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Pedro A Lemos,
Vasim Farooq,
Celso K Takimura,
Paulo S Gutierrez,
Renu Virmani,
Frank Kolodgie,
Uwe Christians,
Alexander Kharlamov,
Manish Doshi,
Prakash Sojitra, Heleen M M Van Beusekom,
Patrick W Serruys
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ABSTRACT: Drug-eluting stents have proven to be effective in reducing the risk of late restenosis. In order to achieve a controlled and prolonged release of the antiproliferative agent, current drug-eluting stents utilise various biodegradable as well as non-erodible polymeric blends to coat the stent surface and to serve as drug carriers. The utilisation of polymeric compounds in current drug-eluting stents may eventually limit their performance as well as their clinical applicability due to the potential induction of undesirable local reactions. The development
of alternative, polymer-free drug carriers has the potential to overcome some of the limitations of current drug-eluting stent formulations. Moreover, improvements in drug carriers may also result in an expansion
of the technological possibilities for other intravascular drug delivery systems, such as metal-free or even implant-free solutions.
This article describes the structure and the preclinical validation profile of a novel phospholipid encapsulated
sirolimus nanocarrier, used as a coating in two formulations: a coronary stent-plus-balloon system and a stand-alone balloon catheter. The nanoparticles provided a stable, even and homogenous coating to the devices in both formulations. Dose-finding studies allowed the most appropriate identification of the best nanoparticle structure associated with an extremely efficient transfer of drug to all layers of the vessel wall, achieving high tissue concentrations that persisted days after the application, with low systemic drug leaks.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 05/2013; 9(1):2013. · 3.29 Impact Factor
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The Journal of thoracic and cardiovascular surgery 04/2013; · 3.41 Impact Factor
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Guillermo J Tearney,
Evelyn Regar,
Takashi Akasaka,
Tom Adriaenssens,
Peter Barlis,
Hiram G Bezerra,
Brett Bouma,
Nico Bruining,
Jin-man Cho,
Saqib Chowdhary, [......],
Giovanni J Ughi, Heleen M M van Beusekom,
Antonius F W van der Steen,
Gerrit-Anne van Es,
Gerrit-Ann van Es,
Gijs van Soest,
Renu Virmani,
Sergio Waxman,
Neil J Weissman,
Giora Weisz
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ABSTRACT: The purpose of this document is to make the output of the International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT) Standardization and Validation available to medical and scientific communities, through a peer-reviewed publication, in the interest of improving the diagnosis and treatment of patients with atherosclerosis, including coronary artery disease.
Intravascular optical coherence tomography (IVOCT) is a catheter-based modality that acquires images at a resolution of ~10 μm, enabling visualization of blood vessel wall microstructure in vivo at an unprecedented level of detail. IVOCT devices are now commercially available worldwide, there is an active user base, and the interest in using this technology is growing. Incorporation of IVOCT in research and daily clinical practice can be facilitated by the development of uniform terminology and consensus-based standards on use of the technology, interpretation of the images, and reporting of IVOCT results.
The IWG-IVOCT, comprising more than 260 academic and industry members from Asia, Europe, and the United States, formed in 2008 and convened on the topic of IVOCT standardization through a series of 9 national and international meetings.
Knowledge and recommendations from this group on key areas within the IVOCT field were assembled to generate this consensus document, authored by the Writing Committee, composed of academicians who have participated in meetings and/or writing of the text.
This document may be broadly used as a standard reference regarding the current state of the IVOCT imaging modality, intended for researchers and clinicians who use IVOCT and analyze IVOCT data.
Journal of the American College of Cardiology 03/2012; 59(12):1058-72. · 14.16 Impact Factor
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ABSTRACT: 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 ET(A) 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.
AJP Heart and Circulatory Physiology 01/2012; 302(1):H85-94. · 3.71 Impact Factor
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EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 12/2011; 7(8):1006-7. · 3.29 Impact Factor
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ABSTRACT: To study the effect of endothelial progenitor cell (EPC) capture on the vascular response to coronary stenting.
The introduction of drug-eluting stents has reduced the need for target lesion revascularization, but their effect on delayed healing, inflammation, and vascular dysfunction has emphasized the need to design strategies that improve current DES. One such strategy is to improve endothelialization by capturing CD34-positive cells (EPC) by the stent surface. The first human clinical trial using coronary EPC capture stents showed stent safety but neointimal thickness (NIT) was not reduced compared to bare metal stents (BMS). To understand these responses we studied the coronary response to the EPC capture stent in swine.
The stent, coated with murine antihuman monoclonal CD34 antibodies, was assessed with QCA guided stent implantation in normal swine coronary arteries for early endothelialization at 2 and 5 days, and NIT at 28 and 90 days in comparison to control stents carrying a non-specific murine antibody or to BMS. The main finding was that while the EPC capture stent significantly improved early endothelialization it did not reduce NIT at 28 and 90 days.
The EPC capture stent improves early endothelialization in swine but this does not affect neointimal thickness as compared to control stents at 28 and 90 days.
Catheterization and Cardiovascular Interventions 08/2011; 79(2):231-42. · 2.29 Impact Factor
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EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 12/2010; 6 Suppl J:J155-60. · 3.29 Impact Factor
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ABSTRACT: 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.
The mechanism of endothelial dysfunction occurring in human coronary conduit arteries up to 9 months after DES implantation is unknown.
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 endothelium-derived hyperpolarizing factors (EDHFs) and cyclic guanosine monophosphate (cGMP) responses to BK-stimulation were determined in vitro.
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.
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 EDHF component of microvascular function seems affected by PES.
07/2010; 3(7):723-30. · 1.07 Impact Factor
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Harald C Groen,
Theo van Walsum,
Sietske Rozie,
Stefan Klein,
Kim van Gaalen,
Frank J H Gijsen,
Piotr A Wielopolski, Heleen M M van Beusekom,
Rini de Crom,
Hence J M Verhagen,
Antonius F W van der Steen,
Aad van der Lugt,
Jolanda J Wentzel,
Wiro J Niessen
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ABSTRACT: 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 degrees , 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.
Journal of biomechanics 05/2010; 43(11):2087-92. · 2.66 Impact Factor
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ABSTRACT: Drug eluting stents (DES) are under scrutiny for late stent thrombosis. Impaired re-endothelialisation is proposed as an explanation but coronary and peripheral-artery models disagree. We assessed physical and functional endothelial restoration within bare (BMS), paclitaxel, sirolimus and tacrolimus eluting stents and the distal microvasculature in porcine coronary arteries.
Endothelium within and distal to DES and BMS was assessed for stent-strut endothelial-restoration (five days) and endothelial-function (five, 28 days, by eNOS and vWF expression) and by in vitro microvascular function. There were no significant differences (P=0.3) in stent strut endothelial-restoration at five days between DES (76-90%) and BMS (95%). However, the microvasculature distal to PES showed a decreased NO bioavailability at five days, which improved at 28 days. Within the stent, however, PES still showed a reduced eNOS expression at 28 days (P</=0.002).
DES in porcine coronary arteries show no significant early differences in re-endothelialisation as compared to BMS. However, PES did affect endothelial function both within and distal to stents. These results extend the concept of delayed healing in DES to include delayed restoration of function rather than endothelial presence as a possible explanation for late unwanted sequelae. Microvascular dysfunction does not predict in-stent delayed endothelialisation in this model.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 05/2010; 6(1):117-25. · 3.29 Impact Factor
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01/2010; 3(1):76-7. · 1.07 Impact Factor
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ABSTRACT: The aim of this study was to compare efficacy of low- and high-dose sirolimus release (25, 40, or 100 microg) from hydroxyapatite (HAp) with Cypher (Cordis, Johnson & Johnson, Warren, New Jersey) (111 microg sirolimus) in porcine coronary arteries.
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.
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 microg sirolimus with Cypher.
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.
Reducing the dose of sirolimus eluting from a biocompatible HAp coated stent reduces signs of delayed vascular healing, without affecting neointimal hyperplasia.
04/2009; 2(4):284-90. · 1.07 Impact Factor
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ABSTRACT: 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.
Ten pigs received phosphorylcholine-coated stents in each of the three major coronary arteries: one loaded with 780 microg 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.
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 mm(2)) and thickness (0.57+/-0.29 mm) in the quinaprilat group; versus solvent (1.98+/-0.57 mm(2) 0.4+/-0.26 mm) and controls (1.92+/-0.50mm(2) and 0.41+/-0.18 mm).
Quinaprilat-eluting stents do not attenuate neointimal thickening following implantation in normal porcine coronary arteries, but rather show a tendency towards the opposite.
Atherosclerosis 01/2009; 205(1):120-5. · 3.79 Impact Factor
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ABSTRACT: Drug eluting stents (DES) have attracted considerable attention due to concerns of late stent thrombosis (LST) thought to be related to delayed endothelialisation. This hypothesis is based on clinical autopsy studies indicating an association between lack of endothelium and LST. However, meta-analysis of clinical trials does not support the notion that all DES induce more late stent thrombosis than BMS. In addition, preclinical data using animal models also do not necessarily support this hypothesis. Most animal models using single non-overlapping stents show no signs of delayed endothelialisation at all. Experiments with several DES in our laboratory using the porcine coronary artery model also suggest that DES show no differences in re-endothelialisation. They can however induce (late) differences in endothelial function, depending on the DES of choice. These phenomena are also described clinically in coronary segments distal from the DES. We hypothesise that DES do not necessarily delay endothelialisation but more likely induce late endothelial dysfunction that varies between DES.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 09/2008; 4 Suppl C:C17-21. · 3.29 Impact Factor
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09/2008; 1(4):449-51. · 1.07 Impact Factor
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ABSTRACT: 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.
Molecular and cellular biology 04/2008; 28(5):1606-15. · 6.06 Impact Factor
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ABSTRACT: 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 approximately 10(8) human 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.
Journal of Molecular and Cellular Cardiology 05/2007; 42(4):735-45. · 5.17 Impact Factor
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ABSTRACT: 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.
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).
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.
European Heart Journal 05/2007; 28(8):974-9. · 10.48 Impact Factor
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ABSTRACT: Implantable biomaterials mainly serve as physical support devices, carriers for bioactive molecules and guidance for tissue growth. For any application within or outside the cardiovascular area, biomaterials are subject to an extended set of requirements in order to establish safe application. These requirements mainly include acceptable biocompatibility and, if the material is to be degraded within the body, safe degradation characteristics. During degradation, biocompatible polymers are broken down into molecules that are metabolized and removed from the body via normal metabolic pathways. Major applications of these polymers include targeted drug delivery systems, resorbable sutures and orthopedic fixation devices. In the cardiovascular area they include biodegradable cardiovascular stents and drug-eluting stent (DES) coatings. This review focuses on general aspects of local drug delivery by implantable polymeric devices, with special emphasis on drug-eluting stents.
Journal of Interventional Cardiology 01/2007; 19(6):500-6. · 1.18 Impact Factor
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ABSTRACT: Implantable biomaterials mainly serve as physical support devices, carriers for bioactive molecules and guidance for tissue growth. For any application within or outside the cardiovascular area, biomaterials are subject to an extended set of requirements in order to establish safe application. These requirements mainly include acceptable biocompatibility and, if the material is to be degraded within the body, safe degradation characteristics. During degradation, biocompatible polymers are broken down into molecules that are metabolized and removed from the body via normal metabolic pathways. Major applications of these polymers include targeted drug delivery systems, resorbable sutures and orthopedic fixation devices. In the cardiovascular area they include biodegradable cardiovascular stents and drug-eluting stent (DES) coatings. This review focuses on general aspects of local drug delivery by implantable polymeric devices, with special emphasis on drug-eluting stents.
Journal of Interventional Cardiology 11/2006; 19(6):500 - 506. · 1.18 Impact Factor
