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EAS2019 From the plenary session on Wednesday May 29

Wednesday 5 June 2019   (0 Comments)
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Looking to the future – novel treatment strategies

The final Plenary session gave a dynamic overview of the future for therapeutic strategies, in which both the immune system and lipoproteins feature.

Opening this session, Professor Laszlo Nagy (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) discussed researches implicating the immune system in muscle regeneration and repair. Macrophages play a pivotal role in this process, initially as inflammatory mediators that help to clear necrotic debris, and subsequently transitioning to repair macrophages involved in the tissue repair and remodelling processes.1 System level approaches, involving a combination of epigenomics, transcriptomics and lipidomics, helped to define critical effectors of this macrophage plasticity that occurs in response to specific environmental cues. Studies identified BACH1 and PPARγ as key transcription factors involved in this phenotypic switch mediated via lipid signalling that controls the expression of final effectors such as HOX1 (via BACH1) and GFD3 (via PPARγ).2,3 Shotgun and targeted lipidomics also identified resolvin D2 as critically involved in in promoting muscle repair process. Taken together, these findings implicate innate immune cells with dynamic lipid mediator signatures in the muscle repair process. Targeting key effectors of this metabolic regulation may offer therapeutic potential not only in muscle regeneration disorders, but also in diabetes, the latter possibly via the involvement of PPARγ.

Is the immune system the next game changer? That was the question posed by Professor Matthias Nahrendorf (Harvard Medical School, Boston, USA) during his plenary lecture. Beyond the role of the innate immune system in atherosclerosis, mediated via interactions with LDL in the vessel wall, it is increasingly recognised that the immune system is also involved in cardiac development, composition and function.4 Monocytes/macrophages play a role in the acute period following myocardial infarction (MI), by controlling inflammation and promoting cardiomyocyte replenishment. In the repair process, haematopoietic progenitors are mobilised from the bone marrow to the spleen, resulting in the development of monocytes and neutrophils, which are then rapidly transported to the site of MI. Emerging evidence shows that the cardiac macrophages can modulate monocytes in the heart, and facilitate conduction at the atrioventricular node. In contrast, macrophages lacking connexin 43, a gap junction protein, promoted second- or third-degree block.5 In addition, unpublished data suggest that cardiac macrophages may have effects beyond the heart, with studies showing a protective effect in the lung possibly involving the tissue or resident alveolar macrophages.

Thus, emerging evidence suggests that macrophages may have a central role in cardiac homeostasis and in the maintenance of sinus rhythm. Understanding the crosstalk between different mediators of these responses may offer novel therapeutic opportunities. So, returning to his original question, Professor Nahrendorf concluded that immunity could well be the next game changer with a role in cardiovascular regenerative medicine.

Back to lipids…

With the advent of the PCSK9 inhibitors, attainment of very low  LDL-C levels now becomes feasible, implying that the time has now come for researchers to turn their attention to other novel targets. Professor Erik Stroes (Amsterdam Medical Center, University of Amsterdam, the Netherlands) discussed apolipoprotein-B containing lipoproteins worthy of contention. Mendelian randomisation studies have validated three potential targets: apo-CIII for triglyceride-rich lipoproteins, apo(a) contained within lipoprotein(a) and angiopoietin like protein 3 (ANGPTL3).

Recent data have established that the clinical benefit from lowering apoB-containing lipoproteins is directly related to the absolute reduction in apoB.6 However, there appears to be a discordance between the magnitude of reduction of triglycerides observed in clinical trials (ranging from 15% to 80%, depending on the drug) and that observed for apoB (5-10%). An exception to this is represented by early clinical trials targeting ANGPTL3, where a comparable and extensive reduction in apoB and triglycerides was observed with the anti ANGPTL3 monoclonal antibody evinacumab in a pilot study in patients with homozygous familial hypercholesterolaemia.7 The mechanism of this effect merits further investigation, but appears to involve lowering of both triglycerides and cholesterol.

In a setting  of finite healthcare resources, it will be become increasingly important to target these costly treatments to patients at highest absolute cardiovascular risk who are likely to benefit most from these treatments. Clinicians will require an improved framework to optimise clinical decision-making, integrating information from biomarkers, genetics and imaging. Ultimately, implementation will require the combination of omics and machine learning, to achieve cost-effective use of highly efficacious but costly therapies in cardiovascular medicine.

A revival for HDL?

The high-density lipoprotein (HDL) story came to an abrupt hiatus following the failure of several clinical trials involving treatments aimed at raising plasma HDL-cholesterol levels. Despite this, researchers including Professor John Chapman (Sorbonne University, Paris, France) believe that this is not the end of the HDL story for a few reasons. First, unlike LDL, human HDL metabolism is complex, and HDL concentrations in the interstitial fluid, which bathes most cells, are approximately 100-fold lower than circulating plasma levels. Second, knowledge about the biological activities of HDL is still incomplete. It is increasingly recognised that the lipid and protein constituents of HDL (the lipidome and proteome) vary, with implications for the heterogeneity of HDL particles. The different HDL particle species also show specialisation in functionality. Third, the metabolism of HDL is perturbed in the setting of insulin resistance, with evidence of functionally defective HDL particles with reduced atheroprotective properties. In individuals with metabolic syndrome, concomitant statin therapy was shown to enhance the capacity of small, dense HDL3 particles to inactivate LDL-derived, redox-active phospholipid hydroperoxides, consistent with preferential enrichment of phosphatidylethanolamine plasmalogens in these HDL particles.8

As Professor Chapman concluded, many gaps remain in knowledge about HDL, especially regarding functionally- and structurally defined HDL protein-lipid complexes. Insights into these questions may offer potential for new therapeutic targets in defined disease states. The HDL story continues for some time yet……………………

References

1. Varga T, Mounier R, Horvath A et al. Highly dynamic transcriptional signature of distinct macrophage subsets during sterile inflammation, resolution, and tissue repair. J Immunol 2016;196:4771-82.

2. Igarashi K, Kurosaki T, Roychoudhuri R. BACH transcription factors in innate and adaptive immunity. Nat Rev Immunol 2017;17:437-50.

3. Giannakis N, Sansbury BE, Patsalos A, et al. Dynamic changes to lipid mediators support transitions among macrophage subtypes during muscle regeneration. Nat Immunol 2019;20:626-36.

4. Swirski FK, Nahrendorf M. Cardioimmunology: the immune system in cardiac homeostasis and disease. Nat Rev Immunol 2018;18:733-44.

5. Hulsmans M, Clauss S, Xiao L et al. Macrophages facilitate electrical conduction in the heart. Cell 2017;169:510-22.

6. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-73.

7. Gaudet D, Gipe DA, Pordy R et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017;377:296-7.

8. Orsoni A, Thérond P, Tan R et al. Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia. J Lipid Res 2016;57:2073-87.


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