Publications

Mechanisms in COPD

Commentary on Asthma: A long and continuing story by Walter E. Brocklehurst

Theophylline in the management of asthma: time for reappraisal?

Theophylline has been used for several decades in the treatment of asthma and remains the most widely prescribed anti-asthma drug worldwide, although the development of newer anti-asthma medications, especially inhaled steroids, has resulted in declining use of theophylline in industrialized countries. Theophylline is now considered to be a bronchodilator, but it is increasingly recognized that theophylline has other anti-asthma activities, which may be more important. Theophylline, even at low plasma concentrations, inhibits the late asthmatic reaction following allergen challenge. These clinical pharmacological observations are substantiated by experimental animal and in vitro data showing that theophylline has several anti-inflammatory activities relevant to asthma. These include the inhibition of cytokine synthesis and release, the inhibition of inflammatory cell activation and microvascular leakage, and the prevention of airway hyperresponsiveness induced by airway inflammation. Theophylline appears to have immunomodulatory effects, even at relatively low plasma concentrations. Based on these considerations, theophylline can be regarded as a useful alternative to other anti-inflammatory drugs for the chronic treatment of mild to moderate asthma. Theophylline should be used at lower doses to achieve plasma concentrations of 5-10 mg.l-1, which will avoid the risk of side-effects. Further studies are required to evaluate the role of low-dose theophylline as an adjunct to low-dose inhaled steroids in the management of chronic asthma. It may now be appropriate to re-evaluate the role of theophylline in asthma management.

Prasugrel or ticagrelor monotherapy vs dual antiplatelet treatment after percutaneous coronary intervention in acute coronary syndromes: a landmark analysis from the NEOMINDSET trial

Abstract Background and Aims The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention in patients with acute coronary syndrome remains uncertain. This analysis examined the temporal patterns of ischaemic and bleeding risks of early aspirin withdrawal compared with DAPT. Methods NEO-MINDSET randomized 3410 acute coronary syndrome patients undergoing successful percutaneous coronary intervention with drug-eluting stents within 4 days of hospital admission to either potent P2Y12 inhibitor monotherapy (prasugrel or ticagrelor) or standard DAPT (aspirin plus a potent P2Y12 inhibitor) for 12 months. This prespecified landmark analysis examined early (0–30 days) and late (31–365 days) follow-up events. Co-primary outcomes were (i) the composite of all cause death, myocardial infarction, stroke, or urgent target-vessel revascularization (ischaemic outcome) and (ii) Bleeding Academic Research Consortium type 2, 3, or 5 bleeding. Results At 30 days, the composite ischaemic outcome occurred in 3.3% of patients receiving monotherapy vs 1.8% with DAPT (risk difference 1.5%, 95% confidence interval .4%–2.6%; P = .006). Bleeding occurred in .6% vs 1.5% (risk difference −.8%, 95% confidence interval -1.5%–.1%; P = .018). In the landmark analysis between Days 31 and 365, ischaemic outcome rates were similar between study groups (3.8% each; P = .977), while bleeding remained less frequent with monotherapy (1.3% vs 3.5%; risk difference -2.2%, 95% confidence interval -3.2%–1.1%; P > .001). Conclusions This prespecified 30-day landmark analysis suggests an excess of ischaemic risk with monotherapy vs DAPT in the first 30 days but not thereafter, whereas an aspirin-free strategy was consistently associated with fewer bleeding events within and after 30 days.

Individual Long-Term Mortality Prediction Following Either Coronary Stenting or Bypass Surgery in Patients With Multivessel and/or Unprotected Left Main Disease

Objectives The study sought to validate the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score II mortality prediction model after percutaneous coronary intervention (PCI) or coronary artery bypass grafting in a large pooled population of patients with multivessel coronary disease (MVD) and/or unprotected left main disease (UPLMD) enrolled in the PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) and BEST (Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) randomized controlled trials. Background For patients with MVD and/or UPLMD, the choice of the best revascularization strategy remains challenging. Methods Pooled individual patient-level data from PRECOMBAT and BEST were used to assess calibration and discrimination of the SYNTAX score II prediction model for all-cause mortality after PCI and coronary artery bypass grafting at 4-year follow-up. The study population comprised 1,480 patients (600 with UPLMD, 880 with MVD). Results The overall incidence of all-cause mortality was 6.1% after a median follow-up period of 4.9 years. Validation plots showed good model calibration overall and across treatment groups but tended to overestimate all-cause mortality in the highest risk quintiles of patients in the whole population and the PCI arm. The SYNTAX score II showed moderate discrimination ability for the whole population (C index = 0.685) but better for patients receiving PCI than CABG (C index = 0.718 vs. 0.662 in patients with UPLMD, C index = 0.700 vs. 0.661 in those with MVD). Observed all-cause mortality was higher when the treatment received was at variance with that recommended by the model and similar when it was concordant. Conclusions The SYNTAX score II has good calibration but only moderate discrimination ability for long-term mortality prediction in this randomized population. This score provides an important tool to help guide the heart team’s decision-making process regarding the selection of the best revascularization strategy for patients with MVD and/or UPLMD. (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease, NCT00422968; Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease, NCT00997828)

Quantitative angiography after directional coronary atherectomy.

OBJECTIVE--To assess by quantitative analysis the immediate angiographic results of directional coronary atherectomy. To compare the effects of successful atherectomy with those of successful balloon dilatation in a series of patients with matched lesions. DESIGN--Case series. SETTING--Tertiary referral centre. PATIENTS--62 patients in whom directional coronary atherectomy was attempted between 7 September 1989 and 31 December 1990. INTERVENTIONS--Directional coronary atherectomy. MAIN OUTCOME MEASURES--Increase in minimal luminal diameter of coronary artery segment. RESULTS--Angiographic success on the basis of intention to treat was obtained in 54 patients (87%). In four patients the lesion could not be crossed by the atherectomy device; all four had an uneventful conventional balloon angioplasty. Four of the 58 patients who underwent atherectomy were subsequently referred for coronary bypass surgery because of failure or complications; three of them sustained a transmural infarction. In the successful cases, coronary atherectomy resulted in an increase in the minimal luminal diameter from 1.1 mm to 2.5 mm with a concomitant decrease of the diameter stenosis from 62% to 22%. In the subset of 37 patients in which the changes induced were compared with conventional balloon angioplasty atherectomy increased the minimal luminal diameter more than balloon angioplasty (1.6 v 0.8 mm; p less than 0.0001). Conventional histology showed media or adventitia in 26% of the atherectomy specimens. In hospital complications occurred in six patients who had undergone a successful procedure: two transmural infarctions, two subendocardial infarctions, one transient ischaemia attack, and one death due to delayed rupture of the atherectomised vessel. All patients were clinically evaluated at one and six months. One patient had persisting angina (New York Heart Association class II), one patient sustained a myocardial infarction, one patient underwent a percutaneous transluminal coronary angioplasty for early restenosis, and one patient underwent coronary bypass surgery because of a coronary aneurysm formation. At six months 80% (36/47) of the patients were symptom free. CONCLUSIONS--Coronary atherectomy achieved a better immediate angiographic result than balloon angioplasty; however, in view of the complication rate in this preliminary series, which may be related to a learning curve, a randomised study is needed to show whether this procedure is as safe as a conventional balloon angioplasty.

Telomere Shortening in Alveolar Macrophages of Smokers and COPD Patients~!2010-02-18~!2010-03-05~!2010-04-15~!

Background: Tobacco smoking is reported to enhance telomere shortening in peripheral blood lymphocytes.However, telomere length of lung resident cells such as alveolar macrophages (AMs) has not been evaluated. Aim:We evaluated effect of tobacco smoking on telomere length in AMs.Methods: AMs were obtained from nine non-smokers (mean age 24.6 years, mean FEV 1 /FVC 93.8%) and ten healthy smokers (mean age 25.2 years, >10 pack-years, mean FEV 1 /FVC 90.6%).We also analyzed tissue macrophages from eight moderate to severe COPD patients (mean age 68.3 years, >10 pack-years, mean FEV 1 /FVC 54.2%, mean %pred.FEV 1 48.8%), age-matched nine healthy smokers (mean age 67.1 years, >10 pack-years, mean FEV 1 /FVC 83.7%, mean % pred.FEV 1 82.4%), and eight healthy non-smokers (mean age 71.2 years, mean FEV 1 /FVC 84.6%, mean %pred.FEV 1 84.1%).Centromere signals and telomere length were analysed using quantitative fluorescence in situ hybridization (QFISH) and confocal microscopy.Results: Telomere length was reduced in bronchoalveolar lavage macrophages of younger smokers compared with that observed in healthy non-smoker's AMs, Importantly, there was no quantitative difference in centromere signals between smokers and non-smokers.A shorter telomere length was also seen in tissue macrophages from older smokers with or without COPD compared with non-smokers.However there was no difference in telomere length between healthy smokers and smokers with COPD. Conclusion:Tobacco smoking enhances telomere shortening in AMs from patients with and without COPD.

Autoradiographic Localization of Autonomic Receptors in Airway Smooth Muscle

Autoradiographic methods were used to determine the distribution of autonomic receptors in airway smooth muscle of ferret from trachea to terminal bronchioles; [3H]dihydroal-prenolol, [3H]prazosin, and [3H]quinuclidinyl benzilate were used to label beta-adrenergic, alpha-adrenergic, and muscarinic receptors, respectively, using experimental conditions that gave maximal specific receptor binding. Marked differences were found in the longitudinal distribution of each receptor and in distribution of the various receptors in each caliber airway. Beta-receptors were present in high density throughout the airways, with the highest density in bronchioles. Alpha-receptors were sparse in large airways, but numerous in small bronchioles, whereas cholinergic receptors were numerous in bronchial smooth muscle, sparse in proximal bronchioles, and almost absent from distal bronchioles. This method may be useful in studying alterations of autonomic receptors distribution in small and large airways after experimental man...

The complexity of the asthma phenotype

Implications of the local haemodynamic forces on the phenotype of coronary plaques

Aim To examine the effect of endothelial shear stress (ESS) on the dynamic changes in plaque phenotype. Methods Patients with myocardial infarction that had intravascular ultrasound-virtual histology (IVUS-VH) and optical coherence tomography (OCT) at baseline and 13-month follow-up were studied. The IVUS-VH data were used to reconstruct the nonculprit vessels, and in the obtained models the ESS was estimated in 3 mm segments. Plaque morphology was derived in each segment from IVUS-VH and OCT. Disease progression was defined as the presence of ≥2 out of the following criteria: reduction in lumen area, increase in plaque burden and change of plaque morphology to a more vulnerable phenotype. Linear mixed effects models were used to assess the effect of ESS in different phenotypes. Results Sixty-eight vessels were included in the analysis. Low ESS was associated with plaque progression in all phenotypes. The effect of ESS on plaque burden (p for interaction=0.467) and phenotype (p for interaction=0.188) was similar in all plaque types, whereas the effect of ESS on the changes in lumen dimensions was more prominent in disease-free (β=0.70, p<0.001) than fibrotic/fibrocalcific (β=0.28, p<0.001) or lipid-rich plaques (β=0.15, p=0.015). Standalone IVUS-VH misclassified plaque morphology in one-third of the cases leading to erroneous estimations about the effect of ESS on plaque evolution in different phenotypes. Conclusions The effect of ESS on plaque progression is similar in all phenotypes and cannot be accurately assessed by standalone IVUS-VH which often misclassifies plaque morphology. Therefore, multimodality imaging should be considered to examine the implications of ESS on plaque evolution. Clinical trial registration NCT00962416 ; Post-results.

Percutaneous transluminal coronary angioplasty for angina pectoris after a non-Q-wave acute myocardial infarction

Despite Initially favorable prognosis in patients with non-Q-wave acute myocardial infarction (AMI), long-term mortality in this subset of patients appears to be similar to or even greater than that in patients with Q-wave AMI. The relatively poor late prognosis is primarily due to a high incidence of unstable angina and recurrent AMI. Between January 1982 and January 1987, 114 patients with suitable coronary narrowing underwent percutaneous transluminal coronary angioplasty (PTCA) for angina pectoris (present either at rest or during mild exertion, and despite optimal pharmacologic therapy), a median of 31 (range 2 to 362) days after a non-Q-wave AMI. Success was achieved in dilating the obstructed artery in 98 patients (113 of the 129 dilated arteries). Emergency bypass surgery was performed in 7 patients. Mean clinical follow-up of 20 (range 3 to 59) months was obtained in all patients and revealed no deaths. Of the 98 patients with successful PTCAs, 6 (6%) developed a nonfatal recurrent AMI and 62 (63%) were asymptomatic. However, recurrent angina affected 31 patients (32%) and was treated by repeat PTCA (n = 18), coronary bypass surgery (n = 5) or pharmacologic therapy (n = 8). At follow-up, 74% of the patients (73 of 98) were asymptomatic after a successful PTCA and, if necessary, a repeat PTCA, without incidence of recurrent AMI, coronary bypass surgery or death. The high initial success rate, low incidence of subsequent death and late recurrent AMI and sustained symptomatic benefit suggest that PTCA is an effective initial treatment strategy in these selected patients.

Diagnostic Accuracy of Coronary CT Angiography for the Evaluation of Bioresorbable Vascular Scaffolds

Objectives The purpose of this study was to assess the diagnostic accuracy of coronary computed tomography angiography (CTA) for bioresorbable vascular scaffold (BVS) evaluation. Background Coronary CTA has emerged as a noninvasive method to evaluate patients with suspected or established coronary artery disease. The diagnostic accuracy of coronary CTA to evaluate angiographic outcomes after BVS implantation has not been well established. Methods In the ABSORB II (A Bioresorbable Everolimus-Eluting Scaffold Versus a Metallic Everolimus-Eluting Stent II) study, patients were randomized either to receive treatment with the BVS or everolimus-eluting metallic stent. At the 3-year follow-up, 238 patients (258 lesions) treated with BVS underwent coronary angiography with intravascular ultrasound (IVUS) evaluation and coronary CTA. The diagnostic accuracy of coronary CTA was assessed by the area under the receiver-operating characteristic curve with coronary angiography and IVUS as references. Results The mean difference in coronary CTA-derived minimal luminal diameter was −0.14 mm (limits of agreement −0.88 to 0.60) with quantitative coronary angiography as reference, whereas the mean difference in minimal lumen area was 0.73 mm2 (limits of agreement −1.85 to 3.30) with IVUS as reference. The per-scaffold diagnostic accuracy of coronary CTA for detecting stenosis based on coronary angiography diameter stenosis of ≥50% revealed an area under the receiver-operating characteristic curve of 0.88 (95% confidence interval [CI]: 0.82 to 0.92) with a sensitivity of 80% (95% CI: 28% to 99%) and a specificity of 100% (95% CI: 98% to 100%), whereas diagnostic accuracy based on IVUS minimal lumen area ≤2.5 mm2 showed an area under the receiver-operating characteristic curve of 0.83 (95% CI: 0.77 to 0.88) with a sensitivity of 71% (95% CI: 44% to 90%) and a specificity of 82% (95% CI: 75% to 87%). The diagnostic accuracy of coronary CTA was similar to coronary angiography in its ability to identify patients with a significant lesion based on the IVUS criteria (p = 0.75). Conclusions Coronary CTA has good diagnostic accuracy to detect in-scaffold luminal obstruction and to assess luminal dimensions after BVS implantation. Coronary angiography and coronary CTA yielded similar diagnostic accuracy to identify the presence and severity of obstructive disease. Coronary CTA might become the method of choice for the evaluation of patients treated with BVS.

Stable isotope labelled amino acid culturing: A novel approach to identify pathways involved in MIF signalling

Chronic obstructive pulmonary disease (COPD) shows poor clinical improvement with steroids. Macrophage Migration Inhibitory Factor (MIF) counter-regulates steroid action although the mechanism is unknown. Stable isotope labelled amino acid cell culture (SILAC) involves incorporating differently labelled amino acids into cells to allow comparison of protein profiles. SILAC was used to investigate the effect of MIF on intracellular signalling pathways. THP-1 cells were grown in SILAC media and then stimulated with or without MIF for 24 hours, the cells were lysed and proteins extracted. Incorporation of the labelled amino acids were measured and analysed by LC-MSMS. Pathways identified were validated by qRT-PCR, ELISA and Western blotting. MIF treatment up-regulated 70 and down-regulated 163 proteins; pathway analysis identified the RIG-I-like receptor (RLR) pathway. In THP-1 cells, as the main MIF target, MIF was induced by Poly I:C in a concentration-dependent manner and RV16 infection induced MIF expression in a time-dependent manner. BAL macrophage proteins were analysed at baseline and 7 days post RV16 infection in non-smokers, smokers and COPD patients. Smokers and COPD patients showed a significant decrease in intracellular MIF post-infection. We used proteomics to define a novel mechanism of MIF action in THP-1 cells and translated this to primary human cells. Viral activation induced MIF release from THP-1 cells and was associated with a loss of intracellular MIF in BAL macrophages 7 days post infection in smokers and COPD patients. This proteomics approach has the ability to define novel mechanisms for understanding drug or disease effects.

3D ICUS

No abstract is provided for this article.

Mechanical properties and performances of contemporary drug-eluting stent: focus on the metallic backbone

<b>Introduction</b>: Drug-eluting stents (DES) are still the standard of care in percutaneous coronary intervention (PCI) since the fall of bioresorbable scaffolds with respect to safety. The unbeatable advantage of a metallic stent when compared with a scaffold is a stronger mechanical property and more sustainable vascular support. Recent development of contemporary metallic stent has focused on the reduction of strut thickness. However, there will always be a trade-off between improvement in deliverability, flexibility, and radial strength. <b>Areas covered</b>: This review aims to discuss the designs of metallic stent platform and mechanical properties as well as mechanical performance of contemporary DES from bench studies and clinical trials. <b>Expert opinion</b>: Mechanical properties of stents affect short- and long-term clinical outcomes. Ultrathin-strut DES have become popular and clinical trials have shown impressive results. Thinner struts may improve device flexibility and deliverability but the radial strength and longitudinal integrity might have been compromised as well. Ultrathin-strut cobalt chromium or platinum chromium DES will become standard of care in PCI practice in the near future. Information on the stent design, stent material and mechanical properties of the stent are essential for a rational selection of the appropriate stent in selected lesions and patients.

Dilemmas, Confusion, and Misconceptions Related to Small Airways Directed Therapy

Delay and disruption claims

Australian Calvinism: An Impressionistic Snapshot on the 500th Anniversary of Calvin's Birth

Australian Calvinism is part of an international movement and it tends to reflect some of the strengths and weaknesses of its counterparts in Britain and the USA. The article traces the history of Calvinism and highlights its various features in Australia.