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.

No abstract

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.

Tissue factor (TF) is a major activator of the coagulation cascade and may play a role in initiating thrombosis after intravascular injury. To investigate whether medial vascular smooth muscle provides a source of TF following arterial injury, the induction of TF mRNA and protein was studied in balloon-injured rat aorta. After full length aortic injury, aortas were harvested at various times and the media and adventitia separated using collagenase digestion and microscopic dissection. In uninjured aortic media, TF mRNA was undetectable by RNA blot hybridization. 2 h after balloon injury TF mRNA levels increased markedly. Return to near baseline levels occurred at 24 h. In situ hybridization with a 35S-labeled antisense rat TF cRNA probe detected TF mRNA in the adventitia but not in the media or endothelium of uninjured aorta. 2 h after balloon dilatation, a marked induction of TF mRNA was observed in the adventitia and media. Using a functional clotting assay, TF procoagulant activity was detected at low levels in uninjured rat aortic media and rose by 10-fold 2 h after balloon dilatation.Return to baseline occurred within 4 d. These data demonstrate that vascular injury rapidly induces active TF in arterial smooth muscle, providing a procoagulant that may result in thrombus initiation or propagation. (J. Clin. Invest. 1993.

Recent data suggests that CD40L is involved in the pathogenesis of atherothrombotic disease. This review will focus on the history of CD40L, its role in platelet-mediated pathogenesis of atherothrombotic disease, its association to clinical syndromes and procedures, and its role in determining plaque rupture.

No abstract

The CK-MB elevation after coronary intervention was observed even in the absence of discernible procedural complications and was more common in patients with diffuse atherosclerosis. In-hospital clinical events requiring prolonged monitoring were higher in >5x CK-MB-elevation patients only. Midterm survival of CK-MB-elevation patients was similar to those with normal CK-MB. Our prospective analysis shows a lack of adverse in-hospital cardiac events and suggests that early discharge of stable 1-5x normal CK-MB-elevation patients after successful coronary intervention is safe.