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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - INTRICARE (International Network for Training on Risks of vascular Intimal Calcification And roads to Regression of cardiovascular diseasE)

Teaser

Summary

Cardiovascular disease remains one of the major challenges of contemporary society, being responsible for a staggering 47% of deaths in Europe. Most cardiovascular diseases arise from thrombotic rupture of an atherosclerotic plaque, the pathologic thickening of (coronary and carotid) artery segment and subsequent distal ischemia in heart or brain (infarct, cardiac arrest and stroke). In fact, 20% of European deaths are directly attributable to thrombotic rupture of a vulnerable plaque; a clear indication that current treatments and preventive measures are insufficient. Recent reports demonstrate that intimal vascular calcification, especially punctuated and spotty calcifications (microcalcifications) in the plaque are life-threatening. Microcalcifications are particularly prominent in the vulnerable atherosclerotic plaque that is at high risk of rupture. Interestingly, a high level of vascular calcification frequently occurs in two major cardiovascular comorbidities, type 2 diabetes and chronic kidney diseases, identifying vascular calcification as a shared culprit in profoundly elevated risk of cardiovascular diseases and as an excellent new target for intervention.

The objective of INTRICARE is to train a new generation of scientist that will be excellently skilled to expedite our understanding of vulnerable plaque formation, with a particular focus on microcalcification, and to develop innovative solutions for the early prevention, treatment and diagnosis of atherosclerosis.

Work performed

First patient samples have been collected from the vitamin K intervention trial (vitaVasK) to be tested on SMCs. Endothelial cells and SMCs in vitro models have successfully been established for testing these patients samples on their atherogeneity. Calcification screening assays to isolate and identify novel regulators of calcification The and first two peptides have been identified and are tested in vitro. In vitro models of diabetic SMC calcification have been set up. The novel role of PRG4 in SMC differentiation towards osteo/chondrogenic cells, thereby facilitating vascular calcification has been established and first paper is published. Finally, therelation between regulatory mechanisms of atherosclerotic microcalcification favoring inflammation are being carried out. Additionally, the role of platelet, endothelial cells and VSMCs in the generation of calcification inducing extracellular vesicles has been set up and a position paper between groups has been published. Novel cell lines containing Cre-LoxP are in progress to further investigate the role of EVs. The generation of iSMCs derived from iPSCs to generate SMCs of different embryonic origins and filed the first three iPSC lines. First imaging peptides are successfully synthesized to be tested in vitro and in animals prone for calcification. Phosphorylcholine (PC) and malonedialdehyde (MDA) are identified as antigens and measures levels of natural antibodies IgM antiPC/antiMDA and IgG antiPC/antiMDA in different cohorts of atherosclerosis. Novel pathway on regulation of Wnt-PPARg signaling during calcification has been identified. The impact of microcalcification on VSMC switching towards an osteochondrogenic VSMC phenotype has been investigated using novels models for biochemical initiation of atherogenesis and three iPSC lines have been registered. A first manuscript (accepted) on the correlation of CT with carotid plaque transcriptomes and association of calcification to lesion-stabilization. The regulatory mechanisms of atherosclerotic microcalcification favouring inflammation are being unravelled. Including marker identification and imaging. SMC isolates from different patients are being screened as SMC donors for the use of metabolomics screening. Fractions from bovine adrenal glands have been fractionated to reveal other mediators of calcification. Co-culturing naÃ¯ve and activated macrophages and contractile and synthetic VSMCs is successfully performed. Next, in vitro data will be compared with in vivo imaging of novel cellular regulators of plaque vulnerability established. PET motion correction using MR data, BOOST sequence for carotid arteries and performance and evaluation of a new dedicated carotid PET/MR coil compared to the Siemens and body coils is done.

Final results

To reach greatest scientific and socio-economic impact, INTRICARE aims to create awareness about the results amongst relevant stakeholders (including the scientific community, industry, policy makers and reimbursement agencies) across the globe (with a particular focus on areas with high incidences of AMI). For this, we aim to contribute to conferences via special sessions on vascular calcification (i.e. ECTH 2019 Glasgow) to create awareness for vascular calcification. We aim at publishing in high-impact journals to reach out to both scientists and medical specialists. We will have external collaborations with other H2020 ITNs (such as EVOluTION, CaReSyAn and TICARDIO) and industry. Finally, we will make use of press-releases to create optimal socio-economic impact. To implement the communication activities, the consortium will exploit and build on the communications expertise available in all partners participating in the consortium.

INTRICARE research activities will give rise to results that could generate IP, mainly patents, and have a significant potential for commercial exploitation. In particular, we envisage that our research will lead to IP on novel drugs targeting vulnerable plaque formation. Moreover, novel imaging tools/compounds will be developed. A thorough exploitation strategy will be applied to (1) identify valuable research outcomes and possible IP; (2) optimally leverages economic and societal benefit of research outcomes; (3) provide the best fit with market conditions; (4) leads to a protectable and distinguishing niche and (4) entails minimal investment need and risk, while (5) maximally leveraging the long term commercial potential of project results. The consortium might encourage the creation of a spin-off company to exploit INTRICAREâ€™s protected results
INTRICARE will work closely with Data Science, to make sure that the requirements of the European Commission regarding data management are met within this programme. Within Maastricht, we have one of the developers of the FAIR standards. This research focuses on the development of computational methods for scalable integration and reproducible analysis of FAIR (Findable, Accessible, Interoperable and Reusable) data across scales - from molecules, tissues, organs, individuals, populations to the environment.