Basic fibroblast growth factor enhances myocardial collateral flow in a canine model

Abstract

Basic fibroblast growth factor (FGF) is a multifunctional peptide that may play an integral role in angiogenesis associated with coronary collateral formation and myocardial infarct healing. We sought to determine the effects of exogenously administered basic FGF on collateral blood flow to ischemic myocardium. Ameroid constrictors were used to cause gradual occlusion of the left circumflex coronary artery in dogs. Basic FGF (110 micrograms, n = 9) or saline (n = 12) was given as a daily bolus injection directly into the collateral-dependent zone, beginning 10 days after placement of the Ameroid and continuing for 28 days. Collateral flow was assessed weekly as the ratio of collateral to normal zone (CZ/NZ) blood flow during maximal pharmacologically induced coronary vasodilation. The CZ/NZ increased in both treated and control dogs as a function of time; however, transmural collateral flow in basic FGF-treated dogs significantly exceeded that of control dogs by the second week of treatment. Final CZ/NZ blood flow ratios were 0.49 +/- 0.05 and 0.35 +/- 0.02 in the treated and control groups, respectively (means +/- SE, P = 0.0002). Treatment with basic FGF was also associated with significant increases in the numerical density of distribution vessels and endothelial cell DNA synthesis within the CZ. We also found that basic FGF had acute effects as a coronary vasodilator. Thus exogenous administration of basic FGF enhances maximal collateral blood flow in dogs with myocardial ischemia secondary to single-vessel coronary occlusion, an effect that is likely mediated through the direct angiogenic effects of the peptide, although its acute vasodilatory effects may also play a role.

Adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor promotes collateral development in a rabbit model of hind limb ischemia

“…In the direct application method for recombinant growth factor protein, an intra-arterial catheter was the major delivery device. 4,5,8 In contrast, it is complicated to apply naked DNA to the myocardium by intramuscular injection. Losordo et al 14 injected naked DNA of VEGF into the ventricular wall via mini-thoracotomy.…”

“…5 Many recent studies, however, selected VEGF as an angiogenic growth factor to induce collateral vessels in ischemic tissue. Isner and colleagues 4,7,8,17 presented several studies using VEGF in a rabbit model of hind limb ischemia and also in clinical trial, and showed favorable effects in improvement of the ischemic state.…”

“…2 In order to develop a therapy to enhance collateral development, these growth factors have been tested in vivo with several delivery techniques. [4][5][6][7] Direct administration of growth factor protein was initially investigated in animal models of ischemia, which showed significant development of collateral vessels and improvement of the ischemic state. 4,5,8 However, high-dose bolus delivery has a high potential risk of systemic toxicity through cytokine diffusion into the systemic circulation.…”

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

“…In preclinical studies, in pig or canine models of chronic myocardial ischemia, others and we have shown that continuous [4] and single intrapericardial [5] or repeated intracoronary [6] administration improved regional blood flow in the ischemic territory. Improvement in cardiac function was observed only after periadventitial delivery [4] and intrapericardial delivery [5].…”

Cardiac expression profiles of the naked DNA vectors encoding vascular endothelial growth factor and basic fibroblast growth factor

“…Recently, therapeutic angiogenesis that is based on exogenous administration of angiogenic growth factors has emerged as a promising strategy for the treatment of tissue ischemia (Lee et al, 2000b;Kim et al, 2004). The potential of therapeutic angiogenesis has been validated in various animal models of limb or myocardial ischemia and recently in patients treated with VEGF and bFGF Harada et al, 1994;Kim et al, 1994;Unger et al, 1994;Lazarous et al, 1996;Koh et al, 2002;Yamamoto et al, 2003;Hughes et al, 2004). Gene transfer can be an effective means to provide localized delivery of a high concentration of angiogenic growth factors to the ischemic tissue.…”