Complex association of apolipoprotein E-containing HDL with coronary artery disease burden in cardiovascular disease

Alexander V Sorokin, Nidhi Patel, Khaled M Abdelrahman, Clarence Ling, Mart Reimund, Giorgio Graziano, Maureen Sampson, Martin P Playford, Amit K Dey, Aarthi Reddy, Heather L Teague, Michael Stagliano, Marcelo Amar, Marcus Y Chen, Nehal N Mehta, Alan T Remaley, Alexander V Sorokin, Nidhi Patel, Khaled M Abdelrahman, Clarence Ling, Mart Reimund, Giorgio Graziano, Maureen Sampson, Martin P Playford, Amit K Dey, Aarthi Reddy, Heather L Teague, Michael Stagliano, Marcelo Amar, Marcus Y Chen, Nehal N Mehta, Alan T Remaley

Abstract

BackgroundAlthough traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed.MethodsIn a prospective, observational study, 795 individuals had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E-containing HDL-cholesterol (ApoE-HDL-C). Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiography (CCTA) characterization of total burden, noncalcified burden (NCB), and fibrous plaque burden (FB) was performed in a subcohort (n = 300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured.ResultsMost patients had a clinical diagnosis of coronary artery disease (CAD) (n = 80.4% of 795), with mean age of 59 years, a majority being male (57%), and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P < 0.001), with higher CAC as compared with high ApoE-HDL-C. On quantitative CCTA, the high ApoE-HDL-C group had lower NCB (β = -0.24, P = 0.0001), which tended to be significant in a fully adjusted model (β = -0.32, P = 0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (β = 0.31; P = 0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P = 0.0001) in a fully adjusted model.ConclusionApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity.Trial RegistrationClinicalTrials.gov: NCT01621594.FundingThis work was supported by the NHLBI at the NIH Intramural Research Program.

Keywords: Cardiology; Cardiovascular disease; Diagnostic imaging; Lipoproteins; Metabolism.

Figures

Figure 1. Results comparing logistic regression models…
Figure 1. Results comparing logistic regression models with AUC ROCs were reported.
Pearson’s χ2 test was applied for estimating P values with significance level of P < 0.05. Predicting of CAD based on CCTA plaque parameters in (A) fibrous plaque burden (P = 0.0001) and (B) necrotic burden (P = 0.01). Base model includes age, sex, current smoking, BMI, statin treatment, hsCRP, LDL-C, and TGs. Hs(CRP), high-sensitivity C-reactive protein.
Figure 2. Recruitment and follow-up scheme of…
Figure 2. Recruitment and follow-up scheme of study participants.

References

    1. Gordon DJ, Rifkind BM. High-density lipoprotein — the clinical implications of recent studies. N Engl J Med. 1989;321(19):1311–1316. doi: 10.1056/NEJM198911093211907.
    1. Pencina MJ, et al. Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study. Circulation. 2009;119(24):3078–3084. doi: 10.1161/CIRCULATIONAHA.108.816694.
    1. Acharjee S, et al. Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: a post-hoc analysis from the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) J Am Coll Cardiol. 2013;62(20):1826–1833. doi: 10.1016/j.jacc.2013.07.051.
    1. Madsen CM, et al. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017;38(32):2478–2486. doi: 10.1093/eurheartj/ehx163.
    1. Ridker PM, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet. 2010;376(9738):333–339. doi: 10.1016/S0140-6736(10)60713-1.
    1. Hamer M, et al. High-density lipoprotein cholesterol and mortality: too much of a good thing? Arterioscler Thromb Vasc Biol. 2018;38(3):669–672. doi: 10.1161/ATVBAHA.117.310587.
    1. Rohatgi A, et al. HDL in the 21st century: a multifunctional roadmap for future HDL research. Circulation. 2021;143(23):2293–2309. doi: 10.1161/CIRCULATIONAHA.120.044221.
    1. Rader DJ, et al. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res. 2009;50(suppl):S189–S194.
    1. Morton AM, et al. Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk. JCI Insight. 2018;3(4):e98045. doi: 10.1172/jci.insight.98045.
    1. Kypreos KE, Zannis VI. Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCAT. Biochem J. 2007;403(2):359–367. doi: 10.1042/BJ20061048.
    1. Mahley RW, et al. Interaction of plasma lipoproteins containing apolipoproteins B and E with heparin and cell surface receptors. Biochim Biophys Acta. 1979;575(1):81–91.
    1. Qi Y, et al. Apolipoprotein E-containing high-density lipoprotein (HDL) modifies the impact of cholesterol-overloaded HDL on incident coronary heart disease risk: a community-based cohort study. J Clin Lipidol. 2018;12(1):89–98. doi: 10.1016/j.jacl.2017.11.003.
    1. Norata GD, et al. Apolipoprotein C-III: from pathophysiology to pharmacology. Trends Pharmacol Sci. 2015;36(10):675–687. doi: 10.1016/j.tips.2015.07.001.
    1. Jensen MK, et al. High-density lipoprotein subspecies defined by presence of apolipoprotein C-III and incident coronary heart disease in four cohorts. Circulation. 2018;137(13):1364–1373. doi: 10.1161/CIRCULATIONAHA.117.031276.
    1. Kwan AC, et al. Beyond coronary stenosis: coronary computed tomographic angiography for the assessment of atherosclerotic plaque burden. Curr Cardiovasc Imaging Rep. 2013;6(2):89–101. doi: 10.1007/s12410-012-9183-z.
    1. Cho I, et al. Prognostic value of coronary computed tomographic angiography findings in asymptomatic individuals: a 6-year follow-up from the prospective multicentre international CONFIRM study. Eur Heart J. 2018;39(11):934–941. doi: 10.1093/eurheartj/ehx774.
    1. Agarwala A, et al. Abstract 12141: ApoE-HDL cholesterol predicts incident cardiovascular events: ARIC study. Circulation. 2016;134:A12141
    1. Aroner SA, et al. High-density lipoprotein subspecies defined by apolipoprotein C-III and subclinical atherosclerosis measures: MESA (The Multi-Ethnic Study of Atherosclerosis) J Am Heart Assoc. 2018;7(6):e007824. doi: 10.1161/JAHA.117.007824.
    1. Brunner FJ, et al. Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium. Lancet. 2019;394(10215):2173–2183. doi: 10.1016/S0140-6736(19)32519-X.
    1. Bowman L, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377(13):1217–1227. doi: 10.1056/NEJMoa1706444.
    1. He Y, et al. High-density lipoprotein function in cardiovascular disease and diabetes mellitus. Arterioscler Thromb Vasc Biol. 2018;38(2):e10–e16.
    1. Rohatgi A, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371(25):2383–2393. doi: 10.1056/NEJMoa1409065.
    1. Ebtehaj S, et al. HDL (high-density lipoprotein) cholesterol efflux capacity is associated with incident cardiovascular disease in the general population: a case-control study from the PREVEND cohort. Arterioscler Thromb Vasc Biol. 2019;39(9):1874–1883. doi: 10.1161/ATVBAHA.119.312645.
    1. Raffaï RL, et al. Hepatocyte-derived ApoE is more effective than non-hepatocyte-derived ApoE in remnant lipoprotein clearance. J Biol Chem. 2003;278(13):11670–11675. doi: 10.1074/jbc.M212873200.
    1. Barlage S, et al. ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response. J Lipid Res. 2001;42(2):281–290. doi: 10.1016/S0022-2275(20)31690-4.
    1. Low-Kam C, et al. Variants at the APOE/C1/C2/C4 locus modulate cholesterol efflux capacity independently of high-density lipoprotein cholesterol. J Am Heart Assoc. 2018;7(16):e009545. doi: 10.1161/JAHA.118.009545.
    1. González-Domínguez R, et al. Apolipoprotein E and sex modulate fatty acid metabolism in a prospective observational study of cognitive decline. Alzheimers Res Ther. 2022;14(1):1. doi: 10.1186/s13195-021-00948-8.
    1. Koch M, et al. Association of apolipoprotein E in lipoprotein subspecies with risk of dementia. JAMA Netw Open. 2020;3(7):e209250. doi: 10.1001/jamanetworkopen.2020.9250.
    1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143–3421. doi: 10.1161/circ.106.25.3143.
    1. Matsuura F, et al. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. J Clin Invest. 2006;116(5):1435–1442. doi: 10.1172/JCI27602.
    1. Rodriguez K, et al. Coronary plaque burden at coronary CT angiography in asymptomatic men and women. Radiology. 2015;277(1):73–80. doi: 10.1148/radiol.2015142551.
    1. Andreini D, et al. Coronary plaque features on CTA can identify patients at increased risk of cardiovascular events. JACC Cardiovasc Imaging. 2020;13(8):1704–1717. doi: 10.1016/j.jcmg.2019.06.019.
    1. Corsetti JP, et al. Apolipoprotein E predicts incident cardiovascular disease risk in women but not in men with concurrently high levels of high-density lipoprotein cholesterol and C-reactive protein. Metabolism. 2012;61(7):996–1002. doi: 10.1016/j.metabol.2011.11.010.
    1. Furtado JD, et al. Distinct proteomic signatures in 16 HDL (high-density lipoprotein) subspecies. Arterioscler Thromb Vasc Biol. 2018;38(12):2827–2842. doi: 10.1161/ATVBAHA.118.311607.
    1. Ruuth M, et al. Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Eur Heart J. 2018;39(27):2562–2573. doi: 10.1093/eurheartj/ehy319.
    1. Larsson M, et al. Apolipoproteins C-I and C-III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets. J Biol Chem. 2013;288(47):33997–34008. doi: 10.1074/jbc.M113.495366.
    1. Tornvall P, et al. Lipoprotein lipase mass and activity in plasma and their increase after heparin are separate parameters with different relations to plasma lipoproteins. Arterioscler Thromb Vasc Biol. 1995;15(8):1086–1093. doi: 10.1161/01.ATV.15.8.1086.
    1. Ramms B, Gordts P. Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol. 2018;29(3):171–179. doi: 10.1097/MOL.0000000000000502.
    1. Gordts PL, et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest. 2016;126(8):2855–2866. doi: 10.1172/JCI86610.
    1. Kohan AB. Apolipoprotein C-III: a potent modulator of hypertriglyceridemia and cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. 2015;22(2):119–125. doi: 10.1097/MED.0000000000000136.
    1. Huang Y, et al. Apolipoprotein E2 transgenic rabbits. Modulation of the type III hyperlipoproteinemic phenotype by estrogen and occurrence of spontaneous atherosclerosis. J Biol Chem. 1997;272(36):22685–22694. doi: 10.1074/jbc.272.36.22685.
    1. Koike T, et al. Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity. J Biol Chem. 2004;279(9):7521–7529. doi: 10.1074/jbc.M311514200.
    1. Peters SAE, et al. Sex differences in the prevalence of, and trends in, cardiovascular risk factors, treatment, and control in the United States, 2001 to 2016. Circulation. 2019;139(8):1025–1035. doi: 10.1161/CIRCULATIONAHA.118.035550.
    1. von Elm E, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573–577. doi: 10.7326/0003-4819-147-8-200710160-00010.
    1. Takahashi Y, et al. Development of homogeneous assay for simultaneous measurement of apoE-deficient, apoE-containing, and total HDL-cholesterol. Clin Chim Acta. 2016;454:135–142. doi: 10.1016/j.cca.2016.01.013.
    1. Freeman LA, et al. Plasma lipoprotein-X quantification on filipin-stained gels: monitoring recombinant LCAT treatment ex vivo. J Lipid Res. 2019;60(5):1050–1057. doi: 10.1194/jlr.D090233.
    1. Wolska A, et al. A dual apolipoprotein C-II mimetic-apolipoprotein C-III antagonist peptide lowers plasma triglycerides. Sci Transl Med. 2020;12(528):eaaw7905. doi: 10.1126/scitranslmed.aaw7905.
    1. Cury RC, et al. Coronary Artery Disease — Reporting and Data System (CAD-RADS): an expert consensus document of SCCT, ACR and NASCI: endorsed by the ACC. JACC Cardiovasc Imaging. 2016;9(9):1099–1113. doi: 10.1016/j.jcmg.2016.05.005.
    1. Salahuddin T, et al. Cholesterol efflux capacity in humans with psoriasis is inversely related to non-calcified burden of coronary atherosclerosis. Eur Heart J. 2015;36(39):2662–2665. doi: 10.1093/eurheartj/ehv339.
    1. Agatston AS, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15(4):827–832. doi: 10.1016/0735-1097(90)90282-T.

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