Reproducibility of Shin's method for necrotic core and calcium content in atherosclerotic coronary lesions treated with bioresorbable everolimus-eluting vascular scaffolds using volumetric intravascular ultrasound radiofrequency-based analysis

Although Virtual Histology intravascular ultrasound (VH-IVUS) is increasingly used in clinical research, the reproducibility of plaque composition remains unexplored in significant coronary artery and stented lesions. The purpose of this study was to assess the reproducibility of necrotic core and calcium content in atherosclerotic coronary lesions that were treated with a bioresorbable everolimus-eluting vascular scaffold (BVS) using a new measurement method (Shin's method) by VH-IVUS. Eight patients treated with a BVS (Abbott Vascular, Santa Clara, CA, USA) were analyzed with serial VH-IVUS assessments, i.e., pre- and post-stenting, and at 6 months and 2 years follow-up. A total of 32 coronary segments were imaged to evaluate the reproducibility of volumetric VH-IVUS measurements. In Shin's method, contours are drawn around the IVUS catheter (instead of the lumen) and vessel. Overall, in the imaged coronary segment, for necrotic core and dense calcium volumes, the relative intra-observer differences were 0.30 ± 0.22, 0.19 ± 0.16% for observer 1 and 0.45 ± 0.41, 0.36 ± 0.47% for observer 2, respectively. The interobserver relative differences of necrotic core and dense calcium volumes were 0.51 ± 0.79 and 0.56 ± 1.01%, respectively. The present study demonstrates a good reproducibility for both, intra-observer and interobserver measurements using Shin's method. This method is suitable for the measurement of necrotic core and dense calcium using VH-IVUS in longitudinal studies, especially studies on bioresorbable scaffolds, because the degradation process will be fully captured independently of the location of the struts and their greyscale appearance

Pharmacogenetic Testing for Clopidogrel Using the Rapid INFINITI Analyzer A Dose-Escalation Study

ObjectivesOur aim was to assess whether a higher clopidogrel maintenance dose has a greater antiplatelet effect in CYP2C19*2 allele carriers compared with noncarriers.BackgroundClopidogrel is a prodrug that is biotransformed by the cytochrome P450 enzymes CYP2C19, 2C9, and 3A4, 2B6, 1A2. The CYPC219*2 loss of function variant has been associated with a reduced antiplatelet response to clopidogrel and a 3-fold risk of stent thrombosis.MethodsForty patients on standard maintenance dosage clopidogrel (75 mg), for 9.4 ± 9.2 weeks, were enrolled into a dose escalation study. Platelet function was assessed at baseline and after 1 week of 150 mg once daily using the VerifyNow platelet function analyzer (Accumetrics Ltd., San Diego, California). Genomic DNA was hybridized to a BioFilmChip microarray on the INFINITI analyzer (AutoGenomics Inc., Carlsbad, California) and analyzed for the CYP19*2, *4, *17, and CYP2C9*2, *3 polymorphisms.ResultsPlatelet inhibition increased over 1 week, mean +8.6 ± 13.5% (p = 0.0003). Carriers of the CYP2C19*2 allele had significantly reduced platelet inhibition at baseline (median 18%, range 0% to 72%) compared with wildtype (wt) (median 59%, range 11% to 95%, p = 0.01) and at 1 week (p = 0.03). CYP2C19*2 allele carriers had an increase in platelet inhibition of (mean +9 ± 11%, p = 0.03) and reduction in platelet reactivity (mean −26 ± 38 platelet response unit, p = 0.04) with a higher dose. Together CYP2C19*2 and CYP2C9*3 loss of function carriers had a greater change in platelet inhibition with 150 mg daily than wt/wt (+10.9% vs. +0.7%, p = 0.04).ConclusionsIncreasing the dose of clopidogrel in patients with nonresponder polymorphisms can increase antiplatelet response. Personalizing clopidogrel dosing using pharmacogenomics may be an effective method of optimizing treatment

Clinical and Angiographic Factors Associated With Asymptomatic Restenosis After Percutaneous Coronary Intervention

BACKGROUND: Angiographic restenosis after percutaneous coronary interventional procedures is more common than recurrent angina. Clinical and angiographic factors associated with asymptomatic versus symptomatic restenosis after percutaneous coronary intervention were compared. METHODS AND RESULTS: All patients with angiographic restenosis from the BENESTENT I, BENESTENT II pilot, BENESTENT II, MUSIC, WEST 1, DUET, FINESS 2, FLARE, SOPHOS, and ROSE studies were analyzed. Multivariate analysis evaluated 46 clinical and angiographic variables, comparing those with and without angina. The 10 studies recruited 2690 patients who underwent percutaneous revascularization and 6-month follow-up angiography (86% of those eligible). Restenosis (>/=50% diameter stenosis) occurred in 607 patients and was clinically silent in 335 (55%). Male sex (P=0.008), absence of antianginal therapy with nitrates (P=0.0002) and calcium channel blockers (P=0.02) at 6 months, greater reference diameter after the procedure (P=0.04), greater reference diameter at follow-up (P=0.004), and lesser lesion severity (percent stenosis) at 6 months (P=0.0004) were univariate predictors of asymptomatic restenosis. By multivariate analysis, only male sex (P=0.04), greater reference diameter at follow-up (P=0.002), and lesser lesion severity at 6 months (P=0.0001) were associated with restenosis without angina. CONCLUSIONS: Approximately half of patients with angiographic restenosis have no symptoms. The only multivariate predictors of silent restenosis at 6 months were male sex, greater reference diameter at follow-up, and lesser lesion severity on follow-up angiography

Assessment of the serial changes of vessel wall contents in atherosclerotic coronary lesion with bioresorbable everolimus-eluting vascular scaffolds using Shin's method: an IVUS study

Although serial changes in necrotic core and calcium are regarded as surrogates for the bioresorption process in patients treated with the bioresorbable everolimus-eluting vascular scaffolds (BVS), these temporal changes have not yet been fully investigated. Shin's method may be offer a more suitable technique for this analysis because it includes all the contents of both the lumen and vessel wall. The purpose of this study was to assess the serial changes of necrotic core and dense calcium content in coronary lesions that were treated with a BVS implant using Virtual Histology intravascular ultrasound (VH-IVUS) analyzed using Shin's method. A total of 29 patients (92 coronary segments) were imaged to evaluate the serial changes in necrotic core and dense calcium using Shin's method. Lesions treated with a BVS implant were analyzed with serial VH-IVUS assessments, i.e., pre- and post-stenting, and at 6 months and 2 years follow-up. In Shin's method contours are drawn around the IVUS catheter (instead of delineating the lumen) and the vessel. The mean necrotic core area decreased by 6.9% from post-stenting to 6 months (1.71 ± 1.03 mm2vs. 1.36 ± 0.91 mm2, P = 0.027), and by 20.5% (1.71 ± 1.03 mm2vs. 1.20 ± 0.70 mm2, P = 0.003) from post-steting to 2 years; while the mean dense calcium areas decreased by 27.2% (1.07 ± 0.55 mm2vs. 0.78 ± 0.64 mm2, P = 0.039) from post-stenting and 2 years. At 2 years, absolute necrotic core and dense calcium content were significantly decreased as compared to post-stenting values. The present study demonstrates that the bioresorption process in patients who undergoing BVS device implantation can be assessed using VH-IVUS analysed using Shin's method

Transcript analysis reveals a specific HOX signature associated with positional identity of human endothelial cells.

The endothelial cell has a remarkable ability for sub-specialisation, adapted to the needs of a variety of vascular beds. The role of developmental programming versus the tissue contextual environment for this specialization is not well understood. Here we describe a hierarchy of expression of HOX genes associated with endothelial cell origin and location. In initial microarray studies, differential gene expression was examined in two endothelial cell lines: blood derived outgrowth endothelial cells (BOECs) and pulmonary artery endothelial cells. This suggested shared and differential patterns of HOX gene expression between the two endothelial lines. For example, this included a cluster on chromosome 2 of HOXD1, HOXD3, HOXD4, HOXD8 and HOXD9 that was expressed at a higher level in BOECs. Quantative PCR confirmed the higher expression of these HOXs in BOECs, a pattern that was shared by a variety of microvascular endothelial cell lines. Subsequently, we analysed publically available microarrays from a variety of adult cell and tissue types using the whole "HOX transcriptome" of all 39 HOX genes. Using hierarchical clustering analysis the HOX transcriptome was able to discriminate endothelial cells from 61 diverse human cell lines of various origins. In a separate publically available microarray dataset of 53 human endothelial cell lines, the HOX transcriptome additionally organized endothelial cells related to their organ or tissue of origin. Human tissue staining for HOXD8 and HOXD9 confirmed endothelial expression and also supported increased microvascular expression of these HOXs. Together these observations suggest a significant involvement of HOX genes in endothelial cell positional identity