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European Collaborative Project on Inflamation and Vascular Wall Remodelling in Atherosclerosis

Final Report Summary - ATHEROREMO (European Collaborative Project on Inflamation and Vascular Wall Remodelling in Atherosclerosis)

Executive Summary:
It has been suggested that inflammation has a key role both in the initial development of the lipid containing atherosclerotic plaque as well as its transformation from “silent” lesion into the “vulnerable” rupture-prone coronary atheroma. The AtheroRemo consortium studied mechanisms behind development of vulnerable plaques, searched biomarkers to identify high risk patients and initiated development of novel treatment strategies.
In the AtheroRemo project the earlier suggested association between dental infections and sudden cardiovascular death was studied in detail. We found that dental periapical abscess following root canal treatment associated significantly with the risk of SCD. Furthermore, it was demonstrated that complicated root canal treatment also associated with the severity of coronary atherosclerosis. In finally, the detailed genomic studies revealed viridans streptococci as the most potent bacterial species behind the CVD complications.
The AtheroRemo’s basic research WP cluster succeeded in the identification of novel molecular mechanisms by which immune and inflammatory events regulate arterial remodelling and atherosclerosis and advanced the discovery of novel therapeutic strategies. In particular, this research contributed to significant advance in the understanding of inflammatory signalling in atherosclerosis. It was established that pattern recognition receptors are not all univocally pro-inflammatory and pro-atherogenic. For instance some signals originated by endosomal TLRs might exert vascular protection. While NODs, like extracellular TLRs appear to have a pro-atherogenic and pro-inflammatory function in the arterial wall. Secondly, the basic science cluster demonstrated that the outcome of TLR signalling varies according to the cell type (myeloid vs. non myeloid) in vascular disease. Thirdly, they clarified the pro-atherosclerotic role of CC and CXC chemokines (i.e. CXCL1 and CCL5) in both mouse intraplaque vulnerability and ischemic injury. In particular, selective antichemokine treatments were shown to reduce atherogenesis and acute myocardial injury. Finally, they highlight the therapeutic potential of IL-28 cytokines in the treatment of atherosclerosis. This work will constitute a solid basis of new therapeutic and preventative approaches that will harness the potential of blocking unwanted inflammation, while enhancing protective pathways in cardiovascular disease.
AtheroRemo revealed a number of novel genetic risk markers of coronary artery disease (CAD) in collaboration with a large international meta-analyses network. In addition, AtheroRemo consortium contributed significantly to genetic research by revealing functional details of the new candidate genes. Furthermore, AtheroRemo evaluated for the first time the potential association between coronary artery histology obtained by intra vascular ultrasound (IVUS) and genetic as well as lipidomic markers. AtheroRemo gene expression studies in turn revealed that atherosclerosis causes significant changes in the gene expression of human arterial wall and some of these changes seem to be site specific, reflecting that atherosclerotic process has unique features in different vascular beds. In addition, the microRNA profiling results indicate that interfering with the miRNA expression in the artery wall may be a potential way to affect atherosclerotic plaque and cardiovascular disease development.
The AtheroRemo consortium identified also novel imaging and lipidomic biomarkers that have a true potential to change current clinical risk evaluation strategies of CAD patients. In the AtheroRemo-IVUS study the amount of the necrotic core in the imaged coronary segment was significantly associated with major acute cardiovascular events, suggesting that imaging biomarkers are useful clinical tools while assessing the future risk of major CVD complications in CAD patients. In addition, a lipidomics approach discovered specific circulating ceramide species that clearly outperformed all currently used lipid measurements including LDL-cholesterol, thus allowing a much better identification of people with a high risk of CVD complications. Based on these findings new diagnostic kits are currently being developed.
Furthermore, based on lipidomic findings potential new drug targets were suggested and they were initially tested in vitro and in vivo by using newly designed liposomal delivery system.