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Xiaodong Ma,
Shizu Oyamada,
Fan Gao,
Tim Wu,
Michael P Robich,
Hao Wu,
Xingwei Wang,
Bryan Buchholz,
Stephen McCarthy,
Zhiyong Gu,
Cesario F Bianchi,
Frank W Sellke, Roger Laham
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ABSTRACT: Paclitaxel and sirolimus are the two major drugs for the treatment of coronary arterial disease in current drug-eluting stents. The two drugs can effectively inhibit the in-stent restenosis through their independent pathways and show synergistic effect in preventing tumor tissue growth. We hypothesize that the combination of the two drugs in a drug-eluting stent (DES) can also effectively suppress the neointima growth in the stented artery. The present work was focused on the investigation of paclitaxel/sirolimus combination release profiles from a novel biodegradable polymer (poly (D, L-lactide-co-glycolide)/amorphous calcium phosphate, PLGA/ACP) coated stent both in vitro and in vivo. For the in vitro, the drug releasing profiles were characterized by measuring the drug concentration in a drug release medium (Dulbecco's phosphate buffered saline, DPBS, pH 7.4) at predetermined time points. For the in vivo, a rat aorta stenting model was employed. The results showed that both paclitaxel and sirolimus had a two-phase release profile both in vitro and in vivo, which is similar to the drug release profile of their individual coated DESs, and there is no evident of interference between two drugs. The data suggest that paclitaxel and sirolimus can be combined pharmacokinetically in a DES for the treatment of coronary arterial diseases.
Journal of pharmaceutical and biomedical analysis 03/2011; 54(4):807-11. · 2.45 Impact Factor
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Shizu Oyamada,
Xiaodong Ma,
Tim Wu,
Michael P Robich,
Hao Wu,
Xingwei Wang,
Bryan Buchholz,
Stephen McCarthy,
Cesario F Bianchi,
Frank W Sellke, Roger Laham
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ABSTRACT: Currently, preclinical stent development requires elaborate large animal models, which are time consuming and expensive. We herein report a high throughput rat aorta stenting model which could provide a rapid and low-cost platform for preclinical stent development.
A total of 86 metal stents (316L stainless steel 13 mm, VasoTech, Inc.) coated with poly (D, L-lactide-co-glycolide)/amorphous calcium phosphate (PLGA/ACP) copolymer were pre-mounted on 1.5 mm × 15 mm balloon catheters and were implanted into aspirin treated Sprague-Dawley rats (500-700 g) initially using either direct placement in the abdominal aorta (group A, n = 7) or a trans-iliac approach (cut-down, group B, n = 79). The surviving rats were sacrificed at 1, 2, 4, and 12 wk post-implantation and the stented arteries were analyzed histopathologically.
Four rats died in group A and nine rats died in group B within 48 h post-stent implantation (mortality: 57% versus 11%, P < 0.05). All animals that died had stent thrombosis/paralysis with visible thrombus on necropsy. Histologically, neointimal growth peaked at approximately 4 wk post-implantation.
This result suggests that human-sized stents can be successfully implanted into the rat aorta via iliac artery insertion with a significantly higher survival rate than trans-aorta implantation. The model system allows rapid (4-12 wk) assessment of stent biocompatibility with mortality/paralysis used as an indicator of stent thrombosis.
Journal of Surgical Research 03/2011; 166(1):e91-5. · 2.25 Impact Factor
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Xiaodong Ma,
Shizu Oyamada,
Tim Wu,
Michael P Robich,
Hao Wu,
Xingwei Wang,
Bryan Buchholz,
Stephen McCarthy,
Cesario F Bianchi,
Frank W Sellke, Roger Laham
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ABSTRACT: The purpose of this study was to optimize a novel biodegradable polymer for drug eluting stent (DES) applications. Degradation profiles of different poly(D,L-lactide-co-glycolide)/amorphous calcium phosphate (PLGA/ACP) composites coated on stents were studied both in vitro and in vivo for three months. For the in vitro study, stents were immersed into the phosphate buffered saline (37 °C, pH 7.4) with constant shaking. The polymer weight loss was measured weekly and morphological changes were analyzed. The results demonstrated that approximately 60% of polymer was degraded within the three-month period and there was no significant difference between the different PLGA/ACP composites. However, the composite of 50% PLGA (65/35) with 50% ACP showed a slightly faster degradation rate than other composites. Morphologically, all stent surfaces changed from a micro-porous before degradation to a corrugated solid micro-net-like structure at two months post degradation. Based on in vitro results, 65% PLGA (65/35) with 35% ACP) coated stents were selected and implanted into rat aortas (n = 12) for the in vivo study. Microscopic observation showed that no composite was found on any of the implanted stents at 12 weeks post implantation, which indicated the selected PLGA/ACP composite is desired for DES applications.
Journal of Biomedical Materials Research Part A 03/2011; 96(4):632-8. · 2.63 Impact Factor
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ABSTRACT: Calcific aortic stenosis remains a major cause of mortality and morbidity in the aging population. Surgical replacement remains the treatment of choice for this disease. Balloon aortic valvuloplasty was introduced as a palliative procedure for these patients, but was tempered by a high rate of recurrence, which has limited its usefulness. However, the introduction of smaller-profile balloons, rapid pacing, and closure devices have brought it back as an alternative treatment strategy in selected patients who are at too high risk for surgery with repeat valvuloplasty as needed for recurrences. We report a case of prosthetic aortic valve stenosis treated with valvuloplasty with intracardiac and fluoroscopic guidance with recurrence treated with repeat valvuloplasty with promising intermediate-term outcome and describe the growing valve in valve procedures.
Catheterization and Cardiovascular Interventions 03/2011; 77(4):589-92. · 2.29 Impact Factor
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ABSTRACT: PET/CT imaging with (18)F-FDG has been used to detect inflammation in carotid and aortic plaque; its use in detecting coronary plaque has been limited by avid (18)F-FDG uptake by the myocardium. We investigated whether (18)F-FDG PET/CT could be used to image inflammation in coronary arteries as a potential noninvasive method to detect vulnerable plaque.
We retrospectively studied 32 patients treated for malignancy who underwent (18)F-FDG PET/CT and concomitant cardiac catheterization. As part of the recently described protocol, all patients were instructed to eat a low-carbohydrate, high-fat meal the night before and drink a vegetable oil drink the morning of the study. We reviewed the patients' baseline characteristics and their (18)F-FDG PET/CT scans for adequacy of myocardial uptake suppression and correlated the presence of angiographically apparent plaque with (18)F-FDG uptake in the major coronary arteries. Two independent observers assessed the angiographic images and (18)F-FDG PET scans.
A total of 95% of patients had 2 or more coronary disease risk factors, and 25% had unstable symptoms; 30% of index catheterizations resulted in intervention. In 20 of 32 patients (63%), myocardial suppression was good (12) or adequate (8). Inadequate suppression was due to self-reported dietary nonadherence. Patients with good, adequate, and poor suppression had maximal myocardial standardized uptake values of 2.8 +/- 0.7, 5.0 +/- 1.3, and 17.0 +/- 9.7, respectively. We identified (18)F-FDG uptake in 15 patients in 1 or more coronary segments. A trend to significance in correlation between presence of angiographic disease and signal in the vessel was observed (P = 0.07; 80 vessels examined). A total of 7 patients with significant coronary artery disease had aortic (18)F-FDG uptake.
In this retrospective study, we demonstrated the potential use of (18)F-FDG PET in imaging of inflammation in coronary arteries. The potential of (18)F-FDG PET is also being investigated in a prospective study.
Journal of Nuclear Medicine 05/2009; 50(4):563-8. · 6.38 Impact Factor
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ABSTRACT: Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can restore endothelial function in coronary disease, in vitro and murine studies have shown their effects on myocardial angiogenesis to be biphasic and dose dependent. We investigated the functional and molecular effects of high-dose atorvastatin on the endogenous angiogenic response to chronic myocardial ischemia in hypercholesterolemic swine.
Yucatan pigs were fed either a normal (NORM group; n=7) or high-cholesterol diet, with (CHOL-ATR group; n=7) or without (CHOL group; n=6) atorvastatin (3 mg/kg per day) for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Seven weeks later, microvessel relaxation responses, myocardial perfusion, and myocardial protein expression were assessed. The CHOL group demonstrated impaired microvessel relaxation to adenosine diphosphate (29+/-3% versus 61+/-6%, CHOL versus NORM; P<0.05), which was normalized in the CHOL-ATR group (67+/-2%; P=NS versus NORM). Collateral-dependent myocardial perfusion, adjusted for baseline, was significantly reduced in the CHOL group (-0.27+/-0.07 mL/min per gram versus NORM; P<0.001) as well as the CHOL-ATR group (-0.35+/-0.07 mL/min per gram versus NORM; P<0.001). Atorvastatin treatment was associated with increased phosphorylation of Akt (5.7-fold increase versus NORM; P=0.001), decreased vascular endothelial growth factor expression (-68+/-8%; P<0.001 versus NORM), and increased expression of the antiangiogenic protein endostatin (210+/-48%; P=0.004 versus NORM).
Atorvastatin improves hypercholesterolemia-induced endothelial dysfunction without appreciable changes in collateral-dependent perfusion. Increased myocardial expression of endostatin, decreased expression of vascular endothelial growth factor, and chronic Akt activation associated with atorvastatin treatment may account for the diminished angiogenic response.
Circulation 08/2006; 114(1 Suppl):I402-8. · 14.74 Impact Factor
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ABSTRACT: Improved treatment options and better management of cardiovascular risk factors have resulted in improved outcomes for patients suffering from severe coronary artery disease. However, coronary artery disease may be of such a diffuse and severe manner that repeated attempts at catheter-based interventions and coronary artery bypass grafting may be unsuccessful at restoring normal myocardial blood flow. It is the goal of therapeutic angiogenesis to restore perfusion to chronically ischemic myocardium using protein growth factors, gene therapy, or, more recently, cell-based therapy, without intervening on the epicardial coronary arteries. However, angiogenesis has not yet provided significant clinical benefit and is still reserved as an experimental treatment for patients who have failed conventional therapies. Once potential endogenous inhibitors of vascular development can be modified, angiogenesis may become more useful for therapeutic purposes. It is hoped that angiogenesis for therapeutic purposes will one day effectively re-create the potent natural processes of vascularization that every human being undergoes during growth and development and become a major modality for the treatment of coronary artery disease.
Seminars in Cardiothoracic and Vascular Anesthesia 07/2006; 10(2):184-8.
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ABSTRACT: Cyclooxygenase-2 (COX-2) is induced by hypoxic stimuli and is also involved in the process of angiogenesis. We previously demonstrated that vascular endothelial growth factor (VEGF) is one of the principal factors produced by hypoxic myocytes and is responsible for the induction of COX-2 expression in endothelial cells. Yet the signaling pathways by which VEGF modulates COX-2 gene expression are still less well defined. We therefore examined the regulation of VEGF-induced COX-2 expression by the mitogen-activated protein kinase (MAPK) family in endothelial cells.
Human umbilical vascular endothelial cells (HUVECs) were incubated with U0126 (ERK1/2 inhibitor, 10 microM), SB203580 (p38 inhibitor, 20 microM), and SP600125 (JNK inhibitor, 20 microM), as well as the COX-2 selective inhibitor, NS398, for 1 h before treating with VEGF (20 ng/ml). COX-2 expression induced by VEGF at both mRNA and protein levels was significantly inhibited by selective p38 and JNK inhibitors but not by the ERK1/2 inhibitor. The phosphorylation of p38 and JNK kinases was observed as early as 5 min in HUVECs after VEGF stimulation. Furthermore, the biological significance of the COX-2 gene in endothelial cells was examined by over-expressing or knocking down COX-2 gene expression. (3)H-Thymidine incorporation and Matrigel techniques were used to determine cell proliferation and vascular structure formation. VEGF-induced cell proliferation was significantly reduced when HUVECs were either pre-treated with NS398 (21.52+/-3.6%) or transfected with COX-2 siRNA (34.12+/-5.81%). In contrast, in HUVECs with over-expression of COX-2, VEGF-induced cell proliferation was increased 42.56+/-7.69%. Moreover, the formation of vascular structure assayed by Matrigel demonstrated that VEGF-induced vascular structure formation was accelerated in COX-2 over-expressing cells but attenuated in COX-2 siRNA-transfected cells.
COX-2 plays an important role in VEGF-induced angiogenesis via p38 and JNK kinase activation pathways. These findings suggest that the cardioprotective role of COX-2 may be, at least in part, through its angiogenic activity.
Cardiovascular Research 03/2006; 69(2):512-9. · 6.06 Impact Factor
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ABSTRACT: Angiogenesis is a promising new therapy for the treatment of patients with coronary artery disease who are not candidates for standard revascularization techniques. The concept of therapeutic angiogenesis is based upon improving myocardial function by increasing blood flow to ischemic areas of the heart. Angiogenic growth factors, including fibroblast growth factor and vascular endothelial growth factor, have been shown to induce functionally significant angiogenesis in preclinical studies. Both protein and gene formulations are under investigation; currently, protein-based therapy is considered the more practical form of therapy. The delivery of these growth factors is another aspect of angiogenic therapy under development, with several techniques used in clinical trials. However, the optimal method of delivery with regard to tissue specificity and duration of exposure is not yet defined. Despite encouraging preclinical data, the results of clinical trials so far have shown only, if any, modest improvements in cardiac function and clinical outcome. Further randomized, double-blind, placebo-controlled trials are necessary to support angiogenesis as a therapy for ischemic cardiac disease.
Current Treatment Options in Cardiovascular Medicine 03/2002; 4(1):65-74.
