Nuisance and alarming bleeding do not correlate with on-treatment platelet reactivity.

AIMS: We hypothesized that patients with a history of either alarming or nuisance bleeding events, compared to those with no history of bleeding, would have lower levels of on-treatment platelet reactivity (aspirin and a thienopyridine). METHODS AND RESULTS: In total, 42 patients with no bleeding, 34 with nuisance bleeding, and 14 with alarming bleeding underwent platelet reactivity testing 1 month to 1 year after PCI with light transmission aggregometry (LTA 5 and 20 µM adenosine disphosphate [ADP]), vasodilator stimulated phosphoprotein phosphorylation (VASP) and VerifyNow P2Y12. Clinical and demographic characteristics of the 3 groups were generally similar, except that patients with alarming bleeding were less likely to be Caucasian; only 6 patients (6.7%) were taking prasugrel. There was considerable overlap between no bleeding, nuisance bleeding and alarming bleeding groups with respect to on-treatment platelet reactivity. Furthermore, there was no difference in the median platelet reactivity values for all assays. Prevalence of high on-treatment platelet reactivity did not differ among the 3 groups; 32.6% of patients had high on-treatment platelet reactivity as measured by LTA with 5 µM ADP (P=.91); 40.0% as measured by VASP (P=.35); and 35.6% as measured by VerifyNow P2Y12 (P=.61). CONCLUSION: The use of platelet reactivity assays to identify patients on thienopyridine therapy at higher risk of bleeding is an unfounded strategy.

Safety and efficacy of everolimus-eluting stents versus paclitaxel-eluting stents in a diabetic population.

OBJECTIVES: This study aimed to analyze the use of everolimus-eluting stents (EES) and paclitaxel-eluting stents (PES) in an unrestricted diabetic population and to compare the performance of these two drug-eluting stents. BACKGROUND: EES have demonstrated superiority in efficacy when compared to PES in a general population. However, it is controversial whether this superiority holds true in a diabetic population. METHODS: From March 2004 to May 2010, 968 patients with consecutive diabetes who underwent percutaneous coronary intervention and implantation of an EES (n = 388) or PES (n = 580) at our institution. In-hospital, 1-month, 6-month, and 1-year clinical outcomes were analyzed and compared. Correlates of major adverse cardiac events (MACE) were identified. RESULTS: Baseline clinical characteristics were similar between stent types except for more family history of coronary artery disease in the PES group and more insulin-dependent diabetes and unstable angina at initial diagnosis in the EES group. The PES group had higher number of lesions treated, longer stents used, and a higher proportion of intravascular ultrasound and glycoprotein IIb/IIIa inhibitor use. The EES group had more type C and distal lesions. There was higher target lesion revascularization (TLR)-MACE in the PES group (3.3% vs. 1.0%, P = 0.03) as well as a higher rate of stent thrombosis (ST) (8 patients vs. 0 in the EES group, P = 0.03). ST continued to be higher in the PES group at 6 and 12 months and mortality was higher at 12 months in the PES group (9.4% vs. 5.2%, P = 0.02). After adjustment, no significant differences were found between stent types on Cox regression analysis for hazard ratios at 1-year follow-up of TLR-MACE. CONCLUSIONS: In a diabetic population undergoing PCI, the use of an EES compared to PES was associated with lower rates of stent thrombosis; but after adjustment the composite TLR-MACE at 1 year was similar between both stents.

Impact of drug-eluting stents on distal vessels.

BACKGROUND: Previous studies have not addressed vessel response >5 mm distal to the stent edge. Therefore, we investigated the impact of paclitaxel-eluting stents (PES) versus bare metal stents (BMS) on distal vessels in the serial intravascular ultrasound substudies of TAXUS IV, V, and VI. METHODS AND RESULTS: TAXUS IV, V, and VI were double-blind, randomized, multicenter, controlled trials comparing PES with BMS. In their intravascular ultrasound substudies, 103 patients (54 BMS, 49 PES) had intravascular ultrasound data ≥10 mm distal to the stent both postprocedure and at 9 months follow-up. Baseline characteristics were similar between the 2 groups. Multilevel modeling was used to account for the variation between patients and within patients among distal segments. Effect of stent type, time, and their interaction was tested using a mixed effect model controlling for distal segments. Postprocedure lumen and vessel were not significantly different between PES versus BMS; however, lumen (P=0.006) and vessel (P=0.0001) were significantly reduced for BMS at 9-month follow-up but not for PES. Conversely, there was a significant plaque increase from postprocedure to 9-month follow-up for PES (P=0.0008) but not for BMS. These vessel responses were statistically consistent among 0- to 5-mm versus 5- to 10-mm versus 10- to 15-mm segments distal to the stent in both groups. CONCLUSIONS: PES use was associated with plaque increase from baseline to 9-month follow-up >5 mm distal to the stent along with positive remodeling, whereas BMS use was associated with negative remodeling and no plaque increase. These vessel responses were consistent in 5-mm long subsegments: 0 to 5 mm versus 5 to 10 mm versus 10 to 15 mm distal to the stent. CLINICAL TRIAL REGISTRATION: URL: HTTP://WWW.CLINICALTRIAL.GOV. Unique identifiers: TAXUS IV: NCT00292474; TAXUS V: NCT00301522; TAXUS VI: NCT00297804.

In vivo comparison of a polymer-free Biolimus A9-eluting stent with a biodegradable polymer-based Biolimus A9 eluting stent and a bare metal stent in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries.

OBJECTIVES: To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries. METHODS: Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry. RESULTS: The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both). CONCLUSION: This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia.

Correlation between light transmission aggregometry, VerifyNow P2Y12, and VASP-P platelet reactivity assays following percutaneous coronary intervention.

BACKGROUND: High on-treatment platelet reactivity is an established risk factor for adverse cardiac events in patients taking clopidogrel following percutaneous coronary intervention (PCI). METHODS: Two hundred patients underwent platelet reactivity testing with VerifyNow P2Y12, vasodilator-stimulated phosphoprotein phosphorylation (VASP), and light transmission aggregometry (LTA) with both 5 and 20 µM of adenosine diphosphate (ADP) following PCI. High on-treatment platelet reactivity was defined as a maximum platelet aggregation ≥46% for LTA ADP 5 µM or ≥60% for 20 µM; platelet reactivity index (PRI) ≥50% for VASP; and platelet reactivity units ≥235 for VerifyNow. Correlation between assays was tested using Spearman coefficients (ρ); agreement among tests in regards to high on-treatment platelet reactivity was evaluated with Kappa statistics (κ). RESULTS: All Spearman correlations had P values <0.001, although ρ ranged from 0.60-0.86. The incidence of high on-treatment platelet reactivity was 39.3% with VASP, 27.3% with VerifyNow, 23.1% with LTA ADP 5 µM, and 16.2% with LTA ADP 20 µM. The strongest correlation was between LTA ADP 5 µM and LTA ADP 20 µM (κ= 0.53, 95% CI 0.37-0.68); the weakest was between VASP and LTA ADP 5 µM (κ= 0.33, 95% CI 0.19-0.47). Overall, the level of agreement between assays was in the moderate to poor range. CONCLUSION: Despite evidence that the most commonly used tests are correlated, agreement among tests is modest at best and demonstrates they are not interchangeable.

In vivo virtual histology intravascular ultrasound comparison of neointimal hyperplasia within drug-eluting- versus bare metal stents.

BACKGROUND: The process of in-stent neointimal hyperplasia (NIH) between drug-eluting stents (DES) and bare metal stents (BMS) might be different. We compared in vivo composition of in-stent NIH between DES and BMS using virtual histology-intravascular ultrasound (VH-IVUS). METHODS AND RESULTS: Volumetric VH-IVUS was used to compare in-stent NIH between 23 DES and 15 BMS in 30 patients who underwent coronary angiography because of angina. The inner and outer VH-IVUS contours were drawn in a way to avoid the stent strut artifacts. Cross-sectional analysis was done at every VH-IVUS frame within the stent, thereby allowing volumetric measurement of stent, lumen, and NIH and its components. Baseline characteristics and IVUS measurements were similar between DES and BMS groups. The duration of follow-up was similar between DES (median 38 months [interquartile range, 7-59]) vs. BMS (median 40 months [interquartile range, 7-99]), (p=0.26). % necrotic core (NC) volume was significantly higher in DES than BMS: 19.5 [16.3, 25.6] vs. 12.1 [8.2, 18.5] (p=0.006). %NC volume significantly increased with time in BMS (p=0.007), but not in DES (p=0.24) so that at any given time point, %NC in DES was greater than in BMS. After adjustment for baseline differences, only DES (p=0.003) and stent age (p=0.043) were independent predictors of %NC volume. VH-IVUS in-stent thin-cap fibroatheromas were detected only in the DES group: 34.8% vs. 0%, p=0.013. CONCLUSION: In vivo composition of in-stent NIH between DES and BMS was different, suggesting that the process of in-stent NIH in DES and BMS is diverse.

Relation of body mass index to on-treatment (clopidogrel + aspirin) platelet reactivity.

Previous research has suggested that obesity is associated with increased high on-treatment platelet reactivity. We therefore tested platelet reactivity in 251 patients with VerifyNow P2Y12, vasodilator-stimulated phosphoprotein phosphorylation, and light transmission aggregometry with adenosine diphosphate 5 and 20 µM 6 to 24 hours after percutaneous coronary intervention. High on-treatment platelet reactivity was defined as a maximum platelet aggregation ≥46% for light transmission aggregometry with adenosine diphosphate 5 µM or ≥60% for 20 µM, platelet reactivity index ≥50% for vasodilator-stimulated phosphoprotein phosphorylation, and P2Y12 reaction units ≥235 for VerifyNow. The relation between body mass index (BMI) and platelet reactivity values was examined with Spearman coefficients; BMI and high on-treatment platelet reactivity were assessed with Student's t test. Multivariable logistic regression for high on-treatment platelet reactivity was also performed. Average BMI was 30.3 ± 5.9 kg/m² and 44% of patients had a BMI ≥30 kg/m². Overall there was very poor correlation between BMI and on-treatment platelet reactivity, with Spearman coefficients ranging from 0.08 to 0.10. BMI was also not associated with the various definitions of high on-treatment platelet reactivity. Multivariable logistic regressions showed no association between BMI and high on-treatment platelet reactivity. In conclusion, and contrary to previous reports, we found no association whatsoever between BMI and on-treatment platelet reactivity as quantified by a variety of platelet function tests.

Platelet reactivity in diabetic patients subjected to acute exercise stress test.

BACKGROUND: Previous studies have reported ambiguous results regarding the effect of acute exercise on platelet reactivity in healthy and cardiac patients. OBJECTIVES: We aimed to assess platelet reactivity among diabetic patients before and immediately after an acute exercise stress test. METHODS: Patients (controls: mean age 53.1 ± 12.1 years; four males; body mass index 27.0 ± 5.7 kg/m(2); HbA(1c) 6.0 ± 1.1%, n = 8) and diabetic patients (52.9 ± 11.3; six males; body mass index 30.7 ± 2.2 kg/m(2); HbA(1c) 7.8 ± 1.7%, n = 8) referred for diagnostic nuclear exercise stress test were recruited. Blood samples obtained at rest and immediately post-exercise were stimulated with adenosine diphosphate (ADP), collagen and arachidonic acid. Expression of CD41 (pan-platelet marker) and CD62p (platelet stimulation marker) were measured by flow cytometry. Aspirin responsiveness was measured using VerifyNow. RESULTS: Although peak systolic blood pressure was significantly higher in the diabetics compared with nondiabetics (186.3 ± 25.4 vs. 157.1 ± 19.1, respectively, P = .028), peak exercise heart rate was similar (156.5 ± 8.3 vs. 155.5 ± 12.1 for diabetics and nondiabetics, respectively). No differences were observed between groups for aspirin resistance. Platelet stimulation with ADP exhibited significantly lower CD62p-positive cell population (%) in the diabetic patients both prior to and following the exercise stress test (P = .03). In addition, although not significant, platelet stimulation was higher post-exercise in the diabetic patients (6.3 ± 4.7% vs. 12.0 ± 5.6%, for pre- and post-exercise, respectively, P = .2) with no difference in controls (9.2 ± 5.5% vs. 8.9 ± 5.9%). CONCLUSION: Platelet stimulation in diabetic patients is blunted and might be explained by the prolonged exposure of platelets to multiple diabetic risk factors.

Currently available methods for platelet function analysis: advantages and disadvantages.

Platelets play a pivotal role in normal hemostasis, and derangement of their function can lead to hemorrhage or thrombosis. While progress has been made in elucidating the molecular mechanisms leading to platelet adhesion, aggregation, shape change and secretion, clinically useful tests of platelet function have lagged. A number of dedicated platelet function instruments that are much simpler to use and are now utilized as point-of-care (POC) instruments have now become available. Some instruments have been incorporated into routine clinical use and can be utilized not only as general screening tests of platelet function but as monitors of antiplatelet therapy and to potentially assess both risk of bleeding and/or thrombosis. Some of the factors that differentiate these tests are sample volume requirements, the use of whole blood, the presence of shear, POC status, need for a technician and expense. The following is a review of some of the commonly used tests of platelet function, along with their advantages and disadvantages. The tests and pertinent instruments described are based on aggregation, shear stress platelet contribution to clot strength, flow cytometry and serum and urinary thromboxane metabolites.

Biodegradable and bioabsorbable stents.

Angioplasty of the coronary arteries has made significant headway in the past 20 years as a treatment for atherosclerotic vascular disease. Though drug-eluting stents are effective, they appear to invoke a thrombogenic response. Biodegradable stents are a promising alternative to permanent stents and may eventually be used to solve the lingering problem of in-stent restenosis. Additionally, fully degradable stents have the ability to deliver more drugs to the target site than a thin coating of drug on metallic stents. A variety of degradable materials have been studied for stent design, including polyesters, polycarbonates, bacterial-derived polymers, and corrodible metals. The ideal biodegradable stent would be reliably deployable under fluoroscopic guidance and situate into the target lesion with minimal endovascular trauma. The stent should degrade into nontoxic byproducts and invoke a minimal degree of inflammation at the target site. Finally, the stent itself should disappear within months (to years) without significant displacement from the deployment site. Although initial data from clinical trials have been sufficient to bring biodegradable materials into the realm of feasibility, future research is undoubtedly necessary to resolve the critical issues of inflammation and mechanical stability.

The clinical significance of hematocrit values before and after percutaneous coronary intervention.

BACKGROUND: The presence of anemia before percutaneous coronary intervention (PCI) and/or the development of bleeding or anemia after PCI has been shown to increase mortality and morbidity rates. However, the definition of severe anemia varies among reports. In this context, the roles of hematocrit at baseline and hematocrit drop after PCI, both treated as continuous variables, have not yet been described in the risk assessment of patients undergoing PCI. METHODS: We analyzed 6,025 consecutive patients who underwent PCI from 2003 to 2007 at our institution. In the entire population, we analyzed by multivariable Cox analysis the clinical value of both hematocrit at baseline and hematocrit drop after PCI as continuous variables. The primary end point was the composite of death and myocardial infarction at 1-year follow-up. RESULTS: The rate of the 1-year composite end point death/myocardial infarction increased continuously every time hematocrit at baseline decreased and/or hematocrit dropped after PCI. After multivariable adjustment using the relevant covariables, both hematocrit at baseline (hazard ratio = 0.92, P < .001) and hematocrit drop after PCI (hazard ratio = 1.11, P < .001) strongly predicted the primary end point at 1-year follow-up. CONCLUSION: Hematocrit at baseline and the drop after PCI should be recognized as important risk factors for adverse outcomes after PCI. The inclusion of hematocrit or hemoglobin values as continuous variables in a risk-stratification scheme should be strongly considered.

Paclitaxel-eluting balloon: from bench to bed.

Since the first clinical angioplasty by Gruntzig in 1977, restenosis has been the primary drawback of percutaneous coronary intervention (PCI). In the balloon era. restenosis was correlated with elastic recoil and negative remodeling of the arterial wall. Later, introduction of stents proved to be a significant advance in reducing the elastic recoil and negative remodeling at the treatment site but stimulated proliferation, migration of smooth muscle cells, and neointimal hyperplasia, thereby generating a new type of restenosis, in-stent restenosis. Brachytherapy and drug-eluting stents (DES) may be considered the two breakthroughs against neointimal hyperplasia. However, concerns about stent thrombosis and incomplete elimination of in-stent restenosis with DES in complex lesions and patients justify the pursuit of research in this field. Non-stent based local drug delivery and particularly the use of paclitaxel-eluting balloons could be one of these strategies. We aimed to review the concept, preclinical-, and clinical data available with non-stent based local drug delivery and, in particular, with paclitaxel-eluting balloons.

Effects of exogenous peripheral-blood-derived endothelial progenitor cells or unfractionated bone-marrow-derived cells on neointimal formation and inflammation in cholesterol-fed, balloon-denuded, and radiated iliac arteries of inbred rabbits.

BACKGROUND: Injection of bone marrow cells (BMC) and endothelial progenitor cells (EPC) or application of stem-cell-mobilizing factors has been associated both with reduction or exacerbation of atherosclerosis and with unstable plaque phenotype. The discrepancies may reflect the cell type, dosing, duration, and route of administration of cells in these studies. The aim of this study was to determine the effects of peripheral-blood-derived endothelial progenitor cells (PBEPC) or unfractionated BMC obtained from inbred siblings on neointimal formation and inflammation in cholesterol-fed, balloon-denuded, and radiated rabbit iliac arteries. METHODS: Rabbits were fed a 1.0% cholesterol diet for 14 days, followed by endothelial denudation in both iliac arteries, and continued on a 0.15% cholesterol diet. On day 42, denuded areas were radiated, and animals were randomized. The first group received PBEPC (n=5), the second group received BMC (n=4), and the third group received heparinized (20 IU) saline (Control; n=3). PBEPC were characterized by flow cytometry. Cells (5x10(6)) or saline was administered twice through the ear vein: the first time at 1 h after radiation and the second time at 2 weeks after radiation. Four weeks after radiation, the animals were sacrificed, and arterial segments were processed for morphometry. RESULTS: Administration of BMC or PBEPC from inbred siblings had no adverse effect. Lumen area (0.93+/-0.53 mm(2)), neointimal area (0.65+/-0.29 mm(2)), percent stenosis (44+/-21), and macrophage score (0.6+/-0.3) in controls were similar to those in cell-treated groups. CONCLUSION: This study demonstrates that, in the current animal model, either PBEPC or BMC failed to affect neointimal formation or inflammation.

Coating bioabsorption and chronic bare metal scaffolding versus fully bioabsorbable stent.

Advances in coronary stent technology, including refinement of the stent alloy, strut thickness, stent geometry, passive coating, and drug elution, have dramatically enhanced the safety and efficacy of percutaneous coronary intervention (PCI) with stenting. Stents are currently used in over 90% of coronary interventions and the use of drug-eluting stents (DES) has been disseminated to more complex lesion subsets such as total occlusions, long lesions, bifurcation lesions, and for patients with acute myocardial infarction. DES continue to demonstrate reduction in restenosis and the need for repeat revascularisation but are associated with delayed healing and re-endothelialisation, which have led to an increased rates of late stent thrombosis, dependency on prolonged dual antiplatelet therapy, impaired in-vessel reactivity, and chronic inflammation. As scientists and clinicians better understand the mechanism for late restenosis and stent thrombosis, a variety of solutions in regard to stent technology have been proposed, including stent coating, polymer bioabsorption, and fully biodegradable stents. Bare metal stents were improved by the reduction of strut thickness, changes in stent geometry, and the addition of passive coating, which lead to improvements in efficacy and reduction of restenosis. In addition, there is continued improvement in the polymer technology for DES, including new biocompatible, thinner durable polymers, and bioabsorbable polymers that completely bioabsorb within 3-12 months after stent implantation. These features potentially minimise the chronic inflammatory response and late stent thrombosis. Finally, fully bioabsorbable stents, both polymeric and metallic, continue to be developed in order to eliminate any late stenting effects and potentially may enable complete vessel restoration. This manuscript will discuss the wide variety of new stent technologies and compare and contrast durable metallic and polymeric stents to current biodegradable stent technology.

Optical coherence tomography and intravascular ultrasound imaging of bioabsorbable magnesium stent degradation in porcine coronary arteries.

BACKGROUND: Absorbable metallic stents (AMS) composed of magnesium alloy were designed to complete degradation within 90-120 days. Among the potential advantages of these stents, when compared to conventional stents, are the elimination of late stent thrombosis, chronic inflammation, and artifacts during noninvasive imaging. METHODS: Magnesium-based AMS were deployed in juvenile domestic pig coronary arteries. Angiography, optical coherence tomography (OCT), and intravascular ultrasound (IVUS) were performed before and after implant and then at 28 days and 3 months following stenting. The animals were sacrificed at 28 days or 3 months following stent implantation. Stented vessels were harvested and analyzed by histomorphometry. RESULTS: Over time, OCT, IVUS, and histologic images revealed a progressive degradation of the stents. Mean stent strut width in the OCT images after implantation was 0.24+/-0.032 mm, then decreased to 0.12+/-0.007 mm (P<.0001) at 28 days and to 0.151+/-0.032 mm at 3 months (P<.0001 vs. implant, P=.078 vs. 28 days). CONCLUSION: Magnesium-based AMS degrade over a 3-month time period in a porcine model. Its structure is not apparent by angiography but is well-visualized by OCT and IVUS. OCT allowed quantitative assessment of stent degradation.

The virtual histology intravascular ultrasound appearance of newly placed drug-eluting stents.

Intravascular ultrasound (IVUS) is used before and after intervention and at follow-up to assess the quality of the acute result as well as the long-term effects of stent implantation. Virtual histology (VH) IVUS classifies tissue into fibrous and fibrofatty plaque, dense calcium, and necrotic core. Although most interventional procedures include stent implantation, VH IVUS classification of stent metal has not been validated. In this study, the VH IVUS appearance of acutely implanted stents was assessed in 27 patients (30 lesions). Most stent struts (80%) appeared white (misclassified as "calcium") surrounded by red (misclassified as "necrotic core"); 2% appeared just white, and 17% were not detectable (compared with grayscale IVUS because of the software-imposed gray medial stripe). The rate of "white surrounded by red" was similar over the lengths of the stents; however, undetectable struts were mostly at the distal edges (31%). Quantitatively, including the struts within the regions of interest increased the amount of "calcium" from 0.23 +/- 0.35 to 1.07 +/- 0.66 mm(2) (p <0.0001) and the amount of "necrotic core" from 0.59 +/- 0.65 to 1.31 +/- 0.87 mm(2) (p <0.0001). Most important, because this appearance occurs acutely, it is an artifact, and the red appearance should not be interpreted as peristrut inflammation or necrotic core when it is seen at follow-up. In conclusion, acutely implanted stents have an appearance that can be misclassified by VH IVUS as "calcium with or without necrotic core." It is important not to overinterpret VH IVUS studies of chronically implanted stents when this appearance is observed at follow-up. A separate classification for stent struts is necessary to avoid these misconceptions and misclassifications.

PhotoPoint photodynamic therapy promotes stabilization of atherosclerotic plaques and inhibits plaque progression.

OBJECTIVES: The purpose of this study was to determine how photodynamic therapy (PDT) promotes stabilization and reduction of regional atherosclerosis. BACKGROUND: Photodynamic therapy, a combination of photosensitizer and targeted light to promote cell apoptosis, has been shown to reduce atherosclerotic plaque inflammation. METHODS: Forty New Zealand White rabbits were fed with cholesterol. The iliac arteries were balloon denuded and randomized to receive either PhotoPoint PDT treatment (photosensitizer and light) (Miravant Medical Technologies, Santa Barbara, California), photosensitizer (MV0611) alone, or light alone and were then compared at 7 and 28 days. Arteries were examined for evidence of plaque volume, cell number, macrophage and smooth muscle cell (SMC) content, and plaque cell proliferation. RESULTS: Compared with contralateral iliac artery controls at 7 days, plaque progression was reduced by approximately 35% (p < 0.01); plaque progression was further reduced to approximately 53% (p < 0.01) by 28 days, leading to an increase in lumen patency (p < 0.05). At 7 days after PDT, percent plaque area occupied by macrophages decreased by approximately 98% (p < 0.001) and SMCs by approximately 72% (p < 0.05). At 28 days after PDT, removal of macrophages was sustained (approximately 92% decrease, p < 0.001) and plaques were repopulated with non-proliferating SMCs (approximately 220% increase, p < 0.001). There was no evidence of negative or expansive arterial remodeling, thrombosis, or aneurysm formation. CONCLUSIONS: Photodynamic therapy simultaneously reduces plaque inflammation and promotes repopulation of plaques with a SMC-rich stable plaque cell phenotype while reducing disease progression. These early healing responses suggest that PDT is a promising therapy for the treatment of acute coronary syndromes.

Role of urotensin II in atherosclerotic cardiovascular diseases.

Urotensin II (U-II) is a powerful vasoconstrictor peptide with a potency greater than that of endothelin 1. Its plasma level correlates positively with body weight and is raised in diabetes, renal failure, hypertension, and other cardiovascular diseases, including congestive heart failure and carotid atherosclerosis. Experimental and clinical studies have revealed increased expression of U-II and U-II receptor (UT) in animals with experimentally induced myocardial infarction, heart failure, and in patients with hypertension, atherosclerosis, and diabetes, suggesting a potential role for U-II in coronary artery disease. Peptide and nonpeptide UT ligands have been shown to be effective in antagonizing the effects of U-II in the cardiovascular system. This article aims to review recent advances in physiology and pathophysiology of U-II with particular reference to its role in atherosclerotic cardiovascular diseases.

Effect of clopidogrel on neointimal formation and inflammation in balloon-denuded and radiated hypercholesterolemic rabbit iliac arteries.

BACKGROUND: Platelet-derived peptide and nonpeptide growth factors are known to play pivotal roles in neointimal proliferation. Along with its antiplatelet activity of reducing P-selectin and hs-CRP, clopidogrel has also been shown to have anti-inflammatory properties. The aim of this study is to find out by modulating inflammation if clopidogrel can affect neointima formation in balloon-denuded iliac arteries of hypercholesterolemic rabbits. METHODS AND RESULTS: Rabbits were fed with 1% cholesterol diet with (n = 20) or without (n = 20) clopidogrel (10 mg/kg body weight) for 7 days followed by balloon-denudation of endothelial layer in both the iliac arteries and continued on 0.15% cholesterol diet with or without clopidogrel. Four weeks later, the denuded area in both iliac arteries was radiated (n = 11, cholesterol-only group; n = 9, clopidogrel group) or sham treated (n = 10 from each group). Four weeks after radiation, animals were sacrificed and arterial segments were processed for morphometry. In the sham-treated clopidogrel group, neointimal area, percent stenosis, and macrophage score were 39% (P = 0.01), 32% (P = 0.02), and 50% (P = 0.02) smaller, respectively, when compared to the cholesterol-only group (0.48 +/- 0.18, 32.42 +/- 13.04, and 1.5 +/- 0.83). There were no differences in the radiated group (0.89 +/- 0.32, 50.34 +/- 13.00, and 1.88 +/- 1.27 vs. 0.93 +/- 0.38, 59.41 +/- 11.41, and 2.00 +/- 0.74, respectively). CONCLUSION: This study demonstrates that clopidogrel reduces inflammation and neointimal formation in balloon-denuded iliac arteries of hypercholesterolemic rabbits.