CLINICAL RESEARCH: CLINICAL TRIAL
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
Jens Kastrup, MD*,
Erik Jørgensen, MD*,
Andreas Rück, MD ,
Kristina Tägil, MD ,
Dietmar Glogar, MD ,
Witold Ruzyllo, MD||,
Hans Erik Bøtker, MD¶,
Dariusz Dudek, MD#,
Viktor Drvota, MD ,
Birger Hesse, MD**,
Leif Thuesen, MD¶,
Pontus Blomberg, PhD ,
Mariann Gyöngyösi, MD ,
Christer Sylvén, MD, FACC ,* the Euroinject One Group
* Cardiac Catheterization Laboratory, University Hospital Rigshospitalet, Copenhagen, Denmark
** Department of Clinical Physiology and Nuclear Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
¶ Department of Cardiology, Skejby Sygehus, Aarhus, Denmark
Department of Cardiology, University of Vienna, Vienna, Austria
|| Institute of Cardiology, Warsaw, Poland
# Institute of Cardiology, Krakow, Poland
Department of Clinical Physiology, Malmö, Sweden
Department of Cardiology and Gene Therapy Center, Karolinska University Hospital at Huddinge, Karolinska Institutet, Stockholm, Sweden
Manuscript received August 5, 2004;
accepted December 6, 2004.
* Reprint requests and correspondence: Dr. Christer Sylvén, Department of Cardiology, M52, Karolinska University Hospital, SE-141 86 Stockholm, Sweden (Email: Christer.Sylven{at}medhs.ki.se).
OBJECTIVES: In the Euroinject One phase II randomized double-blind trial, therapeutic angiogenesis of percutaneous intramyocardial plasmid gene transfer of vascular endothelial growth factor (phVEGF-A165) on myocardial perfusion, left ventricular function, and clinical symptoms was assessed.
BACKGROUND: Evidence for safety and treatment efficacy have been presented in phase I therapeutic angiogenesis trials.
METHODS: Eighty "no-option" patients with severe stable ischemic heart disease, Canadian Cardiovascular Society functional class 3 to 4, were assigned randomly to receive, via the NOGA-MyoStar system (Cordis Corp., Miami Lakes, Florida), either 0.5 mg of phVEGF-A165 (n = 40) or placebo plasmid (n = 40) in the myocardial region showing stress-induced myocardial perfusion defects on 99mTc sestamibi/tetrofosmin single-photon emission computed tomography.
RESULTS: No differences among the groups were recorded at baseline with respect to clinical, perfusion, and wall motion characteristics. After three months, myocardial stress perfusion defects did not differ significantly between the VEGF gene transfer and placebo groups (38 ± 3% and 44 ± 2%, respectively). Similarly, semiquantitative analysis of the change in perfusion in the treated region of interest did not differ significantly between the two groups. Compared with placebo, VEGF gene transfer improved the local wall motion disturbances, assessed both by NOGA (p = 0.04) and contrast ventriculography (p = 0.03). Canadian Cardiovascular Society functional class classification of angina pectoris improved significantly in both groups but without difference between the groups. No phVEGF-A165-related adverse events were observed; however, NOGA procedure-related adverse events occurred in five patients.
CONCLUSIONS: The VEGF gene transfer did not significantly improve stress-induced myocardial perfusion abnormalities compared with placebo; however, improved regional wall motion, as assessed both by NOGA and by ventriculography, may indicate a favorable anti-ischemic effect. This result should encourage more studies within the field. Transient VEGF overexpression seems to be safe.
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Abbreviations and Acronyms
| | CCS = Canadian Cardiovascular Society | | FGF = fibroblast growth factor | | PCI = percutaneous coronary intervention | | ROI = region of interest | | SD/cord = standard deviation/cord | | SPECT = 99mTc sestamibi/tetrofosmin single-photon emission computer tomography | | VEGF = vascular endothelial growth factor |
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|
 |
|

|
 |

|
 |
 
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|
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|

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69(6):
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|
 |
|

|
 |

|
 |
 
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|
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|

|
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|
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M. Ferrarini, N. Arsic, F. A. Recchia, L. Zentilin, S. Zacchigna, X. Xu, A. Linke, M. Giacca, and T. H. Hintze
Adeno-Associated Virus-Mediated Transduction of VEGF165 Improves Cardiac Tissue Viability and Functional Recovery After Permanent Coronary Occlusion in Conscious Dogs
Circ. Res.,
April 14, 2006;
98(7):
954 - 961.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. A. Nordlie, L. E. Wold, B. Z. Simkhovich, C. Sesti, and R. A. Kloner
Molecular Aspects of Ischemic Heart Disease: Ischemia/Reperfusion-Induced Genetic Changes and Potential Applications of Gene and RNA Interference Therapy
Journal of Cardiovascular Pharmacology and Therapeutics,
March 1, 2006;
11(1):
17 - 30.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Hanif, A. Patel, and J. Dunning
Might gene therapy offer symptomatic relief for patients with 'no option' angina?
Interactive CardioVascular and Thoracic Surgery,
December 1, 2005;
4(6):
627 - 632.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y. Tsutsumi and D. W. Losordo
Double Face of VEGF
Circulation,
August 30, 2005;
112(9):
1248 - 1250.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. Leppanen, S. Koota, I. Kholova, J. Koponen, C. Fieber, U. Eriksson, K. Alitalo, and S. Yla-Herttuala
Gene Transfers of Vascular Endothelial Growth Factor-A, Vascular Endothelial Growth Factor-B, Vascular Endothelial Growth Factor-C, and Vascular Endothelial Growth Factor-D Have No Effects on Atherosclerosis in Hypercholesterolemic Low-Density Lipoprotein-Receptor/Apolipoprotein B48-Deficient Mice
Circulation,
August 30, 2005;
112(9):
1347 - 1352.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Gyongyosi, A. Khorsand, S. Zamini, W. Sperker, C. Strehblow, J. Kastrup, E. Jorgensen, B. Hesse, K. Tagil, H. E. Botker, et al.
NOGA-Guided Analysis of Regional Myocardial Perfusion Abnormalities Treated With Intramyocardial Injections of Plasmid Encoding Vascular Endothelial Growth Factor A-165 in Patients With Chronic Myocardial Ischemia: Subanalysis of the EUROINJECT-ONE Multicenter Double-Blind Randomized Study
Circulation,
August 30, 2005;
112(9_suppl):
I-157 - I-165.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|