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Coronary occlusive disease is the leading cause of death in industrial nations and affects one in four adults. Although heart attacks are caused by occlusion of a coronary artery, some patients have occlusions without infarction because they have sufficient collateral vessels providing an alternate pathway for blood supply. Vascular endothelial growth factor (VEGF) is an angiogenic peptide that can stimulate collateral vessel development in the ischaemic myocardium. We used magnetic resonance imaging (MRI) and image processing to identify and quantify non-invasively the benefits related to VEGF infusion on collateral development in the heart. This was accomplished as a placebo-controlled study in the porcine model of chronic ischaemia that most closely mimics the human pathophysiology of progressive coronary occlusion. Image series converted to a space-time map demonstrated that with treatment the ischaemic zone was smaller and the contrast arrival delay was less, which resulted in better ejection fraction and regional wall thickening. These findings demonstrate in a manner applicable to humans, that VEGF improves collateral blood supply, resulting in improved cardiac global and regional function after and in spite of coronary artery occlusion.

The effect of basic fibroblast growth factor (bFGF) administration on regional myocardial function and blood flow in chronically ischemic hearts was studied in 26 pigs instrumented with proximal circumflex coronary artery (LCX) ameroid constrictors. In 13 animals bFGF was administered extraluminally to the proximal left anterior descending (LAD) and LCX arteries with heparin-alginate beads and 13 other animal served as controls. bFGF-treated pigs showed a fourfold reduction in left ventricular infarct size compared to untreated controls (infarct size: 12+0.4% vs. 5.1+13% of LV mass, mean±SEM, P < 0.05). Percent fractional shortening (% FS) in the LCX area at rest was reduced compared with the LAD region in both bFGF and control pigs. However, there was better recovery in the LCX area after rapid pacing in bFGF-treated pigs (% FSLCX/% FSLAD, 22.9_73% -+ 30.5±8.5%, P < 0.05 vs. prepacing) than in controls (16.0±7.8% --143+7.0%, P = NS). Furthermore, LV end-diastolic pressure rise with rapid pacing was less in bFGF-treated than control pigs (pre-pacing; pacing; postpacing, 10±1; 17±3; 11±1* mmHg vs 10±1; 24±4; 15±1 mmivg, *P < 0.05 vs. control). Coronary blood flow in the LCX territory (normalized for LAD flow) was also better during pacing in bFGF-treated pigs than in controls. Thus, periadventitial administration of bFGF in a gradual coronary occlusion model in pigs results in improvement of coronary flow and reduction in infarct size in the compromised territory as well as in prevention of pacing-induced hemodynamic deterioration.(J. Clm Invest 1994. 94:623-630.) Key words: basic fibroblast growth factor -regional myocardial function * chronic ischemia * coronary artery disease * angiogenesis

Vascular endothelial growth factor (VEGF) is a potent mitogen capable of stimulating angiogenesis. We examined the effect of VEGF administration in a model of chronic porcine myocardial ischemia. Nineteen pigs were instrumented with proximal left circumflex coronary artery (LCX) Ameroid constrictors. In eight animals VEGF (2 microgram) with heparin (50 U) was administered extraluminally to the LCX myocardium with an osmotic pump for 4 wk and 11 other animals served as controls. VEGF-treated animals demonstrated higher flow in the LCX territory during both rest and pacing compared with untreated controls (rest: 1.35 +/- 0.1 vs. 0.80 +/- 0.09 ml.min-1.g-1; pacing; 2.01 +/- 0.37 vs. 1.01 +/- 0.07 ml.min-1.g-1, P < 0.05, VEGF vs. controls). The observed improvement in regional coronary flow in VEGF-treated animals resulted in better preservation of endothelium-dependent microvessel relaxation as well as fractional LV shortening in the LCX territory during pacing in the VEGF-treated than in control animals (controls: 7.1 +/ 2.6 vs. 3.6 +/- 2.0%, rest vs. pacing; VEGF: 6.9 +/- 2.9 vs. 6.3 +/- 2.9%, rest vs. pacing). We conclude that VEGF administration in a gradual coronary occlusion model in pigs results in improvement of coronary flow and preservation of regional hemodynamics in the compromised myocardium.

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