Publications

Background: Tobacco smoking is reported to enhance telomere shortening in peripheral blood lymphocytes.However, telomere length of lung resident cells such as alveolar macrophages (AMs) has not been evaluated. Aim:We evaluated effect of tobacco smoking on telomere length in AMs.Methods: AMs were obtained from nine non-smokers (mean age 24.6 years, mean FEV 1 /FVC 93.8%) and ten healthy smokers (mean age 25.2 years, >10 pack-years, mean FEV 1 /FVC 90.6%).We also analyzed tissue macrophages from eight moderate to severe COPD patients (mean age 68.3 years, >10 pack-years, mean FEV 1 /FVC 54.2%, mean %pred.FEV 1 48.8%), age-matched nine healthy smokers (mean age 67.1 years, >10 pack-years, mean FEV 1 /FVC 83.7%, mean % pred.FEV 1 82.4%), and eight healthy non-smokers (mean age 71.2 years, mean FEV 1 /FVC 84.6%, mean %pred.FEV 1 84.1%).Centromere signals and telomere length were analysed using quantitative fluorescence in situ hybridization (QFISH) and confocal microscopy.Results: Telomere length was reduced in bronchoalveolar lavage macrophages of younger smokers compared with that observed in healthy non-smoker's AMs, Importantly, there was no quantitative difference in centromere signals between smokers and non-smokers.A shorter telomere length was also seen in tissue macrophages from older smokers with or without COPD compared with non-smokers.However there was no difference in telomere length between healthy smokers and smokers with COPD. Conclusion:Tobacco smoking enhances telomere shortening in AMs from patients with and without COPD.

Objectives The purpose of this study was to assess the diagnostic accuracy of coronary computed tomography angiography (CTA) for bioresorbable vascular scaffold (BVS) evaluation. Background Coronary CTA has emerged as a noninvasive method to evaluate patients with suspected or established coronary artery disease. The diagnostic accuracy of coronary CTA to evaluate angiographic outcomes after BVS implantation has not been well established. Methods In the ABSORB II (A Bioresorbable Everolimus-Eluting Scaffold Versus a Metallic Everolimus-Eluting Stent II) study, patients were randomized either to receive treatment with the BVS or everolimus-eluting metallic stent. At the 3-year follow-up, 238 patients (258 lesions) treated with BVS underwent coronary angiography with intravascular ultrasound (IVUS) evaluation and coronary CTA. The diagnostic accuracy of coronary CTA was assessed by the area under the receiver-operating characteristic curve with coronary angiography and IVUS as references. Results The mean difference in coronary CTA-derived minimal luminal diameter was −0.14 mm (limits of agreement −0.88 to 0.60) with quantitative coronary angiography as reference, whereas the mean difference in minimal lumen area was 0.73 mm2 (limits of agreement −1.85 to 3.30) with IVUS as reference. The per-scaffold diagnostic accuracy of coronary CTA for detecting stenosis based on coronary angiography diameter stenosis of ≥50% revealed an area under the receiver-operating characteristic curve of 0.88 (95% confidence interval [CI]: 0.82 to 0.92) with a sensitivity of 80% (95% CI: 28% to 99%) and a specificity of 100% (95% CI: 98% to 100%), whereas diagnostic accuracy based on IVUS minimal lumen area ≤2.5 mm2 showed an area under the receiver-operating characteristic curve of 0.83 (95% CI: 0.77 to 0.88) with a sensitivity of 71% (95% CI: 44% to 90%) and a specificity of 82% (95% CI: 75% to 87%). The diagnostic accuracy of coronary CTA was similar to coronary angiography in its ability to identify patients with a significant lesion based on the IVUS criteria (p = 0.75). Conclusions Coronary CTA has good diagnostic accuracy to detect in-scaffold luminal obstruction and to assess luminal dimensions after BVS implantation. Coronary angiography and coronary CTA yielded similar diagnostic accuracy to identify the presence and severity of obstructive disease. Coronary CTA might become the method of choice for the evaluation of patients treated with BVS.

Chronic obstructive pulmonary disease (COPD) shows poor clinical improvement with steroids. Macrophage Migration Inhibitory Factor (MIF) counter-regulates steroid action although the mechanism is unknown. Stable isotope labelled amino acid cell culture (SILAC) involves incorporating differently labelled amino acids into cells to allow comparison of protein profiles. SILAC was used to investigate the effect of MIF on intracellular signalling pathways. THP-1 cells were grown in SILAC media and then stimulated with or without MIF for 24 hours, the cells were lysed and proteins extracted. Incorporation of the labelled amino acids were measured and analysed by LC-MSMS. Pathways identified were validated by qRT-PCR, ELISA and Western blotting. MIF treatment up-regulated 70 and down-regulated 163 proteins; pathway analysis identified the RIG-I-like receptor (RLR) pathway. In THP-1 cells, as the main MIF target, MIF was induced by Poly I:C in a concentration-dependent manner and RV16 infection induced MIF expression in a time-dependent manner. BAL macrophage proteins were analysed at baseline and 7 days post RV16 infection in non-smokers, smokers and COPD patients. Smokers and COPD patients showed a significant decrease in intracellular MIF post-infection. We used proteomics to define a novel mechanism of MIF action in THP-1 cells and translated this to primary human cells. Viral activation induced MIF release from THP-1 cells and was associated with a loss of intracellular MIF in BAL macrophages 7 days post infection in smokers and COPD patients. This proteomics approach has the ability to define novel mechanisms for understanding drug or disease effects.

Aim To examine the effect of endothelial shear stress (ESS) on the dynamic changes in plaque phenotype. Methods Patients with myocardial infarction that had intravascular ultrasound-virtual histology (IVUS-VH) and optical coherence tomography (OCT) at baseline and 13-month follow-up were studied. The IVUS-VH data were used to reconstruct the nonculprit vessels, and in the obtained models the ESS was estimated in 3 mm segments. Plaque morphology was derived in each segment from IVUS-VH and OCT. Disease progression was defined as the presence of ≥2 out of the following criteria: reduction in lumen area, increase in plaque burden and change of plaque morphology to a more vulnerable phenotype. Linear mixed effects models were used to assess the effect of ESS in different phenotypes. Results Sixty-eight vessels were included in the analysis. Low ESS was associated with plaque progression in all phenotypes. The effect of ESS on plaque burden (p for interaction=0.467) and phenotype (p for interaction=0.188) was similar in all plaque types, whereas the effect of ESS on the changes in lumen dimensions was more prominent in disease-free (β=0.70, p<0.001) than fibrotic/fibrocalcific (β=0.28, p<0.001) or lipid-rich plaques (β=0.15, p=0.015). Standalone IVUS-VH misclassified plaque morphology in one-third of the cases leading to erroneous estimations about the effect of ESS on plaque evolution in different phenotypes. Conclusions The effect of ESS on plaque progression is similar in all phenotypes and cannot be accurately assessed by standalone IVUS-VH which often misclassifies plaque morphology. Therefore, multimodality imaging should be considered to examine the implications of ESS on plaque evolution. Clinical trial registration NCT00962416 ; Post-results.

No abstract is provided for this article.

Objectives The study sought to validate the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score II mortality prediction model after percutaneous coronary intervention (PCI) or coronary artery bypass grafting in a large pooled population of patients with multivessel coronary disease (MVD) and/or unprotected left main disease (UPLMD) enrolled in the PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) and BEST (Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) randomized controlled trials. Background For patients with MVD and/or UPLMD, the choice of the best revascularization strategy remains challenging. Methods Pooled individual patient-level data from PRECOMBAT and BEST were used to assess calibration and discrimination of the SYNTAX score II prediction model for all-cause mortality after PCI and coronary artery bypass grafting at 4-year follow-up. The study population comprised 1,480 patients (600 with UPLMD, 880 with MVD). Results The overall incidence of all-cause mortality was 6.1% after a median follow-up period of 4.9 years. Validation plots showed good model calibration overall and across treatment groups but tended to overestimate all-cause mortality in the highest risk quintiles of patients in the whole population and the PCI arm. The SYNTAX score II showed moderate discrimination ability for the whole population (C index = 0.685) but better for patients receiving PCI than CABG (C index = 0.718 vs. 0.662 in patients with UPLMD, C index = 0.700 vs. 0.661 in those with MVD). Observed all-cause mortality was higher when the treatment received was at variance with that recommended by the model and similar when it was concordant. Conclusions The SYNTAX score II has good calibration but only moderate discrimination ability for long-term mortality prediction in this randomized population. This score provides an important tool to help guide the heart team’s decision-making process regarding the selection of the best revascularization strategy for patients with MVD and/or UPLMD. (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease, NCT00422968; Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease, NCT00997828)