-date suggests an angiogenic mechanism of action. Autoradiographic and quantitative histologic studies are nearly completed and should answer this question definitively. We have also shown that subcutaneous injections of purified fibroblast and endothelial growth factor causes a marked increase in DNA synthesis of vascular cells in normal rats. Electron microscopy is being performed to determine if these are predominantly endothelial cells, fibroblasts, or arterial smooth muscle cells. We have also extracted and purified a protein of approximately 17,000 molecular weight from normal dog myocardium which so far appears very similar to the angiogenic proteins extracted from tumors. We are currently trying to determine by radioimmunoassay if there is an increase in this factor in response to ischemia.
