Publications

Summary High von Willebrand factor (VWF) plasma levels are associated with an increased risk of coronary artery disease. It has been suggested that the increase of VWF levels is partly due to endothelial dysfunction and atherosclerosis. Our aim was to investigate the association between coronary plaque burden, the presence of high-risk coronary lesions as measured by intravascular ultrasound virtual histology (IVUS-VH) and VWF levels. In addition, we studied the association between VWF levels and one-year cardiovascular outcome. Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography for acute coronary syndrome (ACS) (n= 318) or stable angina pectoris (SAP) (n= 263). Arterial blood was sampled prior to the coronary angiography. VWF antigen (VWF:Ag) levels were measured using ELISA (n= 577). Patients with ACS had significantly higher VWF:Ag levels than SAP patients (median 1.73 IU/ml [IQR 1.27–2.31] vs 1.26 IU/ml [0.93–1.63], p < 0.001). High coronary plaque burden was associated with higher VWF:Ag levels (β= 0.12, p=0.027) in SAP patients, but not in ACS patients. In ACS patients, VWF:Ag levels were associated with 1-year MACE (HR 4.14 per SD increase of lnVWF:Ag, 95 % CI 1.47–11.6), whereas in SAP patients VWF:Ag levels predicted 1-year all-cause death and hospitalisation for ACS (HR 7.07 95 % CI 1.40–35.6). In conclusion, coronary plaque burden was associated with VWF:Ag levels in SAP patients undergoing coronary angiography. In ACS and SAP patients, high VWF levels are predictive of adverse cardiovascular outcome and death during one-year follow-up.

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No abstract is provided for this article.

Background/Introduction Prediction of bleeding risk in patients receiving dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) has been repeatedly attempted and resulted in multiple risk models. To promote the adoption and use of risk stratification among clinicians, a consortium in the South East of the Netherlands, the "ZON-HR", has created a simple binary variant of the existing logistic models. This model includes commonly available factors which can be incorporated into the PCI report to generate stratification. In this "parsimonious" model, high bleeding risk (HBR) is stratified according to: history of intracranial haemorrhage, previous spontaneous bleeding, Hb < 11 g/dL, eGFR< 30. Purpose We aimed to perform an external validation of our model for bleeding risk and to demonstrate its discriminative value in comparison with the PRECISE DAPT score, an acknowledged risk score. Methods We performed a post hoc analysis of the GLOBAL LEADERS trial, a multicenter randomized trial, comparing ticagrelor monotherapy after one month of DAPT with standard DAPT after PCI. We stratified the patients for HBR according to the ZON-HR or a PRECISE-DAPT score ≥ 25. Bleeding events one year after PCI were compared in the entire population and in subgroups for chronic coronary syndrome (CCS), acute coronary syndrome (ACS), Ticagrelor monotherapy and DAPT. Results Of the 15968 patients included in GLOBAL LEADERS, 1059 patients were excluded due to missing variables required for either model. Among the 14909 patients, 17% had HBR according to the PRECISE DAPT score, 4% according to ZON-HR and 3% according to both. Bleeding events occurred in 8.5% and 13% of HBR defined by PRECISE DAPT or ZON-HR respectively. Patients with HBR according to both models showed 13% bleedings as opposed to 5% in non-HBR. Table 1 presents the sensitivity and specificity. Regression analysis (figure 1) demonstrated that patients with HBR according to either model have significantly more bleedings. This was also significant in all subgroups except for ACS patients receiving standard DAPT when the ZON-HR model was used. Conclusion The ZON-HR model is more conservative compared to the PRECISE DAPT score as depicted by the sensitivity and specificity. This can be explained by the larger number of risk factors used in the PRECISE DAPT score that cumulatively contributes to the sensitivity as opposed to the binary ZON-HR model which is more specific. However, the survival curves and hazard ratios showed good predictive value of both models for bleeding risk in the overall population.Table 1.Figure 1.

Myhre syndrome is a rare, distinctive syndrome due to specific gain‐of‐function mutations in SMAD4 . The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a SMAD4 mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF‐β signaling cascade (Marfan, Loeys–Dietz, or Shprintzen–Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways, including canonical TGF‐β, BMP, and Activin signaling. The co‐occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley Periodicals, Inc.

Activation of the transcription factor signal transducer and activator of transcription (STAT)‐4 is critical for the differentiation of T‐helper 1 cells/type‐1 cytotoxic T‐cells and the production of interferon (IFN)‐γ. Expression of STAT4, phospho‐STAT4, IFN‐γ and T‐box expressed in T‐cells (T‐bet) proteins in bronchial biopsies and bronchoalveolar lavage (BAL)‐derived lymphocytes, obtained from 12 smokers with mild/moderate chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV 1 ) 59±16% predicted), 14 smokers with normal lung function (FEV 1 106±12% pred) and 12 nonsmoking subjects (FEV 1 111±14% pred), was examined by immunohistochemistry and immunocytochemistry. In bronchial biopsies of COPD patients, the number of submucosal phospho‐STAT4+ cells was increased (240 (22–406) versus 125 (0–492) versus 29 (0–511) cells·mm −2 ) when compared with both healthy smokers and control nonsmokers, respectively. In smokers, phospho‐STAT4+ cells correlated with the degree of airflow obstruction and the number of IFN‐γ+ cells. Similar results were seen in BAL (2.8 (0.2–5.9) versus 1.03 (0.09–1.6) versus 0.69 (0–2.3) lymphocytes·mL −1 ×10 3 ). In all smokers who underwent lavage, phospho‐STAT4+ lymphocytes correlated with airflow obstruction and the number of IFNγ+ lymphocytes. T‐bet expression was not altered in bronchial biopsies and BAL‐derived lymphocytes between the three groups. In conclusion, this study suggests that stable mild/moderate chronic obstructive pulmonary disease is associated with an active T‐helper 1 cell/type‐1 cytotoxic T‐cell inflammatory process involving activation of signal transducer and activator of transcription 4 and interferon-gamma production.

This study explores the safety and efficacy of thin strut MeRes100 sirolimus-eluting bioresorbable vascular scaffold (BRS) in patients with de novo coronary artery lesions.In interventional cardiology, the emergence of BRS technology is catalyzing the next paradigm shift.The MeRes-1 Extend was a multicenter, prospective, single-arm, open-label study enrolling 64 patients in Spain, Macedonia, Brazil, South Africa, Malaysia, and Indonesia. The safety endpoint was major adverse cardiac events (MACE) which composed of cardiac death, myocardial infarction (MI), and ischemia-driven target lesion revascularization (ID-TLR). The imaging efficacy endpoint was mean in-scaffold late lumen loss (LLL) evaluated by quantitative coronary angiography (QCA). Optical coherence tomography (OCT) imaging was performed at baseline and 6-month follow-up.A total of 69 target lesions were identified in 64 enrolled patients (mean age 58.30 ± 9.02 years). Of the treated lesions, 49 (71.01%) lesions were of type B2/C. Procedural and device success was achieved in 64 and 62 patients, respectively. At 2-year follow-up, MACE was reported in one patient (1.61%) in the form of ID-TLR. There was no case of MI, cardiac death or scaffold thrombosis through 2-year. In a subset of 32 patients, paired QCA showed mean in-scaffold LLL of 0.18 ± 0.31 mm at 6-month follow-up. In a subset of 21 patients, OCT revealed 97.95 ± 3.69% strut coverage with mean scaffold area of 7.56 ± 1.79 mm2 and no evidence of strut malapposition.The clinical and imaging outcomes of MeRes-1 Extend trial demonstrated favorable safety and efficacy of MeRes100 sirolimus-eluting BRS in patients with de novo coronary artery lesions.

Unstable angina is an acute coronary syndrome associated with substantial short- and medium-term morbidity and mortality.1 The understanding of the pathogenesis of this syndrome has been based largely on postmortem studies of coronary arteries2 and supported by indirect evidence of coronary thrombosis in relation to the syndrome.3–5 Because directional coronary atherectomy is unique in extracting intact atheromatous tissue during coronary recanalization, it may facilitate the study of the processes taking place in the vessel in different coronary syndromes. In the present study the histopathologic characteristics of atherectomy samples retrieved in 93 patients with stable or unstable angina pectoris were compared and related to different clinical variables.

To address the potential role of the chemokine macrophage inflammatory protein‐2 (MIP‐2) in airway inflammation, we examined whether MIP‐2 may play a role in ozone‐induced neutrophilic inflammation of airways and its modulation by dexamethasone in rat lung. Following ozone exposure, MIP‐2 mRNA expression in the lung peaked at 2 h after exposure and slowly declined thereafter. Dexamethasone suppressed ozone‐induced MIP‐2 mRNA expression and neutrophil accumulation in the lung. We suggest that the MIP‐2 mRNA induction may switch on the neutrophilic influx observed in this model of lung inflammation. Furthermore, the MIP‐2 expression is regulated by dexamethasone which may represent one of the mechanisms by which glucocorticoids exert their potent anti‐inflammatory properties.

Potassium (K+) channels are present on airway smooth muscle cells, and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, we examined the activity of the active L-enantiomer of cromakalim, BRL 38227 (lemakalim), a selective K+ channel activator, against a variety of spasmogens in human bronchi in vitro. BRL 38227 produced relaxation of bronchi with either resting tone or tone induced by histamine, carbachol, neurokinin A, or KCl (20 mM) with an efficacy (%Emax) of 60 to 80% of that of isoproterenol and an EC50 (the concentration producing 50% of the maximal response) of 0.2 to 0.6 µM. However, BRL 38227 had a significantly lower potency and efficacy against 80 mM KCl than against the other spasmogens (%Emax, 12% of isoproterenol and EC50, 7.2 µM; p < 0.005 and p < 0.001, respectively), supporting the view that BRL 38227 acts on K+ channels. The D-enantiomer BRL 38226 was less potent (EC50, 2.6 µM) than BRL 38227 and produced only 43% of the isoproterenol relaxation. BRL 38227-induced relaxation was significantly inhibited by the ATP-sensitive K+ channel antagonist glibenclamide (0.1 and 1 µM), with a three-fold and eight-fold shift to the right of the dose-response curve, respectively. In the presence of a maximal relaxation induced by the calcium voltage-dependent channel antagonist verapamil, BRL 38227 was able to produce an additional 37% relaxation response. Thus, BRL 38227 is an effective relaxant of human airway smooth muscle, and this activity results from an action at K+ channels. Its role in the management of airway diseases such as asthma deserves further investigation.