News from EAS Congress 2020 – Virtual
This session is available on demand
In an innovative format, EAS President Professor Lale Tokgözoğlu (Hacettepe University, Ankara, Turkey) opened EAS2020. ‘We welcome over 4,000 participants from across all continents to this virtual meeting, a first for the EAS in its 88th Congress year. We believe that the only way to move forward during difficult times is through science.’
Professor Tokgözoğlu overviewed some of the activities and achievements of the Society over the last 12 months, including:
- New EAS Consensus Panel publication on low-density lipoprotein (LDL) causality, and quantification of atherogenic lipoproteins.
- An EAS Task Force statement on rare dyslipidaemias, with an accompanying slide set.
- The Familial Hypercholesterolaemia Studies Collaboration, which now includes over 62,000 subjects in the registry.
- A case-orientated handbook to complement the 2019 ESC/EAS lipid guidelines (also available in French, Portuguese and Spanish).
- Mentorship as part of the EAS Young Scientists and EAS Young Fellows programmes.
- Ongoing collaboration with both national and international societies, and the development of a Lipid Clinic Network, launching this month.
Congress Co-Chair, Professor Francois Mach (Geneva University Hospital) added his welcome on behalf of his Co-Chair, Professor Arnold von Eckardstein (Institute of Clinical Chemistry, University Hospital Zurich, Switzerland), and Scientific Programme Chair Professor Ruth Frikke-Schmidt (University of Copenhagen, Denmark).
President of the International Atherosclerosis Society (Professor Raul Santos, Lipid Clinic at the Heart Institute (InCor), University of São Paulo Medical School, and the Hospital Israelita Albert Einstein, São Paulo, Brazil) congratulated the EAS for ongoing efforts in reducing the burden of cardiovascular disease. Key among these has been collaboration with other academic societies, as evidenced by Joint Sessions with the ESC, IAS and NLA at EAS2020.
Professor Joseph L. Witztum, San Diego, USA was the recipient of the EAS2020 Anitschkow Award. This award recognizes the outstanding contributions of Professor Witztum in providing a fundamental understanding of the role of oxidized (oxLDL) and immunological mechanisms in atherogenesis.
The Anitschkow Lecture
Professor Joseph L. Witztum – The Oxidation Hypothesis of atherosclerosis revisited: A pivotal role of oxidised phospholipids (OxPL) in atherosclerosis, NASH, and inflammation
In the late 1907’s, there were two distinct views about the aetiology of atherosclerosis: the lipid infiltration hypothesis versus the inflammation hypothesis. These were subsequently revised following the discoveries that modified LDL is taken up by scavenger receptors resulting in foam cell formation, and that this modification involves lipid peroxidation and degradation of LDL phospholipids (1). Together these findings underpinned the oxidation hypothesis of atherosclerosis (2), now considered one of the major concepts underlying the pathogenesis of atherogenesis.
Subsequent to publication, the key question was whether targeting oxLDL impacted human disease. Large trials of antioxidants were negative; however, it should be borne in mind that these were retrospective analyses and not prospective trials. The fundamental issue in testing this hypothesis was lack of understanding into the molecular mechanisms by which oxLDL promote foam cell formation, inflammation and the complex series of events leading to atherogenesis and its clinical sequelae (3). Subsequent studies identified the formation of phosphocholine containing oxidised phospholipids (OxPL) as one of the key mechanisms linking hypercholesterolaemia to both atherosclerosis and nonalcoholic steatohepatitis (NASH).
Oxidative damage of lipids in membranes or lipoproteins alters lipid function resulting in the formation of oxidation-specific epitopes. Notably, OxPL are ubiquitous, formed in many inflammatory tissues, including atherosclerotic lesions (4), and frequently mediate proinflammatory changes in age-related and inflammatory diseases, but are absent in healthy tissue. These oxidation-specific epitopes represent endogenous damage-associated molecular patterns (DAMPs) that are subsequently recognized by receptors in the innate immune system, to ensure maintenance of homeostasis. If, however, the system is dysfunctional, accumulation of such oxidation-specific epitopes can trigger chronic inflammation and subsequent disease.
In an experimental model (hyperlipidaemic Ldlr-/- mice), targeting OxPL reduced the manifestations of NASH, including reduction in steatosis and progression to hepatocellular carcinoma. In the same mouse model fed an AMLN-diet, there was reduction in oxidative stress, together with improvement in hepatic and adipose-tissue mitochondrial function, and fatty-acid oxidation (5). Thus, the underlying mechanisms implicated in the amelioration of NASH include improvement of mitochondrial function, metabolic function (without changing hyperlipidaemia), together with reduced inflammation, fibrogenic gene expression and hepatocyte injury and cell death. Taken together, these findings indicate that targeting OxPL counters the feed-forward cycle that promotes NASH, as well as atherogenesis, suggesting therapeutic potential in both settings.
Beyond these, there is also evidence that OxPL plays a central role in multiple chronic diseases. In addition to pro-inflammatory effects, OxPL are known to influence microcalcification pathways in valve interstitial cells. Insights into the underlying mechanisms of aortic stenosis suggest elevated lipoprotein(a)/OxPL as a potential aetiology, and provide a rationale for targeting this mediator in patients with mild-moderate aortic stenosis (6). Furthermore, there is also evidence of a role of OxPL in osteoporosis (6).
In concluding remarks, Professor Witztum noted that the insights relating to OxPL, provided by both his laboratory and other researchers, indicate a novel path for the development of therapeutic strategies to target both atherosclerosis and NASH, as well as inflammation more broadly. The oxidation hypothesis of atherosclerosis revisited provides much scope for novel therapies for the future.
- Steinberg D, et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-24.
- Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet DOI: https://doi.org/10.1016/S0140-6736(94)92346-9
- Steinberg D, Witztum JL. Oxidized low-density lipoproteins and atherosclerosis. ATVB 2010;HYY
- Shaw PX, et al. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol 2001;21:1333-1339.
- Sun X, et al. Neutralization of oxidized phospholipids ameliorates non-alcoholic steatohepatitis. Cell Metab 2020;31:189-206.
- Zheng KH, et al. Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis. J Am Coll Cardiol 2019;73:2150-2162
- Ambrogini E, et al. Oxidation-specific epitopes restrain bone formation. Nat Commun 2018;9:2193.