Netherlands Heart Institute ICIN

Utrecht, Netherlands

Netherlands Heart Institute ICIN

Utrecht, Netherlands
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Mol E.A.,University Utrecht | Goumans M.-J.,Leiden University | Doevendans P.A.,University Utrecht | Doevendans P.A.,Netherlands Heart Institute ICIN | And 3 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2017

Extracellular vesicles (EVs) are nano-sized, lipid bilayer-enclosed particles involved in intercellular communication. EVs are increasingly being considered as drug delivery vehicles or as cell-free approach to regenerative medicine. However, one of the major challenges for their clinical application is finding a scalable EV isolation method that yields functional EVs. Although the golden standard for EV isolation is ultracentrifugation (UC), a recent study suggested that isolation using size-exclusion chromatography (SEC) yielded EVs with more intact biophysical properties. Whether this also leads to differences in functionality remained to be investigated. Therefore, we investigated possible differences in functionality of cardiomyocyte progenitor cell-derived EVs isolated using UC and SEC. Western blot analysis showed higher pERK/ERK ratios in endothelial cells after stimulation with SEC-EVs compared to UC-EVs, indicating that SEC-EVs bear higher functionality. Therefore, we propose to use SEC-EVs for further investigation of EVs’ therapeutic potential. Further optimization of isolation protocols may accelerate clinical adoption of therapeutic EVs. © 2017 Elsevier Inc.

Pieper P.G.,University of Groningen | Balci A.,University of Groningen | Balci A.,Netherlands Heart Institute ICIN | Aarnoudse J.G.,University of Groningen | And 12 more authors.
Circulation | Year: 2013

BACKGROUND-: Pregnant women with congenital heart disease (CHD) are susceptible to cardiovascular, obstetric, and offspring complications. In women with CHD, cardiac dysfunction may compromise uteroplacental flow and contribute to the increased incidence of obstetric and offspring events. METHODS AND RESULTS-: We performed a prospective multicenter cohort study of pregnant women with CHD and healthy pregnant women. We compared clinical, laboratory, echocardiographic, and uteroplacental Doppler flow (UDF) parameters at 20 and 32 weeks gestation, and pregnancy outcome. We related cardiovascular parameters to UDF parameters and pregnancy outcome in women with CHD. We included 209 women with CHD and 70 healthy women. Cardiovascular parameters (N-terminal pro-B-type natriuretic peptide, left and right ventricular function) differed between both groups. UDF parameters were impaired in CHD women (umbilical artery pulsatility and resistance index at 32 weeks in CHD versus healthy women, P=0.0085 and P=0.017). The following cardiovascular parameters prepregnancy and at 20 weeks gestation were associated with UDF (umbilical artery resistance index) at 32 weeks at multivariable analysis: (1) right ventricular function (tricuspid annular plane systolic excursion) (P=0.002), (2) high N-terminal pro-B-type natriuretic peptide (P=0.085), (3) systemic (P=0.001), and (4) pulmonary (P=0.045) atrioventricular valve regurgitation. Women with CHD had more obstetric (58.9% versus 32.9%, P<0.0001) and offspring events (35.4% versus 18.6%, P=0.008) than healthy women. Impaired UDF was associated with adverse obstetric and offspring outcome. CONCLUSIONS-: UDF parameters are abnormal in pregnant women with CHD. Cardiovascular function is associated with an abnormal pattern of UDF. Compromised UDF may be a key factor in the high incidence of offspring and obstetric complications in this population. © 2013 American Heart Association, Inc.

Kampman M.A.M.,University of Groningen | Kampman M.A.M.,Netherlands Heart Institute ICIN | Bilardo C.M.,University of Groningen | Mulder B.J.M.,University of Amsterdam | And 4 more authors.
Ultrasound in Obstetrics and Gynecology | Year: 2015

Objective To investigate the existing evidence for a link between maternal cardiac function, abnormal uteroplacental flow and poor perinatal outcome in women with and without known cardiac disease. Methods PubMed and EMBASE databases were searched systematically for studies relating cardiac functional parameters and uteroplacental Doppler flow with pregnancy outcome in women with pre-existing congenital cardiac disease and women without known cardiac disease. Only studies based on echocardiography were included. Results From 1732 citations, 10 articles were included. In women with known congenital heart disease, a relationship was found between abnormal uteroplacental Doppler flow patterns and cardiac function before and during pregnancy. Conversely, women without a history of congenital heart disease, but with abnormal uterine artery resistance and pregnancy complications, more often showed global left ventricular diastolic dysfunction (33%; P = 0.0001), impaired myocardial relaxation (72%; P < 0.0001) and left ventricular systolic dysfunction (17%; P = 0.006), even up to 1 year postpartum. Conclusion There is increasing evidence for an association between pre-existing subclinical cardiac dysfunction, poor placentation (reflected by uteroplacental Doppler flow abnormalities) and poor pregnancy outcome. It may be postulated that pre-existing suboptimal cardiac performance, as a result of either congenital heart disease or a subclinical latent condition, is one of the common denominators of poor placentation, leading to poor pregnancy outcome. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

Kampman M.A.M.,University of Groningen | Kampman M.A.M.,Netherlands Heart Institute ICIN | Balci A.,University of Groningen | Van Veldhuisen D.J.,University of Groningen | And 7 more authors.
European Heart Journal | Year: 2014

AimsIn women with congenital heart disease (CHD), cardiovascular complications during pregnancy are common, but the risk assessment of these patients remains difficult. This study sought to determine the independent role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in addition to other parameters in predicting adverse cardiovascular events during pregnancy in women with CHD.Methods and resultsWe conducted a national, prospective multicentre cohort study. Follow-up with clinical evaluation and echocardiography and NT-proBNP measurement was performed at 20-week gestation. Adverse cardiovascular events occurred in 10.3% of 213 pregnancies. N-terminal pro-B-type natriuretic peptide levels >128 pg/mL at 20-week gestation, the presence of a mechanical valve, and subpulmonary ventricular dysfunction before conception were independently associated with events [odds ratio (OR) 10.6 (P = 0.039), OR 12.0 (P = 0.016), and OR 4.2 (P = 0.041), respectively]. The negative predictive value of NT-proBNP levels <128 pg/mL was 96.9%. N-terminal pro-B-type natriuretic peptide levels >128 pg/mL at 20 weeks of gestation had an additional value in predicting the occurrence of adverse cardiovascular events on the top of the other identified predictors (area under the curve 0.90 vs. 0.78, P = 0.035).ConclusionIncreased NT-proBNP levels at 20 weeks of gestation are an independent risk predictor of cardiovascular events during pregnancy in women with CHD. © The Author 2013.

Camporeale A.,University of Turin | Marino F.,University of Turin | Papageorgiou A.,Maastricht University | Papageorgiou A.,Catholic University of Leuven | And 15 more authors.
EMBO Molecular Medicine | Year: 2013

Myocarditis, often triggered by viral infection, may lead to heart auto-immunity and dilated cardiomyopathy. What determines the switch between disease resolution and progression is however incompletely understood. We show that pharmacological inhibition of STAT3, the main mediator of IL-6 signalling and of Th17-cell differentiation, protects mice from the development of Experimental Auto-immune Myocarditis reducing liver production of the complement component C3, and can act therapeutically when administered at disease peak. Further, we demonstrate that STAT3 is sufficient when constitutively active for triggering the onset of immune-mediated myocarditis, involving enhanced complement C3 production and IL-6 signalling amplification in the liver. Disease development can be prevented by C3 depletion and IL-6 receptor neutralization. This appears to be relevant to disease pathogenesis in humans, since acute myocarditis patients display significantly elevated circulating IL-6 and C3 levels and activated heart STAT3. Thus, aberrant IL-6/STAT3-mediated induction of liver acute phase response genes including C3, which occurs as a consequence of pre-existing inflammatory conditions, might represent an important factor determining the degree of myocarditis and its clinical outcome. Aberrant IL-6/STAT3-mediated induction of liver acute phase response genes including C3, a consequence of pre-existing inflammatory conditions, is involved in determining the degree of myocarditis and its clinical outcome. © 2013 The Authors.

Piers S.R.D.,Leiden University | Everaerts K.,Maastricht University | Van Der Geest R.J.,Leiden University | Hazebroek M.R.,Maastricht University | And 7 more authors.
Heart Rhythm | Year: 2015

Background The relation between myocardial scar and different types of ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy (NIDCM) is unknown. Objectives The purpose of this study was to analyze the effect of myocardial scar, assessed by late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR), on the occurrence and type of ventricular arrhythmia in patients with NIDCM. Methods Consecutive patients with NIDCM who underwent LGE-CMR and implantable cardioverter-defibrillator (ICD) implantation at either of 2 centers were included. LGE was defined by signal intensity ≥35% of maximal signal intensity, subdivided into core and border zones (≥50% and 35%-50% of maximal signal intensity, respectively), and categorized according to location (basal or nonbasal) and transmurality. ICD recordings and electrocardiograms were reviewed to determine the occurrence and type of ventricular arrhythmia during follow-up. Results Of 87 patients (age 56 ± 13 y, 62% male, left ventricular ejection fraction 29% ± 12%), 55 (63%) had LGE (median 6.3 g, interquartile range 0.0-13.8 g). During a median follow-up of 45 months, monomorphic ventricular tachycardia (VT) occurred in 18 patients (21%) and polymorphic VT/ventricular fibrillation (VF) in 10 (11%). LGE predicted monomorphic VT (log-rank, P <.001), but not polymorphic VT/VF (log-rank, P =.40). The optimal cutoff value for the extent of LGE to predict monomorphic VT was 7.2 g (area under curve 0.84). Features associated with monomorphic VT were core extent, basal location, and area with 51%-75% LGE transmurality. Conclusions Myocardial scar assessed by LGE-CMR predicts monomorphic VT, but not polymorphic VT/VF, in NIDCM. The risk for monomorphic VT is particularly high when LGE shows a basal transmural distribution and a mass ≥7.2 g. Importantly, patients without LGE on CMR remain at risk for potentially fatal polymorphic VT/VF. © 2015 Heart Rhythm Society.

Deddens J.C.,University Utrecht | Colijn J.M.,University Utrecht | Oerlemans M.I.F.J.,University Utrecht | Pasterkamp G.,University Utrecht | And 5 more authors.
Journal of Cardiovascular Translational Research | Year: 2013

Small non-coding microRNAs (miRNAs) are important physiological regulators of post-transcriptional gene expression. miRNAs not only reside in the cytoplasm but are also stably present in several extracellular compartments, including the circulation. For that reason, miRNAs are proposed as diagnostic biomarkers for various diseases. Early diagnosis of acute coronary syndrome (ACS), especially non-ST elevated myocardial infarction and unstable angina pectoris, is essential for optimal treatment outcome, and due to the ongoing need for additional identifiers, miRNAs are of special interest as biomarkers for ACS. This review highlights the nature and cellular release mechanisms of circulating miRNAs and therefore their potential role in the diagnosis of myocardial infarction. We will give an update of clinical studies addressing the role of circulating miRNA expression after myocardial infarction and explore the diagnostic value of this potential biomarker. © 2013 Springer Science+Business Media New York.

Den Hartog A.G.,University Utrecht | Bovens S.M.,University Utrecht | Bovens S.M.,Netherlands Heart Institute ICIN | Koning W.,University Utrecht | And 5 more authors.
European Journal of Vascular and Endovascular Surgery | Year: 2013

Objective: The article aims to provide an overview of the literature that assessed the agreement between magnetic resonance imaging (MRI) and histology for specific carotid plaque characteristics associated with vulnerability in terms of sensitivity and specificity. Methods: A systematic search strategy was conducted in MEDLINE and EMBASE databases resulting in 1084 articles. Finally, we included 17 papers. Due to variation in presentation, especially in MRI and histology methods, a pooled analysis could not be performed. Results: Two studies were performed on a 3.0-T MRI scanner; all other studies were performed on a 1.5-T scanner. Most performed sequences were two-dimensional (2D) and three-dimensional (3D) T1-weighted and all histology protocols varied slightly. Our results indicate that calcification, fibrous cap, intraplaque haemorrhage and lipid-rich necrotic cores can be identified with moderate-to-good sensitivity and specificity. Conclusions: Based on current literature, it appears premature for routine application of MRI as an imaging modality to assess carotid plaque characteristics associated with plaque vulnerability. Although MRI still holds promise, clinical application for plaque characterisation would require consensus regarding MRI settings and confirmation by histology. Predefined protocols for histology and MR imaging need to be established.© 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

den Adel B.,Leiden University | Bovens S.M.,University Utrecht | Bovens S.M.,Netherlands Heart Institute ICIN | Boekhorst B.T.,Maastricht University | And 4 more authors.
Atherosclerosis | Year: 2012

MRI using targeted contrast agents (CA) has emerged as a promising technique to study atherothrombotic disease in vivo. Particularly, the use of targeted Gd and lipid-based nanoparticles has enabled detailed in vivo imaging of various molecular markers of atherosclerotic plaque pathophysiology. For validation purposes, it is crucial that nanoparticle accumulation in the plaque, cellular association and localization can be assessed by ex vivo immuno-histology or fluorescence microscopy of tissue sections. In this review we discuss the various methods that are available for histological evaluation of targeted MRI contrast agents such as lipid-based nanoparticles and iron oxide particles. We discuss the detection of these contrast agents in paraffin-embedded and in cryopreserved tissue sections of atherosclerotic plaques. During the embedding procedure in paraffin, most components of targeted lipid-based nanoparticles are generally washed out, though the actual targeting moieties may be retained in the embedded sections. Therefore staining of the antibody-antigen complex provides a suitable way to visualize the presence of the nanoparticle in the plaque. In cryosections, the localization of nanoparticles can be assessed directly by measuring the fluorescence of an incorporated fluorophore or by secondary stainings of the Gd-containing DTPA lipids or the iron oxide particles. With certain secondary stainings, be it for the contrast agent or for co-localization with the target, the contrast agent itself may interfere with standard histological protocols, yielding false positive results. The here presented techniques enable proper visualization of MR contrast agent accumulation and localization in atherosclerotic plaque, which will provide the validation necessary to advance these lipid-based nanoparticles to the clinic. © 2012 Elsevier Ireland Ltd.

Arslan F.,University Utrecht | De Kleijn D.P.,Netherlands Heart Institute ICIN | Pasterkamp G.,University Utrecht
Nature Reviews Cardiology | Year: 2011

Despite advances in treatment of patients who suffer from ischemic heart disease, morbidity related to myocardial infarction is increasing in Western societies. Acute and chronic immune responses elicited by myocardial ischemia have an important role in the functional deterioration of the heart. Research on modulation of the inflammatory responses was focused on effector mediators such as leukocytes. However, increasing evidence indicates that various endogenous ligands that act as 'danger signals', also called danger-associated molecular patterns (DAMPs), are released upon injury and modulate inflammation. Originally described as part of the first-line defense against invading microorganisms, several Toll-like receptors (TLRs) on leukocytes and parenchymal cells have now been shown to respond to such signals and to have a pivotal role in noninfectious pathological cardiovascular conditions, such as ischemia-reperfusion injury and heart failure. From a therapeutic perspective, DAMPs are attractive targets owing to their specific induction after injury. In this Review, we will discuss innate immune activation through TLRs in cardiac ischemia mediated by DAMPs. © 2011 Macmillan Publishers Limited. All rights reserved.

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