How does metabolism dysfunction drive inflammation in the vessels?

Monday News from EAS Helsinki 2021 Virtual

The EAS Plenary sessions provide state-of-the-art reviews by leading experts.  Plenary 1 of EAS Helsinki 2021 was no exception.  Mechanistic insights discussed in this session are integral to understanding the unmet clinical need of residual cardiovascular risk.

Professor Gerard Pasterkamp (University Medical Center Utrecht, the Netherlands) discussed new insights into plaque phenotypes derived from collaborative research using the Athero-Express Biobank. The ‘vulnerable plaque’, defined by a distinct morphology, has been a useful concept to guide research around the pathophysiology of acute coronary syndromes. However, with changes in population risk profiles and advances in therapies, comes recognition that plaque morphology has also evolved. Developments in imaging techniques and the use of ‘omics’ technologies have aided characterisation of lesions and prompted a finetuning of plaque phenotypes. Such an approach may be particularly valuable in the context of the unmet clinical need of residual cardiovascular risk (1).

Both genome-wide association studies, which identified genes associated with coronary artery disease, and single cell RNA sequencing of plaques have contributed to understand the molecular mechanisms involved in atherosclerosis. Bulk sequencing of human carotid plaques identified clusters that associate with different symptomatic plaque types. Such insights offer new opportunities to investigate the biological processes that underlie these clusters to characterise phenotypic diversity and plasticity in progression of atherogenesis. In this evolving area, biomarkers for these biological processes, including fibrinolysis and calcification, will help in redefining the vulnerable plaque.  ‘Profiling of the vulnerable plaque may offer new therapeutic approaches for clinical management.’

Apolipoprotein (apo)B-containing lipoproteins play a key role in driving atherogenesis, as discussed by Professor Jan Borén (Dahlgren Academy, University of Gothenburg, Sweden). Entry of these lipoproteins, dependent on size, is now recognised to involve transcytosis, an active and highly regulated process. Accumulation and retention of apoB-containing lipoproteins within the artery wall is thus the first stage of atherogenesis. Much of the focus has been on low-density lipoproteins (LDL), established as causal for atherosclerotic cardiovascular disease (2). However, retention of other lipoprotein species, notably remnant lipoproteins (which contain both apoB100 and apoB48), is also relevant, especially in the context of hypertriglyceridaemia. As apo48 remnant lipoproteins lack the principal proteoglycan binding site (due to their truncated size), binding involves apoE (also present on remnant lipoproteins) which have almost an identical proteoglycan binding site as apoB100. Preclinical studies provide strong evidence that remnant lipoproteins are indeed atherogenic, and bind to the arterial wall proteoglycans with higher affinity than LDL, thus initiating maladaptive processes integral to atherogenesis. 

Characteristics of the artery wall also influence atherogenesis. Intimal hyperplasia is well known to increase susceptibility to atherosclerosis, and together with hypercholesterolaemia accelerates this process. In humans, LDL binding to the arterial wall is also pH dependent; as the region becomes more acidic there is increasing binding to the artery wall. Histidine residues are critical in this process. Thus, both plasma levels of apoB-containing lipoproteins and the characteristics of the artery wall influence the propensity to atherosclerosis. 

Professor Esther Lutgens (Amsterdam University Medical Center, the Netherlands and Ludwig Maximilian University, Munich, Germany) discussed how atherosclerosis is a lipid-driven immune disease. Insights into this process have led to investigation of the therapeutic opportunities for novel immunotherapy in atherosclerosis to counter residual risk beyond LDL. The immune checkpoints are of particular interest, as these comprise co-stimulatory and co-inhibitory molecules that regulate inflammation. Her research has focused on the immune checkpoint protein CD40 and its ligand CD40L, which plays a central role in modulating the inflammatory response during the development of atherosclerosis by influencing interactions between immune cells, as well as between immune cells and non-immune cells (3). Directly targeting this dyad is, however, not feasible due to the risk for immunosuppression and thromboembolic events. Animal studies with CD40-TRAF6, which targets the downstream signalling pathway, showed reduced progression of atherosclerosis, mediated by cell-specific effects. ‘Targeting the CD40/CD40L interaction offers therapeutic potential for tailoring of immune therapy to prevent or slow atherosclerosis.’

Finally, Professor Renu Virmani (Georgetown University, USA) gave a comprehensive overview of the morphology of coronary artery calcification and its progression. Coronary artery calcification initiates as microcalcification, eventually developing to sheet calcification and nodular calcification (4). Whereas spotty calcification has been shown to be a predictor of unstable plaque, more extensive calcification is associated with stable plaque. Nodular calcification, evident in about 5% of cases of sudden death (5), is initiated from the calcified necrotic core rather than collagen rich calcification.

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References

  1. Libby P, Pasterkamp G. Requiem for the ‘vulnerable plaque’. Eur Heart J 2015;36:2984-7.
  2. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020;41:2313-30.
  3. Bosmans LA, Bosch L, Kusters PJH, et al. The CD40-CD40L dyad as immunotherapeutic target in cardiovascular disease. J Cardiovasc TransLAW Res 2021;14:13-22.
  4. Domanial M, Katagiri Y, Module R, et al. Vulnerable plaques and patients: state-of-the-art. Eur Heart J 2020;41:2997-3004.
  5. Torii S, Sato Y, Otsuka F, et al. Eruptive Calcified Nodules as a Potential Mechanism of Acute Coronary Thrombosis and Sudden Death. J Am Coll Cordial. 2021 Apr 6;77(13):1599-1611.
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