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(Circulation. 2003;107:2677.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
From A.I. Virtanen Institute, University of Kuopio (M.H., O.N., S.Y.-H.); the Department of Medicine, Kuopio University Hospital (M.H., J.H., A.H., A.K., S.S., A.R., K.P., M.L., S.Y.-H.), and the Department of Cardiology, University of Helsinki and Helsinki University Central Hospital (M.S., J.S., M.S.N.); the Department of Clinical Physiology and Nuclear Medicine (E.V., H.M., E.K., S.S.,) and the Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland (S.Y.-H.).
Correspondence to Dr Seppo Ylä-Herttuala, A.I. Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. E-mail Seppo.YlaHerttuala{at}uku.fi
| Abstract |
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Methods and Results Patients with coronary heart disease (n=103; Canadian Cardiovascular Society class II to III; mean age, 58±6 years) were recruited in this randomized, placebo-controlled, double-blind phase II study. PTCA was performed with standard methods, followed by gene transfer with a perfusion-infusion catheter. Ninety percent of the patients were given stents; 37 patients received VEGF adenovirus (VEGF-Adv, 2x1010 pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 µg of DNA with 2000 µL of DOTMA:DOPE [1:1 wt/wt]), and 38 control patients received Ringers lactate. Follow-up time was 6 months. Gene transfer to coronary arteries was feasible and well tolerated. The overall clinical restenosis rate was 6%. In quantitative coronary angiography analysis, the minimal lumen diameter and percent of diameter stenosis did not significantly differ between the study groups. However, myocardial perfusion showed a significant improvement in the VEGF-Adv-treated patients after the 6-month follow-up. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups.
Conclusions Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows that (1) intracoronary gene transfer can be performed safely (no major gene transfer-related adverse effects were detected), (2) no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and (3) a significant increase was detected in myocardial perfusion in the VEGF-Adv-treated patients.
Key Words: cardiovascular diseases gene therapy angioplasty stents perfusion
| Introduction |
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See p 2635
Optimization of angioplasty procedure and the use of stents have reduced the frequency of restenosis.15 Recent experiments with drug-coated stents have further improved the success of angioplasty.16 Still, there is evidence of increased cell proliferation, macrophage infiltration, and even neovascularization in the stented arterial segments.17 Local gene therapy is an option that might be used to treat both restenosis/in-stent restenosis and myocardial ischemia.1,4
Vascular endothelial growth factor (VEGF) accelerates endothelial repair by stimulating endothelial cell migration and proliferation.18 In addition to having several cytoprotective properties, it induces angiogenesis, especially in ischemic tissues.1,5 Adenoviruses have shown their potential in vascular gene transfer.8,10 Liposomes may be safer than adenoviruses,9 but their gene transfer efficiency is clearly lower than that of adenoviruses.3 In this study, we examined the safety and feasibility of VEGF-Adv and VEGF-P/L gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of myocardial ischemia.
| Methods |
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End Points
The primary end points were the minimal lumen diameter and percent diameter stenosis measured by quantitative coronary angiography (QCA) at 6-month follow-up. Secondary end points were myocardial perfusion, exercise tolerance, incidence of new cardiac events, emergency or elective angiography or revascularization, functional class, working ability, and need for peroral nitrates at 6-month follow-up. Safety of the local catheter-mediated VEGF gene transfer was also assessed.
PTCA and Gene Transfer
PTCA and stenting were performed according to standard clinical practice, using the femoral approach. Arterial gene transfer was performed at the site of PTCA immediately after the angioplasty but before stent implantation, using an infusion-perfusion catheter (Dispatch catheter; Boston Scientific).9 All patients received aspirin and heparin. Patients receiving stents were prescribed ticlodipine or clopidogrel.
Adenoviruses and Plasmid/Liposomes
Human clinical grade E1-partial, E3-deleted, first-generation adenoviruses were used in this study.8,10 Adenoviruses containing a CMV-hVEGF165 expression cassette were produced under GMP in 293 cells as described.10 Adenoviruses were analyzed for the absence of replication-competent viruses by means of a cytopathic effect assay on A549 cells.8,19 Virus titers were determined by optical density at 260 nm (P:I ratio <35), and viral preparations were analyzed to be free of any microbiological or endotoxin contamination (<20 EU/dose, Whittaker). P/L complexes were prepared as follows: 2000 µg pCMV-hVEGF165 (1 mg/mL; GenBank AB021221) plasmid was complexed with 2000 µL of DOTMA:DOPE (1 mg/mL; 1:1; Valentis Inc) and diluted with 1000 µL Ringers solution.9,10 Plasmids used for the study were manufactured under GMP and analyzed to be free of any microbiological or endotoxin contamination (<200 EU/dose) as described.9,10 Thirty-seven patients received VEGF-Adv, 28 patients received VEGF-P/L, and 38 control patients received Ringers lactate. Some patients were lost from the study after random assignment because of acute respiratory infections before the PTCA procedure, out-of-specification properties of the final P/L formulation, or interruption of the follow-up.
QCA Analysis
Coronary angiography of the target vessel was performed with standard techniques before PTCA, immediately after the gene transfer and stenting, and at the 6-month follow-up with prior intracoronary injection of nitroglycerin. QCA was performed with the use of the Cardiovascular Measurement System (version 3.0, Medis), as described.20 All QCA analyses were performed by a single observer, who was blinded to all clinical information.
Exercise Test and Myocardial Perfusion Imaging
A maximal symptom-limited exercise test was performed for a subgroup of patients with the use of a bicycle ergometer, with a protocol of 20 W as an initial workload with increments of 20 W/min, as described.21 Cardiac SPECT imaging was performed with 99mTc-sestamibi before and 6 months after the gene transfer with prior adenosine infusion (0.14 mg/kg per minute).22 Visual interpretation was performed with short-axis, vertical, and horizontal long-axis tomograms divided into 20 segments for each study. Segments were scored at rest and stress by consensus of two experienced observers using a 5-point scoring system (0=normal; 1=equivocal; 2=moderate; 3=severe reduction; 4=absence of uptake). The final result was expressed as a
score (perfusion score at rest minus perfusion score during adenosine infusion), which indicates the severity of myocardial ischemia.22 The observers were blinded for clinical findings, treatment groups, and time of the analysis.
Safety Analyses
Patients were followed at the hospital for 48 hours. Clinical chemistry was analyzed at Kuopio University Hospital Central Laboratory according to ISO9002 standards before PTCA and 2, 7, 14, and 35 days and 6 months after the gene transfer. Anti-Adv antibody levels were measured before and 2 weeks after the gene transfer. Serum VEGF and interleukin-6 (IL-6) concentrations were analyzed by means of specific ELISA tests (Quantikine; R&D Systems, DVE00 and D6050) and the presence of transgene in serum and urine by a specific PCR.10 All patients were sent a questionnaire 14 to 47 months after the gene transfer to evaluate late outcome of the procedure; 92 patients responded to the questionnaire.
Statistical Analysis
The differences between the treatment groups were calculated by means of ANOVA and Bonferronis modified t test for continuous variables and
2 test for dichotomous variables. Nonparametric Wilcoxon test was used to calculate differences within the study groups (SPSS 9.0 program, SPSS Inc). Results were considered statistically significant at a value of P<0.05. The study was powered to detect a 25% difference at a value of P=0.05, with 80% probability at the 6-month follow-up.
| Results |
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Safety
During mean follow-up of 28 months (range, 14 to 47 months), 1 death was recorded in the VEGF-Adv group (Table 2). This patient died because of a previously undiagnosed, ruptured aortic aneurysm 20 months after the gene transfer. Two new cancers (malignant glioma and hypernephroma) were diagnosed in the VEGF-P/L group during the long-term follow-up. One patient in the VEGF-Adv group had sarcoidosal granulomas in the eye and parotid gland. Procedural complications occurred in 4 patients. Two patients had a "no flow" phenomenon and cardiac arrest during control angiography. One of these patients acquired aspiratory pneumonia and pseudomembranotic colitis as the result of antibiotic treatment. One control patient had a stroke a few hours after PTCA (Table 2). These complications were regarded as serious adverse events but not directly related to gene therapy.
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Regarding other adverse effects, fever was most frequent in the VEGF-Adv group (Table 2). An increase in anti-Adv antibodies was observed in 23 (62%) patients and a transient increase in serum CRP in 20 (54%) patients in the VEGF-Adv group. An increase in anti-Adv antibodies in some control patients was probably due to acute respiratory infections. Other laboratory values did not show any major differences except a transient decrease in the platelet count in all study groups and an increase in LDH in the VEGF-Adv patients (Table 3
). Serum IL-6 level was increased in all study groups 2 days after the gene transfer, and it was highest in the VEGF-Adv group. No increases were detected in serum VEGF levels in the treated groups (Table 3
). No transgene was detected in serum or urine 2 days after the gene transfer.
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Procedural Outcome and Clinical Measurements
A stent was implanted in 92 (90%) patients because an optimal result was not achieved with PTCA. There were no significant differences in minimal lumen diameter or percent of luminal stenosis between the study groups before or immediately after the procedure (Table 4). The overall clinical restenosis rate was 6%. Three patients in the VEGF-Adv group and 3 patients in the control group had clinical restenosis of CCS class II to III angina pectoris during the 6-month follow-up. Three patients in the VEGF-Adv group were treated with coronary bypass operation and 3 patients in the control group with repeated PTCA. Two patients in the control group had acute myocardial infarction (Table 2).
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Of the secondary end points, a significant improvement in myocardial perfusion was detected in the VEGF-Adv group after the 6-month follow-up (Figure). Functional capacity and exercise time in the stress exercise test tended to improve in all study groups (Figure, b and c). No statistically significant differences were observed between the study groups in CCS classification, working ability, or in the need of peroral nitrates (Table 5).
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| Discussion |
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VEGF-Adv or VEGF-P/L administered immediately after PTCA did not have any effects on the percentage of luminal stenosis or minimal lumen diameter as measured by QCA at 6-month follow-up. It is important to note that despite the prolonged catheterization and introduction of the gene transfer catheter, a very low overall restenosis rate (6%) was observed. The frequency of clinical events was also similar among the study groups. No signs of progression of atherosclerosis were detected in the treated patients. However, we saw a significant improvement in regional myocardial perfusion in the VEGF-Adv group. Even though unlikely, we cannot fully exclude a possibility that the adenoviral vector itself could have contributed to the results since, for ethical reasons, we could not use a control group with an empty adenovirus. However, preclinical studies do not support the possibility that adenoviruses could cause beneficial effects without expressed transgenes.24
We saw transient fever and increases in serum CRP and LDH levels in the VEGF-Adv group. Systemic inflammatory reactions may be caused by a systemic release of the Adv-vector, followed by the production of cytokines in the liver, macrophages, and dendritic cells. It is interesting to note that fever was also detected in some VEGF-P/L patients, which is probably due to the higher level of endotoxin in the GMP-grade plasmids than in the adenoviruses. Liposomes may also contain some peroxidized lipids that may contribute to the transient fever reaction. Increase in the LDH level in the VEGF-Adv group may indicate some liver reactions, although no significant changes were seen in transaminases.
During the mean follow-up of 28 months, 1 death was recorded. This occurred in a VEGF-Adv-treated patient and was due to a rupture of a previously undiagnosed aortic aneurysm. The patient was a 70-year-old man with universal atherosclerosis, and the death was considered to be unrelated to gene therapy. Two new cancers (malignant glioma and hypernephroma) were diagnosed in the VEGF-P/L group during the long-term follow-up. Both malignancies were found more than 2 years after the gene transfer. In the VEGF-Adv group, one patient underwent surgery for sarcoidosis in the eye and parotid gland 2 years after the gene transfer. However, these incidences do not differ from those seen in the general population, since according to Finnish Cancer Register, we could anticipate 0.5 to 1 new cancers per 100 persons per year in the general population of this age group.25 It is evident that longer follow-up times are needed to determine cancer incidences after the VEGF gene therapy.
In conclusion, results of the current study suggest that catheter-mediated intracoronary gene transfer is safe and well tolerated. The treatment did not affect the incidence of postangioplasty restenosis, but a significant improvement was seen in myocardial perfusion in the VEGF-Adv-treated patients.
| Acknowledgments |
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| Footnotes |
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Received December 31, 2002; accepted February 28, 2003.
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R. Morishita, M. Aoki, and T. Ogihara Does gene therapy become pharmacotherapy? Exp Physiol, May 1, 2005; 90(3): 307 - 313. [Abstract] [Full Text] [PDF] |
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J. Kastrup, E. Jorgensen, A. Ruck, K. Tagil, D. Glogar, W. Ruzyllo, H. E. Botker, D. Dudek, V. Drvota, B. Hesse, et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris: A randomized double-blind placebo-controlled study: The Euroinject One trial J. Am. Coll. Cardiol., April 5, 2005; 45(7): 982 - 988. [Abstract] [Full Text] [PDF] |
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M. Simons Angiogenesis: Where Do We Stand Now? Circulation, March 29, 2005; 111(12): 1556 - 1566. [Full Text] [PDF] |
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Y. Cao, A. Hong, H. Schulten, and M. J. Post Update on therapeutic neovascularization Cardiovasc Res, February 15, 2005; 65(3): 639 - 648. [Abstract] [Full Text] [PDF] |
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K.B. Bamford, S. Wood, and R.J. Shaw Standards for gene therapy clinical trials based on pro-active risk assessment in a London NHS Teaching Hospital Trust QJM, February 1, 2005; 98(2): 75 - 86. [Abstract] [Full Text] [PDF] |
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A. Chandiwal, V. Balasubramanian, Z. K. Baldwin, M. S. Conte, and L. B. Schwartz Gene Therapy for the Extension of Vein Graft Patency: A Review Vascular and Endovascular Surgery, January 1, 2005; 39(1): 1 - 14. [Abstract] [PDF] |
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A. H. Baker, A. Kritz, L. M. Work, and S. A. Nicklin Cell-selective viral gene delivery vectors for the vasculature Exp Physiol, January 1, 2005; 90(1): 27 - 31. [Abstract] [Full Text] [PDF] |
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C. Weber, A. Schober, and A. Zernecke Chemokines: Key Regulators of Mononuclear Cell Recruitment in Atherosclerotic Vascular Disease Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 1997 - 2008. [Abstract] [Full Text] [PDF] |
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F. Sharif, K. Daly, J. Crowley, and T. O'Brien Current status of catheter- and stent-based gene therapy Cardiovasc Res, November 1, 2004; 64(2): 208 - 216. [Abstract] [Full Text] [PDF] |
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I. Shiojima and K. Walsh The Role of Vascular Endothelial Growth Factor in Restenosis: The Controversy Continues Circulation, October 19, 2004; 110(16): 2283 - 2286. [Full Text] [PDF] |
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K. Ohtani, K. Egashira, K.-i. Hiasa, Q. Zhao, S. Kitamoto, M. Ishibashi, M. Usui, S. Inoue, Y. Yonemitsu, K. Sueishi, et al. Blockade of Vascular Endothelial Growth Factor Suppresses Experimental Restenosis After Intraluminal Injury by Inhibiting Recruitment of Monocyte Lineage Cells Circulation, October 19, 2004; 110(16): 2444 - 2452. [Abstract] [Full Text] [PDF] |
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M. Anton, C. Wittermann, R. Haubner, M. Simoes, S. Reder, B. Essien, B. Wagner, J. Henke, W. Erhardt, S. Noll, et al. Coexpression of Herpesviral Thymidine Kinase Reporter Gene and VEGF Gene for Noninvasive Monitoring of Therapeutic Gene Transfer: An In Vitro Evaluation J. Nucl. Med., October 1, 2004; 45(10): 1743 - 1746. [Abstract] [Full Text] [PDF] |
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G.M Rubanyi The design and preclinical testing of Ad5FGF-4 to treat chronic myocardial ischaemia Eur. Heart J. Suppl., September 1, 2004; 6(suppl_E): E12 - E17. [Abstract] [Full Text] |
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L. Ye, H. K Haider, S.-J. Jiang, and E. K. Sim Therapeutic Angiogenesis Using Vascular Endothelial Growth Factor Asian Cardiovasc Thorac Ann, June 1, 2004; 12(2): 173 - 181. [Abstract] [Full Text] [PDF] |
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O. Leppanen, J. Rutanen, M. O. Hiltunen, T. T. Rissanen, M. P. Turunen, T. Sjoblom, J. Bruggen, G. Backstrom, M. Carlsson, E. Buchdunger, et al. Oral Imatinib Mesylate (STI571/Gleevec) Improves the Efficacy of Local Intravascular Vascular Endothelial Growth Factor-C Gene Transfer in Reducing Neointimal Growth in Hypercholesterolemic Rabbits Circulation, March 9, 2004; 109(9): 1140 - 1146. [Abstract] [Full Text] [PDF] |
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J. Rutanen, T. T. Rissanen, J. E. Markkanen, M. Gruchala, P. Silvennoinen, A. Kivela, A. Hedman, M. Hedman, T. Heikura, M.-R. Orden, et al. Adenoviral Catheter-Mediated Intramyocardial Gene Transfer Using the Mature Form of Vascular Endothelial Growth Factor-D Induces Transmural Angiogenesis in Porcine Heart Circulation, March 2, 2004; 109(8): 1029 - 1035. [Abstract] [Full Text] [PDF] |
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D. W. Losordo, J. M. Isner, and L. J. Diaz-Sandoval Endothelial Recovery: The Next Target in Restenosis Prevention Circulation, June 3, 2003; 107(21): 2635 - 2637. [Full Text] [PDF] |
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