Publications

Intermediate coronary lesions (ICLs) are highly prevalent but ported mixed prognosis. Radial strain has been associated with plaque vulnerability, yet its role in predicting lesion progression is largely unknown. The purpose of this study was to determine the predictive value of angiography-derived radial wall strain (RWS) for progression of untreated non-culprit ICLs.Post-hoc analysis was conducted in a study cohort including 603 consecutive patients with 808 ICLs identified at index procedure with angiographic follow-up of up to two years. RWS analysis was performed on selected angiographic frames with minimal foreshortening and vessel overlap. Lesion progression was defined as ≥ 20% increase in percent diameter stenosis.Lesion progression occurred in 49 ICLs (6.1%) with a median follow-up period of 16.8 months. Maximal RWS (RWSmax), frequently located at the proximal and throat plaque regions, distinguished progressive ICLs from silent ones. The largest area under the curve value of 0.75 (95% CI: 0.67-0.82, P < 0.001) was reached at the optimal RWSmax cutoff value of > 12.6%. According to this threshold, 178 ICLs were classified as having a high strain pattern. Exposure to a high strain amplitude with RWSmax > 12.6% was independently associated with an increased risk of lesion progression (adjusted HR = 6.82, 95% CI: 3.67-12.66, P < 0.001).Assessment of RWS from coronary angiography is feasible and provides independent prognostic value in patients with untreated ICLs.

No abstract is provided for this article.

We welcome the opportunity to expand on how to assess the performance of the SYNTAX score II.1Farooq V van Klaveren D Steyerberg EW et al.Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II.Lancet. 2013; 381: 639-650Summary Full Text Full Text PDF PubMed Scopus (662) Google Scholar First, interactions in the SYNTAX score II are central to more personalised decision making—ie, specific anatomical or clinical factors to be more predictive of mortality with percutaneous coronary intervention (PCI) compared with coronary artery bypass graft (CABG) surgery, or vice versa. All variables in the SYNTAX score II were validated, with the exception of age and left ventricular ejection fraction, which might relate to selection bias inherent to all registries. Hence randomised validation was proposed.1Farooq V van Klaveren D Steyerberg EW et al.Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II.Lancet. 2013; 381: 639-650Summary Full Text Full Text PDF PubMed Scopus (662) Google Scholar Currently, validation of the SYNTAX score II is prespecified as an endpoint in the ongoing randomised EXCEL trial (NCT01205776), and the planned SYNTAX trial II which will use the SYNTAX score II to recruit patients on the grounds of patient safety. Second, substantial differences in treatment assignment (CABG or PCI) were evident using reclassification analyses—ie, comparisons between the SYNTAX score II and conventional tertiles of the anatomical SYNTAX score.2Serruys PW Morice MC Kappetein AP et al.Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease.N Engl J Med. 2009; 360: 961-972Crossref PubMed Scopus (3465) Google Scholar These were quantified and presented in the manuscript, and cannot be deemed misleading, because they are an accepted and important step in assessing performance.3Steyerberg EW Moons KGM van der Windt DA et al.Prognosis research strategy (PROGRESS) 3: prognostic model research.PLoS Med. 2013; 10: e1001381Crossref PubMed Scopus (883) Google Scholar A further step to quantify effect on survival of the population under study requires a clear decision rule. If we simply select CABG or PCI based on a higher or lower expected survival (Kaplan-Meier analyses) with the SYNTAX score II, irrespective of the margin of difference, 4-year mortality would be 7·5% compared with 8·4% using the anatomical SYNTAX score with existing myocardial revascularisation guidelines4Wijns W Kolh P Danchin N et al.Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).Eur Heart J. 2010; 31: 2501-2555Crossref PubMed Scopus (26) Google Scholar (equivalent to using the SYNTAX score II in only 111 patients [100/0·9%] to have one more patient alive at 4 years). Similar analyses selecting CABG or PCI based on statistical comparisons of expected survival showed that 4-year mortality remained unaltered at 8·2%. Notably, using either approach to decision making with the SYNTAX score II resulted in a similar 4-year survival (Kaplan-Meier analyses) between CABG and PCI in both the development and validation populations. Additionally, and contrary to current myocardial revascularisation guidelines,4Wijns W Kolh P Danchin N et al.Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).Eur Heart J. 2010; 31: 2501-2555Crossref PubMed Scopus (26) Google Scholar patients were identified in all tertiles of the anatomical SYNTAX score who would be potentially suitable for CABG, PCI, or both. The choice between CABG and PCI would thus be down to individual patient preference, their perception of short-term and long-term risk, and health economics. We agree that the practical applications of performance statistics are complex, and future work in this evolving field will prove to be of additional value in upcoming validation studies. We declare that we have no conflicts of interest. SYNTAX score IIVasim Farooq and colleagues1 (Feb 23, p 639) developed and validated a new score (SYNTAX II) for the prediction of mortality after coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) in patients with complex coronary artery disease. They added clinical characteristics to the anatomical SYNTAX score to improve individualised treatment decisions. They conclude that the new score can better guide the choice between CABG and PCI. It is very valuable that they used the SYNTAX trial not only to compare the treatment groups but also to develop a decision rule to guide treatment choice. Full-Text PDF Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score IILong-term (4-year) mortality in patients with complex coronary artery disease can be well predicted by a combination of anatomical and clinical factors in SYNTAX score II. SYNTAX score II can better guide decision making between CABG and PCI than the original anatomical SYNTAX score. Full-Text PDF

Abstract IFN-γ is crucial for protection against M. tuberculosis (Mtb). Previously we reported that signaling through SLAM on Mtb-stimulated cells induced CREB activation increasing IFN-γ. Here, we deeply investigated the potential relationship between SLAM-CREB and IFN-γ. After Mtb-stimulation, most of the IFN-γ+ cells co-expressed SLAM and pCREB (48,68 ± 11,18), whereas a smaller percentage of T cells expressed one of the two molecules. These results demonstrate that the induction of IFN-γ mediated by SLAM in TB depends, at least in part, on CREB activation. It was reported that SLAM signaling would induce the activation of the protein kinase Erk. To analyze the signaling pathways induced by SLAM that contribute to CREB activation and IFN-γ secretion in TB, we studied Erk phosphorylation after SLAM activation. The addition of PD90059 (an Erk inhibitor) to Mtb stimulated cells inhibited the percentage of IFN-γ+pCREB+ T cells, indicating that Erk could be involved on CREB activation. Moreover, the addition of PD90059 to Mtb±α-SLAM stimulated cells significantly decreased IFN-γ production (% inhibition: 71,6 ± 7,4). Finally, α-SLAM induced Erk activation in Mtb stimulated cells. These results demonstrate that IFN-γ production induced by SLAM signaling on Mtb stimulated cells is, at least in part, mediated by Erk and CREB phosphorylation. These data contribute new information about the molecular basis operating during SLAM activation that leads to IFN-γ production in human TB.

BackgroundMedication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta2-agonists, similar to the reduction with maintenance budesonide.ObjectiveThis post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents.MethodsSYGMA 1 and 2 were 52-week, double-blind studies (NCT022149199; NCT02224157) in patients 12 years or older with mild asthma. Patients were randomized to twice-daily placebo + as-needed BUD-FORM 200/6 μg, twice-daily BUD 200 μg + as-needed terbutaline (BUD maintenance), or twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to <18 years).ResultsSevere exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P = .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P = .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to <14 years was significantly greater with as-needed BUD-FORM (4.8 cm) versus BUD maintenance (3.9 cm) (pooled: P < .046), and was similar between as-needed BUD-FORM (4.5 cm) and as-needed terbutaline (4.1 cm) (SYGMA 1: P = .500). No new or unexpected safety concerns were identified.ConclusionsIn adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment. Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta2-agonists, similar to the reduction with maintenance budesonide. This post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents. SYGMA 1 and 2 were 52-week, double-blind studies (NCT022149199; NCT02224157) in patients 12 years or older with mild asthma. Patients were randomized to twice-daily placebo + as-needed BUD-FORM 200/6 μg, twice-daily BUD 200 μg + as-needed terbutaline (BUD maintenance), or twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to <18 years). Severe exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P = .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P = .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to <14 years was significantly greater with as-needed BUD-FORM (4.8 cm) versus BUD maintenance (3.9 cm) (pooled: P < .046), and was similar between as-needed BUD-FORM (4.5 cm) and as-needed terbutaline (4.1 cm) (SYGMA 1: P = .500). No new or unexpected safety concerns were identified. In adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment.

Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) is an important predictor of poor prognosis, but the molecular mechanisms of muscle weakness in COPD have not been fully elucidated. The aim of this study was to investigate the role of histone deacetylases(HDAC) in skeletal muscle weakness in COPD. Twelve COPD patients, 8 smokers without COPD (SM) and 4 healthy non-smokers (NS) were recruited to the study. HDAC2 protein expression in quadriceps muscle biopsies of COPD patients (HDAC2/β-actin: 0.59 ± 0.34) was significantly lower than that in SM (1.9 ± 1.1, p = 0.0007) and NS (1.2 ± 0.7, p = 0.029). HDAC2 protein in skeletal muscle was significantly correlated with forced expiratory volume in 1 s % predicted (FEV1 % pred) (rs = 0.53, p = 0.008) and quadriceps maximum voluntary contraction force (MVC) (rs = 0.42, p = 0.029). HDAC5 protein in muscle biopsies of COPD patients (HDAC5/β-actin: 0.44 ± 0.26) was also significantly lower than that in SM (1.29 ± 0.39, p = 0.0001) and NS (0.98 ± 0.43, p = 0.020). HDAC5 protein in muscle was significantly correlated with FEV1 % pred (rs = 0.64, p = 0.0007) but not with MVC (rs = 0.30, p = 0.180). Nuclear factor-kappa B (NF-κB) DNA binding activity in muscle biopsies of COPD patients (10.1 ± 7.4) was significantly higher than that in SM (3.9 ± 7.3, p = 0.020) and NS (1.0 ± 1.2, p = 0.004and significantly correlated with HDAC2 decrease (rs = −0.59, p = 0.003) and HDAC5 (rs = 0.050, p = 0.012). HDAC2 knockdown by RNA interference in primary skeletal muscle cells caused an increase in NF-κB activity, NF-κB acetylation and basal tumour necrosis factor (TNF)-α production, as well as progressive cell death through apoptosis. Skeletal muscle weakness in COPD may result from HDAC2 down-regulation in skeletal muscle via acetylation and activation of NF-κB. The restoration of HDAC2 levels might be a therapeutic target for improving skeletal muscle weakness in COPD.

No abstract is provided for this article.

Optical coherence tomography (OCT) of a bioresorbable vascular scaffold (BVS) produces a highly reflective signal outlining struts. This signal interferes with the measurement of strut thickness, as the boundaries cannot be accurately identified, and with the assessment of coverage, because the neointimal backscattering convolutes that of the polymer, frequently making them indistinguishable from one another. We hypothesise that Gaussian line spread functions (LSFs) can facilitate identification of strut boundaries, improving the accuracy of strut thickness measurements and coverage assessment.Forty-eight randomly selected BVS struts from 12 patients in the ABSORB Cohort B clinical study and four Yucatan minipigs were analysed at baseline and follow-up (six months in humans, 28 days in pigs). Signal intensities from the raw OCT backscattering were fit to Gaussian LSFs for each interface, from which peak intensity and full-width-at-half-maximum (FWHM) were calculated. Neointimal coverage resulted in significantly different LSFs and higher FWHM values relative to uncovered struts at baseline (p<0.0001). Abluminal polymer-tissue interfaces were also significantly different between baseline and follow-up (p=0.0004 in humans, p<0.0001 in pigs). Using the location of the half-max of the LSF as the polymer-tissue boundary, the average strut thickness was 158±11 µm at baseline and 152±20 µm at six months (p=0.886), not significantly different from nominal strut thickness.Fitting the raw OCT backscattering signal to a Gaussian LSF facilitates identification of the interfaces between BVS polymer and lumen or tissue. Such analysis enables more precise measurement of the strut thickness and an objective assessment of coverage.

In a number of studies, synchronized diastolic retroperfusion instituted 20 minutes after coronary artery occlusion has been shown to enhance recovery of regional contractile function.1–3 We hypothesized that, if retroperfusion was started before the onset of ischemia, it might prevent or at least delay the loss of regional function.

No abstract is provided for this article.