Pathophysiology of Atherosclerotic Carotid Disease

Abstract

Carotid artery atherosclerosis is an important etiology of carotid artery stenosis and subsequent cerebrovascular events. Carotid atherosclerosis follows a pattern that begins with endothelial dysfunction, marked by impaired nitric oxide-mediated vasodilation and increased endothelial permeability, and is followed by intimal low-density lipoprotein (LDL) accumulation. Retained oxidized LDL results in a pro-inflammatory environment that results in inflammatory cell inflammation and foam cell formation, the basis of the fatty streak. Migrating medial vascular smooth muscle cells, which undergo phenotypic switching, lead to plaque growth and fibrous cap formation. The unique geometry of the carotid bifurcation contributes to the complex local hemodynamic environment and predisposes the carotid bifurcation to endothelial dysfunction. In later stages of atherosclerosis, higher wall shear stress erodes the fibrous cap and increases the risk of plaque rupture. Several parameters of carotid bifurcation geometry, including the bifurcation angle and relative diameters of the internal and common carotid arteries, also contribute to disturbed flow and atherosclerotic plaque development.

Keywords

carotid stenosis - atherosclerosis - pathophysiology - hemodynamics

Publication History

Received: 11 September 2025

Accepted: 31 October 2025

Article published online:
17 November 2025

• References

• 1 World Health Organization. The top 10 causes of death. World Health Organization. Updated May 24, 2024. Accessed September 11, 2025 at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
• 2 Flaherty ML, Kissela B, Khoury JC. et al. Carotid artery stenosis as a cause of stroke. Neuroepidemiology 2013; 40 (01) 36-41
• 3 Libby P, Buring JE, Badimon L. et al. Atherosclerosis. Nat Rev Dis Primers 2019; 5 (01) 56
• 4 Wang D, Wang Z, Zhang L, Wang Y. Roles of cells from the arterial vessel wall in atherosclerosis. Mediators Inflamm 2017; 2017: 8135934
• 5 Thomas JB, Antiga L, Che SL. et al. Variation in the carotid bifurcation geometry of young versus older adults: implications for geometric risk of atherosclerosis. Stroke 2005; 36 (11) 2450-2456
• 6 Ross R, Glomset JA. The pathogenesis of atherosclerosis (first of two parts). N Engl J Med 1976; 295 (07) 369-377
• 7 Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 1973; 180 (4093): 1332-1339
• 8 Spaet TH, Stemerman MB, Veith FJ, Lejnieks I. Intimal injury and regrowth in the rabbit aorta; medial smooth muscle cells as a source of neointima. Circ Res 1975; 36 (01) 58-70
• 9 Silkworth JB, McLean B, Stehbens WE. The effect of hypercholesterolemia on aortic endothelium studied en face. Atherosclerosis 1975; 22 (03) 335-348
• 10 Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327 (6122): 524-526
• 11 Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987; 84 (24) 9265-9269
• 12 Furchgott R. Studies on Relaxation of Rabbit Aorta by Sodium Nitrite: the Basis for the Proposal that the Acid-activatable Inhibitory Factor from Retractor Penis is Inorganic Nitrite and the Endothelium-derived Relaxing Factor is Nitric Oxide. In: Vanhoutte PM. ed. Vasodilatation: Vascular Smooth Muscle, Peptides, and Endothelium. Raven Press; 1988: 401-414
• 13 Förstermann U, Closs EI, Pollock JS. et al. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension 1994; 23 (6 Pt 2): 1121-1131
• 14 Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991; 88 (11) 4651-4655
• 15 Radomski MW, Palmer RM, Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol 1987; 92 (01) 181-187
• 16 Wang W, Diamond SL. Does elevated nitric oxide production enhance the release of prostacyclin from shear stressed aortic endothelial cells?. Biochem Biophys Res Commun 1997; 233 (03) 748-751
• 17 Sievi E, Lähteenmäki TA, Alanko J, Vuorinen P, Vapaatalo H. Nitric oxide as a regulator of prostacyclin synthesis in cultured rat heart endothelial cells. Arzneimittelforschung 1997; 47 (10) 1093-1098
• 18 Kourembanas S, McQuillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 1993; 92 (01) 99-104
• 19 Weng YH, Kuo CY, Chiu YW, Kuo ML, Liao SL. Alteration of nitric oxide gas on gene expression of endothelin-1 and endothelial nitric oxide synthase by a time- and dose-dependent manner in human endothelial cells. Chin J Physiol 2009; 52 (02) 59-64
• 20 Sverdlov AL, Ngo DT, Chan WP, Chirkov YY, Horowitz JD. Aging of the nitric oxide system: are we as old as our NO?. J Am Heart Assoc 2014; 3 (04) e000973
• 21 Feron O, Dessy C, Moniotte S, Desager JP, Balligand JL. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest 1999; 103 (06) 897-905
• 22 Barua RS, Ambrose JA, Eales-Reynolds LJ, DeVoe MC, Zervas JG, Saha DC. Dysfunctional endothelial nitric oxide biosynthesis in healthy smokers with impaired endothelium-dependent vasodilatation. Circulation 2001; 104 (16) 1905-1910
• 23 Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Chayama K, Oshima T. Effect of obesity on endothelium-dependent, nitric oxide-mediated vasodilation in normotensive individuals and patients with essential hypertension. Am J Hypertens 2001; 14 (10) 1038-1045
• 24 Panza JA, Quyyumi AA, Brush Jr JE, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323 (01) 22-27
• 25 Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993; 88 (06) 2510-2516
• 26 Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007; 87 (01) 315-424
• 27 Huang PL, Huang Z, Mashimo H. et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995; 377 (6546): 239-242
• 28 Lefer DJ, Jones SP, Girod WG. et al. Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice. Am J Physiol 1999; 276 (06) H1943-H1950
• 29 Freedman JE, Sauter R, Battinelli EM. et al. Deficient platelet-derived nitric oxide and enhanced hemostasis in mice lacking the NOSIII gene. Circ Res 1999; 84 (12) 1416-1421
• 30 Nishina PM, Lowe S, Verstuyft J, Naggert JK, Kuypers FA, Paigen B. Effects of dietary fats from animal and plant sources on diet-induced fatty streak lesions in C57BL/6J mice. J Lipid Res 1993; 34 (08) 1413-1422
• 31 Zhang SH, Reddick RL, Burkey B, Maeda N. Diet-induced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption. J Clin Invest 1994; 94 (03) 937-945
• 32 Joris I, Zand T, Nunnari JJ, Krolikowski FJ, Majno G. Studies on the pathogenesis of atherosclerosis. I. Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats. Am J Pathol 1983; 113 (03) 341-358
• 33 Noble MI, Drake-Holland AJ, Vink H. Hypothesis: arterial glycocalyx dysfunction is the first step in the atherothrombotic process. QJM 2008; 101 (07) 513-518
• 34 Vasile E, Simionescu M, Simionescu N. Visualization of the binding, endocytosis, and transcytosis of low-density lipoprotein in the arterial endothelium in situ. J Cell Biol 1983; 96 (06) 1677-1689
• 35 Lampugnani MG. Endothelial cell-to-cell junctions: adhesion and signaling in physiology and pathology. Cold Spring Harb Perspect Med 2012; 2 (10) a006528
• 36 van den Berg BM, Spaan JA, Rolf TM, Vink H. Atherogenic region and diet diminish glycocalyx dimension and increase intima-to-media ratios at murine carotid artery bifurcation. Am J Physiol Heart Circ Physiol 2006; 290 (02) H915-H920
• 37 Keller R, Pratt BM, Furthmayr H, Madri JA. Aortic endothelial cell proteoheparan sulfate. II. Modulation by extracellular matrix. Am J Pathol 1987; 128 (02) 299-306
• 38 Son DJ, Kumar S, Takabe W. et al. The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis. Nat Commun 2013; 4: 3000
• 39 Uchiyama H, Dobashi Y, Ohkouchi K, Nagasawa K. Chemical change involved in the oxidative reductive depolymerization of hyaluronic acid. J Biol Chem 1990; 265 (14) 7753-7759
• 40 Moseley R, Waddington RJ, Embery G. Degradation of glycosaminoglycans by reactive oxygen species derived from stimulated polymorphonuclear leukocytes. Biochim Biophys Acta 1997; 1362 (2-3): 221-231
• 41 Safrankova B, Gajdova S, Kubala L. The potency of hyaluronan of different molecular weights in the stimulation of blood phagocytes. Mediators Inflamm 2010; 2010: 380948
• 42 González D, Herrera B, Beltrán A, Otero K, Quintero G, Rojas A. Nitric oxide disrupts VE-cadherin complex in murine microvascular endothelial cells. Biochem Biophys Res Commun 2003; 304 (01) 113-118
• 43 Monaghan-Benson E, Burridge K. The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species. J Biol Chem 2009; 284 (38) 25602-25611
• 44 Mazzon E, De Sarro A, Caputi AP, Cuzzocrea S. Role of tight junction derangement in the endothelial dysfunction elicited by exogenous and endogenous peroxynitrite and poly(ADP-ribose) synthetase. Shock 2002; 18 (05) 434-439
• 45 Kevil CG, Oshima T, Alexander JS. The role of p38 MAP kinase in hydrogen peroxide mediated endothelial solute permeability. Endothelium 2001; 8 (02) 107-116
• 46 Minick CR, Stemerman MG, Insull Jr W. Effect of regenerated endothelium on lipid accumulation in the arterial wall. Proc Natl Acad Sci U S A 1977; 74 (04) 1724-1728
• 47 Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 1995; 15 (05) 551-561
• 48 Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A 1984; 81 (12) 3883-3887
• 49 Morel DW, DiCorleto PE, Chisolm GM. Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis 1984; 4 (04) 357-364
• 50 Kruth HS, Huang W, Ishii I, Zhang WY. Macrophage foam cell formation with native low density lipoprotein. J Biol Chem 2002; 277 (37) 34573-34580
• 51 Henriksen T, Mahoney EM, Steinberg D. Enhanced macrophage degradation of biologically modified low density lipoprotein. Arteriosclerosis 1983; 3 (02) 149-159
• 52 Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A 1987; 84 (09) 2995-2998
• 53 Cushing SD, Berliner JA, Valente AJ. et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A 1990; 87 (13) 5134-5138
• 54 Rajavashisth TB, Andalibi A, Territo MC. et al. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 1990; 344 (6263): 254-257
• 55 Yui S, Sasaki T, Miyazaki A, Horiuchi S, Yamazaki M. Induction of murine macrophage growth by modified LDLs. Arterioscler Thromb 1993; 13 (03) 331-337
• 56 Quinn MT, Parthasarathy S, Steinberg D. Endothelial cell-derived chemotactic activity for mouse peritoneal macrophages and the effects of modified forms of low density lipoprotein. Proc Natl Acad Sci U S A 1985; 82 (17) 5949-5953
• 57 Escargueil-Blanc I, Meilhac O, Pieraggi MT, Arnal JF, Salvayre R, Nègre-Salvayre A. Oxidized LDLs induce massive apoptosis of cultured human endothelial cells through a calcium-dependent pathway. Prevention by aurintricarboxylic acid. Arterioscler Thromb Vasc Biol 1997; 17 (02) 331-339
• 58 Kugiyama K, Kerns SA, Morrisett JD, Roberts R, Henry PD. Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature 1990; 344 (6262): 160-162
• 59 Autio I, Jaakkola O, Solakivi T, Nikkari T. Oxidized low-density lipoprotein is chemotactic for arterial smooth muscle cells in culture. FEBS Lett 1990; 277 (1-2): 247-249
• 60 McMurray HF, Parthasarathy S, Steinberg D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest 1993; 92 (02) 1004-1008
• 61 McEver RP, Zhu C. Rolling cell adhesion. Annu Rev Cell Dev Biol 2010; 26: 363-396
• 62 Hossain M, Qadri SM, Liu L. Inhibition of nitric oxide synthesis enhances leukocyte rolling and adhesion in human microvasculature. J Inflamm (Lond) 2012; 9 (01) 28
• 63 Allen S, Khan S, Al-Mohanna F, Batten P, Yacoub M. Native low density lipoprotein-induced calcium transients trigger VCAM-1 and E-selectin expression in cultured human vascular endothelial cells. J Clin Invest 1998; 101 (05) 1064-1075
• 64 Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med 2000; 191 (01) 189-194
• 65 Johnson RC, Chapman SM, Dong ZM. et al. Absence of P-selectin delays fatty streak formation in mice. J Clin Invest 1997; 99 (05) 1037-1043
• 66 Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. The combined role of P- and E-selectins in atherosclerosis. J Clin Invest 1998; 102 (01) 145-152
• 67 Berlin C, Bargatze RF, Campbell JJ. et al. Alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 1995; 80 (03) 413-422
• 68 Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci U S A 1996; 93 (17) 9114-9119
• 69 Khan BV, Parthasarathy SS, Alexander RW, Medford RM. Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J Clin Invest 1995; 95 (03) 1262-1270
• 70 Chan JR, Hyduk SJ, Cybulsky MI. Chemoattractants induce a rapid and transient upregulation of monocyte alpha4 integrin affinity for vascular cell adhesion molecule 1 which mediates arrest: an early step in the process of emigration. J Exp Med 2001; 193 (10) 1149-1158
• 71 Chuang KP, Huang YF, Hsu YL, Liu HS, Chen HC, Shieh CC. Ligation of lymphocyte function-associated antigen-1 on monocytes decreases very late antigen-4-mediated adhesion through a reactive oxygen species-dependent pathway. Blood 2004; 104 (13) 4046-4053
• 72 Cybulsky MI, Iiyama K, Li H. et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 2001; 107 (10) 1255-1262
• 73 Dustin ML, Springer TA. Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol 1988; 107 (01) 321-331
• 74 Patel SS, Thiagarajan R, Willerson JT, Yeh ET. Inhibition of alpha4 integrin and ICAM-1 markedly attenuate macrophage homing to atherosclerotic plaques in ApoE-deficient mice. Circulation 1998; 97 (01) 75-81
• 75 Nageh MF, Sandberg ET, Marotti KR. et al. Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1997; 17 (08) 1517-1520
• 76 Rose DM, Alon R, Ginsberg MH. Integrin modulation and signaling in leukocyte adhesion and migration. Immunol Rev 2007; 218: 126-134
• 77 Bazzoni G. The JAM family of junctional adhesion molecules. Curr Opin Cell Biol 2003; 15 (05) 525-530
• 78 Sullivan DP, Muller WA. Neutrophil and monocyte recruitment by PECAM, CD99, and other molecules via the LBRC. Semin Immunopathol 2014; 36 (02) 193-209
• 79 Shaw SK, Bamba PS, Perkins BN, Luscinskas FW. Real-time imaging of vascular endothelial-cadherin during leukocyte transmigration across endothelium. J Immunol 2001; 167 (04) 2323-2330
• 80 Beldman TJ, Malinova TS, Desclos E. et al. Nanoparticle-aided characterization of arterial endothelial architecture during atherosclerosis progression and metabolic therapy. ACS Nano 2019; 13 (12) 13759-13774
• 81 Hurt E, Bondjers G, Camejo G. Interaction of LDL with human arterial proteoglycans stimulates its uptake by human monocyte-derived macrophages. J Lipid Res 1990; 31 (03) 443-454
• 82 Hazen SL. Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity. J Biol Chem 2008; 283 (23) 15527-15531
• 83 Ismail NA, Alavi MZ, Moore S. Lipoprotein-proteoglycan complexes from injured rabbit aortas accelerate lipoprotein uptake by arterial smooth muscle cells. Atherosclerosis 1994; 105 (01) 79-87
• 84 Björkbacka H, Kunjathoor VV, Moore KJ. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 2004; 10 (04) 416-421
• 85 Stary HC, Chandler AB, Glagov S. et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994; 89 (05) 2462-2478
• 86 Raines EW. PDGF and cardiovascular disease. Cytokine Growth Factor Rev 2004; 15 (04) 237-254
• 87 Johnson JL. Matrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability. Expert Rev Cardiovasc Ther 2007; 5 (02) 265-282
• 88 Rocnik EF, Chan BM, Pickering JG. Evidence for a role of collagen synthesis in arterial smooth muscle cell migration. J Clin Invest 1998; 101 (09) 1889-1898
• 89 Yu Y, Cai Y, Yang F. et al. Vascular smooth muscle cell phenotypic switching in atherosclerosis. Heliyon 2024; 10 (18) e37727
• 90 Li G, Scull C, Ozcan L, Tabas I. NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol 2010; 191 (06) 1113-1125
• 91 Seimon TA, Nadolski MJ, Liao X. et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab 2010; 12 (05) 467-482
• 92 Kojima Y, Volkmer JP, McKenna K. et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 2016; 536 (7614): 86-90
• 93 Yancey PG, Ding Y, Fan D. et al. Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6Chigh monocytosis: evidence that the effects are not apolipoprotein E dependent. Circulation 2011; 124 (04) 454-464
• 94 Sambrano GR, Parthasarathy S, Steinberg D. Recognition of oxidatively damaged erythrocytes by a macrophage receptor with specificity for oxidized low density lipoprotein. Proc Natl Acad Sci U S A 1994; 91 (08) 3265-3269
• 95 Olejarz W, Łacheta D, Kubiak-Tomaszewska G. Matrix metalloproteinases as biomarkers of atherosclerotic plaque instability. Int J Mol Sci 2020; 21 (11) 3946
• 96 Kawai K, Kawakami R, Finn AV, Virmani R. Differences in stable and unstable atherosclerotic plaque. Arterioscler Thromb Vasc Biol 2024; 44 (07) 1474-1484
• 97 Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316 (22) 1371-1375
• 98 Stone PH, Coskun AU, Kinlay S. et al. Effect of endothelial shear stress on the progression of coronary artery disease, vascular remodeling, and in-stent restenosis in humans: in vivo 6-month follow-up study. Circulation 2003; 108 (04) 438-444
• 99 Yogo K, Shimokawa H, Funakoshi H. et al. Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice. Arterioscler Thromb Vasc Biol 2000; 20 (11) E96-E100
• 100 Galis ZS, Johnson C, Godin D. et al. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res 2002; 91 (09) 852-859
• 101 Korshunov VA, Schwartz SM, Berk BC. Vascular remodeling: hemodynamic and biochemical mechanisms underlying Glagov's phenomenon. Arterioscler Thromb Vasc Biol 2007; 27 (08) 1722-1728
• 102 Korshunov VA, Nikonenko TA, Tkachuk VA, Brooks A, Berk BC. Interleukin-18 and macrophage migration inhibitory factor are associated with increased carotid intima-media thickening. Arterioscler Thromb Vasc Biol 2006; 26 (02) 295-300
• 103 Inoue K, Motoyama S, Sarai M. et al. Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovasc Imaging 2010; 3 (07) 691-698
• 104 Hattori K, Ozaki Y, Ismail TF. et al. Impact of statin therapy on plaque characteristics as assessed by serial OCT, grayscale and integrated backscatter-IVUS. JACC Cardiovasc Imaging 2012; 5 (02) 169-177
• 105 Nicholls SJ, Puri R, Anderson T. et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 2016; 316 (22) 2373-2384
• 106 Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004; 109 (23, suppl 1): III39-III43
• 107 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
• 108 Marfella R, Prattichizzo F, Sardu C. et al. Evidence of an anti-inflammatory effect of PCSK9 inhibitors within the human atherosclerotic plaque. Atherosclerosis 2023; 378: 117180
• 109 Corti R, Osende J, Hutter R. et al. Fenofibrate induces plaque regression in hypercholesterolemic atherosclerotic rabbits: in vivo demonstration by high-resolution MRI. Atherosclerosis 2007; 190 (01) 106-113
• 110 Inaba T, Yagyu H, Itabashi N. et al. Cholesterol reduction and atherosclerosis inhibition by bezafibrate in low-density lipoprotein receptor knockout mice. Hypertens Res 2008; 31 (05) 999-1005
• 111 Grundy SM, Stone NJ, Bailey AL. et al. 2018 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 2019; 73 (24) e285-e350
• 112 Tsujita K, Sugiyama S, Sumida H. et al; PRECISE–IVUS Investigators. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol 2015; 66 (05) 495-507
• 113 Hussein O, Minasian L, Itzkovich Y, Shestatski K, Solomon L, Zidan J. Ezetimibe's effect on platelet aggregation and LDL tendency to peroxidation in hypercholesterolaemia as monotherapy or in addition to simvastatin. Br J Clin Pharmacol 2008; 65 (05) 637-645
• 114 Sternberg Z, Chichelli T, Sternberg D. et al. Quantitative and qualitative pleiotropic differences between Simvastatin single and Vytorin combination therapy in hypercholesterolemic subjects. Atherosclerosis 2013; 231 (02) 411-420
• 115 Muñoz-Pacheco P, Ortega-Hernández A, Miana M, Cachofeiro V, Fernández-Cruz A, Gómez-Garre D. Ezetimibe inhibits PMA-induced monocyte/macrophage differentiation by altering microRNA expression: a novel anti-atherosclerotic mechanism. Pharmacol Res 2012; 66 (06) 536-543
• 116 Qin L, Yang YB, Yang YX. et al. Inhibition of smooth muscle cell proliferation by ezetimibe via the cyclin D1-MAPK pathway. J Pharmacol Sci 2014; 125 (03) 283-291
• 117 Nerem RM, Cornhill JF. The role of fluid mechanics in atherogenesis. J Biomech Eng 1980; 102 (03) 181
• 118 de Simone G, Devereux RB, Chien S, Alderman MH, Atlas SA, Laragh JH. Relation of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 1990; 81 (01) 107-117
• 119 Zarins CK, Giddens DP, Bharadvaj BK, Sottiurai VS, Mabon RF, Glagov S. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ Res 1983; 53 (04) 502-514
• 120 Motomiya M, Karino T. Flow patterns in the human carotid artery bifurcation. Stroke 1984; 15 (01) 50-56
• 121 Rindt CC, van Steenhoven AA, Janssen JD, Reneman RS, Segal A. A numerical analysis of steady flow in a three-dimensional model of the carotid artery bifurcation. J Biomech 1990; 23 (05) 461-473
• 122 Perktold K, Resch M, Peter RO. Three-dimensional numerical analysis of pulsatile flow and wall shear stress in the carotid artery bifurcation. J Biomech 1991; 24 (06) 409-420
• 123 LoGerfo FW, Nowak MD, Quist WC. Structural details of boundary layer separation in a model human carotid bifurcation under steady and pulsatile flow conditions. J Vasc Surg 1985; 2 (02) 263-269
• 124 Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev 1995; 75 (03) 519-560
• 125 Gimbrone Jr MA, Resnick N, Nagel T, Khachigian LM, Collins T, Topper JN. Hemodynamics, endothelial gene expression, and atherogenesis. Ann N Y Acad Sci 1997; 811: 1-10 , discussion 10–11
• 126 Chiu JJ, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev 2011; 91 (01) 327-387
• 127 Gambillara V, Chambaz C, Montorzi G, Roy S, Stergiopulos N, Silacci P. Plaque-prone hemodynamics impair endothelial function in pig carotid arteries. Am J Physiol Heart Circ Physiol 2006; 290 (06) H2320-H2328
• 128 Conklin BS, Zhong DS, Zhao W, Lin PH, Chen C. Shear stress regulates occludin and VEGF expression in porcine arterial endothelial cells. J Surg Res 2002; 102 (01) 13-21
• 129 Ho BB, Lazcano-Etchebarne C, Schwartz A, Bai H, Ohashi Y, Dardik A. Hemodynamics in carotid artery stenosis. Int Angiol 2025; 44 (04) 271-282
• 130 Yang J, Zhang Y, Xue J. et al. Hemodynamic effects of stenosis with varying severity in different segments of the carotid artery using computational fluid dynamics. Sci Rep 2025; 15 (01) 4896
• 131 Tang D, Teng Z, Canton G. et al. Sites of rupture in human atherosclerotic carotid plaques are associated with high structural stresses: an in vivo MRI-based 3D fluid-structure interaction study. Stroke 2009; 40 (10) 3258-3263
• 132 Krams R, Cheng C, Helderman F. et al. Shear stress is associated with markers of plaque vulnerability and MMP-9 activity. EuroIntervention 2006; 2 (02) 250-256
• 133 Fitzgerald TN, Shepherd BR, Asada H. et al. Laminar shear stress stimulates vascular smooth muscle cell apoptosis via the Akt pathway. J Cell Physiol 2008; 216 (02) 389-395
• 134 Clarke MC, Figg N, Maguire JJ. et al. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med 2006; 12 (09) 1075-1080
• 135 Huang X, Teng Z, Canton G, Ferguson M, Yuan C, Tang D. Intraplaque hemorrhage is associated with higher structural stresses in human atherosclerotic plaques: an in vivo MRI-based 3D fluid-structure interaction study. Biomed Eng Online 2010; 9: 86
• 136 Tuenter A, Selwaness M, Arias Lorza A. et al. High shear stress relates to intraplaque haemorrhage in asymptomatic carotid plaques. Atherosclerosis 2016; 251: 348-354
• 137 dela Paz NG, Walshe TE, Leach LL, Saint-Geniez M, D'Amore PA. Role of shear-stress-induced VEGF expression in endothelial cell survival. J Cell Sci 2012; 125 (Pt 4): 831-843
• 138 Cheng C, van Haperen R, de Waard M. et al. Shear stress affects the intracellular distribution of eNOS: direct demonstration by a novel in vivo technique. Blood 2005; 106 (12) 3691-3698
• 139 Chen A, Chen Z, Su J, Pen J, Luo T, Zhong H. The effects of carotid plaque classification and bifurcation angle on plaque: a computational fluid dynamics simulation. Front Physiol 2025; 16: 1509875
• 140 Apaydin M, Cetinoglu K. Carotid angle in young stroke. Clin Imaging 2021; 70: 10-17
• 141 Phan TG, Beare RJ, Jolley D. et al. Carotid artery anatomy and geometry as risk factors for carotid atherosclerotic disease. Stroke 2012; 43 (06) 1596-1601
• 142 Jiang P, Chen Z, Hippe DS. et al. Association between carotid bifurcation geometry and atherosclerotic plaque vulnerability: a Chinese atherosclerosis risk evaluation study. Arterioscler Thromb Vasc Biol 2020; 40 (05) 1383-1391
• 143 Spanos K, Petrocheilou G, Livieratos L, Labropoulos N, Mikhailidis DP, Giannoukas AD. Carotid bifurcation geometry as assessed by ultrasound is associated with early carotid atherosclerosis. Ann Vasc Surg 2018; 51: 207-216
• 144 Strecker C, Krafft AJ, Kaufhold L. et al. Carotid geometry is an independent predictor of wall thickness - a 3D cardiovascular magnetic resonance study in patients with high cardiovascular risk. J Cardiovasc Magn Reson 2020; 22 (01) 67
• 145 Markl M, Wegent F, Zech T. et al. In vivo wall shear stress distribution in the carotid artery: effect of bifurcation geometry, internal carotid artery stenosis, and recanalization therapy. Circ Cardiovasc Imaging 2010; 3 (06) 647-655