This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (98) Citing Articles via Google Scholar Google Scholar Articles by Kastrup, J. Search for Related Content PubMed PubMed Citation Articles by Kastrup, J.

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.

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

This article has been cited by other articles:

				D. M. Birk, J. Barbato, L. Mureebe, and R. A. Chaer Basic Science Review: Current Insights on the Biology and Clinical Aspects of VEGF Regulation Vascular and Endovascular Surgery, December 1, 2009; 42(6): 517 - 530. [Abstract] [PDF]

				D. J. Hausenloy and D. M. Yellon Cardioprotective growth factors Cardiovasc Res, July 15, 2009; 83(2): 179 - 194. [Abstract] [Full Text] [PDF]

				R. W. Millard and Y. Wang Milieu interieur the search for myocardial arteriogenic signals. J. Am. Coll. Cardiol., June 9, 2009; 53(23): 2148 - 2149. [Full Text] [PDF]

				J. K. Donahue Novel Strategy to Reduce Sudden-Death Risk in the Healing Phase After Myocardial Infarction Circulation, January 6, 2009; 119(1): 6 - 8. [Full Text] [PDF]

				E.M. Mullane, Z. Dong, C.M. Sedgley, J.C.-C. Hu, T.M. Botero, G.R. Holland, and J.E. Nor Effects of VEGF and FGF2 on the Revascularization of Severed Human Dental Pulps Journal of Dental Research, December 1, 2008; 87(12): 1144 - 1148. [Abstract] [Full Text] [PDF]

				M. C. van Oostrom, O. van Oostrom, P. H. A. Quax, M. C. Verhaar, and I. E. Hoefer Insights into mechanisms behind arteriogenesis: what does the future hold? J. Leukoc. Biol., December 1, 2008; 84(6): 1379 - 1391. [Abstract] [Full Text] [PDF]

				A. J. Sinusas Targeted imaging offers advantages over physiological imaging for evaluation of angiogenic therapy. J. Am. Coll. Cardiol. Img., July 1, 2008; 1(4): 511 - 514. [Full Text] [PDF]

				L. L. Johnson, L. Schofield, T. Donahay, M. Bouchard, A. Poppas, and R. Haubner Radiolabeled RGD Peptides to Image Angiogenesis in Swine Model of Hibernating Myocardium. J. Am. Coll. Cardiol. Img., January 1, 2008; 1: 500 - 510. [Abstract] [Full Text] [PDF]

				A R Lyon, M Sato, R J Hajjar, R J Samulski, and S E Harding Gene therapy: targeting the myocardium Heart, January 1, 2008; 94(1): 89 - 99. [Abstract] [Full Text] [PDF]

				K. A. Horvath and Y. Zhou Transmyocardial Laser Revascularization and Extravascular Angiogenetic Techniques to Increase Myocardial Blood Flow Card. Surg. Adult, January 1, 2008; 3(2008): 733 - 752. [Full Text]

				A. Jacquier, C. B. Higgins, A. J. Martin, L. Do, D. Saloner, and M. Saeed Injection of Adeno-associated Viral Vector Encoding Vascular Endothelial Growth Factor Gene in Infarcted Swine Myocardium: MR Measurements of Left Ventricular Function and Strain Radiology, October 1, 2007; 245(1): 196 - 205. [Abstract] [Full Text] [PDF]

				T. Okazaki, S. Ebihara, M. Asada, S. Yamanda, Y. Saijo, Y. Shiraishi, T. Ebihara, K. Niu, H. Mei, H. Arai, et al. Macrophage Colony-Stimulating Factor Improves Cardiac Function after Ischemic Injury by Inducing Vascular Endothelial Growth Factor Production and Survival of Cardiomyocytes Am. J. Pathol., October 1, 2007; 171(4): 1093 - 1103. [Abstract] [Full Text] [PDF]

				S. M. Vartanian and R. Sarkar Therapeutic Angiogenesis Vascular and Endovascular Surgery, July 1, 2007; 41(3): 173 - 185. [Abstract] [PDF]

				G. A Lanza Alternative treatments for angina Heart, May 1, 2007; 93(5): 544 - 546. [Abstract] [Full Text] [PDF]

				M. Saeed, D. Saloner, A. Martin, L. Do, O. Weber, P. C. Ursell, A. Jacquier, R. Lee, and C. B. Higgins Adeno-associated Viral Vector-Encoding Vascular Endothelial Growth Factor Gene: Effect on Cardiovascular MR Perfusion and Infarct Resorption Measurements in Swine Radiology, May 1, 2007; 243(2): 451 - 460. [Abstract] [Full Text] [PDF]

				S. Yla-Herttuala, T. T. Rissanen, I. Vajanto, and J. Hartikainen Vascular Endothelial Growth Factors: Biology and Current Status of Clinical Applications in Cardiovascular Medicine J. Am. Coll. Cardiol., March 13, 2007; 49(10): 1015 - 1026. [Abstract] [Full Text] [PDF]

				E. P. Gurfinkel, V. S. Lernoud, R. P. Laguens, and R. R. Favaloro Advances in Coronary Heart Disease Surgery in Latin America Circulation, March 6, 2007; 115(9): 1147 - 1153. [Abstract] [Full Text] [PDF]

				S. Nikol Viral or non-viral angiogenesis gene transfer-New answers to old questions Cardiovasc Res, February 1, 2007; 73(3): 443 - 445. [Full Text] [PDF]

				O. J. Muller, H. A. Katus, and R. Bekeredjian Targeting the heart with gene therapy-optimized gene delivery methods Cardiovasc Res, February 1, 2007; 73(3): 453 - 462. [Abstract] [Full Text] [PDF]

				X. Hao, A. Mansson-Broberg, K.-H. Grinnemo, A. J. Siddiqui, G. Dellgren, L. A. Brodin, and C. Sylven Myocardial angiogenesis after plasmid or adenoviral VEGF-A165 gene transfer in rat myocardial infarction model Cardiovasc Res, February 1, 2007; 73(3): 481 - 487. [Abstract] [Full Text] [PDF]

				R. de Silva, L. F. Gutierrez, A. N. Raval, E. R. McVeigh, C. Ozturk, and R. J. Lederman X-Ray Fused With Magnetic Resonance Imaging (XFM) to Target Endomyocardial Injections: Validation in a Swine Model of Myocardial Infarction Circulation, November 28, 2006; 114(22): 2342 - 2350. [Abstract] [Full Text] [PDF]

				B. Wagner, M. Anton, S. G. Nekolla, S. Reder, J. Henke, S. Seidl, R. Hegenloh, M. Miyagawa, R. Haubner, M. Schwaiger, et al. Noninvasive Characterization of Myocardial Molecular Interventions by Integrated Positron Emission Tomography and Computed Tomography J. Am. Coll. Cardiol., November 21, 2006; 48(10): 2107 - 2115. [Abstract] [Full Text] [PDF]

				I. Ben-Dor, S. Fuchs, and R. Kornowski Potential Hazards and Technical Considerations Associated With Myocardial Cell Transplantation Protocols for Ischemic Myocardial Syndrome J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1519 - 1526. [Abstract] [Full Text] [PDF]

				H. K. Salem, P. Ranjzad, A. Driessen, C. E. Appleby, A. M. Heagerty, and P. A. Kingston Beta-Adrenoceptor Blockade Markedly Attenuates Transgene Expression From Cytomegalovirus Promoters Within the Cardiovascular System Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2267 - 2274. [Abstract] [Full Text] [PDF]

				J.-S. Choi, K.-B. Kim, W. Han, D. S. Kim, J. S. Park, J. J. Lee, and D. S. Lee Efficacy of Therapeutic Angiogenesis by Intramyocardial Injection of pCK-VEGF165 in Pigs Ann. Thorac. Surg., August 1, 2006; 82(2): 679 - 686. [Abstract] [Full Text] [PDF]

				E. Jorgensen, L. Bindslev, R. S. Ripa, and J. Kastrup Epo 'cytokine-doping' of heart disease patients, will it work? Eur. Heart J., August 1, 2006; 27(15): 1767 - 1768. [Full Text] [PDF]

				R. S. Ripa, Y. Wang, E. Jorgensen, H. E. Johnsen, B. Hesse, and J. Kastrup Intramyocardial injection of vascular endothelial growth factor-A165 plasmid followed by granulocyte-colony stimulating factor to induce angiogenesis in patients with severe chronic ischaemic heart disease Eur. Heart J., August 1, 2006; 27(15): 1785 - 1792. [Abstract] [Full Text] [PDF]

				Y Wang, H E Johnsen, S Mortensen, L Bindslev, R Sejersten Ripa, M Haack-Sorensen, E Jorgensen, W Fang, and J Kastrup Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with acute ST elevation myocardial infarction treated with primary percutaneous coronary intervention Heart, June 1, 2006; 92(6): 768 - 774. [Abstract] [Full Text] [PDF]

				M. E. Wilhide and W. K. Jones Potential Therapeutic Gene for the Treatment of Ischemic Disease: Ad2/Hypoxia-Inducible Factor-1{alpha} (HIF-1)/VP16 Enhances B-Type Natriuretic Peptide Gene Expression via a HIF-1-Responsive Element Mol. Pharmacol., June 1, 2006; 69(6): 1773 - 1778. [Abstract] [Full Text] [PDF]

				S. R. Dixon, C. L. Grines, and W. W. O'Neill The Year in Interventional Cardiology J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1689 - 1706. [Full Text] [PDF]

				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]