Neointimal characteristic changes following drug-coated balloons in lesions with repeated revascularization.

BACKGROUND: Since their emergence, drug-coated balloons (DCBs) have been used widely to treat in-stent lesions with coronary artery disease (CAD). However, despite their superior efficacy to balloon angioplasty, how DCBs affect neointimal characteristics is poorly understood. OBJECTIVES: We aimed to assess the neointimal characteristic changes following DCB treatment. METHODS: Using optical frequency domain imaging (OFDI), we serially observed the in-stent lesion site just after and 1 year after DCB angioplasty in 12 lesions of 11 patients with repeated revascularization. Neoatherosclerosis was defined as lipid-laden neointima with or without calcification in the stented lesion. Progression or regression of neoatherosclerosis, newly formed neointimal calcification, newly formed uncovered strut and newly formed evagination were assessed. Tiny tissue protrusion was also recorded as mushroom-like protrusion. RESULTS: Underlying stents were first-generation (n = 5) or newer (n = 7) drug-eluting stents (DESs) with implantation durations ranging from 1 to 15 years (median 8 years). Surprisingly, two-thirds of the lesions (67%, 8 of 12) showed progression of neoatherosclerosis, while a quarter of lesions (25%, 3 of 12) showed regression of neoatherosclerosis. The maximal lipid arc increased from 122° to 174°. Newly formed neointimal calcification was observed in 2 of 12 lesions (16%). Newly formed uncovered struts (33%; 4 of 12) and newly formed evaginations (33%; 4 of 12) were not rare. Mushroom-like protrusion was found in a quarter of lesions (25%; 3 of 12). CONCLUSION: Our study demonstrated that a considerable number of lesions showed varied neointimal characteristic changes in a small number of patients. Further studies in a larger population are needed to understand the clinical impact of these findings.

Incidence and Predictors of Neoatherosclerosis in Patients with Early In-Stent Restenosis Determined Using Optical Coherence Tomography.

In-stent restenosis (ISR) still exists after drug-eluting stent (DES) implantation, even up to one year. The incidence and risk factors for neoatherosclerosis in patients with early ISR have not yet been elucidated. Here, we used optical coherence tomography (OCT) to evaluate the incidence and predictors of neoatherosclerosis in patients with early ISRs.OCT was performed on ISR lesions in 185 patients in order to detect neoatherosclerosis. The median follow-up was 180 days, and neoatherosclerosis was detected in 37% of early ISR lesions. According to the presence of neoatherosclerosis, patients with ISR were divided into two groups: neoatherosclerosis (group A, n = 69) and non-neoatherosclerosis (group B, n = 116) groups.The risk factors were similar, except for hypercholesterolemia. Moreover, the tissue characteristics were not significantly different between patients with and without neoatherosclerosis. Follow-up low-density lipoprotein-cholesterol (LDL-C) levels were divided into three grades (LDL < 70 mg/dL, 70 mg/dL≤ LDL < 100 mg/dL, and LDL ≥ 100 mg/dL). The incidence of neoatherosclerosis was significantly lower (23% versus 57%, P < 0.0001) in the LDL < 70 mg/dL group. There was no significant difference in the incidence of neoatherosclerosis in patients with lipid levels between 70 and 100 mg/dL (P = 0.53). However, neoatherosclerosis was significantly more common in patients with a follow-up LDL-C level > 100 mg/dL (45% versus 15%, P < 0.0001).In patients with early ISR lesions, the LDL-C levels may be related to the formation and progression of early neoatherosclerosis, and poor LDL-C control may be a risk factor for the occurrence of early-stage neoatherosclerosis following DES implantation.

Hypoxia-inducible factors in arteriovenous fistula maturation: A prospective cohort study.

BACKGROUND: Neointimal hyperplasia is the main cause of arteriovenous fistula (AVF) failure. Hypoxia-inducible factors (HIFs) factors are associated with neointimal hyperplasia. Thus, we investigated the association between HIF-2 alpha (HIF-2α) and AVF maturation in end-stage kidney disease (ESKD) patients. METHODS: This prospective cohort study was conducted in 21 voluntary healthy subjects and 50 patients with ESKD who were eligible for AVF creation. Inclusion criteria were being ESKD patients without a history of AVF surgery and dialysis. Eight patients excluded from the study due to having unavailable veins six patients were excluded due to acute thrombosis after surgery. One patient lost to follow-up. A total of 35 patients were included in final analysis. The blood samples were collected a day before the AVF surgery for biochemical parameters and HIF-2α measurement. HIF-2α levels were measured by the ELISA method. RESULTS: Compared with healthy subjects, ESKD patients had a significantly higher level of HIF-2α. [1.3 (1.0-1.9) vs 2.2 (1.6-3.0)] (P = .002). Patients were divided into two groups after the evaluation of AVF maturation, as the mature group (n = 19) and the failure group (n = 16). Serum HIF-2α level was 1.7 (1.1-1.8) in the mature group; however, it was 3.1 (2.8-3.3 in failure group (P < .001). Multiple logistic regression analyses showed that HIF-2α independently predicted AVF maturation. The ROC curve analysis showed that HIF-2α > 2.65 predicted AVF maturation failure with the 87% sensitivity and 94% specificity [AUC:0.947, 95% CI (0.815-0.994), P < .001]. CONCLUSIONS: HIF-2-α levels were higher in ESKD patients than healthy subjects. HIF-2-α could be a marker of AVF maturation failure.

The occurrence of neointimal hyperplasia after flow-diverter implantation is associated with cardiovascular risks factors and the stent design.

BACKGROUND: Neo-intimal hyperplasia (NIH) is frequently observed after flow-diverter stent (FDS) implantation. Although mostly asymptomatic, this vascular response can sometimes lead to delayed ischemic strokes. This study intended to evaluate the factors potentially influencing the rates of NIH following FDS treatment. MATERIAL AND METHODS: All aneurysm treatments performed with a Pipeline embolization device (PED) or a SILK stent from May 2011 to May 2015 were collected in a prospectively maintained database. Patient demographics, clinical, and angiographic outcomes including both digital subtraction angiography and C-arm cone-beam CT were registered. Two blind reviewers rated the presence of NIH on a binary scale (present/absent). RESULTS: From 148 patients, 63 datasets were available for analysis. Inter-reader agreement was excellent (Kappa=0.88). NIH was positively correlated with smoking, dyslipidemia, and high blood pressure, but not with aneurysm characteristics. At early follow-up (<12 months), NIH was more frequently associated with the use of the SILK stent (68%) rather than the PED (38%): P<0.02. At long-term follow-up, the NIH rate in the total population dropped from 55% to 26% with no more significant difference between the two stents. The complete occlusion rate as seen in early follow-up was higher in the SILK group with 76% vs 65% but without statistical significance (P=0.4). CONCLUSION: NIH is a dual-vessel reaction after FDS implant. When planning a treatment in locations at risk of ischemic complications if severe NIH would occur, then the stent design should be considered. However, minimal NIH might also be needed as it is involved in aneurysm healing. Before treatment patients should be recommended best medical management of their cardiovascular risks factors to prevent an excessive NIH reaction.

Safety and Efficacy of New Biodegradable Polymer-based Sirolimus-Eluting Stents in a Preclinical Model.

INTRODUCTION AND OBJECTIVES: New drug-eluting stents (DES) designed to overcome the limitations of existing devices should initially be tested in preclinical studies. Our objective was to analyze the safety and efficacy of new biodegradable polymer-based DES compared with bare-metal stents (BMS) and commercially available DES in a model of normal porcine coronary arteries. METHODS: We randomly implanted 101 stents (BMS and biodegradable polymer-based sirolimus-eluting stents: 3 test stent iterations [BD1, BD2, and BD3], Orsiro, Biomime and Biomatrix) in the coronary arteries of 34 domestic pigs. Angiographic and histomorphometric studies were conducted 1 month (n = 83) and 3 months (n = 18) later. RESULTS: The stents were implanted at a stent/artery ratio of 1.31 ± 0.21, with no significant differences between groups. At 1 month, the new test stents (BD1, BD2 and BD3) showed less late loss and angiographic restenosis, as well as lower histologic restenosis and neointimal area (P < .0005), than the BMS. There were no differences in endothelialization, vascular injury, or inflammation between the new test stents and BMS, although the new stents showed higher fibrin deposition (P = .0006). At 3 months, all these differences disappeared, except for a lower neointimal area with the new BD1 stent (P = .027). No differences at any time point were observed between the new test stents and commercially available controls. CONCLUSIONS: In this preclinical model, the new biodegradable polymer-based DES studied showed less restenosis than BMS and no significant differences in safety or efficacy vs commercially available DES.

In-stent neoatherosclerosis and tissue characteristics of restenotic lesions following implantation of second generation drug-eluting stents in unrestricted coronary lesions: Optical frequency domain imaging study.

BACKGROUND: Differences in stent platform, polymer coatings, and antirestenotic drugs among the current in use second-generation drug-eluting stents (G2-DESs) may induce significant variations in neointimal response and vascular healing, which may impact the prevalence of neoatherosclerosis (NA) and morphological appearance of the restenotic tissue. METHODS AND RESULTS: Utilizing Optical frequency domain imaging, two independent reviewers, retrospectively compared the prevalence of neoatherosclerosis (NA), and the morphological differences, and tissue characteristics of 50 G2-DESs in-stent restenosis (ISR) lesions (35 everolimus-eluting stent [22 cobalt-chromium (CoCr), 13 platinum-chromium (PtCr)], and 15 biolimus-eluting stent [BES]) implanted liberally in unrestricted coronary lesions. More than half of the stents were implanted in type C lesions, while 40% of the stents were implanted primarily in lesions with recanalized chronic total occlusion. NA, defined as a neointima formation with the presence of lipids or calcification, was observed in fewer than half (24/50) of all ISR lesions with no significant in-between group differences (41%, 69%, and 40% in CoCr, PtCr, and BES respectively, P = 0.22), nor were there any significant differences in the morphological appearance or tissue characteristics between all G2-DESs subtypes. CONCLUSIONS: Acknowledging some limitations, our results may suggest that the prevalence of NA and the morphological appearance of restenotic lesions might not differ when G2-DESs are implanted in unrestricted, rather complex, coronary lesions.

Comparison of Chronic Angioscopic Findings of Bare Metal Stents, 1st-Generation Drug-Eluting Stents and 2nd-Generation Drug-Eluting Stents　- Multicenter Study of Intra-Coronary Angioscopy After Stent (MICASA).

BACKGROUND: No previous study has reported a comprehensive comparison of the chronic angioscopic findings after bare metal stent (BMS), and 1st- and 2nd-generation drug-eluting stents (DES). METHODS AND RESULTS: The Multicenter Study on Intra-Coronary Angioscopy after Stent (MICASA) is a multicenter registry of coronary angioscopy. A total of 264 stents were observed by coronary angioscopy 1 year after PCI. There were 15 BMS, 90 1st-generation DES, and 159 2nd-generation DES. Neointimal coverage (NC) of the stent was classified into 4 grades from 0 (no coverage) to 3 (complete coverage). Yellow color (YC) of plaque at the stented segment was graded from 0 (white) to 3 (bright yellow). Minimum (Min-) and Maximum (Max-) NC grade were significantly lower with 1st- and 2nd-generation DES than with BMS. Although the Max-NC grade was similar, the Min-NC grade was significantly higher for 2nd-generation DES than for 1st-generation DES. Both the YC grade and the incidence of thrombus with 2nd-generation DES were lower than with the 1st-generation DES and were comparable to BMS. Multivariate analysis showed that low-density lipoprotein, 1st-generation DES, and acute coronary syndrome were independent factors for yellow plaque (YG2 or 3), and that hypertension and 1st-generation DES were independent factors for the incidence of thrombus. CONCLUSIONS: Coronary angioscopy revealed more homogeneous coverage with white neointima and less thrombus after 2nd-generation DES as compared with 1st-generation DES. These findings may explain the favorable clinical outcomes observed for patients treated with 2nd-generation DES. (Circ J 2016; 80: 1916-1921).

Clinical and angiographic evaluation of the resolute zotarolimus-eluting coronary stent in Japanese patients ­ long-term outcome in the RESOLUTE Japan and RESOLUTE Japan small vessel study.

BACKGROUND: This study evaluated the safety and efficacy of the RESOLUTE(TM)zotarolimus-eluting stent (R-ZES; Medtronic, Inc, Santa Rosa, CA, USA) in Japanese patients for the treatment of de novo native coronary lesions. METHODS AND RESULTS: Both RESOLUTE Japan (R-Japan) and RESOLUTE Japan Small Vessel Study (R-Japan SVS) were prospective, multicenter, single-arm observational studies. R-Japan enrolled 100 patients (reference vessel diameter, 2.5-3.5 mm) and R-Japan SVS enrolled 65 patients (at least 1 lesion suitable for 2.25-mm stent) treated with R-ZES. In R-Japan, in-stent late lumen loss (LLL; the primary endpoint) at 8 months was 0.12 ± 0.22 mm and volume obstruction on intravascular ultrasound was 2.33 ± 3.51%. At 4 years, there were no cases of clinically driven target lesion revascularization (TLR); the target lesion failure (TLF; composite of cardiac death, target vessel myocardial infarction, and clinically driven TLR) was 5.6% (5/90). In R-Japan SVS, in-stent LLL at 9 months was 0.27 ± 0.33 mm, TLF (primary endpoint) was 4.6% (3/65), without incidence of TLR. At 3 years, TLF was 7.9% (5/63) and clinically driven TLR, 3.2% (2/63). CONCLUSIONS: R-Japan and R-Japan SVS demonstrate substantial suppression of neointimal hyperplasia, low LLL, and excellent and sustained long-term clinical outcome with R-ZES in Japanese patients.

Vascular response to drug-eluting stent with biodegradable vs. durable polymer. Optical coherence tomography substudy of the NEXT.

BACKGROUND: The aim of the present study was to compare vascular healing response between everolimus-eluting stent (EES) and biolimus-eluting stent (BES) using optical coherence tomography (OCT). METHODS AND RESULTS: In the NOBORI Biolimus-Eluting Versus XIENCE V/PROMUS Everolimus-Eluting Stent Trial (NEXT), a formal OCT substudy investigated 91 patients (55 EES-treated lesions in 48 patients and 51 BES-treated lesions in 43 patients) with 8-12 months follow-up imaging at 18 centers. A total of 980 frames with 8,996 struts in EES and 907 frames with 8,745 struts in BES were analyzed. Mean neointima thickness in EES and BES was 105±82µm and 91±80µm, respectively (P<0.001). With regard to stent-treated lesions, the percentage of struts not covered by neointima (3±7% vs. 9±10%, P<0.001) and the frequency of stent-treated lesions with any uncovered struts (n=28, 51% vs. n=42, 82%; P<0.001) were significantly lower in EES compared with BES. In addition, the percentage of malapposed struts (0.2±0.8% vs. 1.3±2.8%, P=0.006) and the frequency of stent-treated lesions with any malapposed struts (n=6, 11% vs. n=14, 27%; P=0.028) were significantly lower in EES compared with BES. CONCLUSIONS: Incomplete vascular healing characterized by the presence of struts not covered by neointima and malapposed struts was less common in EES compared with BES.

Serial observation of drug-eluting absorbable metal scaffold: multi-imaging modality assessment.

BACKGROUND: The drug-eluting absorbable metal scaffold has demonstrated feasibility, safety, and promising clinical and angiographic outcomes at 12 months in human coronary arteries. This study aimed to evaluate the degradation rate and long-term vascular responses to drug-eluting absorbable metal scaffold. METHODS AND RESULTS: BIOSOLVE-I was a multicenter, single-arm, first-in-man trial assessing the safety and performance of drug-eluting absorbable metal scaffold in 46 patients with coronary artery disease. Patients who underwent serial invasive imaging, such as quantitative coronary angiography, intravascular ultrasound, and optical coherence tomography, at 6 and 12 months were included in this study. From postimplantation to follow-up, arterial curvature and angulation were significantly increased by the degradation process. The greatest increase was seen from postimplantation to 6 months. The systolic-diastolic changes of the curvature and angulation gradually improved throughout the follow-up period. At the site of implantation, vasoconstriction (-10% mean reduction) was observed during the acetylcholine test at 6 months. The average percent hyperechogenicity of the scaffolded segments showed a continuous decrease over time, with the most pronounced changes within the first 6 months (from 22.1±7.0% to 15.8±3.7%; P<0.001). Struts discernible on optical coherence tomography at 6 and 12 months showed full neointimal coverage, with stabilization of the mean scaffold area from 6 to 12 months. Furthermore, the mean neointimal area (1.55±0.51 versus 1.58±0.34 mm(2); P=0.794) remained unchanged from 6 to 12 months. CONCLUSIONS: This serial analysis of drug-eluting absorbable metal scaffold confirmed the safety and efficacy of this new device, with vasomotion restoration and continued degradation over time demonstrated by multi-invasive imaging modalities. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01168830.

Correlation between degree of neointimal hyperplasia and incidence and characteristics of neoatherosclerosis as assessed by optical coherence tomography.

Emerging evidence suggests that neointimal degenerative changes with development of neoatherosclerosis (NA) may represent an important mechanism for late stent failure. The aim of the present study was to investigate the relation between degree of neointimal hyperplasia and incidence and characteristics of NA using optical coherence tomography. We identified a total of 252 stents with mean neointimal thickness (NIT) >100 µm in 212 patients: 100 bare metal stents (BMSs) and 152 drug-eluting stents (DESs). Based on the values of mean NIT, we divided stents into tertiles and compared neointimal characteristics among the 3 groups. NA was defined as the presence of lipid-laden intima and/or calcification inside the stent. In both BMS and DES, there was a difference in the prevalence of lipid-laden intima among the tertiles (18.2% vs 36.4% vs 47.1%, p = 0.042 [BMS]; 19.6% vs 56.9% vs 88.0%, p <0.001 [DES]). However, no difference in the prevalence of in-stent calcification was observed (21.2% vs 21.2% vs 2.9%, p = 0.053 [BMS]; 5.9% vs 9.8% vs 2.0%, p = 0.252 [DES]). In a multivariate model adjusting for stent type, follow-up duration, conventional coronary risk factors, statin, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blockade use, mean NIT was independently associated with the presence of NA (odds ratio 2.53, 95% confidence interval 1.96 to 3.27, p <0.001). This study demonstrates the presence of a positive correlation between degree of neointimal hyperplasia after stent implantation and presence of lipid-laden intima. This association is independent from stent type and time from implantation and suggests a possible pathogenic link between the two processes.

Histopathologic validation of optical coherence tomography findings of non-apposed side-branch struts in porcine arteries.

BACKGROUND: The presence of uncovered struts overlying side branch is considered to be a potential risk of stent thrombosis. The accuracy in detection of neointimal strut coverage at branch point by optical coherence tomography (OCT) has not been validated in comparison with histology. METHODS: A total of 5 stents (3 drug-eluting stents and 2 bare-metal stents) were implanted in the bifurcation segment of normal coronary arteries in 4 domestic swine (weight, 25-40 kg). The animals underwent follow-up OCT at 30 days after stent implantation and were then sacrificed for histologic evaluation. The neointimal coverage of the non-apposed struts over the side branch was assessed by light microscopy. Every millimeter of the stent was specified by the OCT frame rate, and comparisons between OCT and pathologic findings were performed through precise histological-OCT frame matching. RESULTS: OCT images at the side branch corresponded well with histological cross-sections. The tissues covering struts as assessed by OCT contained smooth muscle cells with proteoglycan-collagen matrix, but platelets are attached above the neointima in one of them on histologic examination, suggesting that most of the struts were well healed, with normal neointimal coverage. CONCLUSION: This study demonstrated the accuracy of OCT for the detection of neointimal coverage of non-apposed struts over the side branch.

Protective constriction of coronary vein grafts with knitted nitinol.

OBJECTIVES: Different flow patterns and shear forces were shown to cause significantly more luminal narrowing and neointimal tissue proliferation in coronary than in infrainguinal vein grafts. As constrictive external mesh support of vein grafts led to the complete suppression of intimal hyperplasia (IH) in infrainguinal grafts, we investigated whether mesh constriction is equally effective in the coronary position. METHODS: Eighteen senescent Chacma baboons (28.8 ± 3.6 kg) received aorto-coronary bypass grafts to the left anterior descending artery (LAD). Three groups of saphenous vein grafts were compared: untreated controls (CO); fibrin sealant-sprayed controls (CO + FS) and nitinol mesh-constricted grafts (ME + FS). Meshes consisted of pulse-compliant, knitted nitinol (eight needles; 50 µm wire thickness; 3.4 mm resting inner diameter, ID) spray attached to the vein grafts with FS. After 180 days of implantation, luminal dimensions and IH were analysed using post-explant angiography and macroscopic and histological image analysis. RESULTS: At implantation, the calibre mismatch between control grafts and the LAD expressed as cross-sectional quotient (Qc) was pronounced [Qc = 0.21 ± 0.07 (CO) and 0.18 ± 0.05 (CO + FS)]. Mesh constriction resulted in a 29 ± 7% reduction of the outer diameter of the vein grafts from 5.23 ± 0.51 to 3.68 ± 0 mm, significantly reducing the calibre discrepancy to a Qc of 0.41 ± 0.17 (P < 0.02). After 6 months of implantation, explant angiography showed distinct luminal irregularities in control grafts (ID difference between widest and narrowest segment 74 ± 45%), while diameter variations were mild in mesh-constricted grafts. In all control grafts, thick neointimal tissue was present [600 ± 63 µm (CO); 627 ± 204 µm (CO + FS)] as opposed to thin, eccentric layers of 249 ± 83 µm in mesh-constricted grafts (ME + FS; P < 0.002). The total wall thickness had increased by 363 ± 39% (P < 0.00001) in CO and 312 ± 61% (P < 0.00001) in CO + FS vs 82 ± 61% in ME + FS (P < 0.007). CONCLUSIONS: In a senescent non-human primate model for coronary artery bypass grafts, constrictive, external mesh support of saphenous veins with knitted nitinol prevented focal, irregular graft narrowing and suppressed neointimal tissue proliferation by a factor of 2.5. The lower degree of suppression of IH compared with previous infrainguinal grafts coincided with a lesser reduction of calibre mismatch in the coronary grafts.

Evaluation of neointimal coverage and apposition with various drug-eluting stents over 12 months after implantation by optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) is an imaging technology with high resolution which provides new opportunities for evaluating the vascular healing reaction after stent implantation. We used OCT to compare neointimal coverage and stent strut apposition with different types of drug-eluting stent (DES) at more than 12 months follow-up. METHODS: Fifty five patients who accepted 72 DESs (19 sirolimus-eluting stents [SES, Cypher Select], 27 paclitaxel-eluting stents [PES, Taxus Liberte], 26 zotarolimus-eluting stents [ZES, Endeavor]) were enrolled in our study. OCT was performed at 12-18 months after stent implantation. The neointimal hyperplasia (NIH) thickness and stent strut apposition at 1-mm interval and the presence of thrombus in each stent were observed. RESULTS: The average NIH thickness (0.1806 ± 0.1726 mm in SES vs. 0.2558 ± 0.2187 mm in PES vs. 0.2983 ± 0.2567 mm in ZES, p<0.001) and percentage of NIH area (17.21 ± 14.05% in SES vs. 23.09 ± 14.53% in PES vs. 28.73 ± 20.47% in ZES, p=0.002) were significantly greater in ZES than in other DESs. The prevalence of uncovered struts (8.96% in SES vs. 6.19% in PES vs. 2.98% in ZES, p<0.01) and malapposed struts (6.36% in SES vs. 2.32% in PES vs. 1.69% in ZES, p<0.01) was significantly lower in ZES than in other DESs. Thrombus was less frequently observed in ZES than in other DESs (SES 1.70% vs. PES 0.83% vs. ZES 0.17%, p<0.01). CONCLUSIONS: Compared with SES and PES, ZES showed lower prevalence of uncovered struts and malapposed struts at more than 12 months follow-up.

Optical coherence tomography-based evaluation of in-stent neoatherosclerosis in lesions with more than 50% neointimal cross-sectional area stenosis.

AIMS: To use optical coherence tomography (OCT) to evaluate the time course, risk factors, and clinical implication of in-stent neoatherosclerosis. METHODS AND RESULTS: The neointimal characteristics of 152 lesions, 128 drug-eluting stents (DESs) and 24 bare metal stents (BMSs), with >50% percent cross-sectional area (CSA) neointimal stenosis were evaluated. Neoatherosclerosis was defined as neointima with presence of lipid or calcification. Neoatherosclerosis was observed in 54 lesions (35.5%, 35 DESs and 19 BMSs). Median time to follow-up was 70.7 months in lesions with neoatherosclerosis (longer than lesions without neoatherosclerosis [13.4 months, p<0.001]): 58.7 months in DES-treated lesions and 129.5 months in BMS-treated lesions (p<0.001). The optimal cut-off time to predict neoatherosclerosis in DES-treated lesions was 30 months with a sensitivity of 91.4% and a specificity of 72.0% (area under curve: 0.839, 95% confidence interval: 0.764-0.898, p<0.001). Independent risk factors for neoatherosclerosis were stent age, use of first-generation DES and hypertension. Patients with neoatherosclerosis (versus without neoatherosclerosis) had a higher rate of target lesion revascularisation (92.6% vs. 77.6%, respectively, p=0.018) and stent thrombosis (14.8% vs. 0%, respectively, p<0.001). CONCLUSIONS: Neoatherosclerosis occurred in one-third of stented lesions with >50% percent CSA stenosis of neointima. Late-phase development of neoatherosclerosis might be associated with clinical deterioration of stented lesions.

Cre8™ coronary stent: preclinical in vivo assessment of a new generation polymer-free DES with Amphilimus™ formulation.

AIMS: This new generation of DES has attempted to improve clinical safety by avoiding the presence of polymers. The present preclinical in vivo study was designed to investigate the safety profile of Cre8™ stent. This is a new coronary stent based on Amphilimus™, a sirolimus formulated with a polymer-free amphiphilic carrier released from reservoirs machined onto the abluminal stent surface. METHODS AND RESULTS: Cre8™ stents were compared with two controls: R3 (the same platform only loaded with an amphiphilic carrier) and the Cypher Select Plus® stent (Cordis, Johnson & Johnson, Warren, NJ, USA). All devices (48 stents) were implanted in porcine coronary arteries with subsequent histological and morphometric evaluations at seven, 30 and 90 days. Early endothelisation at seven days was almost complete in all stents. Vessel wall histology at 30 days demonstrated a mild inflammation score in all groups (an inflammation score lower than 1 was observed in 100% of Cre8 stent, 71.5% for R3 and 66.7% for Cypher; p=n.s.) while morphometry showed a significantly smaller neointimal area in Cre8™ (Cre8 0.93±0.43 mm2; R3 1.49±0.67 mm2; Cypher 1.81±0.94 mm2; Cre8 vs. Cypher p<0.05); this difference was maintained after 90 days (inflammation score lower than 1 in 100% of Cre8 stent, 100% for R3 and 66.7% for Cypher; p=n.s. Neointimal area was 1.27±0.56 mm2 for Cre8, 1.74±0.60 mm2 for R3 and 2.79±1.14 mm2 for Cypher; Cre8 and R3 vs. Cypher p<0.05 while neointimal thickness was 0.15±0.07 mm for Cre8, 0.21±0.12 mm for R3 and 0.31±0.15 mm for Cypher; Cre8 vs. Cypher p<0.05). CONCLUSIONS: The most significant experimental evidence appears to be the absence of chronic inflammatory response in Cre8™ stent. This is expressed by a reduced neointimal thickness and inflammatory score at all follow-ups. Such an outcome positively compares with the other DES where a trend to neointimal growth and increased cell infiltration was observed.