Atherosclerosis is a complex progressive disease involving intertwined biological mechanisms. We aimed to identify miRNA expression dynamics at the early stages of atherosclerosis using a large swine model (Wisconsin Miniature Swine, WMS). A total of 18 female pigs; 9 familial hypercholesterolemic (WMS-FH) and 9 normal control swine (WMS-N) were studied. miRNA sequencing was performed on plasma cell-free RNA at 3, 6, and 9 months of age. RT-qPCR validated DE miRNAs in a new cohort of animals (n = 30) with both sexes. Gene ontology and mRNA targets for DE miRNAs were identified. In vivo multimodality imaging and histopathology were performed to document the presence of atherosclerosis at termination. 20, 19, and 9 miRNAs were significantly DE between the groups at months 3, 6, and 9, respectively. Most DE miRNAs and their target genes are involved in human atherosclerosis development. Coronary atherosclerosis was documented in 7/9 WMS-FH pigs. Control animals had no lesions. miR-138, miR-152, miR-190a, and miR-196a showed a significant diagnostic power at month 3, whereas miR-486, miR-126-3p, miR-335, and miR-423-5p were of significant diagnostic power at month 9. In conclusion, specific DE miRNAs with significant discriminatory power may be promising biomarkers for the early detection of coronary atherosclerosis.

Background and aim: The complex dynamic interplay between different biological pathways involved in atherosclerosis development has rendered the identification of specific therapeutic targets a challenging quest. We aimed to identify specific genes and mechanistic pathways associated with the early development of fibroatheromas in a swine model of atherosclerosis. Methods: The Wisconsin Miniature SwineTM model of Familial Hypercholesterolemia (WMS-FH, n = 11) and genetically related WMS controls (WMS-N, n = 11) were used. The infrarenal aorta was harvested from both groups for histopathologic and transcriptomic profiling at 12 months. Bioinformatic analysis was performed to identify hub genes and pathways central to disease pathophysiology. The expression of ITGB2, the top ranked hub gene, was manipulated in cell culture and the expression of interconnected genes was tested. Results: Fibro-atheromatous lesions were documented in all WMS-FH aortic tissues and displayed internal elastic lamina (IEL) disruption, significant reduction of myofibroblast presence and disorganized collagen deposition. No fibro-atheromas were observed in the control group. A total of 266 differentially expressed genes (DEGs) were upregulated in WMS-FH aortic tissues, while 29 genes were downregulated. Top identified hub genes included ITGB2, C1QA, LCP2, SPI1, CSF1R, C5AR1, CTSS, MPEG1, C1QC, and CSF2RB. Overexpression of ITGB2 resulted in elevated expression of other interconnected genes expressed in porcine endothelial cells. Conclusion: In a swine translational model of atherosclerosis, transcriptomic analysis identified ITGB2 as a central hub gene associated inflammation and early fibroatheroma development making it a potential therapeutic target at this stage of disease.

During the development of novel transcatheter mitral valve replacement (TMVR) technology, the discrepancy between benchtop models (i.e. silicone), animal models, and human anatomy may be overcome by using human cadaveric hearts, preferably under realistic hemodynamic conditions. The aim of this

Restenosis following endovascular treatment is associated with inflammatory and proliferative responses produced in the artery wall at the time of the procedure which may be ameliorated through delivery of anti-inflammatory or anti-proliferative compounds into the adventitia of the vessel at the

AIMSThe Mitra-Spacer (Cardiosolutions, Bridgewater, MA, USA) is designed to treat mitral regurgitation by introducing a dynamic spacer that constantly adapts to the changing haemodynamic conditions during the cardiac cycle. We aimed to evaluate the performance and safety of this device in the chronic ovine model.METHODS AND RESULTSEight sheep were enrolled in this study. Through a left thoracotomy, the Mitra-Spacer was inserted via the transapical approach and advanced into the left atrium (LA) under imaging guidance. Device performance and safety were evaluated up to 90 days using fluoroscopy, echocardiography and histopathology. The volume within the balloon spacer shifted during the cardiac cycle in all cases. Seven animals survived up to 90 days for terminal imaging and tissue harvest. Echocardiography showed no change in left ventricle (LV) ejection fraction from baseline to 90 days. There were no observations of changes in LV diastolic function, pulmonary vein inflow, or tricuspid valve function. Histological analysis demonstrated no significant injury to the mitral apparatus.CONCLUSIONSIn the healthy ovine model, Mitra-Spacer implantation was feasible and safe. At 90 days, no evidence of structural damage to the mitral apparatus or deterioration of cardiac performance was demonstrated.

BACKGROUND:There is limited comparative clinical data regarding the safety and efficacy profile of paclitaxel delivery via balloon versus stent-polymer matrix. In this study, we aimed to compare the clinical and angiographic results of two different methods of paclitaxel delivery among patients undergoing percutaneous coronary intervention (PCI) for single de novo coronary lesions.METHODS:A total of 202 patients undergoing PCI due to symptomatic heart disease and at least one significant coronary artery lesion were prospectively enrolled in a multicenter non-inferiority trial. Eligible patients were randomized to a revascularization with either a paclitaxel eluting stent (PES = Coroflex Please, B.Braun) or a bare metal stent (BMS) followed by a paclitaxel coated balloon (PCB) dilation (BMS = Coroflex + PCB = Sequent Please, B.Braun). Clinical follow-up was obtained at 9 months in all patients, whereas angiographic in a subset of 94 (46.5%) patients.RESULTS:The baseline characteristics were well balanced between groups. At 9 months, the primary endpoint of in-stent late lumen loss in BMS + PCB was comparable and non-inferior to PES (0.21 ± 0.5 vs. 0.30 ± 0.7 mm, respectively. P(non-inf)  < 0.05). At 9 months, the incidence of MACE (7.0 vs. 6.9%, HR = 1, 95%CI: 0.3-2.8; P = 0.99), comprising the occurrence of myocardial infarction (4.9 vs. 3.0%, HR = 1.62, 95%CI: 0.4-6.5; P = 0.32), target lesion revascularization (6.9 vs. 5.0%, HR = 1.42, 95%CI: 0.4-4.4; p = 0.54) and stent thrombosis (4.9 vs. 3.0%, HR = 2.01, 95%CI: 0.5-7.4; P = 0.74) was comparable between BMS + PCB and PES, respectively. In the BMS + PCB group, thrombosis tended to occur within 30 days (3.9 vs. 1.0%; P = 0.38).CONCLUSIONS:Paclitaxel delivery via drug coated balloon or polymer-stent matrix achieved comparable angiographic and clinical results among patients with de novo coronary lesions. BMS + PCB revascularization was associated with a higher rate of stent thrombosis when compared to newer generation drug eluting stents, therefore, should be recommended as a bail-out for PCB alone angioplasty.

AIMS:To test the feasibility of a thoracoscopically assisted, off-pump, transcatheter ventricular reconstruction (TCVR) approach in an ovine model of left ventricular (LV) anteroapical aneurysm.METHODS AND RESULTS:Myocardial infarction (MI) was induced by coil occlusion of the middle left anterior descending artery and diagonals. Two months after MI creation, TCVR was performed via a minimal thoracotomy in eight sheep. Under endoscopic and fluoroscopic guidance, trans-interventricular septal puncture was performed from the LV epicardial scar. A guidewire was externalised via a snare placed in the right ventricle from the external jugular vein. An internal anchor was inserted over the wire and positioned on the right ventricular septum and an external anchor was deployed on the LV anterior epicardium. Serial pairs of anchors were placed and plicated together to exclude the scar completely. Immediately after TCVR, echocardiography showed LV end-systolic volume decreased from pre-procedure 58.8±16.6 ml to 25.1±7.6 ml (p<0.01) and the ejection fraction increased from 32.0±7.3% to 52.0±7.5% (p<0.01). LV twist significantly improved (3.83±2.21 vs. pre-procedure -0.41±0.94, p=0.01) and the global peak-systolic longitudinal strain increased from -5.64% to -10.77% (p<0.05).CONCLUSIONS:TCVR using minimally invasive access techniques on the off-pump beating heart is feasible and resulted in significant improvement in LV performance.

Bioabsorbable arterial stents (BAS) are emerging as a new paradigm for treatment of coronary disease by promoting vascular restoration rather than just alleviating the obstruction but caging the vessel segment with a metal stent. We aimed to evaluate mechanical integrity and biocompatibility of a

The Tack-It Endovascular Stapler System™ is a novel metallic 6mm spot-treatment technology designed to create tissue apposition to treat local vascular dissections and decrease the risk of vascular injury through low outward radial force and minimal nitinol material in contact with the vessel

Background The biodegradable polymer drug‐eluting stents have been proposed as an alternative to durable polymer DES, theoretically improving vessel healing and reducing the need for prolonged double anti platelet therapy (DAPT), however clinical significance of this technology is under debate. Therefore, we sought to compare the clinical outcomes of two Paclitaxel eluting stents (PES) containing different polymer‐based eluting matrices. Methods In this multicenter registry of 392 consecutive patients who underwent PCI between June 2006 and September 2008, we included patients with stable angina or NSTE‐ACS displaying at least one significant lesion (>50% diameter stenosis) in native coronary arteries. Results Biodegradable polymer PES (BP‐PES, LUC Chopin 2 , Balton, Poland) was implanted in 206 patients, whereas durable polymer PES (DP‐PES, Taxus, Boston Scientific, USA) was implanted in 186 patients. There were no significant differences in baseline characteristics between groups with the exception of increased diabetes and number of lesions for BP‐PES. In risk‐unadjusted analysis at 1‐year follow‐up, there were no significant differences in TLR (BP‐PES: 8.4% vs. DP‐PES: 6%; P = 0.36), TVR (BP‐PES: 11.1% vs. DP‐PES: 8.4%; P = 0.36) and incidence of stent thromboses (BP‐PES: 2.15% vs. DP‐PES: 3.4%; P = 0.42) between groups. There was also no difference in MACCE between groups (17.6% vs. 14.4%, P = 0.49). The mean dual antiplatelet therapy (DAPT) compliance at 1 year was 77% for BP‐PES versus 92% for DP‐PES ( P = 0.03). Kaplan–Meier analysis showed a significantly higher long‐term stroke free survival in BP‐PES ( P = 0.04). After adjustment, this was sustained with an additional tendency toward higher MI free survival for BP‐PES ( P = 0.059). Conclusions In this observational analysis, BP‐PES were comparable to DP‐PES, with regard to incidence of repeated revascularizations, stent thromboses and MACCE despite earlier DAPT discontinuation. © 2012 Wiley Periodicals, Inc.

The Tack-It, a novel metallic 6mm spot-scaffolding technology was designed to seal local vascular dissections and decrease the risk of vascular injury. This is achieved through a lower outward radial force and reduction in the material surface in contact with the vessel compared to the current

Objectives This study sought to evaluate vascular drug uptake, distribution and response of second-generation paclitaxel coated balloon (PCB) (Cotavance, MEDRAD Interventional, Indianola, Pennsylvania) and compare it with first-generation technology, containing identical excipient and drug concentration.Background Original PCB technologies displayed a heterogeneous deposition of crystalline paclitaxel-iopromide inside the balloon folds, whereas second-generation PCBs consisted of more homogeneous, circumferential coatings.Methods Paclitaxel tissue uptake was assessed in 20 iliofemoral arteries of a domestic swine. Vascular healing response was assessed in the familial hypercholesterolemic model of iliofemoral in-stent restenosis. Three weeks after bare-metal stent implantation, vascular segments were randomly revascularized with first-generation PCBs (n = 6), second-generation PCBs (n = 6), or plain balloon angioplasty (PBA) (n = 6). At 28 days, angiographic and histological evaluation was performed in all treated segments.Results One-hour paclitaxel tissue uptake was 42% higher in the second-generation PCBs (p = 0.03) and resulted in more homogeneous segment-to-segment distribution compared with first-generation PCBs. Both angiography (percentage of diameter stenosis: second-generation 11.5 +/- 11% vs. first-generation 21.9 +/- 11% vs. PBA 46.5 +/- 10%; p < 0.01) and histology (percentage of area stenosis: second-generation 50.5 +/- 7% vs. first-generation 54.8 +/- 18% vs. PBA 78.2 +/- 9%; p < 0.01) showed a decrease in neointimal proliferation in both PCB groups. Histological variance of the percentage of area stenosis was lower in second-generation compared with first-generation PCBs (51.7 vs. 328.3; p = 0.05). The presence of peristrut fibrin deposits (0.5 vs. 2.4; p < 0.01) and medial smooth muscle cell loss (0 vs. 1.7; p < 0.01) were lower in the second-generation compared with first-generation PCBs.Conclusions In the experimental setting, second-generation PCB showed a comparable efficacy profile and more favorable vascular healing response when compared to first-generation PCB. The clinical implications of these findings require further investigation. (C) 2013 by the American College of Cardiology Foundation

A Biolimus A9 self-expandable nitinol stent (BA9SES) stent was engineered with a permanent primer layer consisting of parylene and a bioabsorbable abluminal layer of polylactic acid (PLA) and Biolimus A9 (∼22 μg/mm of stent length), in contrast to the permanent polymer-based, sirolimus-

Background: The optical coherence tomography (OCT) characteristics of in-stent neointimal tissue have been associated with histological markers of healing. We aimed to investigate the differences in neointimal characteristics based on OCT analysis of Paclitaxel coated balloon (PCB) treatment versus POBA in the Iliofemoral territory of the familial hypercholesterolemic swine model (FHS). Methods: 14 Iliofemoral arterial segments of 7 FHS were balloon injured followed by a BMS placement. At 14 days, the injured sites were treated with either a PCB or POBA (control). OCT images, acquired at 28 days post inflation, were classified at every 2mm according to previously published classification of neointimal types (homogeneous, heterogeneous and layered). Quantitative morphometric evaluation of vessel, stent, microvessel and peristrut low intensity areas (PLI) presence was also performed. A multivariable logistic regression model was performed dividing the neointima into homogeneous and non-homogeneous. Results: AA total of 150 OCT cross sections were included in the final analysis. PCB resulted in a reduction of percent area stenosis (%AS) by 50% (PCB: 34 18% versus POBA 68 21%, p 0.05). The homogeneous pattern was more frequent in PCB (25%) than in the POBA group (3%, p 0.001). Conversely, the layered pattern was more prevalent in the POBA group (50.7% versus 4%, p 0.001). The homogeneous pattern correlated with less degree of neointimal formation [%AS: 16.68 5.3%, p 0.001) than the non-homogeneous group (heterogeneous: 49.01 24.9% and layered: 67.29 15.6%). The presence of micro vessels (89% versus 58%, p 0.001) and PLI (39% versus 24%, p 0.1) were more frequently found in the POBA group than in the PCB group. The only independent predictor of non-homogeneous patterns was the %AS [OR (95% CI)] [3.98(1.21-13.09)]. Conclusions: In vivo OCT analysis suggests that the biological effect of Paclitaxel delivered via DCB frequently results in the homogeneous development of neointimal formation and lower frequency of PLI and micro-vessels compared to a POBA control. These in vivo findings support the biological efficacy observed in clinical trials using this technology.