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Ann Thorac Surg 1999;68:830-836
© 1999 The Society of Thoracic Surgeons
a Department of Surgery, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
b Department of Anesthesia, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
c Department of Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
Address reprint requests to Dr Symes, 11 Nevins St/306, Boston, MA 02135
e-mail: jsymes{at}semc.org
Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.
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Abstract |
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Methods. phVEGF165 (125 µg, n = 10; 250 µg, n = 10) was injected directly into the myocardium through a mini left anterior thoracotomy as sole therapy in 20 patients (15 male, 5 female, age 48 to 74 years) with class III or IV angina, reversible ischemia on stress sestamibi scans, and "inoperable" coronary artery disease.
Results. All patients tolerated surgery uneventfully and were extubated on the table. No perioperative myocardial infarction, hemodynamic instability, or change in ventricular function occurred. Mean hospital stay was 3.9 days. There was one late death (4 months). Plasma VEGF protein level increased from 30.6 ± 4.1 pg/mL pretreatment to 73.7 ± 10.1 pg/mL 14 days posttreatment (p = 0.0002) and returned to baseline by day 90. All 16 patients followed to day 90 reported a reduction in angina (nitroglycerin use/week = 60.2 ± 4.9 preop vs 3.5 ± 1.6 at 90 days; p < 0.0001). Seventy percent (7 of 10) patients were completely angina free at 6 months. A reduction in ischemic defects on single photon emission computerized tomography sestamibi scans was observed in 13 of 17 patients at 60 days (7 of 8 in the 250-µg group). Stress perfusion score decreased from 19.4 ± 3.7 at baseline to 15.9 ± 3.4 at 60 days (p = 0.025). Angiographic evidence of improved collateral filling of at least one occluded vessel was observed in all patients evaluated at day 60.
Conclusions. Direct myocardial gene transfer with phVEGF165 via a mini-thoracotomy can be performed safely and may result in significant symptomatic improvement in patients with "inoperable" coronary artery disease.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Preclinical studies in animals models of both hindlimb and myocardial ischemia have demonstrated that direct intramuscular gene transfer of naked DNA encoding for vascular endothelial growth factor [1–3] can stimulate angiogenesis and improve perfusion to the ischemic tissue. Preliminary clinical results utilizing intramuscular transfection of phVEGF165 in patients with end-stage critical limb ischemia have documented histologic and angiographic evidence of neovascularization with resultant limb salvage [4, 5]. This report describes the preliminary results on the first 20 patients treated in a phase I clinical trial designed to determine the safety and bioactivity of direct myocardial gene transfer of the angiogenic mitogen vascular endothelial growth factor (phVEGF165) as the sole therapy in patients with medically intractable angina who were not candidates for further conventional revascularization procedures.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Patients were considered eligible for intramyocardial gene therapy if they presented with Canadian Cardiovascular Society functional class III or IV angina refractory to maximum medical therapy and had demonstrable areas of viable but underperfused myocardium on single photon emission computerized tomography (SPECT)-sestamibi nuclear scanning. In addition, they were required to have multivessel coronary occlusive disease and no options in terms of repeat coronary bypass or percutaneous angioplasty. Subjects were excluded if they had had a successful revascularization within the past 6 months or were documented to have cancer, diabetic retinopathy, or a left ventricular ejection fraction of 20% or less.
Plasmid DNA (phVEGF165)
Each patient received a eukaryotic expression vector encoding for the 165-amino acid isoform of the human VEGF gene transcriptionally regulated by a cytomegalovirus promoter/enhancer. Plasmid DNA was prepared and purified from cultures of phVEGF165-transformed Escherichia coli in the Human Gene Therapy Laboratory at St. Elizabeth’s Medical Center using the column method (Plasmid MegaKit; Qiagen, Valencia, CA).
Myocardial gene transfer
The surgical procedure was performed under general anesthesia utilizing the standard protocol for off-pump coronary bypass surgery. This included insertion of both an arterial line and Swan-Ganz pulmonary artery catheter capable of measuring continuous cardiac output. In addition, patients received a spinal injection of morphine (Duramorph, 0.3 to 0.5 mg intrathecal; Cardinal Health, Peabody, MA) for early postoperative pain control.
The heart was exposed through an 8- to 10-cm, left anterior thoracotomy incision in the fourth or fifth intercostal space. The pericardium was opened and carefully dissected off the epicardial surface of the heart in the apical and anterolateral region of the left ventricle. A retractor/stabilizer (Cardiothoracic Systems, Inc, Cupertino, CA) was inserted to immobolize the epicardial surface over the site of each injection. Continuous transesophageal echocardiographic (TEE) monitoring was utilized both to assure no change in regional wall motion and, more importantly, to ascertain that the DNA was injected into the myocardium and not into the left ventricular cavity. The plasmid DNA was injected in 2-cc aliquots at four separate sites utilizing a 3-cc syringe and 25-gauge needle. Each injection of plasmid DNA was preceded by a small injection of agitated sterile saline in order to assure that the needle was positioned in the myocardium. Evidence that it was near the endocardial surface or indeed penetrating the myocardium was provided by the presence of microbubbles visualized with the TEE. Once ultrasound imaging confirmed good needle position, the DNA was slowly injected into the myocardium at each of the four sites. The first 10 patients in the study received a total of 125 µg of phVEGF165, whereas the second group of 10 patients received a total of 250 µg according to the dose-escalating protocol.
Once the injections were completed, a chest tube was positioned in the left pleural space if it was opened and the incision closed. The patients were all extubated in the operating room and transferred to the intensive care unit for 24 hours of postoperative monitoring.
VEGF assay
Plasmid VEGF levels were measured on the day before gene transfer and also on days 3, 7, 14, 30, 60, and 90 after gene transfer utilizing an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN).
Patient follow-up
Safety parameters
All patients were observed in the hospital for 3 days, the first 24 hours in the intensive care unit, the second 24 hours in the step-down unit, and the last 24 hours on the regular surgical floor. Hemodynamic parameters including blood pressure, pulmonary artery pressure, and cardiac output were continuously monitored in the first 24 hours. Myocardial isoenzymes (CPK-MB) were closely followed for the first 48 hours. Serial electrocardiograms (ECGs) and standard transthoracic echocardiograms were performed preop, immediately before discharge, and 14, 30, 60, 90, and 180 days postop. A repeat fundoscopic exam was performed 6 months after gene therapy.
Clinical outcome
The number of angina episodes per week as well as the requirement for nitroglycerin tablets per week were carefully documented at each postop visit over the 180-day follow-up period. In addition, patients were evaluated at each interval for evidence of congestive heart failure in the form of either pulmonary or peripheral edema.
SPECT myocardial perfusion study
All subjects underwent stress dobutamine or persantine SPECT-sestamibi study less than 2 weeks before gene transfer. SPECT images were acquired according to a single-day rest-stress protocol, where image acquisition was performed after 8 mci of sestamibi was injected at rest, followed in 2 to 3 hours by the stress protocol with 20 to 22 mci of sestamibi injected at peak of stress and images acquired 30 to 40 minutes later. Utilizing a 20-segment model, perfusion scores were assigned to each segment based on a visual analysis and were further analyzed using the Cedars-Sinai automated quantification program [6]. A scale of 0 to 4 (0 = normal) was used based on both the automated and the visual analysis. The nuclear perfusion studies were repeated on days 30 and 60 utilizing the identical stress protocol and isotope used for the baseline study.
Coronary angiography
Patients underwent a diagnostic coronary angiogram less than 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- vs posttreatment). Collateral filling of occluded vessels was graded according to the Rentrop score (absent = 0, filling of side branches of the target occluded epicardial vessel without visualization of the vessel itself = 1+, partial filling of the epicardial segment via collaterals = 2+, or complete filling of the epicardial segment of the occluded vessel = 3+).
Statistical analysis
Data are reported as mean ± SEM. Comparisons between paired variables were performed using a paired Student’s t test with statistical significance defined as p less than 0.05.
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Results |
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Perioperative course
All 20 patients underwent myocardial gene transfer successfully. The mean operative time was 75 minutes (range 50 to 120 minutes). All patients were extubated in the operating room within 15 to 20 minutes of the completion of the procedure. Injections caused no change in heart rate, blood pressure, or pulmonary artery pressure. Occasional, unifocal premature ventricular contractions were noted on the initiation of the injections into the myocardium, but no other arrhythmias were encountered intraoperatively. Transesophageal echocardiographic monitoring documented no new wall motion abnormalities after the injection procedure and no change in left ventricular function. Cardiac output fell transiently but had increased significantly in all patients 18 to 24 hours postoperatively (preanesthesia 4.85 ± 0.20 vs postanesthesia 4.1 ± 0.20 vs 6.6 ± 0.45 24 hours postop). Serial ECGs demonstrated no evidence of myocardial infarction in any patient. Serial enzyme determinations documented a transient increase in CPK due to the surgical procedure but no change in the myocardial-specific enzyme creatinine phosphokinase-myocardial fraction (CPK-MB). Intraoperative blood loss was less than 50 cc, and total 24-hour chest tube drainage averaged 148 ± 22 cc (range 30 to 395 cc). All but 2 patients were discharged from hospital on postoperative day 3 or 4. The average length of stay of these patients was 3.5 days.
Plasma VEGF levels
The changes observed in plasma VEGF protein levels are depicted in Figure 1. The mean value increased from 30.6 ± 4.1 pg/mL before gene transfer to a peak of 73.7 ± 10.1 pg/mL (p = 0.0002) on day 14. It had returned to baseline by day 90 in all patients.
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The other 19 patients were discharged home and were followed up at 14, 30, 60, 90, and 180 days. Serial ECGs and standard transthoracic echocardiograms done on each occasion on all patients demonstrated no evidence of myocardial infarction or deterioration in left ventricular ejection fraction. No new wall motion abnormalities were observed. On clinical evaluation, there was no evidence of congestive heart failure in any patient except for mild (1+) pitting ankle edema in 1. The changes in the pattern of angina are documented in Table 2. All patients were experiencing angina with minimal activity on a daily basis before gene therapy. By day 60, all patients had experienced a reduction in angina frequency and 70% of patients followed up for 180 days were completely angina free. All 10 patients at the 6-month follow-up point were experiencing less than one anginal episode per day. The use of nitroglycerin tablets decreased significantly from a mean of 60.2 ± 4.9 per week before gene therapy to a mean of 8.0 ± 2.7 on day 30, 7.2 ± 2.5 on day 60, 3.5 ± 1.6 on day 90, and 2.2 ± 1.3 per week at 6 months (Fig 2).
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Therapeutic angiogenesis is the controlled stimulation of collateral formation in order to reduce the unfavorable tissue effects caused by ischemia [8]. Takeshita and associates were the first to demonstrate that administration of recombinant VEGF protein either as a single intraarterial bolus or by repeated intramuscular injections could be used to achieve therapeutic angiogenesis in a rabbit hindlimb ischemia model [9, 10]. Improvement in myocardial perfusion with the administration of VEGF protein in both canine and porcine models was demonstrated shortly thereafter [11, 12].
The considerable expense associated with production of recombinant protein formulations for clinical use, combined with the demonstrated need to deliver the protein locally over a period of several days or weeks, led to studies using gene transfer as an alternative strategy for accomplishing therapeutic angiogenesis in patients with limb and myocardial ischemia. In the case of VEGF, gene therapy is particularly appealing because the VEGF gene encodes a signal sequence that permits the protein to be naturally secreted by intact cells [13]. Previous studies from our institution have indicated that both arterial and intramuscular gene transfer of naked DNA encoding for VEGF can result in significant improvement in neovascularization [2, 14]. In addition, gene therapy could potentially avoid systemic hypotension, which has been documented to occur with intracoronary administration of the VEGF protein [15].
The phase 1 clinical trial described here was based upon the demonstration in a porcine myocardial ischemia model that direct intramyocardial administration of phVEGF165 could induce improvement in myocardial perfusion [3]. The results described greatly expand upon our preliminary report on the first 5 patients [16] and provide more convincing evidence that this therapeutic approach, in which the gene is delivered through a small anterior thoracotomy incision, can be carried out safely in the majority of patients with extensive diffuse coronary artery disease and stable chronic angina. Aside from the 1 patient who died 4 months after gene therapy, all other patients tolerated the procedure well and had an entirely uneventful postoperative course with follow-up extending out to 6 months.
Documentation of gene expression by serial measurement of VEGF protein levels in the plasma demonstrated a small but fairly consistent rise peaking about 2 weeks posttransfection. Individual levels were quite variable, however, and we have not attempted to correlate these data with clinical outcome because of the relatively small number of patients treated to date.
Virtually all patients experienced a reduction in their anginal symptoms and the requirement for nitrate use. Stress sestamibi perfusion studies done 60 days after therapy demonstrated unequivocal evidence of improved myocardial perfusion in a majority of the patients, and coronary angiography repeated 60 days after gene therapy provided evidence of improved collateral development. In contrast to the study reported by Schumacher and associates [17], as well as that of Selke’s group [18], patients in our study had no other surgical revascularization procedure performed at the time of gene transfer. We believe it is therefore reasonable to attribute the changes documented to the gene therapy procedure.
Half the patients in the study received 125 µg of VEGF DNA, while the second group of 10 patients in this dose-escalating protocol received 250 µg. These two groups were relatively small and not identical in makeup, and therefore, although results of the 60-day perfusion scans appear to show a more consistent improvement with the higher dose, no significant comparison can be made between the efficacy of the two dosages at this time.
Adenovirus-mediated gene transfer has been shown by others to enhance transfection efficiency, and studies by Giordano and associates [19] using fibroblast growth factor 5 and by Mack and associates [20] utilizing VEGF121 have both demonstrated significant improvement in perfusion in the porcine model of chronic myocardial ischemia. Because of the potential for inflammatory and/or immunologic reaction that might be stimulated with the use of adenoviral vectors, we chose to utilize naked plasmid DNA for this study. Because VEGF165 acts only on endothelial cells and, as noted above, has the capability of being secreted by intact cells, an amplified angiogenic effect may be possible despite the lower transfection efficiency.
While this preliminary clinical experience with VEGF gene therapy for inoperable coronary disease is encouraging, several caveats must be recognized. First, this study was designed as a phase 1 nonrandomized study. The FDA as well as the St. Elizabeth’s Medical Center Human Investigation Research and Institutional BioSafety Committee felt that administration of the gene via a mini thoracotomy under general anesthesia would not permit randomization to a placebo group until the safety of the technique had been clearly demonstrated. Furthermore, additional follow-up will be required to definitively document the safety of angiogenic therapy, in particular with regard to the potential adverse effects of tumor growth and retinopathy. With regard to the latter, it is encouraging that none of the patients in this study reexamined at 6 months had evidence of retinal change (45% were diabetic), and no patient treated in our critical limb ischemia trial has developed new retinopathy either [21].
Other clinical trials utilizing adenoviral vectors as well as recombinant protein are currently underway, and until all of these studies are completed, the best method of achieving angiogenesis remains to be determined. It is of interest, anecdotally, that patient 6 in this study presented with class III angina despite having received intracoronary VEGF protein a year earlier, and was angina-free 6 months after VEGF gene therapy. Indeed, for patients who are truly "inoperable," gene transfer achieved percutaneously through a catheter-based system may ultimately be the most efficacious, and trials of such a system are currently underway. On the other hand, if additional studies confirm that gene therapy is effective, then its ultimate role will almost certainly include use as an adjunctive revascularization strategy in patients undergoing coronary bypass surgery who have a significant territory of ischemic myocardium that cannot be revascularized. As the angiographic data in Table 3 indicate, angiogenic therapy appears to work by stimulating the development of bridging collaterals from adequately perfused regions of the heart usually supplied by patent grafts (particulary the LIMA-LAD) to neighboring underperfused zones of otherwise viable myocardium.
In conclusion, while the results reported here are preliminary, they suggest that direct myocardial injection of naked DNA encoding for VEGF165 can be performed safely via a mini thoroacotomy in patients with otherwise inoperable coronary artery disease. Further, this approach appears to result in significant relief of angina and improvement in myocardial perfusion in the majority of patients so treated, and warrants further investigation as an alternative revascularization strategy for medically intractable angina.
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|
|
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|
|
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|
|
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|
|
|
|
 |
|
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|
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|
|
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|
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 J. Bonatti, C. Haeusler, A. Klaus, M. Fink, A. Hammerer-Lercher, and G. Laufer Acceptance of gene therapy by the heart surgery patient Eur J Cardiothorac Surg, June 1, 2002; 21(6): 981 - 986. [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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G. C. Hughes, S. S. Biswas, B. Yin, D. V. Baklanov, B. H. Annex, R. E. Coleman, T. R. DeGrado, C. K. Landolfo, K. P. Landolfo, and J. E. Lowe A comparison of mechanical and laser transmyocardial revascularization for induction of angiogenesis and arteriogenesis in chronically ischemic myocardium J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1220 - 1228. [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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 G. Mozes and P. Gloviczki Adjuvant Therapy in Lower Extremity Revascularization: Prevention of Early and Intermediate Failures Perspectives in Vascular Surgery and Endovascular Therapy, January 1, 2002; 15(2): 161 - 180. [Abstract] [PDF]
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 S. B. Freedman and J. M. Isner Therapeutic Angiogenesis for Coronary Artery Disease Ann Intern Med, January 1, 2002; 136(1): 54 - 71. [Abstract] [Full Text] [PDF]
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H. Huwer, C. Welter, C. ozbek, M. Seifert, U. Straub, P. Greilach, G. Kalweit, and H. Isringhaus Simultaneous surgical revascularization and angiogenic gene therapy in diffuse coronary artery disease Eur J Cardiothorac Surg, December 1, 2001; 20(6): 1128 - 1134. [Abstract] [Full Text] [PDF]
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R. Khurana, J. F. Martin, and I. Zachary Gene Therapy for Cardiovascular Disease: A Case for Cautious Optimism Hypertension, November 1, 2001; 38(5): 1210 - 1216. [Abstract] [Full Text] [PDF]
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C. Seiler, T. Pohl, K. Wustmann, D. Hutter, P.-A. Nicolet, S. Windecker, F. R. Eberli, and B. Meier Promotion of Collateral Growth by Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Coronary Artery Disease: A Randomized, Double-Blind, Placebo-Controlled Study Circulation, October 23, 2001; 104(17): 2012 - 2017. [Abstract] [Full Text] [PDF]
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R. S. Kellar, L. K. Landeen, B. R. Shepherd, G. K. Naughton, A. Ratcliffe, and S. K. Williams Scaffold-Based Three-Dimensional Human Fibroblast Culture Provides a Structural Matrix That Supports Angiogenesis in Infarcted Heart Tissue Circulation, October 23, 2001; 104(17): 2063 - 2068. [Abstract] [Full Text] [PDF]
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 M. Azrin Angiogenesis, protein and gene delivery Br. Med. Bull., October 1, 2001; 59(1): 211 - 225. [Abstract] [Full Text] [PDF]
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J. M. Isner, P. R. Vale, J. F. Symes, and D. W. Losordo Assessment of Risks Associated With Cardiovascular Gene Therapy in Human Subjects Circ. Res., August 31, 2001; 89(5): 389 - 400. [Abstract] [Full Text] [PDF]
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R. A. de Boer, H.-M. J. Siebelink, R. A. Tio, F. Boomsma, and D. J. van Veldhuisen Carvedilol increases plasma vascular endothelial growth factor (VEGF) in patients with chronic heart failure Eur J Heart Fail, June 1, 2001; 3(3): 331 - 333. [Full Text] [PDF]
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P. R. Vale, D. W. Losordo, C. E. Milliken, M. C. McDonald, L. M. Gravelin, C. M. Curry, D. D. Esakof, M. Maysky, J. F. Symes, and J. M. Isner Randomized, Single-Blind, Placebo-Controlled Pilot Study of Catheter-Based Myocardial Gene Transfer for Therapeutic Angiogenesis Using Left Ventricular Electromechanical Mapping in Patients With Chronic Myocardial Ischemia Circulation, May 1, 2001; 103(17): 2138 - 2143. [Abstract] [Full Text] [PDF]
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N. van Royen, J. J. Piek, I. Buschmann, I. Hoefer, M. Voskuil, and W. Schaper Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease Cardiovasc Res, February 16, 2001; 49(3): 543 - 553. [Abstract] [Full Text] [PDF]
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H.K. Hammond and M.D. McKirnan Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials Cardiovasc Res, February 16, 2001; 49(3): 561 - 567. [Abstract] [Full Text] [PDF]
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A. Kawamoto, H.-C. Gwon, H. Iwaguro, J.-I. Yamaguchi, S. Uchida, H. Masuda, M. Silver, H. Ma, M. Kearney, J. M. Isner, et al. Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor Cells for Myocardial Ischemia Circulation, February 6, 2001; 103(5): 634 - 637. [Abstract] [Full Text] [PDF]
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 K. G. Lathi, P. R. Vale, D. W. Losordo, R. M. Cespedes, J. F. Symes, D. D. Esakof, M. Maysky, and J. M. Isner Gene Therapy with Vascular Endothelial Growth Factor for Inoperable Coronary Artery Disease: Anesthetic Management and Results Anesth. Analg., January 1, 2001; 92(1): 19 - 25. [Abstract] [Full Text] [PDF]
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S. L. Meyerson, C. L. Skelly, M. A. Curi, and L. B. Schwartz Gene Therapy for Cardiovascular Disease Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 2000; 4(4): 289 - 300. [Abstract] [PDF]
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A. M. Lansing Transmyocardial laser revascularization Ann. Thorac. Surg., November 1, 2000; 70(5): 1763 - 1763. [Full Text] [PDF]
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C. R. Bridges Reply Ann. Thorac. Surg., November 1, 2000; 70(5): 1763 - 1764. [Full Text] [PDF]
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C. Kalka, H. Tehrani, B. Laudenberg, P. R. Vale, J. M. Isner, T. Asahara, and J. F. Symes VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease Ann. Thorac. Surg., September 1, 2000; 70(3): 829 - 834. [Abstract] [Full Text] [PDF]
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R. Miraliakbari, N. A. Francalancia, R. M. Lust, J. A. Gerardo, P. C. Ng, Y. S. Sun, and W. R. Chitwood Jr Differences in myocardial and peripheral VEGF and KDR levels after acute ischemia Ann. Thorac. Surg., June 1, 2000; 69(6): 1750 - 1754. [Abstract] [Full Text] [PDF]
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 S. C. FRANCIS, M. K. RAIZADA, A. A. MANGI, L. G. MELO, V. J. DZAU, P. R. VALE, J. M. ISNER, D. W. LOSORDO, J. CHAO, M. J. KATOVICH, et al. Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb? Physiol Genomics, December 21, 2001; 7(2): 79 - 94. [Abstract] [Full Text] [PDF]
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D. W. Losordo, P. R. Vale, R. C. Hendel, C. E. Milliken, F. D. Fortuin, N. Cummings, R. A. Schatz, T. Asahara, J. M. Isner, and R. E. Kuntz 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, April 30, 2002; 105(17): 2012 - 2018. [Abstract] [Full Text] [PDF]
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