Publications

Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-κB–mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1β–induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-κB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-κB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-κB–dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression.

Objectives We sought to compare the diagnostic value of multi-slice computed tomography (MSCT) coronary angiography (CA) to detect significant stenoses (≥50% lumen diameter reduction) with that of invasive CA. Background The latest 16-row MSCT scanner has a faster rotation time (375 ms) and permits scanning with a higher X-ray tube current (500 to 600 mA) during MSCT CA when compared with previous scanners. Methods We studied 51 patients (37 men, mean age 58.9 ± 10.0 years) with stable angina or atypical chest pain. Patients with pre-scan heart rates ≥70 beats/min received oral beta-blockade. The heart was scanned after intravenous injection of 100 ml contrast (iodine content, 400 mg/ml). Mean scan time was 18.9 ± 1.0 s. The MSCT scans were analyzed by two observers unaware of the results of invasive angiography, and all available coronary branches ≥2 mm were included. Results Invasive CA demonstrated normal arteries in 16% (8 of 51), non-significant disease in 21% (11 of 51), single-vessel disease in 37% (19 of 51), and multi-vessel disease in 26% (13 of 51) of patients. There were 64 significant lesions. Sensitivity, specificity, and positive and negative predictive values for detection of significant lesions on a segment-based analysis were 95% (61 of 64, 95% confidence interval [CI] 86 to 99), 98% (537 of 546, 95% CI 96 to 99), 87% (61 of 70, 95% CI 76 to 98), and 99% (537 of 540, 95% CI 98 to 99), respectively. All patients with angiographically normal coronary arteries or significant lesions were correctly identified. Three of 11 patients with <50% lesions were incorrectly classified as having single-vessel disease. Conclusions The 16-row MSCT CA reliably detects significant coronary stenoses in patients with atypical chest pain or stable angina pectoris.

Compared with everolimus-eluting metallic stents, the Absorb bioresorbable scaffold (BRS) results in increased rates of myocardial infarction (MI) and scaffold thrombosis (ST) during its three-year bioresorption phase. It is unknown whether prolonged dual antiplatelet therapy (DAPT) duration might decrease the risk of ischaemic events.We sought to evaluate the impact of DAPT duration on ischaemic and bleeding outcomes following BRS implantation.We conducted an individual patient data pooled analysis from four ABSORB randomised trials and one prospective ABSORB registry. Study endpoints were MI, ST, bleeding, and death up to three-year follow-up. Propensity score-adjusted Cox regression analysis was used to account for baseline differences related to DAPT duration.The five ABSORB studies included 2,973 patients. DAPT use was 91.7%, 53.2%, and 48.0% at 1, 2, and 3 years, respectively. DAPT use within the first year after BRS implantation was associated with markedly lower risks of MI (adjusted hazard ratio [aHR] 0.17, 95% CI: 0.10-0.32; p<0.0001) and ST (aHR 0.08, 95% CI: 0.03-0.19; p<0.0001). Conversely, DAPT use between 1 and 3 years did not significantly affect the risk of MI (aHR 1.04, 95% CI: 0.70-1.55; p=0.84) or ST (aHR 0.86, 95% CI: 0.42-1.75; p=0.67). DAPT did not have major effects upon bleeding or death in either period.DAPT use during the first year after BRS implantation was strongly associated with lower risks of ST and MI. However, a benefit of ongoing DAPT use between 1 and 3 years after BRS implantation was not apparent.

BACKGROUND: Eosinophils in induced sputum and exhaled nitric oxide (NO) are currently used as non-invasive markers in the assessment of airway inflammation in asthma. As both sputum eosinophils (%) and exhaled NO are raised in asthmatic subjects not receiving inhaled steroids and decreased following corticosteroid therapy, a relationship between them is plausible. METHODS: Exhaled NO was measured by chemiluminescence analyser, sputum induction by 3.5% saline inhalation, and bronchial responsiveness was measured as PC20FEV1 methacholine in 35 stable asthmatic patients using beta 2 agonist alone and the correlation between these non-invasive markers of airway inflammation was studied. RESULTS: There were significant correlations between exhaled NO and PC20 (r = -0.64), exhaled NO and sputum eosinophils (%) (r = 0.48), and also between sputum eosinophils (%) and PC20 (r = -0.40). CONCLUSION: The correlation between exhaled NO and PC20 suggests that exhaled NO or the mechanisms leading to its increase may contribute to airway hyperresponsiveness in asthma. Furthermore, the relationship between sputum eosinophils (%), exhaled NO, and PC20 highlight the potential use of eosinophils (%) in induced sputum and exhaled NO to monitor the severity of asthma.

No abstract is provided for this article.

Objective We examined whether anxiety has incremental value to depressive symptoms in predicting health status in patients undergoing percutaneous coronary intervention (PCI) treated in the drug-eluting stent era. Methods A series of consecutive patients (n=692) undergoing PCI as part of the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital registry completed the Hospital Anxiety and Depression Scale at 6 months and the Short-Form Health Survey (SF-36) at 6 and 12 months post-PCI. Results Of 692 patients, 471 (68.1%) had no symptoms of anxiety nor depression, 62 (9.0%) had anxiety only, 59 (8.5%) had depressive symptoms only, and 100 (14.5%) had co-occurring symptoms. There was an overall significant improvement in health status between 6 and 12 months post-PCI (P<.001); the interaction effect for time by psychological symptoms was also significant (P=.003). Generally, patients with co-occurring symptoms reported significantly poorer health status compared with the other three groups (Ps <.001). Patients with co-occurring symptomatology were also at greater risk of impaired health status on six of the eight subdomains of the SF-36 compared with the other three symptom groups, adjusting for baseline characteristics and health status at 6 months. Conclusion Patients with co-occurring symptoms of anxiety and depression reported poorer health status compared with anxious or depressed-only patients and no-symptom patients, showing that anxiety has incremental value to depressive symptoms in identifying PCI patients at risk for impaired health status treated in the drug-eluting stent era.

This study sought to investigate the long-term clinical outcomes related to scaffold sizing based on quantitative coronary angiography.A total of 1,248 patients who received Absorb bioresorbable scaffolds in the ABSORB Cohort B, ABSORB EXTEND, and ABSORB II trials were included in the analysis. The incidence of MACE (a composite of cardiac death, any myocardial infarction [MI], and ischaemia-driven target lesion revascularisation [ID-TLR]) was analysed according to the Dmax subclassification of oversized scaffold group versus non-oversized (any undersize) scaffold group. At three years, event rates were similar in both groups in MACE (9.4% vs. 9.8%, p=0.847), target vessel MI (5.2% vs. 4.8%, p=0.795), and ID-TLR (4.8% vs. 5.8%, p=0.445). Landmark analysis after one year showed that the non-oversized scaffold group had higher rates of MACE (3.2% vs. 6.9%, log-rank p=0.004), target vessel MI (0.7% vs. 2.7%, log-rank p=0.007), and ID-TLR (2.5% vs. 4.7%, log-rank p=0.041).Implantation of an undersized scaffold was associated with a higher risk of MACE between one and three years, while in the previous report an oversized scaffold was associated with a higher risk of MACE up to one year. This implies different mechanisms for early and late events after scaffold implantation.

No abstract is provided for this article.