Publications

Background —This study represents the Heart Center Rotterdam’s contribution to the Isostents for Restenosis Intervention Study, a nonrandomized multicenter trial evaluating the safety and feasibility of the radioactive Isostent in patients with single coronary artery disease. Restenosis after stent implantation is primarily caused by neointimal hyperplasia. In animal studies, β-particle–emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation. Methods and Results —The radioisotope 32 P, a β-particle emitter with a half-life of 14.3 days, was directly embedded into the Isostent. The calculated range of radioactivity was 0.75 to 1.5 μCi. Quantitative coronary angiography measurements were performed before and after the procedure and at 6-month follow-up. A total of 31 radioactive stents were used in 26 patients; 30 (97%) were successfully implanted, and 1 was embolized. Treated lesions were in the left anterior descending coronary artery (n=12), the right coronary artery (n=8), or the left circumflex coronary artery (n=6). Five patients received additional, nonradioactive stents. Treated lesion lengths were 13±4 mm, with a reference diameter of 2.93±0.47 mm. Minimum lumen diameter increased from 0.87±0.28 mm preprocedure to 2.84±0.35 mm postprocedure. No in-hospital adverse cardiac events occurred. All patients received aspirin indefinitely and ticlopidine for 4 weeks. Twenty-three patients (88%) returned for 6-month angiographic follow-up; 17% of them had in-stent restenosis, and 13% had repeat revascularization. No restenosis was observed at the stent edges. Minimum lumen diameter at follow-up averaged 1.85±0.69 mm, which resulted in a late loss of 0.99±0.59 mm and a late loss index of 0.53±0.35. No other major cardiac events occurred during the 6-month follow-up. Conclusions —The use of radioactive stents with an activity of 0.75 to 1.5 μCi is safe and feasible.

Objectives We evaluated the pharmacokinetics of the eluted everolimus by assessing systemic drug release and distribution of everolimus-eluting stents. Background Drugs eluted by a coronary stent might cause adverse events such as tumors, infections, or noncardiac death. The systemic exposure of the drugs is unknown because there are only limited data about pharmacokinetics of drug-eluting stents in humans. Methods Venous blood samples in a subset of 39 patients were drawn just before implantation of the first stent (baseline, 0-minute time point) and at 10 and 30 minutes and 1, 2, 4, 6, 12, 24, 36, 48, 72, 168, and 720 hours (30 days) after completion of implantation of the last stent. Whole blood concentrations of everolimus were determined using a sensitive validated high-performance liquid chromatography mass spectrometry/mass spectrometry method. Results The total dose of everolimus received by the patients ranged from 53 to 588 μg. The last time point up to which whole blood concentrations could be quantified ranged per patient from 4 to 720 hours after implantation of the last stent. Across all dose levels, individual T max values ranged from 0.13 and 2.17 hours; individual C max ranged from 0.14 to 2.79 ng/mL. Conclusion This study confirms the limited exposure to the systemic circulation of the eluted drug with the use of the XIENCE V Everolimus-Eluting Coronary Stent System (Abbott Vascular, Santa Clara, CA). Therefore, a systemic cause of adverse events is unlikely.

To compare the renarrowing process after atherectomy (DCA) and stenting, we reviewed the cineangiograms from a prospectively collected series of 234 matched DCA and stent patients (pts) with identical baseline clinical and angiographic characteristics. In addition, we explored whether the process of luminal renarrowing was related to the extent or mechanism of luminal improvement in matched pts with comparable lesion location, vessel size (RD), lesion severity (MLD) and acute gain. Multivariate analyses were performed to determine the correlates of minimal lumen at follow-up and lumen loss. Matching was considered adequate since lesion distribution, RD (3.09 vs 3.09mm) and MLD (1.12 vs 1.12 mm) were equal in both groups. Stenting lesulted in a larger increase in MLD than DCA (1.41 vs 1.20mm; p=0.0002), similar late loss (0.57 vs 0.66mm; p=NS) with subsequently a larger MLD at follow-up (1.96 vs 1.66mm; p=0.0001). However, when additional matching (n=150 pts) for acute gain (1.34 vs 1.33mm) was performed, late lumen loss was significantly smaller after stenting (0.52 vs 0.75mm; p=0.007) leading to a favorable long-term MLD (1.90 vs 1.66mm; p=0.004) when compared with DCA. Multivariate analysis revealed device type, vessel size and lumen gain as independent predictors for MLD at follow-up. The changes in MLD are shown in cumulative distribution curves: Multivariate analysis of MLD at follow-up Intercept Coefficient p-value -0.63 RD 0.19 0.12 MLD pre 0.76 0.004 Gain 0.67 0.0001 Device -24* 0.003 DCA=1. STENT=0 In conclusion the long-term angiographic outcome of stenting seems more favorable than of directional atherectomy due to a larger acute luminal gain and a substantial reduction in late luminal loss. It appears that the late outcome after an intervention is not only related to extent of luminal improvement but also to the mechanism of acute gain (device type).

The anti-inflammatory effect of CHF6001, a novel phosphodiesterase-4 (PDE4) inhibitor delivered via a dry powder inhaler, was evaluated in asthmatics on the airway response to allergen challenge (AC). METHODS: Thirty-six steroid-naive asthmatics with dual response to AC were enrolled in a randomized, double-blind, placebo-controlled, 3-way crossover trial. They received daily treatment with CHF6001 low dose (400 µg), high dose (1200 µg) or placebo for 9 days. On Day 9 subjects underwent AC and pharmacokinetic evaluation. RESULTS: Both doses of CHF6001 significantly attenuated the late asthmatic response (LAR): the weighted FEV1 AUC4-10h was reduced by 20% (p=0.014) and 30% (p<0.01) respectively with low and high dose compared with placebo. The maximum FEV1 fall during LAR was reduced by 16% (p=0.027) and 24% (p<0.01) with low and high dose, respectively. There was no effect on the early asthmatic response (0-2h post AC). Exposure to CHF6001 increased dose proportionally with peak plasma levels at 2 h post-dose and elimination half-lives of approximately 24 h. Systemic exposure to metabolites was low compared to the parent compound, suggesting limited formation in vivo . There were no gastrointestinal adverse events, except dyspepsia in one patient after both CHF6001 400 µg and placebo. CONCLUSIONS: CHF6001, a novel PDE4 inhibitor, optimized for inhaled delivery to improve efficacy and tolerability, significantly reduces LAR after allergen challenge. Both doses of CHF6001 were safe and well tolerated, particularly with respect to gastrointestinal side effects.

Background The safety and efficacy of drug-eluting stents (DES) in the treatment of coronary artery disease have been assessed in several randomised trials. However, none of these trials were powered to assess the safety and efficacy of DES in women because only a small proportion of recruited participants were women. We therefore investigated the safety and efficacy of DES in female patients during long-term follow-up. Methods We pooled patient-level data for female participants from 26 randomised trials of DES and analysed outcomes according to stent type (bare-metal stents, early-generation DES, and newer-generation DES). The primary safety endpoint was a composite of death or myocardial infarction. The secondary safety endpoint was definite or probable stent thrombosis. The primary efficacy endpoint was target-lesion revascularisation. Analysis was by intention to treat. Findings Of 43 904 patients recruited in 26 trials of DES, 11 557 (26·3%) were women (mean age 67·1 years [SD 10·6]). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation DES, and 6278 (54·3%) newer-generation DES. At 3 years, estimated cumulative incidence of the composite of death or myocardial infarction occurred in 132 (12·8%) women in the bare-metal stent group, 421 (10·9%) in the early-generation DES group, and 496 (9·2%) in the newer-generation DES group (p=0·001). Definite or probable stent thrombosis occurred in 13 (1·3%), 79 (2·1%), and 66 (1·1%) women in the bare-metal stent, early-generation DES, and newer-generation DES groups, respectively (p=0·01). The use of DES was associated with a significant reduction in the 3 year rates of target-lesion revascularisation (197 [18·6%] women in the bare-metal stent group, 294 [7·8%] in the early-generation DES group, and 330 [6·3%] in the newer-generation DES group, p<0·0001). Results did not change after adjustment for baseline characteristics in the multivariable analysis. Interpretation The use of DES in women is more effective and safe than is use of bare-metal stents during long-term follow-up. Newer-generation DES are associated with an improved safety profile compared with early-generation DES, and should therefore be thought of as the standard of care for percutaneous coronary revascularisation in women. Funding Women in Innovation Initiative of the Society of Cardiovascular Angiography and Interventions.

Urban et al 1 recently developed the Academic Research Consortium for high bleeding risk (ARC-HBR) trade-off model.The new scores provide the predicted 1-year risk of nonperiprocedural major bleeding (Bleeding Ac ademic Research Consortium [BARC] types 3-5 bleeding) and thrombotic events (myocardial infarction [MI] and/or definite or probable stent thrombosis [ST]) after coronary stenting in patients with HBR.In the development and validation cohorts, the C statistics were 0.68 and 0.74 for major bleeding and 0.68 and 0.74 for thrombotic events, respectively; C statistics in validation cohorts typically are lower than those observed in the development cohort.To support individual optimal antiplatelet therapy, bleeding and thrombotic risk scores should achieve helpful discrimination (C statistics, ≥0.60) in contemporary treatment strategies. 2 We applied the scores to the GLOBAL LEADERS trial population. 3 Methods | The GLOBAL LEADERS trial investigated aspirinfree antiplatelet treatment (experimental arm, 1 month of dual antiplatelet therapy [DAPT] followed by 11 months of ticagrelor monotherapy vs reference arm, 12 months of DAPT) in an all-comers population.All patients provided informed consent.The trial was approved by the institutional review board at each center and followed the ethical principles of the Declaration of Helsinki (Supplement 1).Patients were enrolled between July 2013 to November 2015 and had an outpatient clinic visit at 30 days and 3, 6, 12, 18, and 24 months after the index procedure.Data were analyzed during January 2021.The ARC-HBR trade-off model was externally validated in patients with ARC-HBR in the GLOBAL LEADERS trial.Multiple imputation (20 times) of missing values was conducted based on the correlation between all potential predictors and clinical outcomes to make efficient use of the available data without introducing bias under the missing-at-random assumption. 4 The discriminative abilities for BARC types 3 to 5 bleeding and MI and/or ST between 3 to 365 days were assessed using the Harrell C statistic (C index).Agreement between observed and predicted rates was assessed by calibration plot. 4 The discriminative abilities of the PARIS and PRECISE-DAPT scores were also assessed.Analyses were performed using R, version 3.6.0(R Foundation for Statistical Computing).

Although glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases, a small proportion of patients are resistant to their therapeutic effects. The molecular mechanism for this steroid resistance is unclear. Steroid resistance cannot be explained by pharmacokinetic mechanisms, by a defect in the binding of steroids to glucocorticoid receptors, nor by defective nuclear translocation of this receptor, thereby suggesting that the molecular abnormality lies distal to nuclear translocation. We examined the ability of nuclear translocated glucocorticoid receptors to bind to their DNA binding sites (GRE) using electrophoretic mobility shift assays in PBMC from patients with steroid-sensitive and steroid-resistant asthma. The binding of the glucocorticoid receptor to DNA in these patients was also studied using Scatchard analysis. Dexamethasone induced a significant rapid and sustained twofold increase in GRE binding in PBMCs from steroid-sensitive asthmatic patients and nonasthmatic individuals, but this was markedly reduced in steroid-resistant asthmatic patients. Scatchard analysis of glucocorticoid receptor-GRE binding showed no change in binding affinity but did show a reduced number of receptors available for DNA binding in the steroid-resistant patients. These results suggest that the ability of the glucocorticoid receptor to bind to GRE is impaired in steroid-resistant patients because of a reduced number of receptors available for binding to DNA.

The novel peptide, nociceptin and the mu-opioid agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) produced a concentration-dependent inhibition of electrical field stimulation (EFS)-evoked release of acetylcholine (ACh) from cholinergic nerves innervating guinea-pig trachea. The non-selective opioid receptor antagonist, naloxone, did not antagonize the inhibitory action of nociceptin under conditions where the inhibition of ACh release evoked by DAMGO was completely reversed. It is suggested that DAMGO and nociceptin can inhibit cholinergic, parasympathetic neurotransmission to the airways via the activation of classical (naloxone-sensitive) and novel (naloxone-insensitive) opioid receptors, respectively.

Asthma is a chronic inflammatory disease that is characterized by increased expression of multiple inflammatory genes. Chromatin modification plays a critical role in the regulation of these genes. Acetyaltion of histones by histone acetyltransferases (HATs) is associated with increased gene transcription, whereas hypocetylation induced by histone deacetylases (HDACs) is associated with suppression of gene expression. We have examined the expression and activity of HATs and HDACs in bronchial biopsies from normal subjects and subjects with asthma. There was no difference in the site of HDAC1–HDAC6 expression between normal subjects and subjects with asthma, but subjects with asthma had reduced HDAC enzymatic activity and reduced HDAC1 and HDAC2 protein expression, as measured by Western blotting. In contrast, subjects with asthma treated with inhaled steroids were found to have greater HDAC activity than untreated subjects with asthma, although still lower than control subjects. In contrast, although there was no change in the site of HAT (CREB binding protein and p300/CREB binding protein–associated factor) expression, HAT activity was increased in subjects with asthma. HAT activity was reduced to control levels in subjects with asthma treated with inhaled steroids. The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes, and this is reversed, at least in part, by treatment with inhaled steroids.