Publications

We report three cases of successful implantation of three different stents specially designed for bifurcation lesions, guided by intracoronary ultrasound. The BARD and AVE are true bifurcated stents for side-branch access and the NIR-Side Royal is a single modified NIR stent with an aperture to allow provisional bifurcation stenting. These designs introduce a new era in percutaneous management of coronary bifurcation lesions. Cathet. Cardiovasc. Intervent. 49:105-111, 2000.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease associated with cigarette smoking. Alterations in local lung and systemic iron regulation are associated with disease progression and pathogenesis. Hepcidin, an iron regulatory peptide hormone, is altered in subjects with COPD; however, the molecular role of hepcidin in COPD pathogenesis remains to be determined. In this study, using a murine model of smoke-induced COPD, we demonstrate that lung and circulating hepcidin levels are inhibited by cigarette smoke. We show that cigarette smoke exposure increases erythropoietin and bone marrow-derived erythroferrone and leads to expanded but inefficient erythropoiesis in murine bone marrow and an increase in ferroportin on alveolar macrophages (AMs). AMs from smokers and subjects with COPD display increased expression of ferroportin as well as hepcidin. Notably, murine AMs exposed to smoke fail to increase hepcidin in response to Gram-negative or Gram-positive infection. Loss of hepcidin in vivo results in blunted functional responses of AMs and exaggerated responses to Streptococcus pneumoniae infection.

No abstract is provided for this article.

We studied the effects of OKY-046 (1, 10, and 30 mg/kg iv), a selective thromboxane synthase inhibitor, and of ICI 192605 (0.5 mg/kg), a selective thromboxane A2 receptor antagonist, on airflow obstruction and airway microvascular leakage induced by inhaled platelet-activating factor (PAF). Extravasated Evans blue dye content was measured as a reflection of airway microvascular leakage. In control animals, PAF caused a significantly higher increase in extravasation of dye and significantly less increase in lung resistance (RL) than histamine. OKY-046 significantly inhibited both changes in RL and airway microvascular leakage after PAF in a dose-dependent manner, whereas it inhibited histamine-induced airway microvascular leakage only at main bronchi, without any significant effect on RL. ICI 192605 significantly inhibited both RL and airway microvascular leakage induced by PAF, but not after histamine. After both PAF and histamine, changes in RL correlated significantly with the degree of microvascular leakage. Airway microvascular leakage and airflow obstruction after PAF, but not after histamine, may be dependent on thromboxane A2 generation.

Objectives The aim of the study was to investigate trends over time in the occurrence of left bundle branch block (LBBB) and permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) with the Medtronic CoreValve System (MCS) and Edwards SAPIEN Valve (ESV). Background : TAVI‐induced conduction abnormalities (TAVI‐CAs) such as LBBB and the need for PPI are frequent postoperative complication. New techniques, procedural refinements, and increased awareness are focused on the reduction of these abnormalities. Methods Electrocardiograms of 549 patients without preprocedural LBBB and/or pacemaker were assessed to determine the frequency and nature of TAVI‐CAs. To study the effect of experience, patients were subdivided per center into tertiles based on the number of procedures. Univariate and multivariate logistic regression was used to study predictors of TAVI‐induced LBBB (TAVI‐LBBB) and PPI. Results TAVI‐LBBB occurred in 185 patients (33.7%) and significantly decreased over time, from 42.6% to 27.3% ( P = 0.006). This effect was only significant after implantation of the MCS (59.6% vs. 46.5% vs. 31.1%, P = 0.001, ESV: 22.6% vs. 13.1% vs. 24.8%, P = 0.11). Between tertiles there was no difference in the frequency of PPI after TAVI ( n = 73, 13.1% vs. 14.8% vs. 12%, P = 0.74). Multivariate analysis revealed that, independent from valve type, depth of implantation was the only significant predictor of TAVI‐LBBB (OR [95% C.I.]: 1.16 [1.10–1.24], P < 0.001). In case of PPI pre‐existing RBBB (OR [95% C.I.]: 7.22 [3.28–15.88], P < 0.001) was the only significant predictor. Conclusions Over time the frequency of LBBB after TAVI decreased significantly, especially in patients undergoing TAVI with the MCS. Experience and the subsequent reduction in depth of implantation seem responsible for this reduction. Contrary to TAVI‐LBBB, the incidence of PPI remained unchanged over time and was not affected by experience. Although experience has led to a decrease in new CAs after TAVI, elucidation of pathophysiologic mechanisms underlying these CAs and subsequent changes in patient stratification, valve design and the procedure are needed to further reduce this complication. © 2014 Wiley Periodicals, Inc.

No abstract is provided for this article.

<h3>Background</h3> Chronic obstructive pulmonary disease (COPD) is associated with accelerated lung ageing and cellular senescence. Small airway fibroblasts (SAF) are senescent in COPD and may be implicated in small airways disease. Senescent cells are in a permanent state of cell cycle arrest with increased expression of cell cycle inhibitors p16^Ink4a and p21^Cip1. Senotherapeutics can remove or alter the phenotype of senescent cells. We hypothesised that two senotherapeutics, fisetin and navitoclax, could reduce the senescence markers, p16^Ink4a and p21^Cip1, associated with senescent SAF in COPD. <h3>Objective</h3> Investigate effects of fisetin and navitoclax on p16^Ink4a and p21^Cip1 expression in COPD SAF. <h3>Methods</h3> SAF were isolated from lung resection tissue of COPD patients (n=6) and non-smokers (n=8). Cells were cultured with fisetin (1–100 µM) and navitoclax (0.1–10 M). Cellular senescence was induced using 300 MH₂O₂. Expression of senescence markers, p16^Ink4a and p21^Cip1, was measured using western blots. Cell viability was assessed using MTT assays. <h3>Results</h3> p21^Cip1, but not p16^Ink4a, was significantly increased in COPD SAF compared to non-smoker SAF (p=0.02). Cell viability was decreased in COPD SAF treated with navitoclax by 60.2% (p=0.11, n=4). COPD SAF treated with 100 M navitoclax showed a concentration-dependent decrease in expression of p16^INK4 by 83.3% (p=0.13, n=4) and p21^Cip1 by 86.4% (p=0.13, n=4), which was not seen at any concentration of fisetin. Next, H₂O₂ was used to induce senescence further in COPD SAF. Treatment of COPD SAF with 300 M H₂O₂increased the expression of senescence marker p21^Cip1 by 101.5% (p=0.58, n=7). In this model, the highest concentrations of navitoclax, but not fisetin, significantly reduced cell viability in senescence-induced COPD SAF (by 83.7 ± 2.1%, p=0.038). Both fisetin and navitoclax significantly reduced expression of p16^Ink4a (by 77.1± 8.7%, p=0.024 and 99.8 ± 0.2%, p=0.0082, respectively) and p21^Cip1(by 88.6 ± 2.5%, p=0.024 and 95.4 ± 4.5%, p=0.018, respectively) in senescence-induced COPD SAF. Similar results were seen in senescence-induced non-smoker SAF. <h3>Conclusion</h3> Fisetin and navitoclax both reduce p16^Ink4a and p21^Cip1 expression in senescent COPD SAF. Further work is needed to investigate if these drugs alter other markers of senescence or induce apoptosis.

Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in those with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples from healthy nonsmokers, healthy smokers, and COPD patients. BOEC from smokers and COPD patients showed increased DNA double-strand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin-1 (SIRT1), a protein deacetylase that protects against DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence. Treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or an ATM inhibitor (KU-55933) also rescued the senescent phenotype. Using an in vivo mouse model of angiogenesis, we demonstrated that senescent BOEC from COPD patients are dysfunctional, displaying impaired angiogenic ability and increased apoptosis compared to cells from healthy nonsmokers. Therefore, this study identifies epigenetic regulation of DNA damage and senescence as pathogenetic mechanisms linked to endothelial progenitors' dysfunction in smokers and COPD patients. These defects may contribute to vascular disease and cardiovascular events in smokers and could therefore constitute therapeutic targets for intervention.

The use of sirolimus-eluting coronary stents has been associated with a nearly complete elimination of restenosis at 6 months and with a very low 1-year incidence of major adverse cardiac events (MACE). This analysis examined whether these beneficial effects persist over the longer term.This multicenter trial randomly assigned 238 patients to revascularization of single, de novo, native coronary artery lesions with sirolimus-eluting versus conventional bare-metal stents. Survival free from target lesion revascularization (TLR), target vessel failure (TVF), and MACE up to 3 years of follow-up was compared between the 2 treatment groups. Complete data sets were available in 94.2% of patients treated with sirolimus-eluting stents and in 94.1% of patients randomized to the control group. The cumulative 1-, 2-, and 3-year event-free survival rates were 99.2%, 96.5%, and 93.7% for TLR and 95.8%, 92.3%, and 87.9% for TVF, respectively, in the sirolimus-eluting stent group, versus 75.9%, 75.9%, and 75.0% for TLR and 71.2%, 69.4%, and 67.3% for TVF in the control group (P<0.001 for both comparisons at 3 years). Rates of MACE at 3 years were 15.8% in patients randomly assigned to sirolimus-eluting stents versus 33.1% in patients assigned to bare-metal stents (P=0.002). One patient treated with a sirolimus-eluting stent died of a cardiac cause between 12 and 36 months.Treatment of de novo coronary stenosis with sirolimus-eluting stents was associated with a sustained clinical benefit and very low rates of TLR and of other MACE up to 3 years after device implantation.