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Roos C.J.,Leiden University | Roos C.J.,Interuniversity Cardiology Institute of the Netherlands | Djaberi R.,Leiden University | Schuijf J.D.,Leiden University | And 11 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2011

Purpose: Vascular stiffness may potentially be used as a screening tool to identify asymptomatic patients with diabetes with abnormal myocardial perfusion. The purpose of this study was therefore to determine the association between vascular stiffness, measured in term of pulse wave velocity (PWV) and augmentation index (AIx), and abnormal myocardial perfusion imaging (MPI) in asymptomatic patients with diabetes. Methods: Prospectively, 160 asymptomatic patients with diabetes (mean age 51 years, 87 men) underwent MPI with adenosine stress. The summed stress score (SSS) was determined in each patient according to a 17-segment and five-point score. Abnormal MPI (SSS ≤3) was classified as moderate (SSS 3-7) or severe (SSS ≤8) MPI defects. Using applanation tonometry, the carotid-femoral PWV and the radial AIx corrected to 75 beats per minute were determined noninvasively. Results: MPI was abnormal in 61 patients (38%), with severe MPI defects in 22 patients (14%). Mean PWV increased with deteriorating MPI from 8.4 ± 2.2 m/s in normal MPI to 9.0 ± 2.2 m/s in moderate MPI defects (p = 0.11) and to 11.1 ± 2.5 m/s in severe MPI defects (p < 0.01). Likewise, mean AIx increased from 18.4 ± 13.4% to 19.4 ± 10.7% (p = 0.66) and to 25.4 ± 9.0% (p = 0.03). After adjustment for age and other risk factors, PWV remained a significant predictor of severe MPI defects (p = 0.01, OR 1.50, 95% CI 1.11-2.00), whereas AIx was no longer significant (p = 0.20). Conclusion: Vascular stiffness measured by PWV is associated with severe MPI defects in asymptomatic patients with diabetes. © 2011 The Author(s). Source

Djaberi R.,Leiden University | Schuijf J.D.,Leiden University | De Koning E.J.,Leiden University | Wijewickrama D.C.,Leiden University | And 8 more authors.
Diabetes and Vascular Disease Research | Year: 2013

Purpose: In diabetes, generalised microvascular disease and coronary artery disease (CAD) are likely to occur in parallel. We used a sidestream dark field (SDF) handheld imaging device to determine the relation between the labial microcirculation parameters and CAD in asymptomatic patients with diabetes. Methods: SDF imaging was validated for assessment of labial capillary density and tortuosity. Thereafter, mean labial capillary density and tortuosity were evaluated and compared in non-diabetic controls, and in asymptomatic patients with type 1 and type 2 diabetes. In diabetic patients, mean capillary density and tortuosity were compared according to the presence of CAD. Results: Both type 1 and type 2 diabetes were associated with increased capillary density and tortuosity. In diabetes, mean capillary density was an independent predictor of elevated coronary artery calcium (CAC) (p = 0.03) and obstructive CAD on computed tomography angiography (p = 0.01). Using a cut-off mean capillary density of 24.9 (per 0.63 mm2) the negative predictive value was 84% and 89% for elevated CAC and obstructive CAD. Likewise, capillary tortuosity was an independent predictor of increased CAC (p = 0.01) and obstructive CAD (p = 0.04). Conclusion: Assessment of labial microcirculation parameters using SDF imaging is feasible and conveys the potential to estimate vascular morbidity in patients with diabetes, at bedside. © The Author(s) 2012. Source

Van Der Veer E.P.,Einthoven Laboratory of Experimental Vascular Medicine | Van Der Veer E.P.,Leiden University | De Bruin R.G.,Einthoven Laboratory of Experimental Vascular Medicine | De Bruin R.G.,Leiden University | And 36 more authors.
Circulation Research | Year: 2013

Rationale: RNA-binding proteins are critical post-transcriptional regulators of RNA and can influence pre-mRNA splicing, RNA localization, and stability. The RNA-binding protein Quaking (QKI) is essential for embryonic blood vessel development. However, the role of QKI in the adult vasculature, and in particular in vascular smooth muscle cells (VSMCs), is currently unknown. Objective: We sought to determine the role of QKI in regulating adult VSMC function and plasticity. Methods and results: We identified that QKI is highly expressed by neointimal VSMCs of human coronary restenotic lesions, but not in healthy vessels. In a mouse model of vascular injury, we observed reduced neointima hyperplasia in Quaking viable mice, which have decreased QKI expression. Concordantly, abrogation of QKI attenuated fibroproliferative properties of VSMCs, while potently inducing contractile apparatus protein expression, rendering noncontractile VSMCs with the capacity to contract. We identified that QKI localizes to the spliceosome, where it interacts with the myocardin pre-mRNA and regulates the splicing of alternative exon 2a. This post-transcriptional event impacts the Myocd-v3/Myocd-v1 mRNA balance and can be modulated by mutating the quaking response element in exon 2a of myocardin. Furthermore, we identified that arterial damage triggers myocardin alternative splicing and is tightly coupled with changes in the expression levels of distinct QKI isoforms. Conclusions: We propose that QKI is a central regulator of VSMC phenotypic plasticity and that intervention in QKI activity can ameliorate pathogenic, fibroproliferative responses to vascular injury. © 2013 American Heart Association, Inc. Source

Roos C.J.,Leiden University | Roos C.J.,Interuniversity Cardiology Institute of the Netherlands | Quax P.H.A.,Leiden University | Quax P.H.A.,Einthoven Laboratory of Experimental Vascular Medicine | And 3 more authors.
Biomarkers in Medicine | Year: 2012

Patients with obesity and diabetes mellitus are at increased risk for cardiovascular events and have a higher cardiovascular morbidity and mortality. This worse prognosis is partly explained by the late recognition of coronary heart disease in these patients, due to the absence of symptoms. Early identification of coronary heart disease is vital, to initiate preventive medical therapy and improve prognosis. At present, with the use of cardiovascular risk models, the identification of coronary heart disease in these patients remains inadequate. To this end, biomarkers should improve the early identification of patients at increased cardiovascular risk. The first part of this review describes the pathophysiologic pathway from obesity to coronary heart disease. The second part evaluates several mediators from this pathophysiologic pathway for their applicability as biomarkers for the identification of coronary heart disease. © 2012 Future Medicine Ltd. Source

Hafezqorani S.,Universiteler Mahallesi | Lafzi A.,Universiteler Mahallesi | De Bruin R.G.,Einthoven Laboratory of Experimental Vascular Medicine | Van Zonneveld A.J.,Einthoven Laboratory of Experimental Vascular Medicine | And 3 more authors.
Nucleic Acids Research | Year: 2016

Recent studies show that RNA-binding proteins (RBPs) and microRNAs (miRNAs) function in coordination with each other to control post-transcriptional regulation (PTR). Despite this, the majority of research to date has focused on the regulatory effect of individual RBPs or miRNAs. Here, we mapped both RBP and miRNA binding sites on human 3′UTRs and utilized this collection to better understand PTR. We show that the transcripts that lack competition for HuR binding are destabilized more after HuR depletion. We also confirm this finding for PUM1(2) by measuring genome-wide expression changes following the knockdown of PUM1(2) in HEK293 cells. Next, to find potential cooperative interactions, we identified the pairs of factors whose sites co-localize more often than expected by random chance. Upon examining these results for PUM1(2), we found that transcripts where the sites of PUM1(2) and its interacting miRNA form a stem-loop are more stabilized upon PUM1(2) depletion. Finally, using dinucleotide frequency and counts of regulatory sites as features in a regression model, we achieved an AU-ROC of 0.86 in predicting mRNA half-life in BEAS-2B cells. Altogether, our results suggest that future studies of PTR must consider the combined effects of RBPs and miRNAs, as well as their interactions. © 2016 The Author(s). Source

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