Publications

No abstract is provided for this article.

While primary percutaneous coronary intervention (PCI) has significantly contributed to improve the mortality in patients with ST segment elevation myocardial infarction even in cardiogenic shock, primary PCI is a standard of care in most of Japanese institutions. Whereas there are high numbers of available facilities providing primary PCI in Japan, there are no clear guidelines focusing on procedural aspect of the standardized care. Whilst updated guidelines for the management of acute myocardial infarction were recently published by European Society of Cardiology, the following major changes are indicated; (1) radial access and drug-eluting stent over bare metal stent were recommended as Class I indication, and (2) complete revascularization before hospital discharge (either immediate or staged) is now considered as Class IIa recommendation. Although the primary PCI is consistently recommended in recent and previous guidelines, the device lag from Europe, the frequent usage of coronary imaging modalities in Japan, and the difference in available medical therapy or mechanical support may prevent direct application of European guidelines to Japanese population. The Task Force on Primary Percutaneous Coronary Intervention of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) has now proposed the expert consensus document for the management of acute myocardial infarction focusing on procedural aspect of primary PCI.

<b>Background:</b> Cellular senescence is one of the hallmarks of COPD. The miR-34a and mir-570 are involved in the induction of cellular senescence by inhibiting anti-ageing sirtuins. Extracellular vesicles (EVs) play a key role in intercellular communication. Senescent cells produce high amounts of EVs and contain miRNA that can regulate cellular senescence. The role of EVs in spreading cell senescence remains unclear. <b>Aim:</b> To characterize extracellular vesicles released by epithelial cells in response to oxidative stress and to assess their effect on epithelial cells senescence. <b>Methods:</b> BEAS-2B bronchial epithelial cells were stimulated with H2O2 for 24 or 48h. Microvesicles and exosomes were isolated by differential ultracentrifugation of cell supernatant and characterised by Western blot and labelling membrane with the dye PKH67. The RNA content of EVs was determined by fluorescence and by qRT-PCR. <b>Results:</b> After 48h treatment, EVs are released by cells stimulated with medium or H2O2. The fluorescence intensity of pkh67 increased in response to H2O2 (n=2, from 2.6 fold for microvesicles, and 1.4 fold for exosomes) suggesting that epithelial cells release more EVs in response to oxidative stress. In response to H2O2, miR-34a and miR-570 expression is augmented only in exosomes. <b>Conclusion:</b> These data suggest that in response to oxidative stress, epithelial cells produced exosomes enriched in miRNA involved in cellular senescence. This may contribute to COPD pathophysiology by spreading senescence in adjacent epithelial and other cells.

An imbalance between proteases and antiproteases may play a role in emphysema, which is characterized by increased degradation of extracellular matrix, and in airway remodeling in chronic bronchitis and asthma, in which there is increased collagen deposition. We assessed the effect of smoking on release of matrix metalloprotease-9 (MMP-9) and of its inhibitor, tissue inhibitor of metalloprotease-1 (TIMP-1), from alveolar macrophages, and determined the effects of proinflammatory (interleukin [IL]-1 β and lipopolysaccharide [LPS]) and antiinflammatory (IL-10) stimuli on the release of MMP-9 and TIMP-1. We performed bronchoalveolar lavage in 11 smokers and 11 nonsmokers, and cultured airway macrophages in the presence of control medium, IL-1 β , and LPS. Airway macrophages from smokers released greater amounts of MMP-9 and TIMP-1 at baseline and in response to IL-1 β and LPS than did those of nonsmokers. Airway macrophages from smokers produced more TNF- α and IL-10. IL-10 increased TIMP-1 release without modifying that of MMP-9, leading to a decrease in the MMP-9 to TIMP-1 ratio. Anti-IL-10 antibody had no effect on MMP-9 production induced by LPS. We conclude that the release of proteases and antiproteases by airway macrophages is increased in cigarette smokers, and can be regulated by exogenous IL-10.

The effect of long-term high-intensity statin therapy on coronary atherosclerosis among patients with acute ST-segment elevation myocardial infarction (STEMI) is unknown. The aim of this study was to quantify the impact of high-intensity statin therapy on plaque burden, composition, and phenotype in non-infarct-related arteries of STEMI patients undergoing primary percutaneous coronary intervention (PCI). Between September 2009 and January 2011, 103 STEMI patients underwent intravascular ultrasonography (IVUS) and radiofrequency ultrasonography (RF-IVUS) of the two non-infarct-related epicardial coronary arteries (non-IRA) after successful primary PCI. Patients were treated with high-intensity rosuvastatin (40 mg/day) throughout 13 months and serial intracoronary imaging with the analysis of matched segments was available for 82 patients with 146 non-IRA. The primary IVUS end-point was the change in per cent atheroma volume (PAV). After 13 months, low-density lipoprotein cholesterol (LDL-C) had decreased from a median of 3.29 to 1.89 mmol/L (P < 0.001), and high-density lipoprotein cholesterol (HDL-C) levels had increased from 1.10 to 1.20 mmol/L (P < 0.001). PAV of the non-IRA decreased by −0.9% (95% CI: −1.56 to −0.25, P = 0.007). Patients with regression in at least one non-IRA were more common (74%) than those without (26%). Per cent necrotic core remained unchanged (−0.05%, 95% CI: −1.05 to 0.96%, P = 0.93) as did the number of RF-IVUS defined thin cap fibroatheromas (124 vs. 116, P = 0.15). High-intensity rosuvastatin therapy over 13 months is associated with regression of coronary atherosclerosis in non-infarct-related arteries without changes in RF-IVUS defined necrotic core or plaque phenotype among STEMI patients.

Nitric oxide produced by the inducible enzyme, nitric oxide synthase (iNOS), is implicated in immunological and inflammatory processes. We determined the effects of T‐helper (Th)2‐derived cytokines on the induction of iNOS from an epithelial A549 cell line and human airway epithelial cells stimulated by a mixture of interleukin‐1β (IL‐1β), interferon‐γ (IFN‐γ) and tumour necrosis factor‐α (TNF‐α). Interleukin‐4 (IL‐4) and interleukin‐13 (IL‐13) but not interleukin‐10 (IL‐10) inhibited both iNOS mRNA expression and nitrite release in A549 cells. On human airway epithelial cells, IL‐4 and IL‐13 reduced iNOS mRNA expression. Dexamethasone also inhibited both iNOS expression and nitrite release. Th2 cytokines, IL‐4 and IL‐13, inhibit iNOS upregulation by Th1 cytokines, indicating an important reciprocal role of Th1 and Th2 T‐cell subsets on lung epithelial cells.

Interleukin-1 beta (IL-1 beta) induces bronchial hyperresponsiveness (BHR) to bradykinin but not to acetylcholine. We examined whether this was mediated through the inhibition of neutral endopeptidase (NEP) activity and/or through the enhancement of airway microvascular leakage (AML) by IL-1 beta. We administered human recombinant IL-1 beta (500 U) or saline intratracheally and 24 h later measured the airway responses to bradykinin (1 mM; 45 breaths). IL-1 beta-treated rats showed a decrease of 18.5 and 21.1% of NEP activity in the lungs and tracheobronchial tree, respectively (P &lt; 0.05), associated with an augmented response in total lung resistance to bradykinin but with no increase in Evans blue dye extravasation used as a marker of AML. Phosphoramidon (0.1 and 1 mM; 90 breaths), an NEP inhibitor, induced a dose-dependent increase in lung resistance to bradykinin without further enhancing BHR induced by IL-1 beta. Bradykinin-induced AML was not enhanced by phosphoramidon in either saline- or IL-1 beta-treated rats. Similarly, after captopril (1 mM; 90 breaths), an inhibitor of angiotensin-converting enzyme, there was no further enhancement of BHR to bradykinin induced by IL-1 beta. BHR to bradykinin induced by IL-1 beta may result from an inhibition of peptidase activity, such as NEP and angiotensin-converting enzyme, and is not associated with an enhancement of AML.

No abstract is provided for this article.

Antiplatelet treatment in the elderly post percutaneous coronary interventions (PCI) remains a complex issue. Here we report the results of the pre-specified subgroup analysis of the GLOBAL LEADERS trial evaluating the long-term safety and cardiovascular efficacy of ticagrelor monotherapy among patients categorised according to the pre-specified cut-off value of 75 years of age.This was a pre-specified analysis of the randomised GLOBAL LEADERS trial (n=15,991), comparing 23-month ticagrelor monotherapy (after one month of DAPT) with the reference treatment (12-month DAPT followed by 12 months of aspirin). Among elderly patients (>75 years; n=2,565), the primary endpoint (two-year all-cause mortality or new Q-wave core lab-adjudicated myocardial infarction [MI]) occurred in 7.2% and 9.4% of patients in the ticagrelor monotherapy and the reference group, respectively (hazard ratio [HR] 0.75, 95% confidence interval [CI]: 0.58-0.99, p=0.041; pint=0.23); BARC-defined bleeding type 3/5 occurred in 5.2% and 4.1%, respectively (HR 1.29, 95% CI: 0.89-1.86; p=0.180; pint=0.06). The elderly with stable CAD had a higher rate of BARC 3/5 type bleeding (HR 2.05, 95% CI: 1.18-3.55) with ticagrelor monotherapy versus the reference treatment (pint=0.02). Elderly patients had a lower rate of definite or probable stent thrombosis (ST) with ticagrelor monotherapy (0.4% vs 1.4%, p=0.015, pint=0.01), compared with the reference group.In this pre-specified, exploratory analysis of the overall neutral trial, there was no differential treatment effect of ticagrelor monotherapy (after one-month dual therapy with aspirin) found in elderly patients undergoing PCI with respect to the rate of the primary endpoint of all-cause death or new Q-wave MI. The lower rate of ST in the elderly with ticagrelor monotherapy is hypothesis-generating. ClinicalTrials.gov identifier: NCT01813435.

Background. Acute exacerbations of COPD (AECOPD) are associated with neutrophilic airway inflammation. Inhibition of TNF-α was recently found to be ineffective in AECOPD. We used experimental rhinovirus (RV) infection to investigate neutrophil chemokines in AECOPD. Methods. 9 COPD subjects, 9 smokers (SMK) and 8 non-smokers (NS) were successfully infected with RV. Induced sputum (IS) was collected prior to infection and on days 3, 5, 9, 12, 15, 21 and 42 post-infection. Levels of IL-8, GM-CSF, IL-1β, TNF-α, GRO-α and MMP-9 were measured in IS supernatants using the Meso Scale Discovery (MSD®) platform. Results. MMP-9, IL-8, GM-CSF, IL-1β, and TNF-α in IS increased significantly from baseline following RV infection in the COPD group but not in the SMK or NS, GRO-α was not induced. Peak levels correlated with inflammatory cell counts, neutrophil numbers and neutrophil elastase (NE) in IS in the COPD subjects. Conclusions. IL-8, GM-CSF, IL-1β, and TNF-α, but not GRO-α, are all involved in neutrophilic inflammation in AECOPD. Inhibition of single cytokines is unlikely to be successful in AECOPD. High levels of the protease MMP-9 are induced so NE inhibition may also be unsuccessful. Therapeutic strategies that target multiple chemokines or multiple proteases are likely to be required in AECOPD.

Bioresorbable scaffolds are increasingly used in patients with coronary artery disease undergoing percutaneous coronary interventions. ABSORB EXTEND is an ongoing study that will recruit 800 patients. This report evaluates acute and late scaffold failure in the first 450 patients enrolled in ABSORB EXTEND who have completed 12 months follow-up.Clinical event data from the first 450 patients enrolled in ABSORB EXTEND have demonstrated low rates of ischaemia-driven MACE (4.2%) and target vessel failure (4.7%) at 12 months. There have been seven cases of device failure in this study: three cases of scaffold dislodgement (0.67%) and four cases of subacute or late scaffold thrombosis (0.89%). All scaffold dislodgements occurred in the left circumflex (LCX), and in two cases dislodgement was observed after reinsertion of the same device. Two cases of subacute scaffold thrombosis and two late scaffold thromboses were observed. Two out of four cases of scaffold thrombosis seemed to be related to either premature discontinuation of dual antiplatelet therapy (DAPT) or resistance to clopidogrel.This is the first report specifically describing the incidence and the potential mechanisms of scaffold dislodgement and scaffold thrombosis as seen in the ABSORB EXTEND trial.