Publications

Corticosteroid resistance is one of major barriers to effective management of chronic inflammatory respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma. These patients often experience exacerbations with viral and/or bacterial infection, which may cause continuous corticosteroid insensitive inflammation. In this study, we observed that repeated exposure of lipopolysaccharide (LPS) intranasally attenuated the anti-inflammatory effects of the corticosteroid fluticasone propionate (FP) on neutrophils and CXCL1 levels in bronchoalveolar lavage (BAL) fluid in an in vivo murine model. Histone deacetylase-2 (HDAC2) and NF-E2 related factor 2 (Nrf2) levels in lungs after LPS administration for 3 consecutive days were significantly decreased to 38.9±6.3% (mean±SEM) and 77.5±2.7% of the levels seen after only one day of LPS exposure, respectively. In addition, 3 days LPS exposure resulted in an increase of Akt phosphorylation, indicating activation of the phosphoinositide-3-kinase (PI3K) pathway by 4-fold in lungs compared with 1 day of exposure. Furthermore, combination treatment with theophylline and FP significantly decreased the neutrophil accumulation and CXCL1 concentrations in BAL fluid from 22.5±1.8×104 cells/mL and 214.6±20.6 pg/mL to 7.9±0.5×104 cells/mL and 61.9±13.3 pg/mL, respectively. Combination treatment with IC87114, a selective PI3Kδ inhibitor, and FP also significantly decreased neutrophils and CXCL1 levels from 16.8±0.7×104 cells/mL and 182.4±4.6 pg/mL to 5.9±0.3×104 cells/mL and 71.4±2.7 pg/mL, respectively. Taken together, repeated exposure of LPS causes corticosteroid-insensitive airway inflammation in vivo, and the corticosteroid-resistance induced by LPS is at least partly mediated through the activation of PI3Kδ, resulting in decreased levels of HDAC2 and Nrf2. These findings provide a potentially new therapeutic approach to COPD and severe asthma.

ABSTRACT Background Data regarding the efficacy and safety of drug‐coated balloons (DCBs) versus drug‐eluting stents (DES) in patients with chronic kidney disease (CKD) remains limited. Aims To assess the prognosis of DCB versus DES in patients with and without CKD. Methods REC‐CAGEFREE I was an investigator‐initiated, non‐inferiority trial conducted at 43 sites in China, which randomized 2272 patients to paclitaxel‐coated balloons with the option of rescue stenting (DCB group) or second‐generation sirolimus‐eluting stents (DES group) for treating de novo lesions, regardless of vessel diameter. In this pre‐specified subgroup analysis, patients were stratified based on the presence of CKD (kidney damage or estimated glomerular filtration rate < 60 mL/min per 1.73 m²) at baseline. The primary outcome was the device‐oriented composite endpoint (DoCE; including cardiovascular death, target vessel myocardial infarction, and clinically and physiologically‐indicated target lesion revascularization) at 2 years. Results Of 2272 patients enrolled, 203 (8.9%) had CKD, with 95 and 108 treated with DCB and DES, respectively. At 2 years, the risk of DoCE was significantly higher in CKD versus non‐CKD patients (22/203 [10.9%] vs . 88/2069 [4.3%], HR IPTW : 2.14, 95% CI: 1.13−4.07, p = 0.022). There was no significant interaction between CKD and treatment allocation ( p interaction = 0.352). Among CKD patients, DoCE occurred in 12/95 (12.7%) and 10/108 (9.3%) patients in the DCB and DES groups (HR IPTW : 1.57, 95% CI: 0.66−3.71, p = 0.317), respectively. Among non‐CKD patients, DoCE occurred in 60/1038 (5.8%) versus 28/1031 (2.7%) patients in the DCB and DES groups (HR IPTW : 2.27, 95% CI: 1.38−3.72, p = 0.002), respectively. Conclusion Patients with CKD had worse outcomes compared to those without. DCBs were associated with a higher risk of DoCE than DES, irrespective of CKD status. Trial Registration Unique Identifier: NCT04561739; URL: https://www.clinicaltrials.gov .

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No abstract is provided for this article.

Quantitative coronary angiography (QCA) is a validated and widely accepted method to investigate changes in arterial dimension over time. Calibration of measurements is enabled by the use of the coronary catheter as a scaling device. The dimensions and laminar composition of coronary catheters, however, have changed significantly over recent years and the suitability of the current generation of coronary catheters for calibration purposes has not been validated. We therefore recorded 57 coronary guiding catheters on cinefilm, and compared their automated quantitative measurements (Cardiovascular Angiography Analysis System, CAAS) with their true values (precision micrometer). We found an overall underestimation of quantitatively derived dimensions, ranging from −8.9 to +4% for water‐filled catheters and from −15.5 to −3.9% for contrast‐filled catheters. In conclusion, while the current generation of coronary guiding catheters shows a wide variety in radiological quality, it can be clearly detected by the CAAS system, and is suitable for calibration of QCA measurements (with the exception of the DVI atherectomy catheter), provided that calibration is done on contrast‐empty catheters. © Wiley‐Liss, Inc.

Aims: Bioresorbable scaffolds (BRS) were conceived to ensure transient coronary artery support during antiproliferative drug delivery. However, the Absorb everolimus-eluting bioresorbable scaffold was found to be inferior to everolimus-eluting metallic stents (EES) in moderately complex coronary anatomies. We sought to investigate whether the Absorb represents a valuable option for the percutaneous treatment of patients with ST-elevation myocardial infarction (STEMI). Methods and results: We pooled the individual patient data of two randomised trials specifically designed to investigate the performance of Absorb versus EES in patients with acute myocardial infarction (MI). The primary outcome was lesion (in-segment) diameter stenosis at angiographic follow-up. The main secondary outcome was the device-oriented composite endpoint (DOCE) of cardiac death, target vessel MI and target lesion revascularisation at one year. A total of 388 patients with STEMI were allocated to Absorb (n=227) or EES (n=161). Angiographic follow-up at one year was available for 332 (85.6%) patients. Lesion diameter stenosis was comparable between Absorb and EES (22.8±9.8% versus 23.6±11.2%; mean difference –0.8%, 95% confidence interval [CI]: –3.18-1.48, p=0.47). DOCE occurred in 21 patients at one year, with similar distribution between the Absorb and EES groups (5.3% versus 5.6%; hazard ratio 0.95, 95% CI: 0.40-2.26, p=0.91). Conclusions: This pooled analysis provides evidence for a comparable angiographic performance and suggests similar clinical performance of Absorb and EES in STEMI patients undergoing percutaneous revascularisation. The long-term durability of Absorb and the extent to which newer BRS platforms might have a potential role in STEMI deserve further investigation. Both trials were registered at www.clinicaltrials.gov (NCT01942070 and NCT01986803).

Background Anti-oxidant capacity is crucial defence against environmental or endogenous oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that plays a key defensive role against oxidative and cytotoxic stress and cellular senescence. However, Nrf2 signalling is impaired in several aging-related diseases, such as chronic pulmonary obstructive disease (COPD), cancer, and neurodegenerative diseases. Thus, novel therapeutics that enhance Nrf2 signalling are an attractive approach to treat these diseases. Methodology/Principal Findings Nrf2 was stabilized by SKI-II (2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole), which is a known sphingosine kinase inhibitor, in human bronchial epithelial cell line, BEAS2B, and in primary human bronchial epithelial cells, leading to enhancement of anti-oxidant proteins, such as HO-1, NQO1 and GCLM. The activation of Nrf2 was achieved by the generation of inactive dimerized form of Keap1, a negative regulator of Nrf2 expression, which was independent of sphingosine kinase inhibition. Using mice that were exposed to cigarette smoke, SKI-II induced Nrf2 expression together with HO-1 in their lungs. In addition, SKI-II reduced cigarette smoke mediated oxidative stress, macrophages and neutrophil infiltration and markers of inflammation in mice. Conclusions/Significance SKI-II appears to be a novel activator of Nrf2 signalling via the inactivation of Keap1.

No abstract is provided for this article.

AIMS Randomized trials of drug-eluting stents (DES) have demonstrated their ability to improve clinical outcome in relatively simple lesion/patient subsets. Their potential in patients for whom the risk of coronary bypass grafting is judged prohibitive, remains largely unexplored. To investigate periprocedural and one-year outcome of percutaneous coronary intervention (PCI) using DES in patients refused for coronary artery bypass grafting (CABG). METHODS AND RESULTS At our institution, the therapeutic approach for all patients with multi-vessel disease is decided, by consensus at a conjoint session with the clinical cardiologist, interventionalist and cardiothoracic surgeon enabling unequivocal identification of patients, refused surgery, who were referred for PCI. The EuroSCORE was used to predict peri-operative mortality. From April 2002 to December 2003 we identified 84 such patients. The mean age was 70.9+/-10.1 years and 68% were men. More than one third had prior CABG. Most patients presented with stable or unstable angina pectoris. The reasons for refusal for CABG were: unsuitable coronary anatomy (37%), poor functional status (28%), patent grafts other than the culprit vessel (25%), prior CABG (28%), severe left ventricular dysfunction (13%), co-existing malignancy (18%), prior disabling stroke (12%) and morbid obesity (11%). Using the standard and logistic EuroSCORE methods, the predicted in-hospital mortality rates were 7.8+/-3.3% and 13.2+/-11.1% respectively. In this study, the actual mortality rate was 1.2% at 30 days, 3.6% at 6 months and 4.8% at 1 year follow-up. CONCLUSIONS PCI in high risk patients who were refused for CABG in the DES-era resulted in an early and 1-year mortality rate that was significantly lower than the predicted operative mortality.

Invasive coronary imaging techniques have improved our understanding of atherosclerosis and helped us to evaluate the effectiveness of new drugs and new intravascular devices. We have adopted and integrated them rapidly into our clinical decision making process in the catheterisation laboratory. So far, only significant lesions in the coronary angiogram have been treated either by percutaneous coronary intervention (PCI) or coronary bypass artery grafting (CABG), while normal looking coronary segments in angiography have been regarded as “disease-free”, and mild/moderate stenoses as “non-treatable” by PCI or CABG; from these non-significantly diseased areas, acute coronary events may potentially arise. In response to this, many imaging coronary techniques have been developed to study these areas in order to understand better the pathophysiology of atherosclerotic disease and to assess the performance of medical interventions that may ultimately have an important impact on the prevention of acute myocardial infarction and death. Grey scale intravascular ultrasound (IVUS) has been so far the most useful invasive imaging technique. Using grey scale IVUS, some lipid lowering drugs have been shown to decrease plaque size, and as a result these drugs have been widely included as part of standard of care.w1 w2 Moreover, IVUS guided stenting, following strict criteria of implantation, has been proven to decrease the restenosis ratew3 and more recently it has been published that this approach apparently decreases stent thrombosis.w4 The recent introduction of tissue characterisation by means of radiofrequency data analysis (virtual histology, VH) has offered a more detailed evaluation of the atherosclerotic plaque. This technique brings the possibility of going beyond plaque size evaluation to a more sophisticated approach which is to assess changes in tissue types. In the IBIS 2 study,1 after 12 months and despite high adherence to standard-of-care treatment, the necrotic core continued to expand among patients …

Objective We sought to explore in vivo the relation between mechanical and compositional properties of matched cross sections (CSs) using novel catheter-based techniques. Background Intravascular ultrasound (IVUS) palpography allows the assessment of local mechanical tissue properties. Spectral analysis of IVUS radiofrequency data (IVUS-VH) is a tool to assess plaque morphology and composition. Methods and Results Palpography analysis defined high- and low-strain regions. One hundred twenty-three CSs (27 vessels) were colocalized. The mean strain value was higher in CSs with necrotic core (NC) in contact with the lumen than in CSs with no NC contact with the lumen (1.03 ± 0.5 vs 0.86 ± 0.4, P = .06). Mean relative calcium (1.61 ± 2.5% vs 0.25 ± 0.7%, P = .001) and NC (15.64 ± 10.6% vs 2.8 ± 3.9%, P < .001) content were significantly higher in the CSs with NC in contact with the lumen, whereas the inverse was seen for the fibrotic component of the plaque (64.16 ± 11.6% vs 75.75 ± 13.7, P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value of IVUS-VH to detect high strain were 75.0%, 44.4%, 56.3%, and 65.1%, respectively. A significant inverse relationship was present between calcium and strain levels (r = −0.20, P = .03). After adjusting for univariate predictors, the contact of NC with the lumen was identified as the only independent predictor of high strain (OR 5.0, 95% CI 1.7-14.1, P = .003). Conclusion In the present study, IVUS-VH showed an acceptable sensitivity to detect high strain. In turn, the specificity was low. Of interest, a significant inverse relationship was present between calcium and strain levels.

OBJECTIVES We sought to assess whether coronary stents have modified the predictive value of demographic, clinical and quantitative coronary angiographic (QCA) predictors of coronary restenosis. BACKGROUND A systematic analysis in a large cohort of registries and randomized trials of the percutaneous transluminal coronary angioplasty (PTCA) and stent era has never been performed. METHODS A total of 9,120 treated lesions in 8,156 patients included in nine randomized trials and 10 registries, with baseline, post-procedural and six-month follow-up QCA analyses, were included in this study. Predictors of restenosis were identified with univariate and multivariate logistic regression analyses. Interaction terms were introduced in the regression equation to evaluate whether the predictors of restenosis were common to both eras or specific for either one of the revascularization techniques. RESULTS The restenosis rate was 35% after PTCA and 19% after angioplasty with additional stenting. In the univariate analysis, favorable predictors were previous coronary artery bypass graft surgery (CABG), stent use, stent length and a large pre-procedural minimal lumen diameter (pre-MLD); unfavorable predictors were weight, body mass index, diabetes mellitus, multi-vessel disease, lesion length and a high residual post-procedural diameter stenosis (post-DS). Predictors specific for the PTCA population were a large post-procedural MLD (post-MLD) as favorable and a severe pre-procedural DS (pre-DS) as unfavorable. Favorable predictors specific for the stent population were a large post-MLD and a large pre-procedural reference diameter (pre-RD). In the multivariate analysis, the best model included the following favorable predictors: stent use, a large post-MLD, previous CABG and the interaction term between stent use and a large post-MLD; unfavorable predictors were lesion length and diabetes mellitus. CONCLUSIONS There are no major differences in demographic and clinical predictors of coronary restenosis between PTCA and stent populations. In the modern (stent) era, a severe pre-DS is no longer an unfavorable predictor of restenosis. Still important, but more so in the stent population, is a large post-MLD (optimal result). Finally, a larger pre-RD became a favorable predictor with the advent of stenting.