Publications

Local hemodynamic forces are well-known to modulate atherosclerotic evolution, which remains one of the largest cause of death worldwide. Percutaneous coronary interventions with stent implantation restores blood flow to the downstream myocardium and is only limited by stent failure caused by restenosis, stent thrombosis, or neoatherosclerosis. Cumulative evidence has shown that local hemodynamic forces affect restenosis and the platelet activation process, modulating the pathophysiological mechanisms that lead to stent failure. This article first covers the pathophysiological mechanisms through which wall shear stress regulates arterial disease formation/neointima proliferation and the role of shear rate on stent thrombosis. Subsequently, the article reviews the current evidence on (1) the implications of stent design on the local hemodynamic forces, and (2) how stent/scaffold expansion can influence local flow, thereby affecting the risk of adverse events.

No abstract is provided for this article.

No abstract is provided for this article.

Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long-acting β(2) -agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling.Responsiveness to corticosteroids dexamethasone (Dex), budesonide (Bud) and fluticasone propionate (FP) was determined, as IC(50) values on TNF-α-induced interleukin 8 release, in U937 monocytic cell line treated with hydrogen peroxide (H(2) O(2) ) or peripheral blood mononuclear cells (PBMCs) from patients with COPD or severe asthma.PBMCs from severe asthma and COPD were less sensitive to Dex compared with those from healthy subjects. Both FM (10(-9) M) and salmeterol (SM, 10(-8) M) reversed Dex insensitivity in severe asthma, but only FM restored Dex sensitivity in COPD. Although H(2) O(2) exposure decreased steroid sensitivity in U937 cells, FM restored responsiveness to Bud and FP while the effects of SM were weaker. Additionally, FM, but not SM, partially inhibited H(2) O(2) -induced PI3Kδ-dependent (PKB) phosphorylation. H(2) O(2) decreased SM-induced cAMP production in U937 cells, but did not significantly affect the response to FM. The reduction of SM effects by H(2) O(2) was reversed by pretreatment with LY294002, a PI3K inhibitor, or IC87114, a PI3Kδ inhibitor.FM reversed oxidative stress-induced corticosteroid insensitivity and decreased β(2) adrenoceptor-dependent cAMP production via inhibition of PI3Kδ signalling. FM will be more effective than SM, when combined with corticosteroids, for the treatment of respiratory diseases under conditions of high oxidative stress, such as in COPD.

Meeting report ESC forum on drug eluting stents, European Heart House, Nice, 27-28 September 2007

The additional information provided by automated on-line 3-dimensional (3-D) reconstruction of intracoronary ultrasound (ICUS) was assessed in 42 patients (62 stents) who underwent stent deployment after achieving an optimal quantitative angiographic result. In 10 of 42 patients, 3-D ICUS was also performed before stenting. ICUS images of stents and adjacent reference segments were acquired by using a motorized pullback at a constant speed (1 mm/s) and immediately processed in the catheterization laboratory. Optimal stent expansion was detected by 3-D ICUS in case of complete apposition of stent struts to the vessel wall. Furthermore, an attempt was made to maximize the intrastent lumen area to match lumen area of the reference segment and to cover with stents all the segments with residual significant lesions (plaque burden >50%). Three-dimensional automated reconstruction of ICUS was successful in 8 of 10 patients (80%) before, and in 36 of 42 patients (86%) after stent deployment. In all 8 patients who underwent successful 3-D ICUS assessment before stent implantation, the selection of stent length was facilitated by accurately measuring the lesion length. After stenting, 3-D ICUS modified the management strategy in 21 of 36 patients (58%), triggering additional high-pressure dilatations in 13 patients (36%) and additional stent deployment in 8 (22%). In conclusion, on-line 3-D ICUS facilitates stent selection and strongly modifies the revascularization strategy by accurately detecting stent underexpansion and presence of uncovered lesions.

Restenosis remains a problem following percutaneous coronary intervention in patients with coronary artery disease. Drug-eluting stents (DES), which combine mechanical and pharmacologic properties, have been shown to prevent or reduce neointimal growth after deployment. This review describes the TAXUS paclitaxel-eluting stent clinical trial expansion program (TAXUS Express, Boston Scientific, Natick, MA). This program comprises the largest data set of randomized controlled trials (RCTs) of DES to date, with over 6,200 patients enrolled since 2000. The program includes treatment of de novo lesions, as well as higher-risk lesion and patient populations. In this review, we discuss the results from the TAXUS family of randomized clinical trials, and compare the findings with data from TAXUS registries. The data from the randomized clinical trials suggest that the paclitaxel-eluting stent provides consistent and durable benefits across multiple lesion and patient types. Evidence from peri-and post-approval registries, where patient populations are more heterogeneous than those eligible and included in the RCTs, corroborate these findings, with overall low rates of cardiac events, including reinterventions.

Recent evidence from large-scale clinical trials has not only underscored the potential value of intravascular imaging in detecting plaque characteristics that are associated with disease progression but also demonstrated the poor predictive accuracy of intravascular imaging in identifying the lesions that will evolve and cause a future event. This limitation has been attributed to the fact that all the available intravascular imaging techniques are unable to provide a detailed and complete visualization of plaque pathology and identify features that are related with increased vulnerability. To overcome these drawbacks, fusion of intravascular imaging modalities with different strengths and weaknesses has been proposed. In this chapter we describe the available intravascular imaging techniques, discuss their limitations in the study of atherosclerosis, and present the hybrid intravascular approaches that have been developed for more complete and precise assessment of plaque pathology.

Background Quantitative flow ratio (QFR) is a novel angiography-based approach enabling fast computation of fractional flow reserve without use of pressure wire or adenosine. The objective of this investigator-initiated, multicenter, patient- and clinical assessor-blinded randomized trial is to evaluate the efficacy and cost-effectiveness of a QFR-augmented angiography-guided (QFR-guided) strategy versus an angiography-only guided (angiography-guided) strategy for percutaneous coronary intervention (PCI) in patients with coronary artery disease. Methods Approximately 3,830 patients will be randomized in a 1:1 ratio to a QFR-guided or an angiography-guided strategy. Included subjects scheduled for coronary angiography have at least 1 lesion eligible for PCI with 50%-90% stenosis in an artery with ≥2.5 mm reference diameter. Subjects assigned to the QFR-guided strategy will have QFR measured in each interrogated vessel and undergo PCI when QFR ≤0.80, with deferral for lesions with QFR >0.80. Those assigned to the angiography-guided strategy will undergo PCI based on angiography. Optimal medical therapy will be administered to all treated and deferred patients. The primary end point is the 1-year rate of major adverse cardiac events (MACE), a composite of all-cause mortality, any myocardial infarction, or any ischemia-driven revascularization. The major secondary end point is 1-year MACE excluding periprocedural myocardial infarction. Other secondary end points include the individual components of MACE and cost-effectiveness end points. The sample size affords 85% power to demonstrate superiority of QFR guidance compared with angiography guidance. Conclusions The FAVOR III China study will be the first randomized trial to examine the effectiveness and cost-effectiveness of a QFR-guided versus an angiography-guided PCI strategy in coronary artery disease patients.

COPD is associated with elevated cellular senescence. COPD patients have increased markers of oxidative stress, which can drive cellular senescence. MiR34a is involved in the induction of cellular senescence by inhibiting the anti-aging molecules sirtuin1/-6. Extracellular vesicles (EV), including microvesicles and exosomes, can contain miRNA involved in the induction of cellular senescence. In response to oxidative stress and in senescent cells, EVs cargo is modified. However, the involvement of EVs in epithelial cell senescence remains unclear. The aim is to characterise EV released by airway epithelial cells in response to oxidative stress and to assess their effect on epithelial cell senescence. BEAS2B cells and primary small airway epithelial cells (SAEC) were stimulated with H₂O₂ (100μM) for 48h. EV were isolated and characterised by Western blot and micro-BCA. miRNA expression in EV and cells treated with EVs was determined by qRT-PCR. In response to H₂O₂, epithelial cells release significantly more microvesicles (4.25μg/ml in medium condition and 6.42 μg/ml) in response to H₂O₂ and exosomes (1.89μg/ml in medium vs 4.13μg/ml) in response to H₂O₂. Microvesicles and exosomes produced by BEAS2B stimulated with H₂O₂ showed increased expression of miR34a (1.44 fold, n=4). Microvesicles produced by SAEC from COPD patients exhibit increased expression of miR34a compared to non-smokers (n=7 non-smoker, n=6 COPD). These data suggest that epithelial cells produce extracellular vesicles enriched in miRNA involved in cellular senescence. Further exploration of EVs in senescence may provide useful biomarkers and targets for future COPD therapy.