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EAS2018 Monday’s Plenary session; new insights into the pathogenesis of atherosclerosis

Friday 11 May 2018   (0 Comments)
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Translating from bench to bedside: how understanding of the pathogenesis of atherosclerosis can drive therapeutic innovation

Monday’s Plenary session focused on new insights into the pathogenesis of atherosclerosis and what these may offer patients in the future.

Dr Renu Virmani (CVPath Institute and clinical Professor at Georgetown University; University of Maryland-Baltimore; George Washington University; and Vanderbilt University, USA) focused on neoatherosclerosis, particularly in the setting of stent thrombosis. By definition, neoatherosclerosis is histologically characterized by an accumulation of lipid-laden foamy macrophages with or without necrotic core formation and/or calcification within the neointima. She showed that this is more of an issue for first and second-generation drug-eluting stents (DES) as compared with bare metal stents, although susceptibility to both increases over time. Impaired endothelial barrier function due to the use of the sirolimus group of drugs in DES may be a contributor to the development of early in-stent neoatherosclerosis. This is because sirolimus inhibits the mTOR complex leading to an increase in intracellular calcium levels and endothelial dysfunction. Although rare, complications of late stent thrombosis from rupture are associated with high mortality. Thus, mechanistic insights have an important part to play in improving long term outcome after coronary stenting.1

Professor Iras Tabas (Columbia University, New York, USA) continued the theme of Professor Libby’s discussion of the role of inflammation in Sunday’s Key Note Lecture (see separate report). His focus was on how understanding of the mechanism underlying defective inflammation resolution in atherosclerosis may provide future therapeutic strategies. He emphasized that inflammation resolution is an active process, involving resolving lipids (such as lipoxins or resolvins), proteins (such as annexin) and cells. However, in the setting of chronic inflammatory disease, there is a defective resolution response due to a decrease in resolving mediators, leading to tissue damage, which in turn amplifies the inflammatory response.2 From a clinical perspective, defective inflammation resolution is a hallmark of clinically dangerous or vulnerable plaques, and defective efferocytosis exacerbates this process, with a specific role in necrotic core formation.3 Proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase reduces efferocytosis, thereby promoting plaque necrosis, and this has been correlated with the presence of ischaemic symptoms. The CANTOS trial has been a driver for rethinking therapeutic possibilities for management of atherosclerosis, with lesion-targeted nanoparticles that deliver resolving mediators possibly offering therapeutic application in suppressing plaque progression.

Professor Gerard Pasterkamp (University Medical Center Utrecht, The Netherlands) noted that with a decreasing incidence of STEMI and death due to stroke as a result of therapeutic advances in blood pressure and lipid lowering as well as decreasing smoking rates,4 current understanding of the vulnerable plaque as a pathological substrate for all adverse cardiovascular thrombotic events merits reconsideration. Furthermore, if the underlying pathology of the ‘vulnerable plaque’ is shifting, what are the implications for sample banks that predate 2000 – are these still an inappropriate source for future study?

It may be that genetic insights offer hope on this question, in identifying coronary artery disease susceptibility loci that correlate with (vulnerable) plaque characteristics. In support, Professor Pasterkamp presented novel data indicating that a proportion of risk variants for coronary artery disease also associate with plaque characteristics. Large cohorts with optimally phenotyped human plaques are clearly needed to resolve this highly pertinent question.

Finally, there were novel data presented by Professor Stefanie Dimmeler (Center for Molecular Medicine, University of Frankfurt, Germany) that RNA editing, a post‐transcriptional process, may have a role in control of atherosclerosis. Indeed, there is now evidence that RNA editing is key to the development and function of blood vessels, and that editing may be increased under conditions of hypoxia and inflammation, as well as in patients with coronary artery disease. However, to date the underlying mechanisms are not yet fully elucidated.

This ‘back to the bench’ plenary session offered much food for thought about future possibilities for preventing stent thrombosis and suppressing plaque progression. New insights from genetic studies for loci associated with plaque characteristics may be an important driver of innovation.

References

1. Yahagi K, Kolodgie FD, Otsuka F et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol 2016;13:79-98.

2. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 2013;339:166-72.

3. Cai B, Thorp EB, Doran AC et al. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 2017;127:564-8.

4. Pasterkamp G, den Ruijter HM, Libby P. Temporal shifts in clinical presentation and underlying mechanisms of atherosclerotic disease. Nat Rev Cardiol 2017;14:21-9.


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