Neointimal Thickness Research Articles

Abstract 428: Role of Thrombospondin-1 in Atherosclerotic Complications Associated With Metabolic Syndrome

Atherosclerosis is the leading cause of increased morbidity and mortality in metabolic syndrome (MetS), a constellation of risk factors that include hyperglycemia and visceral obesity. Individuals with MetS have increased incidence of vascular smooth muscle cell (VSMC) migration and proliferation, a key characteristic of VSMC phenotypic transition. We previously reported that high glucose and high leptin, mimicking hyperglycemia and obesity, independently upregulate a potent proatherogenic matricellular protein, thrombospondin-1 (TSP-1), expression in VSMCs. The goal of the present study was to investigate the role of TSP-1 in development of atherosclerosis in MetS. We generated a mouse model of combined MetS and atherosclerosis ( KKAy +/- /ApoE -/- ) by crossing obese hyperglycemic agouti yellow KKAy +/- mice with atherosclerotic ApoE -/- mice. Upon weaning, yellow KKAy +/- /ApoE -/- mice and age-matched black KKAy -/- /ApoE -/- littermates were maintained on regular chow diet from 4-18 wks of age. Mice were euthanized after an overnight fasting; blood, aortae and heart were collected for lipid profiling, immunoblotting and atherosclerotic lesion studies. Yellow KKAy +/- /ApoE -/- mice showed significant increase in body weight, blood glucose and plasma lipid levels vs. black KKAy -/- /ApoE -/- littermates. Aortic root morphometry demonstrated increased lesion burden (Oil red O) and neointimal thickening (H & E) in MetS KKAy +/- /ApoE -/- vs. non-MetS KKAy -/- /ApoE -/- mice. Immunohistochemistry further revealed co-localization of α-SMA (SMC marker) and PCNA (proliferation marker) expression in aortic roots of KKAy +/- /ApoE -/- vs. KKAy -/- /ApoE -/- mice. Notably, lesion formation was associated with an increase in TSP-1 expression in aortic vessels. Consistently, TSP-1 and PCNA expression were elevated in aortic SMC (aSMC) primary cultures derived from obese diabetic KKAy +/- mice vs. lean non-diabetic KKAy -/- littermates. Finally, incubation of aSMC with a TSP-1 blocking peptide reduced PCNA and vimentin (SMC synthetic marker) expression coupled with attenuated SMC proliferation in obese diabetic KKAy +/- mice. Together, these results suggest a putative role of TSP-1 in accelerated atherosclerosis and VSMC phenotypic transition in MetS.

Biological effect of microengineered grooved stents on strut healing: a randomised OCT-based comparative study in humans

ObjectiveTo evaluate the biological effect of microengineered stent grooves (MSG) on early strut healing in humans by performing optical coherence tomography (OCT) analysis 3 weeks following the implantation.BackgroundIn the experimental...

Oral chromium picolinate impedes hyperglycemia-induced atherosclerosis and inhibits proatherogenic protein TSP-1 expression in STZ-induced type 1 diabetic ApoE\u2212/\u2212 mice

Increasing evidence suggests thrombospondin-1 (TSP-1), a potent proatherogenic matricellular protein, as a putative link between hyperglycemia and atherosclerotic complications in diabetes. We previously reported that the micronutrient chromium picolinate (CrP), with long-standing cardiovascular benefits, inhibits TSP-1 expression in glucose-stimulated human aortic smooth muscle cells in vitro. Here, we investigated the atheroprotective action of orally administered CrP in type 1 diabetic apolipoprotein E-deficient (ApoE−/−) mice and elucidated the role of TSP-1 in this process. CrP decreased lipid burden and neointimal thickness in aortic root lesions of hyperglycemic ApoE−/− mice; also, smooth muscle cell (SMC), macrophage and leukocyte abundance was prevented coupled with reduced cell proliferation. Attenuated lesion progression was accompanied with inhibition of hyperglycemia-induced TSP-1 expression and reduced protein O-glycosylation following CrP treatment; also, PCNA and vimentin (SMC synthetic marker) expression were reduced while SM-MHC (SMC contractile marker) levels were increased. To confirm a direct role of TSP-1 in diabetic atherosclerosis, hyperglycemic TSP-1−/−/ApoE−/− double knockout mice were compared with age-matched hyperglycemic ApoE−/− littermates. Lack of TSP-1 prevented lesion formation in hyperglycemic ApoE−/− mice, mimicking the atheroprotective phenotype of CrP-treated mice. These results suggest that therapeutic TSP-1 inhibition may have important atheroprotective potential in diabetic vascular disease.

The REMEDEE-OCT Study: An Evaluation of the Bioengineered COMBO Dual-Therapy CD34 Antibody–Covered Sirolimus-Eluting Coronary Stent Compared With a Cobalt-Chromium Everolimus-Eluting Stent in Patients With Acute Coronary Syndromes: Insights From Optical Coherence Tomography Imaging Analysis

ObjectivesThe aim of the present study was to evaluate vascular healing of the bioengineered COMBO Dual Therapy Stent compared with a cobalt-chromium (CoCr) everolimus-eluting stent (EES) as assessed by optical coherence tomography in patients with acute coronary syndromes. BackgroundCD34+ cells promote endothelial repair after vascular injury. The bioengineered COMBO Dual Therapy Stent combines CD34+ cell–capturing technology with abluminal sirolimus release, but more data from clinical studies evaluating the vascular response are needed. MethodsIn a prospective randomized multicenter clinical trial, 60 patients with acute coronary syndromes were randomized 1:1 to COMBO or CoCr EES implantation. The primary endpoint was the percentage of uncovered stent struts per stent. Stent assessment by optical coherence tomography was performed at baseline and at 60 days, followed by independent core laboratory analysis. ResultsThe percentage of uncovered struts per stent was higher with the COMBO than the CoCr EES at 60 days (median 14.7% vs. 7.7%; p = 0.04). However, no significant difference in uncovered stent struts was observed in the strut level–based analysis at 60 days, which also accounted for clustering (COMBO vs. CoCr EES; 13.6% vs. 6.9%; p = 0.09; generalized linear mixed models–adjusted analysis). Neointimal thickness at 60 days was lower with the COMBO compared with the CoCr EES (median 30.17 vs. 50.26 μm; p = 0.02; stent-level analysis). There were no significant differences in the frequency of major adverse cardiac events and each component of major adverse cardiac events within the study population between the 2 groups at 30, 60, 180, 360, and 540 days post-procedure. No target vessel stent thrombosis has been documented within 540 days. ConclusionsThe present multicenter, prospective clinical study for the first time compared the vascular response of the bioengineered COMBO Dual Therapy Stent with a CoCr EES in patients early after acute coronary syndrome by using intracoronary optical coherence tomographic analysis. The percentage of uncovered stent struts per stent was somewhat higher after COMBO versus CoCr EES implantation as detected by optical coherence tomography, associated with reduced neointimal thickness.

Recombinant human SDF-1α administration accelerates aneurysm neck reendothelialization in rabbit saccular aneurysm after flow diverter treatment.

Reendothelialization in the aneurysm neck is pivotal to vascular repair for intracranial aneurysm after flow diverter (FD) implantation. Recombinant human stromal cell-derived factor 1α (rhSDF-1α) is a vital chemoattractant to stem cells and potentially facilitates reendothelialization. Here, we sought to investigate the therapeutic effects of intravenous administration of rhSDF-1α and uncover its potential mechanism for promoting aneurysm neck reendothelialization. Recombinant pET32a-186 plasmid was transformed into Escherichia coli to produce the rhSDF-1α protein with biological activity. FD was implanted into the elastase-induced saccular aneurysm in New Zealand white rabbits. rhSDF-1α (50 μg/kg/day) was intravenously administrated for consecutive 7 days after FD implantation. After these procedures, aneurysms were harvested after 2 or 4 weeks. Scanning electron microscopy was used to measure the neointima thickness and count the endothelial-like cells at aneurysm neck. Four weeks later, the mRNA levels of endothelial markers in the neointima at aneurysm neck were examined. Migration assay showed that rhSDF-1α could induce migration of endothelial progenitor cells in a dose-dependent manner. Two weeks after stent implantation, follow-up angiography showed partial aneurysm occlusion in one of each group and total aneurysm occlusion in 17 saccular aneurysm rabbits (9 of the rhSDF-1α group and 8 of the control group). No significant change of neointima thickness at aneurysm neck was observed. Intriguingly, more endothelial-like cells were observed at aneurysm neck in the rhSDF-1α group at 2 weeks (55 vs 13 cells per high-power field) and 4 weeks (104 vs 60 cells per high-power field). The mRNA levels of Tie-2, VE-cadherin, KDR and E-selectin were significantly enhanced compared with those of the control group. These results showed that intravenous administration of rhSDF-1α can accelerate reendothelialization in the aneurysm neck after FD implantation. Our study reveals an important role of rhSDF-1α in inducing aneurysm occlusion and suggests that it achieves its function through modulating the reendothelialization.

Patch Angioplasty in the Rat Aorta or Inferior Vena Cava.

Pericardial patches are commonly used in vascular surgery to close vessels. To facilitate studies of the neointimal hyperplasia that forms on the patch, we developed a rat model of patch angioplasty that can be used in either a vein or an artery, creating a patch venoplasty or a patch arterioplasty, respectively. Technical aspects of this model are discussed. The infra-renal IVC or aorta are dissected and then clamped proximally and distally. A 3 mm venotomy or arteriotomy is performed in the infrarenal inferior vena cava or aorta of 6 to 8 week-old Wistar rats. A bovine pericardial patch (3 mm x 1.5 mm x 0.6 mm) is then used to close the site using a 10-0 nylon suture. Compared to arterial patches, venous patches show increased neointimal thickness on postoperative day 7. This novel model of pericardial patch angioplasty can be used to examine neointimal hyperplasia on vascular biomaterials, as well as to compare the differences between the arterial and venous environments.

Early vascular responses after everolimus-eluting stent implantation assessed by serial observations of intracoronary optical coherence tomography.

A recent OCT study revealed that the lack of stent strut endothelial coverage is associated with late stent thrombosis after drug-eluting stent implantation. However, the sequential changes of stent strut endothelial coverage in the extremely early period have never been reported. Serial OCTs were performed in 35 patients with 35 EES (everolimus-eluting stent)-treated de novo lesions at 0, 2, 4, and 12 weeks after EES implantation. Serial changes in quantitative parameters of the neointima (neointimal thickness, stent strut coverage, and apposition of each strut) were analyzed. Mean neointimal thickness significantly increased from 35.9 to 51.8 and 108.2μm at 2, 4, and 12 weeks, respectively (p < 0.001 for all), and the percentage of uncovered stent struts significantly decreased from 74.7 to 19.5% and 0.4% (p < 0.001, respectively). There was no stent malapposition at 4 weeks compared with immediate post-intervention (0 vs. 5.4 %, p = 0.031). This OCT study demonstrates that neointimal coverage of stent struts progresses to about 80 % and malapposition of stent struts completely disappears at 4 weeks after EES implantation. In addition, neointimal coverage of stent struts was almost complete within 12 weeks.

Vascular response profiles following a nano polymer-free sirolimus-eluting stent implantation assessed by optical coherence tomography in a porcine model.

Optical coherence tomography (OCT) is a high resolution imaging modality and has been considered as the ideal tool for the evaluation of neointimal tissue and vascular responses following stent implantation. However, vascular response profiles following the implantation of a novel nano polymer-free sirolimus-eluting stent (SES) assessed by OCT has not been fully investigated. Therefore, the aim of the present study was to determine the effects of a nano polymer-free SES on neointimal formation using OCT. A total of 16 nano polymer-free SESs were implanted in the coronary arteries of 8 pigs. At 3 (n=4) or 6 months (n=4), the animals were euthanized following OCT evaluation and the stented arterial segments were analyzed by histological analysis. Neointimal area, thickness and burden were evaluated by OCT. In addition, strut-associated inflammation, stent endothelialization and arterial injury were investigated by histomorphological analysis. OCT examination showed that at 6 months, neointimal thickness (193.3±109.5 vs. 167.2±119.7 µm, P=0.023) and neointimal burden (29.3±14.3 vs. 24.8±17.4%, P=0.006) significantly increased compared with at 3 months. Histomorphological analysis indicated that the endothelialization score was significantly greater at 6 months compared with at 3 months (2.85±0.36 vs. 2.52±0.60, P<0.001). However, at 3 months, nano polymer-free SES showed a significantly higher inflammatory score [0 (0, 1) vs. 0 (0, 0), P<0.001] compared with at 6 months. In conclusion, nano polymer-free SES achieves endothelialization at 3 months; however, neointimal proliferation is more significant at 6 months and may be attributed to strut-associated inflammation.

Contribution of Vascular Cells to Neointimal Formation

The de-differentiation and proliferation of smooth muscle cells (SMCs) are widely accepted as the major contributor to vascular remodeling. However, recent studies indicate that vascular stem cells (VSCs) also play an important role, but their relative contribution remains to be elucidated. In this study, we used genetic lineage tracing approach to further investigate the contribution of SMCs and VSCs to neointimal thickening in response to endothelium denudation injury or artery ligation. In vitro and in vivo analysis of MYH11-cre/Rosa-loxP-RFP mouse artery showed that SMCs proliferated at a much slower rate than non-SMCs. Upon denudation or ligation injury, two distinct types of neointima were identified: Type-I neointimal cells mainly involved SMCs, while Type II mainly involved non-SMCs. Using Sox10-cre/Rosa-loxP-LacZ mice, we found that Sox10+ cells were one of the cell sources in neointima. In addition, lineage tracing using Tie2-cre/Rosa-LoxP-RFP showed that endothelial cells also contributed to the neointimal formation, but rarely transdifferentiated into mesenchymal lineages. These results provide a novel insight into the contribution of vascular cells to neointima formation, and have significant impact on the development of more effective therapies that target specific vascular cell types.

Adiponectin association with T-cadherin protects against neointima proliferation and atherosclerosis.

Adiponectin, an adipocyte-derived protein abundant in the circulation, is thought to be protective against atherosclerosis. However, it is not fully understood how the association of adiponectin with vascular cells and its antiatherogenic effect are connected. In this study, T-cadherin was essential for accumulation of adiponectin in the neointima and atherosclerotic plaque lesions, and the adiponectin-T-cadherin association protected against vascular injury. In the apolipoprotein E-knockout (ApoE-KO) mice, adiponectin and T-cadherin colocalized on endothelial cells and synthetic smooth muscle cells in the aortic intima. Notably, aortic adiponectin protein disappeared in T-cadherin/ApoE double-knockout (Tcad/ApoE-DKO) mice with significant elevation of blood adiponectin concentration. Furthermore, in Tcad/ApoE-DKO mice, carotid artery ligation resulted in a significant increase of neointimal thickness compared with ApoE-KO mice. Finally, on a high-cholesterol diet, Tcad/ApoE-DKO mice increased atherosclerotic plaque formation, despite a 5-fold increase in plasma adiponectin level compared with that in ApoE-KO mice. In vitro, knockdown of T-cadherin from human aortic smooth muscle cells (HASMCs) with synthetic phenotype significantly reduced adiponectin accumulation on HASMCs and negated the inhibitory effect of adiponectin on proinflammatory change. Collective evidence showed that adiponectin accumulates in the vasculature via T-cadherin, and the adiponectin-T-cadherin association plays a protective role against neointimal and atherosclerotic plaque formations.-Fujishima, Y., Maeda, N., Matsuda, K., Masuda, S., Mori, T., Fukuda, S., Sekimoto, R., Yamaoka, M., Obata, Y., Kita, S., Nishizawa, H., Funahashi, T., Ranscht, B., Shimomura, I. Adiponectin association with T-cadherin protects against neointima proliferation and atherosclerosis.

Optical Coherence Tomography Assessment of Glucose Fluctuation Impact on the Neointimal Proliferation After Stent Implantation in a Diabetic/Hypercholesterolemic Swine Model.

The aim of the present study was to investigate the effects of glucose fluctuation on neointimal proliferation after stent implantation by optical coherence tomography (OCT) in a diabetic/hypercholesterolemic (DM/HC) swine model.A total of 24 everolimus-eluting stents (EES) were implanted in the right coronary artery (RCA) of the animals using a 20% overstretch ratio. The 24 swines were divided into a DM-high glucose fluctuation (HGF) group (n = 8), DMlow glucose fluctuation (LGF) group (n = 8), and a control group (n = 8). Percent diameter stenosis (%DS), late loss (LL), percent area stenosis (%AS), and neointimal thickness (NIT) were analyzed. The differences in neointimal characteristics and circulating oxidative stress and inflammation biomarkers were assessed and measured.At 28 days, the highest values of %DS, LL, %AS, and NIT were achieved in the HGF group followed by the LGF group (P < 0.05) and the control group (P < 0.05). The highest frequency of the heterogeneous pattern was in the HGF group followed by the LGF group (P < 0.05) and the control group (P < 0.05). This was also the case for the oxidative stress and inflammation biomarkers.DM might have a deleterious impact on neointimal proliferation after EES implantation in this DM/HC swine model. The extent of glucose fluctuation may be related to the degree of neointimal proliferation and this needs to be further confirmed by long-term follow-up and histology.

High-dose metformin (420 mg/kg daily p.o.) increases insulin sensitivity but does not affect neointimal thickness in the rat carotid balloon injury model of restenosis

ObjectiveOur laboratory has shown that insulin's effect to decrease neointimal thickness after arterial injury is greatly diminished in insulin resistant conditions. Thus, in these conditions, a better alternative to insulin could be to use an insulin sensitizing agent. Metformin, the most commonly prescribed insulin sensitizer, has a cardiovascular protective role. Therefore, the objective of this study was to investigate the potential benefit of metformin on neointimal area after arterial injury in a rat model of restenosis. MethodsRats fed with either normal or high fat diet and treated with or without oral metformin (420mg/kg daily) underwent carotid balloon injury. Effects of metformin on clamp-determined insulin sensitivity, vessel AMPK (AMP-activated protein kinase) phosphorylation (activation marker) and neointimal area were evaluated. ResultsMetformin increased insulin sensitivity, but did not affect neointimal thickness in either the normal fat or high fat diet-fed rats. Furthermore, metformin activated AMPK in uninjured but not in injured vessels. Similarly, 10mmol/L metformin inhibited proliferation and activated AMPK in smooth muscle cells of uninjured but not injured vessels, whereas 2mmol/L metformin did not have any effect. ConclusionIn rats, metformin does not decrease neointimal growth after arterial injury, despite increasing whole body insulin sensitivity.

Localization of in-stent neoatherosclerosis in relation to curvatures and bifurcations after stenting.

In-stent neoatherosclerosis (ISNA) is a final common pathway of late-stent failure. However, distribution of ISNA has been little reported. This study was to evaluate the localization of ISNA in relation to curvatures and bifurcations after stent implantation using optical coherence tomography (OCT). We retrospectively selected patients who underwent OCT examination ≥12 months after stent (sirolimus-eluting stents, SES) implantation. A stent curvature was defined if the angulation of the stent segment was >29°. Distribution of ISNA in relation to stent curvature and bifurcation was evaluated. Totally, 331 patients were enrolled. The mean follow-up time was 15 months. Forty-one (12.3%) patients were found with ISNA. OCT results showed that stents with ISNA had thicker neointima (mean neointima thickness: 0.16 vs. 0.08 mm, P<0.001) compared to patients without ISNA. Segments with angulation >29° had a higher prevalence of ISNA compared with to angulation ≤29° [18 (18.4%) vs. 23 (9.9%), P=0.032]. ISNA was more frequently located at the "inner curvature" than the "outer curvature" (77.8% vs. 22.2%, P=0.018). If ISNA occurred in a branch, it was more often on the opposite side of the branch compared with the same side of the branch [21 (77.8%) vs. 6 (22.2%), P=0.004]. Localization of ISNA is related to vessel curvatures and bifurcations. ISNA occurs more often on the inner curvature and the opposite side of the branch.

Impact of branching angle on neointimal coverage of drug-eluting stents implanted in bifurcation lesions

To investigate the impact of branching angle (BA) on neointimal coverage of drug-eluting stents (DESs) in bifurcation lesions. Previous experimental studies indicated that BA influences the local flow turbulence and wall shear stress, which are associated with neointimal coverage of DESs. Fifty-five bifurcation lesions in 47 patients were evaluated by serial optical coherence tomography (OCT) before DES implantation and at follow-up. Neointimal coverage was assessed in cross-sectional OCT images containing the side branch; regions including the side branch ostium (SO) and vessel wall (VW) were assessed separately. BA was measured using angiography (Angio-BA) and longitudinal OCT imaging (OCT-BA). In the SO region, a significant negative correlation was found between the uncovered strut percentage and Angio-BA or OCT-BA (r=-0.41, P=0.0024; r=-0.33, P=0.0167, respectively) and a significant positive correlation was found between Angio-BA and average neointimal thickness (r=0.31, P=0.025), whereas no correlation was observed between OCT-BA and average neointimal thickness (r=0.20, P=0.158). In the VW region, no correlation was found between Angio-BA or OCT-BA and the uncovered strut percentage or average neointimal thickness. BA influence the neointimal coverage over DES struts in the SO at coronary bifurcation lesions, but not in those attached to the VW.

Abstract 13902: Comparison of Stent Performance Between ZES and EES

Introduction: Although drug-eluting stents (DESs) have reduced restenosis, a unique issue beyond restenosis, i.e., impairment of re-endothelialization, which may delay wound healing and cause a relapse of inflammation, leading to neoathroma formation at the stented sites, in addition to lack of neointimal coverage, has arisen. Therefore, overall stent performance should be characterized by the abilities of geometric luminal gain acquisition, neointimal coverage of the stent struts, and stabilization of the underlying inflammatory neoatheroma. Hypothesis: Our hypothesis is that stent performance would be different between 2 second generation DESs, zotarolimus-eluting stent (ZES) and everolimus-eluting stent (EES). Methods: We compared stent performance among ZES, EES and bare metal stent (BMS) using optical coherence tomography (OCT) and coronary angioscope (CA). For 37 stented coronary lesions (EES; 16 lesions, ZES; 10 lesions and BMS; 11 lesions) in 20 patients, we observed stented sites by the OCT at 6-12 months after stent placement and measured neointimal area at the site of minimal lumen area and ratio of uncovered stent strut to the whole struts. Also by the CA, neointimal coverage was observed, and neointimal color was simultaneously observed. From the CA findings, the grades of neointimal coverage and yellow color were classified into 0 to 3. Results: The neointimal area (mm 2 ) was 1.30±1.12 in the EES lesions, 2.74±1.17 in the ZES lesions (P&lt;0.05 vs EES), and 3.76±1.01 in the BMS lesions (P&lt;0.001 vs EES, P=0.07 vs ZES). The OCT-based uncovered ratio was 26.9% in the EES lesions, 2.1% in the ZES lesions (P&lt;0.01 vs EES), and 1.2% in the BMS lesions (P&lt;0.001 vs EES, P=0.9 vs ZES). Stent coverage grade by the CA findings was 0.44±0.53 in the EES lesions, 2.00±1.00 in the ZES lesions (P&lt;0.001 vs EES), and 2.33±0.82 in the BMS lesions (P&lt;0.01 vs EES, P=0.5 vs ZES). The yellow grade was 1.67±0.50 in the EES lesions, 0.29±0.48 in the ZES lesions (P&lt;0.001 vs EES), and 0.17±0.41 in the BMS lesions (P&lt;0.001 vs EES, P=0.7 vs ZES). Conclusions: ZES might be better than BMS in terms of neointimal thickening, and better than EES in terms of neointimal coverage as well as stabilization of inflammatory neoatheroma. ZES may have superior stent performance, compared to EES.

Characteristic of apoptosis of coronary artery cells with atherosclerotic lesions

To study apoptosis of endothelial cells (EC), macrophages (MF) and smooth muscle cells (SMC) in the early atherosclerotic process (prior to plaque formation), elucidate mechanisms of its realization and evaluate effect on progression of atherosclerosis. Histopathological studies were performed on coronary arteries affected by atherosclerosis taken at autopsy of patients with coronary heart disease (n = 63). To detect apoptosis, the TUNEL method was used for calculating the apoptotic index (AI) in paraffin sections. Phenotyping the cells and test for expression of active caspase 3 (AC-3) and apoptosis-inducing factor (AIF) were performed using sections of coronary arteries stained by immunohistochemistry. The study of apoptosis showed a significant (p <0.0001) increase in AI of SMC, EC, MF coronary arteries affected by atherosclerosis compared with unaffected vessels. Progression of the atherosclerotic process led to a decrease of AI of SMC and EC. Statistical analysis revealed moderate feedback between AI of SMC and neointimal thickness in the development of atherosclerotic lesions (r = -0,44, p <0.0001). The amount of the AC-positive SMC and EC at the stage of lipoidosis significantly (p <0.0001) exceeded the number of AC -positive SMC at the liposclerosis stage. Expression of AIF was observed in the nuclei of EC in the newly formed vessels of hyperplastic intima. Early atherosclerotic lesions of the coronary arteries are accompanied by intense apoptosis of SMC, EC and MF. The intensity of apoptosis of SMC and EC decreases with the development of atherosclerosis. Progression of intimal hyperplasia at the early stages of atherosclerosis is associated with reduced apoptosis of smooth muscle cells and enhanced macrophage apoptosis. Apoptosis of SMC and MF is caspase-dependent. Apoptosis of endothelial cells can occur both with the participation of caspases and independently of them (with AIF).

Neointimal response to everolimus-eluting bioresorbable scaffolds implanted at bifurcating coronary segments: insights from optical coherence tomography.

Heterogeneity of neointimal thickness is observed after drug-eluting stents implantation in bifurcation lesions (BL). We evaluated the vascular response of everolimus-eluting bioresorbable scaffold (BRS) struts deployed at BL using optical coherence tomography (OCT). 50 patients (64 scaffolds) underwent follow-up OCT after BRS implantation. Cross-sectional areas of each BL with a side branch more than 1.5mm were analyzed using OCT every 200µm. All images were divided into three regions according to shear stress: the 1/2 circumference of the vessel opposite to the ostium (OO), the vessel wall adjacent to the ostium (AO) and the side-branch ostium (SO). The %uncovered strut and the averaged neointimal thickness (NIT) were calculated. Overall, there were significant differences in both NIT and %uncovered strut among the three regions (OO, 119.2 ± 68.5μm vs. AO, 94.2 ± 35.7μm vs. SO, 80.5 ± 41.4μm, p = 0.03; OO, 0.4 %vs. AO, 1.4 %vs. SO, 4.8 %, p = 0.02). Scaffolds were divided into two groups: a large-ratio side-branch group (LRSB; n = 32) and a small-ratio side-branch group (SRSB; n = 32), based on the median value of the ratio of the diameter of side branch ostium (Ds) to that of the main branch (Dm). In the LRSB alone, there were significant differences in both NIT and %uncovered strut among the three regions (OO, 128.0 ± 61.1μm vs. AO, 97.3 ± 34.3μm vs. SO, 75.9 ± 39.4μm, p < 0.01; OO, 0.3 % vs. AO, 2.3 % vs. SO, 8.7 %, p < 0.01). After BRS implantation in BL, neointimal response was pronounced at the vessel wall opposite to the side branch ostium, especially in those with large side branches.

Intravascular imaging comparison of two metallic limus-eluting stents abluminally coated with biodegradable polymers: IVUS and OCT results of the DESTINY trial

We sought to compare, by means of IVUS and OCT imaging, the performance of a novel sirolimus-eluting drug-eluting stent (DES) with biodegradable polymer (Inspiron™) to the Biomatrix™ DES. From the DESTINY trial, a total of 70 randomized patients (2:1) were enrolled in the IVUS substudy (Inspiron™, n = 46; Biomatrix™: n = 20) while 25 patients were evaluated with OCT (Inspiron™, n = 19; Biomatrix™: n = 06) at 9-month follow-up. The main endpoints were % of neointimal tissue obstruction (IVUS) and neointimal stut coverage (OCT) at 9months. Patients treated with both DES had very little NIH formation at 9months either by IVUS (% of NIH obstruction of 4.9 ± 4.1 % with Inspiron™ vs. 2.7 ± 2.9 % with Biomatrix™, p = 0.03) or by OCT (neointimal thickness of 144.2 ± 72.5µm Inspiron™ vs. 115.0 ± 53.9µm with Biomatrix™, p = 0.45). Regarding OCT strut-level assessment, again both devices showed excellent 9-month performance, with high rates of strut coverage (99.49 ± 1.01 % with Inspiron™ vs. 97.62 ± 2.21 % with Biomatrix™, p < 0.001) and very rare malapposition (0.29 ± 1.06 % with Inspiron™ vs. 0.53 ± 0.82 % with Biomatrix™, p = 0.44). Patients with any uncovered struts were more frequently identified in the Biomatrix™ group (9.78 ± 7.13 vs. 2.29 ± 3.91 %, p < 0.001). In the present study, midterm IVUS and OCT evaluations showed that both new generation DES with biodegradable polymer were effective in terms of suppressing excessive neointimal response, with very high rates of apposed and covered struts, suggesting a consistent and benign healing pattern.

Endothelial‑like cells differentiated from mesenchymal stem cells attenuate neointimal hyperplasia after vascular injury.

The present study investigated the contribution of bone marrow-derived mesenchymal stem cells (BM-MSCs) to neointimal formation, and whether endothelial-like cells (ELCs) differentiated from BM-MSCs could attenuate intimal hyperplasia following vascular injury. BM-MSCs were isolated from rat femurs and tibias and expanded ex vivo. Differentiation into ELCs was induced by cultivation in the presence of 50 ng/ml vascular endothelial growth factor (VEGF). MSCs and ELCs were labeled with BrdU and injected via the femoral vein on the day of a balloon-induced carotid artery injury. Carotid artery morphology and histology were examined using ultrasound biomicroscopy and immunohistochemistry. Flow cytometry analysis measured CD31 and CD34 expression, and immunofluorescence analysis measured von Willebrand factor and VEGF receptor 2 expression in ELCs. Ultrasound biomicroscopy observed a significantly increased intima-media thickness in the phosphate-buffered saline (PBS) and BM-MSCs groups compared with the ELCs group. Intima/media ratios were significantly reduced in the ELCs group compared with the PBS and BM-MSCs groups. At 4 weeks of administration, the cells labeled with BrdU were abundantly located in the adventitial region and neointima. MSCs were able to differentiate into ELCs in vitro. Cell therapy with BM-MSCs was not able to attenuate neointima thickness, however transplantation with ELCs significantly suppressed intimal hyperplasia following vascular injury.

Delivery of bevacizumab to atheromatous porcine carotid tissue using echogenic liposomes

Ultrasound is both a valuable diagnostic tool and a promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. Vascular effects can be mediated by mechanical oscillations of circulating microbubbles that may also encapsulate and shield therapeutic agents in the bloodstream. Here, the effect of color-Doppler ultrasound exposure on bevacizumab-loaded liposome delivery into the vascular bed was assessed in atheromatous porcine carotids. Bevacizumab, an anti-angiogenic antibody to vascular endothelial growth factor (VEGF-A), was loaded into echogenic liposomes (BEV-ELIP) and confirmed to be immunoreactive. BEV-ELIP flowing within the lumen were exposed to color-Doppler ultrasound at three acoustic pressures for 3.5 min during treatment at physiologic temperature and fluid pressure. To confirm the presence of bubble activity, cavitation was detected within the lumen by a single-element passive cavitation detector. After treatment, the artery was fixed at physiologic pressure and subjected to immunohistochemical analysis to assess the penetration of bevacizumab within the carotid wall. The results suggest that other factors may more strongly influence the deposition of bevacizumab into carotid tissue than color-Doppler ultrasound and cavitation. In both sets of arteries, preferential accumulation of bevacizumab occurred in locations associated with atheroma progression and neointimal thickening: fibrous tissue, necrotic plaque and areas near macrophage infiltration. The delivery of bevacizumab to carotid vascular tissue correlated with the properties of the tissue bed, such as permeability, or affinity for growth-factor binding. Future investigations using this novel therapeutic strategy may focus on characterizing the spatial extent of delivery and bevacizumab colocalization with biochemical markers of atheroma.