The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.

Background-The present article is a report of our animal experiments and also of the first clinical results of a new treatment for coronary heart disease using the human growth factor FGF-I (basic fibroblast growth factor) to induce neoangiogenesis in the ischemic myocardium. Methods and Results-FGF-I was obtained from strains of Escherichia coli by genetic engineering, then isolated and highly purified.Several series of animal experiments demonstrated the apathogenic action and neoangiogenic potency of this factor. After successful conclusion of the animal experiments, it was used clinically for the first time. FGF-I (0.01 mg/kg body weight) was injected close to the vessels after the completion of internal mammary artery (IMA)/left anterior descending coronary artery (LAD) anastomosis in 20 patients with three-vessel coronary disease. All the patients had additional peripheral stenoses of the LAD or one of its diagonal branches. Twelve weeks later, the IMA bypasses were selectively imaged by intra-arterial digital subtraction angiography and quantitatively evaluated. In all the animal experiments, the development of new vessels in the ischemic myocardium could be demonstrated angiographically. The formation of capillaries could also be demonstrated in humans and was found in all cases around the site of injection. A capillary network sprouting from the proximal part of the coronary artery could be shown to have bypassed the stenoses and rejoined the distal parts of the vessel. Conclusions-We believe that the use of FGF-I for myocardial revascularization is in principle a new concept and that it may be particularly suitable for patients with additional peripheral stenoses that cannot be revascularized surgically. (Circulation. 1998;97:645-650.)

Currently available approaches for treating human coronary heart disease aim to relieve symptoms and the risk of myocardial infarction either by reducing myocardial oxygen demand, preventing further disease progression, restoring coronary blood flow pharmacologically or mechanically, or bypassing the stenotic lesions and obstructed coronary artery segments. Gene therapy, especially using angiogenic growth factors, has emerged recently as a potential new treatment for cardiovascular disease. Following extensive experimental research on angiogenic growth factors, the first clinical studies on patients with coronary heart disease and peripheral vascular lesions have been performed. The polypeptides fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) appear to be particularly effective in initiating neovascularisation (neo-angiogenesis) in hypoxic or ischaemic tissues. The first clinical study on patients with coronary heart disease treated by local intramyocardial injection of FGF-1 showed a 3-fold increase of capillary density mediated by the growth factor. Angiogenic therapy of the human myocardium introduces a new modality of treatment for coronary heart disease in terms of regulation of blood vessel growth. Beyond drug therapy, angioplasty and bypass surgery, this new approach may evolve into a fourth principle of treatment of atherosclerotic cardiovascular disease.

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Esophageal resection was performed in 119 patients between 1968 and 1977. The esophagus was replaced by stomach in 94 patients with a hospital mortality rate of 17%, and by an interposed segment of colon in 25 patients with a hospital mortality rate of 20%. Anastomotic leakage occurred in 10 patients (8.4%), of whom 6 died. Anastomotic leakage in the neck was not fatal, while two‐thirds of patients with intrathoracic leakage died. Stenosis of the anastomosis developed in 11 patients (9%), 6 of whom required dilatation or resection. The incidence of stricture was highest in patients with esophagocolic anastomoses in the neck. Development of esophageal reflux was investigated in 55 patients with gastroesophageal anastomoses 6–46 months postoperatively by questions about symptoms, x‐ray examination and, in 37 patients, by endoscopy. Mild symptoms of reflux occurred in 6 of 26 patients with high intrathoracic anastomoses, while regular symptoms of reflux were reported by 17 of 29 patients with low intrathoracic anastomoses and only 2 such patients were free of symptoms. Similarly, 25 of 26 patients with high anastomoses had no reflux on x‐ray or had reflux only in the head‐down position, while all 29 patients with low anastomoses had reflux on x‐ray, and 24 had reflux in the upright and/or supine positions. On endoscopy, 12 of 17 patients with high anastomoses had no esophagitis, while only 1 of 20 patients with low anastomoses had no esophagitis and in 9 patients, esophagitis was moderate or severe. There was a low incidence of reflux in patients with colon interposition. These results indicate that replacement of the esophagus with a high intrathoracic gastroesophageal anastomosis or with interposed colon is the preferable procedure.