Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society

Authors: GINSBERG, HENRY - Columbia University; PACKARD, CHRIS - University Of Glasgow; CHAPMAN, M. - Institut National De La Sante Et De La Recherche Medicale (INSERM); BOREN, JAN - University Of Gothenburg; AGUILAR-SALINAS, CARLOS - National Institute Of Health Sciences And Nutrition “salvador Zubirán”; AVERNA, MAURIZIO - University Of Palermo Italy; FERENCE, BRIAN - University Of Cambridge; GAUDET, DANIEL - Chicoutimi Hospital; HEGELE, ROBERT - Western University; KERSTEN, SANDER - Wageningen University; LEWIS, GARY - University Of Toronto; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MOULIN, PHILIPPE - Hospices Civils De Lyon; NORDESTGAARD, BORGE - Rigshospitalet - Copenhagen University Hospital; REMELEY, ALAN - National Institutes Of Health (NIH); STAELS, BART - Universite De Lille; STROES, ERIK - Academic Medical Center; TASKINEN, MARJA-RIITTA - University Of Helsinki; TOKGOZOGLU, LALE - Hacettepe University, Turkey; TYBJAERG-HANSEN, ANNE - University Of Copenhagen; STOCK, JANE - European Atherosclerosis Society (EAS); CATAPANO, ALBERICO - Dipartimento Di Agraria, Universita Degli Studi Di Sassari

Submitted to: European Heart Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/30/2021
Publication Date: 9/2/2021
Citation: Ginsberg, H.N., Packard, C., Chapman, M.J., Boren, J., Aguilar-Salinas, C.A., Averna, M., Ference, B.A., Gaudet, D., Hegele, R.A., Kersten, S., Lewis, G.F., Lichtenstein, A.H., Moulin, P., Nordestgaard, B.G., Remeley, A.T., Staels, B., Stroes, E.S., Taskinen, M., Tokgozoglu, L.S., Tybjaerg-Hansen, A., Stock, J.K., Catapano, A.L. 2021. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. European Heart Journal. 42(47):4791-4806. https://doi.org/10.1093/eurheartj/ehab551.
DOI: https://doi.org/10.1093/eurheartj/ehab551

Interpretive Summary: Concentrations of plasma triglyceride, and triglyceride-rich lipoproteins and their remnants, are positively associated with cardiovascular disease including heart attacks, strokes and other heart problems. This report from the European Atherosclerosis Society Panel on Triglycerides critically appraises the current understanding of the structure, function and metabolism of triglyceride-rich lipoprotein particles, and influence of lifestyle modification, primarily diet. Key points addressed include a consensus definition of normo- and hyper- triglyceridemic states and their relation to cardiovascular disease risk, conceptual framework for the generation and metabolism of triglyceride-rich lipoprotein particles, compilation of dietary factors associated with plasma triglyceride and triglyceride-rich lipoprotein concentrations, comparison of triglyceride-rich lipoprotein and the major carrier of cholesterol in plasma, low density lipoprotein, in terms of cardiovascular disease risk, and mechanistic strategies for lowering TRL and remnants to reduce cardiovascular risk.

Technical Abstract: Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.