This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zoldhelyi, P. Articles by Willerson, J. T. Search for Related Content PubMed PubMed Citation Articles by Zoldhelyi, P. Articles by Willerson, J. T. Related Collections Animal models of human disease Anticoagulant mechanisms Angioplasty and Stenting Gene therapy Platelets

(Circulation. 2000;101:289.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor

Pierre Zoldhelyi, MD; Janice McNatt; Harnath S. Shelat, MS; Yasutaka Yamamoto, MD, PhD; Zhi-Qiang Chen, MD; James T. Willerson, MD

From the Wafic Said Molecular Cardiology and Gene Therapy Research Laboratory, Texas Heart Institute (P.Z., H.S.S., Y.Y., Z.-Q.C., J.T.W.) and the Department of Medicine (Cardiology), University of Texas-Houston Medical School (P.Z., J.M., H.S.S., Z.-Q.C., J.T.W.), Houston, Tex.

Correspondence to Pierre Zoldhelyi, Texas Heart Institute, MC 2-255, 1101 Bates St, Houston, TX 77030. E-mail zoldhely{at}aol.com

Background—Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of factor Xa and the coagulant initiator complex tissue factor/factor VIIa.

Methods and Results—To study the effects of TFPI gene transfer on thrombus formation, balloon-injured porcine carotid arteries were treated locally with an adenovirus encoding human TFPI (Ad-TFPI) or control virus. Gene transfer of TFPI was confirmed by detection of human TFPI in the conditioned medium of porcine carotid arteries kept in culture after in vivo transduction. When carotid flow was measured with Doppler probe 5 days after surgery, cyclic flow variations (CFVs) developed in 7 of 8 control pigs after constriction of the injured carotid artery by 40%, and all control-treated arteries occluded after 70% constriction. In contrast, CFVs were observed in only 1 of 8 Ad-TFPI–treated pigs after 40% constriction, and only 3 of 8 occluded after constriction by 70% (P=0.0027 and P=0.007, respectively). None of the 5 TFPI-transduced arteries open after 70% constriction developed CFVs during an incremental epinephrine infusion.

Conclusions—Compared with baseline, systemic hemostatic variables and platelet aggregation were unimpaired, suggesting that TFPI gene transfer can prevent arterial thrombosis in the presence of severe shear stress and without detectable hemostatic impairment.

Key Words: angioplasty • cerebrovascular disorders • coagulation • genes • thrombosis

This article has been cited by other articles:

				M. Tobu, Q. Ma, O. Iqbal, C. Schultz, W. Jeske, D. A. Hoppensteadt, and J. Fareed Comparative Tissue Factor Pathway Inhibitor Release Potential of Heparins Clinical and Applied Thrombosis/Hemostasis, January 1, 2005; 11(1): 37 - 47. [Abstract] [PDF]

				L.G Melo, M Gnecchi, A.S Pachori, K Wang, and V.J Dzau Gene- and cell-based therapies for cardiovascular diseases: current status and future directions Eur. Heart J. Suppl., September 1, 2004; 6(suppl_E): E24 - E35. [Abstract] [Full Text]

				P.E. Morange, C. Simon, M.C. Alessi, G. Luc, D. Arveiler, J. Ferrieres, P. Amouyel, A. Evans, P. Ducimetiere, I. Juhan-Vague, et al. Endothelial Cell Markers and the Risk of Coronary Heart Disease: The Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study Circulation, March 23, 2004; 109(11): 1343 - 1348. [Abstract] [Full Text] [PDF]

				O. D. Suleymanov, J. A. Szalony, A. K. Salyers, R. M. LaChance, J. J. Parlow, M. S. South, R. S. Wood, and N. S. Nicholson Pharmacological Interruption of Acute Thrombus Formation with Minimal Hemorrhagic Complications by a Small Molecule Tissue Factor/Factor VIIa Inhibitor: Comparison to Factor Xa and Thrombin Inhibition in a Nonhuman Primate Thrombosis Model J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1115 - 1121. [Abstract] [Full Text] [PDF]

				X. Yin, C. Yutani, Y. Ikeda, K. Enjyoji, H. Ishibashi-Ueda, S. Yasuda, Y. Tsukamoto, H. Nonogi, Y. Kaneda, and H. Kato Tissue factor pathway inhibitor gene delivery using HVJ-AVE liposomes markedly reduces restenosis in atherosclerotic arteries Cardiovasc Res, December 1, 2002; 56(3): 454 - 463. [Abstract] [Full Text] [PDF]

				J.-Y. Qian, A. Haruno, Y. Asada, T. Nishida, Y. Saito, T. Matsuda, and H. Ueno Local Expression of C-Type Natriuretic Peptide Suppresses Inflammation, Eliminates Shear Stress-Induced Thrombosis, and Prevents Neointima Formation Through Enhanced Nitric Oxide Production in Rabbit Injured Carotid Arteries Circ. Res., November 29, 2002; 91(11): 1063 - 1069. [Abstract] [Full Text] [PDF]

				E. Cavusoglu, I. Chen, J. Rappaport, and J. D. Marmur Inhibition of Tissue Factor Gene Induction and Activity Using a Hairpin Ribozyme Circulation, May 14, 2002; 105(19): 2282 - 2287. [Abstract] [Full Text] [PDF]

				H. Kato Regulation of Functions of Vascular Wall Cells by Tissue Factor Pathway Inhibitor: Basic and Clinical Aspects Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 539 - 548. [Abstract] [Full Text] [PDF]

				A. H.M Moons, M. Levi, and R. J.G Peters Tissue factor and coronary artery disease Cardiovasc Res, February 1, 2002; 53(2): 313 - 325. [Abstract] [Full Text] [PDF]

				P. Golino, P. Cirillo, P. Calabro', M. Ragni, D. D'Andrea, E. V. Avvedimento, F. Vigorito, N. Corcione, F. Loffredo, and M. Chiariello Expression of exogenous tissue factor pathway inhibitor in vivo suppresses thrombus formation in injured rabbit carotid arteries J. Am. Coll. Cardiol., August 1, 2001; 38(2): 569 - 576. [Abstract] [Full Text] [PDF]

				R. J. Westrick, P. F. Bodary, Z. Xu, Y.-C. Shen, G. J. Broze, and D. T. Eitzman Deficiency of Tissue Factor Pathway Inhibitor Promotes Atherosclerosis and Thrombosis in Mice Circulation, June 26, 2001; 103(25): 3044 - 3046. [Abstract] [Full Text] [PDF]

				E. M. Antman The Search for Replacements for Unfractionated Heparin Circulation, May 8, 2001; 103(18): 2310 - 2314. [Full Text] [PDF]

				P. Zoldhelyi, Z.-Q. Chen, H. S. Shelat, J. M. McNatt, and J. T. Willerson Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries PNAS, March 27, 2001; 98(7): 4078 - 4083. [Abstract] [Full Text] [PDF]

				U. Rauch, J. I. Osende, V. Fuster, J. J. Badimon, Z. Fayad, and J. H. Chesebro Thrombus Formation on Atherosclerotic Plaques: Pathogenesis and Clinical Consequences Ann Intern Med, February 6, 2001; 134(3): 224 - 238. [Abstract] [Full Text] [PDF]

				H. S. Shelat, T.-J. Liu, D. L. Hickman-Bick, M. K. Barnhart, T. Vida, P. M. Dillard, J. T. Willerson, and P. Zoldhelyi Growth Suppression of Human Coronary Vascular Smooth Muscle Cells by Gene Transfer of the Transcription Factor E2F-1 Circulation, January 23, 2001; 103(3): 407 - 414. [Abstract] [Full Text] [PDF]

				M. Kubo-Inoue, K. Egashira, M. Usui, M. Takemoto, K. Ohtani, M. Katoh, H. Shimokawa, and A. Takeshita Long-term inhibition of nitric oxide synthesis increases arterial thrombogenecity in rat carotid artery Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1478 - H1484. [Abstract] [Full Text] [PDF]

				H. Kato Regulation of Functions of Vascular Wall Cells by Tissue Factor Pathway Inhibitor: Basic and Clinical Aspects Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 539 - 548. [Abstract] [Full Text] [PDF]