(Circulation. 1997;95:449-454.)
© 1997 American Heart Association, Inc.
Articles |
Continuous Subcutaneous Angiopeptin Treatment Significantly Reduces Neointimal Hyperplasia in a Porcine Coronary In-Stent Restenosis Model
the Department of Internal Medicine (Cardiology Division) of the Washington (DC) Hospital Center; the Department of Pathology, University of Texas at San Antonio (F.O.T.); and the Department of Surgery, Georgetown University Medical Center, Washington, DC (M.F., S.S.C.).
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Abstract |
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Background In-stent restenosis results primarily from neointimal hyperplasia. This study evaluated the efficacy and the optimal mode of administration of angiopeptin, a somatostatin analogue with antiproliferative activity, in a porcine coronary in-stent restenosis model.
Methods and Results Forty pigs were randomly assigned to one of four groups (n=10 per group): (1) controls receiving saline infusion at the site of stent implantation via a local delivery catheter, (2) local treatment group receiving one-time treatment (200 µg angiopeptin) at the site of stent placement, (3) systemic treatment group receiving continuous angiopeptin over a 1-week period via a subcutaneous osmotic pump (200 µg/kg total dose), and (4) combined local and systemic treatment group. Then, one oversized Palmaz-Schatz stent (mean ratio of stent to artery diameters, 1.3:1) was implanted in the left anterior descending coronary artery. The degree of neointimal reaction was evaluated 4 weeks later by angiography (maximal percent diameter stenosis), intravascular ultrasound (total in-stent neointimal volume), and histology (maximal area stenosis). Systemic treatment produced the least neointimal hyperplasia and significantly reduced in-stent restenosis compared with the control group by all end points, despite similar degrees of injury. Angiography showed 25±17% versus 50±17% diameter stenosis in the systemic angiopeptin group versus the control group (P<.0001), intravascular ultrasound revealed 23±10 versus 58±27 mm3 neointimal volume in the systemic angiopeptin versus control group (P=.0002), and histology showed 41±16% versus 69±18% area stenosis (P=.0016) in the systemic angiopeptin versus control group. Plasma angiopeptin levels revealed rapid clearance (within 6 hours) after local therapy, whereas the levels persisted for up to 2 weeks in the systemic group.
Conclusions This study shows that continuous subcutaneous treatment with angiopeptin after stent implantation significantly reduces in-stent restenosis by inhibiting neointimal hyperplasia.
Key Words: stents • restenosis • angioplasty
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Introduction |
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Stents reduce restenosis by eliminating geometric remodeling and by improving the initial angiographic result. Recent randomized studies1 2 indeed demonstrated that tubular slotted metallic stents reduce restenosis compared with balloon angioplasty in native coronary arteries. Although stents can reduce restenosis, there is still significant late lumen loss at the stent site, with restenosis in >20% in most patient subgroups. Intravascular ultrasound studies show that the mechanism of in-stent restenosis is purely neointimal hyperplasia.3 Furthermore, stents seem to result in a greater neointimal response, with much more late tissue growth at the treatment site than other angioplasty procedures.1 2 4 Thus, an in-stent restenosis model may be the optimal means to study the efficacy of antiproliferative agents. The agents found to be effective in this model may enable further reduction in clinical restenosis after a successful stent procedure in human coronary arteries.
Angiopeptin, a somatostatin analogue, has been shown to inhibit neointimal formation in various animal models.5 6 7 8 9 10 11 Its mechanism of action is thought to be inhibition of growth factors12 13 and possibly growth hormones14 and may involve activation of a membrane-bound phosphatase, which will inhibit tyrosine kinase–dependent ligands, such as various known growth factors.15 Although angiopeptin has been shown to reduce neointimal reaction in various animal studies and to decrease late cardiac events after balloon angioplasty,16 17 its role in reducing in-stent restenosis has not been evaluated.
The objectives of this study were to evaluate the efficacy and optimal mode of administration (systemic or local delivery via a catheter) of angiopeptin in a porcine coronary in-stent restenosis model by three independent end points (maximal percent diameter stenosis at follow-up angiography, in-stent neointimal volume as assessed by intravascular ultrasound, and maximal area stenosis by histology).
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Animal Study Protocol
The animal study was approved by the Animal Care and Use Committee of the Medlantic Research Institute and conformed to the tenets of the American Heart Association on research animal use. Forty specific-pathogen-free domestic pigs (n=10 surviving pigs per groupx4 groups) weighing 45 to 50 kg (Hidden Valley Farm, Reisterstown, MD) were pretreated with aspirin 325 mg, ticlopidine 250 mg, and verapamil SR 120 mg PO 1 day before the procedure. On the day of the stent implantation, they were anesthetized with ketamine (20 mg/kg, Fort Dodge Laboratories) and xylazine (2 mg/kg, Mobay Corp) IM and intubated. They received 2 L/min supplemental oxygen continuously via a respirator and sodium pentobarbital (10 mg/kg) IV as needed. Under sterile conditions, the left carotid artery and external jugular vein were surgically exposed, and 8F and 6F sheaths, respectively, were inserted. Continuous hemodynamic and surface ECG monitoring was maintained throughout the procedure (Marquette Electronics, Inc). The animals were then randomly assigned to one of four groups before initial angiography (treatment groups as below). After systemic heparinization (300 U/kg IV), control angiograms of the left coronary arteries were performed with a femoral left Judkins 3.5 guiding catheter (SciMed Life Systems, Inc) and a nonionic contrast agent (Optiray 320, Mallinckrodt Medical Inc) in two orthogonal views. Then, over a 0.014-in guide wire (SciMed), a 3.0-mm Dispatch catheter (SciMed) was inserted into the left anterior descending coronary artery (ratio of catheter to artery diameters [catheter/artery],
1.1:1) in those receiving local delivery. With a pressure-driven infusion pump (Baxter Healthcare Corp), local delivery was performed for 30 minutes. Then, the catheter was exchanged for a 3.5-mm balloon catheter (balloon/artery, 1.3:1) with one 15-mm Palmaz-Schatz stent (Johnson & Johnson Interventional Systems Co) manually crimped onto the balloon. The stent was deployed by inflation of the balloon to nominal pressure (8 atm) for 1 minute at the site of local delivery or in a segment with balloon/artery 1.3:1 in the systemic treatment group. Repeat angiograms were obtained immediately after stent implantation, and all angiograms were recorded on an s-VHS tape for off-line analysis. After stent implantation, all equipment was removed, and the artery and vein were ligated. Those receiving subcutaneous treatment had Alzet osmotic pumps (ALZA Corp) implanted at the skin incision site before wound closure. All animals received aspirin 325 mg and ticlopidine 250 mg PO daily until they were killed. Serial plasma levels were measured as below. Four weeks after the procedure, the animals underwent repeat angiograms and intravascular ultrasound studies before they were killed, and the coronary arteries were perfusion-fixed for histological analysis. Intravascular ultrasound was performed with a system (Cardiovascular Imaging Systems Inc) that used a single-element beveled transducer mounted on the tip of a flexible shaft and rotated at 1800 rpm within a 3.2F short monorail imaging sheath. The imaging transducer was withdrawn at 0.5 mm/s with a motorized automatic pullback device, and the studies were recorded on 1/2-in high-resolution s-VHS tapes for off-line volumetric assessment.
For histological analysis, the perfusion-fixed hearts were harvested and sent to the study pathologist after 24 hours in 10% buffered formalin. Then, the specimens were embedded in methyl methacrylate, and sections were cut with a low-speed diamond wafer mounted to a Buehler Isomet saw (Buehler Ltd), leaving the stent wires intact in the cross sections to minimize potential artifacts from removal of stent wires. Fifty- to 100-µm sections were obtained at about 1 mm apart and stained with metachromatic stain. Measurements were carried out with Sigmascan software (Jandel Scientific) through an optical microscope integrated to a digitizing tablet.
Treatment Groups
The pigs were assigned randomly to one of the following four groups before initial angiography: (1) control group without any angiopeptin (Henri Beaufour Institute USA) treatment but given saline locally via the Dispatch catheter before stent implantation, (2) local treatment group receiving one-time delivery of 200 µg angiopeptin at the site of stent implantation before stent implantation, (3) systemic treatment group receiving continuous subcutaneous angiopeptin (200 µg/kg total dose) over a 1-week period via an Alzet osmotic pump implanted subcutaneously at the end of the stent implantation procedure, and (4) combined treatment group receiving both local (200 µg) and continuous subcutaneous (200 µg/kg total dose) angiopeptin treatments. The Alzet pump was primed in saline solution starting the night before implantation with the amount of drug necessary for steady state added to the weekly dose. All of the treatment groups received angiopeptin pretreatment of 500 µg IV immediately after insertion of the sheath, because a previous study showed the necessity of pretreatment.11 Local delivery of saline infusion in the control group and angiopeptin in the treatment groups (local and combined groups) was performed at 0.5 mL/min via the Dispatch catheter for 30 minutes at the site of subsequent stent implantation. All groups except for the systemic treatment group had local delivery via the Dispatch catheter before stent implantation.
This study design should allow comparisons among the control group and the treatment groups as well as evaluation of the optimal route of angiopeptin administration. The results may elucidate whether one-time local delivery of angiopeptin via the Dispatch catheter at a lower dose than the systemic dose is equally effective and whether there is a synergistic benefit from combined local and systemic treatment.
Plasma Angiopeptin Levels
Plasma angiopeptin levels were measured serially by radioimmunoassay, as described previously, in all groups at 5, 10, and 30 minutes, at 1, 2, 6, and 24 hours, and weekly thereafter until the animals were killed.18 Furthermore, intracoronary injections of 200 µg angiopeptin were given to 3 additional pigs, and serial levels were measured up to 6 hours after the administration. In brief, the radioimmunoassay was carried out as follows. The immunoassay buffer used was 100 mmol/L phosphate buffer, pH 7.4, containing 0.5% BSA, 150 nmol/L NaCl, and 0.01% NaN3. Standard curves were established in the peptide-free plasma to compensate for the nonspecific interference from plasma. Standard or plasma samples in triplicate (100 µL) were preincubated with 100 µL (initial dilution of 1:800) of antiserum (gift from Plessey, Robinson, France) for 24 hours at 4°C, then iodinated angiopeptin (150 Bq in 100 µL) prepared by a modification of the procedure of Hunter and Greenwood19 was added, and incubation was continued further for 24 hours at 4°C. The mixture was precipitated with cold ethanol at 4°C for 30 minutes and spun in a cold centrifuge at 3000 rpm for 30 minutes. The supernatant was discarded, and the pellets were counted in a gamma counter (LKB Wallac 1272 Clinigamma). The minimal detectable dose (95% confidence limits) was 50 pg/mL. The cross-reactivity of endogenous peptides, such as somatostatin 14, was <0.005%.
Evaluation of Neointimal Hyperplasia
Three separate end points, (1) maximal percent diameter stenosis at follow-up angiography, (2) total neointimal volume within the stent assessed by intravascular ultrasound, and (3) morphometric analysis of the neointima from histology slides, were analyzed by independent observers unaware of the treatment assignment.
Quantitative analysis of initial and follow-up angiograms was performed with an electronic hand-held caliper (Brown and Sharpe) and the guiding catheter for calibration and consisted of the following measurements: (1) mean reference diameter [(proximal+distal) reference diameters/2], (2) mean diameter of the stent at full expansion, (3) stent/artery [(2)/(1)], (4) minimal stent diameter at follow-up, and (5) percent diameter stenosis at follow-up {[(2)-(4)/(2)]x100}. All initial and follow-up measurements were made during end diastole in the same left anterior oblique projection.
For intravascular ultrasound analysis, 15 images of each stent were selected every 2 seconds of videotape (each 2 seconds of video playback corresponds to 1 mm of axial lesion length, given a pullback speed of 0.5 mm/s, and each Palmaz-Schatz stent measures 15 mm in axial length). With computerized planimetry, the stent and lumen cross-sectional areas of each image slice were traced manually, and the cross-sectional area of neointimal hyperplasia present within the stent on each image slice was calculated as stent cross-sectional area minus lumen cross-sectional area. Stent and lumen volumes (in cubic millimeters) were calculated according to Simpson's rule, and the neointimal volume was calculated as follows20 : (1) stent volume=
stent cross-sectional area; (2) lumen volume= lumen cross-sectional area; and (3) neointimal volume=stent volume-lumen volume.
Histological evaluation included the degree of injury21 and the morphometric analysis of the stent area, lumen area, neointimal area, and percent area stenosis (neointimal area/stent areax100). These measurements were made on four cross sections from each stent visually estimated to be the most narrowed segments that would correspond to the minimal lumen diameter by angiography and were averaged for each stent.
Statistical Analysis
All data are presented as mean±SD. Each end point among the four groups was analyzed by two-way ANOVA with the SAS statistical package. The planned comparisons of each end point among the control group versus the treatment groups were performed with post hoc analysis of Fisher's protected least significant difference. A value of P<.05 was considered significant.
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Angiographic Results
No differences among the groups were present for reference vessel size (2.73±0.36 mm) or stent/artery ratio (1.28±0.16) during the initial procedure. At follow-up, however, the percent diameter stenosis (Fig 1
) was significantly different among the groups (P=.0001 by ANOVA). It was most significantly reduced in the systemic treatment group compared with the control group (25±17% versus 50±17% in the control group, P<.0001). There were also significant differences between the control group and the other two treatment groups (P=.013 versus local treatment group and P=.0013 versus combined treatment group). There were no significant differences among any of the treatment groups.
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Intravascular Ultrasound Results
Intravascular ultrasound was analyzable in 37 of 40 animals. One control animal had subtotal occlusion and died immediately after follow-up angiogram before intravascular ultrasound could be performed. One systemic treatment animal had suboptimal intravascular ultrasound images and was excluded. Ultrasound images could not be obtained from one local treatment animal despite attempts with multiple catheters because of marked tortuosity of the vessel.
There were 4 control animals, whose occlusive neointima "hugged" the ultrasound catheter. In these animals, the lumen area had to be assumed to be that of the ultrasound catheter (1.3 mm2). Stent volume was not different among the groups. Although the lumen volume tended to be greater in the treatment groups (P=.055 by ANOVA), it did not reach statistical significance, most likely because of the overestimation of lumen volume in the 4 control animals. However, the neointimal volume within the stent (Fig 2) was significantly different among the groups (P=.0011). It was most significantly reduced (Fig 3) in the systemic treatment group compared with the control group (23±10 mm3 versus 58±27 mm3 in the control group, P=.0002). There was no significant difference between the control group and the local treatment group. Furthermore, there was a significant difference between the control group and the combined treatment group (P=.0047). The systemic and the combined treatment groups were not different.
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Histological Results
Two stents (one control and one systemic stent) were divided longitudinally for scanning electron microscopy and were not available for morphometric analysis. There was no statistically significant difference in injury score among the groups. Histology of the remaining 38 stents showed marked neointimal formation in the control group (Fig 4A). The percent area stenosis was most significantly reduced in the systemic treatment group (Fig 4B) compared with the controls (41±16% versus 69±18% in the control group, P=.0016, Fig 5). The control group was also significantly different compared with the combined treatment group (P=.039) but was not different from the local treatment group (P=NS). The combined and the systemic treatment groups were not different.
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Plasma Angiopeptin Levels
Serial plasma angiopeptin levels were measured from the four groups, as well as from 3 animals receiving intracoronary injection of 200 µg of angiopeptin. The control group had no detectable levels at any time point. In all groups, the peak level was obtained within 5 minutes after the initial treatment. Both the local and intracoronary groups had rapid clearance (within 6 hours) after angiopeptin administration (Fig 6), although a minute amount was still detectable at 6 hours after local delivery. Interestingly, intracoronary injection of the same amount of drug resulted in higher mean plasma levels than local delivery, suggestive of a transient "depot" effect from the local delivery. On the other hand, both the systemic and the combined treatment groups had sustained plasma levels even up to 2 weeks after the initial treatment (Fig 6).
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Discussion |
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This study shows that at the dosages selected, continuous subcutaneous angiopeptin treatment was the optimal mode of angiopeptin therapy and resulted in maximal reduction in neointimal hyperplasia after stent implantation in a porcine coronary artery overstretch in-stent restenosis model. Systemic angiopeptin treatment resulted in a 50% reduction in percent diameter stenosis, a 41% reduction in area stenosis, and a 61% reduction in stent neointimal volume compared with controls without angiopeptin treatment. The mechanism for this efficacy may be the sustained plasma angiopeptin level for up to 2 weeks after stent implantation.
Mechanisms of Restenosis and Appropriate Models
Previous animal and clinical restenosis studies have evaluated the antiproliferative effects of various agents after balloon angioplasty, on the hypothesis that restenosis occurs mostly from neointimal hyperplasia.22 The results have been uniformly disappointing,23 with a few exceptions, such as two recently published studies with short-term continuous infusion of angiopeptin.16 17 However, recent serial intravascular ultrasound studies4 24 as well as animal studies25 26 suggest that the mechanisms of restenosis are multifactorial. Whereas in-stent restenosis results mostly from neointimal hyperplasia,3 the restenosis process after balloon angioplasty or angioplasty with other devices results from combination of neointimal hyperplasia and chronic remodeling, which causes late lumen narrowing from vessel retraction rather than neointimal thickening. Although it is unknown whether there is a cause-and-effect relationship between initial neointimal proliferation and subsequent vessel contraction, the intravascular ultrasound mechanistic observations may explain the negative results of clinical studies despite promising results in animal studies with antiproliferative agents. It is unknown whether any of the agents play a role in modifying the chronic remodeling process. Thus, the optimal model to study the efficacy of antiproliferative agents may be an in-stent restenosis model.
Results of the Present Study
In addition to the in-stent restenosis model, the present study used intravascular ultrasound volumetric assessment as a critical end point of the efficacy of angiopeptin. Recent intravascular ultrasound studies27 suggest that there are discrepancies between angiography and intravascular ultrasound, especially in accurately assessing stent dimensions. Furthermore, intravascular ultrasound enables estimation of in-stent neointimal volume in vivo, overcoming potential disadvantages of angiography.28
The continuous systemic treatment group showed the greatest reduction in neointima, similar to a human study after balloon angioplasty.17 Plasma angiopeptin levels suggest that a prolonged drug effect may be necessary to most effectively reduce neointimal hyperplasia. This hypothesis is supported by the finding that the one-time local angiopeptin treatment at the chosen dose with the Dispatch drug delivery catheter was not consistently effective in significantly reducing neointimal hyperplasia in this study. Other possible explanations include ineffective intramural delivery by Dispatch catheter, low efficiency of intramural deposition, and/or transient local residency time after successful delivery.29 These potential reasons may also explain the absence of a synergistic effect from the combined local and systemic treatments compared with the systemic group. It is unknown whether other means of local angiopeptin delivery30 may enhance its antiproliferative effect or whether higher doses of angiopeptin with the Dispatch catheter may elicit a greater response.
Results of this study appear to confirm the utility of an in-stent restenosis model to evaluate the efficacy of antiproliferative agents, the valuable role of intravascular ultrasound in detecting reduction in overall neointimal volume in vivo, and the differential effects of various modes of treatment with the same drug.
Clinical Implications
For the first time, stents have been able to affect the restenosis rates compared with balloon angioplasty.1 2 The encouraging results of this study suggest that restenosis rate after stent implantation may be further reduced by angiopeptin treatment. If angiopeptin treatment could reduce in-stent restenosis rates by 50%, it might be possible to achieve angiographic restenosis rates of <10% in patients. Furthermore, the role of stents may be extended to unfavorable lesion morphologies, such as smaller vessels and diffuse lesions, which have been associated with high in-stent restenosis rates.31
Limitations of the Study
This study does not answer whether one-time local angiopeptin treatment at the site of stent implantation could reduce in-stent restenosis. The local treatment dose was arbitrarily chosen and deliberately selected at a lower dose than the systemic dose, because a previous angiopeptin study with the Dispatch catheter demonstrated greater relative efficacy with a lower local dose.32 Furthermore, it is unknown whether different local delivery catheters with potential for greater intramural drug deposition or balloon injury before the Dispatch catheter use might yield better results. The latter was not performed so as to eliminate any potential confounding effects from the balloon injury. Also, because of the expense and the large number of animals involved, dose-response studies to determine the optimal angiopeptin dose could not be performed. We did not demonstrate the intramural deposition of angiopeptin by use of radiolabeled angiopeptin and autoradiography.6 However, the drug delivery efficiency with radiolabeled octreotide, a different eight-amino-acid analogue of somatostatin, was <1% and retention time <8 hours in a human study.33 Finally, we cannot extrapolate the findings of this study in normal porcine coronary arteries stimulated with oversized stents for neointimal proliferation to a human clinical scenario with preexisting atherosclerosis and stent sizes matched to the reference vessel size.
Intravascular ultrasound can underestimate the neointimal volume, especially in subtotal lesions, because the sheath size is 1.3 mm and the minimal lumen diameter is assumed to be 1.3 mm for those segments that "hug" the catheter. In the control group, there were 4 animals with the tissue hugging the catheter, and we had to assume that the minimal lumen areas for these segments were equal to the catheter area. Likewise, the use of intravascular ultrasound before perfusion fixation in these animals may have resulted in a Dottering effect, with less area stenosis on histological examination.
The systemic treatment group did not have a sham local delivery catheter insertion. Any additional injury induced by the local delivery catheter would have resulted in more neointimal hyperplasia in other groups.
Future Directions
Although the results of this study, especially for the continuous systemic treatment, are encouraging and 5-day subcutaneous angiopeptin infusion via insulin pump has been successful in patients undergoing balloon angioplasty,16 17 an extended release from impregnation on a stent30 or a one-time intramuscular injection of slow-release formulation34 may be more desirable. Furthermore, it may be important to identify the patient-, lesion-, and procedure-related factors in those patients undergoing stent implantation that are associated with increased restenosis so that preferential therapy of these high-risk patients may be instituted with an antiproliferative agent, such as angiopeptin.
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Acknowledgments |
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This research was supported by grants from the Cardiology Research Foundation of the Washington Cardiology Center and Henri Beaufour Institute USA. The authors thank O. Bramwell for technical assistance and M. Mehlman for illustrations. Palmaz-Schatz stents were supplied by Johnson & Johnson Interventional Systems and Dispatch catheters by SciMed Life Systems.
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Footnotes |
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Reprint requests to Martin B. Leon, MD, Director, Cardiovascular Research, Washington Cardiology Center, Suite 4B-1, 110 Irving St NW, Washington, DC 20010. E-mail mbl1@mhg.edu.
Received June 3, 1996; revision received July 29, 1996; accepted August 28, 1996.
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