Publications

Statins are highly effective in reducing major adverse clinical events, but the direct effects on coronary plaque composition remain debatable. Our aim was to mechanistically evaluate the treatment effect of high-intensity statin therapy on compositional coronary plaque changes.The third Integrated Biomarker and Imaging Study (IBIS-3) was a prospective, investigator-initiated, single-centre study. Serial radiofrequency intravascular ultrasound (RF-IVUS) measurements of a predefined non-stenotic segment in a non-culprit coronary artery were performed to evaluate the effect of rosuvastatin (intended dose: 40 mg daily) on necrotic core (NC) volume in patients with stable angina or acute coronary syndrome. Changes in lipid core burden index (LCBI) were evaluated through serial near-infrared spectroscopy (NIRS) imaging in a subset. Serial RF-IVUS (and NIRS) data of a median segment of 41 mm (interquartile range: 32 to 49 mm) were complete in 164 (103) patients. Follow-up measurements were performed at six and 12 months in 30 (26) and 134 (77) patients, respectively. Mean levels of low-density lipoprotein cholesterol decreased by 30%, from 2.49 mmol/l to 1.73 mmol/l at the end of follow-up. High-dose rosuvastatin therapy resulted in a non-significant change of -1.4 mm3 (95% CI: -3.0, 0.1) in NC volume during follow-up (p=0.074). The change in NC percentage of total plaque volume was -1.4% (95% CI: -2.4 to -0.4; p=0.006). A neutral effect was also observed on LCBI. Indications of significant regression of NC volume and LCBI in the highest baseline quartiles were observed, which should cautiously be regarded as hypothesis-generating.High-intensity rosuvastatin therapy during one year resulted in a neutral effect on NC and LCBI within non-stenotic, non-culprit coronary segments with a relatively low atheroma burden. This study has been registered in The Netherlands Trial Register (NTR) nr. 2872.

No abstract is provided for this article.

Objectives We compared the 5-year outcomes of diabetic patients with multivessel disease treated with sirolimus-eluting stents (SES), bare-metal stents (BMS), and coronary artery bypass graft surgery (CABG) enrolled in the ARTS (Arterial Revascularization Therapy Study) I and II studies. Background Diabetes is an established risk factor for major adverse cardiac events after revascularization. Recent trials suggest that revascularization with drug-eluting stents has equivalent safety to CABG up to 2 years. Methods The ARTS I and II studies included 367 diabetic patients (SES: 159, CABG: 96, and BMS: 112) compared with respect to 5-year clinical outcomes. Results The rate of major adverse cardiovascular and cerebrovascular events was significantly higher in patients treated with BMS (BMS 53.6% vs. CABG 23.4% vs. SES 40.5%; log-rank, p < 0.01 for SES vs. BMS and SES vs. CABG). There was no significant difference in mortality among all 3 groups. There was, however, a statistically significant difference in the myocardial infarction rate between BMS and CABG arms (BMS 11.0%, CABG 5.2%, SES 4.8%, p = 0.04 for SES vs. BMS and p = 0.76 for SES vs. CABG). The rate of repeat revascularization was significantly lower in patients treated with CABG compared with SES (SES 33.2% vs. CABG 10.7%, p < 0.001). Revascularization rate of patients treated with SES at 5 years approached that of patients treated with BMS although remained significantly lower. This “catch-up” phenomenon was not apparent in the nondiabetic population. Conclusions At 5-year follow-up, CABG has comparable safety and superior efficacy compared with BMS and SES in the treatment of diabetic patients with multivessel disease.

Adenosine deaminase (ADA) and osteopontin (OPN) may play opposing roles in the pathogenesis of COPD. Deficiency of ADA results in enhanced adenosine signaling which up-regulates OPN expression. Although statins suppress OPN in cancer cells, little is known about their effects on ADA and OPN in COPD patients. We extended a previous randomized double-blind placebo crossover study to investigate the effects of simvastatin (20 mg/day) on sputum ADA and OPN expression and explored the underlying signaling pathways involved by conducting in vitro experiments with cigarette smoke extract (CSE)-treated monocyte-derived macrophages (MDM) from COPD patients and healthy subjects. Simvastatin decreased sputum IL-13, OPN and CD73, while increasing ADA expression, irrespective of inhaled corticosteroid treatment and smoking status in parallel to increased inosine levels. The degree of simvastatin-restored ADA activity was significantly correlated with the magnitude of changes in pre-bronchodilator FEV1. Mechanistic exploration showed that CSE enhanced the expression of IL-13, which induced an increase in OPN and inhibited ADA mRNA accumulation in MDM from COPD patients but not healthy subjects through a STAT6-dependent mechanism. Simvastatin treatment inhibited IL-13 transcription in a dose-dependent manner, and therefore diminished the IL-13-induced increase in OPN and restored IL-13-suppressed ADA. There was no effect of simvastatin on adenosine receptors in CSE-stimulated MDM, indicating that its effects were on the adenosine pathway. Simvastatin reversed IL-13-suppressed ADA activity that leads to the down-regulation of adenosine signaling and therefore inhibits OPN expression through the direct inhibition of IL-13-activated STAT6 pathway. Inhibition of IL-13 may reverse the imbalance between ADA and OPN in COPD and therefore may prevent COPD progression.

Computed tomographic coronary angiography (CTCA) is a non-invasive imaging modality, which allows plaque burden and composition assessment and detection of plaque characteristics associated with increased vulnerability. In addition, CTCA-based coronary artery reconstruction enables local haemodynamic forces assessment, which regulate plaque formation and vascular inflammation and prediction of lesions that are prone to progress and cause events. However, the use of CTCA for vulnerable plaque detection in the clinical arena remains limited. To unlock the full potential of CTCA and enable its broad use, further work is needed to develop user-friendly processing tools that will allow fast and accurate analysis of CTCA, computational fluid dynamic modelling, and evaluation of the local haemodynamic forces. The present study aims to develop a seamless platform that will overcome the limitations of CTCA and enable fast and accurate evaluation of plaque morphology and physiology. We will analyse imaging data from 70 patients with coronary artery disease who will undergo state-of-the-art CTCA and near-infrared spectroscopy-intravascular ultrasound imaging and develop and train algorithms that will take advantage of the intravascular imaging data to optimise vessel segmentation and plaque characterisation. Furthermore, we will design an advanced module that will enable reconstruction of coronary artery anatomy from CTCA, blood flow simulation, shear stress estimation, and comprehensive visualisation of vessel pathophysiology. These advances are expected to facilitate the broad use of CTCA, not only for risk stratification but also for the evaluation of the effect of emerging therapies on plaque evolution.

Background and Aim Intramyocardial injection of alginate-hydrogel, an emerging and promising strategy for patients with advanced heart failure (HF), is limited by the paucity of commercially available intramyocardial delivery methods. This study investigates the feasibility and safety of a novel X-DROP catheter injection system (Figure 1) for delivery of the alginate-hydrogel to pre-defined target areas in the treatment of HF with reduced ejection fraction. Methods and results Prior to the First-in-man, we demonstrated that transcatheter endo-myocardial alginate-hydrogel implantation (TEAi) was successfully and precisely performed with the X-DROP catheter system under TEE and fluoroscopy guidance in a healthy porcine model (Figure 2). Acute animal results (n = 15) showed no mortality, perforation, and sustained ventricular arrhythmias. Gross examination revealed the retention of the alginate-hydrogel in the pre-defined endocardial area at six months post-procedure (n = 4, Figure 2). The histological assessment showed that alginate-hydrogel was encapsulated by multiple layers of fibrosis without causing damage to the nearby myocardium. Expanding from the animal result, we conducted a first-in-human trial to evaluate the TEAi in patients with heart failure. Ten patients with NYHA class III-IV were enrolled, and all patients were successfully treated with TEAi without the device or procedure-related complications. At the 30-day follow-up, there were no serious adverse device events. One death occurred at a 3-month follow-up. The mean LVEF evaluated by MRI improved from 17.7±3.82 % at baseline to 24.94±11.15 % at 6 months post-procedure (p = 0.046). Also, ESV (297.50±67.85 vs 264.79±101.41, p = 0.029), EDV (359.5±71.92 vs 341.56±67.85, p = 0.105), six minutes walking test (339.7±37.6 m vs 370.4±64.8 m, p = 0.184), NYHA functional class (30% Class III and 70% Class IV vs 100% Class II), and KCCQ score (49.7±3.91 vs 79.0±8.1) were improved at 6-month follow-up. Holter monitor data showed no sustained ventricular arrhythmia during the TEAi or follow-up. Conclusions Our results established the safety and feasibility of TEAi using a novel platform, the X-DROP system and paved the way for the clinical application of intramyocardial injection of alginate-hydrogel in patients with HF.Figure 1Figure 2

No abstract is provided for this article.

In 33 asthmatics (17 males) estimates of breathlessness during exercise were compared with lung volumes, peak flow (PEF) variation, six minute walking distance (6-MWD) and disability (MRC dyspnoea scale).The patients' mean age was 44 years (range 17-70), mean FEV, was 85% predic- ted (range 33-118%).Lung volumes (VC, RV, TLC, RV/TLC) were measured spiro- metrically and by helium dilution.PEF was recorded twice daily for 14 days.Variation in PEF was estimated using the amplitude or the standard deviation of the daily variation as a percentage of the mean or as a percentage of predicted PEF.Exercise was performed on a cycle ergometer.A one minute increment protocol was followed with work rates selected according to size and sex.Minute ventila- tion (VE) and dyspnoea were measured every minute.Dyspnoea was measured using the modified Borg scale and defined as "an uncom- fortable need to breathe."The mean number of work increments was 10 (range 6-14).The median r value for the dyspnoea/VE relation- ship was 0-88 (range 0-0 99).In three patients r was < 0-8; these were excluded from further analysis.The dyspnoea/VE relationship was normalised between patients by fitting height, sex, and a height-sex term to the regression.None of the measurements of lung volume, spirometry, or peak flow correlated with the dyspnoea/VE relationship (p > 0 3 in all cases).6MWD was negatively correlated with dyspnoea/VE (p = -0-46, p = 0-014) and MRC dyspnoea grade was positively correlated (p 0 38, p = 0 034).These results indicate that patients giving low scores for breathlessness relative to ventilation (after adjustment for height and sex) indicated less disability and walked faster than patients who indicated high levels of dyspnoea.These findings suggest that patients' perception of the level of their dyspnoea during exercise may condition their exercise tolerance and ensuing disability, but dyspnoea perception appears to be unrelated to disturbances in lung volumes and measures of airflow limitation.

This article provides an overview on procedure-related issues and uncertainties in outcomes after transcatheter aortic valve implantation (TAVI). The different access sites and how to select them in an individual patient are discussed. Also, the occurrence and potential predictors of aortic regurgitation (AR) after TAVI are addressed. The different methods to quantify AR are reviewed, and it appears that accurate and reproducible quantification is suboptimal. Complications such as prosthesis-patient mismatch and conduction abnormalities (and need for permanent pacemaker) are discussed, as well as cerebrovascular events, which emphasize the development of optimal anti-coagulative strategies. Finally, recent registries have shown the adoption of TAVI in the real world, but longer follow-up studies are needed to evaluate the outcome (but also prosthesis durability). Additionally, future studies are briefly discussed, which will address the use of TAVI in pure AR and lower-risk patients.

Eosinophilic Esophagitis (EoE) is an inflammatory esophageal disease which is increasing in prevalence. The diagnostic gold-standard involves manual review of a patient's biopsy tissue sample by a clinical pathologist for the presence of 15 or greater eosinophils within a single high-power field (400× magnification). Diagnosing EoE can be a cumbersome process with added difficulty for assessing the severity and progression of disease. We propose an automated approach for quantifying eosinophils using deep image segmentation. A U-Net model and post-processing system are applied to generate eosinophil-based statistics that can diagnose EoE as well as describe disease severity and progression. These statistics are captured in biopsies at the initial EoE diagnosis and are then compared with patient metadata: clinical and treatment phenotypes. The goal is to find linkages that could potentially guide treatment plans for new patients at their initial disease diagnosis. A deep image classification model is further applied to discover features other than eosinophils that can be used to diagnose EoE. This is the first study to utilize a deep learning computer vision approach for EoE diagnosis and to provide an automated process for tracking disease severity and progression.

Scattering centers (SC) are often observed with optical coherence tomography (OCT) in some struts of bioresorbable vascular scaffolds (BVS). These SC might be caused by crazes in the polymer during crimp-deployment (more frequent at inflection points) or by other processes, such as physiological loading or hydrolysis (eventually increasing with time). The spatial distribution and temporal evolution of SC in BVS might help to understand their meaning.Three patients were randomly selected from 12 imaged with Fourier-domain OCT at both baseline and 6 months in the ABSORB cohort B study (NCT00856856). Frame-by-frame analysis of the SC distribution was performed using spread-out vessel charts, and the results from baseline and 6 months were compared. A total of 4,328 struts were analyzed. At baseline and follow-up all SC appeared at inflection points. No significant difference was observed between baseline and 6 months in the number of SC struts (14.9 vs. 14.5%, P=0.754) or in the distribution of SC. The proportion and distribution of SC did not vary substantially among the patients analyzed.The SC observed in OCT imaging of the BVS are located exclusively at inflection points and do not increase with time. These findings strongly suggest that SC are caused by crazes in the polymer during crimp-deployment, ruling out any major role of hydrolysis or other time-dependent processes.