PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in Cardiovascular Prevention

Abstract

Since increased cholesterol levels are crucial in determining the development of atheroma, their reduction represents a mainstay in primary and secondary cardiovascular prevention. The most recent spectacular advancement in cholesterol-lowering therapy is represented by proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors. Although their benefit over currently available treatments has been ascribed primarily to their strong low-density lipoprotein (LDL)-cholesterol reducing action, several clues suggest that PCSK9 inhibitors may also influence platelet function and blood coagulation. PCSK9 knockout mice develop less venous and arterial thrombosis and show reduced in vivo platelet activation upon arterial injury. In patients with acute coronary syndromes (ACSs) treated with P2Y₁₂ inhibitors, a direct association between PCSK9 serum levels and residual platelet reactivity was found. A direct correlation between urinary excretion of 11-dehydro-thromboxane-B₂, a marker of in vivo platelet activation, and circulating PCSK9 levels was reported in patients with atrial fibrillation. Moreover, recombinant human PCSK9 added in vitro to human platelets potentiated activation induced by weak agonists. Finally, blood clotting factor VIII (FVIII), which is associated with stroke and ACS risk, is cleared from the circulation by members of the LDL receptor (LDLR) family. Given that PCSK9 degrades LDLR, it is conceivable that PCSK9 inhibitors by enhancing the expression of LDLR may slightly decrease circulating FVIII, in this way contributing to the prevention of cardiovascular events. This review aims to discuss the possible and hypothetical interactions between PCSK9 and the haemostatic system and to examine the possible pleiotropic effects of PCSK9 inhibitors in cardiovascular prevention.

Keywords

atherothrombosis - CD36 - dyslipidaemia - FVIII - LOX-1

• References

• 1 Goldstein JL, Brown MS. Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation 1987; 76 (03) 504-507
• 2 Grundy SM, Stone NJ, Bailey AL. , et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol 2018 Doi: 10.1016/j.jacc.2018.11.002
• 3 Santos-Gallego CG, Badimon JJ, Rosenson RS. Beginning to understand high-density lipoproteins. Endocrinol Metab Clin North Am 2014; 43 (04) 913-947
• 4 Pedersen TR. The success story of LDL cholesterol lowering. Circ Res 2016; 118 (04) 721-731
• 5 Segrest JP, Jones MK, De Loof H, Dashti N. Structure of apolipoprotein B-100 in low density lipoproteins. J Lipid Res 2001; 42 (09) 1346-1367
• 6 Brown MS, Anderson RG, Basu SK, Goldstein JL. Recycling of cell-surface receptors: observations from the LDL receptor system. Cold Spring Harb Symp Quant Biol 1982; 46 (Pt 2): 713-721
• 7 Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986; 232 (4746): 34-47
• 8 Zhang DW, Garuti R, Tang WJ, Cohen JC, Hobbs HH. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc Natl Acad Sci U S A 2008; 105 (35) 13045-13050
• 9 Abifadel M, Varret M, Rabès JP. , et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34 (02) 154-156
• 10 Kent ST, Rosenson RS, Avery CL. , et al. PCSK9 loss-of-function variants, low-density lipoprotein cholesterol, and risk of coronary heart disease and stroke: data from 9 studies of blacks and whites. Circ Cardiovasc Genet 2017; 10 (04) e001632
• 11 Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A 2004; 101 (18) 7100-7105
• 12 Lagace TA. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol 2014; 25 (05) 387-393
• 13 Sabatine MS, Giugliano RP, Keech AC. , et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376 (18) 1713-1722
• 14 Navarese EP, Kolodziejczak M, Schulze V. , et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 2015; 163 (01) 40-51
• 15 Ridker PM. Mortality differences associated with treatment responses in CANTOS and FOURIER: insight and implications. Circulation 2018; 137 (17) 1763-1766
• 16 Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45: 89-118
• 17 Ridker PM, Danielson E, Fonseca FA. , et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 (21) 2195-2207
• 18 Baigent C, Keech A, Kearney PM. , et al; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366 (9493): 1267-1278
• 19 Ludman A, Venugopal V, Yellon DM, Hausenloy DJ. Statins and cardioprotection--more than just lipid lowering?. Pharmacol Ther 2009; 122 (01) 30-43
• 20 Blum A, Shamburek R. The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis. Atherosclerosis 2009; 203 (02) 325-330
• 21 Krysiak R, Okopień B, Herman Z. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes. Drugs 2003; 63 (17) 1821-1854
• 22 Antonopoulos AS, Margaritis M, Shirodaria C, Antoniades C. Translating the effects of statins: from redox regulation to suppression of vascular wall inflammation. Thromb Haemost 2012; 108 (05) 840-848
• 23 Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res 2017; 120 (01) 229-243
• 24 Silverman MG, Ference BA, Im K. , et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016; 316 (12) 1289-1297
• 25 Filippatos TD, Kei A, Rizos CV, Elisaf MS. Effects of PCSK9 Inhibitors on other than low- density lipoprotein cholesterol lipid variables. J Cardiovasc Pharmacol Ther 2018; 23 (01) 3-12
• 26 Gaudet D, Kereiakes DJ, McKenney JM. , et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol 2014; 114 (05) 711-715
• 27 Bittner V. Pleiotropic effects of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors?. Circulation 2016; 134 (22) 1695-1696
• 28 Santos-Gallego CG, Picatoste B, Badimón JJ. Pathophysiology of acute coronary syndrome. Curr Atheroscler Rep 2014; 16 (04) 401-409
• 29 Santos-Gallego CG, Bayón J, Badimón JJ. Thrombi of different pathologies: implications for diagnosis and treatment. Curr Treat Options Cardiovasc Med 2010; 12 (03) 274-291
• 30 Gresele P, Momi S, Migliacci R. Endothelium, venous thromboembolism and ischaemic cardiovascular events. Thromb Haemost 2010; 103 (01) 56-61
• 31 Migliacci R, Becattini C, Pesavento R. , et al. Endothelial dysfunction in patients with spontaneous venous thromboembolism. Haematologica 2007; 92 (06) 812-818
• 32 Camera M, Rossetti L, Barbieri SS. , et al. PCSK9 as a positive modulator of platelet activation. J Am Coll Cardiol 2018; 71 (08) 952-954
• 33 Kassassir H, Siewiera K, Sychowski R, Watała C. Can the antiplatelet effects of cangrelor be reliably studied in mice under in vivo and in vitro conditions using flow cytometry?. Pharmacol Rep 2013; 65 (04) 870-883
• 34 Dwivedi DJ, Grin PM, Khan M. , et al. Differential expression of PCSK9 modulates infection, inflammation, and coagulation in a murine model of sepsis. Shock 2016; 46 (06) 672-680
• 35 Wang H, Wang Q, Wang J. , et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency is protective against venous thrombosis in mice. Sci Rep 2017; 7 (01) 14360
• 36 Emmerechts J, Vanassche T, Loyen S. , et al. Partial versus complete factor VIII inhibition in a mouse model of venous thrombosis. Thromb Res 2012; 129 (04) 514-519
• 37 Golder M, Mewburn J, Lillicrap D. In vitro and in vivo evaluation of the effect of elevated factor VIII on the thrombogenic process. Thromb Haemost 2013; 109 (01) 53-60
• 38 Falcinelli E, Francisci D, Belfiori B. , et al. In vivo platelet activation and platelet hyperreactivity in abacavir-treated HIV-infected patients. Thromb Haemost 2013; 110 (02) 349-357
• 39 Navarese EP, Kolodziejczak M, Winter MP. , et al. Association of PCSK9 with platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: the PCSK9-REACT study. Int J Cardiol 2017; 227: 644-649
• 40 Gresele P, Falcinelli E, Momi S. Potentiation and priming of platelet activation: a potential target for antiplatelet therapy. Trends Pharmacol Sci 2008; 29 (07) 352-360
• 41 Rossetti L, Ferri N, Marchiano S. , et al. PCSK9 beyond its role in cholesterol homeostasis: co-activator of platelet function. Eur Heart J 2017; 38: 446-447
• 42 Gresele P, Guglielmini G, De Angelis M. , et al. Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus. J Am Coll Cardiol 2003; 41 (06) 1013-1020
• 43 Gresele P, Marzotti S, Guglielmini G. , et al. Hyperglycemia-induced platelet activation in type 2 diabetes is resistant to aspirin but not to a nitric oxide-donating agent. Diabetes Care 2010; 33 (06) 1262-1268
• 44 Rowley JW, Oler AJ, Tolley ND. , et al. Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood 2011; 118 (14) e101-e111
• 45 Cecchetti L, Tolley ND, Michetti N, Bury L, Weyrich AS, Gresele P. Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood 2011; 118 (07) 1903-1911
• 46 Brambilla M, Facchinetti L, Canzano P. , et al. Human megakaryocytes confer tissue factor to a subset of shed platelets to stimulate thrombin generation. Thromb Haemost 2015; 114 (03) 579-592
• 47 Radziwon-Balicka A, Lesyk G, Back V. , et al. Differential eNOS-signalling by platelet subpopulations regulates adhesion and aggregation. Cardiovasc Res 2017; 113 (14) 1719-1731
• 48 Li S, Zhu CG, Guo YL. , et al. The relationship between the plasma PCSK9 levels and platelet indices in patients with stable coronary artery disease. J Atheroscler Thromb 2015; 22 (01) 76-84
• 49 Cariou B, Guérin P, Le May C. , et al. Circulating PCSK9 levels in acute coronary syndrome: results from the PC-SCA-9 prospective study. Diabetes Metab 2017; 43 (06) 529-535
• 50 Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315 (16) 983-989
• 51 Gresele P, Falcinelli E, Loffredo F. , et al. Platelets release matrix metalloproteinase-2 in the coronary circulation of patients with acute coronary syndromes: possible role in sustained platelet activation. Eur Heart J 2011; 32 (03) 316-325
• 52 De Servi S, Crimi G, Calabrò P. , et al. Relationship between diabetes, platelet reactivity, and the SYNTAX score to one-year clinical outcome in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention. EuroIntervention 2016; 12 (03) 312-318
• 53 Hu D, Yang Y, Peng DQ. Increased sortilin and its independent effect on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in statin-naive patients with coronary artery disease. Int J Cardiol 2017; 227: 61-65
• 54 Gustafsen C, Kjolby M, Nyegaard M. , et al. The hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion. Cell Metab 2014; 19 (02) 310-318
• 55 Pastori D, Nocella C, Farcomeni A. , et al; ATHERO-AF Study Group. Relationship of PCSK9 and urinary thromboxane excretion to cardiovascular events in patients with atrial fibrillation. J Am Coll Cardiol 2017; 70 (12) 1455-1462
• 56 Catella F, FitzGerald GA. Paired analysis of urinary thromboxane B2 metabolites in humans. Thromb Res 1987; 47 (06) 647-656
• 57 Tatsumi K, Mackman N. Tissue factor and atherothrombosis. J Atheroscler Thromb 2015; 22 (06) 543-549
• 58 Wang M, Li YF, Guo YG, Chen MM, Jiang ZL, Song JY. Positive correlation between plasma PCSK9 and tissue factors levels in patients with angiographically diagnosed coronary artery disease and diabetes mellitus. J Geriatr Cardiol 2016; 13 (04) 312-315
• 59 Ochoa E, Iriondo M, Manzano C. , et al. LDLR and PCSK9 are associated with the presence of antiphospholipid antibodies and the development of thrombosis in aPLA carriers. PLoS One 2016; 11 (01) e0146990
• 60 Urbanus RT, de Laat B. Antiphospholipid antibodies and the protein C pathway. Lupus 2010; 19 (04) 394-399
• 61 Bontadi A, Ruffatti A, Falcinelli E. , et al. Platelet and endothelial activation in catastrophic and quiescent antiphospholipid syndrome. Thromb Haemost 2013; 109 (05) 901-908
• 62 Obermayer G, Afonyushkin T, Binder CJ. Oxidized low-density lipoprotein in inflammation-driven thrombosis. J Thromb Haemost 2018; 16 (03) 418-428
• 63 Chen K, Febbraio M, Li W, Silverstein RL. A specific CD36-dependent signaling pathway is required for platelet activation by oxidized low-density lipoprotein. Circ Res 2008; 102 (12) 1512-1519
• 64 Hofmann A, Brunssen C, Morawietz H. Contribution of lectin-like oxidized low-density lipoprotein receptor-1 and LOX-1 modulating compounds to vascular diseases. Vascul Pharmacol 2017 Doi: 10.1016/j.vph.2017.10.002
• 65 Magwenzi S, Woodward C, Wraith KS. , et al. Oxidized LDL activates blood platelets through CD36/NOX2-mediated inhibition of the cGMP/protein kinase G signaling cascade. Blood 2015; 125 (17) 2693-2703
• 66 Yoshimoto R, Fujita Y, Kakino A, Iwamoto S, Takaya T, Sawamura T. The discovery of LOX-1, its ligands and clinical significance. Cardiovasc Drugs Ther 2011; 25 (05) 379-391
• 67 Marwali MR, Hu CP, Mohandas B. , et al. Modulation of ADP-induced platelet activation by aspirin and pravastatin: role of lectin-like oxidized low-density lipoprotein receptor-1, nitric oxide, oxidative stress, and inside-out integrin signaling. J Pharmacol Exp Ther 2007; 322 (03) 1324-1332
• 68 Carnevale R, Bartimoccia S, Nocella C. , et al. LDL oxidation by platelets propagates platelet activation via an oxidative stress-mediated mechanism. Atherosclerosis 2014; 237 (01) 108-116
• 69 Biswas S, Xin L, Panigrahi S. , et al. Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE-/- mice and activate platelets via TLR2. Blood 2016; 127 (21) 2618-2629
• 70 Leibundgut G, Scipione C, Yin H. , et al. Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J Lipid Res 2013; 54 (10) 2815-2830
• 71 Riches K, Porter KE. Lipoprotein(a): cellular effects and molecular mechanisms. Cholesterol 2012; 2012: 923289
• 72 Calkin AC, Drew BG, Ono A. , et al. Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. Circulation 2009; 120 (21) 2095-2104
• 73 Shattil SJ, Anaya-Galindo R, Bennett J, Colman RW, Cooper RA. Platelet hypersensitivity induced by cholesterol incorporation. J Clin Invest 1975; 55 (03) 636-643
• 74 Nofer JR, Walter M, Kehrel B. , et al. HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinositide-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. Arterioscler Thromb Vasc Biol 1998; 18 (06) 861-869
• 75 Riddell DR, Graham A, Owen JS. Apolipoprotein E inhibits platelet aggregation through the L-arginine:nitric oxide pathway. Implications for vascular disease. J Biol Chem 1997; 272 (01) 89-95
• 76 van der Stoep M, Korporaal SJ, Van Eck M. High-density lipoprotein as a modulator of platelet and coagulation responses. Cardiovasc Res 2014; 103 (03) 362-371
• 77 Panes O, González C, Hidalgo P. , et al. Platelet tissue factor activity and membrane cholesterol are increased in hypercholesterolemia and normalized by rosuvastatin, but not by atorvastatin. Atherosclerosis 2017; 257: 164-171
• 78 Ding Z, Liu S, Wang X. , et al. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc Res 2015; 107 (04) 556-567
• 79 Barale C, Bonomo K, Noto F. , et al. Effects of PCSK9 inhibitors on platelet function in adults with hypercholesterolemia. Atherosclerosis 2017; 263: e30-e31
• 80 Kotani K, Banach M. Lipoprotein(a) and inhibitors of proprotein convertase subtilisin/kexin type 9. J Thorac Dis 2017; 9 (01) E78-E82
• 81 Geddings JE, Mackman N. New players in haemostasis and thrombosis. Thromb Haemost 2014; 111 (04) 570-574
• 82 Ding Z, Liu S, Wang X. , et al. Cross-talk between PCSK9 and damaged mtDNA in vascular smooth muscle cells: role in apoptosis. Antioxid Redox Signal 2016; 25 (18) 997-1008
• 83 Li J, Liang X, Wang Y, Xu Z, Li G. Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis. Mol Med Rep 2017; 16 (02) 1817-1825
• 84 Kaufman RJ, Pipe SW, Tagliavacca L, Swaroop M, Moussalli M. Biosynthesis, assembly and secretion of coagulation factor VIII. Blood Coagul Fibrinolysis 1997; 8 (02) (Suppl. 02) S3-S14
• 85 Bank I, Libourel EJ, Middeldorp S. , et al. Elevated levels of FVIII:C within families are associated with an increased risk for venous and arterial thrombosis. J Thromb Haemost 2005; 3 (01) 79-84
• 86 Siegler JE, Samai A, Albright KC, Boehme AK, Martin-Schild S. Factoring in factor VIII with acute ischemic stroke. Clin Appl Thromb Hemost 2015; 21 (07) 597-602
• 87 Rumley A, Lowe GD, Sweetnam PM, Yarnell JW, Ford RP. Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study. Br J Haematol 1999; 105 (01) 110-116
• 88 Tracy RP, Arnold AM, Ettinger W, Fried L, Meilahn E, Savage P. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol 1999; 19 (07) 1776-1783
• 89 Folsom AR, Peacock JM, Boerwinkle E. ; Atherosclerosis Risk in Communities (ARIC) Study Investigators. Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease. Atherosclerosis 2009; 202 (01) 211-215
• 90 Milgrom A, Lee K, Rothschild M. , et al. Thrombophilia in 153 patients with premature cardiovascular disease ≤age 45. Clin Appl Thromb Hemost 2018; 24 (02) 295-302
• 91 Rosendaal FR, Briët E, Stibbe J. , et al. Haemophilia protects against ischaemic heart disease: a study of risk factors. Br J Haematol 1990; 75 (04) 525-530
• 92 Machlus KR, Lin FC, Wolberg AS. Procoagulant activity induced by vascular injury determines contribution of elevated factor VIII to thrombosis and thrombus stability in mice. Blood 2011; 118 (14) 3960-3968
• 93 Kawasaki T, Kaida T, Arnout J, Vermylen J, Hoylaerts MF. A new animal model of thrombophilia confirms that high plasma factor VIII levels are thrombogenic. Thromb Haemost 1999; 81 (02) 306-311
• 94 Brummel-Ziedins K, Undas A, Orfeo T. , et al. Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition. J Thromb Haemost 2008; 6 (01) 104-110
• 95 Rice GI, Grant PJ. FVIII coagulant activity and antigen in subjects with ischaemic heart disease. Thromb Haemost 1998; 80 (05) 757-762
• 96 Lenting PJ, Neels JG, van den Berg BM. , et al. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem 1999; 274 (34) 23734-23739
• 97 Saenko EL, Yakhyaev AV, Mikhailenko I, Strickland DK, Sarafanov AG. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. J Biol Chem 1999; 274 (53) 37685-37692
• 98 Bovenschen N, Herz J, Grimbergen JM. , et al. Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. Blood 2003; 101 (10) 3933-3939
• 99 Bovenschen N, Mertens K, Hu L, Havekes LM, van Vlijmen BJ. LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Blood 2005; 106 (03) 906-912
• 100 Martinelli N, Girelli D, Lunghi B. , et al. Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile. Blood 2010; 116 (25) 5688-5697
• 101 Hamik A, Setiadi H, Bu G, McEver RP, Morrissey JH. Down-regulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein. J Biol Chem 1999; 274 (08) 4962-4969
• 102 Adams NB, Lutsey PL, Folsom AR. , et al. Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis. J Thromb Haemost 2013; 11 (06) 1078-1084
• 103 Biedermann JS, Kruip MJHA, van der Meer FJ. , et al. Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. Eur Heart J 2018; 39 (19) 1740-1747
• 104 Tiwari V, Khokhar M. Mechanism of action of anti-hypercholesterolemia drugs and their resistance. Eur J Pharmacol 2014; 741: 156-170
• 105 Moon JH, Kang SB, Park JS. , et al. Up-regulation of hepatic low-density lipoprotein receptor-related protein 1: a possible novel mechanism of antiatherogenic activity of hydroxymethylglutaryl-coenzyme A reductase inhibitor Atorvastatin and hepatic LRP1 expression. Metabolism 2011; 60 (07) 930-940
• 106 Ridker PM, Everett BM, Thuren T. , et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease; CANTOS Trial Group. N Engl J Med 2017; 377 (12) 1119-1131
• 107 Schwartz GG, Steg PG, Szarek M. , et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379: 2097-2107