Yanming Huang

Study of antirestenosis with the BiodivYsio dexamethasone-eluting stent (STRIDE): A first-in-human multicenter pilot trial

The aim of this multicenter pilot study was to evaluate the acute safety and efficacy of the dexamethasone‐eluting stent (0.5 μg/mm2 of stent) implanted in patients with de novo single‐vessel disease. This study included 71 patients, 42% of whom had unstable angina pectoris. An appropriately sized BiodivYsio Matrix Lo stent loaded with a total dexamethasone dose of 0.5 μg/mm2 of stent was used. Technical device success rate was 95%. Six‐month MACE occurred in two patients (3.3%). Binary restenosis rate was 13.3%. Late loss was 0.45. Late loss and percent diameter stenosis were lower in the unstable angina pectoris patients compared to the stable patients (0.32 ± 0.39 vs. 0.60 ± 0.55 mm, P < 0.07, and 26.86 ± 14 vs. 38.40 ± 16%, P < 0.02). This study demonstrated the feasibility and safety of the implantation of a dexamethasone‐eluting stent and its effect on in‐stent neointimal hyperplasia. Catheter Cardiovasc Interv 2003;60:172–178.

In-vivo biocompatibility evaluation of stents coated with a new biodegradable elastomeric and functional polymer

BackgroundIn-stent restenosis may be prevented by impregnating an antiproliferative agent in a polymer from a stent platform. This approach requires both an antiproliferative agent effective in small doses and a biocompatible polymer. MethodsA series of new biodegradable elastomeric poly(ester-amide)(co-PEA) polymers having functional carboxyl groups for drug conjugation were synthesized from non-toxic building blocks. The in-vivo biocompatibility was tested in porcine coronary arteries, by comparing the polymer-coated stents with bare metal stents in 10 pigs. ResultsAll animals survived until sacrifice 28 days later and follow-up angiography prior to sacrifice revealed identical diameter stenosis (21 ± 23%) in both groups. Histology confirmed similar injury scores (0.34 ± 0.34 compared with 0.34 ± 0.32), inflammatory reaction (1.18 ± 0.38 compared with 1.11 ± 0.32) and area stenosis (26 ± 17% compared with 28 ± 22%). ConclusionsThis study suggests that the newly developed copoly(ester-amide) elastomers may be suitable for stent-based local drug delivery.

Long-term biocompatibility evaluation of a novel polymer-coated stent in a porcine coronary stent model

Background Polymer coatings have been used to modify the surface of stents and to serve as a matrix for local drug delivery. Methods Bare stainless steel stents or poly‐bis‐trifluorethoxy phosphazene (PTFEP) dip‐coated stents (Coroflex, Germany) were randomly implanted into porcine coronary arteries with a balloon‐to‐artery ratio of 1.1‐1.2:1. Scanning electron microscopy (SEM), repeat quantitative coronary angiography (QCA) and histomorphometric analysis were performed at 5 days, 6 weeks and 6 months. Results At 5 days, complete endothelial cell coverage with fibrin strands was detected in both the bare and the coated stents with SEM. Late loss, determined by QCA, of coated and bare stents was identical at all time points. Histomorphometric analysis showed that coated and bare stents elicited a similar tissue response at 5 days. At 6 weeks, the coated stents showed a moderate peri‐strut inflammatory response, resulting in increased neointimal hyperplasia. Compared to the bare stents, however, no significant differences were observed. At 6 months, peri‐strut inflammation was minimal and similar in the coated and the bare stent groups. Neointimal hyperplasia of the coated and bare stent groups was also comparable (1.37 ±0.44 compared with 1.15 ±0.40mm2, P = 0.213) and decreased compared to the 6‐week response. Conclusion This PTFEP stent coating showed a long‐term biocompatibility in a porcine coronary stent model. Because no increased proliferative response was observed up to 6 months, this phosphazene coating may serve as a vehicle for local drug delivery. Coron Artery Dis 14:401‐408 •c 2003 Lippincott Williams & Wilkins.

Methotrexate loaded SAE coated coronary stents reduce neointimal hyperplasia in a porcine coronary model

Objective: To evaluate the effect of stent based methotrexate delivery on neointimal hyperplasia. Methods: Stainless steel coronary stents and biological polymer coated (SAE) stents were randomly implanted in coronary arteries of pigs with a stent to artery ratio of 1.1:1. The pigs were killed after five days (10 stents) or four weeks (20 stents). Second, stainless steel coronary stents were dip coated in a 10 mg/ml methotrexate–SAE polymer solution, resulting in a total load of 150 μg methotrexate/stent. SAE coated stents and methotrexate loaded stents were randomly implanted in porcine coronary arteries with a stent to artery ratio of 1.2:1 and followed up to four weeks. Results: SAE coated stents and bare stents elicited a similar tissue response at five days. At four weeks, neointimal hyperplasia induced by the coated stents was less pronounced than with the bare stents (1.32 (0.66) v 1.73 (0.93) mm2, p > 0.05). In vitro drug release studies showed that 50% of the methotrexate was released in 24 hours, and all drug was released within four weeks. No impact on vascular smooth muscle cell proliferation or viability was observed in in vitro cell cultures. At four weeks the arteries with methotrexate loaded stents had decreased peristrut inflammation and neointimal hyperplasia (1.22 (0.34) v 2.25 (1.28) mm2, p < 0.01). Conclusions: SAE coating had an excellent biocompatibility with vascular tissue. Stent based delivery of methotrexate in the SAE coating effectively reduced neointimal hyperplasia in a porcine coronary stent model, potentially due to reduced peristrut inflammation.

Local methylprednisolone delivery using a BiodivYsio phosphorylcholine-coated drug-delivery stent reduces inflammation and neointimal hyperplasia in a porcine coronary stent model

Phosphorylcholine (PC)-coated stents have shown excellent blood and tissue biocompatibility in porcine coronary arteries. The purpose of this study was to determine the efficacy of local methylprednisolone (MP) delivery using PC-coated stents to inhibit inflammatory response and in-stent neointimal hyperplasia in an overstretched porcine coronary model. BiodivYsio (Biocompatibles, Farnham, Surrey, UK) PC-coated drug delivery (DD) stents and DD stents loaded with a high dose of MP (269 μg) were implanted in the coronary arteries of 20 pigs with a balloon/artery ratio of 1.2 : 1. At five days the peri-strut inflammatory response score and thrombus score of the MP-loaded DD stents were lower than in the control stents. The neointimal hyperplasia of MP-loaded DD stents was significantly reduced (0.80 ± 0.10 versus 0.48 ± 0.10 mm2, p < 0.01). At four-week follow-up, the inflammatory response of MP-loaded stents was lower than the control stents, but without significant difference. The MP-loaded stents showed decreased peri-strut arterial injury and in-stent neointimal hyperplasia (2.42 ± 0.87 versus 1.62 ± 0.71 mm2, p < 0.05). It is concluded that local vascular delivery of a high dose of MP from PC-coated DD stents could effectively decrease inflammatory response and thrombus formation after oversized stent deployment and result in a significant reduction of neointimal hyperplasia. (Int J Cardiovasc Intervent 2003; 5: 166-171)

Stent-mediated methylprednisolone delivery reduces macrophage contents and in-stent neointimal formation.

ObjectiveCorticosteroids have a wide range of biological effects. Stent-based methylprednisolone delivery could effectively suppress peri-strut inflammation and neointima induced by a polymer matrix. We tested the safety and efficacy of local stent-mediated methylprednisolone delivery using a biological coating on in-stent neointimal formation in a porcine coronary stent model. MethodsStainless steel coronary stents were dip-coated in a biological polymer/ methylprednisolone solution, resulting in total load of 530 μg methylprednisolone per stent. In-vitro drug release was performed. Stainless steel bare stents, polymer-only and methylprednisolone-coated stents (MP) were implanted in coronary arteries of pigs with a stent/artery ratio of 1.2 : 1. Histopathologic evaluation, morphometry and immunohistochemistic staining were analyzed at 4-week follow-up. ResultsIn-vitro drug release studies showed sustained release up to 10 weeks. In vivo the vascular response of polymer-only-coated stents was comparable with the bare stents. No increased peri-strut inflammation and neointimal hyperplasia were observed. The in-stent neointimal formation of methylprednisolone-coated stents was significantly reduced compared with the bare and polymer-only-coated stents (bare, 1.92±0.73; polymer-only, 2.14±1.50; MP, 1.01±0.47 mm2, P=0.019). The macrophage content of methylprednisolone-coated stents (bare, 30.74±48.67; polymer-only, 19.55±24.60; MP, 1.16±3.33/mm2, P=0.072) was dramatically decreased. However, there were no significant difference among the three group in terms of the proliferating cells expressed by proliferation cell nuclear antigens. ConclusionStent-based local methylprednisolone delivery could effectively decrease both vascular macrophage infiltration and in-stent neointimal hyperplasia.

Assessment of myocardial viability in a porcine model of chronic coronary artery stenosis with dual dose dobutamine magnetic resonance imaging

In a non-surgical porcine coronary stenosis model resulting in chronic left ventricle dysfunction, we aimed in this study to evaluate the potential of magnetic resonance imaging (MRI) to distinguish dysfunctional but viable from necrotic myocardium by using multiple levels of dobutamine inotropic stimulation during a cine MRI protocol (F.P. van Rugge et al. Circulation 1994; 90: 127–138). We compared our results with histopathology. We were able to demonstrate a biphasic effect at increasing doses of dobutamine in a subgroup of animals with a high-grade coronary stenosis, while in another subgroup the coronary stenosis produced a chronic myocardial infarction, in which no functional recovery could be obtained. In this experimental protocol, dual dose dobutamine MRI proved to be an accurate and reproducible technique to perform viability studies in chronic obstructive coronary artery disease. It permits distinguishing chronic ischemic, but viable myocardium from infarcted tissue. The detection of chronically underperfused but potentially salvageable myocardium is of significant clinical importance since it may aid in determining which patients are eligible for revascularization.

A nonsurgical porcine model of left ventricular dysfunction. Validation of myocardial viability using dobutamine stress echocardiography and positron emission tomography

BACKGROUND: Although several shortterm animal models of stunning and hibernation have been studied extensively, it has been difficult to produce a consistent animal model of chronic hibernation. The aim of the present study was to develop a nonsurgical porcine stent model of coronary stenosis in order to investigate the relationship between chronic dysfunctional myocardium and viability using 2D-echo, dobutamine stress echo (DSE) and positron emission tomography (PET). METHODS AND RESULTS: Focal progressive coronary stenosis was induced by implantation of an oversized stent in the left anterior descending (LAD) and/or circumflex (LCX) coronary artery in a total of 115 pigs, according to various experimental protocols: copper stent in the LAD (group I, n = 5); noncoated stainless steel stent in the LAD combined with balloon overstretch (group II, n = 7); poly(organo)phosphazene-coated stent in the LAD (group III, n = 77); and poly(organo)phosphazene-coated stent in both the LAD and the LCX (group IV, n = 26). Occurrence of left ventricular dysfunction was evaluated weekly by 2D-echo. At the time of left ventricular dysfunction the presence of viable myocardium within the dysfunctional region was investigated with DSE and PET, and confirmed by histology. The degree of coronary artery stenosis was measured by quantitative coronary angiography and morphometry. Severe coronary artery stenosis in the presence of dysfunctional, but viable, myocardium was induced in groups III and IV (47% and 11% of the animals, respectively). CONCLUSIONS: The authors developed a nonsurgical porcine stent model of progressive coronary stenosis using an oversized polymer-coated stent resulting in chronically decreased myocardial function, with residual inotropic reserve and viable myocardium. This condition may arise from repetitive periods of ischemia, or from sustained hypoperfusion, or a combination of these processes eventually leading to myocardial hibernation. (Int J Cardiovasc Intervent 2000; 3: 111-120)