The Changing Face of Atherosclerosis

Anna Meiliana, Andi Wijaya


BACKGROUND: Statins have been used for around three decades as the primary way to lower cholesterol and reduce the risk of atherosclerosis, but in some groups, statin resistance is common, and the danger of atherosclerosis is still high.

CONTENT: Atherosclerosis was once believed to be caused by cholesterol and thrombotic material passively accumulating in the walls of arteries. However, current knowledge shows that the immune cells and inflammatory processes are essential in the formation, progression, and consequences of atherosclerotic lesions, characterized by a persistent inflammatory response, including thrombotic complications. Study of genetic, creating risk score for atherosclerosis, add more information to create more new therapies targeting low density lipoprotein cholesterol (LDL-C) receptor, and shows prospect.

SUMMARY: Over time, atherosclerosis theories and treatment strategies have changed. While statins were widely used, they have now been supplanted by alternative options like the proprotein convertase subtilisin/kexin type 9 (PSCK9) inhibitor that manage atherosclerosis more effectively and comprehensive.

KEYWORDS: atherosclerosis, cholesterol, inflammation, immune system, metabolism

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Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics — 2016 update: A report from the American Heart Association. Circulation. 2016; 133(4): e38–360, CrossRef.

Shapiro MD, Fazio S. From lipids to inflammation: New approaches to reducing atherosclerotic risk. Circ Res. 2016; 118(4): 732–49, CrossRef.

Brown MS, Goldstein JL. Heart attacks: Gone with the century? Science. 1996; 272(5262): 629, CrossRef.

Björkegren JLM, Lusis AJ. Atherosclerosis: Recent developments. Cell. 2022; 185(10): 1630–45, CrossRef.

Libby P. The changing landscape of atherosclerosis. Nature. 2021; 592(7855): 524–33, CrossRef.

Libby P, Hansson GK. From focal lipid storage to systemic inflammation. J Am Coll Cardiol. 2019; 74(12): 1594–607, CrossRef.

Hansen SEJ, Madsen CM, Varbo A, Nordestgaard BG. Low-grade inflammation in the association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis: A study of more than 115000 individuals from the general population. Clin Chem. 2019; 65(2): 321–32, CrossRef.

Xiao L, Harrison DG. Inflammation in hypertension. Can J Cardiol. 2020; 36(5): 635–47, CrossRef.

Ridker PM, Koenig W, Kastelein JJ, Mach F, Lüscher TF. Has the time finally come to measure hsCRP universally in primary and secondary cardiovascular prevention? Eur Heart J. 2018; 39(46): 4109–11, CrossRef.

Ridker PM. A test in context: High-sensitivity C-reactive protein. J Am Coll Cardiol. 2016; 67(6): 712–23, CrossRef.

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med. 2017; 377(12): 1119–31, CrossRef.

Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: Update and therapeutic implications. Circulation. 2007; 116(16): 1832–44, CrossRef.

Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995; 15(5): 551–61, CrossRef.

Borén J, Olin K, Lee I, Chait A, Wight TN, Innerarity TL. Identification of the principal proteoglycan-binding site in LDL-C. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL-C receptor binding. J Clin Invest. 1998; 101(12): 2658–64, CrossRef.

Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999; 340(2): 115–26, CrossRef.

van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med. 1968; 128(3): 415–35, CrossRef.

Lutgens E, de Muinck ED, Kitslaar PJ, Tordoir JH, Wellens HJ, Daemen MJ. Biphasic pattern of cell turnover characterizes the progression from fatty streaks to ruptured human atherosclerotic plaques. Cardiovasc Res. 1999; 41(2): 473–9, CrossRef.

Zhu SN, Chen M, Jongstra-Bilen J, Cybulsky MI. GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. J Exp Med. 2009; 206(10): 2141–9, CrossRef.

Llodrá J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci USA. 2004; 101(32): 11779–84, CrossRef.

van Gils JM, Ramkhelawon B, Fernandes L, Stewart MC, Guo L, Seibert T, et al. Endothelial expression of guidance cues in vessel wall homeostasis dysregulation under proatherosclerotic conditions. Arterioscler Thromb Vasc Biol. 2013; 33(5): 911–9, CrossRef.

Angeli V, Llodrá J, Rong JX, Satoh K, Ishii S, Shimizu T, et al. Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. Immunity. 2004; 21(4): 561–74, CrossRef.

Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL-C and may contribute to macrophage trapping in the arterial intima. J Clin Invest. 2009; 119(1): 136–45, CrossRef.

Wu C, Hussein MA, Shrestha E, Leone S, Aiyegbo MS, Lambert WM, et al. Modulation of macrophage gene expression via liver X receptor α serine 198 phosphorylation. Mol Cell Biol. 2015; 35(11): 2024–34, CrossRef.

Cybulsky MI, Cheong C, Robbins CS. Macrophages and dendritic cells: Partners in atherogenesis. Circ Res. 2016; 118(4): 637–52, CrossRef.

Scheiermann C, Kunisaki Y, Frenette PS. Circadian control of the immune system. Nat Rev Immunol. 2013; 13(3): 190–8, CrossRef.

Scheiermann C, Kunisaki Y, Lucas D, Chow A, Jang JE, Zhang D, et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity. 2012; 37(2): 290–301, CrossRef.

Schloss MJ, Horckmans M, Nitz K, Duchene J, Drechsler M, Bidzhekov K, et al. The time‐of‐day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment. EMBO Mol Med. 2016; 8(8): 937–48, CrossRef.

Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007; 117(1): 195–205, CrossRef.

Nguyen KD, Fentress SJ, Qiu Y, Yun K, Cox JS, Chawla A. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C hi inflammatory monocytes. Science. 2013; 341(6153): 1483–8, CrossRef.

Steffens S, Winter C, Schloss MJ, Hidalgo A, Weber C, Soehnlein O. Circadian control of inflammatory processes in atherosclerosis and its complications. Arterioscler Thromb Vasc Biol. 2017; 37(6): 1022–8, CrossRef.

Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007; 117(1): 185–94, CrossRef.

Gerhardt T, Ley K. Monocyte trafficking across the vessel wall. Cardiovasc Res. 2015; 107(3): 321–30, CrossRef.

Randolph GJ. Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res. 2014; 114(11): 1757–71, CrossRef.

Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: A dynamic balance. Nat Rev Immunol. 2013; 13(10): 709–21, CrossRef.

Moore KJ, Kunjathoor VV, Koehn SL, Manning JJ, Tseng AA, Silver JM, et al. Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J Clin Invest. 2005; 115(8): 2192–201, CrossRef.

Manning-Tobin JJ, Moore KJ, Seimon TA, Bell SA, Sharuk M, Alvarez-Leite JI, et al. Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler Thromb Vasc Biol. 2009; 29(1): 19–26, CrossRef.

Ricci R, Sumara G, Sumara I, Rozenberg I, Kurrer M, Akhmedov A, et al. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science. 2004; 306(5701): 1558–61, CrossRef.

Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2010; 10(1): 36–46, CrossRef.

Tawakol A, Singh P, Mojena M, Pimentel-Santillana M, Emami H, MacNabb M, et al. HIF-1α and PFKFB3 mediate a tight relationship between proinflammatory activation and anerobic metabolism in atherosclerotic macrophages. Arterioscler Thromb Vasc Biol. 2015; 35(6): 1463–71, CrossRef.

Nishizawa T, Kanter JE, Kramer F, Barnhart S, Shen X, Vivekanandan-Giri A, et al. Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis. Cell Rep. 2014; 7(2): 356–65, CrossRef.

Tabas I, Bornfeldt KE. Macrophage phenotype and function in different stages of atherosclerosis. Circ Res. 2016; 118(4): 653–67, CrossRef.

Hackett D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction. Value of combined thrombolytic and vasodilator therapy. N Engl J Med. 1987; 317(17): 1055–9, CrossRef.

Pristipino C, Beltrame JF, Finocchiaro ML, Hattori R, Fujita M, Mongiardo R, et al. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation. 2000; 101(10): 1102–8, CrossRef.

Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105(9): 1135–43, CrossRef.

Pease DC, Paule WJ. Electron microscopy of elastic arteries; the thoracic aorta of the rat. J Ultrastruct Res. 1960; 3: 469–83, CrossRef.

Imai H, Lee KT, Pastori S, Panlilio E, Florentin R, Thomas WA. Atherosclerosis in rabbits. Architectural and subcellular alterations of smooth muscle cells of aortas in response to hyperlipemia. Exp Mol Pathol. 1966; 5(3): 273–310, CrossRef.

Clarke MCH, Littlewood TD, Figg N, Maguire JJ, Davenport AP, Goddard M, et al. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ Res. 2008; 102(12): 1529–38, CrossRef.

Lee SH, Hungerford JE, Little CD, Iruela-Arispe ML. Proliferation and differentiation of smooth muscle cell precursors occurs simultaneously during the development of the vessel wall. Dev Dyn Off Publ Am Assoc Anat. 1997; 209(4): 342–52, PMID.

Poole JC, Cromwell SB, Benditt EP. Behavior of smooth muscle cells and formation of extracellular structures in the reaction of arterial walls to injury. Am J Pathol. 1971; 62(3): 391–414, PMID.

Grootaert MO, da Costa Martins PA, Bitsch N, Pintelon I, De Meyer GR, Martinet W, et al. Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis. Autophagy. 2015; 11(11): 2014–32, CrossRef.

Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, et al. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: Effects of telomerase and oxidative stress. Circ Res. 2006; 99(2): 156–64, CrossRef.

Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLOS Biol. 2008; 6(12): e301, CrossRef.

Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011; 479(7374): 547–51, CrossRef.

Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016; 354(6311): 472–7, CrossRef.

Basatemur GL, Jørgensen HF, Clarke MCH, Bennett MR, Mallat Z. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol. 2019; 16(12): 727–44, CrossRef.

Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: Role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 1993; 69(5): 377–81, CrossRef.

O’Brien ER, Alpers CE, Stewart DK, Ferguson M, Tran N, Gordon D, et al. Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy. Circ Res. 1993; 73(2): 223–31, CrossRef.

Geng YJ, Libby P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme. Am J Pathol. 1995; 147(2): 251–66, PMID.

Isner JM, Kearney M, Bortman S, Passeri J. Apoptosis in human atherosclerosis and restenosis. Circulation. 1995; 91(11): 2703–11, CrossRef.

Bauriedel G, Hutter R, Welsch U, Bach R, Sievert H, Lüderitz B. Role of smooth muscle cell death in advanced coronary primary lesions: Implications for plaque instability. Cardiovasc Res. 1999; 41(2): 480–8, CrossRef.

Clarke MCH, Figg N, Maguire JJ, Davenport AP, Goddard M, Littlewood TD, et al. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med. 2006; 12(9): 1075–80, CrossRef.

Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest. 1995; 95(5): 2266–74, CrossRef.

Patel VA, Zhang QJ, Siddle K, Soos MA, Goddard M, Weissberg PL, et al. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling. Circ Res. 2001; 88(9): 895–902, CrossRef.

Lyon CA, Johnson JL, Williams H, Sala-Newby GB, George SJ. Soluble N-cadherin overexpression reduces features of atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol. 2009; 29(2): 195–201, CrossRef.

Roy P, Orecchioni M, Ley K. How the immune system shapes atherosclerosis: Roles of innate and adaptive immunity. Nat Rev Immunol. 2022; 22(4): 251–65, CrossRef.

Ketelhuth DFJ, Lutgens E, Bäck M, Binder CJ, Van den Bossche J, Daniel C, et al. Immunometabolism and atherosclerosis: Perspectives and clinical significance: A position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology. Cardiovasc Res. 2019; 115(9): 1385–92, CrossRef.

Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019; 381(26): 2497–505, CrossRef.

Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med. 2006; 354(19): 2034–45, CrossRef.

Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014; 505(7483): 327–34, CrossRef.

Pinho S, Frenette PS. Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol. 2019; 20(5): 303–20, CrossRef.

Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013; 339(6116): 161–6, CrossRef.

Roufaiel M, Gracey E, Siu A, Zhu SN, Lau A, Ibrahim H, et al. CCL19-CCR7-dependent reverse transendothelial migration of myeloid cells clears Chlamydia muridarum from the arterial intima. Nat Immunol. 2016; 17(11): 1263–72, CrossRef.

Choi JH, Do Y, Cheong C, Koh H, Boscardin SB, Oh YS, et al. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J Exp Med. 2009; 206(3): 497–505, CrossRef.

Lim HY, Lim SY, Tan CK, Thiam CH, Goh CC, Carbajo D, et al. Hyaluronan receptor LYVE-1-expressing macrophages maintain arterial tone through hyaluronan-mediated regulation of smooth muscle cell collagen. Immunity. 2018; 49(2): 326-341.e7, CrossRef.

Dutta P, Sager HB, Stengel KR, Naxerova K, Courties G, Saez B, et al. Myocardial infarction activates CCR2(+) hematopoietic stem and progenitor cells. Cell Stem Cell. 2015; 16(5): 477–87, CrossRef.

Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy JA. Leukocytes and the risk of ischemic diseases. JAMA. 1987; 257(17): 2318–24, CrossRef.

Madjid M, Awan I, Willerson JT, Casscells SW. Leukocyte count and coronary heart disease: Implications for risk assessment. J Am Coll Cardiol. 2004; 44(10): 1945–56, CrossRef.

Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, del Zoppo GJ. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol. 1994; 144(1): 188–99, PMID.

Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009; 40(5): 1849–57, CrossRef.

Potteaux S, Gautier EL, Hutchison SB, van Rooijen N, Rader DJ, Thomas MJ, et al. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression. J Clin Invest. 2011; 121(5): 2025–36, CrossRef.

Drechsler M, de Jong R, Rossaint J, Viola JR, Leoni G, Wang JM, et al. Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ Res. 2015; 116(5): 827–35, CrossRef.

Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: From mice to humans. Immunity. 2013; 38(6): 1092–104, CrossRef.

King KR, Aguirre AD, Ye YX, Sun Y, Roh JD, Ng RP, et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat Med. 2017; 23(12): 1481–7, CrossRef.

Lin JD, Nishi H, Poles J, Niu X, Mccauley C, Rahman K, et al. Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression. JCI Insight. 2019; 4(4): e124574, CrossRef.

Cochain C, Vafadarnejad E, Arampatzi P, Pelisek J, Winkels H, Ley K, et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ Res. 2018; 122(12): 1661–74, CrossRef.

Zernecke A. Dendritic cells in atherosclerosis: Evidence in mice and humans. Arterioscler Thromb Vasc Biol. 2015; 35(4): 763–70, CrossRef.

Choi JH, Cheong C, Dandamudi DB, Park CG, Rodriguez A, Mehandru S, et al. Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity. 2011; 35(5): 819–31, CrossRef.

Sage AP, Tsiantoulas D, Binder CJ, Mallat Z. The role of B cells in atherosclerosis. Nat Rev Cardiol. 2019; 16(3): 180–96, CrossRef.

Butcher MJ, Wu CI, Waseem T, Galkina EV. CXCR6 regulates the recruitment of pro-inflammatory IL-17A-producing T cells into atherosclerotic aortas. Int Immunol. 2016; 28(5): 255–61, CrossRef.

Winkels H, Ehinger E, Vassallo M, Buscher K, Dinh HQ, Kobiyama K, et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ Res. 2018; 122(12): 1675–88, CrossRef.

Li J, McArdle S, Gholami A, Kimura T, Wolf D, Gerhardt T, et al. CCR5+T-bet+FoxP3+ effector CD4 T cells drive atherosclerosis. Circ Res. 2016; 118(10): 1540–52, CrossRef.

Cole JE, Park I, Ahern DJ, Kassiteridi C, Danso Abeam D, Goddard ME, et al. Immune cell census in murine atherosclerosis: Cytometry by time of flight illuminates vascular myeloid cell diversity. Cardiovasc Res. 2018; 114(10): 1360–71, CrossRef.

O’Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016; 16(9): 553–65, CrossRef.

Raud B, Roy DG, Divakaruni AS, Tarasenko TN, Franke R, Ma EH, et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab. 2018; 28(3): 504-515.e7, CrossRef.

Sarrazy V, Viaud M, Westerterp M, Ivanov S, Giorgetti-Peraldi S, Guinamard R, et al. Disruption of Glut1 in hematopoietic stem cells prevents myelopoiesis and enhanced glucose flux in atheromatous plaques of ApoE(-/-) mice. Circ Res. 2016; 118(7): 1062–77, CrossRef.

Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE, et al. Glucose-6-phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E(-/-) mice. Arterioscler Thromb Vasc Biol. 2006; 26(4): 910–6, CrossRef.

Polyzos KA, Ovchinnikova O, Berg M, Baumgartner R, Agardh H, Pirault J, et al. Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice. Cardiovasc Res. 2015; 106(2): 295–302, CrossRef.

Cole JE, Astola N, Cribbs AP, Goddard ME, Park I, Green P, et al. Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development. Proc Natl Acad Sci USA. 2015; 112(42): 13033–8, CrossRef.

Forteza MJ, Polyzos KA, Baumgartner R, Suur BE, Mussbacher M, Johansson DK, et al. Activation of the regulatory T-cell/indoleamine 2,3-dioxygenase axis reduces vascular inflammation and atherosclerosis in hyperlipidemic mice. Front Immunol. 2018; 9: 950, CrossRef.

Fatkhullina AR, Peshkova IO, Dzutsev A, Aghayev T, McCulloch JA, Thovarai V, et al. An interleukin-23-interleukin-22 axis regulates intestinal microbial homeostasis to protect from diet-induced atherosclerosis. Immunity. 2018; 49(5): 943-957.e9, CrossRef.

Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014; 510(7503): 92–101, CrossRef.

Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN. Vagus nerve controls resolution and pro-resolving mediators of inflammation. J Exp Med. 2014; 211(6): 1037–48, CrossRef.

Bäck M, Yurdagul A, Tabas I, Öörni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: Mediators and therapeutic opportunities. Nat Rev Cardiol. 2019; 16(7): 389–406, CrossRef.

Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O’Neill LAJ, et al. Resolution of inflammation: State of the art, definitions and terms. FASEB J Off Publ Fed Am Soc Exp Biol. 2007; 21(2): 325–32, CrossRef.

Serhan CN. Novel lipid mediators and resolution mechanisms in acute inflammation: To resolve or not? Am J Pathol. 2010; 177(4): 1576–91, CrossRef.

Perretti M, D’Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol. 2009; 9(1): 62–70, CrossRef.

Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: Challenges and opportunities. Science. 2013; 339(6116): 166–72, CrossRef.

Kojima Y, Weissman IL, Leeper NJ. The role of efferocytosis in atherosclerosis. Circulation. 2017; 135(5): 476–89, CrossRef.

Thul S, Labat C, Temmar M, Benetos A, Bäck M. Low salivary resolvin D1 to leukotriene B4 ratio predicts carotid intima media thickness: A novel biomarker of non-resolving vascular inflammation. Eur J Prev Cardiol. 2017; 24(9): 903–6, CrossRef.

Li X, Ballantyne LL, Che X, Mewburn JD, Kang JX, Barkley RM, et al. Endogenously generated omega-3 fatty acids attenuate vascular inflammation and neointimal hyperplasia by interaction with free fatty acid receptor 4 in mice. J Am Heart Assoc. 2015; 4(4): e001856, CrossRef.

Breitzig M, Bhimineni C, Lockey R, Kolliputi N. 4-Hydroxy-2-nonenal: A critical target in oxidative stress? Am J Physiol Cell Physiol. 2016; 311(4): C537–43, CrossRef.

Lehti S, Nguyen SD, Belevich I, Vihinen H, Heikkilä HM, Soliymani R, et al. Extracellular lipids accumulate in human carotid arteries as distinct three-dimensional structures and have proinflammatory properties. Am J Pathol. 2018; 188(2): 525–38, CrossRef.

Westerterp M, Gautier EL, Ganda A, Molusky MM, Wang W, Fotakis P, et al. Cholesterol accumulation in dendritic cells links the inflammasome to acquired immunity. Cell Metab. 2017; 25(6): 1294–304.e6, CrossRef.

Rajamäki K, Mäyränpää MI, Risco A, Tuimala J, Nurmi K, Cuenda A, et al. p38δ MAPK: A novel regulator of NLRP3 inflammasome activation with increased expression in coronary atherogenesis. Arterioscler Thromb Vasc Biol. 2016; 36(9): 1937–46, CrossRef.

van der Heijden T, Kritikou E, Venema W, van Duijn J, van Santbrink PJ, Slütter B, et al. NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein e-deficient mice-brief report. Arterioscler Thromb Vasc Biol. 2017; 37(8): 1457–61, CrossRef.

Patel MN, Carroll RG, Galván-Peña S, Mills EL, Olden R, Triantafilou M, et al. Inflammasome priming in sterile inflammatory disease. Trends Mol Med. 2017; 23(2): 165–80, CrossRef.

He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016; 41(12): 1012–21, CrossRef.

Kozarov EV, Dorn BR, Shelburne CE, Dunn WA, Progulske-Fox A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol. 2005; 25(3): e17–18, CrossRef.

Caesar R, Fåk F, Bäckhed F. Effects of gut microbiota on obesity and atherosclerosis via modulation of inflammation and lipid metabolism. J Intern Med. 2010; 268(4): 320–8, CrossRef.

Dichlberger A, Kovanen PT, Schneider WJ. Mast cells: From lipid droplets to lipid mediators. Clin Sci. 2013; 125(3): 121–30, CrossRef.

Werz O, Klemm J, Samuelsson B, Rådmark O. 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. Proc Natl Acad Sci USA. 2000; 97(10): 5261–6, CrossRef.

Fredman G, Ozcan L, Spolitu S, Hellmann J, Spite M, Backs J, et al. Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B4 synthesis by inhibiting a calcium-activated kinase pathway. Proc Natl Acad Sci USA. 2014; 111(40): 14530–5, CrossRef.

Cai B, Thorp EB, Doran AC, Subramanian M, Sansbury BE, Lin CS, et al. MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc Natl Acad Sci USA. 2016; 113(23): 6526–31, CrossRef.

Cai B, Kasikara C, Doran AC, Ramakrishnan R, Birge RB, Tabas I. MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci Signal. 2018; 11(549): eaar3721, CrossRef.

Lopategi A, Flores-Costa R, Rius B, López-Vicario C, Alcaraz-Quiles J, Titos E, et al. Frontline science: Specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J Leukoc Biol. 2019; 105(1): 25–36, CrossRef.

Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, et al. Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7. Br J Pharmacol. 2014; 171(15): 3551–74, CrossRef.

Winkels H, Ehinger E, Ghosheh Y, Wolf D, Ley K. Atherosclerosis in the single-cell era. Curr Opin Lipidol. 2018; 29(5): 389–96, CrossRef.

Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8(12): 958–69, CrossRef.

Italiani P, Boraschi D. From monocytes to M1/M2 macrophages: Phenotypical vs. functional differentiation. Front Immunol. 2014; 5: 514, CrossRef.

Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, Sebti Y, et al. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ Res. 2011; 108(8): 985–95, CrossRef.

Herová M, Schmid M, Gemperle C, Hersberger M. ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages. J Immunol. 2015; 194(5): 2330–7, CrossRef.

Fredman G, Kamaly N, Spolitu S, Milton J, Ghorpade D, Chiasson R, et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci Transl Med. 2015; 7(275): 275ra20, CrossRef.

Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol. 2015; 16(9): 907–17, CrossRef.

Yurdagul A, Doran AC, Cai B, Fredman G, Tabas IA. Mechanisms and consequences of defective efferocytosis in atherosclerosis. Front Cardiovasc Med. 2018; 4: 86, CrossRef.

Kawano M, Nagata S. Efferocytosis and autoimmune disease. Int Immunol. 2018; 30(12): 551–8, CrossRef.

Szondy Z, Garabuczi E, Joós G, Tsay GJ, Sarang Z. Impaired clearance of apoptotic cells in chronic inflammatory diseases: therapeutic implications. Front Immunol. 2014; 5: 354, CrossRef.

Elliott MR, Ravichandran KS. The dynamics of apoptotic cell clearance. Dev Cell. 2016; 38(2): 147–60, CrossRef.

Campana L, Starkey Lewis PJ, Pellicoro A, Aucott RL, Man J, O’Duibhir E, et al. The STAT3-IL-10-IL-6 pathway is a novel regulator of macrophage efferocytosis and phenotypic conversion in sterile liver injury. J Immunol Baltim Md 1950. 2018; 200(3): 1169–87, CrossRef.

Proto JD, Doran AC, Gusarova G, Yurdagul A, Sozen E, Subramanian M, et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity. 2018; 49(4): 666–677.e6, CrossRef.

Cardilo-Reis L, Gruber S, Schreier SM, Drechsler M, Papac-Milicevic N, Weber C, et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med. 2012; 4(10): 1072–86, CrossRef.

Thorp E, Tabas I. Mechanisms and consequences of efferocytosis in advanced atherosclerosis. J Leukoc Biol. 2009; 86(5): 1089–95, CrossRef.

Tajbakhsh A, Rezaee M, Kovanen PT, Sahebkar A. Efferocytosis in atherosclerotic lesions: Malfunctioning regulatory pathways and control mechanisms. Pharmacol Ther. 2018; 188: 12–25, CrossRef.

Tait SWG, Ichim G, Green DR. Die another way--non-apoptotic mechanisms of cell death. J Cell Sci. 2014; 127(Pt 10): 2135–44, CrossRef.

Karunakaran D, Geoffrion M, Wei L, Gan W, Richards L, Shangari P, et al. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci Adv. 2016; 2(7): e1600224, CrossRef.

Greenberg S, Grinstein S. Phagocytosis and innate immunity. Curr Opin Immunol. 2002; 14(1): 136–45, CrossRef.

Dalli J, Serhan C. Macrophage proresolving mediators-the when and where. Microbiol Spectr. 2016;4(3): 0001-2014, CrossRef.

Schif-Zuck S, Gross N, Assi S, Rostoker R, Serhan CN, Ariel A. Saturated-efferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids. Eur J Immunol. 2011; 41(2): 366–79, CrossRef.

Kavurma MM, Rayner KJ, Karunakaran D. The walking dead: macrophage inflammation and death in atherosclerosis. Curr Opin Lipidol. 2017; 28(2): 91–8, CrossRef.

Das G, Shravage BV, Baehrecke EH. Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb Perspect Biol. 2012 ; 4(6): a008813, CrossRef.

Ouimet M, Franklin V, Mak E, Liao X, Tabas I, Marcel YL. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 2011; 13(6): 655–67, CrossRef.

Otsuka F, Kramer MCA, Woudstra P, Yahagi K, Ladich E, Finn AV, et al. Natural progression of atherosclerosis from pathologic intimal thickening to late fibroatheroma in human coronary arteries: A pathology study. Atherosclerosis. 2015; 241(2): 772–82, CrossRef.

Schrijvers DM, De Meyer GRY, Kockx MM, Herman AG, Martinet W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol. 2005; 25(6): 1256–61, CrossRef.

Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352(16): 1685–95, CrossRef.

Tsai RK, Discher DE. Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J Cell Biol. 2008; 180(5): 989–1003, CrossRef.

Kojima Y, Volkmer JP, McKenna K, Civelek M, Lusis AJ, Miller CL, et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature. 2016; 536(7614): 86–90, CrossRef.

Kojima Y, Downing K, Kundu R, Miller C, Dewey F, Lancero H, et al. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis. J Clin Invest. 2019; 124(3): 1083–97, CrossRef.

Gillotte-Taylor K, Boullier A, Witztum JL, Steinberg D, Quehenberger O. Scavenger receptor class B type I as a receptor for oxidized low density lipoprotein. J Lipid Res. 2001; 42(9): 1474–82, CrossRef.

Chang MK, Bergmark C, Laurila A, Hörkkö S, Han KH, Friedman P, et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: Evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci. 1999; 96(11): 6353–8, CrossRef.

Shaw PX, Hörkkö S, Tsimikas S, Chang MK, Palinski W, Silverman GJ, et al. Human-derived anti-oxidized LDL-C autoantibody blocks uptake of oxidized LDL-C by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol. 2001; 21(8): 1333–9, CrossRef.

Bae YS, Lee JH, Choi SH, Kim S, Almazan F, Witztum JL, et al. Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein. Circ Res. 2009; 104(2): 210–8, CrossRef.

Miller YI, Viriyakosol S, Binder CJ, Feramisco JR, Kirkland TN, Witztum JL. Minimally modified LDL-C binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J Biol Chem. 2003; 278(3): 1561–8, CrossRef.

Thorp E, Subramanian M, Tabas I. The role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis. Eur J Immunol. 2011; 41(9): 2515–8, CrossRef.

Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000; 407(6805): 784–8, CrossRef.

Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL-C cholesterol reduction with statins: The evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep. 2012; 14(1): 1–10, CrossRef.

Cai B, Thorp EB, Doran AC, Sansbury BE, Daemen MJAP, Dorweiler B, et al. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest. 2017; 127(2): 564–8, CrossRef.

Fredman G, Hellmann J, Proto JD, Kuriakose G, Colas RA, Dorweiler B, et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun. 2016; 7: 12859, CrossRef.

Sugimoto MA, Ribeiro ALC, Costa BRC, Vago JP, Lima KM, Carneiro FS, et al. Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1. Blood. 2017; 129(21): 2896–907, CrossRef.

Tang WHW, Hazen SL. The gut microbiome and its role in cardiovascular diseases. Circulation. 2017; 135(11): 1008–10, CrossRef.

Cerf-Bensussan N, Gaboriau-Routhiau V. The immune system and the gut microbiota: friends or foes? Nat Rev Immunol. 2010; 10(10): 735–44, CrossRef.

Ohira H, Tsutsui W, Fujioka Y. Are short chain fatty acids in gut microbiota defensive players for inflammation and atherosclerosis? J Atheroscler Thromb. 2017; 24(7): 660–72, CrossRef.

Tang TWH, Chen HC, Chen CY, Yen CYT, Lin CJ, Prajnamitra RP, et al. Loss of gut microbiota alters immune system composition and cripples postinfarction cardiac repair. Circulation. 2019; 139(5): 647–59, CrossRef.

Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease. J Am Coll Cardiol. 2019; 73(16): 2089–105, CrossRef.

Vinkhuyzen AAE, Wray NR, Yang J, Goddard ME, Visscher PM. Estimation and partition of heritability in human populations using whole-genome analysis methods. Annu Rev Genet. 2013; 47: 75–95, CrossRef.

Lloyd-Jones DM, Nam BH, D’Agostino RB, Levy D, Murabito JM, Wang TJ, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA. 2004; 291(18): 2204–11, CrossRef.

Zdravkovic S, Wienke A, Pedersen NL, Marenberg ME, Yashin AI, De Faire U. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J Intern Med. 2002; 252(3): 247–54, CrossRef.

Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet. 2011; 43(4): 333–8, CrossRef.

McPherson R. A gene-centric approach to elucidating cardiovascular risk. Circ Cardiovasc Genet. 2009; 2(1): 3–6, CrossRef.

Shah S, Casas JP, Drenos F, Whittaker J, Deanfield J, Swerdlow DI, et al. Causal relevance of blood lipid fractions in the development of carotid atherosclerosis: Mendelian randomization analysis. Circ Cardiovasc Genet. 2013; 6(1): 63–72, CrossRef.

Brautbar A, Ballantyne CM, Lawson K, Nambi V, Chambless L, Folsom AR, et al. Impact of adding a single allele in the 9p21 locus to traditional risk factors on reclassification of coronary heart disease risk and implications for lipid-modifying therapy in the atherosclerosis risk in communities study. Circ Cardiovasc Genet. 2009; 2(3): 279–85, CrossRef.

Ripatti S, Tikkanen E, Orho-Melander M, Havulinna AS, Silander K, Sharma A, et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet Lond Engl. 2010; 376(9750): 1393–400, CrossRef.

Ganna A, Magnusson PKE, Pedersen NL, de Faire U, Reilly M, Ärnlöv J, et al. Multilocus genetic risk scores for coronary heart disease prediction. Arterioscler Thromb Vasc Biol. 2013; 33(9): 2267–72, CrossRef.

Tikkanen E, Havulinna AS, Palotie A, Salomaa V, Ripatti S. Genetic risk prediction and a 2-stage risk screening strategy for coronary heart disease. Arterioscler Thromb Vasc Biol. 2013; 33(9): 2261–6, CrossRef.

Herapath CEK, Perry CB. The coronary arteries in a case of familial liability to sudden death. Br Med J. 1930; 1(3614): 685–7, CrossRef.

Gertler MM. Young candidates for coronary heart disease. J Am Med Assoc. 1951; 147(7): 621–5, CrossRef.

Thomas C, Cohen B. The familial occurrence of hypertension and coronary artery disease, with observations concerning obesity and diabetes. Ann Intern Med. 1955; 42(1): 90–127, CrossRef.

White PD. Genes, the heart and destiny. N Engl J Med. 1957; 256(21): 965–9, CrossRef.

Nora JJ, Lortscher RH, Spangler RD, Nora AH, Kimberling WJ. Genetic--epidemiologic study of early-onset ischemic heart disease. Circulation. 1980; 61(3): 503–8, CrossRef.

Erdmann J, Kessler T, Munoz Venegas L, Schunkert H. A decade of genome-wide association studies for coronary artery disease: the challenges ahead. Cardiovasc Res. 2018; 114(9): 1241–57, CrossRef.

Paynter NP, Ridker PM, Chasman DI. Are genetic tests for atherosclerosis ready for routine clinical use? Circ Res. 2016 Feb 19; 118(4): 607–19, CrossRef.

Aragam KG, Natarajan P. Polygenic scores to assess atherosclerotic cardiovascular disease risk: Clinical perspectives and basic implications. Circ Res. 2020; 126(9): 1159–77, CrossRef.

Christensen KD, Vassy JL, Jamal L, Lehmann LS, Slashinski MJ, Perry DL, et al. Are physicians prepared for whole genome sequencing? a qualitative analysis. Clin Genet. 2016; 89(2): 228–34, CrossRef.

Seeger T, Porteus M, Wu JC. Genome editing in cardiovascular biology. Circ Res. 2017; 120(5): 778–80, CrossRef.

Jaé N, Dimmeler S. Noncoding RNAs in vascular diseases. Circ Res. 2020; 126(9): 1127–45, CrossRef.

Feinberg MW, Moore KJ. MicroRNA regulation of atherosclerosis. Circ Res. 2016; 118(4): 703–20, CrossRef.

Goedeke L, Rotllan N, Canfrán-Duque A, Aranda JF, Ramírez CM, Araldi E, et al. MicroRNA-148a regulates LDL-C receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med. 2015; 21(11): 1280–9, CrossRef.

Wagschal A, Najafi-Shoushtari SH, Wang L, Goedeke L, Sinha S, deLemos AS, et al. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat Med. 2015; 21(11): 1290–7, CrossRef.

Gerin I, Clerbaux LA, Haumont O, Lanthier N, Das AK, Burant CF, et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem. 2010; 285(44): 33652–61, CrossRef.

Vickers KC, Landstreet SR, Levin MG, Shoucri BM, Toth CL, Taylor RC, et al. MicroRNA-223 coordinates cholesterol homeostasis. Proc Natl Acad Sci USA. 2014; 111(40): 14518–23, CrossRef.

Suárez Y, Wang C, Manes TD, Pober JS. Cutting Edge: TNF-induced MicroRNAs regulate TNF-induced expression of E-selectin and intercellular adhesion molecule-1 on human endothelial cells: Feedback control of inflammation. J Immunol. 2010; 184(1): 21–5, CrossRef.

Sun X, Belkin N, Feinberg MW. Endothelial MicroRNAs and atherosclerosis. Curr Atheroscler Rep. 2013; 15(12): 372, CrossRef.

Larsen LE, Stoekenbroek RM, Kastelein JJP, Holleboom AG. Moving targets: Recent advances in lipid-lowering therapies. Arterioscler Thromb Vasc Biol. 2019; 39(3): 349–59, CrossRef.

Bell DA, Hooper AJ, Burnett JR. Mipomersen, an antisense apolipoprotein B synthesis inhibitor. Expert Opin Investig Drugs. 2011; 20(2): 265–72, CrossRef.

Geary RS, Wancewicz E, Matson J, Pearce M, Siwkowski A, Swayze E, et al. Effect of dose and plasma concentration on liver uptake and pharmacologic activity of a 2′-methoxyethyl modified chimeric antisense oligonucleotide targeting PTEN. Biochem Pharmacol. 2009; 78(3): 284–91, CrossRef.

Bennett CF, Swayze EE. RNA targeting therapeutics: Molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010; 50(1): 259–93, CrossRef.

Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL-C cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010; 375(9719): 998–1006, CrossRef.

Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013; 381(9860): 40–6, CrossRef.

Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K, et al. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013; 33(7): 1706–13, CrossRef.

Gusarova V, Alexa CA, Wang Y, Rafique A, Kim JH, Buckler D, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res. 2015; 56(7): 1308–17, CrossRef.

Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003; 34(2): 154–6, CrossRef.

Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL-C cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005; 37(2): 161–5, CrossRef.

Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL-C, and protection against coronary heart disease. N Engl J Med. 2006; 354(12): 1264–72, CrossRef.

Fasano T, Cefalù AB, Di Leo E, Noto D, Pollaccia D, Bocchi L, et al. A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol. 2007; 27(3): 677–81, CrossRef.

Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis. 2007; 193(2): 445–8, CrossRef.

Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006; 79(3): 514–23, CrossRef.

Thomson R, Genovese G, Canon C, Kovacsics D, Higgins MK, Carrington M, et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci USA. 2014; 111(20): E2130–9, CrossRef.

Heinecke JW. The HDL proteome: a marker–and perhaps mediator–of coronary artery disease. J Lipid Res. 2009; 50: S167–71, CrossRef.

Kontush A, Lhomme M, Chapman MJ. Unraveling the complexities of the HDL lipidome. J Lipid Res. 2013; 54(11): 2950–63, CrossRef.

Villines TC, Stanek EJ, Devine PJ, Turco M, Miller M, Weissman NJ, et al. The ARBITER 6-HALTS Trial (arterial biology for the investigation of the treatment effects of reducing cholesterol 6–HDL and LDL-C treatment strategies in atherosclerosis). J Am Coll Cardiol. 2010; 55(24): 2721–6, CrossRef.

The AIM-HIGH investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365(24): 2255–67, CrossRef.

Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013; 45(11): 1345–52, CrossRef.

Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2008; 372(9645): 1223–30, CrossRef.

Grey A, Bolland M. Clinical trial evidence and use of fish oil supplements. JAMA Intern Med. 2014; 174(3): 460–2, CrossRef.

Gallone G, Baldetti L, Pagnesi M, Latib A, Colombo A, Libby P, et al. Medical therapy for long-term prevention of atherothrombosis following an acute coronary syndrome: JACC state-of-the-art review. J Am Coll Cardiol. 2018; 72(23 Pt A): 2886–903, CrossRef.

Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004; 95(8): 764–72, CrossRef.

Steinberg D. The LDL modification hypothesis of atherogenesis: an update. J Lipid Res. 2009; 50 (Suppl): S376–381, CrossRef.

Wilensky RL, Macphee CH. Lipoprotein-associated phospholipase A(2) and atherosclerosis. Curr Opin Lipidol. 2009; 20(5): 415–20, CrossRef.

Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019; 380(1): 33–44, CrossRef.

O’Donoghue ML, Glaser R, Cavender MA, Aylward PE, Bonaca MP, Budaj A, et al. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: A randomized clinical trial. JAMA. 2016; 315(15): 1591–9, CrossRef.


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