Background — The angiogenic response to myocardial ischemia can be augmented in animal models by gene transfer with the use of a replication defective adenovirus (Ad) containing a human fibroblast growth factor (FGF) gene. Methods and Results — The objectives of the Angiogenic GENe Therapy (AGENT) trial were to evaluate the safety and anti-ischemic effects of 5 ascending doses of Ad5-FGF4 in patients with angina and to select potentially safe and effective doses for subsequent study. Seventy-nine patients with chronic stable angina Canadian Cardiovascular Society class 2 or 3 underwent double-blind randomization (1:3) to placebo (n=19) or Ad5-FGF4 (n=60). Safety evaluations were performed at each visit and exercise treadmill testing (ETT) at baseline and at 4 and 12 weeks. Single intracoronary administration of Ad5-FGF4 seemed to be safe and well tolerated with no immediate adverse events. Fever of <1-day duration occurred in 3 patients in the highest-dose group. Transient, asymptomatic elevations in liver enzymes occurred in 2 patients in lower-dose groups. Serious adverse events during follow-up (mean, 311 days) were not different between placebo and Ad5-FGF4. Overall, patients who received Ad5-FGF4 tended to have greater improvements in exercise time at 4 weeks (1.3 versus 0.7 minutes, P =NS, n=79). A protocol-specified, subgroup analysis showed the greatest improvement in patients with baseline ETT ≤10 minutes (1.6 versus 0.6 minutes, P =0.01, n=50). Conclusions — Results show evidence of favorable anti-ischemic effects with Ad5-FGF4 compared with placebo, and it appears to be safe. Angiogenic gene transfer with Ad5-FGF4 shows promise as a new therapeutic approach to the treatment of angina pectoris.

TF contributes to the procoagulant activity of most atherosclerotic lesions treated with DCA. The association of immunohistochemically detectable TF with plaque thrombus suggests that TF plays a role in coronary thrombosis. Diminished TF expression in restenotic lesions may in part account for the lower complication rate that has been associated with DCA of restenotic versus de novo lesions. Inhibition of TF may represent a therapeutic goal for the prevention of thrombotic complications associated with percutaneous coronary interventions.

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Thrombosis is integral to the development and progression and clinical sequelae of atherosclerosis. Acute thrombosis can occur spontaneously, leading to catastrophic arterial occlusion and resulting in myocardial infarction, unstable angina, stroke, and sudden death (1,2). Acute thrombosis also occurs as a complication of arterial bypass surgery, balloon angioplasty, atherectomy, or coronary artery stenting (3-5). Non-occlusive thrombus is an important component of the atherosclerotic plaque. Thrombus is comprised principally of platelets and fibrin. White blood cells and circulating proteins are also trapped within the platelet-fibrin thrombus. Activated platelets release a variety of growth factors and cytokines that have been implicated in vessel inflammation and in vascular smooth muscle cell (SMC) proliferation and migration (6,7). Thrombin (8) and factor XlXa (9,10) also have direct effects on SMC and may play a role in the development of intimal hyperplasia. In addition, products secreted by leukocytes trapped within the thrombus may have direct effects on the vessel wall. Tissue factor (TF) is a membrane-bound glycoprotein that initiates coagulation (11,12).Human TF consists of three domains: a short cytoplasmic domain of 19 residues, a single transmembrane domain of 23 residues, and a large extracellular domain of 219 residues. In addition, there is a 32 residue amino-terminal leader sequence which is cleaved to produce the mature molecule. TF binds to factor VIIA/IIa, and the resulting complex acts as a catalyst for the conversion of factors IX and X to IXa and Xa respectively, triggering the clotting cascade. This ultimately leads to the generation of thrombin, which in turn cleaves fibrinogen to fibrin, the major ingredient of the thrombus. Recent studies suggest that the accumulation of TF in atherosclerotic plaques plays a major role in determining plaque thrombogenicity. TF is also rapidly induced in the vessel wall as a consequence of acute arterial injury. Both phenomena may be important in the thrombotic complications of atherosclerotic heart disease.