Publications

The airway epithelium is critical in the pathogenesis of chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease, and, by expressing numerous inflammatory genes, plays a prominent role in disease exacerbations. Since inflammatory gene expression often involves the transcription factor nuclear factor (NF)-κB, this signaling pathway represents a site for anti-inflammatory intervention. As the airway epithelium is targeted by inhaled therapeutic agents, for example corticosteroids, human A549 pulmonary cells and primary human bronchial epithelial (HBE) cells were selected to evaluate inhibitor of κB kinase (IKK) inhibitors. In A549 cells, interleukin (IL)-1β and tumor necrosis factor (TNF) α increased phosphorylation of IκBα, and this was followed by loss of IκBα, induction of NF-κB DNA binding, and the induction of NF-κB-dependent transcription. These events were repressed by the IKK-selective inhibitors, PS-1145 [<i>N</i>-(6-chloro-9<i>H</i>-β-carbolin-8-ly) nicotinamide] and ML120B [<i>N</i>-(6-chloro-7-methoxy-9<i>H</i>-β-carbolin-8-yl)-2-methyl-nicotinamide]. Inhibition of NF-κB-dependent transcription was concentration-dependent and correlated with loss of intercellular adhesion molecule (ICAM)-1 expression. Similarly, IL-1β- and TNFα-induced expression of IL-6, IL-8, granulocyte macrophage-colony-stimulating factor (GM-CSF), regulated and activation normal T cell expressed and secreted (RANTES), growth-related oncogene α, and monocyte chemotactic protein-1 (MCP-1) was also significantly repressed. Likewise, PS-1145 and ML120B profoundly reduced NF-κB-dependent transcription induced by IL-1β and TNFα in primary HBE cells. Parallel effects on ICAM-1 expression and a significant repression of IL-8 release were observed. In contrast, the corticosteroid, dexamethasone, was without effect on NF-κB-dependent transcription or the expression of ICAM-1. The above data provide strong support for an anti-inflammatory effect of IKK2 inhibitors acting on the pulmonary epithelium and suggest that such compounds may prove beneficial in situations where traditional corticosteroid therapies prove inadequate.

No abstract is provided for this article.

Airway inflammation is important in the development and progression of many lung diseases, including bronchiectasis. Activation of inflammatory cells such as neutrophils, eosinophils, and macrophages induces a respiratory burst resulting in the production of reactive oxygen species such as hydrogen peroxide (H2O2). We have measured exhaled H2O2 in patients with documented bronchiectasis and investigated whether the concentration of H2O2 is related to the disease severity, as defined by lung function. We also investigated whether the concentrations of expired H2O2 were different in bronchiectatic patients who received inhaled corticosteroids compared with steroid-naı̈ve patients. In 37 patients with bronchiectasis (mean age, 45 ± 2.5 yr; FEV1, 59 ± 3% pred), mean H2O2 concentration in exhaled breath condensate was significantly elevated as compared with the values in 25 age-matched (mean age, 42 ± 2 yr) normal subjects (0.87 ± 0.01 versus 0.26 ± 0.04 μ M, p < 0.001). There was a significant negative correlation between H2O2 and FEV1 (r = − 0.76, p < 0.0001). Patients treated with inhaled corticosteroids had values of H2O2 similar to those of steroid-naı̈ve patients (0.8 ± 0.1 versus 0.9 ± 0.1, p > 0.05). We conclude that H2O2 is elevated in exhaled air condensate of patients with bronchiectasis and is correlated with disease severity. Measurement of H2O2 may be used as a simple noninvasive method to monitor airway inflammation and oxidative stress.

Objectives The aim of this study was to examine whether stent length per patient and stent length per lesion are negative markers for 3-year outcomes in women following percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DES). Background In the era of advanced stent technologies, whether stent length remains a correlate of adverse outcomes is unclear. Methods Women treated with new-generation DES in 14 randomized trials from the WIN-DES (Women in Innovation and Drug-Eluting Stents) pooled database were evaluated. Total stent length per patient, which was available in 5,403 women (quartile 1, 8 to 18 mm; quartile 2, 18 to 24 mm; quartile 3, 24 to 36 mm; quartile 4, ≥36 mm), and stent length per lesion, which was available in 5,232 women (quartile 1, 8 to 18 mm; quartile 2, 18 to 20 mm; quartile 3, 20 to 27 mm; quartile 4, ≥27 mm) were analyzed in quartiles. The primary endpoint was 3-year major adverse cardiovascular events (MACE), defined as a composite of all-cause death, myocardial infarction, or target lesion revascularization. Results In the per-patient analysis, a stepwise increase was observed with increasing stent length in the adjusted risk for 3-year MACE (p for trend <0.0001), myocardial infarction (p for trend <0.001), cardiac death (p for trend = 0.038), and target lesion revascularization (p for trend = 0.011) but not definite or probable stent thrombosis (p for trend = 0.673). In the per-lesion analysis, an increase was observed in the adjusted risk for 3-year MACE (p for trend = 0.002) and myocardial infarction (p for trend <0.0001) but not other individual endpoints. On landmark analysis for late event rates between 1 and 3 years, stent length per patient demonstrated weak associations with target lesion revascularization (p = 0.0131) and MACE (p = 0.0499), whereas stent length per lesion was not associated with higher risk for any late events, suggesting that risk was established early within the first year after PCI. Conclusions In this pooled analysis of women undergoing PCI with new-generation DES, increasing stent length per patient and per lesion were independent predictors of 3-year MACE but were not associated with definite or probable stent thrombosis.

No abstract is provided for this article.

Transcatheter aortic valve replacement (TAVR) is a recommended intervention for selected population with severe aortic stenosis (AS). Bicuspid aortic valve (BAV) anatomy has been categorized as an unfavorable anatomy for TAVR due to multiple considerations as exclusion from randomized trials in addition to the challenging and unpredictable anatomy. The anatomical constraints of BAV include the large anatomy of the annulus, sinus of Valsalva, and aorta (aortopathy), in addition to significant calcifications of the device landing zone. Most commercial transcatheter heart valves (THV) have upper dimension limits of the annulus and area in which the device can be implanted safely without significant oversizing. Myval-XL THVs (Meril Life Sciences Pvt. Ltd., India) are balloon-expandable valves (BEV) that have been developed with two new sizes, 30.5 and 32 mm, aiming to treat patients with large annulus dimensions and that exceed the upper limit of an ordinary device's sizing matrix. This case series report describes TAVR using the XL-Myval 32 mm THV in three European patients with symptomatic severe bicuspid aortic stenosis with significant calcifications and large annular dimensions exceeding the limits of the other THVs.

To determine (1) the medium-term effect of rosiglitazone and glipizide on intra-stent neointima hyperplasia, (2) restenosis pattern as assessed by intra-vascular ultrasound (IVUS) and quantitative coronary angiography (QCA) in patients with T2DM and coronary artery disease. A total of 462 patients with T2DM were randomized to rosiglitazone or glipizide for up to 18 months in the APPROACH trial, and had evaluable baseline and follow-up IVUS examinations. There was no significant difference in the size of plaque behind stent between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (−5.6 mm3 vs. 1.9 mm3; P = 0.61) or with a drug-eluting stent (12.1 mm3 vs. 5.5 mm3; P = 0.09). Similarly, there was no significant difference in percentage intimal hyperplasia volume between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (24.1% vs. 19.8%; P = 0.38) or with a drug-eluting stent (9.8% vs. 8.3%; P = 0.57). QCA data (intra-stent late loss, intra-stent diameter stenosis or binary restenosis) were not different between the rosiglitazone and glipizide groups. This study suggests that both rosiglitazone and glipizide have a similar effect on neointimal growth at medium term follow-up, a finding that warrants investigation in dedicated randomized trials.