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Ann Thorac Surg 2003;75:S685-S690
© 2003 The Society of Thoracic Surgeons

II: Surgical myocardial protection

Vascular growth factors and angiogenesis in cardiac surgery

Frank W. Sellke, MDa*, Marc Ruel, MD, MPHa

a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

* Address reprint requests to Dr Sellke, Division of Cardiothoracic Surgery, BIDMC, LMOB 2A, 110 Francis Street, Boston, MA 02215, USA
e-mail: fsellke{at}caregroup.harvard.edu

Presented at the 3rd International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002.

Abstract

Therapeutic angiogenesis, in the form of growth factor protein administration or gene therapy, has emerged as a new method of treatment for patients with severe, inoperable coronary artery disease. Improved myocardial perfusion and function after administration of angiogenic growth factors has been demonstrated in animal models of chronic myocardial ischemia. Recently, preliminary clinical trials using growth factor proteins or genes encoding these angiogenic factors have demonstrated clinical and other objective evidence of relevant angiogenesis. A recent study reported beneficial long-term effects of therapeutic angiogenesis using fibroblast growth factor (FGF)–2 protein in terms of freedom from angina and perfusion on single-photon emission computed tomographic imaging. Thus, therapeutic angiogenesis has the potential to extend treatment options to patients who are not optimal candidates for conventional methods of myocardial revascularization. However, endogenous antiangiogenic influences, intrinsic lack of response of patients with severe endothelial dysfunction, and other limitations will need to be overcome before angiogenesis becomes a standard therapy for the treatment of patients with severe coronary disease.

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in the western world. Treatment has been based on pharmacologic agents and on methods that restore myocardial perfusion, such as percutaneous coronary interventions and coronary artery bypass grafting (CABG). These treatments are effective and have reduced the death rate from CAD. However, up to 15% of patients either cannot undergo these procedures or receive incomplete revascularization by these techniques [1,2], usually because of diffuse inoperable coronary disease. The failure to revascularize even a single ischemic myocardial territory because of poor graftability is associated with decreased survival and freedom from angina, regardless of the presence of a patent left internal thoracic artery bypass to the left anterior descending coronary artery [3]. These patients therefore continue to experience residual myocardial ischemia despite maximal medical therapy, and are in need of an alternative revascularization strategy such as therapeutic angiogenesis.

Three different types of neovascularization can occur in mature adult tissues: true angiogenesis, arteriogenesis, and vasculogenesis [4]. True angiogenesis refers to the formation of thin-walled, endothelium-lined blood vessels lacking a smooth muscle layer. Arteriogenesis is the growth of arteries that possess a fully developed tunica media and smooth muscle wall. Vasculogenesis is the formation of new vascular structures from stem cells, as is seen during embryonic development. Despite some evidence that vasculogenesis may be involved in new vessel development within mature adult tissue, the significance of this process remains to be proved [5, 6]. Several investigators believe that arteriogenesis may be required to significantly improve myocardial perfusion, and that true angiogenesis or vasculogenesis alone does not provide enough blood flow to result in alleviation of myocardial ischemia [4].

Growth factors, delivery strategies, and surgical technique

Despite the complexity of the angiogenic process, therapeutic angiogenesis regimens have mainly focused on the administration of a single growth factor, with select isoforms of vascular endothelial growth factor (VEGF)–A (VEGF121, VEGF165) and FGF (FGF-1, FGF-2) being the most extensively studied angiogenic drugs (Table 1). Growth factor proteins may be administered either directly or through gene-based approaches, using naked plasmid DNA or a viral vector that encodes the gene to be incorporated by the host endothelial cells. Advantages of gene-based therapy include the potential for persistent long-term expression of an angiogenic gene, as well as the ability to target this gene to a specific tissue or cell type (Table 2). However, the local concentration of the angiogenic factor is highly dependent on the level of expression of its gene (which is difficult to regulate), and safety concerns exist regarding the exposure of patients to foreign genetic material and viral vectors. Furthermore, preformed antibodies and inflammatory responses may significantly limit the effectiveness of gene transfection methods and increase the likelihood of inactivation with readministration. At present, protein therapy may seem more likely to reach common clinical use than gene therapy, as dosing of the angiogenic factor at the time of administration, pharmacokinetics, and tissue therapeutic levels are much more predictable. Furthermore, the use of surgically implanted, slow-release delivery systems allows prolonged exposure and compensates for the short biological half-life of angiogenic proteins.


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  		Table 1. Angiogenic Substances Used Experimentally (Partial Listing)

 

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  		Table 2. Characteristics of Protein Versus Gene Therapy

 
"Master-switch" regulatory genes such as hypoxia-inducible factor (HIF)-1{alpha}, PR39, and relaxin are genes capable of inducing expression of a number of growth factor families as well as molecules such as nitric oxide and substance P [7, 8]. Clinical trials are currently underway to examine the effects of exogenous HIF-1{alpha} stimulation. Still, there are safety concerns related to the high number of genes that are upregulated as a result of induction of these master-switch genes.

Whether gene or protein therapy is chosen for angiogenesis therapy, a practical delivery strategy is required. In addition to a surgical perivascular route, several routes of administration have been developed to deliver angiogenic substances to the ischemic myocardium in a single or repeated fashion, such as intravenous, intracoronary, left atrial, intrapericardial (through a catheter placed under echocardiographic guidance), and catheter-based intramyocardial approaches. Many nonsurgical approaches, with the exception of LV electromechanical mapping and catheter-based myocardial injections [9], are less specific than surgical perivascular delivery in their tissue distribution. In studies of swine, Laham and colleagues [5] showed that the liver accounted for the majority of iodine-125 (I125)–labeled FGF-2 activity after intracoronary and intravenous administration, and that total cardiac specific activity at 1 hour was 0.88% for intracoronary and 0.26% for intravenous administration, further decreasing to 0.05% and 0.04% at 24 hours, respectively. In another study comparing the distribution of intravenous injections of FGF-2 with that of perivascular sustained-release delivery, the amount of FGF-2 deposited in arteries adjacent to sustained-release devices was 40 times that deposited in animals who received a single intravenous bolus of FGF-2 [10]. FGF-2 was 5- to 30-fold more abundant in the kidney, liver, and spleen after intravenous injection than after perivascular release.

The surgical perivascular implantation of angiogenic growth factors can be conducted in conjunction with CABG or as sole therapy [11, 12]. Both strategies are potentially amenable to the use of minimally invasive approaches in combination with multivessel off-pump CABG, ipsilateral or contralateral MIDCAB, or as a sole therapy (through a subxiphoid or small thoracotomy incision). In the future, the safe implantation of angiogenic growth factors by means of a closed-chest, videoscopic approach could constitute the ideal method of delivery.

Although a surgical approach can be used for the administration of virtually any type of angiogenic protein or gene vector, most of the experience has involved perivascular delivery of FGF-2 protein using sustained-release beads implanted at the time of CABG (Fig 1) [11, 13, 14]. Controlled release of the FGF-2 is derived from its avidity for heparin, which is bound to sepharose beads and hardened into a capsule using a calcium chloride-alginate solution, without causing any substantial reduction in the biological activity of FGF-2 [10, 15, 16]. Once implanted, release of FGF-2 from the polymer occurs by means of first-order kinetics over a 4- to 5-week period, with no inflammatory reaction resulting from polymer placement.



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  		Fig 1. Implantation of sustained-release FGF-2 beads in the myocardial distribution of an ungraftable right coronary artery, in conjunction with coronary artery bypass grafting. FGF-2 = fibroblast growth factor-2; LAD = left anterior descending coronary artery; LCx = left circumflex artery; LVB = left ventricular branches of the right coronary artery; PDA = posterior descending artery. Adapted with permission from [11].

 
Perivascular implantation of FGF-2 using this delivery system in conjunction with CABG was first reported in 1998 [11]. The procedure is carried out through a median sternotomy (Fig 1) [11, 13]. After the institution of total cardiopulmonary bypass and cardioplegic arrest, distal coronary anastomoses are performed on graftable coronaries, and the nongraftability of the target territory is confirmed by direct inspection of the vessel. Multiple linear incisions are made in the epicardial fat surrounding the ungraftable vessel as well as in the transition zone between the target territory and that supplied by a grafted or patent coronary artery, to enable the development of subepicardial collaterals between ischemic and normally perfused myocardium. Ten heparin-alginate beads, each containing 1 or 10 µg of human recombinant FGF-2, are inserted into the subepicardium and secured in place with a 6-0 polypropylene suture, with up to three beads placed in a single incision. Proximal anastomoses are constructed, the patient is separated from cardiopulmonary bypass, and the sternotomy incision is closed. As a quality control measure, two to six heparin-alginate beads from each batch may be cultured aerobically and anaerobically to ensure sterility.

Clinical studies

Protein therapy
Perivascular delivery
The safety of surgical FGF-1 administration was demonstrated in a series of 20 patients conducted by Schumacher and colleagues [17] and by Pecher and Schumacher [18], who injected 0.01 mg/kg of FGF-1 directly into the myocardium along a diffusely diseased left anterior descending coronary artery to which the left internal thoracic artery was also grafted. Patients were followed up 12 weeks and 3 years later, when the left internal thoracic artery was selectively injected and the degree of anterior myocardial collateralization quantitatively evaluated by digital subtraction angiography. Although a local increase in collateral blush was observed along the left anterior descending coronary artery, nuclear imaging assessments of ischemia or functional variables such as exercise capacity, Candadian Cardiovascular Society (CCS) angina class, or freedom from angina recurrence were not reported.

The safety and efficacy of perivascular FGF-2 administration was evaluated in a phase I, double-blind, randomized controlled trial that involved 24 patients concomitantly undergoing coronary artery bypass surgery [13]. In this study, FGF-2 (10 or 100 µg) or placebo was delivered in the ungraftable myocardial territory of patients concomitantly undergoing CABG. Inclusion criteria included demonstration of an ischemic, viable myocardial territory supplied by a major coronary artery that was considered by both a cardiothoracic surgeon and an interventional cardiologist to be unamenable to bypass grafting or percutaneous intervention on the basis of its angiographic appearance. Patients with clinically significant valvular disease, left ventricular ejection fraction less than 20%, serum creatinine greater than 2.5 mg/dL, a history of malignancy in the previous 5 years, or a severe, fixed nuclear perfusion defect in the ungraftable territory were excluded from the study. Patients were followed up to a mean of 32 ± 7 months postoperatively with clinical assessment and nuclear perfusion imaging [14]. There were two late deaths, one from pancreatic cancer and one of undetermined cause (both in the 100-µg FGF-2 group). Two patients (both in the control group) underwent a total of six repeat cardiac catheterizations for recurrent coronary events. Mean CCS angina class improved from base line at 6 months and at late follow-up in all groups (p <= 0.02); however, patients treated with either dose of FGF-2 had significantly more freedom from angina recurrence than those treated with placebo (p = 0.03; Fig 2). Late nuclear perfusion scans revealed a persistent reversible or a new fixed perfusion defect in the ungraftable territory of 4 of 5 patients who received placebo, versus only 1 of 9 patients treated with FGF-2 (p = 0.02; Fig 3). The overall sum of LV stress perfusion defect scores was also lower in FGF-2–treated patients than in controls (1.3 ± 1.4 vs 3.9 ± 2.1, respectively; p = 0.04). A trend toward a higher late LVEF was noted in FGF-2–treated patients (55% ± 15% vs 44% ± 7%, FGF-2–treated vs control patients; p = 0.12). Significant reductions in the nuclear perfusion defects and target wall ischemic zones by magnetic resonance imaging were also observed at 6-month follow-up in the 100-µg group. Overall, these data suggested that surgical angiogenic therapy with sustained-release FGF-2 resulted in a prolonged myocardial revascularization effect that could translate into clinical benefit.



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  		Fig 2. Base line and 3 years postoperative single-photon emission computed tomographic imaging images of patients who received fibroblast growth factor–2 (FGF-2) versus placebo beads implanted in an ungraftable inferoapical myocardial territory at the time of coronary artery bypass grafting [14]. Horizontal long-axis views show complete resolution of the large inferoapical perfusion defect at rest and stress in the patient who received fibroblast growth factor–2, and no detectable change from base line in the patient who received placebo.

 


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  		Fig 3. Freedom from recurrent angina by treatment group, from the time of coronary artery bypass grafting. Patients treated with either dose of fibroblast growth factor–2 (FGF-2) had significantly more freedom from angina recurrence postoperatively than those who received placebo (log-rank test, p = 0.03). Adapted from [14], with permission.

 
Intravascular delivery
Laham and colleagues [19] conducted a phase I, open-label, dose-escalation trial that evaluated the efficacy and safety of a single-bolus intracoronary administration of FGF-2 in 52 patients, which suggested that this therapy may improve symptoms and myocardial perfusion. These investigators then proceeded to a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of FGF-2 at 0, 0.3, 3, or 30 µg/kg in 337 patients (FGF initiating revascularization trial) [20]. Efficacy was evaluated at 90 and 180 days by exercise tolerance test, nuclear perfusion imaging, and angina questionnaire. Exercise tolerance was increased at 90 days in all groups but was not significantly different between the placebo- and FGF-treated groups. FGF-2 reduced angina symptoms, and these differences were more pronounced in highly symptomatic patients with base line CCS angina class scores of III or IV. However, this benefit did not persist at 180 days because of continued improvement in the placebo group, and the trial was considered negative with respect to all main end points. Adverse events were similar across all groups, except with regard to hypotension, which occurred more frequently in the 30-µg/kg FGF-2 group.

Intravenous and intracoronary administration of VEGF were studied in a randomized, double-blind, phase II study, the VEGF in Ischemia for Vascular Angiogenesis (VIVA) trial [21, 22]. In this study, both treatment and placebo groups showed improved exercise tolerance but no overall improvement in the size of ischemic defects on stress nuclear imaging. It is possible that the effects of FGF-2 and VEGF in the FIRST and VIVA trials may have been jeopardized by the choice of intravascular delivery routes, which not only are nonspecific in their tissue distribution, but also carry the potential to worsen arteriosclerosis [23].

Gene therapy
Perivascular delivery
Rosengart and colleagues [24] have examined the effects of direct administration of an adenoviral vector encoding for VEGF121, either as an adjunct to conventional CABG (in 15 patients) or as sole therapy (in 6 patients). There was no control group in this phase I trial, and the main end points were related to safety. In this regard, no systemic or cardiac-related adverse events pertaining to vector administration were observed. All patients reported improvements in angina class, and postoperative nuclear imaging suggested increased contractility during stress conditions in the area of vector administration, but did not reveal an increase in myocardial perfusion.

Losordo and colleagues [25] initiated a small phase I trial to determine the safety and bioactivity of direct myocardial gene transfer (using naked plasmid DNA) of VEGF165 as sole therapy in 5 patients with inoperable CAD and symptomatic myocardial ischemia. The vector was administered by four 2.0-mL needle injections into the anterolateral left ventricular free wall through a small left anterolateral thoracotomy. The injections were not associated with any side effect other than isolated premature ventricular complexes at the time of needle penetration. All patients had a significant reduction in angina as measured by nitroglycerin use, improved collateral scores on angiography, and reduced size of the ischemic defect on dobutamine nuclear imaging. These data were reproduced in another open-label, uncontrolled study in which 20 patients received either 125 or 250 µg of naked plasmid VEGF121 injected directly into the myocardium through a minimally invasive thoracotomy [26]. Plasma VEGF concentrations increased at 14 days to a level two-fold over pretreatment values and returned to base line by 3 months. As in the previous study, patients reported decreased angina and reduced nitroglycerine use, and improvement was seen on radionuclide perfusion imaging [26].

Catheter-based delivery
A pilot study of catheter-based myocardial gene transfer involved 6 patients with chronic myocardial ischemia who were randomized to receive 200 µg of VEGF-2 or placebo [27]. A steerable, deflectable 8F catheter incorporating a 27-guage needle was advanced percutaneously and guided into the left ventricular myocardium by electromechanical mapping. Despite the small number of patients, end points of angina frequency, nitroglycerin consumption, and stress myocardial perfusion on nuclear imaging showed a trend in favor of the group transfected with VEGF-2 versus controls. These trends were confirmed in a subsequent phase 1/2 trial involving 19 patients by the same group of investigators [9].

Safety and efficacy issues

Although overexpression of VEGF in mice has been associated with formation of angiomas and vascular tumors [28, 29], the occurrence of these adverse events and of proliferative retinopathy has not been reported in any study of growth factor therapy that has involved humans or large animals. However, most of these studies were of short-term duration and may not have involved a sufficient number of animals or patients to detect these rare events.

Both VEGF and FGF-2 are known to be associated with systemic hypotension that occurs in a dose-dependent fashion; in this regard, the doses of FGF-2 leading to hypotension are substantially higher than for VEGF [30, 31]. FGF-2 has also been associated with proliferative membranous nephropathy leading to proteinuria in mice, but this has not been observed in preclinical or clinical studies [32, 33]. Still, FGF-2 should not be used in patients with decreased creatinine clearance.

One major efficacy issue is the role of NO and other endothelially derived substances in angiogenesis. There is an interaction between the local availability of NO and the regulation of blood vessel growth mediated by the actions of VEGF and FGF-2 [34–37]. Diminished NO availability has been implicated in the inhibition of spontaneous and exogenous angiogenic responses in hypercholesterolemic rodents [38, 39] and, recently, in preclinical, large-animal models of hypercholesterolemia-induced endothelial dysfunction (Ruel M, Sellke FW; submitted manuscript). Given these data and the fact that therapeutic angiogenesis is not nearly as effective in patients with inoperable CAD as it is in laboratory animals, the failure of effect observed in clinical trials may relate to a deficiency in the stimulated release of NO, whose production as well as that of other endothelium-derived substances is altered in end-stage CAD. The current clinical indications for angiogenic therapy may therefore paradoxically target a subgroup of patients for whom the modality is least likely to work, and it is possible that the clinical efficacy of angiogenesis may depend on concomitant functional modulation of the coronary microvascular endothelium. Research aimed at elucidating these questions is ongoing and may identify a missing link between successful animal models and relatively disappointing clinical trials of angiogenic therapy.

In conclusion, angiogenesis is a promising modality for the treatment of coronary disease. It is at present still experimental, reserved for selected patients with inoperable diffuse distal coronary disease, and best performed using a surgical, protein-based approach. With ongoing research efforts, it is likely that therapeutic angiogenesis will successfully and reproducibly recreate the natural process of vascularization that all humans undergo during growth and development, and will become a major modality for the treatment of coronary artery disease.

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Marc Ruel
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