The High-Density Lipoprotein Puzzle Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict?
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TLDR
In this paper, the authors investigated the relationship between HDL cholesterol and the future risk of myocardial infarction and found that statin therapy interferes with ATP-binding cassette transporter-mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties.Abstract:
Classical epidemiology has established the incremental contribution of the high-density lipoprotein (HDL) cholesterol measure in the assessment of atherosclerotic cardiovascular disease risk; yet, genetic epidemiology does not support a causal relationship between HDL cholesterol and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic cardiovascular risk. However, therapeutic interventions such as niacin, cholesteryl ester transfer protein inhibitors increase HDL cholesterol in patients treated with statins, but have repeatedly failed to reduce cardiovascular events. Statin therapy interferes with ATP-binding cassette transporter-mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties. Unraveling the HDL puzzle will require continued technical advances in the characterization and quantification of multiple HDL subclasses and their functional properties. Key mechanistic criteria for clinical outcomes trials with HDL-based therapies include formation of HDL subclasses that improve the efficiency of macrophage cholesterol efflux and compositional changes in the proteome and lipidome of the HDL particle that are associated with improved antioxidant and anti-inflammatory properties. These measures require validation in genetic studies and clinical trials of HDL-based therapies on the background of statins.read more
Citations
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Interaction between adipocytes and high-density lipoprotein:new insights into the mechanism of obesity-induced dyslipidemia and atherosclerosis.
TL;DR: The cross-talk between adipocytes and HDL related to cardiovascular disease is summarized, new insights of the potential mechanism underlying obesity and HDL dysfunction are focused on and adipose tissue is targeted for the treatment of HDL metabolism in obesity.
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Polygenic determinants in extremes of high-density lipoprotein cholesterol.
Jacqueline S. Dron,Jian Wang,Cécile Low-Kam,Sumeet A. Khetarpal,John F. Robinson,Adam D. McIntyre,Matthew R. Ban,Henian Cao,David Rhainds,Marie-Pierre Dubé,Daniel J. Rader,Guillaume Lettre,Jean-Claude Tardif,Robert A. Hegele +13 more
TL;DR: The genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants.
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Genetics, Dyslipidemia, and Cardiovascular Disease: New Insights
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Lipids, Apolipoproteins, and Risk of Atherosclerotic Cardiovascular Disease in Persons With CKD.
Archna Bajaj,Dawei Xie,Esteban Cedillo-Couvert,Jeanne Charleston,Jing Chen,Rajat Deo,Harold I. Feldman,Alan S. Go,Jiang He,Edward Horwitz,Radhakrishna R. Kallem,Mahboob Rahman,Matthew R. Weir,Amanda H. Anderson,Amanda H. Anderson,Daniel J. Rader,Lawrence J. Appel,John W. Kusek,James P. Lash,Panduranga S. Rao,Raymond R. Townsend +20 more
TL;DR: The findings support future investigations into pharmacologic targeting of lipoproteins beyond LDL-C, such as triglyceride-rich lipopoteins, to reduce residual risk for ASCVD among individuals with CKD.
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Impact of Diabetes Mellitus.
TL;DR: This review highlights manuscripts published in ATVB within the past 2 years, focusing on novel pathways that might contribute to vascular complications of diabetes mellitus, which is a major healthcare problem that needs to find solutions to.
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