© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution
Experimental Physiology and Pharmacology Section, Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
* Corresponding author. Cardiology Branch, NHLBI, NIH, Building 10, Room 7B15, 10 Center Drive MSC 1650, Bethesda, MD 20892-1650, Tel.: +1-301-496-0021; Fax: +1-301-402-0888; e-mail: lazaroud@gwgate.nhlbi.nih.gov
Received 3 January 1997; accepted 6 May 1997
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Abstract |
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Objective: We have shown that basic fibroblast growth factor (bFGF/FGF-2) enhances myocardial collateral development in a canine model of progressive coronary occlusion when delivered via the left atrial or intracoronary routes; however, we have found intravenous bFGF ineffective in the same model. Data on the fate and efficacy of intravenous bFGF are limited. We hypothesized that first pass lung uptake might limit myocardial bFGF availability after intravenous injection. We postulated that delivery of bFGF through the distal port of a wedged Swan Ganz catheter might circumvent this problem by restricting exposure of bFGF to a limited number of pulmonary binding sites. This study evaluated differential regional uptake of 125I labeled bFGF following bolus intravenous, Swan Ganz, left atrial, intracoronary, and pericardial delivery. Methods: Mongrel dogs were used. Human recombinant bFGF, monoiodinated with 125I, was mixed with cold bFGF to a specific activity of 0.03 µCi/µg. Approximately 100 µg/kg was injected per animal by the intravenous, left atrial, Swan Ganz, intracoronary, or pericardial route. Dogs were killed 15 min or 150 min later. The heart, lungs, liver, spleen, and kidneys were harvested and 125I activity was assessed. Immunohistochemical and pharmacokinetic studies were also performed. Results: Serum half life of bFGF was comparable after intracoronary, intravenous and left atrial delivery (50 min); however, there were significant differences with regard to pharmacodynamics. After intracoronary administration, 3–5% of the total bFGF dose was recovered from the heart, with the peptide immunolocalized to the extracellular matrix and vascular endothelium. In contrast, only 1.3% of the injected bFGF was localized to the heart after left atrial administration, and 0.5% was recovered after intravenous or Swan Ganz delivery. Pericardial administration resulted in substantial cardiac bFGF delivery; 19% was present at 150 min. Myocardial uptake was similar with Swan Ganz and intravenous delivery, suggesting that the administered dose did not saturate available pulmonary binding sites. Conclusions: These data predict efficacy of intracoronary, left atrial, and pericardial bFGF for myocardial angiogenesis, and a lack of efficacy after bolus intravenous and Swan Ganz administration.
KEYWORDS Angiogenesis; bFGF; Pharmacodynamics; Myocardium; Growth factors; Dog
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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We have previously shown that the angiogenic peptide basic fibroblast growth factor (bFGF/FGF-2) enhances canine coronary collateral development when administered via the left atrial (LA) [1, 2], or intracoronary (IC), routes [3, 4]. In contrast, we have found intravenous (IV) bFGF ineffective in promoting myocardial angiogenesis (unpublished data, 1993). Data on the fate and efficacy of IV bFGF are limited [5, 6]. We hypothesized that first pass lung uptake might limit myocardial bFGF availability after IV injection. We postulated that delivery of bFGF through the distal port of a wedged Swan Ganz (SG) catheter might circumvent this problem by restricting exposure of bFGF to a limited number of pulmonary binding sites. This investigation was designed to assess bFGF pharmacodynamics by examining differential regional uptake of 125I labeled bFGF following bolus IV, SG, LA, IC, and pericardial delivery.
We have also shown that bFGF follows first order kinetics after systemic arterial administration, with an elimination half life of approximately 50 min [1]. In the present study, we investigated the pharmacokinetics of bFGF after IV and IC administration, and performed immunohistochemical localization of bFGF following IC delivery.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Chemicals
Human recombinant bFGF was generously supplied by Scios Nova, Mountainview, CA. Monoiodinated bFGF (125I-Bolton Hunter reagent, specific activity
70 µCi/µg) [7], was obtained from New England Nuclear (Boston, MA). Monoiodinated bFGF was diluted with cold bFGF to a specific activity of 0.03 µCi/µg. The quantity of bFGF injected was approximately 100 µg/kg, equivalent to that used in our previous studies [1, 2, 4].
2.2 General preparation of dogs
The experimental protocol was approved by the Animal Care and Use Committee of the National Heart, Lung, and Blood Institute, and conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, (Department of Health and Human Services Publication No. (NIH) 86-23, revised 1992), and NIH issuance 3040-2, "Animal Care and Use in the Intramural Program." Nineteen mongrel dogs of both sexes were obtained from Haycock Kennels, Quakertown, PA. Dogs were killed 15 min [IV (n = 2), LA (n = 2), SG (n = 2), IC (n = 1)] or 150 min [IV (n = 2), SG (n = 2), IC (n = 1), pericardial (n = 2)] after 125I labeled bFGF administration. Immunohistochemical studies were carried out in three dogs; pharmacokinetic studies were performed in two dogs.
2.3 Treatment groups
2.3.1 Pulmonary artery bFGF injection (Swan Ganz catheter)
Dogs were anesthetized with thiopental sodium, 15 mg/kg IV. Using sterile technique, the external jugular vein was cannulated with an 8F sheath (Cordis Corp, Miami, FL). A balloon-tipped, 7 Fr SG catheter (Baxter, Columbia, MD) was advanced through the sheath, guided by the pressure tracing, into the left (or right) pulmonary artery. The catheter was advanced until a typical pulmonary capillary wedge (PCW) pressure tracing was obtained. The balloon was then deflated and the catheter was placed into final position by advancing it until a PCW waveform was again evident. Radiolabeled bFGF was injected into the distal infusion port of the SG catheter, followed by 2 ml methylene blue to assess the extent of lung parenchyma exposed to the peptide.
2.3.2 Intrapericardial bFGF injection
Dogs were anesthetized with acepromazine 0.2 mg/kg IM, thiopental sodium 15 mg/kg IV, and inhaled methoxyflurane. A left thoracotomy was performed using sterile technique. A 6.6 Fr silastic catheter with end hole (Bard Access Systems, Salt Lake City, UT), was positioned in the pericardial space. Multiple side holes were fashioned in the distal 2 cm of the catheter. The pericardium and chest were closed in layers, and the terminus of the pericardial catheter was secured in the subcutaneous tissue of the back. The dogs were allowed to recover. The analgesic buprenorphine was administered as needed. Ten days after surgery, 2 ml of contrast agent (Hypaque) was injected into the pericardial space under fluoroscopy to visualize any pericardial leak. Once the integrity of the pericardium was established, 125I labeled bFGF was injected into the subcutaneous port of the catheter.
2.3.3 Intracoronary bFGF injection
A left thoracotomy was performed under general anesthesia (thiopental sodium, 15 mg/kg IV), and the proximal left anterior descending coronary artery (LAD) was isolated. A 25 gauge butterfly was inserted gently into the LAD and the labeled bFGF was injected under electrocardiographic monitoring. Hemostasis was established by applying light pressure at the site for several minutes.
2.3.4 Left atrial bFGF injection
General anesthesia was induced and maintained with thiopental sodium, 15 mg/kg IV. The chest was opened and a 25 gauge butterfly was placed in the left atrial appendage under direct vision, followed by injection of labeled bFGF.
2.4 Regional tissue deposition of 125I labeled bFGF
The electrocardiogram was continuously recorded during drug administration, and the dogs were kept warm and well hydrated. The dogs were killed 15 or 150 min after bFGF injection with an overdose of sodium pentobarbital and KCl. The heart, lungs, liver, spleen, and kidneys were harvested and 125I activity was assessed. The specific activity of the injected bFGF was determined for each experiment, and the volume of labeled bFGF injected was obtained by subtracting the weight of the syringe before and after injection. The total weight of each organ was determined. Representative samples were obtained from different regions of the organ, weighed, and counted in a gamma well counter (model 5530, Packard Instruments, Downers Grove, IL). Counts were corrected for background, and whole organ counts were calculated as:
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2.5 Regional myocardial deposition of 125I labeled bFGF (intracoronary injections)
The unfixed heart was cut into 7 mm slices in the short axis orientation. The left ventricular portions of the two central slices were divided into 8 wedges for analyses of 125I counts. Representative samples were also obtained from the left atrial appendage, the right ventricle, the septum, and the dissected LAD and the left circumflex coronary arteries (LCx).
2.6 Pharmacokinetics of bFGF
In two animals, venous blood samples were obtained at multiple time points after injection of 100 µg/kg bFGF IV or 7 µg/kg IC. Samples were centrifuged at 4°C for 10 min, and serum was assayed for human bFGF using a solid-phase ELISA kit according to the manufacturer's instructions (catalog no. DBF00, R&D Systems, Inc., Minneapolis, MN).
2.7 Immunolocalization of bFGF
Tissue samples were obtained from three animals 15 min after IC bFGF administration, fixed in 10% buffered formalin and embedded in paraffin. Immunohistochemical localization of bFGF was performed in 5 µm sections using an avidin biotin peroxidase technique as previously described [8, 9]. After endogenous peroxidase activity was quenched with 1% hydrogen peroxide, the sections were digested with protease and incubated overnight with rabbit polyclonal anti-bFGF antibody (1:50 dilution, R&D Systems, Inc.). Biotinylated secondary antibody from the Vector Elite ABC kit (Vector-Novocastra Laboratories, Burlingame, CA) was used in a 1:200 dilution, followed by the peroxidase substrate and hematoxylin counterstain. Sections in which non-immune serum was substituted for the primary antibody served as negative controls.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Regional tissue deposition of bFGF
After IC administration, 3–5% of the total injected dose of bFGF was recovered from the heart, in contrast to 1.3% after LA administration, and approximately 0.5% when the peptide was given by the IV or SG routes (Fig. 1). The heart/lung ratio, an approximation of relative myocardial bFGF delivery, was lowest after IV bFGF administration. LA administration increased the heart/lung ratio 5-fold (relative to IV), IC delivery 10-fold, and pericardial administration 100-fold. The cumulative counts recovered from the five organs examined ranged from 20–63% (Fig. 1). The greatest proportion of bFGF was recovered from the liver.
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IC bFGF administration was associated with pronounced regional disparity in myocardial drug delivery, with substantial levels in the territory of the injected LAD coronary artery, but relatively little peptide present in the uninjected LCx territory (Fig. 2). Cardiac bFGF levels were greatest after pericardial administration, with 19% of the injected dose recovered after 150 min. Labeled bFGF was recovered throughout the entire epimyocardial surface, and not confined to the anterior surface of the heart (the site of the indwelling pericardial catheter). There was a transmural gradient of bFGF from epimyocardium to endomyocardium, with approximately an order of magnitude difference between the two (data not shown). Removal of the pericardium at the time of analysis did not affect epimyocardial activity appreciably.
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Six percent of the injected bFGF dose was present in lung after IV delivery. After SG administration, bFGF was inhomogeneously distributed throughout the lungs, such that there was a marked disparity in bFGF deposition between the injected methylene blue-stained parenchyma and the unstained parenchyma. 15 min after administration, [bFGF] in injected lung was 62-fold higher than in uninjected lung; after 150 min, the concentration was 9-fold higher.
3.2 Pharmacokinetics of bFGF
After IV and IC injection of bFGF, there was a rapid distribution phase followed by an elimination phase with first order kinetics. The elimination half life was approximately 50 min (Fig. 3), identical to that reported previously with LA administration [1].
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3.3 Immunolocalization of bFGF
Previous studies have reported conflicting immunohistochemical localization patterns for bFGF in the kidneys [9, 10]. We noted marked glomerular staining after exogenous administration of bFGF (Fig. 4).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The efficacy of bFGF as an agent to promote therapeutic angiogenesis has been well established in animal models of ischemia [1–4, 11–16]. Our laboratory, for example, has shown that bFGF enhances coronary collateral development in dogs subjected to progressive ameroid-induced coronary occlusion. In this model, bFGF has been effective when administered into the systemic arterial circulation (through an indwelling LA catheter) [1, 2], or when delivered repeatedly via intracoronary routes [3, 4]. These studies have stimulated considerable interest in clinical trials for therapeutic angiogenesis; indeed, Phase I trials for acute cerebrovascular accidents, coronary artery disease, and peripheral vascular disease have commenced at our Institution and others. From the standpoint of clinical practicality and safety, repeated IV bFGF administration would be an ideal means of drug delivery; however, we found that administration of bFGF by a central venous route (via the right atrium) was ineffective in promoting myocardial collateral development (unpublished data, 1993).
bFGF is a heparin-binding growth factor that interacts with low-affinity cell surface receptors (heparan sulfate proteoglycans in subendothelial matrix), as well as specific high-affinity tyrosine kinase receptors [17–20]. We hypothesized that significant bFGF binding to low-affinity receptors throughout the vast cross sectional area of the pulmonary circulation could lead to pronounced first pass lung uptake, leading to decreased myocardial bFGF availability following IV administration. This phenomenon could account for the difference in efficacy between central venous and LA delivery. We postulated that administration of bFGF through a wedged SG catheter, a route that is clinically feasible and practical, might have advantages over IV injection that would lead to increased myocardial bFGF exposure and improved efficacy. We hypothesized that delivery of undiluted bFGF through a selective pulmonary artery (SG) catheter would expose a relatively small segment of lung to the peptide at a high concentration during its first pass through the pulmonary circulation, thereby saturating the FGF receptors, leading to spillover of substantial unbound peptide into the pulmonary venous and thence the systemic arterial circulation. In contrast, after IV administration, the bFGF would be diluted immediately and exposed (at lower concentration) to the entire vasculature of the lungs, increasing the efficiency of lung uptake, and limiting the quantity of bFGF that would reach the heart. To test this hypothesis, we determined the distribution of radiolabeled bFGF following IV, SG, LA, IC, and pericardial delivery.
4.1 bFGF pharmacodynamics
bFGF tissue deposition was concentration-dependent, in that there was maximal uptake at the point of delivery, where the intravascular concentration was highest. Accordingly, myocardial bFGF delivery was most substantial following pericardial and IC administration, lowest following IV administration, and intermediate following systemic arterial (LA) delivery (Fig. 1). Moreover, following IC administration, there was marked regional disparity in [bFGF] between the territories of the injected LAD and uninjected LCx coronary arteries, confirming localized myocardial bFGF uptake (Fig. 2).
Swan Ganz delivery resulted in striking bFGF uptake in the injected pulmonary lobe, and did not increase myocardial bFGF recovery appreciably (relative to IV administration). Because of the heterogeneous pulmonary bFGF uptake after SG administration, the overall lung uptake was not computed; however, total lung uptake appeared to approximate that following IV administration (6.2%). Not surprisingly, pulmonary bFGF uptake was substantially lower after pericardial (0.9%) and LA (1.8%) administration.
Our finding of comparable recovery of myocardial bFGF after SG and IV administration, coupled with our finding of pronounced [bFGF] at the site of SG injection suggests that, contrary to our hypothesis, the local pulmonary receptors are not saturable using this bFGF dose. Hence, delivery of bFGF through a SG appears to offer no advantage over IV administration. To conclusively determine the degree of pulmonary clearance of the administered dose of radiolabeled bFGF by first pass lung uptake, multiple indicator-dilution technique may be necessary [21]. However, for purposes of this study, we concentrated on the regional disparity in bFGF tissue distribution following different modes of administration in an attempt to explain the results of our previous studies. The ideal method of bFGF administration is a clinically relevant issue because bFGF has entered into Phase I clinical trials.
With all routes of administration (with the exception of the pericardial route), an appreciable fraction of injected bFGF was found in the liver (11–40%), and there was an apparent time-dependent increase in hepatic [bFGF], consistent with hepatic uptake, storage, and/or elimination (Fig. 1). Following pericardial injection, the peptide remained confined largely to the cardiac structures, with only 3% of the bFGF recoverable from the liver after 175 min.
These results are consistent with our experience in a canine myocardial ischemia model, in which we showed salutary effects of IC [3, 4]and LA [1, 2]bFGF on myocardial perfusion, but a lack of efficacy after IV delivery (unpublished data, 1993). We should emphasize that these results were obtained following bolus IV delivery. The efficacy of IV infusion of bFGF has not been tested for myocardial angiogenesis, although it has been found to be effective in other models. Terjung et al. have shown continuous IV bFGF to be efficacious in promoting collateralization in a rat ischemic hindlimb model [22]. Interestingly, the efficacy of bFGF was dependent on the duration of therapy: two weeks of continuous IV bFGF delivery were effective whereas one week of therapy was not, again suggesting that the amount of bFGF reaching the target tissue is limited following IV delivery.
Recently, IV infusion of bFGF has been reported to be cerebroprotective in models of acute cerebral ischemia in rats [23, 24], and cats [25]. Our findings suggest that very little of an intravenously injected bFGF dose would reach the brain; in fact, these investigators recovered only 0.01% of the injected bFGF dose from the ischemic hemisphere in rats with acute cerebral ischemia [23]. Thus, it is possible that the levels of bFGF required for neuroprotection are lower than those necessary for angiogenesis.
Pericardial administration represents a unique mode of delivery in which the vasculature is exposed to bFGF via its adventitial rather than its luminal surface. The vasa vasorum may play a role in transporting compounds from the adventitial surface into the vascular wall and thence the lumen. Recent reports suggest that pericardial bFGF may be effective in promoting myocardial angiogenesis [26], and in limiting infarct size after coronary occlusion [27]. In the present investigation, pericardial delivery resulted in a striking transmural gradient of bFGF, with an epimyocardial concentration approximately an order of magnitude greater than that of the mid- or endocardium (data not shown). Whether bFGF would improve myocardial perfusion when administered through the pericardial route is yet to be determined.
4.2 bFGF pharmacokinetics
We have previously reported that the distribution half life of bFGF administered into the left atrium is 3 min, with elimination half life of 50 min [1]. Identical kinetics were observed after IV and IC bFGF in the present study (Fig. 3). Although serum levels of bFGF are similar after IC, LA, and IV administration, only IC and LA delivery were efficacious in enhancing collateral development in this model. Thus, serum levels alone do not predict the biological activity of bFGF, and local intravascular/perivascular concentrations of peptide at the site of action are probably more important for efficacy.
The serum half life of bFGF has been previously reported to be on the order of 1.5 to 3 min after IV delivery [5, 6]. Edelman et al. reported that deposition of bFGF was greater in the kidney, liver and spleen, compared to the lung and heart after IV injection in rats [6]. The dose of bFGF used in previous studies was extremely low (0.0007 to 0.001 µg/kg bFGF). In those studies, it is likely that much of the injected bFGF bound rapidly to low-affinity receptors, and the extremely low serum concentrations of bFGF were beyond the sensitivity of the methods used.
Heparin binds bFGF and stabilizes it against deactivation and proteolytic cleavage [28–30]. Co-administration of heparin with bFGF has been shown to prolong serum half life and facilitate excretion of intact bFGF by the kidneys [5]. Thus, it is likely that tissue deposition as well as serum half life of bFGF would be altered by heparin, and the therapeutic implications of concomitant heparin and bFGF use are unclear at the present time.
4.3 Tissue localization of bFGF
Previous studies have reported conflicting immunohistochemical localization patterns for bFGF (FGF-2) and acidic FGF (aFGF or FGF-1) in the kidneys. Endogenous bFGF has been localized in renal tubular cells, whereas aFGF has been localized in the glomerular endothelial and mesangial cells [9]. Other investigators have found bFGF in the visceral (podocytes) and parietal (Bowman's capsule) glomerular epithelial cells, and have noted variation in immunolocalization patterns for FGFs based on differences in fixative, technique of preparation, and antibody specificity [31]. We observed that there was significant glomerular localization after exogenous bFGF injection. This is consistent with the recognized pattern of renal toxicity of bFGF (glomerulopathy with proteinuria and hypoalbuminemia) [32].
4.4 Implications
The serum concentrations and pharmacokinetics of bFGF are similar following IV, IC, and LA delivery; however, the pharmacodynamics are dependent on the site of administration. Regional distribution of bFGF is concentration-dependent, with most pronounced uptake at the point of delivery. Relative myocardial bFGF levels were highest following pericardial and IC administration; intermediate following LA delivery, and lowest after IV and SG administration. Taken together, these data predict efficacy of bFGF for myocardial angiogenesis following IC, LA, and pericardial delivery, and predict a lack of efficacy after bolus IV and SG administration. These observations correlate well with our previous studies in which IC and LA administration were effective in promoting myocardial angiogenesis and repeated bolus IV therapy was ineffective. Clearly, serum bFGF levels alone should not be used to predict tissue distribution or therapeutic efficacy. Finally, we found that delivery of bFGF through a SG catheter affords no advantage over IV administration, as we found comparable myocardial recovery of bFGF after SG and IV administration.
Time for primary review 26 days.
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Acknowledgements |
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The authors thank Victoria Hampshire, DVM, John Bacher, DVM, and their staffs for providing veterinary care and Scios Nova, Inc. for supplying bFGF.
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References |
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G. von Degenfeld, P. Raake, C. Kupatt, C. Lebherz, R. Hinkel, F. J. Gildehaus, W. Munzing, A. Kranz, J. Waltenberger, M. Simoes, et al. Selective Pressure-Regulated retroinfusion of fibroblast growth factor-2 into the coronary vein enhances regional myocardial blood flow and function in pigs with chronic myocardial ischemia J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1120 - 1128. [Abstract] [Full Text] [PDF]
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J. J. R. Hermans, H. van Essen, H. A. J. Struijker-Boudier, R. M. Johnson, F. Theeuwes, and J. F. M. Smits Pharmacokinetic Advantage of Intrapericardially Applied Substances in the Rat J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 672 - 678. [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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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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R. Kornowski, M. B. Leon, S. Fuchs, Y. Vodovotz, M. A. Flynn, D. A. Gordon, A. Pierre, I. Kovesdi, J. A. Keiser, and S. E. Epstein Electromagnetic guidance for catheter-based transendocardial injection: a platform for intramyocardial angiogenesis therapy: Results in normal and ischemic porcine models J. Am. Coll. Cardiol., March 15, 2000; 35(4): 1031 - 1039. [Abstract] [Full Text] [PDF]
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M. A. S. Rajanayagam, M. Shou, V. Thirumurti, D. F. Lazarous, A. A. Quyyumi, L. Goncalves, J. Stiber, S. E. Epstein, and E. F. Unger Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs J. Am. Coll. Cardiol., February 1, 2000; 35(2): 519 - 526. [Abstract] [Full Text] [PDF]
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R. Kornowski, S. Fuchs, M. B. Leon, and S. E. Epstein Delivery Strategies to Achieve Therapeutic Myocardial Angiogenesis Circulation, February 1, 2000; 101(4): 454 - 458. [Abstract] [Full Text] [PDF]
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G.C. Hughes, B. H. Annex, B. Yin, A. M. Pippen, P. Lin, A. P. Kypson, K. G. Peters, J. E. Lowe, and K. P. Landolfo Transmyocardial laser revascularization limits in vivo adenoviral-mediated gene transfer in porcine myocardium Cardiovasc Res, October 1, 1999; 44(1): 81 - 90. [Abstract] [Full Text] [PDF]
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J. R Kersten, P. S Pagel, W. M Chilian, and D. C Warltier Multifactorial basis for coronary collateralization: a complex adaptive response to ischemia Cardiovasc Res, July 1, 1999; 43(1): 44 - 57. [Abstract] [Full Text] [PDF]
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S. Waxman, R. Moreno, K. A. Rowe, and R. L. Verrier Persistent primary coronary dilation induced by transatrial delivery of nitroglycerin into the pericardial space: a novel approach for local cardiac drug delivery J. Am. Coll. Cardiol., June 1, 1999; 33(7): 2073 - 2077. [Abstract] [Full Text] [PDF]
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R. L. Verrier, S. Waxman, E. G. Lovett, and R. Moreno Transatrial Access to the Normal Pericardial Space : A Novel Approach for Diagnostic Sampling, Pericardiocentesis, and Therapeutic Interventions Circulation, November 24, 1998; 98(21): 2331 - 2333. [Abstract] [Full Text] [PDF]
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