(Circulation. 1999;100:1865-1871.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Angiogenesis Research Center (R.J.L., J.D.P., M.S.) and Interventional Cardiology Section (R.J.L.), Department of Medicine, and Department of Surgery (F.W.S.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Mass; Massachusetts Institute of Technology (E.R.E.), Cambridge, Mass; and Departments of Medicine (J.A.W., D.L.B.) and Cardiothoracic Surgery (J.P.G.), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.
Correspondence to Michael Simons, MD, Angiogenesis Research Center, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail msimons{at}bidmc.harvard.edu
| Abstract |
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Methods and ResultsWe conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 µg versus placebo) delivered via sustained-release heparin-alginate microcapsules implanted in ischemic and viable but ungraftable myocardial territories in patients undergoing CABG. Twenty-four patients were randomized to 10 µg of bFGF (n=8), 100 µg of bFGF (n=8), or placebo (n=8), in addition to undergoing CABG. There were 2 operative deaths and 3 Q-wave myocardial infarctions. There were no treatment-related adverse events, and there was no rise in serum bFGF levels. Clinical follow-up was available for all patients (16.0±6.8 months). Three control patients had recurrent angina, 2 of whom required repeat revascularization. One patient in the 10-µg bFGF group had angina, whereas all patients in the 100-µg bFGF group remained angina-free. Stress nuclear perfusion imaging at baseline and 3 months after CABG showed a trend toward worsening of the defect size in the placebo group (20.7±3.7% to 23.8±5.7%, P=0.06), no significant change in the 10-µg bFGF group, and significant improvement in the 100-µg bFGF group (19.2±5.0% to 9.1±5.9%, P=0.01). Magnetic resonance assessment of the target ischemic zone in a subset of patients showed a trend toward a reduction in the target ischemic area in the 100-µg bFGF group (10.7±3.9% to 3.7±6.3%, P=0.06).
ConclusionsThis study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable myocardium that cannot be adequately revascularized.
Key Words: heart diseases angiogenesis growth substances myocardium
| Introduction |
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The availability of various angiogenic growth factors, particularly basic fibroblast growth factor (bFGF) and vascular endothelial growth factor, and their implication in developmental, ischemia-induced, and tumor angiogenesis have led to studies that have demonstrated their therapeutic benefit in animal models of myocardial ischemia.2 3 4 5 6 7 8 9 We previously demonstrated that epicardially implanted heparin-alginate pellets containing either 10 or 100 µg of bFGF resulted in functionally significant angiogenesis in a porcine model of chronic myocardial ischemia, with very low plasma bFGF levels, no acute hemodynamic effects, and no significant toxicity.5 8 Based on these preclinical results, we designed and implemented a phase I randomized, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of local periadventitial bFGF as an adjunct to CABG surgery. In this trial, patients with a viable and ischemic myocardial area that could not be revascularized were randomized to receive heparin-alginate pellets containing 10 or 100 µg of bFGF or placebo that were placed on the epicardial surface during CABG.
| Methods |
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The design and performance of the study were approved by the Food and Drug Administration under an investigator-sponsored investigational new drug (BB-IND 5725). The study was approved by the Committee for Clinical Investigation at both institutions. The first patient was enrolled in September 1996 and the last patient in May 1998.
Preparation of bFGF-Containing Heparin-Alginate Pellets
Calcium alginate pellets provide a stable platform for bFGF
because of enhanced retention of activity and storage time and thus
were used as devices for controlled bFGF release in
vivo.5 8 10 Heparin-sepharose beads (Pharmacia LKB) were
sterilized under ultraviolet light for 30 minutes and then mixed with
filter-sterilized sodium alginate.8 10 The mixed slurry
was dropped through a needle into a beaker containing a hardened
solution of CaCl2 (1.5% wt/vol). Beads formed
instantaneously. Uniformly cross-linked capsule envelopes were obtained
by incubating the capsules in the CaCl2 solution
for 5 minutes under gentle mixing and then for 10 minutes without
mixing. The beads were washed with sterile water and stored in 0.9%
NaCl1 mmol/L CaCl2 at 4°C. bFGF loading
was performed by incubating 10 capsules in 0.9% NaCl1 mmol/L
CaCl20.05% gelatin with 12.5 µ (for 10-µg
dose) or 125 µ (for 100-µg dose) of bFGF (GMP grade human
recombinant bFGF provided by Scios, Inc) for 16 hours under gentle
agitation at 4°C. Previous studies have shown that under these
conditions, 80% of bFGF in solution is absorbed into heparin-alginate
pellets.8 10 11 The end product was sterilized under
ultraviolet light for 30 minutes. With each preparation, several beads
were cultured to ensure sterility. Blank or bFGF-loaded pellets were
identical in appearance, which ensured that the surgeons and
investigators were blinded with regard to which pellet was being
used.
bFGF Heparin-Alginate Delivery
After completion of coronary bypasses to all areas of
the heart that could be revascularized and failure to graft the target
vessel (which on occasions involved probing of the target vessel),
multiple linear incisions were made in the epicardial fat surrounding
the target vessel. Heparin-alginate pellets (containing bFGF or
placebo) were inserted into the epicardial fat overlying the artery and
secured in place by a 6.0 prolene suture to close the subepicardial
incision. A total of 10 pellets were used in each patient (2 to 3
pellets were placed in each incision; Figure 1
).12 The left internal
mammary artery (LIMA) was placed on the left anterior descending artery
(LAD), and proximal veinto-aorta anastomoses were constructed.
Ventilation was reestablished, and cardiopulmonary bypass was
terminated. Routine closure was then performed.
|
In-Hospital Follow-Up
The postoperative course was evaluated, including
hemodynamic parameters, duration of
ventilatory support, postoperative ECGs, postoperative cardiac
isoenzymes, duration of hospitalization, and any evidence of infection.
Serum bFGF levels were measured (ELISA, R&D Systems) before
implantation and on the first, third, and fifth postoperative days.
Complete blood count, coagulation parameters, serum
chemistries, and urinalysis were performed before treatment and at days
3 and 5 after treatment. In the first 10 patients, stress nuclear
perfusion imaging and MRI (at the Beth Israel Deaconess Medical Center)
were performed before CABG; however, owing to the confounding effect of
CABG (realized after an interim analysis of the first 10
patients by the Data Safety and Monitoring Committee), the remaining
patients underwent stress nuclear perfusion scans
(rest-thallium/dipyridamole sestamibi) and MRI
after CABG (before discharge). The surgeon, other investigators, and
patients were blinded to treatment assignment.
Long-Term Follow-Up
All patients were contacted by the investigators at 6 weeks; 2,
3, 4, and 6 months; 1 year; and then yearly thereafter to assess
clinical events (death, myocardial infarction, recurrent angina, or any
repeat revascularization). Complete blood count,
coagulation parameters, serum chemistries, urinalysis, and
serum bFGF level measurements were repeated at 3 months. Patients
underwent stress nuclear scans at 3 months (dual-isotope studies with
rest thallium and stress [pharmacological stress with
dipyridamole sestamibi]). In addition, patients at the
Beth Israel Deaconess Medical Center underwent repeat MRI 3 months
after CABG. Clinical follow-up of
6 months was available for all
patients, with a mean follow-up of 16.0±6.8 months.
Imaging Studies
Rest thallium/dipyridamole sestamibi studies
were performed according to the ADAC protocol. We compared baseline and
90-day nuclear scans using the size of the stress perfusion defect, as
determined by pixel analysis. MRI was performed in the body
coil of a 1.5-T whole-body Siemens Vision system as previously
described and validated.7 Baseline anatomic images were
obtained by a turboFLASH (turbo Fast Low-Angle SHot) technique to
identify coordinates for apical 4-chamber, 2-chamber, and short-axis
views. Functional imaging was performed during breathhold by use of
shared-center turboFLASH in each of the 3 mutually perpendicular
standard views, producing 24 sequential image frames each, collected
over 12 heartbeats to measure regional wall motion. MR perfusion
imaging was performed as follows: a series of 4 inversion recovery
images (1 every second heartbeat) was obtained as inversion time (TI)
and adjusted to minimize the signal intensity from
myocardium in the fourth frame. With the best TI determined
by these scout images, a series of concurrent parallel images were
acquired in diastole during breathhold, 1 every other
heartbeat, at baseline and again with contrast injection (0.05
mmol/kg gadodiamide).7 In addition, complete blood count,
coagulation parameters, serum chemistries, urinalysis, and
serum bFGF level measurements were repeated at 3 months.
Statistical Methods
Data are expressed as mean±SD. Continuous variables were
compared by paired Student's t test (baseline and
follow-up). Nuclear perfusion scans were also compared by ANOVA. All
reported probability values were 2-tailed, and a P value
0.05 was considered statistically significant.
| Results |
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Forty-six patients who met all eligibility criteria and agreed to
participate in the study underwent CABG, during which a noninvestigator
cardiac surgeon determined whether the target area was indeed
ungraftable. Bypass surgery of the target vessel was performed in 22
cases, and those patients were excluded from additional study. The
remaining 24 patients (19 patients at Beth Israel Deaconess Medical
Center and 5 at Montefiore Medical Center, Bronx, NY) who had a
coronary artery that could not receive a graft at the time of
surgery were randomized to receive 10 heparin-alginate pellets
containing placebo or 1 of 2 doses of bFGF (10 or 100 µg). Baseline
clinical characteristics of these patients are summarized in Table 1
. There was no significant
difference between the study groups in any of the clinical
parameters, including the extent of coronary
disease or presence of any risk factor, except that patients in both
10- and 100-µg bFGF treatment groups were somewhat older than
controls, and there were more women in the 10-µg bFGF group. The
baseline resting ejection fraction was 50.3±13.8%, and 5 of the 24
patients had an ejection fraction <30%.
|
Short-Term Results
The extent of CABG surgery was the same in all treatment groups;
there were no significant differences with regard to the number of
grafts, duration of surgery (average 3.0±0.9 hours), or cross-clamp
time (average 56±13 minutes) (Table 2
).
The target vessel was the right coronary artery (RCA) in 15
patients, left circumflex artery in 7, and diagonal branch of the LAD
in 2.
|
One patient in the control group died 24 hours after surgery secondary to an autopsy-documented occlusion of 1 of the saphenous vein grafts, with a large myocardial infarction in that territory. A second death occurred in a patient in the 100-µg bFGF group who could not be weaned off cardiopulmonary bypass (preoperative ejection fraction of 20%); an autopsy revealed patent grafts with extensive myocardial scarring and a thin rim of epicardial viable myocardium. Two other patients (both in the control group) required intra-aortic balloon pump support after surgery (in 1 patient, the intra-aortic balloon pump was inserted before surgery). Two patients (1 in the control group and 1 in the 10-µg bFGF group) had a Q-wave myocardial infarction in the target myocardial distribution, and 1 patient in the 10-µg bFGF group had a Q-wave myocardial infarction in a nontarget myocardial distribution.
Placement of bFGF-containing heparin-alginate microspheres had
no significant short-term effects on blood pressure (Table 2
) or heart rate; the mean arterial pressure
was 84.8±10.6 mm Hg before bypass, 89±12 mm Hg on day 1,
93±7 mm Hg on day 3, and 83.4±11.1 mm Hg on day 5 and was
not different among the treatment groups. Pharmacokinetic evaluation
did not reveal any significant increase in serum bFGF levels above
baseline in any of the groups (average bFGF levels in 15 patients:
17.4±3.3, 15.90±1.4, 15.9±1.8, and 16±1.8 pg/mL at baseline and
postoperative days 1, 3, and 5, respectively), and there were no
significant differences in bFGF levels between the different treatment
groups. The average postoperative hospital stay was 5.30±1.3 days
(range 4 to 8 days). There were no acute effects on serum chemistries,
hematologic and coagulation profiles, liver function tests, or
urinalysis. Two patients developed superficial wound infections along
the chest incision that necessitated surgical debridement, and another
patient with diabetes mellitus had delayed healing of the saphenous
vein graft harvest site. Microbiological evaluation of the beads showed
no aerobic or anaerobic growth in samples from 28 of the 46
preparations.
Clinical Follow-Up
Clinical follow-up was available in the 22 surviving patients (7
from the placebo group, 8 from the 10 µg-bFGF group, and 7 from the
100 µg-bFGF group) and averaged 16.0±6.8 months. At last follow-up,
all patients were angina-free except for 3 patients in the placebo
group (Canadian Cardiovascular Society [CCS]
class II in 1 and class III in 2 patients) and 1 patient in the 10-µg
bFGF group (CCS class II). Two of the 3 placebo patients with angina
underwent successful percutaneous
revascularization (1 involved the target vessel and
the second involved a vein graft stenosis). After hospital
discharge, none of the patients died or sustained a myocardial
infarction. There were no delayed wound infections, no clinical
evidence of pericarditis, and no other adverse events. Laboratory
evaluation at 90 days (available in 21 patients) did not show any
adverse effect on complete blood count, coagulation
parameters, serum chemistries, or urinalysis.
Myocardial Perfusion Studies
Nuclear Perfusion Imaging
Twenty of the surviving 22 patients underwent stress nuclear
perfusion imaging 90 days after CABG. In the first 10 patients,
baseline studies were performed before CABG. It became clear as the
study progressed, however, that this was not a true baseline because of
the confounding effect of CABG. Therefore, in the remaining 12
patients, rest-thallium/dipyridamole sestamibi nuclear
testing was performed after CABG and before hospital discharge. The
baseline stress target area defect size was 20.6±5.2% of the left
ventricle and was similar in all 3 treatment groups (22.3±5.4% in
controls, 19.2±5.0% for the 10-µg bFGF group, and 20.4±5.7% for
the 100-µg bFGF group, ANOVA P=0.56). At the time of
follow-up nuclear scans, when paired t tests were used,
there was a trend toward worsening (increase in the defect size) in the
placebo group (Figure 2
; 20.7±3.7% at
baseline to 23.8±5.7% at follow-up, P=0.06). Studies in
the 10-µg bFGF group showed no change in defect size (19.2±5.0% to
16.9±8.1%, P=0.39), whereas defect size in the 100-µg
bFGF group was significantly improved compared with baseline
(19.2±5.0% to 9.1±5.9%, P=0.01). The change in defect
size was significantly different among the 3 groups (ANOVA
P=0.005). Semiquantitative analysis of stress images
demonstrated worsening of the defect in 3 of 6 patients and no change
in 3 of 6 patients in the control group. Of 8 patients in the 10-µg
bFGF group, the target nuclear defect size worsened in 2 patients,
remained unchanged in 2, and improved in 4. Finally, of the 6 patients
in the 100-µg bFGF group who underwent follow-up nuclear testing,
there was improvement in 5 patients and no change in 1 patient (Figure 3
).
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Magnetic Resonance Imaging
Functional and perfusion MRI were performed in 8 patients at the
Beth Israel Deaconess Medical Center at baseline and at 90-day
follow-up (4 controls and 4 bFGF-treated patients [1 patient in the
10-µg bFGF group and 3 in the 100-µg bFGF group]). Baseline
resting target wall motion (radial wall motion) was 21.7±6.7% in the
placebo group and 27.3±17.0% in patients treated with 100 µg of
bFGF (compared with 35.7±10.9% for normal revascularized wall). No
changes in resting target wall motion were seen at follow-up
(23.7±9.3% in placebo and 32.3±12.4% in 100-µg bFGFtreated
subjects). The extent of the resting delayed contrast arrival zone,
which reflects underperfused myocardium,2 7 13
for placebo and bFGF-treated patients was 10.7±3.9% and 15.7±2.3%
at baseline and decreased to 7.8±6.9% (P=0.37) and
3.7±6.3% (P=0.06) at follow-up, respectively, with a trend
toward improvement in the 100-µg bFGF group.
| Discussion |
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Approximately 500 000 PTCA and 375 000 CABG procedures are performed annually in the United States. A significant number of patients are suboptimal candidates for CABG or PTCA or do not receive complete revascularization with these procedures.18 19 20 These patients would likely benefit from additional measures to achieve complete revascularization,1 18 19 20 21 and therapeutic angiogenesis may serve this role. Although several phase I open-label angiogenesis studies have been completed to date,16 22 the interpretation of data is confounded by the lack of placebo control and blinding.
Because of the protracted course of new collateral development, the potential for hemodynamic disturbances associated with bolus intravascular delivery, and the possibility for toxicity from elevated circulating levels of angiogenic growth factors, we used a local sustained bFGF delivery strategy using heparin-alginate microcapsules. This delivery system allows prolonged (4 to 6 weeks) sustained release (first-order kinetics).8 10 23 In animal studies, there was a dose-dependent effect of bFGF that was not associated with detectable serum levels, hemodynamic effects, or local or systemic toxicity.5 8
Of the 46 patients judged to have a major coronary artery that could not be grafted on the basis of angiographic appearance, 22 patients were actually successfully grafted at the time of CABG. Thus, preoperative assessment of arterial suitability for bypass proved to be inaccurate in almost 50% of cases. In accordance with prior observations, the major epicardial artery most likely to be unsuitable for grafting was the RCA.18 In no case was the LAD considered ungraftable. This paucity of LAD cases is probably a reflection of the reluctance to refer those patients in whom the LAD may not be bypassed for surgical intervention.
The combination CABG/bFGF therapy was not associated with an excess rate of complications. Two operative deaths in this study most likely reflect the higher operative risk in patients with advanced coronary disease and left ventricular dysfunction who have incomplete revascularization. The absence of hemodynamic abnormalities associated with heparin-alginate bFGF delivery is consistent with the undetectable serum levels of bFGF at any time after growth factor administration. In addition, the lack of short- or intermediate-term adverse effects on serum chemistries, hematologic profile, liver function tests, or urinalysis also suggests that this mode of delivery is not associated with systemic toxicity. These observations therefore emphasize the safety of heparin-alginate bFGF delivery at the time of CABG.
Despite the small numbers of patients in the study, several observations point to a potential therapeutic effect of this mode of bFGF therapy in the selected group of patients. The frequency of recurrent angina 90 days after CABG in 4 (18%) of 22 patients is probably related to incomplete revascularization. More importantly, the lack of angina in all patients treated with 100 µg of bFGF and the presence of angina in 3 of 7 (repeat revascularization in 2 of 7) patients who received placebo are provocative and suggest a treatment-related beneficial effect. This surmise is substantiated by the analysis of imaging end points. (It should be noted that the imaging protocol was altered midway through the study.) Quantitative analysis of perfusion images showed a significant improvement in the size of the target perfusion defect in 5 of 6 patients in the 100-µg bFGF group. At the same time, the defect size remained unchanged in 3 of 6 and worsened in the remaining 3 placebo patients, with the 10-µg bFGF group showing no significant changes. This trend toward improved perfusion in the 100-µg bFGF group is supported by the MR perfusion scans, which showed a trend toward reduction in the size of the ischemic zone.7 13
Schumacher and colleagues16 reported the use of wild-type acidic fibroblast growth factor injections close to the LIMA touchdown site on the LAD in 20 patients undergoing CABG. Twelve weeks after injection, digital substraction angiography showed a pronounced accumulation of contrast medium extending peripherally distal to the LIMA touchdown site. In this nonrandomized study, however, the authors did not report on clinical or functional measures of angiogenesis. In contrast, in our randomized, double-blind, placebo-controlled investigation, there was a suggestion of clinical benefit and myocardial perfusion enhancement in bFGF-treated patients (particularly in the 100-µg group).
In conclusion, this randomized, double-blind, placebo-controlled study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable and ischemic but unrevascularizable myocardium. These results warrant a larger multicenter trial to assess the clinical benefit of this combination approach to myocardial revascularization, which is currently under way.
| Acknowledgments |
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Received February 16, 1999; revision received July 6, 1999; accepted July 12, 1999.
| References |
|---|
|
|
|---|
2. Laham R, Simons M. Therapeutic angiogenesis in myocardial ischemia. In: Ware JA, Simons M, eds. Angiogenesis and Cardiovascular Disease. London, UK: Oxford University Press; 1999:289320.
3.
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;89:21832189.
4. Cuevas P, Gimenez-Gallego G, Carceller F, Cuevas B, Crespo A. Single topical application of human recombinant basic fibroblast growth factor (rbFGF) promotes neovascularization in rat cerebral cortex. Surg Neurol. 1993;39:380384.[Medline] [Order article via Infotrieve]
5.
Lopez JJ, Edelman ER, Stamler A, Hibberd MG, Prasad P,
Caputo RP, Carrozza JP, Douglas PS, Sellke FW, Simons M. Basic
fibroblast growth factor in a porcine model of chronic myocardial
ischemia: a comparison of angiographic,
echocardiographic and coronary flow
parameters. J Pharmacol Exp Ther. 1997;282:385390.
6.
Unger EF, Banai S, Shou M, Lazarous DF, Jaklitsch MT,
Scheinowitz M, Correa R, Klingbeil C, Epstein SE. Basic fibroblast
growth factor enhances myocardial collateral flow in a canine model.
Am J Physiol. 1994;266:H1588H1595.
7. Pearlman JD, Hibberd MG, Chuang ML, Harada K, Lopez JJ, Gladstone SR, Friedman M, Sellke FW, Simons M. Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis. Nat Med. 1995;1:10851089.[Medline] [Order article via Infotrieve]
8. Harada K, Grossman W, Friedman M, Edelman ER, Prasad PV, Keighley CS, Manning WJ, Sellke FW, Simons M. Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts. J Clin Invest. 1994;94:623630.
9.
Harada K, Friedman M, Lopez JJ, Wang SY, Li J, Prasad
PV, Pearlman JD, Edelman ER, Sellke FW, Simons M. Vascular
endothelial growth factor administration in chronic
myocardial ischemia. Am J Physiol. 1996;270:H1791H1802.
10. Edelman ER, Mathiowitz E, Langer R, Klagsbrun M. Controlled and modulated release of basic fibroblast growth factor. Biomaterials. 1991;12:619626.[Medline] [Order article via Infotrieve]
11.
Edelman ER, Nugent MA, Karnovsky MJ. Perivascular and
intravenous administration of basic fibroblast growth
factor: vascular and solid organ deposition. Proc Natl Acad Sci
U S A. 1993;90:15131517.
12.
Sellke FW, Laham RJ, Edelman ER, Pearlman JD, Simons M.
Therapeutic angiogenesis with basic fibroblast growth factor: technique
and early results. Ann Thorac Surg. 1998;65:15401544.
13. Laham R, Sellke F, Pearlman J. Magnetic resonance blood-arrival maps provides accurate assessment of myocardial perfusion and collateralization in therapeutic angiogenesis. Circulation. 1998;98(suppl I):I-373. Abstract.
14. Isner JM, Walsh K, Symes J, Pieczek A, Takeshita S, Lowry J, Rosenfield K, Weir L, Brogi E, Jurayj D. Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease. Hum Gene Ther. 1996;7:959988.[Medline] [Order article via Infotrieve]
15.
Yanagisawa-Miwa A, Uchida Y, Nakamura F, Tomaru T, Kido
H, Kamijo T, Sugimoto T, Kaji K, Utsuyama M, Kurashima C. Salvage of
infarcted myocardium by angiogenic action of basic
fibroblast growth factor. Science. 1992;257:14011403.
16.
Schumacher B, Pecher P, von Specht B, Stegmann T.
Induction of neoangiogenesis in ischemic myocardium
by human growth factors. Circulation. 1998;97:645650.
17. Ware JA, Simons M. Angiogenesis in ischemic heart disease. Nat Med. 1997;3:158164.[Medline] [Order article via Infotrieve]
18. Ballester Ribera R, Garcia-Dorado D, Barrabes Riu JA, Soler Soler J. Complete or incomplete revascularization: the influence of the terminology on clinical practice. Rev Esp Cardiol. 1995;48:17.
19. Glazier JJ, Verwilghen J, Morgan JM, Rickards AF. Outcome following incomplete revascularisation by coronary balloon angioplasty in patients with multivessel coronary artery disease. Ir Med J. 1992;85:142144.[Medline] [Order article via Infotrieve]
20. Breisblatt WM, Barnes JV, Weiland F, Spaccavento LJ. Incomplete revascularization in multivessel percutaneous transluminal coronary angioplasty: the role for stress thallium-201 imaging. J Am Coll Cardiol. 1988;11:11831190.[Abstract]
21. Bolli R, Brandon TA, Luck JC, Miller RR, Entman ML. Deleterious effects of incomplete myocardial reperfusion on ventricular arrhythmias. J Am Coll Cardiol. 1983;1:11111118.[Medline] [Order article via Infotrieve]
22. Henry T, Rocha-Singh K, Isner J, Kereiakes DJ, Giordano F, Simons M, Losordo D, Hendel R, Bonow R, Rothman J, Borbas E, McCluskey TR. Results of intracoronary recombinant human vascular endothelial growth factor (rhVEGF) administration trial. J Am Coll Cardiol. 1998;31:65A. Abstract.
23. Downs EC, Robertson NE, Riss TL, Plunkett ML. Calcium alginate beads as a slow-release system for delivering angiogenic molecules in vivo and in vitro. J Cell Physiol. 1992;152:422429.[Medline] [Order article via Infotrieve]
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P. Voisine, J. Li, C. Bianchi, T. A. Khan, M. Ruel, S.-H. Xu, J. Feng, A. Rosinberg, T. Malik, Y. Nakai, et al. Effects of L-Arginine on Fibroblast Growth Factor 2-Induced Angiogenesis in a Model of Endothelial Dysfunction Circulation, August 30, 2005; 112(9_suppl): I-202 - I-207. [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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M. E. Davis, P. C.H. Hsieh, A. J. Grodzinsky, and R. T. Lee Custom Design of the Cardiac Microenvironment With Biomaterials Circ. Res., July 8, 2005; 97(1): 8 - 15. [Abstract] [Full Text] [PDF] |
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K. A. Horvath, C. Y. J. Lu, E. Robert, G. F. Pierce, R. Greene, B. A. Sosnowski, and J. Doukas Improvement of myocardial contractility in a porcine model of chronic ischemia using a combined transmyocardial revascularization and gene therapy approach J. Thorac. Cardiovasc. Surg., May 1, 2005; 129(5): 1071 - 1077. [Abstract] [Full Text] [PDF] |
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M. Simons Angiogenesis: Where Do We Stand Now? Circulation, March 29, 2005; 111(12): 1556 - 1566. [Full Text] [PDF] |
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B. H. Annex and M. Simons Growth factor-induced therapeutic angiogenesis in the heart: protein therapy Cardiovasc Res, February 15, 2005; 65(3): 649 - 655. [Abstract] [Full Text] [PDF] |
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R. J. Filion and A. S. Popel Intracoronary administration of FGF-2: a computational model of myocardial deposition and retention Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H263 - H279. [Abstract] [Full Text] [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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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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K. Ueyama, G. Bing, Y. Tabata, M. Ozeki, K. Doi, K. Nishimura, H. Suma, and M. Komeda Development of biologic coronary artery bypass grafting in a rabbit model: Revival of a classic concept with modern biotechnology J. Thorac. Cardiovasc. Surg., June 1, 2004; 127(6): 1608 - 1615. [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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A. Askari, S. Unzek, C. K. Goldman, S. G. Ellis, J. D. Thomas, P. E. DiCorleto, E. J. Topol, and M. S. Penn Cellular, but not direct, adenoviral delivery of vascular endothelial growth factor results in improved left ventricular function and neovascularization in dilated ischemic cardiomyopathy J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1908 - 1914. [Abstract] [Full Text] [PDF] |
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Z.-S. Jiang, W. Srisakuldee, F. Soulet, G. Bouche, and E. Kardami Non-angiogenic FGF-2 protects the ischemic heart from injury, in the presence or absence of reperfusion Cardiovasc Res, April 1, 2004; 62(1): 154 - 166. [Abstract] [Full Text] [PDF] |
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A. Iwakura, Y. Tabata, T. Koyama, K. Doi, K. Nishimura, K. Kataoka, M. Fujita, and M. Komeda Gelatin sheet incorporating basic fibroblast growth factor enhances sternal healing after harvesting bilateral internal thoracic arteries J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 1113 - 1120. [Abstract] [Full Text] [PDF] |
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V. Chhokar and A. L. Tucker Angiogenesis: Basic Mechanisms and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 253 - 280. [Abstract] [PDF] |
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Y. Sakakibara, K. Tambara, G. Sakaguchi, F. Lu, M. Yamamoto, K. Nishimura, Y. Tabata, and M. Komeda Toward surgical angiogenesis using slow-released basic fibroblast growth factor Eur. J. Cardiothorac. Surg., July 1, 2003; 24(1): 105 - 112. [Abstract] [Full Text] [PDF] |
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J. Raymond, A. Metcalfe, A.-C. Desfaits, E. Ribourtout, I. Salazkin, K. Gilmartin, G. Embry, and R. J. Boock Alginate for Endovascular Treatment of Aneurysms and Local Growth Factor Delivery AJNR Am. J. Neuroradiol., June 1, 2003; 24(6): 1214 - 1221. [Abstract] [Full Text] [PDF] |
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T. D. Henry, B. H. Annex, G. R. McKendall, M. A. Azrin, J. J. Lopez, F. J. Giordano, P.K. Shah, J. T. Willerson, R. L. Benza, D. S. Berman, et al. The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis Circulation, March 18, 2003; 107(10): 1359 - 1365. [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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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] |
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K. A. Detillieux, F. Sheikh, E. Kardami, and P. A. Cattini Biological activities of fibroblast growth factor-2 in the adult myocardium Cardiovasc Res, January 1, 2003; 57(1): 8 - 19. [Abstract] [Full Text] [PDF] |
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G. Lutter, T. Attmann, C. Heilmann, P. von Samson, B. von Specht, and F. Beyersdorf The combined use of transmyocardial laser revascularization (TMLR) and fibroblastic growth factor (FGF-2) enhances perfusion and regional contractility in chronically ischemic porcine hearts Eur. J. Cardiothorac. Surg., November 1, 2002; 22(5): 753 - 761. [Abstract] [Full Text] [PDF] |
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K. A. Horvath, J. Doukas, C.-Y. J. Lu, N. Belkind, R. Greene, G. F. Pierce, and D. A. Fullerton Myocardial functional recovery after fibroblast growth factor 2 gene therapy as assessed by echocardiography and magnetic resonance imaging Ann. Thorac. Surg., August 1, 2002; 74(2): 481 - 487. [Abstract] [Full Text] [PDF] |
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M. Ruel, R. J. Laham, J. A. Parker, M. J. Post, J. A. Ware, M. Simons, and F. W. Sellke Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein J. Thorac. Cardiovasc. Surg., July 1, 2002; 124(1): 28 - 34. [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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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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J. T. A. Meij, F. Sheikh, S. K. Jimenez, P. W. Nickerson, E. Kardami, and P. A. Cattini Exacerbation of myocardial injury in transgenic mice overexpressing FGF-2 is T cell dependent Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H547 - H555. [Abstract] [Full Text] [PDF] |
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R. J. Laham, M. Simons, J. D. Pearlman, K. K. L. Ho, and D. S. Baim Magnetic resonance imaging demonstrates improved regional systolic wall motion and thickening and myocardial perfusion of myocardial territories treated by laser myocardial revascularization J. Am. Coll. Cardiol., January 2, 2002; 39(1): 1 - 8. [Abstract] [Full Text] [PDF] |
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K.S. MOULTON Plaque Angiogenesis: Its Functions and Regulation Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 471 - 482. [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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W. Roethy, E. Fiehn, K. Suehiro, A. Gu, G. H. Yi, J. Shimizu, J. Wang, G. Zhang, J. Ranieri, R. Akella, et al. A Growth Factor Mixture That Significantly Enhances Angiogenesis in Vivo J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 494 - 500. [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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T. Visted, R. Bjerkvig, and P. O. Enger Cell encapsulation technology as a therapeutic strategy for CNS malignancies Neuro-oncol, July 1, 2001; 3(3): 201 - 210. [Abstract] [PDF] |
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S. Fuchs, R. Baffour, Y. F. Zhou, M. Shou, A. Pierre, F. O. Tio, N. J. Weissman, M. B. Leon, S. E. Epstein, and R. Kornowski Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1726 - 1732. [Abstract] [Full Text] [PDF] |
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M. Simons Therapeutic coronary angiogenesis: a fronte praecipitium a tergo lupi? Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1923 - H1927. [Full Text] [PDF] |
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F. J. Giordano, H.-P. Gerber, S.-P. Williams, N. VanBruggen, S. Bunting, P. Ruiz-Lozano, Y. Gu, A. K. Nath, Y. Huang, R. Hickey, et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function PNAS, April 25, 2001; (2001) 91415198. [Abstract] [Full Text] |
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X. Xu, J. Li, M. Simons, J. Li, R. J. Laham, and F. W. Sellke Expression of vascular endothelial growth factor and its receptors is increased, but microvascular relaxation is impaired in patients after acute myocardial ischemia J. Thorac. Cardiovasc. Surg., April 1, 2001; 121(4): 735 - 742. [Abstract] [Full Text] [PDF] |
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F. Sheikh, D. P. Sontag, R. R. Fandrich, E. Kardami, and P. A. Cattini Overexpression of FGF-2 increases cardiac myocyte viability after injury in isolated mouse hearts Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1039 - H1050. [Abstract] [Full Text] [PDF] |
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L. M. Goncalves, S. E. Epstein, and J. J. Piek Controlling collateral development: the difficult task of mimicking mother nature Cardiovasc Res, February 16, 2001; 49(3): 495 - 496. [Full Text] [PDF] |
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M. J. Post, R. Laham, F. W. Sellke, and M. Simons Therapeutic angiogenesis in cardiology using protein formulations Cardiovasc Res, February 16, 2001; 49(3): 522 - 531. [Abstract] [Full Text] [PDF] |
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S. E. Epstein, S. Fuchs, Y. F. Zhou, R. Baffour, and R. Kornowski Therapeutic interventions for enhancing collateral development by administration of growth factors: basic principles, early results and potential hazards Cardiovasc Res, February 16, 2001; 49(3): 532 - 542. [Abstract] [Full Text] [PDF] |
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J. Waltenberger Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications Cardiovasc Res, February 16, 2001; 49(3): 554 - 560. [Abstract] [Full Text] [PDF] |
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K. Sato, T. Wu, R. J. Laham, R. B. Johnson, P. Douglas, J. Li, F. W. Sellke, S. Bunting, M. Simons, and M. J. Post Efficacy of intracoronary or intravenous VEGF165 in a pig model of chronic myocardial ischemia J. Am. Coll. Cardiol., February 1, 2001; 37(2): 616 - 623. [Abstract] [Full Text] [PDF] |
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R. J. Laham, N. A. Chronos, M. Pike, M. E. Leimbach, J. E. Udelson, J. D. Pearlman, R. I. Pettigrew, M. J. Whitehouse, C. Yoshizawa, and M. Simons Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a Phase I open-label dose escalation study J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2132 - 2139. [Abstract] [Full Text] [PDF] |
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K. Sato, R. J. Laham, J. D. Pearlman, D. Novicki, F. W. Sellke, M. Simons, and M. J. Post Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia Ann. Thorac. Surg., December 1, 2000; 70(6): 2113 - 2118. [Abstract] [Full Text] [PDF] |
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J. E. Udelson, V. Dilsizian, R. J. Laham, N. Chronos, J. Vansant, M. Blais, J. R. Galt, M. Pike, C. Yoshizawa, and M. Simons Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 Improves Stress and Rest Myocardial Perfusion Abnormalities in Patients With Severe Symptomatic Chronic Coronary Artery Disease Circulation, October 3, 2000; 102(14): 1605 - 1610. [Abstract] [Full Text] [PDF] |
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D. F. Lazarous, E. F. Unger, S. E. Epstein, A. Stine, J. L. Arevalo, E. Y. Chew, and A. A. Quyyumi Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1239 - 1244. [Abstract] [Full Text] [PDF] |
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M. Simons, R. O. Bonow, N. A. Chronos, D. J. Cohen, F. J. Giordano, H. K. Hammond, R. J. Laham, W. Li, M. Pike, F. W. Sellke, et al. Clinical Trials in Coronary Angiogenesis: Issues, Problems, Consensus : An Expert Panel Summary Circulation, September 12, 2000; 102 (11): e73 - e86. [Abstract] [Full Text] [PDF] |
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P. R. Vale, D. W. Losordo, C. E. Milliken, M. Maysky, D. D. Esakof, J. F. Symes, and J. M. Isner Left Ventricular Electromechanical Mapping to Assess Efficacy of phVEGF165 Gene Transfer for Therapeutic Angiogenesis in Chronic Myocardial Ischemia Circulation, August 29, 2000; 102(9): 965 - 974. [Abstract] [Full Text] [PDF] |
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Y. Jin, F. Sheikh, K. A. Detillieux, and P. A. Cattini Role for Early Growth Response-1 Protein in alpha 1-Adrenergic Stimulation of Fibroblast Growth Factor-2 Promoter Activity in Cardiac Myocytes Mol. Pharmacol., May 1, 2000; 57(5): 984 - 990. [Abstract] [Full Text] |
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M. O Hiltunen, M. P Turunen, M. Laitinen, and S. Yla-Herttuala Insights into the molecular pathogenesis of atherosclerosis and therapeutic strategies using gene transfer Vascular Medicine, February 1, 2000; 5(1): 41 - 48. [Abstract] [PDF] |
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F. J. Giordano, H.-P. Gerber, S.-P. Williams, N. VanBruggen, S. Bunting, P. Ruiz-Lozano, Y. Gu, A. K. Nath, Y. Huang, R. Hickey, et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function PNAS, May 8, 2001; 98(10): 5780 - 5785. [Abstract] [Full Text] [PDF] |
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M. Simons, B. H. Annex, R. J. Laham, N. Kleiman, T. Henry, H. Dauerman, J. E. Udelson, E. V. Gervino, M. Pike, M.J. Whitehouse, et al. Pharmacological Treatment of Coronary Artery Disease With Recombinant Fibroblast Growth Factor-2: Double-Blind, Randomized, Controlled Clinical Trial Circulation, February 19, 2002; 105(7): 788 - 793. [Abstract] [Full Text] [PDF] |
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