PROMOTION OF MYOCARDIAL ANGIOGENESIS USING PEPTIDE GROWTH FACTORS

几种多肽有可能导致血管生长

Several polypeptides with the potential to cause blood vessel growth (angiogenesis) have been sequenced and synthesized during the last few years. Our ultimate goal is to utilize these angiogenic agent(s) to facilitate myocardial revascularization in patients with coronary heart disease. Basic fibroblast growth factor (BFGF) is one such peptide that may play an important role in coronary collateral formation. We recently demonstrated that systemic administration of BFGF accelerates coronary collateral development in a canine model of single coronary occlusion; however, collateral growth in control dogs improved towards the 5 week end-point of the study, such that the gain in collateral flow in the BFGF treated dogs was essentially erased at the end of the study. This "catch up" phenomenon suggested that BFGF would accelerate the formation of collaterals, but have little effect on the final magnitude of collateral flow. A long-term crossover study was undertaken to examine whether: 1) the BFGF-induced increase in collateral blood flow is sustained beyond 5 weeks, 2) treatment beyond 5 weeks further improves collateral blood flow, and 3) withdrawal of treatment results in regression of collateral blood flow. Dogs were subjected to ameroid-induced occlusion of the left circumflex coronary artery, and randomized to receive BFGF 1.74 mg/d for 9 weeks, BFGF 1.74 mg/d for 5 weeks, crossing over to placebo, or saline for 9 weeks. Collateral blood flow was assessed with microspheres during maximal coronary vasodilatation. Maximal collateral blood flow in dogs treated with BFGF for 9 weeks was similar to that of dogs treated for 5 weeks, and collateral flow in both groups was significantly better than controls. The major improvement in BFGF-treated dogs occurred during 10- 17 day interval after ameroid placement. Thus, the BFGF-induced increase in collateral flow was sustained beyond 5 weeks, collateral blood flow in controls did not "catch up" to that of treated dogs (difference between groups at 9 weeks = 25%, p<0.005). Regression did not occur when treatment was stopped. Treatment for 9 weeks afforded no advantage over 5 week treatment, and early treatment appeared to be highly important.