Rapamycin eluting stent: the onset of a new era in interventional cardiology.
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Angina Pectoris↗
Biomedical subjects
A J Carter
Publications and source records attributed to A J Carter.
Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model.
BACKGROUND: The purpose of this study was to determine the efficacy of stent-based delivery of sirolimus (SRL) alone or in combination with dexamethasone (DEX) to reduce in-stent neointimal hyperplasia. SRL is a potent immunosuppressive agent that inhibits SMC proliferation by blocking cell cycle progression. METHODS AND RESULTS: Stents were coated with a nonerodable polymer containing 185 microgram SRL, 350 microgram DEX, or 185 microgram SRL and 350 microgram DEX. Polymer biocompatibility studies in the porcine and canine models showed acceptable tissue response at 60 days. Forty-seven stents (metal, n=13; SRL, n=13; DEX, n=13; SRL and DEX, n=8) were implanted in the coronary arteries of 16 pigs. The tissue level of SRL was 97+/-13 ng/artery, with a stent content of 71+/-10 microgram at 3 days. At 7 days, proliferating cell nuclear antigen and retinoblastoma protein expression were reduced 60% and 50%, respectively, by the SRL stents. After 28 days, the mean neointimal area was 2.47+/-1.04 mm(2) for the SRL alone and 2.42+/-1.04 mm(2) for the combination of SRL and DEX compared with the metal (5.06+/-1.88 mm(2), P<0.0001) or DEX-coated stents (4.31+/-3.21 mm(2), P<0.001), resulting in a 50% reduction of percent in-stent stenosis. CONCLUSIONS: Stent-based delivery of SRL via a nonerodable polymer matrix is feasible and effectively reduces in-stent neointimal hyperplasia by inhibiting cellular proliferation.
Animals↗
Pathological analysis of local delivery of paclitaxel via a polymer-coated stent.
BACKGROUND: Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis. Early and late intimal growth and local vascular pathological changes associated with paclitaxel delivered via stents have not been fully explored. METHODS AND RESULTS: Localized drug delivery was accomplished with balloon-expandable stainless steel stents coated with a cross-linked biodegradable polymer, chondroitin sulfate and gelatin (CSG), containing various doses of paclitaxel. CSG-coated stents with paclitaxel (42.0, 20.2, 8.6, or 1.5 microgram of paclitaxel per stent), CSG-coated stents without paclitaxel, and uncoated stents (without paclitaxel or CSG) were deployed in the iliac arteries of New Zealand White rabbits, which were killed 28 days after implant. Mean neointimal thickness at stent strut sites was reduced 49% (P<0.0003) and 36% (P<0.007) with stents containing 42.0 and 20.2 microgram of paclitaxel per stent, respectively, versus CSG-coated stents without paclitaxel. However, histological findings suggested incomplete healing in the higher-dose (42.0 and 20.2 microgram) paclitaxel-containing stents consisting of persistent intimal fibrin deposition, intraintimal hemorrhage, and increased intimal and adventitial inflammation. Stents coated with CSG alone (without paclitaxel) had similar neointimal growth as uncoated stents. In a separate group of rabbits killed at 90 days, neointimal growth was no longer suppressed by CSG-coated stents containing 42.0 or 21.0 microgram of paclitaxel CONCLUSIONS: CSG coating appears to be a promising medium for localized drug delivery. Paclitaxel polymer-coated stents reduce neointima formation but are associated with evidence of incomplete healing at 28 days. However, neointimal suppression was not maintained at 90 days.
Angiogenesis Inhibitors↗
"Metaling" with new stent designs.
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Alloys↗
Will there always be an edge to radiation for the prevention of restenosis?
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Brachytherapy↗
Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats.
1. Although sodium channel blockers are effective analgesics in neuropathic pain, their effectiveness in inflammatory pain has been little studied. Sodium channels are substantially up-regulated in inflamed tissue, which suggests they play a role in maintenance of chronic inflammatory pain. We have examined the effects of sodium channel blockers on mobility, joint hyperalgesia and inflammation induced by complete Freund's adjuvant injected in one ankle joint of adult rats. The clinically effective sodium channel blocker, mexiletine, was compared with crobenetine (BIII 890 CL), a new, highly use-dependent sodium channel blocker. 2. Rats were treated for 5 days, starting on the day of induction of arthritis and were tested daily for joint hyperalgesia, hind limb posture and mobility. At post-mortem, joint stiffness and oedema were assessed. Dose response curves were constructed for each test compound (3 - 30 mg kg day(-1)). Control groups were treated with vehicle or with the non-steroidal anti-inflammatory drug, meloxicam (4 mg kg day(-1) i.p.). 3. Both sodium channel blockers produced dose dependent and significant reversal of mechanical joint hyperalgesia and impaired mobility with an ID50 of 15.5+/-1.1 mg kg day(-1) for crobenetine and 18.1+/-1.2 mg kg day(-1) for mexiletine. Neither compound affected the responses of the contralateral non-inflamed joint, nor had any effect on swelling and stiffness of the inflamed joint. 4. We conclude that sodium channel blockers are analgesic and anti-hyperalgesic in this model of arthritis. These data suggest that up regulation of sodium channel expression in primary afferent neurones may play an important role in the pain and hyperalgesia induced by joint inflammation.
Analgesics↗
The drug-eluting stent: is it the Holy Grail?
Although the restenosis rate of coronary stenting is generally 10% to 20%, it can go as high as 60% in patients with diabetes or complex lesions. Currently, the only effective treatment for restenosis is brachytherapy. Drug-eluting stents may be the way to prevent restenosis that cardiologists have been seeking: the drug-coated stents are simple to use and help prevent negative remodeling and the intimal hyperplasia caused by stenting. In studies comparing sirolimus-coated and bare-metal stents, the sirolimus-coated stents resulted in less smooth muscle cell colonization, minimal intimal hyperplasia, and no edge effect; moreover, no adverse clinical events were reported. Currently ongoing, multicenter clinical trials of drug-eluting stents may soon come up with the answers that cardiologists have been hoping for.
Angioplasty, Balloon, Coronary↗
Gene conversion may aid adaptive peak shifts.
Gene conversion is often viewed as a homogenizing force that opposes adaptive evolution. The objective of this study is to suggest a potential role for gene conversion in adaptive evolution of proteins through aiding the transfer of a population from one adaptive peak to another. Our hypothesis starts with the observation that a tandem gene duplication may result in an extra gene copy that is released from selective constraints. In such cases, individually deleterious mutations may accumulate on the extra copy of the gene, and through gene conversion these mutations may subsequently be presented to the functioning gene for selection en masse. Thus, groups of mutations that jointly confer a selective advantage may regularly be made available for selection. We present a mathematical model of this process and identify the range of rates of gene conversion, gene duplication and mutation under which it may operate. The results indicate that the process may be biologically feasible if the rate of appearance of the potentially beneficial mutations is not too small in relation to the rates of null mutation and of gene conversion. This process appears to be a possible mechanism for effecting adaptive peak shifts in large populations. We show that all the evolutionary steps in the proposed model may have occurred in the evolution of primate gamma -globin genes. We suggest that hide-and-release mechanisms for genetic variation may constitute a more general principal of evolvability.
Adaptation, Physiological↗
Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL.
We have synthesized a new benzomorphan derivative, 2R-[2alpha,3(S*), 6alpha]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-3-[2-(phenylmethoxy)propyl]-2, 6-methano-3-benzazocin-10-ol hydrochloride (BIII 890 CL), which displaced [(3)H]batrachotoxinin A-20alpha-benzoate from neurotoxin receptor site 2 of the Na(+) channel in rat brain synaptosomes (IC(50) = 49 nM), but exhibited only low affinity for 65 other receptors and ion channels. BIII 890 CL inhibited Na(+) channels in cells transfected with type IIA Na(+) channel alpha subunits and shifted steady-state inactivation curves to more negative potentials. The IC(50) value for the inactivated Na(+) channel was much lower (77 nM) than for Na(+) channels in the resting state (18 microM). Point mutations F1764A and Y1771A in transmembrane segment S6 in domain IV of the alpha subunit reduced the voltage- and frequency-dependent block, findings which suggest that BIII 890 CL binds to the local anesthetic receptor site in the pore. BIII 890 CL inhibited veratridine-induced glutamate release in brain slices, as well as glutamate release and neurotoxicity in cultured cortical neurons. BIII 890 CL (3-30 mg/kg s.c.) reduced lesion size in mice and rats when administered 5 min after permanent focal cerebral ischemia at doses that did not impair motor coordination. In contrast to many other agents, BIII 890 CL was neuroprotective in both cortical and subcortical regions of the rat brain. Our results demonstrate that BIII 890 CL is a potent, selective, and highly use-dependent Na(+) channel blocker that protects brain tissue from the deleterious effects of focal cerebral ischemia in rodents.
Animals↗
Experimental evaluation of a short transitional edge protection balloon for intracoronary stent deployment.
The purpose of this study was to determine if balloon injury to the adjacent arterial wall during intracoronary stent deployment influences late in-stent neointimal formation. Stent design and deployment techniques are considered important factors in determining acute and long-term success with intracoronary stenting. Experimental and clinical studies support that the extent of neointimal formation and the probability for restenosis are influenced by the magnitude of arterial trauma induced with stenting. Nineteen 18-mm-long balloon-expandable stainless steel stents (MULTI-LINK Duet) were implanted at a 1:1 stent-to-artery ratio in the coronary arteries of swine with a conventional noncompliant balloon (n = 10) or a novel noncompliant balloon with short tapered shoulders to prevent edge dissection (n = 9). Quantitative coronary angiography and histology were used to evaluate balloon and artery interactions and the chronic vascular responses to the stents. Nineteen stents were implanted in the coronary arteries of seven swines at an inflation pressure of 14 atm using a standard noncompliant (n = 10) or a unique short transitional edge protection (n = 9) balloon. Histologic analysis at 28 days demonstrated balloon-associated barotrauma in 13 of 20 (65%) of adjacent nonstented arterial segments with the conventional balloon and only 3 of 18 (17%) of the adjacent nonstented arterial segments with the short transition edge protection balloon (P = 0.022). In-stent neointimal area and % stenosis correlated with the severity of peristent arterial injury (r = 0.43, P = 0.01). In-stent vessel injury scores were similar for stents with peristent injury (1.0+/-0.3) versus stents without peristent injury (1.0+/-0.03, P = 0.73). In-stent neointimal area and % stenosis were greater for stents with peristent injury (2.36+/-0.74 mm(2), 32%+/-9%) as compared to stents without peristent injury (1.39+/-0.70 mm(2), 20%+/-10%, P = 0.01). Arterial wall injury adjacent to a stent after high-pressure deployment contributes to late in-stent neointimal hyperplasia in this model. These experimental data suggest that further study is warranted to refine stent implantation techniques and that modifications of balloon shape or material may be useful to optimize stent deployment and reduce arterial trauma.
Angioplasty, Balloon, Coronary↗
Selective regional myocardial infiltration by the percutaneous coronary venous route: A novel technique for local drug delivery.
Recent advances in the treatment of heart disease, in particular cardiovascular gene therapy and therapeutic angiogenesis, highlight the need for efficient and practical local delivery methods for the heart. We assessed the feasibility of percutaneous selective coronary venous cannulation and injection as a novel approach to local myocardial drug delivery. In anesthetized swine, the coronary sinus was cannulated percutaneously and a balloon-tipped catheter advanced to the anterior interventricular vein (AIV) or middle cardiac vein (MCV). During balloon occlusion, venous injection of radiographic contrast caused regional infiltration of targeted myocardial regions. Complete AIV occlusion had no impact on LAD flow parameters. Videodensitometric analysis following venous injection showed that radiographic contrast persisted for at least 30 min. Selective regional myocardial infiltration is feasible by this approach, targeting selected myocardial beds, including the apex, anterior wall, septum, and inferoposterior wall. This novel technique has potential application for local myocardial drug or growth factor delivery. Cathet. Cardiovasc. Intervent. 51:358-363, 2000.
Animals↗
The effects of uncontrolled hyperglycemia on thrombosis and formation of neointima after coronary stent placement in a novel diabetic porcine model of restenosis.
BACKGROUND: Results of recent clinical studies suggest that patients with diabetes mellitus have a higher than normal rate of restenosis after percutaneous transluminal coronary angioplasty or coronary stenting. The mechanism for this exaggerated neointimal response is not known. OBJECTIVES: To determine the technical feasibility of a model of in-stent restenosis in swine with streptozotocin-induced hyperglycemia and to compare the late arterial responses to injury induced by placement of oversized coronary stents in diabetic and nondiabetic animals. METHODS: Eighteen 25-40 kg castrated male or intact female Yucatan miniature swine aged 6 months were obtained from a commercial supplier. Twelve of the miniature swine were randomly selected for intravenous treatment with 125 mg/kg streptozotocin to induce a hyperglycemic state. Twelve weeks after treatment, all animals underwent placement of oversized balloon-expandable stainless steel stents in the coronary arteries. After 28 days, histomorphometric analysis of the stented coronary arteries to determine the neointimal responses for the diabetic and nondiabetic animals was completed. RESULTS: Sudden death due to stent thrombosis occurred for five of 11 (45%) of the diabetic animals and none of the age-matched nondiabetic control animals (P=0.05). For histology after 28 days, the neointimal response was correlated to the extent of arterial injury for the diabetic (r=0.79, P < 0.0001) and nondiabetic (r=0.86, P < 0.0001) animals. The surviving diabetic animals had areas of neointimal (1.67 +/- 0.74 mm2) and percentages of in-stent stenosis (28 +/- 14) similar to those of the nondiabetic swine (1.36 +/- 0.40 mm2, P=0.26; 22 +/- 6, P=0.17). Multiple regression analysis also demonstrated that arterial injury (P < 0.0001) alone, not hyperglycemia (P=0.237), was independently correlated to formation of neointima. CONCLUSIONS: Uncontrolled hyperglycemia results in greater than normal thrombosis after coronary-stent placement in swine with streptozotocin-induced diabetes. These data suggest that greater than normal early formation of thrombus rather than proliferation of smooth muscle cells contributes to restenosis after coronary stenting in patients with diabetes mellitus.
Angioplasty, Balloon, Coronary↗
Dose-response effects of 32P radioactive stents in an atherosclerotic porcine coronary model.
BACKGROUND: Experimental studies have demonstrated that 32P radioactive stents reduce neointimal formation at 28 days in porcine iliac and coronary arteries. Our objective was to determine the long-term dose-response effects of 1.0- to 12.0-microCi 32P radioactive stents in a porcine atherosclerotic coronary model. METHODS AND RESULTS: Control (n=19) and 1.0- to 12.0-microCi 32P radioactive (n=43) stents (total, n=62) were implanted in the coronary arteries of 31 miniature swine at 28 days after creation of a fibrocellular plaque by overstretch balloon injury and cholesterol feeding. Angiography and histomorphometry were performed at 6 months. Stent thrombosis occurred in 3 radioactive (7.7%) and no control stents (P=0.54). On histology, the mean neointimal area and the percent in-stent stenosis correlated positively with increasing stent activity (r=0.64, P<0.001). The mean neointimal area (mm2) for the stents with >/=3.0 microCi 32P (3.57+/-1.21) was significantly greater than that for the nonradioactive stents (1.78+/-0.68, P<0.0001). The neointima of the stents with >/=3.0 microCi 32P was composed of smooth muscle cells, matrix proteoglycans, calcification, foam cells, and cholesterol clefts. CONCLUSIONS: Continuous low-dose-rate irradiation delivered by high-activity (32)P radioactive stents promotes the formation of an "atheromatous" neointima after 6 months in this experimental model. These data may be useful for predicting late tissue responses to radioactive stents in human coronary arteries.
Animals↗
Histopathology of postpercutaneous transluminal coronary angioplasty remodeling in human coronary arteries.
BACKGROUND: We studied the histomorphometric correlates of long-term successful coronary balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]). Restenosis after PTCA may occur secondary to the failure of compensatory arterial enlargement or post-PTCA arterial constriction. The histopathology of this process in human subjects remains poorly defined. METHODS: Forty-two coronary segments from 41 patients treated with PTCA 60 +/- 58 weeks before death were studied. The histomorphometric findings at the PTCA site were compared with those obtained at a proximal reference site. RESULTS: Histologic long-term success was seen in 18 (43%) of 42 arteries. Histologically successful PTCA arteries (PTCA site lumen of >/=50% of the reference lumen) demonstrated a larger acute lumen, smaller plaque size (normalized to the internal elastic lamina area), and thinner adventitia compared with histologic failures. Relative to the reference sites, histologically successful PTCA showed expansion of the external elastic lamina. In contrast, histologic failures showed a reduced external elastic lamina area, suggesting constrictive remodeling. Neointimal area correlated with the extent of internal elastic lamina disruption, but neither variable was related to histologic PTCA success or failure. CONCLUSIONS: These data provide histomorphometric confirmation of the hypothesis that constrictive remodeling, not neointimal formation, determines the long-term outcome of PTCA.
Angioplasty, Balloon, Coronary↗
Official satellite symposium of the forum meeting of the European Neuroscience Association. Signal transduction pathways in the blood-brain barrier. Hotel Intercontinental, Berlin, Germany.
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Animals↗
Stent design favorably influences the vascular response in normal porcine coronary arteries.
OBJECTIVES: The purpose of this study was to compare the arterial response following implantation of a stainless-steel, balloon-expandable, tubular slotted stent with that of a novel computer-designed, multi-cellular stent in normal porcine coronary arteries. BACKGROUND: Intracoronary stent placement has evolved into the primary strategy for percutaneous revascularization of symptomatic coronary arterial lesions. Presently there is intense interest in developing new stent designs to improve stent delivery and biocompatability. METHODS: Computer-assisted design was utilized to develop a balloon-expandable stent with symmetric expansion properties, uniform arterial wall coverage, longitudinal flexibility and radial strength. Quantitative coronary angiography and histological assessment of the stented arteries was used to evaluate the acute and chronic vascular responses to a stainless-steel, balloon-expandable, tubular slotted stent as compared to the computer-designed BX stent in the normolipemic swine. RESULTS: Forty stents (24 BX, 16 tubular slotted) were implanted in 19 miniature swine at a mean inflation pressure of 9 atm using identical delivery systems. Eight of the BX and none of the tubular slotted stents were post-dilated with a non-compliant balloon at 12-14 atm. The mean stent-to-artery ratio was similar for the BX (1.03 +/- 0.06) and tubular slotted (1.04 +/- 0.11; p = 0.59) designs. Protrusion or asymmetric radial flaring of a strut at the stent margin was present in 1 of 23 BX stents (4.3%) and 10 of 15 tubular slotted stents (66.7%; p < 0.0001). The mean arterial injury score was significantly less for the BX stent (0.2 +/- 0.2) as compared with the tubular slotted stents (0.4 +/- 0.4; p = 0.025). At 3 days, thrombus area was similar for the BX and tubular slotted designs (0.42 +/- 0.16 mm2 versus 0.44 +/- 0.18 mm2, respectively; p = 0.88). The mean neointimal area was significantly less for the BX at 2 months (1.09 +/- 0.25 mm2 versus 2.93 +/- 2.26 mm2 in the tubular slotted stent) and at 6 months (1.10 +/- 0.26 mm2 versus 2.07 +/- 0.65 mm2 in the tubular slotted stent; p = 0.01), resulting in approximately 50% less in-stent stenosis. CONCLUSIONS: The arterial response to a balloon-expandable stent can be favorably influenced by computer-assisted modification of design in an experimental model. Further study is warranted to determine the impact of stent design upon clinical in-stent restenosis.
Angioplasty, Balloon, Coronary↗
Current status of radioactive stents for the prevention of in-stent restenosis.
PURPOSE: The objective of this paper was to provide an update on the clinical and experimental evaluation of radioactive stents for the prevention of restenosis. MATERIALS AND METHODS: Direct ion implantation of 32P onto the surface of a 15-mm length balloon expandable stainless-steel Palmaz-Schatz stent was employed to render this commercially available vascular stent radioactive. 32Phosphorous, a pure beta-particle-emitting radioisotope, was selected because of its short half-life (14.3 days) and limited range of tissue penetration (3-4 mm). The vascular response to radioactive 7-mm length Palmaz-Schatz stents with activities 0.14 to 23 microCi of 32P were evaluated in animal models of arterial injury and restenosis. The Phase-1 isostent for restenosis intervention study (IRIS trial) was a nonrandomized safety trial designed to evaluate the use of a low activity 32P (0.5 to 1.5 microCi) 15-mm length Palmaz-Schatz stent for the treatment of de novo or restenosis native coronary arterial lesions. RESULTS: In the porcine coronary restenosis model, at < or =0.5 microCi and > or =3.0 microCi stent activities, there was a 30% reduction in the neointimal and percent area stenosis as compared to nonradioactive stents. The 1.0 microCi stents, however, had nearly 2-fold greater neointimal formation and more luminal narrowing than the control stents. In the Phase 1 IRIS trial, 57 patients with symptomatic de novo or restenosis native coronary lesions have been treated with low activity (0.5 to 1.5 microCi) 32P Palmaz-Schatz coronary stents. Fifty-seven stents were successfully implanted without a major procedural complication (death, urgent coronary bypass, Q-wave myocardial infarction). There were no cases of stent thrombosis, target vessel revascularization, or other adverse events in the first 30 days after implant. CONCLUSION: The early clinical results with a low-activity 32P Palmaz-Schatz radioactive stent demonstrate sufficient procedural and 30-day event-free survival to warrant consideration of additional clinical studies to determine the safety and efficacy of this therapy for the prevention of restenosis. Future studies will focus on optimal stent design for delivery of radiation, and will further evaluate safe and effective dosing strategies.
Animals↗
Progressive vascular remodeling and reduced neointimal formation after placement of a thermoelastic self-expanding nitinol stent in an experimental model.
Despite the improvements afforded by intracoronary stenting, restenosis remains a significant problem. The optimal physical properties of a stent have not been defined. We compared the vascular response to a thermoelastic self-expanding nitinol stent with a balloon-expandable tubular slotted stainless steel stent in normal porcine coronary arteries. Twenty-two stents (11 nitinol and 11 tubular slotted) were implanted in 11 miniature swine. The nitinol stents were deployed using the intrinsic thermal properties of the metal, without adjunctive balloon dilation. The tubular slotted stents were implanted using a noncompliant balloon with a mean inflation pressure of 12 atm. Intravascular ultrasound (IVUS) and histology were used to evaluate the vascular response to the stents. The mean cross-sectional area (CSA) of the nitinol stents (mm2) as measured by IVUS increased from 8.13 +/- 1.09 at implant to 9.10 +/- 0.99 after 28 days (P = 0.038), while the mean CSA of the tubular slotted stents was unchanged (7.84 +/- 1.39 mm2 vs. 7.10 +/- 1.07 mm2, P = 0.25). On histology at 3 days, the tubular slotted stents had more inflammatory cells adjacent to the stent wires (5.7 +/- 1.5 cells/0.1 mm2) than the nitinol (3.9 +/- 1.3 cells/0.1 mm2, P = 0.016). The tubular slotted also had increased thrombus thickness (83 +/- 85 microm) than the nitinol stents (43 +/- 25 microm, P = 0.0014). After 28 days, the vessel injury score was similar for the nitinol (0.6 +/- 0.3) and the tubular slotted (0.5 +/- 0.1, P = 0.73) designs. The mean neointimal area (0.97 +/- 0.46 mm2 vs. 1.96 +/- 0.34 mm2, P = 0.002) and percent area stenosis (15 +/- 7 vs. 33 +/- 7, P = 0.003) were significantly lower in the nitinol than in the tubular slotted stents, respectively. We conclude that a thermoelastic nitinol stent exerts a more favorable effect on vascular remodeling, with less neointimal formation, than a balloon-expandable design. Progressive intrinsic stent expansion after implant does not appear to stimulate neointimal formation and, therefore, may provide a mechanical solution to prevent in-stent restenosis.
Alloys↗