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Circulation. 1998;98:2800-2804

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(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

Douglas W. Losordo, MD; Peter R. Vale, MD; James F. Symes, MD; Cheryl H. Dunnington, MS; Darryl D. Esakof, MD; Michael Maysky, MD; Alan B. Ashare, MD; Kishor Lathi, MD; Jeffrey M. Isner, MD

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.


*    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


*    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.


*    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.


*    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 1Down.


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Table 1. Demographic and Clinical Data

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 1Up). 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 1Down) SPECT-sestamibi imaging (Table 2Down). 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 2Down). 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 2Down).



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Figure 1. SPECT-sestamibi perfusion imaging. Top, Example of improvement in a "fixed" defect (perfusion abnormality on resting image). In patient (Pt.) 4, a moderate area of decreased perfusion is seen in the infero-lateral wall (arrow) before gene therapy. After gene therapy, perfusion is improved. Bottom, Example of improvement in an area of ischemia. In Pt. 2, a small zone of decreased perfusion is seen in the inferior wall (arrow) before treatment. After treatment, the matching scan shows no evidence of this perfusion defect while a zone of ischemia on the anterior (opposite) wall persists.


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Table 2. Perfusion Scan Results



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Figure 2. SPECT-sestamibi perfusion imaging: summary of findings in 5 patients. Short-axis views were divided into a total of 13 segments and graded as normal (no perfusion defect), reversible (perfusion defect during stress that partially or completely reversed at rest), or fixed (perfusion defect during stress that persists at rest). Values represent mean±SEM for all 5 patients at baseline, 30 days, and 60 days post–gene therapy. *P<0.05 compared with baseline.

Coronary Angiography
Selective coronary angiography was performed before and 59.8±1.5 days after gene transfer (Table 3Down). 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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Table 3. Angiographic Results


*    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.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
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up arrowResults
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*References
 
1. Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987;235:442–447.[Abstract/Free Full Text]

2. Takeshita S, Zheng LP, Brogi E, Kearney M, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM. Therapeutic angiogenesis: a single intra-arterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hindlimb model. J Clin Invest. 1994;93:662–670.

3. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–1309.[Abstract/Free Full Text]

4. Tischer E, Mitchell R, Hartmann T, Silva M, Gospodarowicz D, Fiddes J, Abraham J. The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991;266:11947–11954.[Abstract/Free Full Text]

5. Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara T, Rosenfield K, Razvi S, Walsh K, Symes J. Clinical evidence of angiogenesis following arterial gene transfer of phVEGF165. Lancet. 1996;348:370–374.[Medline] [Order article via Infotrieve]

6. Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K, Isner JM. Constitutive expression of phVEGF165 following intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation. 1998;97:1114–1123.[Abstract/Free Full Text]

7. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in coronary collateral filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. J Am Coll Cardiol. 1985;5:587–592.[Abstract]

8. Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, Epstein SE, Unger EF. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation. 1994;89:2183–2189.[Abstract/Free Full Text]

9. Pearlman JD, Hibberd MG, Chuang ML, Harada K, Lopez JJ, Gladston SR, Friedman M, Sellke FW, Simons M. Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis. Nature Med. 1995;1:1085–1089.[Medline] [Order article via Infotrieve]

10. Losordo DW, Pickering JG, Takeshita S, Leclerc G, Gal D, Weir L, Kearney M, Jekanowski J, Isner JM. Use of the rabbit ear artery to serially assess foreign protein secretion after site specific arterial gene transfer in vivo: evidence that anatomic identification of successful gene transfer may underestimate the potential magnitude of transgene expression. Circulation. 1994;89:785–792.[Abstract/Free Full Text]

11. Takeshita S, Losordo DW, Kearney M, Isner JM. Time course of recombinant protein secretion following liposome-mediated gene transfer in a rabbit arterial organ culture model. Lab Invest. 1994;71:387–391.[Medline] [Order article via Infotrieve]

12. Takeshita S, Tsurumi Y, Couffinhal T, Asahara T, Bauters C, Symes JF, Ferrara N, Isner JM. Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo. Lab Invest. 1996;75:487–502.[Medline] [Order article via Infotrieve]

13. Schumacher B, Pecher P, von Specht BU, Stegmann TH. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation. 1998;97:645–650.[Abstract/Free Full Text]

14. Vale PR, Losordo DW, Symes JF, Isner JM. Gene therapy for myocardial angiogenesis. Circulation. 1998;98(suppl I):I-322. Abstract

15. Henry TD, Rocha-Singh K, Isner JM, Kereiakes DJ, Giordano FJ, Simons M, Losordo DW, Hendel RC, Bonow RO, Rothman JM, Borbas ER, McCluskey ER. Results of intracoronary recombinant human vascular endothelial growth factor (rhVEGF) administration trial. Circulation. 1998;31:65A. Abstract.

16. Mack CA, Patel SR, Schwarz EA, Zanzonico P, Hahn RT, Ilercil A, Devereux RB, Goldsmith SJ, Christian TF, Sanborn TA, Kovesdi I, Itackett N, Isom OW, Crystal RG, Rosengart TK. 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;115:168–176.[Abstract/Free Full Text]

17. Selke FW, Jianyi L, Stamler A, Lopez JJ, Thomas KA, Simons M. Angiogenesis induced by acidic fibroblast growth factor as an alternative method of revascularization for chronic myocardial ischemia. Surgery. 1996;120:182–188.[Medline] [Order article via Infotrieve]

18. Harada K, Grossman W, Friedman M, Edelman ER, Prasad PV, Keighlcy CS, Manning WJ, Selke FW, Simons M. Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts. J Clin Invest. 1994;94:623–630.

19. Giordano FJ, Ping P, McKirnan D, Nozaki S, DeMaria AN, Dillmann WH, Mathieu-Costello O, Hammond HK. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nature Med. 1996;2:534–539.Five patients with refractory angina underwent successful gene transfer by direct myocardial injection of naked plasmid DNA. All 5 patients experienced decreased angina and demonstrated evidence of improved myocardial perfusion by dobutamine SPECT-sestamibi imaging after gene transfer. These data provide the first evidence that angiogenic gene therapy can be used as sole therapy for patients with angina pectoris.




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Home page
Arterioscler. Thromb. Vasc. Bio.Home page
N. Inoue, T. Kondo, K. Kobayashi, M. Aoki, Y. Numaguchi, M. Shibuya, and T. Murohara
Therapeutic Angiogenesis Using Novel Vascular Endothelial Growth Factor-E/Human Placental Growth Factor Chimera Genes
Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 99 - 105.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
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]


Home page
Ann. Thorac. Surg.Home page
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]


Home page
SEMIN CARDIOTHORAC VASC ANESTHHome page
F. W. Sellke, R. Laham, E. J. Suuronen, and M. Ruel
Angiogenesis for the treatment of inoperable coronary disease: the future.
Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2006; 10(2): 184 - 188.
[Abstract] [PDF]


Home page
J CARDIOVASC PHARMACOL THERHome page
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]


Home page
ICVTSHome page
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]


Home page
ANGIOLOGYHome page
R. Topsakal, N. K. Eryol, A. Abaci, S. Oymak, I. Ozdogru, Y. Yilmaz, E. Seyfeli, A. Oguzhan, and A. Ergin
The Relation Between Chronic Obstructive Pulmonary Disease and Coronary Collateral Vessels
Angiology, November 1, 2005; 56(6): 651 - 656.
[Abstract] [PDF]


Home page
JCOHome page
D. R. D'Adamo, S. E. Anderson, K. Albritton, J. Yamada, E. Riedel, K. Scheu, G. K. Schwartz, H. Chen, and R. G. Maki
Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue Sarcomas
J. Clin. Oncol., October 1, 2005; 23(28): 7135 - 7142.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
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]


Home page
CirculationHome page
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]


Home page
Drug Metab. Dispos.Home page
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]


Home page
RadiologyHome page
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]


Home page
Exp PhysiolHome page
R. Morishita, M. Aoki, and T. Ogihara
Does gene therapy become pharmacotherapy?
Exp Physiol, May 1, 2005; 90(3): 307 - 313.
[Abstract] [Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
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]


Home page
Asian Cardiovasc. Thorac. Ann.Home page
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]


Home page
FASEB J.Home page
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]


Home page
HeartHome page
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]


Home page
CirculationHome page
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]


Home page
J CARDIOVASC PHARMACOL THERHome page
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]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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]


Home page
J. Pharmacol. Exp. Ther.Home page
X. Deng, S. Szabo, T. Khomenko, M. R. Jadus, and M. Yoshida
Gene Therapy with Adenoviral Plasmids or Naked DNA of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor Accelerates Healing of Duodenal Ulcer in Rats
J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 982 - 988.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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]


Home page
Proc. Natl. Acad. Sci. USAHome page
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]


Home page
CirculationHome page
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]


Home page
CirculationHome page
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]


Home page
J CARDIOVASC PHARMACOL THERHome page
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]


Home page
Mayo Clin Proc.Home page
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]


Home page
CirculationHome page
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]


Home page
JNMHome page
R. A. Tio, E. S. Tan, G. A.J. Jessurun, N. Veeger, P. L. Jager, R. H.J.A. Slart, R. M. de Jong, J. Pruim, G. A.P. Hospers, A. T.M. Willemsen, et al.
PET for Evaluation of Differential Myocardial Perfusion Dynamics After VEGF Gene Therapy and Laser Therapy in End-Stage Coronary Artery Disease
J. Nucl. Med., September 1, 2004; 45(9): 1437 - 1443.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart J SupplHome page
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]


Home page
J Am Coll CardiolHome page
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]


Home page
Endocr. Rev.Home page
N. Ferrara
Vascular Endothelial Growth Factor: Basic Science and Clinical Progress
Endocr. Rev., August 1, 2004; 25(4): 581 - 611.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
R. Morishita, M. Aoki, N. Hashiya, H. Makino, K. Yamasaki, J. Azuma, Y. Sawa, H. Matsuda, Y. Kaneda, and T. Ogihara
Safety Evaluation of Clinical Gene Therapy Using Hepatocyte Growth Factor to Treat Peripheral Arterial Disease
Hypertension, August 1, 2004; 44(2): 203 - 209.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
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]


Home page
Exp PhysiolHome page
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]


Home page
INT J LOW EXTREM WOUNDSHome page
C. Theopold, F. Yao, and E. Eriksson
Gene Therapy in the Treatment of Lower Extremity Wounds
International Journal of Lower Extremity Wounds, June 1, 2004; 3(2): 69 - 79.
[Abstract] [PDF]


Home page
Ann. Thorac. Surg.Home page
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]


Home page
Asian Cardiovasc. Thorac. Ann.Home page
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]


Home page
RadiologyHome page
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]


Home page
CirculationHome page
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]


Home page
CirculationHome page
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]


Home page
FASEB J.Home page
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]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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]


Home page
Cardiovasc ResHome page
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]


Home page
CirculationHome page
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]


Home page
CirculationHome page
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]


Home page
J Am Coll CardiolHome page
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]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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]


Home page
Circ. Res.Home page
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]


Home page
CirculationHome page
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]


Home page
CirculationHome page
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]


Home page
Ann. Thorac. Surg.Home page
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]


Home page
CirculationHome page
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]


Home page
Ann. Thorac. Surg.Home page
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]


Home page
Ann. Thorac. Surg.Home page
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]


Home page
Card Surg AdultHome page
M. Ruel, R. A. Kelly, and F. W. Sellke
Therapeutic Angiogenesis, Transmyocardial Laser Revascularization, and Cell Therapy
Card. Surg. Adult, January 1, 2003; 2(2003): 715 - 750.
[Full Text]


Home page
CirculationHome page
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]


Home page
Physiol. GenomicsHome page
T. H. Kim, K. A. Skelding, E. G. Nabel, and R. D. Simari
What can cardiovascular gene transfer learn from genomics: and vice versa?
Physiol Genomics, December 3, 2002; 11(3): 179 - 182.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
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]


Home page
J. Thorac. Cardiovasc. Surg.Home page
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]


Home page
Eur Heart JHome page
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]


Home page
CirculationHome page
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]


Home page
CirculationHome page
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]


Home page
J. Appl. Physiol.Home page
Y. Yang, J.-Y. Min, J. S. Rana, Q. Ke, J. Cai, Y. Chen, J. P. Morgan, and Y.-F. Xiao
VEGF enhances functional improvement of postinfarcted hearts by transplantation of ESC-differentiated cells
J Appl Physiol, September 1, 2002; 93(3): 1140 - 1151.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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]


Home page
Proc. Natl. Acad. Sci. USAHome page
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]


Home page
HypertensionHome page
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]


Home page
J Am Coll CardiolHome page
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]


Home page
J. Thorac. Cardiovasc. Surg.Home page
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]


Home page
HypertensionHome page
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]


Home page
Ann. Thorac. Surg.Home page
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]


Home page
J Am Coll CardiolHome page
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]


Home page
CirculationHome page
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]


Home page
Ann. Thorac. Surg.Home page
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]


Home page
J. Pharmacol. Exp. Ther.Home page
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]


Home page
HeartHome page
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]


Home page
Cardiovasc ResHome page
M. Shimpo, U. Ikeda, Y. Maeda, M. Takahashi, H. Miyashita, H. Mizukami, M. Urabe, A. Kume, T. Takizawa, M. Shibuya, et al.
AAV-mediated VEGF gene transfer into skeletal muscle stimulates angiogenesis and improves blood flow in a rat hindlimb ischemia model
Cardiovasc Res, March 1, 2002; 53(4): 993 - 1001.
[Abstract] [Full Text] [PDF]


Home page
HeartHome page
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]


Home page
CirculationHome page
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]


Home page
Cold Spring Harb Symp Quant BiolHome page
J.A. NAGY, E. VASILE, D. FENG, C. SUNDBERG, L.F. BROWN, E.J. MANSEAU, A.M. DVORAK, and H.F. DVORAK
VEGF-A Induces Angiogenesis, Arteriogenesis, Lymphangiogenesis, and Vascular Malformations
Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 227 - 238.
[Abstract] [PDF]


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