Inflammation and Microcalcification are Processes That May be Non-Invasively Identified Via Molecular Imaging as Markers for Vulnerable Plaques

EJVES Vascular Forum, vol. 48, pp. 50

Abstract

Introduction: microRNAs (miRNAs) have been identified as posttranscriptional inhibitors of gene expression, thought to fine tune the translational output of target mRNAs.We explored the diagnostic and prognostic value of miRNAs in abdominal aortic aneurysm (AAA), a disease for which currently no established plasma biomarker exists.Methods: Using a miRNA OpenArray platform, we profiled the expression of 754 human miRNAs in plasma from 195 patients with AAA and 184 matched non-aneurysmal control individuals with a similar cardiovascular risk profile from the Dutch Second Manifestations of Arterial disease (SMART) cohort.To evaluate the potential prognostic value of discovered miRNA candidates we used a separate longitudinal patient cohort, consisting of 31 AAA patients who underwent computed tomography AAA diameter measurements and plasma sampling at baseline (n ¼ 31) and after six months (n ¼ 31) and 12 months (n ¼ 11) of follow up.Results: Among 12 differentially expressed miRNAs, miR-15a (4.4 fold; p ¼ .041)and -659 (6.8 fold; p ¼ .037)were the most significantly upregulated miRNAs, whereas miR-1183 (0.16 fold; p ¼ .007)and -192 (0.29 fold; p ¼ .013)were the most significantly downregulated ones.Further, expression of miR-15a in plasma was significantly correlated (n ¼ 36, p ¼ .019;R 2 ¼0.15) with aortic diameter increase after six months.Among known targets of miR-15a are Reck and Fgf2, both known to be involved in human AAA pathogenesis.Upon administration of anti-miR-15a in vivo in an elastase induced mouse model of AAA, the observed aortic diameter increase at day 7 was significantly lower compared with mice treated with scrambled control (1.22-vs.1.49 fold; p ¼ .008;n ¼ 4+5).In a separate mouse AAA model (AngII infusion), a similar trend could be observed at several timepoints -days 7/14/28.Conclusion: Our findings suggest that miR-15a is a potential diagnostic and prognostic AAA biomarker.Through in vivo studies and based on its target profile, we show that miR-15a seems to be involved in AAA pathogenesis and is thus a potential treatment strategy.In vitro studies are currently ongoing to better elucidate the underlying mechanisms behind these observations.

Authors 5

1. Alexandru Florea Aachen Department of Nuclear Medicine

   Maastricht University Medical Centre · Universitätsklinikum Aachen

   Affiliation as printed

   Maastricht University Medical Centre, Department of Radiology and Nuclear Medicine, Maastricht, Netherlands

   Uniklinik RWTH Aachen, Department of Nuclear Medicine, Aachen, Germany

2. Agnieszka Morgenroth Aachen Department of Nuclear Medicine

   Universitätsklinikum Aachen

   Affiliation as printed

   Uniklinik RWTH Aachen, Department of Nuclear Medicine, Aachen, Germany

3. Jan A. Bucerius

   Maastricht University Medical Centre · Maastricht University · University of Göttingen

   Affiliation as printed

   Maastricht University Medical Centre, Department of Radiology and Nuclear Medicine, Maastricht, Netherlands

   Maastricht University, School for Cardiovascular Diseases (CARIM), Maastricht, Netherlands

   University of Göttingen, Department of Nuclear Medicine, Göttingen, Germany

4. Leon J. Schurgers

   Maastricht University Medical Centre · Maastricht University

   Affiliation as printed

   Maastricht University Medical Centre, Department of Biochemistry, Maastricht, Netherlands

   Maastricht University, School for Cardiovascular Diseases (CARIM), Maastricht, Netherlands

5. Felix Manuel Mottaghy Aachen Department of Nuclear Medicine

   Maastricht University Medical Centre · Universitätsklinikum Aachen

   Affiliation as printed

   Maastricht University Medical Centre, Department of Radiology and Nuclear Medicine, Maastricht, Netherlands

   Uniklinik RWTH Aachen, Department of Nuclear Medicine, Aachen, Germany