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Ann Thorac Surg 1998;65:1540-1544
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Therapeutic Angiogenesis With Basic Fibroblast Growth Factor: Technique and Early Results

^a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
^b Angiogenesis Research Center, Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
^c Department of Radiology at Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Address reprint requests to Dr Sellke, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, East Campus, Dana 905, 330 Brookline Ave, Boston, MA 02215
e-mail: (fsellke{at}bidmc.harvard.edu)

Presented at the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.

	Abstract

Top Abstract Introduction Material and methods Results Comment Discussion Acknowledgments References

 
Background. Patients not amenable to complete myocardial revascularization by conventional methods present a difficult clinical problem. Here we present the early results and technical considerations of the administration of basic fibroblast growth factor for the induction of collateral growth using heparin-alginate slow-release devices in patients undergoing coronary artery bypass grafting.

Methods. Eight patients were enrolled. Patients were candidates if they had at least one graftable obstructed coronary artery and at least one major arterial distribution not amenable to revascularization, a serum creatinine level less than 3 mg/dL, ejection fraction greater than 0.20, and estimated operative mortality of less than 25%. During conventional coronary artery bypass grafting, 10 heparin-alginate devices, each containing either 1 µg or 10 µg of basic fibroblast growth factor, were implanted in the epicardial fat in multiple regions of the unrevascularizable territory and also in the distal distribution of a grafted or patent artery.

Results. There was no mortality and no evidence of renal, hematologic, or hepatic toxicity during follow-up. Three months after the operation, all patients remain free of angina. Seven patients were examined with stress perfusion scans. Three patients had clear enhancement of perfusion to the unrevascularized myocardium, 1 patient had a new fixed defect, and 3 had minimal overall change but had evidence of new small, fixed perfusion defects. Seven patients had improved or similar myocardial contractile function (ejection fraction at 3-month follow-up = 0.53 ± 0.22 versus 0.47 ± 0.14 preoperatively). One patient suffered a perioperative myocardial infarction in the area of basic fibroblast growth factor administration.

Conclusions. This preliminary study demonstrates the safety and technical feasibility of therapeutic angiogenesis with basic fibroblast growth factor delivered by heparin-alginate slow-release devices. Further studies examining the safety, clinical efficacy, and long-term results are ongoing.

	Introduction

Top Abstract Introduction Material and methods Results Comment Discussion Acknowledgments References

 
Patients with severe, symptomatic coronary artery disease not amenable to percutaneous transluminal angioplasty or coronary artery bypass grafting present a difficult clinical problem. Options for the management of these patients have been continued medical treatment with generally poor results and a significant risk of future cardiac events, investigational transmyocardial laser revascularization, and high-risk intervention despite the likelihood of a poor long-term outcome. Therapeutic angiogenesis using naked DNA plasmids encoding angiogenic growth factors, DNA delivered by an adenoviral or liposomal vector, or the administration of authentic growth factor proteins has been advocated to improve perfusion in ischemic regions of myocardium [1, 2] and in patients with peripheral vascular disease [3]. Although both gene transfection and growth factor protein delivery have relative advantages and disadvantages, the delivery of the protein as opposed to the DNA encoding the protein has a potential advantage of simplicity, consistent delivery, and safety [2]. Basic fibroblast growth factor (bFGF) is a 16-kD single-chain peptide in the fibroblast growth factor family with both angiogenic and mitogenic potential. Basic fibroblast growth factor and other angiogenic protein growth factors have been reported to improve myocardial perfusion and function in animals models of acute [4, 5] and chronic myocardial ischemia [6–8]. Recently, Lopez and colleagues [9] demonstrated that this angiogenic effect of bFGF is dose-dependent. Here we present the early results and technical considerations of therapeutic angiogenesis using bFGF protein contained in heparin-alginate slow-release microcapsules in 8 patients with symptomatic, severe coronary artery disease not amenable to complete revascularization by either percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. This preliminary phase I trial was intended to determine the feasibility and safety of bFGF administration with heparin-alginate devices. It was anticipated that some indication of efficacy would also be evident during the postoperative evaluation.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Discussion Acknowledgments References

 
Patient selection
Patients were candidates for this phase I trial if they had severe, symptomatic coronary artery disease with at least one major coronary arterial myocardial territory demonstrably ischemic and viable, and not amenable to complete revascularization by either percutaneous transluminal coronary angioplasty or coronary artery bypass grafting because of the severe diffuse nature of the atherosclerotic disease. In addition, at least one graftable diseased arterial territory was required for enrollment. Other exclusion criteria included left ventricular ejection fraction less than 0.20, significant valvular disease requiring concomitant valve replacement or repair, serum creatinine level greater than 3 mg/dL, a history of malignancy, or an estimated operative mortality greater than 25%. Preoperative resting thallium and exercise sestamibi technetium scans were performed to ensure viability and ischemia in the myocardial territory of interest. Baseline complete blood count, measurement of serum electrolytes and serum creatinine level, liver function tests, urinalysis, electrocardiography, and chest radiography were performed before the operation. This study was approved by the Clinical Research Committee of Beth Israel Deaconess Medical Center and conducted under a physician-initiated investigational new drug authorization from the Food and Drug Administration. All patients in the study were treated at Beth Israel Deaconess Medical Center.

Preparation of bFGF-containing heparin-alginate beads
Basic fibroblast growth factor (human recombinant, 155 amino acids) was obtained from Scios, Inc, Mountain View, CA. Calcium alginate microcapsules served as a stable platform for bFGF, enhanced retention of activity and storage time, and served as a means for the controlled release of bFGF to the vessels in vivo. As previously described [10], heparin-sepharose beads (Pharmacia LKB, Piscataway, NJ) were sterilized under ultraviolet light for 30 minutes and then mixed with filter-sterilized sodium alginate (1.2%, weight/volume; Sigma, St. Louis, MO). The mixed slurry was dropped through a needle into a beaker containing a hardened solution of CaCl₂ (1.5% weight/volume). Microcapsules were formed instantaneously. Uniformly crosslinked capsule envelopes were obtained by incubating the capsules in the CaCl₂ solution for 5 minutes under gentle mixing, and then for 10 minutes without mixing. The microcapsules were washed three times with sterile water and stored in 0.9% NaCl/1 mmol/L CaCl₂ at 4°C. Each capsule in its hydrated state contained 0.05 mg heparin-sepharose, 0.18 mg of alginate, and 11 mg of water. Basic fibroblast growth factor (1 or 10 µg/microcapsule) was incorporated within the microcapsule after calcium alginate matrix formation and hardening by incubation in 0.9% CaCl₂/1 mmol/L CaCl₂/0.05% gelatin with bFGF for 16 hours under gentle agitation at 4°C. Beads were sterilized with gamma radiation for 15 minutes and stored in sterile saline solution at 4°C before use. The release of bFGF from heparin-alginate beads is under first-order kinetics, at a rate of approximately 30 or 300 ng/day, and complete after 3 to 4 weeks [11].

Surgical procedure and implantation of bFGF-containing beads
Patients were prepared and draped in the usual sterile manner and given perioperative cefazolin. A sternotomy was performed and patients were heparinized and cannulated in preparation for cardiopulmonary bypass. After activated clotting time was determined to be greater than 500 seconds, total cardiopulmonary bypass was instituted, ventilation was discontinued, and patients were systemically cooled to 28° to 30°C. After the aorta was clamped, 0.8 to 1.0 L of cold blood cardioplegic solution was infused into the aortic root with a mean pressure of 50 to 70 mm Hg. Infusion of 200 to 500 mL was repeated at 10- to 20-minute intervals. Cold saline solution was used to provide topical hypothermia. Distal coronary anastomoses were performed first. Systemic rewarming was initiated before the final distal anastomosis. After all distal anastomoses were completed, ten heparin-alginate beads each containing either 1 or 10 µg of bFGF (10 µg or 100 µg of total bFGF, respectively) were implanted into the epicardial fat or subepicardium in the nongraftable myocardial region in pockets through 2- to 3-mm stab incisions. One to four beads were placed in each pocket both in the ischemic territory and in the border territory of a grafted or patent coronary artery (Fig 1). The epicardial stab incisions were closed with 5-0 polypropylene suture. Proximal anastomoses were then performed while the aorta was still clamped. After rewarming was complete, the aorta was unclamped and ventilation was resumed. Patients were separated from cardiopulmonary bypass, decannulated, and closed routinely. Two to six heparin-alginate beads from each batch were cultured aerobically and anaerobically to ensure sterility.

View larger version (32K): [in this window] [in a new window]   Fig 1. Placement of heparin-alginate beads containing basic fibroblast growth factor (bFGF) in the nongraftable ischemic right coronary artery myocardial territory and border zone between the ischemic right coronary artery and grafted left anterior descending coronary artery territories.

	Results

Top Abstract Introduction Material and methods Results Comment Discussion Acknowledgments References

 
Eight patients (5 men, 3 women) were enrolled into this unblinded phase I study. One patient had previously undergone coronary artery bypass grafting. The mean age was 66 ± 6 years (range, 55 to 73 years). Two patients were diabetic (1 insulin-dependent). Preoperative ejection fraction was 0.47 ± 0.14. An average of 3.1 ± 0.8 arteries were grafted, and all patients received one internal mammary artery graft. Preoperative intraaortic balloon counterpulsation had been placed in 2 patients. All patients were successfully separated from cardiopulmonary bypass. Heparin-alginate bFGF beads were placed in the right coronary artery distribution in 4 patients, and they were placed in the circumflex artery territory in 4 patients. Four patients received a total of 10 µg of bFGF and 4 patients received 100 µg of bFGF. All patients were discharged an average of 5 days after coronary artery bypass grafting (range, 4 to 8 days).

Hemodynamic and physiologic data
There were no significant acute effects on blood pressure or heart rate (mean arterial pressure was 91 ± 13 mm Hg at baseline and 93 ± 8 mm Hg 4 days postoperatively) (Table 1). Pharmacokinetic evaluation did not reveal any significant increase in serum levels of bFGF above baseline (17.4 ± 3.4 pg/mL at baseline versus 16.0 ± 1.8 pg/mL at 96 hours) (see Table 1). There were no acute or long-term (3 months) effects on serum creatinine level, hematologic profile, liver function tests, or urinalysis. All patients remained free of angina at 3 month follow-up. There were no deaths or subsequent need for revascularization.

Perfusion scanning
One patient refused postoperative myocardial perfusion scanning. Resting thallium and exercise sestamibi technetium scans performed on 7 patients 3 months after the operation demonstrated markedly enhanced perfusion to the nonbypassed myocardium in 3 patients (2 receiving 10 µg of bFGF and 1 receiving 100 µg). In 3 patients, minimal overall change was observed in the region of interest. However, small fixed perfusion defects were detected in the bFGF-treated myocardial territory. One patient in whom bFGF beads were applied to the right coronary artery distribution suffered a perioperative inferior myocardial infarction and had a new fixed perfusion defect. This patient’s global ejection fraction decreased from a preoperative value of 0.35 to 0.28 3 months after the operation. Seven patients had improved or similar contractile function and ejection fraction compared with that before the operation and remained free of angina (global ejection fraction, 0.47 ± 0.14 versus 0.53 ± 0.22, preoperative versus 3 months postoperative, respectively) (Fig 2).

View larger version (85K): [in this window] [in a new window]   Fig 2. Resting thallium (REST TL) and exercise sestamibi (EX MIBI) technetium scans demonstrating improved perfusion at rest and during exercise in the nongrafted inferior wall (arrows) myocardium 3 months after (B) placement of heparin-alginate beads containing basic fibroblast growth factor compared with that before (A) placement of beads. (ANT = anterior; AP = apex; HLA = horizontal long axis; INF = inferior; SA = short axis; SEP = septal; VLA = vertical long axis.)

	Comment

Top Abstract Introduction Material and methods Results Comment Discussion Acknowledgments References

The relative benefits and risks and problems of using angiogenic growth factor protein as opposed to the DNA encoding the growth factors deserve mention. Growth factor protein administration does not require the incorporation of DNA into the nucleus of recipient tissue and thus has the benefit of simplicity and predictability of dose. Presently, the cost of large-scale production of high-grade protein may be greater than that of a relatively small amount of DNA. However, with the widespread use of bFGF and other angiogenic proteins for clinical use, the cost of production will decrease. The potential problems associated with all forms of therapeutic angiogenesis need to be considered. Angiogenic growth factors may increase the growth or expression of dormant or suppressed malignancies. Furthermore, type 1 diabetic patients may be at risk for the development of retinal neovascularity and renal insufficiency. Viral vectors used in gene transfer have created few clinical problems thus far. However, foreign DNA taken up by a virus could conceivably be transformed into a virulent pathogen. The optimal method to induce angiogenesis needs to be investigated, and the best growth factor or combination of growth factors will be examined. Basic fibroblast growth factor and vascular endothelial growth factor have been found to be synergistic in vivo [17]. Also, the optimal route of administration, method of delivery, and toxicity will likely be resolved in the future.

Presently, patients with inoperable coronary artery disease or who are incompletely revascularized have a poor long-term prognosis. Transmyocardial laser revascularization may be of some benefit, but its efficacy is still being debated and the outlook for its widespread use appears doubtful at present. Therapeutic angiogenesis using bFGF or other angiogenic growth factors has been found to be feasible and safe. However, the efficacy of bFGF-induced angiogenesis in providing clinically significant treatment for severe coronary artery disease will be the subject of future investigation.

	Discussion

Top Abstract Introduction Material and methods Results Comment Discussion Acknowledgments References

 
DR TODD K. ROSENGART (New York, NY): Doctor Sellke, I congratulate you on your pioneering work, including institution of this clinical trial.

We have now administered vascular endothelial growth factor to 3 patients, using an adenovirus as the transfection vector. All 3 have done well. Our study was designed very similar to yours. Our question now as we begin to analyze results, and as you have alluded to, is the importance of a watershed effect based on collaterals from bypass vessels. My first question is, do you have any data regarding the baseline occurrence of collateralization in standard coronary bypass patients, and are you going to be looking at that in any way? Second, would not angiography be useful in terms of defining the collaterals, and do you have any intentions of including angiography in your studies?

DR SELLKE: To answer your first question, everyone with coronary disease has a degree of collateralization. Some patients have an occluded left anterior descending artery and have very little functional detriment. However, we tend to operate on patients with anginal symptoms. Therefore, in most cases, collateralization is not complete. The way to answer your question is to add a control arm in which the heparin alginate slow-release devices are administered without concurrent administration of basic fibroblast growth factor. We have now initiated a phase II clinical trial with the addition of this control arm, so hopefully we will know the answer to your question soon.

Angiography will pick up collateral vessels of a certain size, those greater than several hundred micrometers in diameter. However, many of these collaterals are similar to what you see in the porcine model. They are of small caliber and do not show up very well on angiography. However, they do have physiologic importance. Angiography therefore may have some utility in detecting new collateral vessel formation; however, magnetic resonance imaging and perhaps other perfusion studies may be a better gold standard.

DR BRUCE W. LYTLE (Cleveland, OH): I have one question. In your abstract you state that all patients examined demonstrated enhanced perfusion to the unrevascularized myocardium and improved or similar myocardial contractile function by magnetic resonance imaging and a near-normal stress test. Let me make certain that I understand this. When you showed your thallium scans you said that 3 patients got better and the rest of them did not.

DR SELLKE: Right.

DR LYTLE: Now, are you saying, then, that by magnetic resonance imaging all of them looked good in terms of increased perfusion?

DR SELLKE: When we initially looked at the scans, it appeared like there was clear enhancement. But, again, you have to compare the ungrafted area with the normally perfused or grafted territory. So it is difficult to know the absolute change just on a thallium or a sestamibi scan. What I am presenting here is the more conservative estimate, whereas in the initial review, it appeared as if there was significant enhancement in all patients.

DR LYTLE: The reason for the discrepancy is that you went back over your scans and you changed your mind, is that right?

DR SELLKE: Exactly. What we present now is very conservative. There is probably efficacy, but I did not want to say that without knowing for sure.

	Acknowledgments

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Supported by National Institutes of Health grants R01 HL46716 (F.W.S.), M01-RR01032 (R.J.L.), R01 HL49039 (E.R.E.), R01 HL 58072 (J.D.P.), and R01 HL53793 and P50 HL 56993 (M.S.).

	References

Top Abstract Introduction Material and methods Results Comment Discussion Acknowledgments References

 

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