Local Perivascular Delivery of Basic Fibroblast Growth Factor in Patients Undergoing Coronary Bypass Surgery

Abstract

Background —Angiogenesis is a promising treatment strategy for patients who are not candidates for standard revascularization, because it promotes the growth of new blood vessels in ischemic myocardium. Methods and Results —We conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 μg versus placebo) delivered via sustained-release heparin-alginate microcapsules implanted in ischemic and viable but ungraftable myocardial territories in patients undergoing CABG. Twenty-four patients were randomized to 10 μg of bFGF (n=8), 100 μg of bFGF (n=8), or placebo (n=8), in addition to undergoing CABG. There were 2 operative deaths and 3 Q-wave myocardial infarctions. There were no treatment-related adverse events, and there was no rise in serum bFGF levels. Clinical follow-up was available for all patients (16.0±6.8 months). Three control patients had recurrent angina, 2 of whom required repeat revascularization. One patient in the 10-μg bFGF group had angina, whereas all patients in the 100-μg bFGF group remained angina-free. Stress nuclear perfusion imaging at baseline and 3 months after CABG showed a trend toward worsening of the defect size in the placebo group (20.7±3.7% to 23.8±5.7%, P =0.06), no significant change in the 10-μg bFGF group, and significant improvement in the 100-μg bFGF group (19.2±5.0% to 9.1±5.9%, P =0.01). Magnetic resonance assessment of the target ischemic zone in a subset of patients showed a trend toward a reduction in the target ischemic area in the 100-μg bFGF group (10.7±3.9% to 3.7±6.3%, P =0.06). Conclusions —This study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable myocardium that cannot be adequately revascularized.

Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia

“…If a single intracoronary infusion of FGF-2 proves to be effective in patients with chronically ischemic myocardium, this strategy will greatly increase the number of patients that might benefit from adjunctive growth factor therapy, especially in view of the minimal side effects [3]. Each patient undergoing percutaneous revascularization is a candidate for angiogenic therapy because most interventions are local and aimed at the most severe stenoses in epicardial arteries.…”

“…factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF), are being studied as a safe and potentially effective therapy to reduce myocardial ischemia either in conjunction with bypass surgery or percutaneous catheter-based recanalization, or as a monotherapy in "no option" patients [1][2][3]. All the current strategies involve invasive approaches in high-risk patients to deliver the growth factors locally.…”

“…The angiogenic efficacy of FGF-2 was confirmed in numerous animal models [11,12]. Although the first phase I clinical trial has shown the safety of intracoronary FGF-2 over a wide range of dosages [3], the optimal dose regimen and delivery strategy for efficacy with respect to cardiac angiogenesis have not been established yet. We chose a porcine ameroid model for preclinical testing of delivery strategies because of several unique aspects.…”

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

“…In CAD patients, slow-release FGF2 capsules implanted in the myocardium in a phase I clinical trial caused a significant reduction in size of the ischemic region and treated patients had more freedom from angina recurrence than controls [235,236]. Also, single-bolus intracoronary FGF2 infusion showed transient beneficial effects, including reduction of angina symptoms, increase of treadmill tolerance and quality of life [237].…”

The Efficacy of Therapeutic Angiogenesis Using Basic Fibroblast Growth Factor in Patients With Coronary Artery Disease: A Double-Blind, Placebo-Controlled Study

“…Body mass index (BMI) and nulliparity are two main risk factors for EH. Other risk factors include chronic anovulation, early menarche, late onset of menopause and diabetes [3], which are related to increased circulating estrogen [4]. The treatment of EH is challenging and previous studies report conflicting results [5].…”