Therapeutic Application of Ultrasound Contrast Agents

  • Mario J. García


In patients with chronic ischemic heart disease, restoring blood flow is the only means of preventing loss of myocardial function. Not infrequently, myocardial revascularization using surgical placement of bypass grafts or percutaneous angioplasty is either not feasible or fails to provide complete restoration of blood flood to ischemic myocardium. In such cases, the development of collateral vessels can mitigate myocardial ischemia [1]. Collateral circulation can also limit myocyte apoptosis during coronary occlusion [2], reducing infarct size [3]. The extent of collateral development varies among individuals, and until recently, the factors that determine angiogenesis were not understood. Recent advances in the understanding of vascular biology, however, have brought attention to the study of therapeutic angiogenesis, the promotion of new vessel growth using vascular growth factor [4–6] (Fig. 16.1).


Vascular Endothelial Growth Factor Myocardial Blood Flow Basic Fibroblast Growth Factor Ultrasound Contrast Agent Contrast Echocardiography 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Levin DC. Pathways and functional significance of coronary collateral circulation. Circulation 1974; 50: 831–7PubMedCrossRefGoogle Scholar
  2. 2.
    Sabia RJ, Powers ER, Jayaweera AR, et al. Functional significance of collateral blood flow in patients with recent acute myocardial infarction: a study using myocardial contrast echocardiography. N Engl J Med 1992; 327: 1825–31PubMedCrossRefGoogle Scholar
  3. 3.
    Hirai T, Fujita M, Nakajima H, et al. Importance of collateral circulation for prevention of left ventricular aneurysm formation on acute myocardial infarction. Circulation 1989; 79: 791–6PubMedCrossRefGoogle Scholar
  4. 4.
    Lewis BS, Flugelman MY, Weisz A, et al. Angiogenesis by gene therapy: a new horizon for myocardial revascularization? Cardiovasc Res 1997; 35: 490–7PubMedCrossRefGoogle Scholar
  5. 5.
    Folkman J. Angiogenic therapy of the human heart. Circulation 1998; 97: 628–9PubMedCrossRefGoogle Scholar
  6. 6.
    Kornowski R, Fuchs S, Leon M, et al. Delivery strategies to achieve therapeutic myocardial angiogenesis. Circulation 2000; 101: 454–8PubMedCrossRefGoogle Scholar
  7. 7.
    Schaper W, Ito W. Molecular mechanisms of collateral vessel growth. Circ Res 1996; 79: 911–9PubMedCrossRefGoogle Scholar
  8. 8.
    Freedman SB and Isner JM. Therapeutic angiogenesis for ischemic cardiovascular disease. J Mol Cell Cardiol 2001; 33: 379–393PubMedCrossRefGoogle Scholar
  9. 9.
    Epstein SE, Fuchs S, Zhou YF, et al. Therapeutic interventions for enhancing collateral development by administration of growth factors: basic principles, early results and potential hazards. Cardiovasc Res 2001; 49: 531–542CrossRefGoogle Scholar
  10. 10.
    Lazarous DF, Shou M, Scheinowitz M, et al. Comparative effect of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circulation 1996; 94: 1074–1082PubMedCrossRefGoogle Scholar
  11. 11.
    Harada K, Friedman M, Lopez JJ, et al. Vascular endothelial growth factor administration in chronic myocardial ischemia. Am J Physiol 1996; 270: H1791–H1802PubMedGoogle Scholar
  12. 12.
    Laham RJ, Rezaee M, Post M, et al. Intracoronary and intravenous administration of basic fibroblast growth factor: myocardial and tissue distribution. Drug Metab Dispos 1999; 27: 821–826PubMedGoogle Scholar
  13. 13.
    Hariawala MD, Horowitz JJ, Esakof D, et al. VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts. J Surg Res 1996; 63: 77–82PubMedCrossRefGoogle Scholar
  14. 14.
    Ku DD, Zaleski JK, Liu S, Brock TA. Vascular endothelial growth factor induces EDGF-dependent relaxation in coronary arteries. Am J Physiol 1993; 265: H586–H592PubMedGoogle Scholar
  15. 15.
    Jochem W, Soto B, Karp RB, et al. Radiographic anatomy of the coronary collateral circulation. Am J Roent Rad Ther Nuc Med 1972; 116: 50–61CrossRefGoogle Scholar
  16. 16.
    Pearlman JD, Hibberd MG, Chuang ML, et al. Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angio-genesis. Nature Med 1995; 1: 1085–9PubMedCrossRefGoogle Scholar
  17. 17.
    Beller GA. Clinical Nuclear Cardiology. Philadelphia: W.B. Saunders Co, 1995Google Scholar
  18. 18.
    Jayaweera AR, Edwards N, Glasheen WP, et al. In vivo myocardial kinetics of air-filled albumin microbubbles during myocardial contrast echocardiography. Comparison with radio-labeled red blood cells. Circ Res 1994; 74: 1157–65PubMedCrossRefGoogle Scholar
  19. 19.
    Ragosta M, Camarano G, Kaul S, et al. Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction. New insights using myocardial contrast echocardiography. Circulation 1994; 89: 2562–9PubMedCrossRefGoogle Scholar
  20. 20.
    Villanueva FS, Glasheen WP, Sklenar J, et al. Characterization of spatial patterns of flow within the re perfused myocardium by myocardial contrast echocardiography. Implications in determining extent of myocardial salvage. Circulation 1993; 88: 2596–606PubMedCrossRefGoogle Scholar
  21. 21.
    Lindner JR, Firschke C, Wei K, et al. Myocardial perfusion characteristics and hemodynamic profile of MRX-115, a venous echocardiographic contrast agent, during acute myocardial infarction. J Am Soc Echo 1998; 11: 36–46CrossRefGoogle Scholar
  22. 22.
    Porter TR, Xie F. Transient myocardial contrast after initial exposure to diagnostic ultrasound pressures with minute doses of intravenously injected microbubbles. Demonstration and potential mechanisms. Circulation 1995; 92: 2391–5PubMedCrossRefGoogle Scholar
  23. 23.
    Mulvagh SL, Foley DA, Aeschbacher BC, et al. Second harmonic imaging of an intravenously administered echocardiographic contrast agent: visualization of coronary arteries and measurement of coronary blood flow. J Am Coll Cardiol 1996; 27: 1519–2525PubMedCrossRefGoogle Scholar
  24. 24.
    Wei K, Jayaweera AR, Firoozan S, et al. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 1998; 97: 473–83PubMedCrossRefGoogle Scholar
  25. 25.
    Villanueva FS, Camarano G, Ismail S, et al. Coronary reserve abnormalities in the infarcted myocardium. Assessment of myocardial viability immediately versus late after reflow by contrast echocardiography. Circulation 1996; 94: 748–54PubMedCrossRefGoogle Scholar
  26. 26.
    Mills JD, Fischer D, Villanueva FS. Coronary collateral development during chronic ischemia: Serial assessment using harmonic myocardial contrast Echocardiography. J Am Coll Cardiol 2000; 36: 618–24PubMedCrossRefGoogle Scholar
  27. 27.
    Wei K, Skyba DM, Firschke C, et al. Interactions between microbubbles and ultrasound: in vitro and in vivo observations. J Am Coll Cardiol 1997; 29: 1081–8PubMedCrossRefGoogle Scholar
  28. 28.
    Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333: 1757–63PubMedCrossRefGoogle Scholar
  29. 29.
    Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1306–1309PubMedCrossRefGoogle Scholar
  30. 30.
    Plate KH, Breier G, Weich HA, et al. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992; 359: 845–848PubMedCrossRefGoogle Scholar
  31. 31.
    Ferrara N, Houck K, Jakeman L, et al. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocrinol Rev 1992; 13: 18–32Google Scholar
  32. 32.
    Tuder R, Flook B, Voekel N. Increased gene expression for VEGF and the VEGF receptors KDR/flk and flt in lungs exposed to acute or chronic hypoxia. J Clin Invest 1995; 95: 1798–1807PubMedCrossRefGoogle Scholar
  33. 33.
    Takeshita S, Zheng L, Brogi E, et al. Therapeutic angiogenesis: a single intra-arterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hindlimb model. J Clin Invest 1994; 93: 662–670PubMedCrossRefGoogle Scholar
  34. 34.
    Banai S, Jaklitsch M, Shou M, et al. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 1994; 89: 2183–2189PubMedCrossRefGoogle Scholar
  35. 35.
    Mack C, Patel S, Schwarz E, et al. Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart. J Thorac Cardiovasc Surg 1998; 115: 168–176PubMedCrossRefGoogle Scholar
  36. 36.
    Hendel RC, Henry TD, Rocha-Singh K, et al. Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: Evidence for a dose-dependent effect. Circulation 2000; 101: 118–121PubMedCrossRefGoogle Scholar
  37. 37.
    Faham S, Hileman RE, Fromm JR, et al. Heparin structure and interactions with basic fibroblast growth factor. Science 1996; 271: 1116–20PubMedCrossRefGoogle Scholar
  38. 38.
    Rosenberg RD, Shworak NW, Liu J, et al. Heparan sulfate proteoglycans of the cardiovascular system. J Clin Invest 1997; 99: 2062–70PubMedCrossRefGoogle Scholar
  39. 39.
    Slavin J. Fibroblast growth factors: at the heart of angiogenesis. Cell Biol Int 1995; 19: 431–44PubMedCrossRefGoogle Scholar
  40. 40.
    Cuevas P, Carceller F, Ortega S, et al. Hypotensive activity of fibroblast growth factor. Science 1991; 254: 1208–10PubMedCrossRefGoogle Scholar
  41. 41.
    Sellke FW, Wang SY, Friedman M, et al. Basic FGF enhances endothelium-dependent relaxation of the collateral-perfused coronary microcirculation. Am J Physiol 1994; 267: H1303–11PubMedGoogle Scholar
  42. 42.
    Casscells W, Speir E, Sasse J, et al. Isolation, characterization, and localization of heparin-binding growth factors in the heart. J Clin Invest 1990; 85: 433–41PubMedCrossRefGoogle Scholar
  43. 43.
    Bernotat-Danielowski S, Sharma HS, Schott RJ, et al. Generation and localisation of monoclonal antibodies against fibroblast growth factors in ischaemic collateralised porcine myocardium. Cardiovasc Res 1993; 27: 1220–8PubMedCrossRefGoogle Scholar
  44. 44.
    Padua RR, Sethi R, Dhalla NS, et al. Basic fibroblast growth factor is cardioprotective in ischemia- reperfusion injury. Mol Cell Biochem 1995; 143: 129–35PubMedCrossRefGoogle Scholar
  45. 45.
    Schneider H, Huse K. Arterial gene therapy. Lancet 1996; 348:1380–1; discussion 1381-2PubMedCrossRefGoogle Scholar
  46. 46.
    Yanagisawa-Miwa A, Uchida Y, Nakamura F, et al. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science 1992; 257: 1401–3PubMedCrossRefGoogle Scholar
  47. 47.
    Battler A, Scheinowitz M, Bor A, et al. Intracoronary injection of basic fibroblast growth factor enhances angiogenesis in infarcted swine myocardium. J Am Coll Cardiol 1993; 22: 2001–6PubMedCrossRefGoogle Scholar
  48. 48.
    Horrigan MC, Malycky JL, Ellis SG, et al. Reduction in myocardial infarct size by basic fibroblast growth factor following coronary occlusion in a canine model. Int J Cardiol 1999; 68 Suppl 1: S85–91PubMedCrossRefGoogle Scholar
  49. 49.
    Unger EF, Banai S, Shou M, et al. Basic fibroblast growth factor enhances myocardial collateral flow in a canine model. Am J Physiol 1994; 266: H1588–95PubMedGoogle Scholar
  50. 50.
    Lazarous DF, Scheinowitz M, Shou M, et al. Effects of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart. Circulation 1995; 91: 145–53PubMedCrossRefGoogle Scholar
  51. 51.
    Laham RJ, Chronos NA, Pike M et al. Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: Results of a phase I open-label dose escalation study. J Am Coll Cardiol 2000; 36: 2132–9PubMedCrossRefGoogle Scholar
  52. 52.
    Laham RJ, Simons M, Tofukuji M, et al. Modulation of myocardial perfusion and vascular reactivity by pericardial basic fibroblast growth factor: insight into ischemia-induced reduction in endothelium-dependent vasodilatation. J Thorac Cardiovasc Surg 1998; 116: 1022–8PubMedCrossRefGoogle Scholar
  53. 53.
    Lazarous DF, Unger EF, Epstein SE et al. Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial. J Am Coll Cardiol 2000; 36: 1239–44PubMedCrossRefGoogle Scholar
  54. 54.
    Mazue G, Bertolero F, Jacob C, et al. Preclinical and clinical studies with recombinant human basic fibroblast growth factor. Ann N Y Acad Sci 1991; 638: 329–40PubMedCrossRefGoogle Scholar
  55. 55.
    Bertolini F, Paolucci M, Peccatori F, et al. Angiogenic growth factors and endostatin in non-Hodgkirís lymphoma. Br J Haematol 1999; 106: 504–9PubMedCrossRefGoogle Scholar
  56. 56.
    Cuevas P, Gonzalez AM, Carceller F, et al. Vascular response to basic fibroblast growth factor when infused onto the normal adventitia or into the injured media of the rat carotid artery. Circ Res 1991; 69: 360–9PubMedCrossRefGoogle Scholar
  57. 57.
    Edelman ER, Nugent MA, Smith LT, et al. Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vaso-rum in injured rat arteries. J Clin Invest 1992; 89: 465–73PubMedCrossRefGoogle Scholar
  58. 58.
    Casey R, Li WW. Factors controlling ocular angiogenesis. Am J Ophthalmol 1997; 124: 521–9PubMedGoogle Scholar
  59. 59.
    Sharp PS. The role of growth factors in the development of diabetic retinopathy. Metabolism 1995; 44: 72–5PubMedCrossRefGoogle Scholar
  60. 60.
    Wiedow O, Schroder JM, Gregory H, et al. Elafin: an elastase-specific inhibitor of human skin: purification, characterization, and complete amino acid sequence. J Biol Chem 1990; 265: 14791–14795PubMedGoogle Scholar
  61. 61.
    Cappelluti E, Strom SC, Harris RB. Potential role of two novel elastase- like enzymes in processing protransforming growth factor-alpha. Biochemistry 1993; 32: 551–560PubMedCrossRefGoogle Scholar
  62. 62.
    Thompson K, Rabinovitch M. Exogenous leucocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular-matrix bound basic fibroblast growth factor. J Cell Physiol 1996; 166: 495–505PubMedCrossRefGoogle Scholar
  63. 63.
    Hazuda DJ, Strickler J, Kueppers F, et al. Processing of precursor inter-leukin 1 beta and inflammatory disease. J Biol Chem 1990; 265: 6318–6322PubMedGoogle Scholar
  64. 64.
    Watanabe H, Hattori S, Katsuda S, et al. Human neutrophil elastase: degradation of basement membrane components and immunolocalization in the tissue. J Biochem (Tokyo) 1990; 108: 753–759Google Scholar
  65. 65.
    Foster JA, Rich CB, Miller MF. Pulmonary fibroblasts: an in vitro model of emphysema: regulation of elastin gene expression. J Biol Chem 1990; 265: 15544–15549PubMedGoogle Scholar
  66. 66.
    Tobias JW, Bern MM, Netland PA, et al. Monocyte adhesion to subendothelial components. Blood 1987; 69: 1265–1268PubMedGoogle Scholar
  67. 67.
    Bobryshev YV, Lord RS. Accumulation of co-localized unesterified cholesterol and neutral lipids within vacuolized elastin fibers in atheroprone areas of the human aorta. Atherosclerosis 1999; 142: 121–131PubMedCrossRefGoogle Scholar
  68. 68.
    O’Blenes SB, Zaidi SH, Cheah AY, et al. Gene transfer of the serine elastase inhibitor elafin protects against vein graft degeneration. Circulation 2000; 102[suppl III]: III-289-III–295Google Scholar
  69. 69.
    Cowan B, Molossi C, Coulber C, et al. Interleukin (IL)-1B stimulated fibronectin synthesis in coronary smooth muscle cells requires endogenous vascular elastase activity. Mol Biol Cell 1994; 5: 429aGoogle Scholar
  70. 70.
    Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97: 1114–1123PubMedCrossRefGoogle Scholar
  71. 71.
    Rosengart TK, Lee LY, Patel SR, et al. Angiogenic gene therapy. Phase I assessment of direct intramy-ocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 1999; 100: 468–74PubMedCrossRefGoogle Scholar
  72. 72.
    Weig H-J, Laugwitz K-L, Moretti A, et al. Enhanced cardiac contractility after gene transfer of V2 vasopressin receptors in vivo by ultrasound-guided injection or transcoronary delivery. Circulation 2000; 101: 1578–1585PubMedCrossRefGoogle Scholar
  73. 73.
    McNally PG, Watt PAC, Rimmer T, et al. Impaired contraction and endothelium-dependent relaxation in isolated resistance vessels from patients with insulin-dependent diabetes mellitus. Clin Sci 1994; 87: 31–36PubMedGoogle Scholar
  74. 74.
    McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and independent vasodilatation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992; 35: 771–776PubMedGoogle Scholar
  75. 75.
    Lund DD, Faraci FM, Ooboshi H, et al. Adenovirus-mediated gene transfer is augmented in basilar and carotid arteries of heritable hyperlipidemic rabbits. Stroke 1998; 29: 120–125Google Scholar
  76. 76.
    Ooboshi H, Rios CD, Chu Y, et al. Augmented ade-novirus-mediated gene transfer in athero-sclerotic vessels. Arterioscler Thromb Vasc Biol 1997; 17: 1786–1792PubMedCrossRefGoogle Scholar
  77. 77.
    Lund DD, Faraci FM, Miller FJ, et al. Gene transfer of endothelial nitric oxide synthase improves relaxation of carotid arteries from diabetic rabbits. Circulation 2000; 101: 1027–1033PubMedCrossRefGoogle Scholar
  78. 78.
    Kamata K, Miyata N, Kasuya Y. Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in aorta from streptozotocin-induced diabetic rats. Br J Pharmacol 1989; 97: 614–618PubMedCrossRefGoogle Scholar
  79. 79.
    Meraji S, Joakody L, Senaratene MP, Thomson ABR, Kappagoda T. Endothelium-dependent relaxation in aorta of BB rat. Diabetes 1987; 36: 978–981PubMedCrossRefGoogle Scholar
  80. 80.
    Pieper GM, Mei DA, Langenstroer P, et al. Bioassay of endothelium- derived relaxing factor in diabetic rat aorta. Am J Physiol 1988; 263: H676–H680Google Scholar
  81. 81.
    Hattori Y, Kawasaki H, Abe K, et al. Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol 1991; 261: H1086–H1094PubMedGoogle Scholar
  82. 82.
    Pieper GM, Siebeneich W, Rosa AM, et al. Chronic treatment in vivo with dimethylthiourea, a hydrox-yl radical scavenger, prevents diabetes-induced endothelial dysfunction. J Cardiovasc Pharmacol 1996; 28: 741–745PubMedCrossRefGoogle Scholar
  83. 83.
    Pagano PJ, Griswold MC, Ravel D, et al. Vascular action of the hypoglycaemic agent gliclazide in diabetic rabbits. Diabetologia 1998; 41: 9–15PubMedCrossRefGoogle Scholar
  84. 84.
    Lindquist S. The heat-shock response. Annu Rev Biochem 1986; 55: 1151–1191PubMedCrossRefGoogle Scholar
  85. 85.
    Lindquist S, Craig EA. The heat-shock proteins. Annu Rev Genet 1988; 22: 631–677PubMedCrossRefGoogle Scholar
  86. 86.
    Vayssier M, Polla BS. Heat shock proteins: chaperoning life and death. Cell Stress Chaperones 1998; 3: 221–227PubMedCrossRefGoogle Scholar
  87. 87.
    Currie RW, Karmazyn M, Kloc M, et al. Heat-shock response is associated with enhanced postischemic ventricular recovery. Circ Res 1988; 63: 543–549PubMedCrossRefGoogle Scholar
  88. 88.
    Amrani M, Corbett J, Allen NJ, et al. Induction of heat-shock proteins enhances myocardial and endothelial functional recovery after prolonged cardioplegic arrest. Ann Thorac Surg 1994; 57: 157–160PubMedCrossRefGoogle Scholar
  89. 89.
    Jayakumar J, Suzuki K, Khan M, et al. Gene therapy for myocardial protection transfection of donor hearts with heat shock protein 70 gene protects cardiac function against ischemia-reperfusion injury. Circulation 2000; 102[suppl III]: III-302-III–306Google Scholar
  90. 90.
    Allen MD. Myocardial protection: is there a role for gene therapy? Ann Thorac Surg 1999; 68: 1924–1928. 25PubMedCrossRefGoogle Scholar
  91. 91.
    Isner JM, Pieczek A, Schainfeld R, et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischemic limb. Lancet 1996; 348: 370–4PubMedCrossRefGoogle Scholar
  92. 92.
    Tsurumi Y, Takeshita S, Chen D, et al. Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation 1996; 94: 3281–3290PubMedCrossRefGoogle Scholar
  93. 93.
    Losordo DW, Vale PR, Symes JF, et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998; 98: 2800–2804PubMedCrossRefGoogle Scholar
  94. 94.
    Vale PR, Losordo DW, Milliken CE, et al. Left ventricular electromechanical mapping to assess efficacy of phVEGF165 gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 2000; 102: 965–974PubMedCrossRefGoogle Scholar
  95. 95.
    Baumgartner I, Rauh G, Pieczek A. et al. Lower-extremity edema associated with gene transfer of naked DNA vascular endothelial growth factor. Ann Int Med 2000; 132: 880–884PubMedGoogle Scholar
  96. 96.
    Lopez JJ, Laham RJ, Stamler A, et al. VEGF administration in chronic myocardial ischemia in pigs. Cardiovasc Res 1998; 40: 272–281PubMedCrossRefGoogle Scholar
  97. 97.
    Henry TD, Annex BH, Azrin MA, et al. Final results of the VIVA trial of rhVEGF for human therapeutic angiogenesis. Circulation 1999; 100: I–476. (Abstract)Google Scholar
  98. 98.
    Guzman RJ, Lemarchand P, Crystal RG, et al. Efficient gene transfer into myocardium by direct injection of adenovirus vectors. Circ Res 1993; 73:1202–1207PubMedCrossRefGoogle Scholar
  99. 99.
    Svensson EC, Marshall DJ, Woodard K, et al. Efficient and stable transduction of cardiomyocytes after intramyocardial injection or intracoronary perfusion with recombinant adeno-associated virus vectors. Circulation 1999; 99: 201–205PubMedCrossRefGoogle Scholar
  100. 100.
    Schumacher B, Pecher P, von Specht BU, et al. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation 1998; 97: 645–650PubMedCrossRefGoogle Scholar
  101. 101.
    Sanborn TA, Tarazona N, Deutsch E, et al. Percutaneous endocardial gene therapy: in vivo gene transfer and expression. J Am Coll Cardiol 1999; 33(suppl A): 262A. AbstractGoogle Scholar
  102. 102.
    Kornowski R, Fuchs S, Vodovotz Y, et al. Successful gene transfer in a porcine ischemia model using the Biosense guided transendocardial injection catheter. J Am Coll Cardiol 1999; 33(suppl A): 355A. AbstractGoogle Scholar
  103. 103.
    Vale PR, Losordo DW, Tkebuchava T, et al. Catheter-based myocardial gene transfer utilizing nonfluo-roscopic electromechanical left ventricular mapping. J Am Coll Cardiol 1999; 34: 246–254PubMedCrossRefGoogle Scholar
  104. 104.
    Losordo DW, Vale PR, Hendel RC et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002; 105: 2012–2018PubMedCrossRefGoogle Scholar
  105. 104a.
    Schwarz ER, Speakman MT, Patterson M, Hale SS, Isner JM, Kedes LH, Kloner RA. Evaluation of the effects of intramyocardial injection of DNA expressing vascular endothelial growth factor (VEGF) in a myocardial infarction model in the rat-angio-genesis and angioma formation. J Am Coll Cardiol 2000; 35: 1323–30PubMedCrossRefGoogle Scholar
  106. 105.
    Landau C, Jacobs AK, Haudenschild CC. Intraperi-cardial basic fibroblast growth factor induces myocardial angiogenesis in a rabbit model of chronic ischemia. Am Heart J 1995; 129: 924–931. 29PubMedCrossRefGoogle Scholar
  107. 106.
    Uchida Y, Yanagisawa-Miwa A, Nakamura F, et al. Angiogenic therapy of acute myocardial infarction by intrapericardial injection of basic fibroblast growth factor and heparin sulfate: an experimental study. Am Heart J 1995; 130: 1182–1188PubMedCrossRefGoogle Scholar
  108. 107.
    Lopez JJ, Edelman ER, Stamler A, et al. Angiogenic potential of perivascularly delivered aFGF in a porcine model of chronic myocardial ischemia. Am J Physiol 1998; 274: H930–H936PubMedGoogle Scholar
  109. 108.
    Laham RJ, Hung D, Simons M. Therapeutic myocardial angiogenesis using percutaneous intrapericardial drug delivery. Clin Cardiol 1999; 22(suppl 1): I-6-I–9Google Scholar
  110. 109.
    Lazarous DF, Shou M, Stiber JA, et al. Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution. Cardiovasc Res 1997; 36: 78–85PubMedCrossRefGoogle Scholar
  111. 110.
    Laham RJ, Sellke FW, Ware JA, et al. Results of a randomized, double-blind, placebo-controlled study of local perivascular basic fibroblasts growth factor (bFGF) treatment in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol 1999; 33(suppl A): 383A. AbstractGoogle Scholar
  112. 111.
    Harada K, Grossman W, Friedman M, et al. Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts. J Clin Invest 1994; 94: 623–30PubMedCrossRefGoogle Scholar
  113. 112.
    Lopez JJ, Edelman ER, Stamler A, et al. Basic fibroblast growth factor in a porcine model of chronic myocardial ischemia: a comparison of angiographic, echocardiographic and coronary flow parameters. J Pharmacol Exp Ther 1997; 282: 385–90PubMedGoogle Scholar
  114. 113.
    March KL, Woody M, Mehdi K, et al. Efficient in vivo catheter-based pericardial gene transfer mediated by adenoviral vectors. Clin Cardiol 1999; 22: I23–I29PubMedCrossRefGoogle Scholar
  115. 114.
    Giordano FJ, Ping P, Mckirnan D, et al. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med 1996; 2: 534–539PubMedCrossRefGoogle Scholar
  116. 115.
    Weintraub WS, Culler SD, Kosinski A, et al. Economics, health-related quality of life, and cost-effectiveness methods for the TACTICS (Treat Angina With Aggrastat [tirofiban] and Determine Cost of Therapy with Invasive or Conservative Strategy)-TIMI18 trial. Am J Cardiol 1999; 83: 317–22PubMedCrossRefGoogle Scholar
  117. 116.
    Dougherty CM, Dewhurst T, Nichol WP, et al. Comparison of three quality of life instruments in stable angina pectoris: Seattle Angina Questionnaire, Short Form Health Survey (SF-36), and Quality of Life Index-Cardiac Version III. J Clin Epidemiol 1998; 51: 569–75PubMedCrossRefGoogle Scholar
  118. 117.
    Thirumurti V, Shou M, Hodge E, et al. Lack of efficacy of intravenous basic fibroblast growth factor in promoting myocardial angiogenesis. J Am Coll Cardiol 1998; 31: 54A. AbstractCrossRefGoogle Scholar
  119. 118.
    Unger EF, Banai S, Shou M, et al. Basic fibroblast growth factor enhances myocardial collateral flow in a canine model. Am J Physiol 1994; 266: H1588–H1595PubMedGoogle Scholar
  120. 119.
    Lazarous DF, Scheinowitz M, Shou M, et al. Effect of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart. Circulation 1995; 91: 145–153PubMedCrossRefGoogle Scholar
  121. 120.
    Yang R, Thomas GR, Bunting S, et al. Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. J Cardiovasc Pharmacol 1996; 27: 838–844PubMedCrossRefGoogle Scholar
  122. 121.
    Lopez J, Laham RJ, Carrozza JC, et al. Hemodynamic effects of intracoronary VEGF delivery: evidence of tachyphylaxis and NO dependence of response. Am J Physiol 1997; 273: H1317–H1323PubMedGoogle Scholar
  123. 122.
    Sato K, Wu T, Laham RJ et al. Efficacy of intracoronary or intravenous VGEF-165 in a pig model of chronic myocardial ischemia. J Am Coll Cardiol 2001; 37: 616–23PubMedCrossRefGoogle Scholar
  124. 123.
    Ziche M, Morbidelli L, Choudhuri R, et al. Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest 1997; 99: 2625–34PubMedCrossRefGoogle Scholar
  125. 124.
    Montrucchio G, Lupia E, de Martino A, et al. Nitric oxide mediates angiogenesis induced in vivo by platelet-activating factor and tumor necrosis factor-alpha. Am J Pathol 1997; 151: 557–63PubMedGoogle Scholar
  126. 125.
    Papapetropoulos A, Desai KM, Rudic RD, et al. Nitric oxide synthase inhibitors attenuate transforming-growth-factor-beta 1-stimulated capillary organization in vitro. Am J Pathol 1997; 150: 1835–44PubMedGoogle Scholar
  127. 126.
    Nabel EG, Yang ZY, Plautz G, et al. Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo. Nature. 1993; 362: 844–846PubMedCrossRefGoogle Scholar
  128. 127.
    Flugelman MY, Virmani R, Correa R, et al. Smooth muscle cell abundance and fibroblast growth factors in coronary lesions of patients with nonfatal unstable angina: a clue to the mechanism of transformation from the stable to the unstable clinical state. Circulation 1993; 88: 2493–2500PubMedCrossRefGoogle Scholar
  129. 128.
    Inoue M, Itoh H, Ueda M, et al. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation 1998; 98: 2108–2116PubMedCrossRefGoogle Scholar
  130. 129.
    Siegel et al. Circulation 2000; 101: 2026–2029PubMedCrossRefGoogle Scholar
  131. 130.
    Baffour R, Berman J, Garb JL, et al. Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic fibroblast growth factor in a rabbit model of acute lower limb ischemia: dose-dependent effect of basic fibroblast growth factor. J Vasc Surg 1992; 16: 181–191PubMedCrossRefGoogle Scholar
  132. 131.
    Unger EC, McCreery TP, Sweitzer RH. Ultrasound enhances gene expression of liposomal transfection. Invest Radiol 1997; 32: 723–727PubMedCrossRefGoogle Scholar
  133. 132.
    Feichheimer M, Boylan JF, Parker S, et al. Transfection loading of mammalian cells with plasmid DNA by scrape loading and sonication loading. Proc Natl Acad Sci USA 1987; 84: 8463–8467CrossRefGoogle Scholar
  134. 133.
    Takeshita S, Isshiki T, Sato T. Increased expression of direct gene transfer into skeletal muscle observed after acute ischemic injury in rats. Lab Invest. 1996; 74: 1061–1065PubMedGoogle Scholar
  135. 134.
    Tata DB, Dunn F, Tindall DJ. Selective clinical ultra sound signals mediate differential gene transfer and expression in two human prostate cancer cell lines: LnCap and PC-3. Biochem Biophys Res Commun 1997; 23: 64–7CrossRefGoogle Scholar
  136. 135.
    Kim HJ, Greenleaf JF, Kinnick RR, et al. Ultrasound mediated transfection of mammalian cells. Hum Gene Ther 1996; 7: 1339–46PubMedCrossRefGoogle Scholar
  137. 136.
    Bao S, Thrall BD, Miller DL. Transfection of a reporter plasmid into cultured cells by sonoporation in vitro. Ultrasound Med Biol 1997; 23: 953–9PubMedCrossRefGoogle Scholar
  138. 137.
    Lawrie A, Brisken AF, Francis SE, et al. Ultrasound enhances reporter gene expression after transfection of vascular cells in vitro. Circulation 1999; 99: 2617–20PubMedCrossRefGoogle Scholar
  139. 138.
    Gao X, Huang L. Cationic liposome-mediated gene transfer. Gene Ther 1995; 2: 710–722PubMedGoogle Scholar
  140. 139.
    Tata DB, Dunn F. Interaction of ultrasound and model membrane systems: analyses and predictions. J Phys Chem 1992; 96: 3548–3555CrossRefGoogle Scholar
  141. 140.
    Tata DB, Dunn F, Tindall DJ. Selective clinical ultrasound signals mediate differential gene transfer and expression in two human prostate cancer cell lines: LnCap and PC-3. Biochem Biophys Res Commun 1997; 234: 64–67PubMedCrossRefGoogle Scholar
  142. 141.
    Greenleaf WJ, Bolander ME, Sarkar G, et al. Artificial cavitation nuclei significantly enhance acoustically induced cell transfection. Ultrasound Med Biol 1998; 24: 587–595PubMedCrossRefGoogle Scholar
  143. 142.
    Kim HJ, Greenleaf JF, Kinnick RR, et al. Ultrasound-mediated transfection of mammalian cells. Hum Gene Ther 1996; 7: 1339–1346PubMedCrossRefGoogle Scholar
  144. 143.
    Tata DB, Dunn F, Tindall DJ. Selective clinical ultrasound signals mediate differential gene transfer and expression in two human prostate cancer cell lines: LnCap and PC-3. Biochem Biophys Res Commun 1997; 234: 64–67PubMedCrossRefGoogle Scholar
  145. 144.
    Ramirez A, Schwane JA, McFarland C, et al. The effect of ultrasound on collagen synthesis and fibroblast proliferation in vitro. Med Sci Sports Exerc. 1997; 29: 326–332PubMedCrossRefGoogle Scholar
  146. 145.
    Koster R, Hamm CW, Terres W, et al. Effects of sonication with catheter-delivered low frequency ultrasound on proliferation, migration and drug uptake of vascular smooth muscle cells. J Am Coll Cardiol 1997; 29: 97554. AbstractGoogle Scholar
  147. 146.
    Amabile PG, Waugh JM, Lewis TN, et al. High-efficiency endovascular gene delivery via therapeutic ultrasound. J Am Coll Cardiol 2001; 37: 1975–1980PubMedCrossRefGoogle Scholar
  148. 147.
    Campbell AIM, Monge JC, Latter DA, et al. Direct DNA injection of vascular endothelial growth factor induces angiogenesis in nonischemic myocardium. J Am Coll Cardiol 1998; 31: 25ACrossRefGoogle Scholar
  149. 148.
    Skyba DM, Price RJ, Linka AZ, et al. Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation 1998; 98: 290–293PubMedCrossRefGoogle Scholar
  150. 149.
    Price RJ, Skyba DM, Kaul S, et al. Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. Circulation 1998; 98: 1264–1267PubMedCrossRefGoogle Scholar
  151. 150.
    Porter TR, Iversen PL, Li S, et al. Interaction of diagnostic ultrasound with synthetic oligonucleotide-labeled perfluorocarbon-exposed sonicated dextrose albumin microbubbles. J Ultrasound Med 1996; 15: 577–584PubMedGoogle Scholar
  152. 151.
    Main ML, Grayburn PA. Clinical applications of transpulmonary contrast echocardiography. Am Heart J 1999; 137:144–153PubMedCrossRefGoogle Scholar
  153. 152.
    Shohet RV, Chen S, Zhou VT, et al. Echocardiographic destruction of albumin microbubbles directs gene delivery to myocardium. Circulation 2000; 101: 2554–2556PubMedCrossRefGoogle Scholar
  154. 153.
    Porter TR, Xie F, Kricsfeld D, Armbruster RW. Improved myocardial contrast with second harmonic transient ultrasound response imaging in humans using intravenous perfluorocarbon exposed sonicated dextrose albumin. J Am Coll Cardiol 1996; 27: 1497–501PubMedCrossRefGoogle Scholar
  155. 154.
    Porter TR, Iversen PL, Shouping L, et al. Interaction of diagnostic ultrasound with synthetic oligonucleotide-labeled perfluorocarbon exposed sonicated dextrose albumin microbubbles. J Ultrasound Med 1996; 15: 577–84PubMedGoogle Scholar
  156. 155.
    Mukherjee D, Wong J, Griffin B, et al. Ten-fold augmentation of endothelial uptake of vascular endothellal growth factor with ultrasound after systemic administration. J Am Coll Cardiol. 2000; 35: 1678–1686PubMedCrossRefGoogle Scholar
  157. 156.
    Wong J, Mukherjee D, Porter T, et al. Ultrasound enhances PESDA linked oligonucleotide deposition into myocardial tissue. J Am Soc Echo 1998; 11: RCGoogle Scholar
  158. 157.
    Henderson J, Willson K, Jago JR, Whittingham. A survey of the acoustic outputs of diagnostic ultrasound equipment in current clinical use. Ultrasound Med Biol 1995; 21: 699–705PubMedCrossRefGoogle Scholar
  159. 158.
    Miller DL, Thomas RM, Frazier ME. Ultrasonic cavitation indirectly induces strand breaks in DNA of viable cells in vitro by the action of residual hydrogen peroxide. Ultrasound Med Biol 1991; 17: 729–35PubMedCrossRefGoogle Scholar
  160. 159.
    Ashush H, Rozenszajin LA, Blass M, et al. Apoptosis induction of human myeloid leukemic cells by ultrasound exposure. Cancer Res 2000; 60: 1014–20PubMedGoogle Scholar
  161. 160.
    Miller MW, Miller DL, Brayman AA. A review of in vitro bioeffects of inertial ultrasonic cavitation from a mechanistic perspective. Ultrasound Med Biol 1996; 22: 1131–54PubMedCrossRefGoogle Scholar
  162. 161.
    Kondo T, Kano E. Effect of free radicals induced by ultrasonic cavitation on cell killing. Int J Radiat Biol 1988; 54: 475–86PubMedCrossRefGoogle Scholar
  163. 162.
    Huxley VH, Curry FE. Albumin modulation of capillary permeability: test of an adsorption mechanism. Am J Physiol 1985; 248(2 pt 2): H264–73PubMedGoogle Scholar
  164. 163.
    Ausprunk DH, Folkman J. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res 1977; 14: 53–65PubMedCrossRefGoogle Scholar
  165. 164.
    Sholley MM, Ferguson GP, Seibel HR. Mechanisms of revascularization: vascular sprouting can occur without proliferation of endothelial cells. Lab Invest 1984;54:624–34Google Scholar
  166. 165.
    Takeshita S, Pu L-Q, Zheng LP. Vascular endothelial growth factor induces dose-dependent revascularization in a rabbit model of persistent limb ischemia. Circulation 1994; 90: II-228–34Google Scholar
  167. 166.
    Zhou Z, Mukherjee D, Wang K, et al. Induction of angiogenesis in a canine model of chronic myocardial ischemia with intravenous infusion of vascular endothelial growth factor (VGEF) combined with ultrasound energy and echo contrast agent. Circulation, 2001 (Abstract)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • Mario J. García

There are no affiliations available

Personalised recommendations