(Circulation. 1998;98:2800-2804.)
© 1998 American Heart Association, Inc.
Brief Rapid Communications |
Gene Therapy for Myocardial Angiogenesis
Initial Clinical Results With Direct Myocardial Injection of phVEGF165 as Sole Therapy for Myocardial Ischemia
From the Departments of Medicine, Biomedical Research, Surgery, and Anesthesiology, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass.
Correspondence to Jeffrey M. Isner, MD, St. Elizabeth's Medical Center, 736 Cambridge St., Boston, MA 02135.
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Abstract |
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Background—We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia.
Methods and Results—VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF165) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75±15/min versus post-GTx=80±16/min, P=NS), systolic BP (114±7 versus 118±7 mm Hg, P=NS), or diastolic BP (57±2 versus 59±2 mm Hg, P=NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm3, and total chest tube drainage was 110 to 395 cm3. Postoperative cardiac output fell transiently but increased within 24 hours (preanesthesia=4.8±0.4 versus postanesthesia=4.1±0.3 versus 24 hours postoperative=6.3±0.8, P=0.02). Time to extubation after closure was 18.4±1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] use=53.9±10.0/wk pre-GTx versus 9.8±6.9/wk post-GTx, P<0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (n=3) or improved (n=2, mean increase in LVEF=5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients.
Conclusions—This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.
Key Words: angiogenesis • ischemia • myocardium
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Introduction |
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Intramuscular transfection of genes encoding angiogenic cytokines1 may constitute an alternative treatment strategy for patients with severe myocardial ischemia. This strategy is designed to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries, a strategy termed "therapeutic angiogenesis."2
This study describes the initial clinical experience with myocardial gene transfer as sole therapy for refractory angina pectoris. Five patients with chronic, severe angina underwent direct myocardial gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF). There were no operative complications. All patients experienced marked symptomatic improvement and/or objective evidence of improved myocardial perfusion. This preliminary clinical experience suggests that therapeutic angiogenesis represents a potentially useful strategy for patients with coronary artery disease.
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Methods |
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Patients
Patients were eligible for intramyocardial gene therapy if they had functional class 3 or 4 exertional angina, refractory to maximum medical therapy, areas of viable but underperfused myocardium, and multivessel occlusive coronary artery disease. Subjects were excluded if they had any of the following: a successful revascularization within the previous 6 months, cancer, retinopathy, or an ejection fraction (EF) <20%.
Plasmid DNA (phVEGF165)
All patients received eukaryotic expression vector
encoding the 165-amino acid isoform of the human VEGF gene (previously
described)3 4 transcriptionally regulated by the
cytomegalovirus promoter/enhancer
(phVEGF165).5 6
Myocardial phVEGF165 Transfer
Plasmid DNA (125 µg) was administered by direct myocardial
injection in 4 aliquots of 2.0 mL each via a mini-thoracotomy to the
anterolateral left ventricular free wall. Continuous
transesophageal echocardiographic
monitoring was performed throughout the procedure. Patients were
extubated in the operating room and monitored according to the protocol
used for minimally invasive CABG.
SPECT Myocardial Perfusion Study
Subjects underwent a dobutamine single photon
emission computed tomography (SPECT)-sestamibi study <2 weeks before
gene transfer, with the use of dobutamine infusion up to 40
µg · kg-1 · min
-1. The acquisition of the poststress SPECT
image began 10 minutes after the end of the stress period.
Redistribution images were recorded either before or at least 4
hours after stress with the subject at rest. Redistribution and
reinjection data were reconstructed in short-axis, vertical, and
longitudinal long-axis views for analysis. With the use of the
13-segment model, viability and perfusion scores were assigned to each
segment on the basis of the results of the nuclear scan. Perfusion was
recorded as normal or abnormal. Segments were visually
characterized as fixed, partially reversible, or totally reversible. On
days 30 and 60, subjects underwent repeat nuclear perfusion testing
using the identical stress protocol and isotope used at baseline.
Coronary Angiography
Patients underwent diagnostic angiography <1 month
before and 60 days after gene transfer. All angiograms were interpreted
by a reviewer blinded to the patient's name, date of study, and
sequence of study (ie, pre- versus posttreatment). Collaterals were
graded7 as absent (0); filling of side-branches of a
target-occluded epicardial coronary artery via collaterals
without visualization of the epicardial coronary artery itself
(1+); partial filling of the epicardial segment via collateral arteries
(2+); and complete filling of the epicardial segment (3+). Each pair of
films (baseline and follow-up) was scored independently.
Statistical Analysis
Data are reported as mean±SEM. Comparisons between paired
variables were performed using a Student t test with a
significance level of P<0.05.
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Results |
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Patients
Demographic and clinical data for the 5 men (aged 63.8±3.4 years) treated with phVEGF165 are shown in Table 1
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Perioperative Course
All patients underwent successful myocardial gene transfer. Mean
operative time was 101.6±8.9 minutes. Patients were extubated
18.4±1.4 minutes postoperatively. Injections caused no changes in
heart rate (75±15/min versus 80±16/min), systolic blood
pressure (114±7 versus 118±7 mm Hg), or
diastolic BP (57±2 versus 59±2 mm Hg).
Ventricular arrhythmias were limited to unifocal
extrasystolic beats (maximum n=5) at the moment of injection.
Postoperative Cardiac output fell transiently but increased within 24
hours (preanesthesia=4.8±0.4 versus
postanesthesia=4.1±0.3 versus 24 hours
postoperative=6.3±0.8, P=0.02). Serial ECGs showed no
evidence of myocardial infarction in any patient; no patient had an
increase in creatine kinase isoenzyme above normal limits.
Intraoperative blood loss was 5 to 50 cm3, and
total chest tube drainage was 110 to 395 cm3.
There were no major perioperative complications.
Postoperative LVEF was either unchanged (n=3) or improved (n=2, mean
increase in LVEF=5%). All patients were discharged on postoperative
day 4 except patient 2 who was discharged on postoperative day 3.
Change in Clinical Status
All 5 patients experienced a decrease in anginal frequency and
severity (Table 1
). There was no change in the anginal pattern
in any patient up to 10 days post–gene transfer. All patients began to
experience a reduction in angina between 10 and 30 days after gene
transfer. Angina was completely abolished in 2 patients (patients 1 and
4); patient 5, who has previously experienced daily angina, had only 2
episodes of angina between the day 30 and day 60 follow-up visits.
Patients 2 and 3 continued to experience occasional angina but with
reduced frequency and at much higher levels of activity.
Nitroglycerin (NTG) use for the group of 5 patients
decreased from 7.7±1.4 to 1.4±1.0 tablets per day by 60 days
post–gene transfer (P<0.05). Brief synopses of the
clinical courses of these 5 patients are provided below.
Patient 1, a 67-year-old man, experienced daily angina induced by mild activity requiring an average of 8 tablets NTG/d. All native vessels and 3 of 4 bypass grafts were occluded. Several institutions had advised the patient that the small caliber of his remaining native vessels precluded repeat CABG. Beginning 21 days after gene transfer, the patient experienced a decrease in the frequency and severity of his angina. By postoperative day 60, the patient was no longer experiencing angina and was no longer requiring NTG. He was able to engage in activities, such as swimming, which were previously impossible because of anginal pain.
Patient 2, a 69-year-old man, experienced daily angina precipitated by activity such as walking 10 yards; for several months he had been taking 12 tablets NTG/d. A vein graft to the left obtuse marginal (LOM) was occluded, and a diffusely diseased vein graft to a diagonal branch of the left anterior descending (LAD) coronary artery was not amenable to percutaneous revascularization. Additional surgery was not feasible because of poor target vessels. For 3 weeks after gene transfer, his symptoms remained unchanged. The patient then began to notice a decrease in NTG consumption accompanied by the ability to increase his level of activity. By day 60, the patient was able to exercise on the bicycle at his local gymnasium for up to 30 minutes. The patient's NTG requirement decreased to a maximum of 2 tablets/d for occasional episodes of mild angina.
Patient 3, a 53-year-old man, experienced daily angina induced by
walking 
50 yards and used 6 NTG tablets/d. All native vessels were
occluded; grafts to the LAD and right coronary artery (RCA)
were patent, whereas an LOM graft was occluded.
Percutaneous revascularization was
not possible and a third bypass operation for single vessel bypass to a
small-caliber target vessel was not feasible. The patient experienced
no change in anginal symptoms until postoperative week 2, when he
noticed an increase in the level of activity required to induce angina.
At that time, he was able to perform activities (eg, planting in his
garden) that he had not previously engaged in for several months; NTG
use decreased to 5 tablets per week. By 60 days after gene transfer, he
was able to walk up to one-half of a mile without experiencing
angina.
Patient 4, a 71-year-old man, complained of daily angina precipitated by walking <100 yards. All native vessels and grafts to the RCA and LOM were occluded. Percutaneous revascularization was not possible and repeat surgery was not feasible because of small-caliber target vessels. Beginning on postoperative day 10, the patient noted increased exercise capacity accompanied by decreased NTG use. By day 30 follow-up, the patient was requiring no NTG and had returned to his 5 hour per day position doing maintenance for his church. Between days 30 and 60, the patient developed dyspnea, associated with inadvertent discontinuation of his daily diuretic (furosemide, 80 mg). After resumption of his diuretic, his symptoms resolved and he resumed his increased activity level without anginal symptoms, dyspnea, or NTG use.
Patient 5, a 59-year-old man with daily angina precipitated by walking 10 to 20 yards, also required continuous oxygen because of severe chronic obstructive pulmonary disease. He had been recently hospitalized for several months because of intractable angina requiring intravenous NTG. All native vessels and grafts to RCA and diagonal branch of the LAD were occluded. Percutaneous revascularization was not possible and a third bypass operation was not feasible because of poor distal vessels. By postoperative day 30, the patient noted that he was experiencing no angina and was able to walk distances of up to 500 yards. Additionally, he found that his use of supplemental oxygen had decreased. At day 60 follow-up, he reported a total of 2 anginal episodes in the previous month, each of which was resolved with a single NTG tablet.
SPECT-Sestamibi Perfusion Imaging
All patients had improvement in myocardial perfusion, revealed by
comparison between pre- and posttreatment (Figure 1) SPECT-sestamibi
imaging (Table 2). The mean number of normally perfused segments
per patient increased from 6.0±1.1 before gene transfer to 8.0±0.7
(P<0.05) at day 60 after gene transfer (Figure 2). This was accompanied by a decrease in
the mean number of irreversibly ischemic segments from 2.4±0.2
to 1.2±0.4 (P<0.05) at day 60 follow-up examination
(Figure 2).
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Coronary Angiography
Selective coronary angiography was performed before and
59.8±1.5 days after gene transfer (Table 3). Angiographic
evidence for improved collateral flow into ischemic areas of
the myocardium was observed in all 5 patients. The evidence
of new collateral vessels consisted of improved filling of 4 previously
identified vessels as well as the development of collaterals to 3
vessels which previously had no collateral filling. In 2 patients,
there was improvement by a single Rentrop grade in one vessel
territory; the other 3 patients demonstrated improvement in 2
territories by 1 to 3 Rentrop grades.
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Discussion |
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The finding that VEGF could be used to achieve angiogenesis that was therapeutic was first demonstrated by Takeshita et al,2 who administered rhVEGF as a single intra-arterial bolus to rabbits with unilateral hindlimb ischemia. Similar findings with rhVEGF administration in canine8 and porcine9 models of myocardial ischemia were published shortly thereafter.
Gene transfer constitutes an alternative strategy for accomplishing therapeutic angiogenesis in patients with limb and myocardial ischemia. In VEGF, this is a particularly appealing strategy because the VEGF gene encodes a signal sequence which permits the protein to be naturally secreted from intact cells.4 Previous studies from our laboratory10 11 indicated that arterial gene transfer of cDNA encoding for a secreted protein could yield meaningful biological outcomes despite a low transfection efficiency. Indeed, preclinical animal studies established the feasibility of achieving therapeutic angiogenesis after site-specific gene transfer of naked DNA encoding VEGF121, VEGF165, and VEGF189.12 Subsequent clinical experience documented histological and angiographic evidence of phVEGF165-induced neovascularization in patients with critical limb ischemia.5 6 These findings established proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit.
The present study provides the first evidence for a favorable clinical effect of direct myocardial injection of naked plasmid DNA encoding for VEGF. Each patient experienced a reduction in anginal symptoms and nitrate use, and there is objective evidence for reduced ischemia by perfusion imaging. Because each patient enrolled in this study had long-standing, stable, severe angina, the change in clinical status observed for these 5 patients is unlikely to represent random chance. In contrast to work recently reported by Schumacher et al,13 in which administration of fibroblast growth factor-1 (FGF-1) was combined with conventional surgical revascularization,13 the present study used VEGF gene transfer as the sole therapeutic intervention.
This early experience, although encouraging from the standpoint of therapeutic angiogenesis and gene therapy, leaves several issues unresolved. Optimizing the anatomic site, number, and dose of intramyocardial injections will require further investigation. The FDA, Recombinant Advisory Committee of the NIH, and St. Elizabeth Medical Center Human Investigation Research and Institutional Biosafety Committees all concurred that the strategy of gene therapy alone administered via a mini-thoracotomy would not permit randomization against placebo (untreated controls). We anticipate that incorporation of a placebo group and clinical testing of alternative dosing regimens, including multiple treatments, will be addressed on availability of a catheter-based system for reliable percutaneous myocardial gene delivery; this is currently under preclinical investigation.14
Furthermore, the choice of appropriate formulation or vector in the case of VEGF remains to be determined. As indicated above, rhVEGF protein has been shown to be efficacious for treatment of limb and myocardial ischemia in preclinical studies, and preliminary clinical investigation of rhVEGF15 together with the aforementioned studies of Schumacher et al have suggested the potential usefulness of recombinant protein for therapeutic angiogenesis. The use of an adenoviral vector expressing VEGF121 has been shown to improve myocardial perfusion and function in a swine model of myocardial ischemia16 and is now being tested in human subjects. Likewise, alternatives to VEGF, including FGF-1,17 FGF-2,18 and FGF-519 are or will be investigated as genes or recombinant proteins in clinical trials of therapeutic angiogenesis.
Received September 8, 1998; revision received October 28, 1998; accepted November 9, 1998.
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 D. Hou, E. A.-S. Youssef, T. J. Brinton, P. Zhang, P. Rogers, E. T. Price, A. C. Yeung, B. H. Johnstone, P. G. Yock, and K. L. March Radiolabeled Cell Distribution After Intramyocardial, Intracoronary, and Interstitial Retrograde Coronary Venous Delivery: Implications for Current Clinical Trials Circulation, August 30, 2005; 112(9_suppl): I-150 - I-156. [Abstract] [Full Text] [PDF]
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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]
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 R. J. Laham, M. Post, M. Rezaee, L. Donnell-Fink, J. J. Wykrzykowska, S. U. Lee, D. S. Baim, and F. W. Sellke TRANSENDOCARDIAL AND TRANSEPICARDIAL INTRAMYOCARDIAL FIBROBLAST GROWTH FACTOR-2 ADMINISTRATION: MYOCARDIAL AND TISSUE DISTRIBUTION Drug Metab. Dispos., August 1, 2005; 33(8): 1101 - 1107. [Abstract] [Full Text] [PDF]
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G. A. Krombach, J. G. Pfeffer, S. Kinzel, M. Katoh, R. W. Gunther, and A. Buecker MR-guided Percutaneous Intramyocardial Injection with an MR-compatible Catheter: Feasibility and Changes in T1 Values after Injection of Extracellular Contrast Medium in Pigs Radiology, May 1, 2005; 235(2): 487 - 494. [Abstract] [Full Text] [PDF]
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M. Ono, Y. Sawa, Y. Miyamoto, N. Fukushima, H. Ichikawa, T. Ishizaka, Y. Kaneda, and H. Matsuda The effect of gene transfer with hepatocyte growth factor for pulmonary vascular hypoplasia in neonatal porcine model J. Thorac. Cardiovasc. Surg., April 1, 2005; 129(4): 740 - 745. [Abstract] [Full Text] [PDF]
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 C. J Teng, K. Lachapelle, and R. C. Chiu Reappraisal of Recent Clinical Trials of Angiogenic Therapy in Myocardial Ischemia Asian Cardiovasc Thorac Ann, March 1, 2005; 13(1): 90 - 97. [Abstract] [Full Text] [PDF]
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 J. Smith, R. E. Kontermann, J. Embleton, and S. Kumar Antibody phage display technologies with special reference to angiogenesis FASEB J, March 1, 2005; 19(3): 331 - 341. [Abstract] [Full Text] [PDF]
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H F Alber, M Frick, J Dulak, J Dorler, R-H Zwick, W Dichtl, O Pachinger, and F Weidinger Vascular endothelial growth factor (VEGF) plasma concentrations in coronary artery disease Heart, March 1, 2005; 91(3): 365 - 366. [Full Text] [PDF]
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J. E. Sousa, M. A. Costa, E. M. Tuzcu, J. S. Yadav, and S. Ellis New Frontiers in Interventional Cardiology Circulation, February 8, 2005; 111(5): 671 - 681. [Full Text] [PDF]
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A. Schuh, S. Breuer, R. Al Dashti, N. Sulemanjee, P. Hanrath, C. Weber, B. F. Uretsky, and E. R. Schwarz Administration of Vascular Endothelial Growth Factor Adjunctive to Fetal Cardiomyocyte Transplantation and Improvement of Cardiac Function in the Rat Model Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2005; 10(1): 55 - 66. [Abstract] [PDF]
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W. Li, K. Tanaka, A. Ihaya, Y. Fujibayashi, S. Takamatsu, K. Morioka, M. Sasaki, T. Uesaka, T. Kimura, N. Yamada, et al. Gene therapy for chronic myocardial ischemia using platelet-derived endothelial cell growth factor in dogs Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H408 - H415. [Abstract] [Full Text] [PDF]
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T.-B. Liu, P. W. M. Fedak, R. D. Weisel, T. Yasuda, G. Kiani, D. A. G. Mickle, Z.-Q. Jia, and R.-K. Li Enhanced IGF-1 expression improves smooth muscle cell engraftment after cell transplantation Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2840 - H2849. [Abstract] [Full Text] [PDF]
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H. Su, S. Joho, Y. Huang, A. Barcena, J. Arakawa-Hoyt, W. Grossman, and Y. W. Kan Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts PNAS, November 16, 2004; 101(46): 16280 - 16285. [Abstract] [Full Text] [PDF]
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T. Nishida, H. Shimokawa, K. Oi, H. Tatewaki, T. Uwatoku, K. Abe, Y. Matsumoto, N. Kajihara, M. Eto, T. Matsuda, et al. Extracorporeal Cardiac Shock Wave Therapy Markedly Ameliorates Ischemia-Induced Myocardial Dysfunction in Pigs in Vivo Circulation, November 9, 2004; 110(19): 3055 - 3061. [Abstract] [Full Text] [PDF]
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Q. Dai, J. Huang, B. Klitzman, C. Dong, P. J. Goldschmidt-Clermont, K. L. March, J. Rokovich, B. Johnstone, E. J. Rebar, S. K. Spratt, et al. Engineered Zinc Finger-Activating Vascular Endothelial Growth Factor Transcription Factor Plasmid DNA Induces Therapeutic Angiogenesis in Rabbits With Hindlimb Ischemia Circulation, October 19, 2004; 110(16): 2467 - 2475. [Abstract] [Full Text] [PDF]
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E. R. Schwarz, D. A. Meven, N. Z. Sulemanjee, P. H. Kersting, T. Tussing, E. C. Skobel, P. Hanrath, and B. F. Uretsky Monocyte Chemoattractant Protein 1-Induced Monocyte Infiltration Produces Angiogenesis but Not Arteriogenesis in Chronically Infarcted Myocardium Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2004; 9(4): 279 - 289. [Abstract] [PDF]
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 E. H. Yang, G. W. Barsness, B. J. Gersh, K. Chandrasekaran, and A. Lerman Current and Future Treatment Strategies for Refractory Angina Mayo Clin. Proc., October 1, 2004; 79(10): 1284 - 1292. [Abstract] [PDF]
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A. Kawamoto, T. Murayama, K. Kusano, M. Ii, T. Tkebuchava, S. Shintani, A. Iwakura, I. Johnson, P. von Samson, A. Hanley, et al. Synergistic Effect of Bone Marrow Mobilization and Vascular Endothelial Growth Factor-2 Gene Therapy in Myocardial Ischemia Circulation, September 14, 2004; 110(11): 1398 - 1405. [Abstract] [Full Text] [PDF]
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 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]
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I. Kondo, K. Ohmori, A. Oshita, H. Takeuchi, S. Fuke, K. Shinomiya, T. Noma, T. Namba, and M. Kohno Treatment of acute myocardial infarction by hepatocyte growth factor gene transfer: The first demonstration of myocardial transfer of a "functional" gene using ultrasonic microbubble destruction J. Am. Coll. Cardiol., August 4, 2004; 44(3): 644 - 653. [Abstract] [Full Text] [PDF]
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V. van Weel, M. M.L. Deckers, J. M. Grimbergen, K. J.M. van Leuven, J. H.P. Lardenoye, R. O. Schlingemann, G. P. van Nieuw Amerongen, J. H. van Bockel, V. W.M. van Hinsbergh, and P. H.A. Quax Vascular Endothelial Growth Factor Overexpression in Ischemic Skeletal Muscle Enhances Myoglobin Expression In Vivo Circ. Res., July 9, 2004; 95(1): 58 - 66. [Abstract] [Full Text] [PDF]
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N. M. Degabriele, U. Griesenbach, K. Sato, M. J. Post, J. Zhu, J. Williams, P. K. Jeffery, D. M. Geddes, and E. W. F. W. Alton Critical appraisal of the mouse model of myocardial infarction Exp Physiol, July 1, 2004; 89(4): 497 - 505. [Abstract] [Full Text] [PDF]
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I. Friehs, A. M. Moran, C. Stamm, Y.-H. Choi, D. B. Cowan, F. X. McGowan, and P. J. del Nido Promoting angiogenesis protects severely hypertrophied hearts from ischemic injury Ann. Thorac. Surg., June 1, 2004; 77(6): 2004 - 2010. [Abstract] [Full Text] [PDF]
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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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M. Saeed, R. Lee, A. Martin, O. Weber, G. A. Krombach, S. Schalla, M. Lee, D. Saloner, and C. B. Higgins Transendocardial Delivery of Extracellular Myocardial Markers by Using Combination X-ray/MR Fluoroscopic Guidance: Feasibility Study in Dogs Radiology, June 1, 2004; 231(3): 689 - 696. [Abstract] [Full Text] [PDF]
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D. W. Losordo and S. Dimmeler Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease: Part I: Angiogenic Cytokines Circulation, June 1, 2004; 109(21): 2487 - 2491. [Full Text] [PDF]
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L. G. Melo, A. S. Pachori, D. Kong, M. Gnecchi, K. Wang, R. E. Pratt, and V. J. Dzau Molecular and Cell-Based Therapies for Protection, Rescue, and Repair of Ischemic Myocardium: Reasons for Cautious Optimism Circulation, May 25, 2004; 109(20): 2386 - 2393. [Full Text] [PDF]
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L. G. MELO, A. S. PACHORI, D. KONG, M. GNECCHI, K. WANG, R. E. PRATT, and V. J. DZAU Gene and cell-based therapies for heart disease FASEB J, April 1, 2004; 18(6): 648 - 663. [Abstract] [Full Text] [PDF]
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T.-S. Li, M. Hayashi, Z.-L. Liu, H. Ito, A. Mikamo, A. Furutani, M. Matsuzaki, and K. Hamano Low angiogenic potency induced by the implantation of ex vivo expanded CD117+ stem cells Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1236 - H1241. [Abstract] [Full Text] [PDF]
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K. Pels, C. Deiner, S. E Coupland, M. Noutsias, A. P Sutter, H.-P. Schultheiss, S. Yla-Herttuala, and P. L Schwimmbeck Effect of adventitial VEGF165 gene transfer on vascular thickening after coronary artery balloon injury Cardiovasc Res, December 1, 2003; 60(3): 664 - 672. [Abstract] [Full Text] [PDF]
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K. Hiraoka, H. Koike, S. Yamamoto, N. Tomita, C. Yokoyama, T. Tanabe, T. Aikou, T. Ogihara, Y. Kaneda, and R. Morishita Enhanced Therapeutic Angiogenesis by Cotransfection of Prostacyclin Synthase Gene or Optimization of Intramuscular Injection of Naked Plasmid DNA Circulation, November 25, 2003; 108(21): 2689 - 2696. [Abstract] [Full Text] [PDF]
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T. Namba, H. Koike, K. Murakami, M. Aoki, H. Makino, N. Hashiya, T. Ogihara, Y. Kaneda, M. Kohno, and R. Morishita Angiogenesis Induced by Endothelial Nitric Oxide Synthase Gene Through Vascular Endothelial Growth Factor Expression in a Rat Hindlimb Ischemia Model Circulation, November 4, 2003; 108(18): 2250 - 2257. [Abstract] [Full Text] [PDF]
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F. J. Giordano Retrograde coronary perfusion: a superior route to deliver therapeutics to the heart? J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1129 - 1131. [Full Text] [PDF]
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T.-S. Li, K. Hamano, M. Nishida, M. Hayashi, H. Ito, A. Mikamo, and M. Matsuzaki CD117+ stem cells play a key role in therapeutic angiogenesis induced by bone marrow cell implantation Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H931 - H937. [Abstract] [Full Text] [PDF]
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Y.-s. Yoon and D. W. Losordo All in the Family: VEGF-B Joins the Ranks of Proangiogenic Cytokines Circ. Res., July 25, 2003; 93(2): 87 - 90. [Full Text] [PDF]
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M. Hedman, J. Hartikainen, M. Syvanne, J. Stjernvall, A. Hedman, A. Kivela, E. Vanninen, H. Mussalo, E. Kauppila, S. Simula, et al. Safety and Feasibility of Catheter-Based Local Intracoronary Vascular Endothelial Growth Factor Gene Transfer in the Prevention of Postangioplasty and In-Stent Restenosis and in the Treatment of Chronic Myocardial Ischemia: Phase II Results of the Kuopio Angiogenesis Trial (KAT) Circulation, June 3, 2003; 107(21): 2677 - 2683. [Abstract] [Full Text] [PDF]
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S. Fleury, E. Simeoni, C. Zuppinger, N. Deglon, L. K. von Segesser, L. Kappenberger, and G. Vassalli Multiply Attenuated, Self-Inactivating Lentiviral Vectors Efficiently Deliver and Express Genes for Extended Periods of Time in Adult Rat Cardiomyocytes In Vivo Circulation, May 13, 2003; 107(18): 2375 - 2382. [Abstract] [Full Text] [PDF]
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I. Ahmet, Y. Sawa, T. Yamaguchi, and H. Matsuda Gene transfer of hepatocyte growth factor improves angiogenesis and function of chronic ischemic myocardium in canine heart Ann. Thorac. Surg., April 1, 2003; 75(4): 1283 - 1287. [Abstract] [Full Text] [PDF]
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N. Tomita, R. Morishita, Y. Taniyama, H. Koike, M. Aoki, H. Shimizu, K. Matsumoto, T. Nakamura, Y. Kaneda, and T. Ogihara Angiogenic Property of Hepatocyte Growth Factor Is Dependent on Upregulation of Essential Transcription Factor for Angiogenesis, ets-1 Circulation, March 18, 2003; 107(10): 1411 - 1417. [Abstract] [Full Text] [PDF]
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M. Nishida, T.-S. Li, K. Hirata, M. Yano, M. Matsuzaki, and K. Hamano Improvement of cardiac function by bone marrow cell implantation in a rat hypoperfusion heart model Ann. Thorac. Surg., March 1, 2003; 75(3): 768 - 773. [Abstract] [Full Text] [PDF]
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F. W. Sellke and M. Ruel Vascular growth factors and angiogenesis in cardiac surgery Ann. Thorac. Surg., February 1, 2003; 75(2): S685 - 690. [Abstract] [Full Text] [PDF]
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D. W. Losordo and A. Kawamoto Biological Revascularization and the Interventional Molecular Cardiologist: Bypass for the Next Generation Circulation, December 10, 2002; 106(24): 3002 - 3005. [Full Text] [PDF]
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J.-S. Silvestre, N. Kamsu-Kom, M. Clergue, M. Duriez, and B. I. Levy Very-Low-Dose Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Induces an Early and Sustained Increase in Neovascularization in Rat Ischemic Legs J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1038 - 1043. [Abstract] [Full Text] [PDF]
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T. Funatsu, Y. Sawa, S. Ohtake, T. Takahashi, G. Matsumiya, N. Matsuura, T. Nakamura, and H. Matsuda Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor J. Thorac. Cardiovasc. Surg., December 1, 2002; 124(6): 1099 - 1105. [Abstract] [Full Text]
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A. Tandar, G.M. Saperia, and D.H. Spodick Direct myocardial revascularization and therapeutic angiogenesis Eur. Heart J., October 1, 2002; 23(19): 1492 - 1502. [Full Text] [PDF]
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M. C. Cid, J. Hernandez-Rodriguez, M.-J. Esteban, M. Cebrian, Y. S. Gho, C. Font, A. Urbano-Marquez, J. M. Grau, and H. K. Kleinman Tissue and Serum Angiogenic Activity Is Associated With Low Prevalence of Ischemic Complications in Patients With Giant-Cell Arteritis Circulation, September 24, 2002; 106(13): 1664 - 1671. [Abstract] [Full Text] [PDF]
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M. Ono, Y. Sawa, K. Matsumoto, T. Nakamura, Y. Kaneda, and H. Matsuda In Vivo Gene Transfection With Hepatocyte Growth Factor via the Pulmonary Artery Induces Angiogenesis in the Rat Lung Circulation, September 24, 2002; 106(12_suppl_1): I-264 - I-269. [Abstract] [Full Text] [PDF]
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T.-S. Li, K. Hamano, K. Suzuki, H. Ito, N. Zempo, and M. Matsuzaki Improved angiogenic potency by implantation of ex vivo hypoxia prestimulated bone marrow cells in rats Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H468 - H473. [Abstract] [Full Text] [PDF]
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H. Su, J. Arakawa-Hoyt, and Y. W. Kan Adeno-associated viral vector-mediated hypoxia response element-regulated gene expression in mouse ischemic heart model PNAS, July 9, 2002; 99(14): 9480 - 9485. [Abstract] [Full Text] [PDF]
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Y. Taniyama, R. Morishita, M. Aoki, K. Hiraoka, K. Yamasaki, N. Hashiya, K. Matsumoto, T. Nakamura, Y. Kaneda, and T. Ogihara Angiogenesis and Antifibrotic Action by Hepatocyte Growth Factor in Cardiomyopathy Hypertension, July 1, 2002; 40(1): 47 - 53. [Abstract] [Full Text] [PDF]
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H. Franz Alber, J. Dulak, M. Frick, W. Dichtl, S. Paul Schwarzacher, O. Pachinger, and F. Weidinger Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1951 - 1955. [Abstract] [Full Text] [PDF]
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E. Leotta, G. Patejunas, G. Murphy, J. Szokol, L. McGregor, J. Carbray, A. Hamawy, D. Winchester, N. Hackett, R. Crystal, et al. Gene therapy with adenovirus-mediated myocardial transfer of vascular endothelial growth factor 121 improves cardiac performance in a pacing model of congestive heart failure J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1101 - 1113. [Abstract] [Full Text] [PDF]
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S.-i. Yoshimura, R. Morishita, K. Hayashi, J. Kokuzawa, M. Aoki, K. Matsumoto, T. Nakamura, T. Ogihara, N. Sakai, and Y. Kaneda Gene Transfer of Hepatocyte Growth Factor to Subarachnoid Space in Cerebral Hypoperfusion Model Hypertension, May 1, 2002; 39(5): 1028 - 1034. [Abstract] [Full Text] [PDF]
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K. Hamano, T.-S. Li, T. Kobayashi, K. Hirata, M. Yano, M. Kohno, and M. Matsuzaki Therapeutic angiogenesis induced by local autologous bone marrow cell implantation Ann. Thorac. Surg., April 1, 2002; 73(4): 1210 - 1215. [Abstract] [Full Text] [PDF]
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M. C. Kim, A. Kini, and S. K. Sharma Refractory angina pectoris: Mechanism and therapeutic options J. Am. Coll. Cardiol., March 20, 2002; 39(6): 923 - 934. [Abstract] [Full Text] [PDF]
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C. L. Grines, M. W. Watkins, G. Helmer, W. Penny, J. Brinker, J. D. Marmur, A. West, J. J. Rade, P. Marrott, H. K. Hammond, et al. Angiogenic Gene Therapy (AGENT) Trial in Patients With Stable Angina Pectoris Circulation, March 19, 2002; 105(11): 1291 - 1297. [Abstract] [Full Text] [PDF]
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M.-H. Liu, H. Jin, H. S. Floten, Z. Ren, A. P.C. Yim, and G.-W. He Vascular endothelial growth factor-mediated, endothelium-dependent relaxation in human internal mammary artery Ann. Thorac. Surg., March 1, 2002; 73(3): 819 - 824. [Abstract] [Full Text] [PDF]
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A. Scherpereel, J. J. Rome, R. Wiewrodt, S. C. Watkins, D. W. Harshaw, S. Alder, M. Christofidou-Solomidou, E. Haut, J.-C. Murciano, M. Nakada, et al. Platelet-Endothelial Cell Adhesion Molecule-1-Directed Immunotargeting to Cardiopulmonary Vasculature J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 777 - 786. [Abstract] [Full Text] [PDF]
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J M Cotton, M R Thomas, B J Dunmore, J Salisbury, A M Shah, and N P J Brindle Angiogenesis in chronically ischaemic human heart following percutaneous myocardial revascularisation Heart, March 1, 2002; 87(3): 281 - 283. [Full Text] [PDF]
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H El-Gendi, A G Violaris, R Foale, H S Sharma, and D J Sheridan Endogenous, local, vascular endothelial growth factor production in patients with chronic total coronary artery occlusions: further evidence for its role in angiogenesis Heart, February 1, 2002; 87(2): 158 - 159. [Full Text] [PDF]
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J. Rockstroh and B. G. Brown Coronary Collateral Size, Flow Capacity, and Growth: Estimates From the Angiogram in Patients With Obstructive Coronary Disease Circulation, January 15, 2002; 105(2): 168 - 173. [Abstract] [Full Text] [PDF]
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