Publications

Objective— Previous proteomics experiments have demonstrated that several proteins are differentially expressed in vulnerable human carotid plaques compared with stable plaques. This study aims to investigate the prognostic value of 13 such circulating biomarkers in patients with coronary artery disease. Approach and Results— Between 2008 and 2011, 768 patients who underwent coronary angiography for acute coronary syndrome or stable angina pectoris were included in a prospective biomarker study. Plasma concentrations of 13 biomarkers were measured in 88 patients who experienced a major adverse cardiovascular event (MACE) within 1 year and 176 control patients without MACE who were matched on age, sex, and number of diseased coronary vessels. MACE comprised all-cause mortality, acute coronary syndrome, unplanned coronary revascularization, and stroke. After adjustment for established cardiovascular risk factors, osteoglycin (OGN; odds ratio per SD increase in ln-transformed OGN, 1.53; 95% confidence interval, 1.11–2.11; P =0.010) and neutrophil gelatinase–associated lipocalin/matrix metalloproteinase 9 (NGAL/MMP9; odds ratio per SD increase in ln-transformed NGAL/MMP9, 1.37; 95% confidence interval, 1.01–1.85; P =0.042) complex were independently associated with MACE during follow-up. These associations were independent of C-reactive protein levels. Adding OGN or NGAL/MMP9 to a model containing conventional risk factors did not significantly improve discriminatory power (OGN: area under receiver operating characteristic curve, 0.75 versus 0.67; NGAL/MMP9: 0.73 versus 0.67) but did significantly improve risk reclassification (OGN: net reclassification index=0.29; 95% confidence interval, 0.05–0.53; P <0.019; NGAL/MMP9: net reclassification index=0.44; 95% confidence interval, 0.20–0.69; P <0.001). Conclusions— Circulating OGN and NGAL/MMP9 complex are promising biomarkers that are expressed in vulnerable atherosclerotic plaques and may have incremental value for prediction of MACE within 1 year after coronary angiography.

No abstract is provided for this article.

Aims Studies in animals and patients indicate that rapamycin affects vasodilatation differently in outer and inner curvatures of blood vessels.We evaluated in this study whether rapamycin affects endothelial nitric oxide synthase (eNOS) responsiveness to shear stress under normo-and hypercholesteraemic conditions to explain these findings.Methods and results Shear stress levels were varied over a large range of values in carotid arteries of transgenic mice expressing human eNOS fused to enhanced green fluorescence protein.The mice were divided into control, low-dose rapamycin (3 mg/kg/day), and high-dose rapamycin (3 mg/kg/day) groups and into normocholesteraemic and hypercholesteraemic (ApoE2/2 on high cholesterol diet for 3-4 weeks) groups.The effect of rapamycin treatment on eNOS was evaluated by quantification of eNOS expression and of intracellular protein levels by en face confocal microscopy.A sigmoid curve fit was used to described these data.The efficacy of treatment was confirmed by measurement of rapamycin serum levels (2.0 + 0.5 ng/mL), and of p27 kip1 expression in vascular tissue (increased by 2.4 + 0.5fold).In control carotid arteries, eNOS expression increased by 1.8 + 0.3-fold in response to rapamycin.In the treated vessels, rapamycin reduced maximal eNOS expression at high shear stress levels (.5 Pa) in a dose-dependent way and shifted the sigmoid curve to the right.Hypercholesteraemia had a tendency to increase the leftward shift and the reduction in maximal eNOS expression (P ¼ 0.07).Conclusion Rapamycin is associated with high eNOS in low shear regions, i.e. in atherogenic regions, protecting these regions against atherosclerosis, and is associated with a reduction of eNOS at high shear stress affecting vasomotion in these regions.

In order to evaluate the effect of coronary recanalization in acute myocardial infarction, thallium scintigrams were made on admission in 23 patients in whom thrombolysis was attempted and in 27 patients treated conventionally. The scintigrams were repeated immediately after the procedure or after 3 h in the control group. No significant differences were apparent between the initial thallium uptake in treated patients or controls. Some degree of thallium redistribution occurred in 43 out of 50 patients. The degree of redistribution was greater in patients with open or recanalized arteries (redistribution 35%, s.d. 24% of initial defect) than in patients in whom the artery remained occluded (17%, s.d. 12%). No differences were apparent in six patients between the late scintigrams and a third series of images made after an additional injection of thallium. Global left ventricular function was analysed in 30 patients with anteroseptal infarction and in 35 patients with inferior wall infarction. Ejection fractions were lower in patients with anterior wall infarction. Between one and seven days after admission, ejection fractions were similar in patients with open or occluded arteries in pilot studies and in randomized patients with inferior wall infarction after thrombolysis or conventional treatment. In patients with anterior wall infarction, left ventricular ejection fraction after streptokinase (45%, s.d. 7%) was greater than after conventional treatment (38%, s.d. 12%). Analysis of segmental left ventricular function suggests that this difference is due in part to the improvement of segmental function in the non-infarcted areas. No differences were observed between ejection fractions measured early (1–7 days) or late (10–20 days) after myocardial infarction. The data show considerable overlap between patients treated with streptokinase and those treated conventionally. Further randomized trials are needed to determine whether thrombolysis in acute myocardial infarction does indeed result in permanent improvement of myocardial function.

Aims: Newer-generation everolimus-eluting stents (EES) have been shown to improve clinical outcomes compared with early-generation sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) in patients undergoing percutaneous coronary intervention (PCI).Whether this benefit is maintained among patients with saphenous vein graft (SVG) disease remains controversial. Methods and results:We assessed cumulative incidence rates (CIR) per 100 patient years after inverse probability of treatment weighting to compare clinical outcomes.The pre-specified primary endpoint was the composite of cardiac death, myocardial infarction (MI), and target vessel revascularisation (TVR).Out of 12,339 consecutively treated patients, 288 patients (5.7%) underwent PCI of at least one SVG lesion with EES (n=127), SES (n=103) or PES (n=58).Up to four years, CIR of the primary endpoint were 58.7 for EES, 45.2 for SES and 45.6 for PES with similar adjusted risks between groups (EES vs. SES; HR 0.94, 95% CI: 0.55-1.60,EES vs. PES; HR 1.07, 95% CI: 0.60-1.91).Adjusted risks showed no significant differences between stent types for cardiac death, MI and TVR.Conclusions: Among patients undergoing PCI for SVG lesions, newer-generation EES have similar safety and efficacy to early-generation SES and PES during long-term follow-up to four years.

No abstract is provided for this article.

Backgrounds The impact of quantitative assessment to differentiate total occlusions (TOs) from severe stenoses on coronary computed tomography angiography (CCTA) remains unknown. Objective This study investigated whether quantitative characteristics assessed on CCTA could help differentiate a TO from a severe stenosis on invasive coronary angiography (ICA). Methods This study is a sub-analysis of the FASTTRACK CABG (NCT04142021) in which both CCTA and ICA were routinely performed. Quantitative analysis was performed with semi-automated CCTA plaque-analysis software. Blinded analysts compared TOs on CCTA, defined as a complete lack of contrast opacification within the coronary occlusion, with corresponding ICA. Results Eighty-four TOs were seen on CCTA in 59 of the 114 patients enrolled in the trial. The concordance in diagnosing a TO between ICA and CCTA was 56.0% (n ​= ​47). Compared to severe stenoses, TOs had a significantly longer lesion length (25.1 ​± ​23.0 ​mm vs 9.4 ​± ​11.2 ​mm, P ​< ​0.001). The best cut-off value to differentiate a TO from severe stenosis was a lesion length of 5.5 ​mm (area under the curve 0.77, 95% CI: 0.66–0.87), with a 91.1% sensitivity and 61.1% specificity. Dense calcium percentage atheroma volume (PAV) was significantly higher in TOs compared to severe stenoses (18.7 ​± ​19.6% vs. 6.6 ​± ​13.0%, P ​< ​0.001), whilst the opposite was seen for fibro-fatty PAV (31.3 ​± ​14.2% vs. 19.5 ​± ​10.5%, P ​< ​0.001). On a multivariable logistic regression analysis, lesion length (>5.5 ​mm) was the only parameter associated with differentiating a TO from a severe stenosis. Conclusion In quantitative CCTA analysis, a lesion length >5.5 ​mm was the only independent predictor differentiating a TO from a severe stenosis. NCT registration number NCT04142021.

No abstract is provided for this article.

We investigated early and late effects of percutaneous revascularization for chronic total coronary occlusion on left ventricular (LV) function and volumes. Magnetic resonance imaging was performed in 21 patients before and 5 months and 3 years after recanalization. Global LV function and volumes and segmental wall thickening (SWT) were quantified on cine images. The 2 viability indexes used were the transmural extent of infarction (TEI) on delayed contrast enhancement images and end-diastolic wall thickness at baseline. Significant decreases in mean end-diastolic (86 ± 14 to 78 ± 15 ml/m2; p = 0.02) and mean end-systolic volume indexes (35 ± 13 to 30 ± 13 ml/m2; p = 0.03) were observed 3 years after recanalization. Mean ejection fraction tended to improve (60 ± 9% to 63 ± 11%; p = 0.11). SWT significantly increased at 5-months’ follow-up (p <0.001), and an additional improvement was found at 3 years’ (p = 0.04) follow-up in segments with TEI <25%. In segments with TEI of 25% to 75%, SWT was unchanged at 5-month follow-up (p = 0.89), but improved at 3 years (p = 0.04). SWT was unchanged in segments with transmural scars. For segmental functional recovery, TEI was a better predictor than end-diastolic wall thickness at baseline (odds ratio 5.6, 95% confidence interval 1.5 to 21.1, p = 0.01 vs odds ratio 2.5, 95% confidence interval 0.7 to 8.3, p = 0.14). In conclusion, a positive effect on LV remodeling and ejection fraction was observed up to 3 years after recanalization. Both early and late improvements in regional LV function were observed in the perfusion territory of chronic total coronary occlusion and were related to the transmural extent of infarction on pretreatment magnetic resonance imaging.

Abstract Background The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response. Methods Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO &gt; 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 μg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV 1 , L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV 1 area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV 1 and analysis of variance for AMP challenge. Results Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p &lt; 0.0001 and -20.5 ppb, p &lt; 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p &lt; 0.0001; low dose: 3.7 mg/mL, p &lt; 0.0001), and a significant dose response (p = 0.0185). FEV 1 was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response. Conclusions The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients. Trial Registration ClinicalTrials.gov: NCT01343745

The pathogenesis of non-allergic rhinitis (NAR) is still largely unknown. Furthermore, it is unclear whether there is a correlation between the effect of nasal glucocorticoids on nasal inflammation and on nasal symptoms and quality of life.In this pilot study we recruited 12 healthy subjects and 24 patients with recently diagnosed persistent NAR [12 untreated and 12 under regular treatment with nasal fluticasone furoate (two sprays of 27.5 μg each in each nostril once daily, total daily dose = 110 μg) for at least 20 days]. Each subject filled a mini rhinoconjunctivitis quality of life questionnaire (mini RQLQ). Nasal scrapings were obtained from each subject and used to prepare slides for Diff-Quik and immunocytochemical staining for inflammatory and epithelial cells count, MUC5AC expression and the general pro-inflammatory transcription factor nuclear factor kB (NF-kB) activation.The nasal score of the mini RQLQ, the number of nasal inflammatory cells (neutrophils, eosinophils) and the number of goblet cells are significantly higher in untreated patients with persistent NAR compared with control subjects and treated NAR patients. The percentage of MUC5AC+ nasal epithelial cells is significantly increased in untreated patients with persistent NAR compared with the control subjects (41.8 ± 6.4 vs 22.3 ± 4.8, respectively; p = 0.0403) without significant differences between control subjects and patients with persistent NAR on regular fluticasone furoate treatment (33.9 ± 5.0 %; p = 0.0604) nor between the 2 groups of persistent NAR subjects (p = 0.3260). The number of cytosolic and/or nuclear p65+ nasal epithelial and inflammatory cells was not significantly different between the three groups.Patients with persistent untreated NAR, compared with normal control subjects and patients with persistent NAR under regular treatment with nasal fluticasone furoate by at least 20 days, have more nasal symptoms, worst quality of life and an increased number of nasal inflammatory cells (neutrophils, eosinophils), goblet cells and MUC5AC+ nasal epithelial cells. This nasal inflammation seems unrelated to NF-kB activation.