Beusekom, H.M.M. van

Do we have a future with transcatheter adventitial delivery of stem cells? (Article)

2012-12-05T00:00:00Z

Critically evaluating the methodology of the adventitial delivery of stem cells, some specific options should be underlined. Adventitia as the most superficial layer, consisting of connective tissue has to be distinguished of perivascular tissues. By strict definition, an adventitia is the outermost connective tissue covering any organ, or vessel. The "adventitial" delivery of stem cells with a 1 mm micro-needle means a delivery to superficial so called pericardial myocardium, perivascular fat tissues, including a risk of perforation and injury of soft tissues. In fact, the mapping of the artery with visualization of the three-layer vessel structure and perivascular tissues as well as pericardial space with the state-of-the-art imaging approaches including IVUS (intravascular ultrasound) or OCT (optical coherence tomography) allows to find an optimal site for injection, prevents any technical complications and improves efficacy. NOGA magnetic navigation system still remains the optimal tool for the stem cell delivery to myocardium with appropriate visualization of necrosis and peri-infarct tissues. Potentially, more advanced imaging provides a chance to deliver infusate to the adventitial layer, which is a gate to the vessel wall for inflammation as well as a source of stem and progenitor cells, and myofibroblasts.

Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes (Article)

2012-01-01T00:00:00Z

Detailed evaluation of coronary function early in diabetes mellitus (DM)-associated coronary artery disease (CAD) development is difficult in patients. Therefore, we investigated coronary conduit and small artery function in a preatherosclerotic DM porcine model with type 2 characteristics. Streptozotocin-induced DM pigs on a saturated fat/cholesterol (SFC) diet (SFC + DM) were compared with control pigs on SFC and standard (control) diets. SFC + DM pigs showed DM-associated metabolic alterations and early atherosclerosis development in the aorta. Endothelium-dependent vasodilation to bradykinin (BK), with or without blockade of nitric oxide (NO) synthase, endothelium-independent vasodilation to an exogenous NO-donor (S-nitroso-N-acetylpenicillamine), and vasoconstriction to endothelin (ET)-1 with blockade of receptor subtypes, were assessed in vitro. Small coronary arteries, but not conduit vessels, showed functional alterations including impaired BK-induced vasodilatation due to loss of NO (P < 0.01 vs. SFC and control) and reduced vasoconstriction to ET-1 (P < 0.01 vs. SFC and control), due to a decreased ETa receptor dominance. Other vasomotor responses were unaltered. In conclusion, this model demonstrates specific coronary microvascular alterations with regard to NO and ET-1 systems in the process of early atherosclerosis in DM. In particular, the altered ET-1 system correlated with hyperglycemia in atherogenic conditions, emphasizing the importance of this system in DM-associated CAD development.

Dietary saturated fat/cholesterol, but not unsaturated fat or starch, induces C-reactive protein associated early atherosclerosis and ectopic fat deposition in diabetic pigs (Article)

2011-07-14T00:00:00Z

Background: Diabetes is thought to accelerate cardiovascular disease depending on the type of diet. This study in diabetic subjects was performed to investigate the metabolic, inflammatory and cardiovascular effects of nutritional components typically present in a Western, Mediterranean or high glycaemic diet.Methods: Streptozotocin-diabetic pigs (~45 kg) were fed for 10 weeks supplemental (40% of dietary energy) saturated fat/cholesterol (SFC), unsaturated fat (UF) or starch (S) in an eucaloric dietary intervention study.Results: Fasting plasma total, LDL and HDL cholesterol concentrations were 3-5 fold higher (p < 0.01) in SFC compared to UF and S pigs. Fasting plasma NEFA concentrations (mmol/L) were highest (p < 0.05) in SFC (1.09 ± 0.17), intermediate in UF (0.80 ± 0.14) and lowest in S pigs (0.58 ± 0.14) whereas plasma glucose (~13 mmol/L), triglyceride (~0.5 mmol/L) and insulin (~24 pmol/L) concentrations were comparable among SFC, UF and S pigs. The postprandial response area under the curves (AUC, 0-4 h) for glucose but not for insulin and triglyceride responses were intermediate in SFC (617 ± 144) and lowest (p < 0.05) in UF (378 ± 157) compared to S pigs (925 ± 139). Fasting hepatic glucose production, hepatic and peripheral insulin sensitivity and blood pressure were not different among pigs. C-reactive protein (CRP) concentrations (mg/L) were highest (p < 0.05) in SFC (25 ± 4), intermediate in S (21 ± 3) and lowest in UF pigs (14 ± 2). Liver weights, liver and muscle triglyceride concentrations, and the surface area of aorta fatty streaks were highest (p < 0.01) in SFC pigs. A positive correlation between postprandial plasma CRP and aorta fatty streaks was observed in SFC pigs (R2= 0.95). Retroperitoneal fat depot weight (g) was intermediate in SFC (260 ± 72), lowest in S (135 ± 51) and highest (p < 0.05) in UF (571 ± 95) pigs.Conclusion: Dietary saturated fat/cholesterol induces inflammation, atherosclerosis and ectopic fat deposition whereas an equally high dietary unsaturated fat load does not induce these abnormalities and shows beneficial effects on postprandial glycaemia in diabetic pigs.

Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting bioresorbable vascular scaffolds in a porcine coronary artery model: An attempt to decipher the human optical coherence tomography images in the ABSORB trial (Article)

2010-11-30T00:00:00Z

Background-: With the use of optical coherence tomography (OCT), alterations of the reflectance characteristics of everolimus-eluting bioresorbable vascular scaffold (BVS) struts have been reported in humans. In the absence of histology, the interpretation of the appearances of the struts by OCT remains speculative. We therefore report OCT findings with corresponding histology in the porcine coronary artery model immediately after and at 28 days and 2, 3, and 4 years after BVS implantation. Methods and results-: Thirty-five polymeric BVS (3.0×12.0 mm) were singly implanted in the main coronary arteries of 17 pigs that underwent OCT and were then euthanized immediately (n=2), at 28 days (n=2), at 2 years (n=3), at 3 years (n=5), or at 4 years (n=5) after implantation. All BVS-implanted arteries in these animals were evaluated by histology except for 5 arteries examined at 2 years with gel permeation chromatography to assess the biodegradation of the polymeric device. Fourteen arteries with BVS from an additional 6 pigs were examined by gel permeation chromatography at 1 (n=1), 1.5 (n=2), and 3 (n=2) years. Corresponding OCT and histology images were selected with the distal and proximal radiopaque markers used as landmarks. At 28 days, by OCT, 82% of struts showed sharply defined, bright reflection borders, best described as a box-shaped appearance. Histologically, all struts appeared intact with no evidence of resorption. At 2 years, by OCT, 60±20 struts were discernible per BVS with 80.4% of the strut sites as a box-shaped appearance. Despite their defined appearance by OCT, by histology, these structures appeared to be composed of proteoglycan, with polymeric material being at such low level as to be no longer quantifiable by chromatography. At 3 years, by OCT, recognizable struts decreased to 28±9 struts per BVS: 43.7% showed dissolved black box; 34.8%, dissolved bright box; 16.1%, open box; and 5.4%, preserved box appearance. Histology shows that connective tissue cells within a proteoglycan-rich matrix replaced the areas previously occupied by the polymeric struts and coalesced into the arterial wall. At 4 years, by OCT, 10±6 struts were recognizable as either dissolved black or dissolved bright box. In histology, these struts are minimally discernible as foci of low-cellular-density connective tissue. Relative to the prediction of histological type by OCT appearance, the preserved box appearance of OCT corresponds well with 2-year histology (86.4%), whereas the dissolved bright and black box appearances correspond to 3-year histology (88.0% and 90.7%, respectively). Struts indiscernible by OCT correspond to the integrated strut footprints seen at 4 years (100%). Conclusions-: Struts that are still discernible by OCT at 2 years are compatible with largely bioresorbed struts, as demonstrated by histological and gel permeation chromatography analysis. At 3 and 4 years, both OCT and histology confirm complete integration of the struts into the arterial wall.

Three-dimensional registration of histology of human atherosclerotic carotid plaques to in-vivo imaging (Article)

2010-08-01T00:00:00Z

An accurate spatial relationship between 3D in-vivo carotid plaque and lumen imaging and histological cross sections is required to study the relationship between biomechanical parameters and atherosclerotic plaque components. We present and evaluate a fully three-dimensional approach for this registration problem, which accounts for deformations that occur during the processing of the specimens. By using additional imaging steps during tissue processing and semi-automated non-linear registration techniques, a 3D-reconstruction of the histology is obtained.The methodology was evaluated on five specimens obtained from patients, operated for severe atherosclerosis in the carotid bifurcation. In more than 80% of the histology slices, the quality of the semi-automated registration with computed tomography angiography (CTA) was equal to or better than the manual registration. The inter-observer variability was between one and two in-vivo CT voxels and was equal to the manual inter-observer variability. Our technique showed that the angles between the normals of the registered histology slices and the in-vivo CTA scan direction ranged 6-56°, indicating that proper 3D-registration is crucial for establishing a correct spatial relation with in-vivo imaging modalities. This new 3D-reconstruction technique of atherosclerotic plaque tissue opens new avenues in the field of biomechanics as well as in the field of image processing, where it can be used for validation purposes of segmentation algorithms.

Specific coronary drug-eluting stents interfere with distal microvascular function after single stent implantation in pigs (Article)

2010-07-01T00:00:00Z

Objectives The aim of this study was to compare the effects of single drug-eluting stents (DES) on porcine coronary function distal to the stent in vivo and in vitro. Background The mechanism of endothelial dysfunction occurring in human coronary conduit arteries up to 9 months after DES implantation is unknown. Methods A sirolimus-eluting stent (SES), paclitaxel-eluting stent (PES), and a bare-metal stent (BMS) were implanted in the 3 coronary arteries of 11 pigs. After 5 weeks, in vivo responses in distal coronary flow to different doses of bradykinin (BK) and nitrates were measured. In vitro, vasodilation to BK and nitrates, as well as vasoconstriction to endothelin (ET)-1 were assessed in both distal coronary conduit and small arteries. In addition, contributions of nitric oxide (NO) and endotheliumderived hyperpolarizing factors (EDHFs) and cyclic guanosine monophosphate (cGMP) responses to BK-stimulation were determined in vitro. Results Both DES did not alter in vivo distal vasomotion. In vitro distal conduit and small arterial responses to BK were also unaltered; DES did not alter the BK-induced increase in cGMP. However, after NO synthase blockade, PES showed a reduced BK-response in distal small arteries as compared with BMS and SES (p < 0.05). The ET-1-induced vasoconstriction and vascular smooth muscle cell function were unaltered. Conclusions In this study of single stenting in healthy porcine coronaries for 5 weeks, SES did not affect distal coronary vascular function, whereas PES altered distal endothelial function of small arteries under conditions of reduced NO bioavailability. Therefore, specifically the EDH-component of microvascular function seems affected by PES.

Intriguing peri-strut low-intensity area detected by optical coherence tomography after coronary stent deployment (Article)

2010-06-18T00:00:00Z

Background: Although peri-strut low-intensity area (PLIA) is frequently observed on post-stenting optical coherence tomography (OCT) images, the histology associated with PLIA is undocumented. Methods and Results: The 36 porcine coronary lesions treated with bare-metal (BMS: n=16) or drug-eluting (DES: n=20) stents were assessed by OCT and histology at 28 days. DES showed a significantly higher incidence of PLIA than BMS. Also, +PLIA stents had greater neointima than -PLIA stents. Histological analysis revealed the existence of fibrinoid and proteoglycans at the site of PLIA. Conclusions: PLIA might be represented by the presence of fibrinoid and proteoglycans, and associated with neointimal proliferation after stenting.

Drug-Eluting Stent Endothelium. Presence or Dysfunction (Article)

2010-01-01T00:00:00Z

Optical coherence tomography patterns of stent restenosis (Article)

2009-08-01T00:00:00Z

Background: Stent restenosis is an infrequent but poorly understood clinical problem in the drug-eluting stent era. The aim of the study was to evaluate the morphologic characteristics of stent restenosis by optical coherence tomography (OCT). Methods: Patients (n = 24, 25 vessels) presenting with angiographically documented stent restenosis were included. Quantitative OCT analysis consisted of lumen and stent area measurement and calculation of restenotic tissue area and burden. Qualitative restenotic tissue analysis included assessment of tissue structure, backscattering and symmetry, visible microvessels, lumen shape, and presence of intraluminal material. Results: By angiography, restenosis was classified as diffuse, focal, and at the margins in 9, 11, and 5 vessels, respectively. By OCT, restenotic tissue structure was layered in 52%, homogeneous in 28%, and heterogeneous in 20%. The predominant backscatter was high in 72%. Microvessels were visible in 12%. Lumen shape was irregular in 28% and there was intraluminal material in 20%. The mean restenotic tissue symmetry ratio was 0.58 ± 0.19. Heterogeneous and low scattering restenotic tissue was more frequent in focal (45.5% and 54.5%, respectively) than in diffuse (0 and 11.1%) and margin restenosis (0 and 0%) (P = .005 for heterogeneous, P = .03 for low scattering). Restenosis patients with unstable angina symptoms presented more frequently irregular lumen shape (60 vs 6.7%, P = .007). Stents implanted ≤12 months ago had more frequently restenotic tissue with layered appearance (84.6% vs 16.7%, P = .003). Conclusions: We demonstrate the ability of OCT to identify differential patterns of restenotic tissue after stenting. This information could help in understanding the mechanism of stent restenosis.

Quinaprilat-eluting stents do not attenuate intimal thickening following stenting in porcine coronary arteries (Article)

2009-07-01T00:00:00Z

Objective: Vascular injury increases angiotensin-converting enzyme (ACE) activity in the vessel wall, and experimental evidence suggests that high-dose oral ACE inhibition reduces intimal hyperplasia following balloon angioplasty. Local drug delivery can achieve high local concentrations which may be especially efficacious in inhibiting tissue growth following stent implantation. The aim of this study was to evaluate the angiographic and histomorphologic effects of quinaprilat-eluting stents in normal porcine coronary arteries. Methods: Ten pigs received phosphorylcholine-coated stents in each of the three major coronary arteries: one loaded with 780 μg quinaprilat, one with the solvent and one non-loaded control. Quantitative angiography was performed before and after stenting and at 4 weeks follow-up. At this time point the stented arteries were also analyzed using histology and morphometry. Results: Repeated measures ANOVA yielded significantly smaller angiographic lumen in both quinaprilat and solvent groups: 2.62 ± 0.31 and 2.65 ± 0.31 mm, respectively versus control: 2.70 ± 0.32 mm at follow-up, p < 0.05. Histology confirmed this finding with an increment in intimal area (2.5 ± 0.86 mm2) and thickness (0.57 ± 0.29 mm) in the quinaprilat group; versus solvent (1.98 ± 0.57 mm20.4 ± 0.26 mm) and controls (1.92 ± 0.50 mm2and 0.41 ± 0.18 mm). Conclusion: Quinaprilat-eluting stents do not attenuate neointimal thickening following implantation in normal porcine coronary arteries, but rather show a tendency towards the opposite.

MAHOROBA, first-in-man study: 6-month results of a biodegradable polymer sustained release tacrolimus-eluting stent in de novo coronary stenoses (Article)

2009-06-01T00:00:00Z

AimsTo report the 4-month angiographic and 6-month clinical follow-up in first-in-man study using the tacrolimus-eluting bioabsorbable polymer-coated cobalt-chromium MAHOROBA™ stent.Methods and resultsA total of 47 patients with either stable angina or unstable angina, or silent myocardial ischaemia, based on a de novo coronary stenosis that could be covered by a single 18 mm stent in a native coronary artery with a diameter between 3.0 and 3.5 mm were enrolled at three sites. The primary endpoint was in-stent late loss at 4 months. The secondary endpoints include volume obstruction of the stents assessed by intravascular ultrasound (IVUS) at 4 months and major adverse cardiac events (MACE) at 6 months. Forty-seven patients were enrolled. Procedural success was achieved in 97.9. At 4-month follow-up, in-stent late loss was 0.99 ± 0.46 mm, whereas in-stent volume obstruction in IVUS was 34.8 ± 15.8. At 6 months, there were no deaths, but 2 patients suffered from a myocardial infarction and 11 patients required ischaemia-driven repeat revascularization. The composite MACE rate was 23.4.ConclusionThis tacrolimus-eluting stent failed to prevent neointimal hyperplasia, despite the theoretical advantages of the tacrolimus, which has less inhibitory effects on endothelial cells than smooth muscle cells.

Lowering the Dose of Sirolimus, Released From a Nonpolymeric Hydroxyapatite Coated Coronary Stent, Reduces Signs of Delayed Healing (Article)

2009-04-01T00:00:00Z

Objectives: The aim of this study was to compare efficacy of low- and high-dose sirolimus release (25, 40, or 100 μg) from hydroxyapatite (HAp) with Cypher (Cordis, Johnson & Johnson, Warren, New Jersey) (111 μg sirolimus) in porcine coronary arteries. Background: Polymer-based sirolimus-eluting stents such as Cypher interfere with vascular healing, probably due to the permanent presence of the polymer coating and the high sirolimus dose. The use of low-dose sirolimus and inert nonpolymeric but biodegradable coatings such as HAp might be more appropriate. Methods: Stents (n = 68) were implanted, guided by quantitative coronary angiography. All swine received clopidogrel and acetylsalicylic acid during 28 days follow-up. Safety of the coating in absence of drugs was studied by comparing HAp with and without a lipid-based release regulating layer (HApR) with bare-metal stents. Efficacy was studied by comparing the release of 25, 40, and 100 μg sirolimus with Cypher. Results: The safety study (without drug) revealed no differences in neointimal thickening in response to HAp and HApR with complete healing in all groups. Dose response analysis showed that neointimal thickening was similar in all groups regardless of sirolimus dose, with a normal appearance of the endothelium. There was, however, a dose-dependent increase in fibrinoid (p = 0.028), considered to be a marker of delayed healing. The Cypher stent induced the highest amount of fibrinoid. Conclusions: Reducing the dose of sirolimus eluting from a biocompatible HAp coated stent reduces signs of delayed vascular healing, without affecting neointimal hyperplasia.

Late stent thrombosis, endothelialisation and drug-eluting stents (Article)

2009-04-01T00:00:00Z

Drug-eluting stents (DES) significantly reduce the risk of restenosis after percutaneous coronary revascularisation, but an increased risk of late stent thrombosis (LST) has been put forward as a major safety concern. Meta-analysis of clinical trials, however, does not support this caveat. Even so, many interventional cardiologists think that LST is associated with DES and related to delayed endothelialisation. This hypothesis is based on autopsy studies and clinical intracoronary angioscopy. In autopsy studies, differences between endothelialisation of DES and baremetal stents (BMS) have been reported. Most preclinical studies, however, have failed to show any significant differences in endothelialisation between DES and BMS. Our own studies, using the porcine coronary artery model, also suggest that DES show no differences in re-endothelialisation. However, DES do delay vascular healing and induce endothelial dysfunction. This paper will review clinical and animal studies which consider re-endothelialisation and LST.

Endothelial dysfunction after drug eluting stent implantation. (Article)

2009-01-01T00:00:00Z

Endothelial dysfunction has been implicated in the pathological process of coronary artery disease as well as an adverse event after coronary drug eluting stent (DES) implantation. In this review, an overview will be given of the evidence to date regarding the effects of coronary DES on endothelial function obtained from both clinical and experimental studies. Stenting in general and DES seem to impair several aspects of endothelial function: provision of a permeable barrier function; modulation of adhesion, thrombosis and inflammation; and regulation of vascular tone. However, new insights show that the effects of DES can extend beyond the stent and peri-stent area: the vascular bed distal to the stent, starting with the distal conduit vessels up to the distal microvasculature, might be at risk. In addition, insight into the mechanism of DES induced endothelial dysfunction has been gained. To finalize this review, clinical complications and solutions of DES associated endothelial dysfunction will be discussed.

Optical Coherence Tomography Findings in Very Late (4 Years) Paclitaxel-Eluting Stent Thrombosis (Article)

2008-08-01T00:00:00Z

Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis (Article)

2008-04-01T00:00:00Z

Distal to a chronic coronary artery stenosis, structural remodeling of the microvasculature occurs. The microvascular functional changes distal to the stenosis have not been studied in detail. We tested the hypothesis that microvascular structural remodeling is accompanied by altered regulation of coronary vasomotor tone with increased responsiveness to endothelin-1. Vasomotor tone was studied in coronary microvessels from healthy control swine and from swine 3 to 4 months after implantation of an occluder that causes a progressive coronary narrowing, resulting in regional left ventricular dysfunction and blunted myocardial vasodilator reserve. Arterioles (≈200-μm passive inner diameter at 60 mm Hg) were isolated from regions perfused by the stenotic left anterior descending and normal left circumflex coronary arteries and studied in vitro. Passive pressure-diameter curves demonstrated reduced distensibility of subendocardial left anterior descending compared with subendocardial left circumflex or control arterioles, suggestive of structural remodeling. Myogenic responses were blunted in subendocardial left anterior descending compared with left circumflex arterioles, reflecting altered smooth muscle function. However, vasodilator responses to nitroprusside and bradykinin were not different in the endocardium, suggesting preserved endothelium and smooth muscle responsiveness. Finally, vasoconstrictor responses to endothelin-1 were enhanced in left anterior descending arterioles compared with left circumflex or control arterioles. Regional myocardial vascular conductance responses to bradykinin and endothelin in vivo confirmed the in vitro observations. In conclusion, inward remodeling of coronary microvessels distal to a stenosis is accompanied by exaggerated vasoconstrictor responses to endothelin-1. These structural and functional alterations may aggravate flow abnormalities distal to a chronic coronary artery stenosis.

Deubiquitylating enzyme UBP64 controls cell fate through stabilization of the transcriptional repressor tramtrack (Article)

2008-03-01T00:00:00Z

Protein ubiquitylation plays a central role in multiple signal transduction pathways. However, the substrate specificity and potential developmental roles of deubiquitylating enzymes remain poorly understood. Here, we show that the Drosophila ubiquitin protease UBP64 controls cell fate in the developing eye. UBP64 represses neuronal cell fate but promotes the formation of nonneuronal cone cells. Using a proteomics approach, we identified the transcriptional repressor Tramtrack (TTK) as a primary UBP64 substrate. In common with TTK, reduced UBP64 levels lead to a loss of cone cells, supernumerary photoreceptors, and mechanosensory bristle cells. Previously, it was demonstrated that the blockade of neuronal cell fate was relieved by SINA-dependent ubiquitylation and degradation of TTK. We found that UBP64 counteracts SINA function by deubiquitylating TTK, leading to its stabilization and thereby promoting a nonneuronal cell fate. Mass spectrometric mapping revealed that SINA ubiquitylates multiple sites dispersed throughout TTK, which are duly deubiquitylated by UBP64. This observation suggests that both E3 SINA and UBP64 use a scanning mechanism to (de)ubiquitylate TTK. We conclude that the balance of TTK ubiquitylation by SINA and deubiquitylation by UBP64 constitutes a specific posttranslational switch controlling cell fate. Copyright

Intracoronary delivery of umbilical cord blood derived unrestricted somatic stem cells is not suitable to improve LV function after myocardial infarction in swine (Article)

2007-04-01T00:00:00Z

Regeneration of infarcted myocardium by injecting stem cells has been proposed to prevent heart failure. We studied the i.c. administration of human umbilical cord blood stem cells (USSC) in a porcine model of myocardial infarction (MI) and reperfusion. In 15 swine, MI was induced by balloon-occlusion of the left circumflex coronary artery (LCX) for 2 h followed by reperfusion. Five swine served as healthy controls. One week later, magnetic resonance imaging (MRI) was performed to assess left ventricular (LV) function and infarct size. Then, under immune suppression, 6 of the 12 surviving MI swine received intracoronary injection of ∼ 108human USSC in the LCX while the other MI-swine received medium. Four weeks later all swine underwent follow-up MRI, and were sacrificed for histology. One week after MI, end-diastolic volume (92 ± 3 mL) and LV mass (75 ± 2 g) were larger, while ejection fraction (42 ± 2%) was smaller than in healthy control (68 ± 3 mL, 66 ± 3 g and 55 ± 3%, all P < 0.05). Regional wall thickening (- 7 ± 2%) in the LCX area became akinetic. No difference in global and regional LV function at 5 weeks was observed between MI animals receiving USSC or medium. Infarct size after USSC treatment was significantly larger (20 ± 3 g vs. 8 ± 2 g, P < 0.05). USSC survived only in the infarct border zone at 5 weeks and did not express cardiomyocyte or endothelial markers. Histology showed that intracoronary injection of USSC caused micro infarctions by obstructing blood vessels. In swine with a 1 week old MI, injection of USSC via the intracoronary route does not improve LV function 4 weeks later.

Drug-eluting stents show delayed healing: Paclitaxel more pronounced than sirolimus (Article)

2007-04-01T00:00:00Z

Aims: To understand wound healing after drug-eluting stents (DES) placement in humans, we studied the histology of in-stent restenosis (ISR) tissue obtained by atherectomy from bare metal stents (BMS) and DES in comparison with de novo atherosclerosis. Methods and results: The tissue was retrieved from ISR in ten sirolimus-eluting stents (SES) and nine paclitaxel-eluting stents (PES), six BMS, and nine stenotic de novo atherosclerotic lesions and processed for histology and immunocytochemistry. Patients with ISR in PES showed a significantly higher incidence of unstable angina upon presentation for re-intervention (P = 0.046). De novo tissue tended to be more collagen rich, whereas ISR tissue tended to be more proteoglycan rich. In all groups, cell content consisted almost exclusively of smooth muscle cells. Histology showed that fibrinoid in ISR tissue was present only in DES (P = 0.004), as late as 2 years following DES placement, indicating a persistent incomplete healing response. The amount of fibrinoid, given as a percentage of total tissue in each atherectomy specimen, was greater in PES than in SES (17 vs. 5%, P = 0.026). Conclusion: ISR in DES shows incomplete neointimal healing as late as 2 years after implantation. Patients with ISR in PES presented with more unstable angina and showed more pronounced signs of delayed healing than SES.

A new intracoronary measurement catheter, MetriCath, compared to intravascular ultrasound and quantitative coronary angiography in a stented porcine coronary model. (Article)

2002-09-01T00:00:00Z

The purpose of this study was to compare measurements by MetriCath to intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA). The MetriCath system consists of a low-pressure (200 mm Hg) balloon catheter connected to a pressure transducer and infusion pump linked to a computer that records pressure-volume curves. Cross-sectional area of blood vessels is obtained directly from the unrestrained and in-stent pressure-volume measurements. We compared stent cross-sectional area measurements by MetriCath, IVUS, and QCA in a porcine stented coronary artery model. Comparison of area measurements in 14 stents showed no significant differences between the three methods (P = 0.66). On average, values differed 0.37 ± 0.60mm2 between MetriCath and QCA, 0.13 ± 0.55 mm2 between MetriCath and IVUS, and 0.22 ± 0.80 mm2 between IVUS and QCA. This corresponds to 6.2% ± 10%, 3.0% ± 9.0%, and 3.1% ± 12.9% relative difference from the average of two corresponding measurements. Linear regression analysis showed excellent correlation between measurements (r ± 0.99 for all comparisons). The differences in in-stent area measurements between MetriCath and both QCA and IVUS were small. Considering the ease and rapidity of obtaining MetriCath results, this technique may form an alternative to the others in evaluating stent expansion. Based on these findings, clinical evaluation seems warranted.

"Edge Effect" of 32P Radioactive Stents Is Caused by the Combination of Chronic Stent Injury and Radioactive Dose Falloff (Article)

2001-01-01T00:00:00Z

BACKGROUND: Radioactive stents have been reported to reduce in-stent neointimal thickening. An unexpected increase in neointimal response was observed, however, at the stent-to-artery transitions, the so-called "edge effect." To investigate the factors involved in this edge effect, we studied stents with 1 radioactive half and 1 regular nonradioactive half, thereby creating a midstent radioactive dose-falloff zone next to a nonradioactive stent-artery transition at one side and a radioactive stent-artery transition at the other side. METHODS AND RESULTS: Half-radioactive stents (n=20) and nonradioactive control stents (n=10) were implanted in the coronary arteries of Yucatan micropigs. Animals received aspirin and clopidogrel as antithrombotics. After 4 weeks, a significant midstent stenosis was observed by angiography in the half-radioactive stents. Two animals died suddenly because of coronary occlusion at this mid zone at 8 and 10 weeks. At 12-week follow-up angiography, intravascular ultrasound and histomorphometry showed a significant neointimal thickening at the midstent dose-falloff zone of the half-radioactive stents, but not at the stent-to-artery transitions at both extremities. Such a midstent response (mean angiographic late loss 1.0 mm) was not observed in the nonradioactive stents (mean loss 0.4 to 0.6 mm; P< 0.01). CONCLUSIONS: The edge effect of high-dose radioactive stents in porcine coronary arteries is associated with the combination of stent injury and radioactive dose falloff.

Coronary stent implantation changes 3-D vessel geometry and 3-D shear stress distribution. (Article)

2000-10-01T00:00:00Z

Mechanisms of in-stent restenosis are not fully understood. Shear stress is known to play a role in plaque and thrombus formation and is sensitive to changes in regional vessel geometry. Hence, we evaluated the regional changes in 3-D geometry and shear stress induced by stent placement in coronary arteries of pigs.Methods. 3-D reconstruction was performed, applying a combined angiographic and IVUS technique (ANGUS), from seven Wallstents (diameter 3.5 (n=3) and 5mm (n=4)), which were implanted in seven coronary arteries of five pigs. This 3-D geometry was used to calculate locally the curvature, while the shear stress distribution was obtained by computational fluid dynamics. Local changes in shear stress were obtained at the entrance and exit of the stent for baseline (0. 65+/-0.22 ml/s) and hyperemic flow (2.60+/-0.86 ml/s) conditions. Results. After stent implantation, the curvature increased by 121% at the entrance and by 100% at the exit of the stent, resulting in local changes in shear stress. In general, at the entrance of the stent local maxima in shear stress were generated, while at the exit both local maxima and minima in shear stress were observed (p<0.05). Additionally, the shear stress at the entrance and exit of the stent were correlated with the local curvature (r: 0.30-0.84).Conclusion. Stent implantation changes 3-D vessel geometry in such a way that regions with decreased and increased shear stress occur close to the stent edges. These changes might be related to the asymmetric patterns of in-stent restenosis.

Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries (Article)

2000-01-01T00:00:00Z

OBJECTIVE: To improve the biocompatibility of stents using a phosphorylcholine coated stent as a form of biomimicry. INTERVENTIONS: Implantation of phosphorylcholine coated (n = 20) and non-coated (n = 21) stents was performed in the coronary arteries of 25 pigs. The animals were killed after five days (n = 6), four weeks (n = 7), and 12 weeks (n = 8), and the vessels harvested for histology, scanning electron microscopy, and morphometry. MAIN OUTCOME MEASURES: Stent performance was assessed by studying early endothelialization, neointima formation, and vessel wall reaction to the synthetic coating. RESULTS: Stent thrombosis did not occur in either group. Morphometry showed no significant differences between the two study groups at any time point. At five days both the coated and non-coated stents were equally well endothelialised (91% v 92%, respectively). At four and 12 weeks there was no difference in intimal thickness between the coated and non-coated stents. Up to 12 weeks postimplant the phosphorylcholine coating was still discernible in the stent strut voids, and did not appear to elicit an adverse inflammatory response. CONCLUSION: In this animal model the phosphorylcholine coating showed excellent blood and tissue compatibility, unlike a number of other polymers tested in a similar setting. Given that the coating was present up to 12 weeks postimplant with no adverse tissue reaction, it may be a potential candidate polymer for local drug delivery.

Reduction in Thrombotic Events With Heparin-Coated Palmaz-Schatz Stents in Normal Porcine Coronary Arteries. (Article)

1996-01-01T00:00:00Z

Background The use of stents improves the result after balloon coronary angioplasty. Thrombogenicity of stents is, however, a concern. In the present study, we compared stents with an antithrombotic coating with regular stents. Methods and Results Regular stents were placed in coronary arteries of pigs receiving no aspirin (group 1; n=8) or aspirin over 4 weeks (group 2, n=10) or 12 weeks (group 3, n=9). Stents coated with heparin (antithrombin III uptake, 5 pmol/stent) were placed in 7 pigs that did not receive aspirin (group 4). The other animals received aspirin and coated stents with a heparin activity of 12 pmol antithrombin III/stent (group 5, n=10) or 20 pmol/stent (group 6, n=10; group 7, n=10). Quantitative arteriography was performed at implantation and after 4 (groups 1, 2, and 4 through 6) or 12 weeks (groups 3 and 7). In an additional 5 animals, five regular and five coated stents (20 pmol/stent) were placed and explanted after 5 days for examination of the early responses to the implants. Thrombotic occlusion of the regular stent occurred in 9 of 27 in groups 1 through 3. However, in 0 of 30 of the animals receiving high-activity heparin-coated stents (groups 5 through 7), thrombotic stent occlusion was observed (P<.001). Histological analysis at 4 weeks showed that the neointima in group 6 was thicker compared with its control group 2 (259±104 and 117±36 µm, P<.01), but at 12 weeks the thickness was similar (152±61 and 198±49 µm, respectively). Comparison at 5 days suggested delayed endothelialization of the coating.

Stenting or balloon angioplasty of stenosed autologous saphenous vein grafts in pigs (Article)

1994-01-01T00:00:00Z

Coronary stent coatings (Article)

1994-01-01T00:00:00Z

Vessel wall reactions to endovascular stent implantation (Doctoral Thesis)

1993-11-17T00:00:00Z

In order to gain insight in the effects of stenting, we studied the process of wound healing and the short- and long-term effect of these permanently present foreign bodies. Both thrombogenic and less thrombogenic metals were evaluated with respect to thrombogenicity and tissue response. Synthetic polymers were evaluated with respect to improving the haemocompatibility and tissue-compatibility profile of these devices. Stenting of normal porcine arteries. In Chapter 2, a balloon-expandable tantalum stent is described, tested in normal porcine coronary arteries for one and four weeks, and an indication is given of the process of wound healing and of the extent of intimal hyperplasia in these arteries. In chapter 3 a self-expanding stainless steel stent was tested in normal porcine coronary arteries. Luminal change was assessed at one, four, and twelve weeks using quantitative angiography, while histologic analysis was performed at twelve weeks only. Additionally, the efficacy of a polymer coating as well as pharmacological treatment (antiplatelet and anti-coagulant treatment) aimed at reducing acute thrombotic complications and intimal hyperplasia was studied. In an attempt to improve some of the features of stents, early thrombogenicity and barotrauma, a polymeric stent was developed and tested in vitro and in vivo and the results are discussed in Chapter 4, Stenting of vein grafts. Using a model of early vein graft narrowing in pigs, stenting was studied to assess the potential benefit of single and mnltiple stent implantation, compared to plain balloon angioplasty (Chapter 5). Stenting of both diseased and healthy arteries in animals of similar age and using the same stent, enables the assessment of behaviour of this stent under different circumstances. Pathologic examination of human saphenous vein bypass grafts treated with the self-expanding stainless steel stent (used in pigs in Chapter 3), is discussed in Chapters 6 and 7. This allowed for a comparison between the effect of stents when implanted in healthy porcine coronary arteries, porcine arteriovenous grafts and diseased human arteriovenous grafts. Vascular (dys)function. To assess long-term effects of stenting, a physiological study was undertaken to determine vascular function (Chapter 8). Aogiotensin metabolism in stented porcine coronary arteries was studied, as angiotensin IT is implicated as a growth factor or as a modifier of growth response of smooth muscle cells.

Histology after stenting of human saphenous vein bypass grafts: observations from surgically excised grafts 3 to 320 days after stent implantation (Article)

1993-01-01T00:00:00Z

OBJECTIVES. To gain insight into the mechanism of stenting in humans and its short- and long-term implications, we studied the vascular wall of saphenous vein aortocoronary bypass grafts after implantation of the Wallstent. BACKGROUND. The implantation of a stent in aortocoronary bypass grafts may provide an alternative solution for revascularization in patients who are poor candidates for reoperation. Because human histopathologic findings after stenting with the Wallstent have not previously been described in detail, we examined graft segments that were surgically retrieved from 10 patients (21 stents) at 3 days to 10 months after implantation of the stent. METHODS. The grafts were examined by a combination of the following techniques: light microscopy, immunocytochemistry and both scanning and transmission electron microscopy. RESULTS. Early observations revealed that large amounts of platelets and leukocytes adhered to the stent wires during the first few days. At 3 months, the wires were embedded in a layered new intimal thickening, consisting of smooth muscle cells in a collagenous matrix. In addition, foam cells were abundant near the wires. Extracellular lipids and cholesterol crystals were found after 6 months. Smooth muscle cells and extracellular matrix formed the predominant component of restenosis. This new intimal thickening was lined with endothelium, in some cases showing defect intercellular junctions and abnormal adherence of leukocytes and platelets as late as 10 months after implantation. CONCLUSIONS. This type of stent is potentially thrombogenic and seems to be associated with extracellular lipid accumulation in venous aortocoronary bypass grafts.

Development of a polymer endovascular prosthesis and its implantation in porcine arteries (Article)

1992-01-01T00:00:00Z

A polyethylene-terephthalate braided mesh stent has been developed for application in the (coronary) arterial tree. In vitro measurements showed that the radial pressure delivered by this device was in the same range as that of a stainless steel stent. Hysteresis-like behavior, however, occurred after constraining the polyester stent for a period of only 15 minutes on a delivery system for percutaneous implantation. This implies that the polymer stent must be mounted on this delivery system immediately before the placement procedure, and that either a diameter in the unconstrained condition must be selected, which is considerably larger than the diameter of the target vessel, or stent expansion has to be enhanced by balloon expansion. Taking into account the results obtained during the in vitro studies, we investigated the angiographic patency and histologic features after implantation of this polyester stent in peripheral arteries of pigs. In four animals eight stents were placed. Except for heparin during the implantation procedure only, antithrombotic or antiplatelet drugs were not administered. After 4 weeks repeat angiography was performed. Angiography revealed that five of the six correctly placed stents were patent. At autopsy, two additional patent stents proved to be located in the aortic bifurcation, probably due to failure of the delivery system. Quantitative assessment showed that the mean luminal diameters of the site of stent placement were 3.3 +/- 0.2 mm before, 3.2 +/- 0.2 mm immediately after, and 3.1 +/- 0.3 mm at 4 weeks after implantation. Histology demonstrated an inflammatory reaction of variable severity around the stent fibers. Quantitative histologic measurements showed that the thickness of the neointima was 114 +/- 38 mum after 4 weeks. In conclusion, polyester stents can be constructed with mechanical properties similar to stainless steel stents. Hysteresis-like behavior of polyester stents, however, influences the selection of the nominal stent diameter as well as the forces exerted to the vessel wall. After implantation in porcine peripheral arteries, five of six correctly placed stents were patent at 4 weeks. The extent of neointimal proliferation was similar to that observed after placement of metal stents in swine, despite the presence of a more pronounced inflammatory reaction.

Coronary stenting with a new, radiopaque, balloon-expandable endoprosthesis in pigs (Article)

1991-01-01T00:00:00Z

BACKGROUND. Intracoronary stents may be effective when used as "bail-out" devices for acute complications after percutaneous transluminal coronary angioplasty. Furthermore, preliminary reports have demonstrated some promising results with stents with regard to the reduction of restenosis. Several stent devices are available for preclinical and clinical evaluation. The use of these stainless-steel stents has been limited by poor visibility during fluoroscopy and thrombogenicity during the first days to weeks after implantation. We therefore investigated the immediate and short-term effects on arterial patency of a new, radiopaque, balloon-expandable coil stent in normal coronary arteries of pigs. METHODS AND RESULTS. In 10 animals, a stent was placed in two of the three epicardial coronary arteries. During the implantation procedure, the animals received heparin; after the procedure, no antithrombotic drugs were administered. After 1 week (five animals and 10 stents) or 4 weeks (five animals and 10 stents), repeat angiography was performed, followed by pressure-fixation of the coronary arteries for light and electron microscopic examination. Angiographic analysis revealed that all stented coronary segments were patent and without signs of intraluminal defects. Scanning electron microscopy showed complete endothelial covering of all stents within 7 days. Light microscopy showed a reduced tunica media locally under the stent wires, which resulted from exerted pressure. The neointima on top of the stent wires measured 56 microns (range, 42-88 microns) after 1 week and 139 microns (range, 84-250 microns) after 4 weeks. CONCLUSIONS. Results from this study show that this radiopaque endoprosthesis can be safely placed in normal coronary arteries of pigs. After 4 weeks, all stents were patent and there was no need for additional antithrombotic treatment, whereas neointimal proliferation was limited.

Stenting of coronary arteries: has a modern Pandora's box been opened (Article)

1991-01-01T00:00:00Z

Interventional cardiology has recently witnessed the growth of several alternatives to percutaneous transluminal angioplasty, including coronary stenting. Although stenting appears to be useful in treating abrupt closure after coronary angioplasty, its effectiveness in limiting the complex processes responsible for late restenosis is much less certain. Pathologic examination of stented human saphenous bypass grafts shows extensive deposits of platelets, fibrin and leukocytes along the stent wires within the 1st week and formation of a neointima of variable thickness after 3 months without evidence of foreign body reaction. The long-term effects of continuous barotrauma induced by the expanded stent remain unknown. It is difficult to assess the relative merits of the new devices, but stenting has several theoretic advantages. It seems less disruptive to the underlying architecture of the vessel wall and enjoys favorable theoretic and effective expansion ratios. Wide-spread clinical acceptance for stenting will depend on demonstrating that its safety, efficacy and cost efficiency are superior to those of balloon angioplasty.