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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Review Article

PCSK 9: A Link Between Inflammation and Atherosclerosis

Author(s): Dimitri Patriki, Seyed Soheil Saeedi Saravi, Giovanni G. Camici, Luca Liberale and Jürg H. Beer*

Volume 29, Issue 2, 2022

Published on: 07 July, 2021

Page: [251 - 267] Pages: 17

DOI: 10.2174/0929867328666210707192625

Price: $65

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Abstract

Proprotein convertase subtilisin/Kexin 9 (PCSK 9) is revealed to be a key player in lipid metabolism and, therefore, in the development and progression of atherosclerosis. PCSK 9 binds to the low-density lipoprotein (LDL) receptor, induces its degradation, and increases circulating blood LDL. As a result, PCSK 9 inhibitors represent an essential pillar in cardiovascular risk reduction therapies due to their highly sufficient LDL decreasing properties. While the influence of PCSK 9 on lipid metabolism has been widely investigated, the full pathophysiological spectrum of PCSK 9 is yet to be determined. Statins have already been demonstrated to have beneficial anti-inflammatory effects. In this context, evidence suggests that PCSK 9 also interferes with inflammatory processes, thereby contributing to the development of atherosclerosis. As lipid metabolism on its own affects inflammatory processes, it is difficult to distinguish between lipid-dependent and -independent inflammatory properties of PCSK 9. A body of evidence has revealed that PCSK9 LDL-independently regulates the secretion of pro-inflammatory cytokines and inflammation-underlying pathways in vascular walls, whereas recent observations suggest that PCSK9 also interacts with lectin-like oxidized LDL receptor-1 (LOX-1) and dampens inflammatory responses through LDL reduction. In conclusion, this review provides mounting evidence indicating how PCSK9 promotes vascular inflammation and subsequent atherosclerosis to shed light on the anti-inflammatory effects of PCSK9 inhibitors in the prevention of atherosclerosis.

Keywords: PCSK9, inflammation, lipid, LDL, atherosclerosis, cardiovascular disease.

[1]
Mathers, C.D, ; Loncar, D, Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med., 2006, 3(11)e442.
[http://dx.doi.org/10.1371/journal.pmed.0030442] [PMID: 17132052]
[2]
Townsend, N.; Wilson, L.; Bhatnagar, P.; Wickramasinghe, K.; Rayner, M.; Nichols, M. Cardiovascular disease in Europe: epidemiological update 2016. Eur. Heart J., 2016, 37(42), 3232-3245.
[http://dx.doi.org/10.1093/eurheartj/ehw334] [PMID: 27523477]
[3]
Camici, G.G.; Liberale, L. Aging: the next cardiovascular disease? Eur. Heart J., 2017, 38(21), 1621-1623.
[http://dx.doi.org/10.1093/eurheartj/ehx239] [PMID: 29447349]
[4]
Virmani, R.; Burke, A.P.; Farb, A.; Kolodgie, F.D. Pathology of the vulnerable plaque. J. Am. Coll. Cardiol., 2006, 47(8)(Suppl.), C13-C18.
[http://dx.doi.org/10.1016/j.jacc.2005.10.065] [PMID: 16631505]
[5]
Sugiyama, S.; Okada, Y.; Sukhova, G.K.; Virmani, R.; Heinecke, J.W.; Libby, P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am. J. Pathol., 2001, 158(3), 879-891.
[http://dx.doi.org/10.1016/S0002-9440(10)64036-9] [PMID: 11238037]
[6]
van der Sijde, J.N.; Karanasos, A.; Villiger, M.; Bouma, B.E.; Regar, E. First-in-man assessment of plaque rupture by polarization-sensitive optical frequency domain imaging in vivo. Eur. Heart J., 2016, 37(24), 1932.
[http://dx.doi.org/10.1093/eurheartj/ehw179] [PMID: 27174288]
[7]
Liberale, L.; Montecucco, F.; Schwarz, L.; scher, T.F.; Camici, G.G. Inflammation and cardiovascular diseases: lessons from seminal clinical trials. Cardiovasc. Res., 2021, 117(2), 411-422.
[http://dx.doi.org/10.1093/cvr/cvaa211] [PMID: 32666079]
[8]
Ference, B.A.; Kastelein, J.J.P.; Catapano, A.L. Lipids and Lipoproteins in 2020. JAMA, 2020, 324(6), 595-596.
[http://dx.doi.org/10.1001/jama.2020.5685] [PMID: 32717042]
[9]
Mundi, S.; Massaro, M.; Scoditti, E.; Carluccio, M.A.; van Hinsbergh, V.W.M.; Iruela-Arispe, M.L.; De Caterina, R. Endothelial permeability, LDL deposition, and cardiovascular risk factors-a review. Cardiovasc. Res., 2018, 114(1), 35-52.
[http://dx.doi.org/10.1093/cvr/cvx226] [PMID: 29228169]
[10]
Leitinger, N.; Berliner, J.A. MM-LDL and atherogenesis-A major role for phospholipid oxidation products.Oxidative Stress and Vascular Disease; Keaney, J.F., Ed.; Developments in Cardiovascular MedicineSpringer: Boston, 2000, 224, pp. 119-134;
[http://dx.doi.org/10.1007/978-1-4615-4649-8_7]
[11]
Rajavashisth, T.B.; Andalibi, A.; Territo, M.C.; Berliner, J.A.; Navab, M.; Fogelman, A.M.; Lusis, A.J. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature, 1990, 344(6263), 254-257.
[http://dx.doi.org/10.1038/344254a0] [PMID: 1690354]
[12]
Navab, M.; Berliner, J.A.; Watson, A.D.; Hama, S.Y.; Territo, M.C.; Lusis, A.J.; Shih, D.M.; Van Lenten, B.J.; Frank, J.S.; Demer, L.L.; Edwards, P.A.; Fogelman, A.M. The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler. Thromb. Vasc. Biol., 1996, 16(7), 831-842.
[http://dx.doi.org/10.1161/01.ATV.16.7.831] [PMID: 8673557]
[13]
Cushing, S.D.; Berliner, J.A.; Valente, A.J.; Territo, M.C.; Navab, M.; Parhami, F.; Gerrity, R.; Schwartz, C.J.; Fogelman, A.M. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl. Acad. Sci. USA, 1990, 87(13), 5134-5138.
[http://dx.doi.org/10.1073/pnas.87.13.5134] [PMID: 1695010]
[14]
Pryma, C.S.; Ortega, C.; Dubland, J.A.; Francis, G.A. Pathways of smooth muscle foam cell formation in atherosclerosis. Curr. Opin. Lipidol., 2019, 30(2), 117-124.
[http://dx.doi.org/10.1097/MOL.0000000000000574] [PMID: 30664015]
[15]
Berliner, J.A.; Subbanagounder, G.; Leitinger, N.; Watson, A.D.; Vora, D. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc. Med., 2001, 11(3-4), 142-147.
[http://dx.doi.org/10.1016/S1050-1738(01)00098-6] [PMID: 11686004]
[16]
Moore, K.J.; Sheedy, F.J.; Fisher, E.A. Macrophages in atherosclerosis: A dynamic balance. Nat. Rev. Immunol., 2013, 13(10), 709-721.
[http://dx.doi.org/10.1038/nri3520] [PMID: 23995626]
[17]
Liberale, L.; Dallegri, F.; Montecucco, F.; Carbone, F. Pathophysiological relevance of macrophage subsets in atherogenesis. Thromb. Haemost., 2017, 117(1), 7-18.
[http://dx.doi.org/10.1160/TH16-08-0593] [PMID: 27683760]
[18]
Yang, L.; Zhou, X.; Guo, R.; Shi, Y.; Liang, X.; Heng, X. Role of Küppel-like factor 2 and protease-activated receptor-1 in vulnerable plaques of ApoE(-/-) mice and intervention with statin. Can. J. Cardiol., 2013, 29(8), 997-1005.
[http://dx.doi.org/10.1016/j.cjca.2012.11.012] [PMID: 23395513]
[19]
Schrijvers, D.M.; De Meyer, G.R.Y.; Kockx, M.M.; Herman, A.G.; Martinet, W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 2005, 25(6), 1256-1261.
[http://dx.doi.org/10.1161/01.ATV.0000166517.18801.a7] [PMID: 15831805]
[20]
Flores, A.M.; Hosseini-Nassab, N.; Jarr, K.U.; Ye, J.; Zhu, X.; Wirka, R.; Koh, A.L.; Tsantilas, P.; Wang, Y.; Nanda, V.; Kojima, Y.; Zeng, Y.; Lotfi, M.; Sinclair, R.; Weissman, I.L.; Ingelsson, E.; Smith, B.R.; Leeper, N.J. Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis. Nat. Nanotechnol., 2020, 15(2), 154-161.
[http://dx.doi.org/10.1038/s41565-019-0619-3] [PMID: 31988506]
[21]
Kinlay, S. Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein: A meta-analysis. J. Am. Coll. Cardiol., 2007, 49(20), 2003-2009.
[http://dx.doi.org/10.1016/j.jacc.2007.01.083] [PMID: 17512355]
[22]
Ruscica, M.; Tokgözoğlu, L.; Corsini, A.; Sirtori, C.R. PCSK9 inhibition and inflammation: A narrative review. Atherosclerosis, 2019, 288, 146-155.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.07.015] [PMID: 31404822]
[23]
Golia, E.; Limongelli, G.; Natale, F.; Fimiani, F.; Maddaloni, V.; Pariggiano, I.; Bianchi, R.; Crisci, M.; DAcierno, L.; Giordano, R.; Di Palma, G.; Conte, M.; Golino, P.; Russo, M.G.; Calabrò, R.; Calabrò, P. Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr. Atheroscler. Rep., 2014, 16(9), 435.
[http://dx.doi.org/10.1007/s11883-014-0435-z] [PMID: 25037581]
[24]
Abifadel, M.; Varret, M.; RabA"s, J-P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; Derré, A.; Villéger, L.; Farnier, M.; Beucler, I.; Bruckert, E.; Chambaz, J.; Chanu, B.; Lecerf, J-M.; Luc, G.; Moulin, P.; Weissenbach, J.; Prat, A.; Krempf, M.; Junien, C.; Seidah, N.G.; Boileau, C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet., 2003, 34(2), 154-156.
[http://dx.doi.org/10.1038/ng1161] [PMID: 12730697]
[25]
Dhyani, A.; Tibolla, G.; Baragetti, A.; Garlaschelli, K.; Pellegatta, F.; Grigore, L.; Norata, G.D.; Catapano, A.L. IDOL N342S Variant, Atherosclerosis progression and cardiovascular disorders in the Italian general population. PLoS One, 2015, 10(4)e0122414
[http://dx.doi.org/10.1371/journal.pone.0122414] [PMID: 25927920]
[26]
Kathiresan, S.; Voight, B.F.; Purcell, S.; Musunuru, K.; Ardissino, D.; Mannucci, P.M.; Anand, S.; Engert, J.C.; Samani, N.J.; Schunkert, H.; Erdmann, J.; Reilly, M.P.; Rader, D.J.; Morgan, T.; Spertus, J.A.; Stoll, M.; Girelli, D.; McKeown, P.P.; Patterson, C.C.; Siscovick, D.S.; O Donnell, C.J.; Elosua, R.; Peltonen, L.; Salomaa, V.; Schwartz, S.M.; Melander, O.; Altshuler, D.; Ardissino, D.; Merlini, P.A.; Berzuini, C.; Bernardinelli, L.; Peyvandi, F.; Tubaro, M.; Celli, P.; Ferrario, M.; Fetiveau, R.; Marziliano, N.; Casari, G.; Galli, M.; Ribichini, F.; Rossi, M.; Bernardi, F.; Zonzin, P.; Piazza, A.; Mannucci, P.M.; Schwartz, S.M.; Siscovick, D.S.; Yee, J.; Friedlander, Y.; Elosua, R.; Marrugat, J.; Lucas, G.; Subirana, I.; Sala, J.; Ramos, R.; Kathiresan, S.; Meigs, J.B.; Williams, G.; Nathan, D.M.; MacRae, C.A.; ODonnell, C.J.; Salomaa, V.; Havulinna, A.S.; Peltonen, L.; Melander, O.; Berglund, G.; Voight, B.F.; Kathiresan, S.; Hirschhorn, J.N.; Asselta, R.; Duga, S.; Spreafico, M.; Musunuru, K.; Daly, M.J.; Purcell, S.; Voight, B.F.; Purcell, S.; Nemesh, J.; Korn, J.M.; McCarroll, S.A.; Schwartz, S.M.; Yee, J.; Kathiresan, S.; Lucas, G.; Subirana, I.; Elosua, R.; Surti, A.; Guiducci, C.; Gianniny, L.; Mirel, D.; Parkin, M.; Burtt, N.; Gabriel, S.B.; Samani, N.J.; Thompson, J.R.; Braund, P.S.; Wright, B.J.; Balmforth, A.J.; Ball, S.G.; Hall, A.; Schunkert, H.; Erdmann, J.; Linsel-Nitschke, P.; Lieb, W.; Ziegler, A.; KAnig, I.; Hengstenberg, C.; Fischer, M.; Stark, K.; Grosshennig, A.; Preuss, M.; Wichmann, H.E.; Schreiber, S.; Schunkert, H.; Samani, N.J.; Erdmann, J.; Ouwehand, W.; Hengstenberg, C.; Deloukas, P.; Scholz, M.; Cambien, F.; Reilly, M.P.; Li, M.; Chen, Z.; Wilensky, R.; Matthai, W.; Qasim, A.; Hakonarson, H.H.; Devaney, J.; Burnett, M.S.; Pichard, A.D.; Kent, K.M.; Satler, L.; Lindsay, J.M.; Waksman, R.; Knouff, C.W.; Waterworth, D.M.; Walker, M.C.; Mooser, V.; Epstein, S.E.; Rader, D.J.; Scheffold, T.; Berger, K.; Stoll, M.; Huge, A.; Girelli, D.; Martinelli, N.; Olivieri, O.; Corrocher, R.; Morgan, T.; Spertus, J.A.; McKeown, P.; Patterson, C.C.; Schunkert, H.; Erdmann, E.; Linsel-Nitschke, P.; Lieb, W.; Ziegler, A.; KAnig, I.R.; Hengstenberg, C.; Fischer, M.; Stark, K.; Grosshennig, A.; Preuss, M.; Wichmann, H.E.; Schreiber, S.; HA3lm, H.; Thorleifsson, G.; Thorsteinsdottir, U.; Stefansson, K.; Engert, J.C.; Do, R.; Xie, C.; Anand, S.; Kathiresan, S.; Ardissino, D.; Mannucci, P.M.; Siscovick, D.; ODonnell, C.J.; Samani, N.J.; Melander, O.; Elosua, R.; Peltonen, L.; Salomaa, V.; Schwartz, S.M.; Altshuler, D. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet., 2009, 41(3), 334-341.
[http://dx.doi.org/10.1038/ng.327] [PMID: 19198609]
[27]
Han, D.; Ma, J.; Zhang, X.; Cai, J.; Li, J.; Tuerxun, T.; Hao, C.; Du, L.; Lei, J. Correlation of PCSK9 gene polymorphism with cerebral ischemic stroke in Xinjiang Han and Uygur populations. Med. Sci. Monit., 2014, 20, 1758-1767.
[http://dx.doi.org/10.12659/MSM.892091] [PMID: 25266949]
[28]
Guo, Y.; Yan, B.; Gui, Y.; Tang, Z.; Tai, S.; Zhou, S.; Zheng, X.L. Physiology and role of PCSK9 in vascular disease: Potential impact of localized PCSK9 in vascular wall. J. Cell. Physiol., 2021, 236(4), 2333-2351.
[http://dx.doi.org/10.1002/jcp.30025] [PMID: 32875580]
[29]
Tang, Z.H.; Li, T.H.; Peng, J.; Zheng, J.; Li, T.T.; Liu, L.S.; Jiang, Z.S.; Zheng, X.L. PCSK9: A novel inflammation modulator in atherosclerosis? J. Cell. Physiol., 2019, 234(3), 2345-2355.
[http://dx.doi.org/10.1002/jcp.27254] [PMID: 30246446]
[30]
Ding, Z.; Wang, X.; Liu, S.; Zhou, S.; Kore, R.A.; Mu, S.; Deng, X.; Fan, Y.; Mehta, J.L. NLRP3 inflammasome via IL-1β regulates PCSK9 secretion. Theranostics, 2020, 10(16), 7100-7110.
[http://dx.doi.org/10.7150/thno.45939] [PMID: 32641981]
[31]
Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; Graham, I.M.; Halliday, A.; Landmesser, U.; Mihaylova, B.; Pedersen, T.R.; Riccardi, G.; Richter, D.J.; Sabatine, M.S.; Taskinen, M.R.; Tokgozoglu, L.; Wiklund, O.; Mueller, C.; Drexel, H.; Aboyans, V.; Corsini, A.; Doehner, W.; Farnier, M.; Gigante, B.; Kayikcioglu, M.; Krstacic, G.; Lambrinou, E.; Lewis, B.S.; Masip, J.; Moulin, P.; Petersen, S.; Petronio, A.S.; Piepoli, M.F.; Pinto, X.; Raber, L.; Ray, K.K.; Reiner, Z.; Riesen, W.F.; Roffi, M.; Schmid, J.P.; Shlyakhto, E.; Simpson, I.A.; Stroes, E.; Sudano, I.; Tselepis, A.D.; Viigimaa, M.; Vindis, C.; Vonbank, A.; Vrablik, M.; Vrsalovic, M.; Gomez, J.L.Z.; Collet, J.P.; Windecker, S.; Dean, V.; Fitzsimons, D.; Gale, C.P.; Grobbee, D.E.; Halvorsen, S.; Hindricks, G.; Iung, B.; Jüni, P.; Katus, H.A.; Leclercq, C.; Lettino, M.; Merkely, B.; Sousa-Uva, M.; Touyz, R.M.; Nibouche, D.; Zelveian, P.H.; Siostrzonek, P.; Najafov, R.; Van De Borne, P.; Pojskic, B.; Postadzhiyan, A.; Kypris, L.; Spinar, J.; Larsen, M.L.; Eldin, H.S.; Strandberg, T.E.; FerriA"res, J.; Agladze, R.; Laufs, U.; Rallidis, L.; Bajnok, L.; Gudjonsson, T.; Maher, V.; Henkin, Y.; Gulizia, M.M.; Mussagaliyeva, A.; Bajraktari, G.; Kerimkulova, A.; Latkovskis, G.; Hamoui, O.; Slapikas, R.; Visser, L.; Dingli, P.; Ivanov, V.; Boskovic, A.; Nazzi, M.; Visseren, F.; Mitevska, I.; RetterstA,l, K.; Jankowski, P.; Fontes-Carvalho, R.; Gaita, D.; Ezhov, M.; Foscoli, M.; Giga, V.; Pella, D.; Fras, Z.; De Isla, L.P.; HagstrAm, E.; Lehmann, R.; Abid, L.; Ozdogan, O.; Mitchenko, O.; Patel, R.S. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J., 2020, 41(1), 111-188.
[http://dx.doi.org/10.1093/eurheartj/ehz455] [PMID: 31504418]
[32]
Li, S.; Zhang, Y.; Xu, R.X.; Guo, Y.L.; Zhu, C.G.; Wu, N.Q.; Qing, P.; Liu, G.; Dong, Q.; Li, J.J. Proprotein convertase subtilisin-kexin type 9 as a biomarker for the severity of coronary artery disease. Ann. Med., 2015, 47(5), 386-393.
[http://dx.doi.org/10.3109/07853890.2015.1042908] [PMID: 26153823]
[33]
Rosenson, R.S.; Hegele, R.A.; Fazio, S.; Cannon, C.P. The evolving future of PCSK9 inhibitors. J. Am. Coll. Cardiol., 2018, 72(3), 314-329.
[http://dx.doi.org/10.1016/j.jacc.2018.04.054] [PMID: 30012326]
[34]
Cariou, B.; Guérin, P.; Le May, C.; Letocart, V.; Arnaud, L.; Guyomarch, B.; Pichelin, M.; Probst, V. Circulating PCSK9 levels in acute coronary syndrome: Results from the PC-SCA-9 prospective study. Diabetes Metab., 2017, 43(6), 529-535.
[http://dx.doi.org/10.1016/j.diabet.2017.07.009] [PMID: 28865748]
[35]
Shapiro, M.D.; Fazio, S. PCSK9 and atherosclerosis - lipids and beyond. J. Atheroscler. Thromb., 2017, 24(5), 462-472.
[http://dx.doi.org/10.5551/jat.RV17003] [PMID: 28302950]
[36]
Liberale, L.; Carbone, F.; Bertolotto, M.; Bonaventura, A.; Vecchié, A.; Mach, F.; Burger, F.; Pende, A.; Spinella, G.; Pane, B.; Camici, G.G.; Palombo, D.; Dallegri, F.; Montecucco, F. Serum PCSK9 levels predict the occurrence of acute coronary syndromes in patients with severe carotid artery stenosis. Int. J. Cardiol., 2018, 263, 138-141.
[http://dx.doi.org/10.1016/j.ijcard.2018.03.081] [PMID: 29754909]
[37]
Choi, I.J.; Lim, S.; Lee, D.; Lee, W.J.; Lee, K.Y.; Kim, M.J.; Jeon, D.S. Relation of Proprotein convertase subtilisin/kexin Type 9 to Cardiovascular outcomes in patients undergoing percutaneous coronary intervention. Am. J. Cardiol., 2020, 133, 54-60.
[http://dx.doi.org/10.1016/j.amjcard.2020.07.032] [PMID: 32798044]
[38]
Qiu, C.; Zhou, Q.; Li, X.; Zhang, Z.; Zeng, P.; Cao, Z.; Pan, B.; Li, X.; Chen, A.F. High circulating proprotein convertase subtilisin/Kexin type 9 concentration associates with cardiovascular risk: A meta-analysis of cohort studies. Medicine (Baltimore), 2017, 96(48)e8848
[http://dx.doi.org/10.1097/MD.0000000000008848] [PMID: 29310364]
[39]
Robinson, J.G.; Farnier, M.; Krempf, M.; Bergeron, J.; Luc, G.; Averna, M.; Stroes, E.S.; Langslet, G.; Raal, F.J.; El Shahawy, M.; Koren, M.J.; Lepor, N.E.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Kastelein, J.J.P. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1489-1499.
[http://dx.doi.org/10.1056/NEJMoa1501031] [PMID: 25773378]
[40]
Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; Sever, P.S.; Pedersen, T.R.; Fish, M.P.; Abrahamsen, T.E.; Kanevsky, E.; Bonaca, M.P.; Lira Pineda, A.; Hanlon, K.; Knusel, B.; Somaratne, R.; Kurtz, C.; Scott, R.; Accini Mendoza, J.L.; Amerena, J.; Badariene, J.; Burgess, L.; Ceska, R.; Charng, M.J.; Choi, D.; Cobos, J.L.; Dan, G.A.; De Ferrari, G.M.; Deedwania, P.C.; Chopra, V.K.; Erglis, A.; Ezhov, M.V.; Ferreira, J.; FilipovA­, S.; Gaciong, Z.A.; Pasierski, T.; Georgiev, B.G.; Gonzalez-Galvez, G.; Gouni-Berthold, I.; SchAufele, T.; Hirayama, A.; Huber, K.; Rammer, M.; Kjaerulf Jensen, H.; Wermuth, S.; Jiang, L.; Jukema, J.W.; Kraydashenko, O.; Leiter, L.A.; Lewis, B.S.; LA3pez-Miranda, J.; Lorenzatti, A.J.; Mach, F.; McAdam, B.; Nilsson, L.; Olsson, A.; Rallidis, L.; Rogelio, G.G.; Kerr Saraiva, J.F.; Scheen, A.; Schiele, F.; Connolly, D.; Siu, C.W.; Tay, L.; Thorgeirsson, G.; Tikkanen, M.J.; Tokgozoglu, S.L.; Toth, K.; Viigimaa, M.; Wan Ahmad, W.A.; Hennekens, C.H.; Andreotti, F.; Baigent, C.; Brown, W.V.; Davis, B.R.; Newcomer, J.W.; Wood, S.K.; LaRosa, J.; Ansell, B.; Lowe, C.; Zahn, L.; Awtry, E.; Berger, C.; Croce, K.; Desai, A.; Gelfand, E.; Ho, C.; Leeman, D.; Link, M.; Norden, A.; Pande, A.; Rost, N.; Ruberg, F.; Silverman, S.; Singhal, A.; Vita, J.; Mackinnon, I.; Vogel, D.R.; Leon de la Fuente, R.; Perna, E.; Amuchastegui, M.; Pacora, F.; Hershson, A.; Blumberg, E.; Glenny, J.A.; Colombo, H.; Cuadrado, J.A.; Nicolosi, L.; Rojas, C.G.; Ulla, M.R.; Hasbani, E.G.; Cuneo, C.; Lopez Santi, R.G.; Sanabria, H.D.; Hrabar, A.; Lozada, A.; Begg, A.; Lehman, S.; Wittert, G.; Juergens, C.; Kostner, K.; Beltrame, J.; Simpson, R.; Sinhal, A.; Adams, M.; Kritharides, L.; Roberts Thomson, P.; Cross, D.; Thompson, P.; Van Gaal, W.; Cox, N.; Farshid, A.; Hammett, C.; Garrahy, P.; Prasan, A.; Horrigan, M.; Ebenbichler, C.; Hanusch, U.; Prager, R.; Schernthaner, G.; Luger, A.; Siostrzonek, P.; Toplak, H.; Bergler-Klein, J.; Paulweber, B.; Sinzinger, H.; Buysschaert, I.; Thoeng, J.; Vandekerckhove, H.; Catez, E.; Verheye, S.; Descamps, O.; Hoffer, E.; Wollaert, B.; Chenu, P.; van de Borne, P.; De Meulemeester, M.; Friart, A.; Charlier, F.; De Raedt, H.; Rietzschel, E.; Roelandt, R.; Lalmand, J.; Tavares Russo, L.A.; Reis, G.; Duarte Barbosa, E.C.; Vidotti, M.H.; Fernandes Manenti, E.R.; Dutra, O.; Leaes, P.E.; Rech, R.L.; Bertolim Precoma, D.; Nicolau, J.C.; Amoedo, R.; Eliaschewitz, F.G.; Pereira, A.; Kurtz Lisboa, H.R.; Soares Piegas, L.; Cunha Borges, J.L.; Ferreira Rossi, P.R.; Pimentel Filho, P.; Bodanese, L.C.; de Sa Cunha, R.; Moura Jorge, J.C.; Ardito, W.R.; Barroso de Souza, W.K.; Hissa, M.; Izar, M.C.; Manolova, A.; Kitova, L.; Kinova, E.; Tzekova, M.; Velchev, V.; Tarnovska-Kadreva, R.; Gotchev, D.; Petrov, I.; Raev, D.; Trendafilova-Lazarova, D.; Yotov, Y.; Lazov, P.; Rahimi, S.; St Amour, E.; Constance, C.; Pesant, Y.; Hess, A.; Anderson, T.; Sussex, B.; Henein, S.; Tsoukas, G.; Pandey, A.S.; Bergeron, J.; Hart, R.; Gosselin, G.; Chehayeb, R.; Hamet, P.; Hartleib, M.; Mukherjee, A.; Halperin, F.; Petrella, R.; Bhargava, R.; Lonn, E.; Sabbah, E.; Bata, I.; Cha, J.; Gaudet, D.; Chapman, K.; Murthy, D.; Nigro, F.; Rupka, D.; Gossard, D.; Gupta, M.; Dowell, A.; Mansour, S.; Baass, A.; Geadah, C.; Huynh, T.; Peterson, S.; Poirier, P.; Sabe-Affaki, G.; Vertes, G.; Crowley, D.; Duchesne, L.; Pincetti Jofre, C.P.; Potthoff Cardenas, S.; Conejeros Kindel, C.; Saavedra Gajardo, V.A.; Lanas Zanetti, F.; Sepulveda Varela, P.A.; Stockins Fernandez, B.A.; Li, W.; Li, D.; Zhao, S.; Li, Z.; Wang, J.; Yang, Y.; Zhang, L.; Yang, P.; Zhang, X.; Huang, H.; Xue, L.; Zheng, Z.; Huang, W.; Dai, H.; Su, H.; Zeng, X.; Zheng, Y.; Tang, Y.; Yao, Z.; Sun, Y.; Du, Y.; Ge, Z.; Yan, J.; Chen, X.; Liu, F.; Pei, H.; Yang, X.; Cui, H.; Gu, Y.; Yang, Z.; Li, J.; Lian, Y.; Cui, Y.; Wang, D.; Jiang, J.; Li, X.; Chen, J.; Mo, Z.; Xu, P.; He, Y.; Zhou, C.; Qu, P.; Zhu, Y.; Liu, Y.; Shen, X.; Gao, X.; Terront Lozano, M.A.; Moncada Corredor, M.A.; Hernandez Triana, E.; Botero Lopez, R.; Coronel Arroyo, J.A.; Quintero Baiz, A.E.; Sanchez Vallejo, G.; Arana LondoAño, C.; Molina de Salazar, D.I.; Castellanos Bueno, R.; Manzur Jattin, F.; Cure, C.; Machkova, M.; Klimsa, Z.; Polasek, R.; Jerabek, O.; Kazdera, P.; Pozdisek, Z.; Vaclavik, J.; Frana, P.; Elbl, L.; Kucera, D.; Kryza, R.; Malecha, J.; Reichert, P.; Sochor, K.; Ludka, O.; Kellnerova, I.; Peterka, K.; Zidkova, E.; Cech, V.; Brabec, T.; Fiserova, N.; Kvasnicka, J.; Rosolova, H.; Nemecek, E.; Adamkova, V.; Dunaj, M.; Pojsl, S.; Cepelak, M.; Podpera, I.; Kuchar, L.; Rysava, D.; Burianova, H.; Spinarova, L.; Skrobakova, J.; Charvat, J.; Homza, M.; Zemanek, J.; Koleckar, P.; Karen, I.; Krupicka, J.; Blaha, V.; Matuska, J.; Brotanek, J.; Cifkova, R.; Kuchar, R.; Vomacka, Z.; Kosek, Z.; Hulinsky, V.; Krejcova, H.; Kuchar, J.; Jelinek, Z.; Jelinek, P.; Markdanner Lindgren, L.; Saetre Lihn, A.; Korsgaard Thomsen, K.; Bronnum-Schou, J.; Nielsen, H.; Nielsen, T.; Egstrup, K.; Klausen, I.C.; Mickley, H.; Hove, J.; Jeppesen, J.; Melchior, T.; Schmidt, E.B.; Valter, I.; Rosenthal, A.; Kaik, J.; Kork, A.; Alt, I.; Strand, J.; Nieminen, S.; Kahri, J.; Suomi, J.; Nyman, K.; Strandberg, T.E.; Piippo, T.; Savolainen, M.; Vikman, S.; Pucheu, Y.; Cariou, B.; Henry, P.; Ferrari, E.; Montalescot, G.; Ferrieres, J.; Roubille, F.; Bonnet, B.; Angoulvant, D.; Range, G.; Bammert, A.; Delarche, N.; Mariat, C.; Cayla, G.; Durlach, V.; Coisne, D.; Paillard, F.; Rouzier, R.; Goralski, M.; Khanoyan, P.; Cottin, Y.; Ziegler, O.; Khalife, K.; Le Corvoisier, P.; Motreff, P.; Spaulding, C.; VanBelle, E.; Bourhaial, H.; Opitz, C.; Kahrmann, G.; Contzen, C.; Appel, K.; Schenkenberger, I.; Rinke, A.; Trenk, D.; Maus, O.; Karakas, M.; Hanefeld, M.; Darius, H.; Hetzel, G.; Münzel, T.; WAhrle, J.; Stawowy, P.; Marten, I.; Isermann, B.; Kast, P.; Vorpahl, M.; Bosiljanoff, P.; Hengstenberg, C.; Kassner, U.; Salbach, P.; Fischer, M.; Steiner, S.; Wagner, S.; Kraatz, U.; von Hodenberg, E.; Weyland, K.; Mantas, I.; Tziakas, D.; Bousboulas, S.; Patsilinakos, S.; Mertzanos, G.; Panagoulis, C.; Bilianou, H.; Skoumas, I.; Elisaf, M.; Manolis, A.; Moschos, N.; Kochiadakis, G.; Ntaios, G.; Richter, D.; Athyros, V.; Kolovou, G.; Danias, P.; Melidonis, A.; Fan, K.Y.Y.; Siu, S.C.; Hornyik, A.; Lakatos, F.; Zilahi, Z.; Nagy, K.; Laszlo, Z.; Peterfai, E.; Lupkovics, G.; Andreka, P.; Merkely, B.; Herczeg, B.; Piros, G.A.; Salamon, C.; Mark, L.; Papp, A.; Szakal, I.; Edes, I.; Mohacsi, A.; Tomcsanyi, J.; Hajko, E.; Nagy, A.; Papp, E.; Kiss, R.; Karadi, I.; Sigurdsson, A.; Jain, A.; Pai, R.; Kothiwale, V.; Kulkarni, G.; Mahajan, A.; Aggarwal, S.; Mehta, V.; Rajadhyaksha, G.; Joshi, A.; Khandait, V.; Parmar, M.; Tyagi, S.; Airody Govinda, R.; Dwivedi, S.K.; Parikh, K.; Pothineni, R.B.; Solanki, B.; ODonnell, M.; Crean, P.; Barton, J.; Shechter, M.; Shotan, A.; Klutstein, M.; Chorin, E.; Gavish, D.; Kracoff, O.; Atar, S.; Rigler, S.; Hasin, Y.; Schiff, E.; Merlini, P.; Rapezzi, C.; Pirro, M.; Gonnelli, S.; Floresta, A.M.; Mennuni, M.; Ardissino, D.; Senni, M.; Marenzi, G.; Marcucci, R.; Sampietro, T.; Cosmi, F.; Perrone Filardi, P.; De Caterina, R.; Fedele, F.; Moretti, L.; Biasucci, L.M.; Ferri, C.; Go, Y.; Kiyosue, A.; Higashi, Y.; Tokunaga, T.; Kawasaki, T.; Sakagami, S.; Namba, S.; Saku, K.; Oku, K.; Arakawa, T.; Iida, H.; Nakamura, Y.; Yamamoto, K.; Hata, Y.; Katsuda, Y.; Koga, Y.; Shimizu, M.; Uehara, H.; Kajiyama, S.; Okamoto, H.; Shinozaki, T.; Fujino, Y.; Funazaki, T.; Higa, N.; Kaigawa, K.; Koike, A.; Nakane, H.; Sato, K.; Satoh, Y.; Shirasawa, K.; Sugino, H.; Tanabe, J.; Uemura, O.; Yoshimichi, G.; Akai, A.; Himeno, H.; Inage, T.; Inoko, M.; Kadokami, T.; Noguchi, Y.; Yamashita, K.; Yasumura, Y.; Yuge, M.; Hosokawa, S.; Kawamitsu, K.; Kozuma, K.; Matsuo, H.; Nakashima, E.; Okada, M.; Wada, A.; Yokoya, K.; Iwade, K.; Kawabata, K.; Tanno, H.; Ako, J.; Fujita, H.; Izumiya, Y.; Kanno, M.; Nunohiro, T.; Ohmura, H.; Ueno, T.; Kakurina, N.; Jasinkevica, I.; Stukena, I.; Veze, I.; Eglite, R.; Teterovska, D.; Sime, I.; Strazdiene, V.; Venceviciene, L.; Gustiene, O.; Radzeviciene-Jurgute, R.; Kucinskiene, A.; Maskon, O.; Lee, C.Y.; Erng, T.; Gan, H.W.; Mohamed Yusof, A.K.; Ramanathan, G.L.; Liew, H.; Lopez Alvarado, A.; Nevarez Ruiz, L.A.; De los Rios Ibarra, M.O.; Bazzoni Ruiz, A.E.; Ramos Lopez, G.A.; Llamas Esperon, G.A.; De la PeAña Topete, G.D.J.; Violante Ortiz, R.M.; Illescas Diaz, J.J.; Leon Gonzalez, S.; Sanchez Diaz, C.J.; Mendez Machado, G.F.; Venegas Carrillo, L.A.; Aldrete Velasco, J.A.; Cardona MuAñoz, E.G.; Leiva Pons, J.L.; Perez Alva, J.C.; van der Zwaan, C.; Oomen, A.; van de Wal, R.; Magro, M.; Boswijk, D.; Janus, C.; Groutars, R.; Tonino, W.; Cornel, J.H.; Oude Ophuis, A.; Troquay, R.; Liem, A.; Westendorp, I.; Van Hessen, M.; Lok, D.; De Nooijer, C.; Den Hartog, F.; Van Beek, E.; Bendermacher, P.; Jansen, R.; RAmer, T.; Rensing, B.; Hersbach, F.; Herrman, J.; Ladyjanskaia, G.; Karalis, I.; Linssen, G.; Bokern, M.; Visman, A.; Kooij, A.; Monajemi, H.; Lieverse, A.; Baker, J.; Tie, S.; Risberg, K.; Hysing, J.; Hoivik, H.O.; Norheim, P.; Solnor, L.; Hovland, A.; Kjaernli, T.; Jocson, G.; Coching, R.M.; Batalla, E.; Go, A.; Habaluyas, R.; Barcinas, R.; Sy, R.A.; Estepar, R.A.; Germar, A.; Trebacz, J.; Szymkowiak, K.; Wnetrzak-Michalska, R.; Kopaczewski, J.; Przekwas-Jaruchowska, M.; Kania, G.; Zabowka, M.; Mirek-Bryniarska, E.; Dabrowska, M.; Napora, P.; Konieczny, M.; Spyra, J.; Lysek, R.; Pijanowski, Z.; Grzegorzewski, B.; Bednarkiewicz, Z.; Kinasz, L.; Antkowiak-Piatyszek, K.; Stania, K.; Szpajer, M.; Staneta, P.; Skonieczny, G.; Ksiezycka-Majczynska, E.; Blicharski, T.; Piepiorka, M.; Wozakowska-Kaplon, B.; Zechowicz, T.; Ilkowski, J.; Lubiszewska, B.; Hiczkiewicz, J.; Wierzbicka, K.; Kosior, D.; Garbocz, P.; Kubica, J.; Raczak, G.; Wozniak, I.; Cygler, J.; Kramarczuk, E.; Bystryk, L.; Pentela-Nowicka, J.; Dabrowski, M.; Podolec, P.; Zieba, B.; Mosiewicz, J.; Dubaniewicz, W.; Banach, M.; Tyszecka, G.; Lepich, T.; Rychlewska-Hanczewska, A.; Guzik, T.; Monteiro, P.; Pereira, H.; Oliveira, L.; Matos, P.; Soares Goncalves, S.; Leitao, A.; Vasco Salgado, A.; Timoteo, A.T.; Pintilei, E.; Badila, E.; Militaru, C.; Tudoran, M.; Arsenescu-Georgescu, C.; Mitu, F.; Zdrenghea, D.; Lighezan, D.; Teodorescu, I.; Popescu, M.I.; Coman, I.; Vintila, M.M.; Vishnevsky, A.; Lukyanov, Y.; Blokhin, A.; Kostenko, V.; Shvarts, Y.; Markov, V.; Motylev, I.; Dronov, D.; Sherenkov, A.; Barbarash, O.; Shutemova, E.; Bolshakova, O.; Kobalava, Z.; Voevoda, M.; Treshkur, T.; Zrazhevskiy, K.; Pimenov, L.; Solovev, O.; Tarasov, N.; Arkhipov, M.; Freidlin, M.; Shalaev, S.; Yakhontova, P.; Shustov, S.; Goloshchekin, B.; Panov, A.; Bart, B.; Bubnova, M.; Gordeev, I.; Osipova, I.; Tereshenko, S.; Solovieva, E.; Meshkov, A.; Zateyshchikov, D.; Tan, J.L.; Subramaniam, T.; Pella, D.; Fulop, P.; Antalik, L.; Dzupina, A.; Banikova, A.; Sosovec, D.; Urgeova, L.; Mazur, J.; Hranai, M.; Banik, M.; Vinanska, D.; Lennerova, J.; Kovar, F.; Pastrnakova, E.; Uhliar, R.; Blasko, P.; Gonsorcik, J.; Lukacova, J.; Oriesek, R.; Hatalova, K.; du Toit, M.; Ebrahim, I.; Vawda, G.; Lipschitz, S.; Blignaut, S.; Engelbrecht, J.; Coetzer, T.F.; Pretorius, M.; Urbach, D.; Badat, A.; Pillay, S.; Van Zyl, L.; Abelson, M.; van der Walt, E.; Moodley, R.; Jacovides, A.; Oosthuysen, W.M.; Klug, E.; Lottering, H.; Kok, J.; Saaiman, J.; Dawood, S.; De Jong, D.M.; Kapp, C.; Makotoko, E.; Bayat, J.; Sarvan, M.; Vally, T.; Stapelberg, A.; Kim, M.; Bae, J.; Cho, Y.; Kim, S.; Han, K.H.; Her, S.; Kim, B.; Lee, S.; Hong, B.; Kim, W.; Rha, S.; Jeong, M.; Shin, G.J.; Vida Gutierrez, M.; Valdes Chavarri, M.; Pinto Sala, X.; Gonzalez Juanatey, J.R.; Civeira Murillo, F.; Zamorano Gomez, J.L.; Lekuona Goya, I.; IAñiguez Romo, A.; Cordero Fort, A.; Ascaso Gimilio, J.F.; Millan NuAñez-Cortes, J.; Lindholm, C.; SAderberg, S.; Suutari, A.; Berglund, S.; Mooe, T.; Kusiak, D.; Bandh, S.; Dahlén, G.; Olsson, S.; Witt, N.; Tydén, P.; Johansson, P.; Cizinsky, S.; Falck, G.; Pettersson, S.I.; Rasmanis, G.; A-stergren, J.; Moccetti, T.; Beer, H.J.; Eberli, F.; KrAhenbühl, S.; Linka, A.; Ackermann, D.; Michel, P.; Yeh, H.; Tsai, C.F.; Wu, C.; Hsia, C.; Juang, J.; Hsieh, I.; Lai, W.; Huang, C.; Hsieh, Y.; Sahin, T.; Duzenli, M.; Yigit, Z.; Demir, M.; Yilmaz, M.B.; Muderrisoglu, I.H.; Kirma, C.; Ercan, E.; Kayikcioglu, L.; Balbay, Y.; Lymar, I.; Kulynych, O.; Prokhorov, O.; Karpenko, O.; Kraiz, I.; Vakaliuk, I.; Stanislavchuk, M.; Korzh, O.; Rudyk, I.; Zhurba, S.; Svishchenko, Y.; Tseluyko, V.; Gyrina, O.; Reshotko, D.; Kopytsya, M.; Volkov, V.; Myshanych, G.; Rebrov, B.; Rishko, M.; Rudenko, L.; Shatylo, V.; Parkhomenko, O.; Yena, L.; Golovchenko, O.; Sorokina, I.; Malynovsky, Y.; Ivan, P.; Blagden, M.; Dear, H.; Mathew, A.; Lagocki, S.; Kondagunta, V.; Ahsan, A.; McKinnon, C.; Douglas, F.; Thom, S.; Fiore, G.; Caulfield, M.; Lynch, M.; Thomas, H.; Bain, S.; Hall, A.; McNally, D.; Fisher, M.; Keeling, P.; Al-Bahrani, A.; Lip, G.; Ellery, A.; Purohit, J.; Travill, C.; Cappuccio, F.; Davis, G.; Gaunt, R.; Adlam, D.; Asamoah, N.; Jaafar, F.; McCormack, T.; Jupp, B.; Pye, M.; Ainsworth, P.; Chauhan, A.; Paul, N.; Fairlie, H.; Fox, C.; Muzulu, S.; Trevelyan, J.; Aggarwal, R.; Issa, B.; Saravanan, P.; Cruickshank, K.; Gorog, D.; Heller, S.; Newby, D.; Nicolson, A.; Hare, P.O.; Donnelly, P.; Rutherfurd, S.; de Belder, M.; Finlayson, J.; Harvey, J.; Hoye, A.; Kingston, D.; Sarkar, D.; Negahban, A.; Webster, J.; Wyatt, N.; Muir, S.; Cummings, M.; Mackenzie, I.; Senior, R.; Capps, N.; Fotherby, K.; McIntyre, H.; Aldegather, J.; Dixon, L.; Saksena, R.; Butler, R.; Ramstad, D.; Pierpont, B.; Levinson, D.; Mohammed, A.; Haddad, T.; Goel, A.; Dave, K.; Haught, W.H.; Desire, A.; Hershon, K.; Napoli, M.; Tami, L.; Rothschild, R.; Khurana, S.; Gupta, D.; Cheung, D.; Hearne, S.; Grubb, S.; Miller, A.; Baird, I.; Marcus, A.; Srivastava, S.; Forgosh, L.; Fritz, R.; Mays, M.; Bertolet, B.; Reddy, J.; Khan, M.; Nakhle, S.; Dill, S.; Fishbein, G.; Khan, B.; Marais, H.; Reschak, M.; Malone, M.; Nadar, V.; Whitney, R.; Reichman, A.; Reyes, H.; El Shahawy, M.; Rabinowitz, A.; Weinstein, D.; Farhat, N.; Onyema, D.; Potu, R.; Runquist, L.; Barnum, O.; Crater, T.; Fialkow, J.; Shah, A.; Thompson, C.; Wiseman, A.; Doyle, T.; Henderson, D.; Herzog, W.; Schnitzler, R.; Carr, K.; Davis, M.; Nagajothi, N.; Olsen, S.; Rogers, W.; Rubino, J.; Singh, I.; Tarleton, G.; Bhagwat, R.; Clardy, D.; Jardula, M.; Robinson, J.; Torres, M.; Vijay, N.; Farris, N.; Lillo, J.; Moriarty, P.; Recknor, C.; Berlacher, P.; Christensen, T.; Gabra, N.; Issa, M.; Janik, M.; Lawless, A.; Molter, D.; Stout, E.; Brezina, B.; Claxton, E.; Linsky, R.; Poock, J.; Remler, R.; Roseman, H.; Schramm, E.; Al-Joundi, T.; Amin, J.; Hitchcock, J.; Isserman, S.; Kirstein, J.; Rider, J.; Shalek, M.; Sherman, H.; Bernstein, M.; Chandra, L.; Hatharasinghe, R.; Ibrahim, H.; Iteld, B.; Linzmeyer, K.; Seaton, B.; Zeig, S.; Christofides, E.; Dunbar, R.; Griffin, S.; Kohli, N.; Koren, M.; Pharr, W.; Purdy, D.; Spencer, R.; Yeoman, G.; Banerjee, S.; Cheek, H.B.; Engel, E.; Hamroff, G.; Huling, R.; Kozlowski, L.; Levin, P.; Makam, S.; Meengs, M.; Bhushan, R.; Erickson, B.; Herman, L.; Lo, E.; McDowell, E.; McGrew, F.; Miller, M.; Ord, J.; Webel, R.; Wilhoit, G.; Wise, J.; Yang, E.; Budoff, M.; Collins, J.; Dauber, I.; Dobkin, L.; Focil, A.; Gandy, W.; Pasquini, J.; Ramos, M.; Rodriguez, D.; Rosenson, R.; Sanford, K.; Schlau, A.; Snyder, B.; Stonesifer, L.; Tang, A.; De Souza, J.; Elam, M.; French, J.; Guyton, J.; Hage Korban, E.; Kereiakes, D.; King, M.; Loh, I.; Navarro, J.; Simons, R.; Tobin, T.; Younis, L.; Aboufakher, R.; Baldari, D.; Ballantyne, C.; Broughton, R.; Eaton, C.; Johnston, J.; Simon, W.; Thomson, S.; Vora, K.; Youngman, D.; Alzohaili, O.; Auerbach, E.; Brown, C.; Burrough, B.; Chen, Y.; Gilpatrick, M.; Landzberg, J.; Mitchell, C.; Rice, L.; Rubenfire, M.; Sofley, C.W.; Strobl, D.; Atassi, K.; Davila, W.; Diogo, J.; Fagan, T.; Joffe, I.; Krishna, J.; Osea, E.; Penny, W.; Rowe, W.; Shapiro, M.; Welker, J.; Benton, R.; Dobratz, D.; Fortuin, F.; Graham, J.; Henry, B.; Kusnick, B.; Lutskiy, M.; McRae, A.; Saway, W.; Scott, J.; Shah, M.; Weinberg, B.; Zarich, S.; Acheatel, R.; Case, C.; Earl, J.; Fernandez, S.; Giugliano, G.; Handelsman, Y.; Hermany, P.; Holder, S.; Kashyap, M.; Khan, A.; Lader, E.; Peniston, J.; Raoof, T.; Sacco, J.; Shore, K.; Spriggs, D.; Stringam, S.; Tahirkheli, N.; Delgado, E.; Derian, W.; Greenwald, J.; Harris, M.; Jackson, R.; Marhefka, G.; McElveen, W.; Mooss, A.; Morris, P.; Murray, J.; Pearlstein, P.; Raisinghani, A.; Rezkalla, S.; Sakhrani, L.; Schreibman, D.; Shaoulian, E.; Steinsapir, J.; Yataco, A.; De La Cruz, A.; Fredrick, M.; Goldenberg, E.; Lee, D.; McCullum, K.; McLellan, B.; Stephens, L.; Wilson, S.; Alfieri, A.; Mandviwala, M. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med., 2017, 376(18), 1713-1722.
[http://dx.doi.org/10.1056/NEJMoa1615664] [PMID: 28304224]
[41]
Nissen, S.E.; Tuzcu, E.M.; Schoenhagen, P.; Brown, B.G.; Ganz, P.; Vogel, R.A.; Crowe, T.; Howard, G.; Cooper, C.J.; Brodie, B.; Grines, C.L.; DeMaria, A.N. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: A randomized controlled trial. JAMA, 2004, 291(9), 1071-1080.
[http://dx.doi.org/10.1001/jama.291.9.1071] [PMID: 14996776]
[42]
Nissen, S.E.; Nicholls, S.J.; Sipahi, I.; Libby, P.; Raichlen, J.S.; Ballantyne, C.M.; Davignon, J.; Erbel, R.; Fruchart, J.C.; Tardif, J.C.; Schoenhagen, P.; Crowe, T.; Cain, V.; Wolski, K.; Goormastic, M.; Tuzcu, E.M. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA, 2006, 295(13), 1556-1565.
[http://dx.doi.org/10.1001/jama.295.13.jpc60002] [PMID: 16533939]
[43]
Okazaki, S.; Yokoyama, T.; Miyauchi, K.; Shimada, K.; Kurata, T.; Sato, H.; Daida, H. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study. Circulation, 2004, 110(9), 1061-1068.
[http://dx.doi.org/10.1161/01.CIR.0000140261.58966.A4] [PMID: 15326073]
[44]
Daida, H.; Dohi, T.; Fukushima, Y.; Ohmura, H.; Miyauchi, K. The goal of achieving atherosclerotic plaque regression with lipid-lowering therapy: Insights from IVUS trials. J. Atheroscler. Thromb., 2019, 26(7), 592-600.
[http://dx.doi.org/10.5551/jat.48603] [PMID: 31118346]
[45]
Filippatos, T.D.; Kei, A.; Rizos, C.V.; Elisaf, M.S. Effects of PCSK9 Inhibitors on other than low-density lipoprotein cholesterol lipid variables. J. Cardiovasc. Pharmacol. Ther., 2018, 23(1), 3-12.
[http://dx.doi.org/10.1177/1074248417724868] [PMID: 28826253]
[46]
Naoumova, R.P.; Tosi, I.; Patel, D.; Neuwirth, C.; Horswell, S.D.; Marais, A.D.; van Heyningen, C.; Soutar, A.K. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler. Thromb. Vasc. Biol., 2005, 25(12), 2654-2660.
[http://dx.doi.org/10.1161/01.ATV.0000190668.94752.ab] [PMID: 16224054]
[47]
Sabatine, M.S.; Giugliano, R.P.; Wiviott, S.D.; Raal, F.J.; Blom, D.J.; Robinson, J.; Ballantyne, C.M.; Somaratne, R.; Legg, J.; Wasserman, S.M.; Scott, R.; Koren, M.J.; Stein, E.A. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1500-1509.
[http://dx.doi.org/10.1056/NEJMoa1500858] [PMID: 25773607]
[48]
Reiner Ž., Hypertriglyceridaemia and risk of coronary artery disease. Nat. Rev. Cardiol., 2017, 14(7), 401-411.
[http://dx.doi.org/10.1038/nrcardio.2017.31] [PMID: 28300080]
[49]
Aung, L.H.H.; Yin, R.X.; Miao, L.; Hu, X.J.; Yan, T.T.; Cao, X.L.; Wu, D.F.; Li, Q.; Pan, S.L.; Wu, J.Z. The proprotein convertase subtilisin/kexin type 9 gene E670G polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Lipids Health Dis., 2011, 10, 5.
[http://dx.doi.org/10.1186/1476-511X-10-5] [PMID: 21232153]
[50]
Hagens, V.E.; Rienstra, M.; Van Veldhuisen, D.J.; Crijns, H.J.G.M.; Van Gelder, I.C. Determinants of sudden cardiac death in patients with persistent atrial fibrillation in the rate control versus electrical cardioversion (RACE) study. Am. J. Cardiol., 2006, 98(7), 929-932.
[http://dx.doi.org/10.1016/j.amjcard.2006.04.038] [PMID: 16996876]
[51]
Kamstrup, P.R.; TybjAÝrg-Hansen, A.; Nordestgaard, B.G. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J. Am. Coll. Cardiol., 2013, 61(11), 1146-1156.
[http://dx.doi.org/10.1016/j.jacc.2012.12.023] [PMID: 23375930]
[52]
Erqou, S.; Kaptoge, S.; Perry, P.L.; Di Angelantonio, E.; Thompson, A.; White, I.R.; Marcovina, S.M.; Collins, R.; Thompson, S.G.; Danesh, J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA, 2009, 302(4), 412-423.
[http://dx.doi.org/10.1001/jama.2009.1063] [PMID: 19622820]
[53]
Rigamonti, F.; Carbone, F.; Montecucco, F.; Bonaventura, A.; Liberale, L.; Burger, F.; Roth, A.; Bertolotto, M.; Spinella, G.; Pane, B.; Palombo, D.; Pende, A.; Dallegri, F.; Mach, F.; Bertolini, S.; Pisciotta, L. Serum lipoprotein (a) predicts acute coronary syndromes in patients with severe carotid stenosis. Eur. J. Clin. Invest., 2018, 48(3)e12888
[http://dx.doi.org/10.1111/eci.12888] [PMID: 29327345]
[54]
Tsimikas, S. A Test in context: Lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J. Am. Coll. Cardiol., 2017, 69(6), 692-711.
[http://dx.doi.org/10.1016/j.jacc.2016.11.042] [PMID: 28183512]
[55]
Gaudet, D.; Watts, G.F.; Robinson, J.G.; Minini, P.; Sasiela, W.J.; Edelberg, J.; Louie, M.J.; Raal, F.J. Effect of alirocumab on lipoprotein(a) Over ƒ%1.5 years (from the phase 3 ODYSSEY program). Am. J. Cardiol., 2017, 119(1), 40-46.
[http://dx.doi.org/10.1016/j.amjcard.2016.09.010] [PMID: 27793396]
[56]
Raal, F.J.; Giugliano, R.P.; Sabatine, M.S.; Koren, M.J.; Blom, D.; Seidah, N.G.; Honarpour, N.; Lira, A.; Xue, A.; Chiruvolu, P.; Jackson, S.; Di, M.; Peach, M.; Somaratne, R.; Wasserman, S.M.; Scott, R.; Stein, E.A. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: An analysis of 10 clinical trials and the LDL receptors role. J. Lipid Res., 2016, 57(6), 1086-1096.
[http://dx.doi.org/10.1194/jlr.P065334] [PMID: 27102113]
[57]
Momtazi-Borojeni, A.A.; Sabouri-Rad, S.; Gotto, A.M.; Pirro, M.; Banach, M.; Awan, Z.; Barreto, G.E.; Sahebkar, A. PCSK9 and inflammation: A review of experimental and clinical evidence. Eur. Heart J. Cardiovasc. Pharmacother., 2019, 5(4), 237-245.
[http://dx.doi.org/10.1093/ehjcvp/pvz022] [PMID: 31236571]
[58]
Liberale, L.; Montecucco, F.; Camici, G.G.; Dallegri, F.; Vecchie, A.; Carbone, F.; Bonaventura, A. Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to reduce cardiovascular inflammation and outcomes. Curr. Med. Chem., 2017, 24(14), 1403-1416.
[http://dx.doi.org/10.2174/0929867324666170303123734] [PMID: 28260498]
[59]
Bickel, C.; Rupprecht, H.J.; Blankenberg, S.; Espiniola-Klein, C.; Schlitt, A.; Rippin, G.; Hafner, G.; Treude, R.; Othman, H.; Hofmann, K-P.; Meyer, J. Relation of markers of inflammation (C-reactive protein, fibrinogen, von Willebrand factor, and leukocyte count) and statin therapy to long-term mortality in patients with angiographically proven coronary artery disease. Am. J. Cardiol., 2002, 89(8), 901-908.
[http://dx.doi.org/10.1016/S0002-9149(02)02236-1] [PMID: 11950425]
[60]
Ridker, P.M.; Danielson, E.; Fonseca, F.A.H.; Genest, J.; Gotto, A.M., Jr; Kastelein, J.J.P.; Koenig, W.; Libby, P.; Lorenzatti, A.J.; Macfadyen, J.G.; Nordestgaard, B.G.; Shepherd, J.; Willerson, J.T.; Glynn, R.J. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: A prospective study of the JUPITER trial. Lancet, 2009, 373(9670), 1175-1182.
[http://dx.doi.org/10.1016/S0140-6736(09)60447-5] [PMID: 19329177]
[61]
Zhang, Y.; Zhu, C.G.; Xu, R.X.; Li, S.; Guo, Y.L.; Sun, J.; Li, J.J. Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease. J. Clin. Lipidol., 2014, 8(5), 494-500.
[http://dx.doi.org/10.1016/j.jacl.2014.07.001] [PMID: 25234562]
[62]
Walley, K.R.; Thain, K.R.; Russell, J.A.; Reilly, M.P.; Meyer, N.J.; Ferguson, J.F.; Christie, J.D.; Nakada, T-A.; Fjell, C.D.; Thair, S.A.; Cirstea, M.S.; Boyd, J.H. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci. Transl. Med., 2014, 6(258)258ra143
[http://dx.doi.org/10.1126/scitranslmed.3008782] [PMID: 25320235]
[63]
Cariou, B.; Le May, C.; Costet, P. Clinical aspects of PCSK9. Atherosclerosis, 2011, 216(2), 258-265.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.04.018] [PMID: 21596380]
[64]
Denis, M.; Marcinkiewicz, J.; Zaid, A.; Gauthier, D.; Poirier, S.; Lazure, C.; Seidah, N.G.; Prat, A. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation, 2012, 125(7), 894-901.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.057406] [PMID: 22261195]
[65]
Tang, Z.H.; Peng, J.; Ren, Z.; Yang, J.; Li, T.T.; Li, T.H.; Wang, Z.; Wei, D.H.; Liu, L.S.; Zheng, X.L.; Jiang, Z.S. New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-I§B pathway. Atherosclerosis, 2017, 262, 113-122.
[http://dx.doi.org/10.1016/j.atherosclerosis.2017.04.023] [PMID: 28535426]
[66]
Ding, Z.; Liu, S.; Wang, X.; Deng, X.; Fan, Y.; Sun, C.; Wang, Y.; Mehta, J.L. Hemodynamic shear stress via ROS modulates PCSK9 expression in human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxid. Redox Signal., 2015, 22(9), 760-771.
[http://dx.doi.org/10.1089/ars.2014.6054] [PMID: 25490141]
[67]
Klinghammer, L.; Urschel, K.; Cicha, I.; Lewczuk, P.; Raaz-Schrauder, D.; Achenbach, S.; Garlichs, C.D. Impact of telmisartan on the inflammatory state in patients with coronary atherosclerosis--influence on IP-10, TNF-Iñ and MCP-1. Cytokine, 2013, 62(2), 290-296.
[http://dx.doi.org/10.1016/j.cyto.2013.02.001] [PMID: 23541900]
[68]
Lin, J.; Kakkar, V.; Lu, X. Impact of MCP-1 in atherosclerosis. Curr. Pharm. Des., 2014, 20(28), 4580-4588.
[http://dx.doi.org/10.2174/1381612820666140522115801] [PMID: 24862889]
[69]
Xing, S.; Zheng, F.; Zhang, W.; Wang, D.; Xing, Q. Relationship between toll-like receptor 4 levels in aorta and severity of atherosclerosis. J. Int. Med. Res., 2014, 42(4), 958-965.
[http://dx.doi.org/10.1177/0300060514534645] [PMID: 24925583]
[70]
Boyd, J.H.; Fjell, C.D.; Russell, J.A.; Sirounis, D.; Cirstea, M.S.; Walley, K.R. Increased plasma PCSK9 levels are associated with reduced endotoxin clearance and the development of acute organ failures during sepsis. J. Innate Immun., 2016, 8(2), 211-220.
[http://dx.doi.org/10.1159/000442976] [PMID: 26756586]
[71]
Dwivedi, D.J.; Grin, P.M.; Khan, M.; Prat, A.; Zhou, J.; Fox-Robichaud, A.E.; Seidah, N.G.; Liaw, P.C. Differential expression of PCSK9 modulates infection, inflammation, and coagulation in a murine model of sepsis. Shock, 2016, 46(6), 672-680.
[http://dx.doi.org/10.1097/SHK.0000000000000682] [PMID: 27405064]
[72]
Jennings, L.K. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb. Haemost., 2009, 102(2), 248-257.
[http://dx.doi.org/10.1160/TH09-03-0192] [PMID: 19652875]
[73]
Qi, Z.; Hu, L.; Zhang, J.; Yang, W.; Liu, X.; Jia, D.; Yao, Z.; Chang, L.; Pan, G.; Zhong, H.; Luo, X.; Yao, K.; Sun, A.; Qian, J.; Ding, Z.; Ge, J. PCSK9 (proprotein convertase subtilisin/kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation, 2021, 143(1), 45-61.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046290] [PMID: 32988222]
[74]
Förstermann, U.; Xia, N.; Li, H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ. Res., 2017, 120(4), 713-735.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.309326] [PMID: 28209797]
[75]
Akhmedov, A.; Crucet, M.; Simic, B.; Kraler, S.; Bonetti, N.; Ospelt, C.; Distler, O.; Ciurea, A.; Liberale, L.; Jauhiainen, M.; Metso, J.; Miranda, M.; Cydecian, R.; Schwarz, L.; Fehr, V.; Zilinyi, R.; Amrollahi-Sharifabadi, M.; Ntari, L.; Karagianni, N.; Ruschitzka, F.; Laaksonen, R.; Vanhoutte, P.M.; Kollias, G.; Camici, G.G.; Lüscher, T.F. TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: Reversal by monoclonal TNFα antibodies. Cardiovasc. Res., 2021, cvab005 Online Ahead of Print.,
[http://dx.doi.org/10.1093/cvr/cvab005] [PMID: 33483748]
[76]
Akhmedov, A.; Bonetti, N.R.; Reiner, M.F.; Spescha, R.D.; Amstalden, H.; Merlini, M.; Gaul, D.S.; Diaz-CaAñestro, C.; Briand-Schumacher, S.; Spescha, R.S.; Semerano, A.; Giacalone, G.; Savarese, G.; Montecucco, F.; Kulic, L.; Nitsch, R.M.; Matter, C.M.; Kullak-Ublick, G.A.; Sessa, M.; Lüscher, T.F.; Beer, J.H.; Liberale, L.; Camici, G.G. Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury. J. Cereb. Blood Flow Metab., 2019, 39(11), 2233-2245.
[http://dx.doi.org/10.1177/0271678X18793266] [PMID: 30073881]
[77]
Ding, Z.; Liu, S.; Wang, X.; Deng, X.; Fan, Y.; Shahanawaz, J.; Shmookler Reis, R.J.; Varughese, K.I.; Sawamura, T.; Mehta, J.L. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc. Res., 2015, 107(4), 556-567.
[http://dx.doi.org/10.1093/cvr/cvv178] [PMID: 26092101]
[78]
Lim, S.; Park, S. Role of vascular smooth muscle cell in the inflammation of atherosclerosis. BMB Rep., 2014, 47(1), 1-7.
[http://dx.doi.org/10.5483/BMBRep.2014.47.1.285] [PMID: 24388105]
[79]
Chistiakov, D.A.; Orekhov, A.N.; Bobryshev, Y.V. LOX-1-mediated effects on vascular cells in atherosclerosis. Cell. Physiol. Biochem., 2016, 38(5), 1851-1859.
[http://dx.doi.org/10.1159/000443123] [PMID: 27160316]
[80]
Badimon, L.; Luquero, A.; Crespo, J.; PeAña, E.; Borrell-Pages, M. PCSK9 and LRP5 in macrophage lipid internalization and inflammation. Cardiovasc. Res., 2021, 117(9), 2054-2068.
[http://dx.doi.org/10.1093/cvr/cvaa254] [PMID: 32991689]
[81]
Schmidt, H.H.H.W.; Stocker, R.; Vollbracht, C.; Paulsen, G.; Riley, D.; Daiber, A.; Cuadrado, A. Antioxidants in translational medicine. Antioxid. Redox Signal., 2015, 23(14), 1130-1143.
[http://dx.doi.org/10.1089/ars.2015.6393] [PMID: 26154592]
[82]
Steven, S.; Frenis, K.; Oelze, M.; Kalinovic, S.; Kuntic, M.; Bayo Jimenez, M.T.; Vujacic-Mirski, K.; HelmstAdter, J.; KrAller-SchAn, S.; Münzel, T.; Daiber, A. Vascular inflammation and oxidative stress: major triggers for cardiovascular disease. Oxid. Med. Cell. Longev., 2019, 20197092151
[http://dx.doi.org/10.1155/2019/7092151] [PMID: 31341533]
[83]
Wenzel, P.; Rossmann, H.; Müller, C.; Kossmann, S.; Oelze, M.; Schulz, A.; Arnold, N.; Simsek, C.; Lagrange, J.; Klemz, R.; SchAnfelder, T.; Brandt, M.; Karbach, S.H.; Knorr, M.; Finger, S.; Neukirch, C.; HAuser, F.; Beutel, M.E.; KrAller-SchAn, S.; Schulz, E.; Schnabel, R.B.; Lackner, K.; Wild, P.S.; Zeller, T.; Daiber, A.; Blankenberg, S.; Münzel, T. Heme oxygenase-1 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans. Eur. Heart J., 2015, 36(48), 3437-3446.
[http://dx.doi.org/10.1093/eurheartj/ehv544] [PMID: 26516175]
[84]
Datla, S.R.; Dusting, G.J.; Mori, T.A.; Taylor, C.J.; Croft, K.D.; Jiang, F. Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress. Hypertension, 2007, 50(4), 636-642.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.092296] [PMID: 17679649]
[85]
Ferrucci, L.; Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol., 2018, 15(9), 505-522.
[http://dx.doi.org/10.1038/s41569-018-0064-2] [PMID: 30065258]
[86]
Ferrucci, L.; Harris, T.B.; Guralnik, J.M.; Tracy, R.P.; Corti, M.C.; Cohen, H.J.; Penninx, B.; Pahor, M.; Wallace, R.; Havlik, R.J. Serum IL-6 level and the development of disability in older persons. J. Am. Geriatr. Soc., 1999, 47(6), 639-646.
[http://dx.doi.org/10.1111/j.1532-5415.1999.tb01583.x] [PMID: 10366160]
[87]
Liberale, L.; Montecucco, F.; Tardif, J.C.; Libby, P.; Camici, G.G. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. Eur. Heart J., 2020, 41(31), 2974-2982.
[http://dx.doi.org/10.1093/eurheartj/ehz961] [PMID: 32006431]
[88]
Liberale, L.; Kraler, S.; Camici, G.G.; Lüscher, T.F. Ageing and longevity genes in cardiovascular diseases. Basic Clin. Pharmacol. Toxicol., 2020, 127(2), 120-131.
[http://dx.doi.org/10.1111/bcpt.13426] [PMID: 32357271]
[89]
Liberale, L.; Camici, G.G. The role of vascular aging in atherosclerotic plaque development and vulnerability. Curr. Pharm. Des., 2019, 25(29), 3098-3111.
[http://dx.doi.org/10.2174/1381612825666190830175424] [PMID: 31470777]
[90]
van Bussel, B.C.; Schouten, F.; Henry, R.M.; Schalkwijk, C.G.; de Boer, M.R.; Ferreira, I.; Smulders, Y.M.; Twisk, J.W.; Stehouwer, C.D. Endothelial dysfunction and low-grade inflammation are associated with greater arterial stiffness over a 6-year period. Hypertension, 2011, 58(4), 588-595.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.174557] [PMID: 21859964]
[91]
Tyrrell, D.J.; Goldstein, D.R. Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6. Nat. Rev. Cardiol., 2021, 18(1), 58-68.
[http://dx.doi.org/10.1038/s41569-020-0431-7] [PMID: 32918047]
[92]
Franceschi, C.; Garagnani, P.; Vitale, G.; Capri, M.; Salvioli, S. Inflammaging and 'Garb-aging. Trends Endocrinol. Metab., 2017, 28(3), 199-212.
[http://dx.doi.org/10.1016/j.tem.2016.09.005] [PMID: 27789101]
[93]
Swanson, K.V.; Deng, M.; Ting, J.P.Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol., 2019, 19(8), 477-489.
[http://dx.doi.org/10.1038/s41577-019-0165-0] [PMID: 31036962]
[94]
Tousoulis, D.; Oikonomou, E.; Economou, E.K.; Crea, F.; Kaski, J.C. Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur. Heart J., 2016, 37(22), 1723-1732.
[http://dx.doi.org/10.1093/eurheartj/ehv759] [PMID: 26843277]
[95]
Abderrazak, A.; Couchie, D.; Mahmood, D.F.D.; Elhage, R.; Vindis, C.; Laffargue, M.; Matéo, V.; Büchele, B.; Ayala, M.R.; El Gaafary, M.; Syrovets, T.; Slimane, M.N.; Friguet, B.; Fulop, T.; Simmet, T.; El Hadri, K.; Rouis, M. Anti-inflammatory and antiatherogenic effects of the NLRP3 inflammasome inhibitor arglabin in ApoE2.Ki mice fed a high-fat diet. Circulation, 2015, 131(12), 1061-1070.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.013730] [PMID: 25613820]
[96]
Ridker, P.M.; Cannon, C.P.; Morrow, D.; Rifai, N.; Rose, L.M.; McCabe, C.H.; Pfeffer, M.A.; Braunwald, E. C-reactive protein levels and outcomes after statin therapy. N. Engl. J. Med., 2005, 352(1), 20-28.
[http://dx.doi.org/10.1056/NEJMoa042378] [PMID: 15635109]
[97]
Elias-Smale, S.E.; Kardys, I.; Oudkerk, M.; Hofman, A.; Witteman, J.C.M. C-reactive protein is related to extent and progression of coronary and extra-coronary atherosclerosis; results from the Rotterdam study. Atherosclerosis, 2007, 195(2), e195-e202.
[http://dx.doi.org/10.1016/j.atherosclerosis.2007.07.006] [PMID: 17714718]
[98]
Bohula, E.A.; Giugliano, R.P.; Leiter, L.A.; Verma, S.; Park, J.G.; Sever, P.S.; Lira Pineda, A.; Honarpour, N.; Wang, H.; Murphy, S.A.; Keech, A.; Pedersen, T.R.; Sabatine, M.S. Inflammatory and cholesterol risk in the FOURIER Trial. Circulation, 2018, 138(2), 131-140.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034032] [PMID: 29530884]
[99]
Pradhan, A.D.; Aday, A.W.; Rose, L.M.; Ridker, P.M. Residual inflammatory risk on treatment with PCSK9 inhibition and statin therapy. Circulation, 2018, 138(2), 141-149.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034645] [PMID: 29716940]
[100]
Everett, B.M.; MacFadyen, J.G.; Thuren, T.; Libby, P.; Glynn, R.J.; Ridker, P.M. Inhibition of interleukin-1β and reduction in atherothrombotic cardiovascular events in the CANTOS Trial. J. Am. Coll. Cardiol., 2020, 76(14), 1660-1670.
[http://dx.doi.org/10.1016/j.jacc.2020.08.011] [PMID: 33004131]
[101]
Nidorf, M.; Thompson, P.L. Effect of colchicine (0.5 mg twice daily) on high-sensitivity C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary artery disease. Am. J. Cardiol., 2007, 99(6), 805-807.
[http://dx.doi.org/10.1016/j.amjcard.2006.10.039] [PMID: 17350370]
[102]
Nidorf, S. M.; Fiolet, A. T. L.; Mosterd, A.; Eikelboom, J. W.; Schut, A.; Opstal, T. S. J.; The, S. H. K.; Xu, X.-F.; Ireland, M. A.; Lenderink, T.; Latchem, D.; Hoogslag, P.; Jerzewski, A.; Nierop, P.; Whelan, A.; Hendriks, R.; Swart, H.; Schaap, J.; Kuijper, A. F. M.; Hessen, M. W. J. aklani, P.; Tan, I.; Thompson, A. G.; Morton, A.; Judkins, C.; Bax, W. A.; Dirksen, M.; Alings, M.; Hankey, G. J.; Budgeon, C. A.; Tijssen, J. G.P.; Cornel, J. H.; Thompson, P. L. Colchicine in patients with chronic coronary disease. 2020, 383(19), 1838-1847..
[http://dx.doi.org/10.1056/NEJMoa2021372]
[103]
Everett, B.M.; Pradhan, A.D.; Solomon, D.H.; Paynter, N.; Macfadyen, J.; Zaharris, E.; Gupta, M.; Clearfield, M.; Libby, P.; Hasan, A.A.K.; Glynn, R.J.; Ridker, P.M. Rationale and design of the Cardiovascular Inflammation Reduction Trial: A test of the inflammatory hypothesis of atherothrombosis. Am. Heart J., 2013, 166(2), 199-207.e15.
[http://dx.doi.org/10.1016/j.ahj.2013.03.018] [PMID: 23895801]
[104]
Ridker, P.M.; Everett, B.M.; Pradhan, A.; MacFadyen, J.G.; Solomon, D.H.; Zaharris, E.; Mam, V.; Hasan, A.; Rosenberg, Y.; Iturriaga, E.; Gupta, M.; Tsigoulis, M.; Verma, S.; Clearfield, M.; Libby, P.; Goldhaber, S.Z.; Seagle, R.; Ofori, C.; Saklayen, M.; Butman, S.; Singh, N.; Le May, M.; Bertrand, O.; Johnston, J.; Paynter, N.P.; Glynn, R.J. Low-dose methotrexate for the prevention of atherosclerotic events. N. Engl. J. Med., 2019, 380(8), 752-762.
[http://dx.doi.org/10.1056/NEJMoa1809798] [PMID: 30415610]
[105]
Larsen, C.M.; Faulenbach, M.; Vaag, A.; VA,lund, A.; Ehses, J.A.; Seifert, B.; Mandrup-Poulsen, T.; Donath, M.Y. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med., 2007, 356(15), 1517-1526.
[http://dx.doi.org/10.1056/NEJMoa065213] [PMID: 17429083]
[106]
Geovanini, G.R.; Libby, P. Atherosclerosis and inflammation: overview and updates. Clin. Sci. (Lond.), 2018, 132(12), 1243-1252.
[http://dx.doi.org/10.1042/CS20180306] [PMID: 29930142]
[107]
Liberale, L.; Carbone, F.; Montecucco, F.; Sahebkar, A. Statins reduce vascular inflammation in atherogenesis: A review of underlying molecular mechanisms. Int. J. Biochem. Cell Biol., 2020, 122105735
[http://dx.doi.org/10.1016/j.biocel.2020.105735] [PMID: 32126319]
[108]
Liberale, L.; Carbone, F.; Camici, G.G.; Montecucco, F. IL-1β and Statin treatment in patients with myocardial infarction and diabetic cardiomyopathy. J. Clin. Med., 2019, 8(11), 1764.
[http://dx.doi.org/10.3390/jcm8111764] [PMID: 31652822]
[109]
Ray, K.K.; Wright, R.S.; Kallend, D.; Koenig, W.; Leiter, L.A.; Raal, F.J.; Bisch, J.A.; Richardson, T.; Jaros, M.; Wijngaard, P.L.J.; Kastelein, J.J.P. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N. Engl. J. Med., 2020, 382(16), 1507-1519.
[http://dx.doi.org/10.1056/NEJMoa1912387] [PMID: 32187462]
[110]
Wang, X.; Chen, X.; Zhang, X.; Su, C.; Yang, M.; He, W.; Du, Y.; Si, S.; Wang, L.; Hong, B. A small-molecule inhibitor of PCSK9 transcription ameliorates atherosclerosis through the modulation of FoxO1/3 and HNF1Iñ. EBioMedicine, 2020, 52102650
[http://dx.doi.org/10.1016/j.ebiom.2020.102650] [PMID: 32058941]
[111]
Ray, K.K.; Landmesser, U.; Leiter, L.A.; Kallend, D.; Dufour, R.; Karakas, M.; Hall, T.; Troquay, R.P.T.; Turner, T.; Visseren, F.L.J.; Wijngaard, P.; Wright, R.S.; Kastelein, J.J.P. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med., 2017, 376(15), 1430-1440.
[http://dx.doi.org/10.1056/NEJMoa1615758] [PMID: 28306389]
[112]
Landlinger, C.; Pouwer, M.G.; Juno, C.; van der Hoorn, J.W.A.; Pieterman, E.J.; Jukema, J.W.; Staffler, G.; Princen, H.M.G.; Galabova, G. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur. Heart J., 2017, 38(32), 2499-2507.
[http://dx.doi.org/10.1093/eurheartj/ehx260] [PMID: 28637178]
[113]
Galabova, G.; Brunner, S.; Winsauer, G.; Juno, C.; Wanko, B.; Mairhofer, A.; Lührs, P.; Schneeberger, A.; von Bonin, A.; Mattner, F.; Schmidt, W.; Staffler, G. Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management. PLoS One, 2014, 9(12)e114469
[http://dx.doi.org/10.1371/journal.pone.0114469] [PMID: 25474576]
[114]
Bernelot Moens, S.J.; Neele, A.E.; Kroon, J.; van der Valk, F.M.; Van den Bossche, J.; Hoeksema, M.A.; Hoogeveen, R.M.; Schnitzler, J.G.; Baccara-Dinet, M.T.; Manvelian, G.; de Winther, M.P.J.; Stroes, E.S.G. PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemia. Eur. Heart J., 2017, 38(20), 1584-1593.
[http://dx.doi.org/10.1093/eurheartj/ehx002] [PMID: 28329114]
[115]
Zhang, Y.X.; Cliff, W.J.; Schoefl, G.I.; Higgins, G. Coronary C-reactive protein distribution: its relation to development of atherosclerosis. Atherosclerosis, 1999, 145(2), 375-379.
[http://dx.doi.org/10.1016/S0021-9150(99)00105-7] [PMID: 10488966]
[116]
Hirschfield, G.M.; Gallimore, J.R.; Kahan, M.C.; Hutchinson, W.L.; Sabin, C.A.; Benson, G.M.; Dhillon, A.P.; Tennent, G.A.; Pepys, M.B. Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice. Proc. Natl. Acad. Sci. USA, 2005, 102(23), 8309-8314.
[http://dx.doi.org/10.1073/pnas.0503202102] [PMID: 15919817]
[117]
Cao, Y.X.; Li, S.; Liu, H.H.; Li, J.J. Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels: A systematic review and meta-analysis of randomised controlled trials. BMJ Open, 2018, 8(9)e022348
[http://dx.doi.org/10.1136/bmjopen-2018-022348] [PMID: 30287608]
[118]
Albert, M.A.; Danielson, E.; Rifai, N.; Ridker, P.M. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): A randomized trial and cohort study. JAMA, 2001, 286(1), 64-70.
[http://dx.doi.org/10.1001/jama.286.1.64] [PMID: 11434828]
[119]
Ridker, P.M.; Rifai, N.; Clearfield, M.; Downs, J.R.; Weis, S.E.; Miles, J.S.; Gotto, A.M. Jr Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N. Engl. J. Med., 2001, 344(26), 1959-1965.
[http://dx.doi.org/10.1056/NEJM200106283442601] [PMID: 11430324]
[120]
Ridker, P.M.; Danielson, E.; Fonseca, F.A.H.; Genest, J.; Gotto, A.M., Jr; Kastelein, J.J.P.; Koenig, W.; Libby, P.; Lorenzatti, A.J.; MacFadyen, J.G.; Nordestgaard, B.G.; Shepherd, J.; Willerson, J.T.; Glynn, R.J. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med., 2008, 359(21), 2195-2207.
[http://dx.doi.org/10.1056/NEJMoa0807646] [PMID: 18997196]
[121]
Stiekema, L.C.A.; Stroes, E.S.G.; Verweij, S.L.; Kassahun, H.; Chen, L.; Wasserman, S.M.; Sabatine, M.S.; Mani, V.; Fayad, Z.A. Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment. Eur. Heart J., 2019, 40(33), 2775-2781.
[http://dx.doi.org/10.1093/eurheartj/ehy862] [PMID: 30561610]
[122]
Cannon, C.P.; Blazing, M.A.; Giugliano, R.P.; McCagg, A.; White, J.A.; Theroux, P.; Darius, H.; Lewis, B.S.; Ophuis, T.O.; Jukema, J.W.; De Ferrari, G.M.; Ruzyllo, W.; De Lucca, P. Im, K.; Bohula, E.A.; Reist, C.; Wiviott, S.D.; Tershakovec, A.M.; Musliner, T.A.; Braunwald, E.; Califf, R.M. Im, K.; Bohula, E.A.; Reist, C.; Wiviott, S.D.; Tershakovec, A.M.; Musliner, T.A.; Braunwald, E.; Califf, R.M. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med., 2015, 372(25), 2387-2397.
[http://dx.doi.org/10.1056/NEJMoa1410489] [PMID: 26039521]

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