Stabilisation of atherosclerotic plaques

Summary

Plaque rupture and subsequent thrombotic occlusion of the coronary artery account for as many as three quarters of myocardial infarctions. The concept of plaque stabilisation emerged about 20 years ago to explain the discrepancy between the reduction of cardiovascular events in patients receiving lipid lowering therapy and the small decrease seen in angiographic evaluation of atherosclerosis. Since then, the concept of a vulnerable plaque has received a lot of attention in basic and clinical research leading to a better understanding of the pathophysiology of the vulnerable plaque and acute coronary syndromes. From pathological and clinical observations, plaques that have recently ruptured have thin fibrous caps, large lipid cores, exhibit outward remodelling and invasion by vasa vasorum. Ruptured plaques are also focally inflamed and this may be a common denominator of the other pathological features. Plaques with similar characteristics, but which have not yet ruptured, are believed to be vulnerable to rupture. Experimental studies strongly support the validity of anti-inflammatory approaches to promote plaque stability. Unfortunately, reliable non-invasive methods for imaging and detection of such plaques are not yet readily available. There is a strong biological basis and supportive clinical evidence that low-density lipoprotein lowering with statins is useful for the stabilisation of vulnerable plaques. There is also some clinical evidence for the usefulness of antiplatelet agents, beta blockers and renin-angiotensin-aldosterone system inhibitors for plaque stabilisation. Determining the causes of plaque rupture and designing diagnostics and interventions to prevent them are urgent priorities for current basic and clinical research in cardiovascular area.

Atherosclerosis - imaging - plaque stabilisation - treatment - vulnerable plaques

• References

• 1 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
• 2 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
• 3 Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006; 47: C7-12.
• 4 Davies MJ. The pathophysiology of acute coronary syndromes. Heart 2000; 83: 361-366.
• 5 Schaar JA. et al. Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on the vulnerable plaque, June 17 and 18,2003, Santorini, Greece. Eur Heart J 2004; 25: 1077-1082.
• 6 Lloyd-Jones D. et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119: 480-486.
• 7 Mackay J, Mensah G. The Atlas of Heart Disease and Stroke. World Health Organization and US Centers for Disease Control and Prevention. 2004 Available at: http://www.who.int/cardiovascular_diseases/resources/atlas/en/
• 8 Brown BG. et al. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993; 87: 1781-1791.
• 9 Ambrose JA. In search of the „vulnerable plaque”: can it be localized and will focal regional therapy ever be an option for cardiac prevention?. J Am Coll Cardiol 2008; 51: 1539-1542.
• 10 Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart 1999; 82: 265-268.
• 11 Burke AP. et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 2001; 103: 934-940.
• 12 Falk E. et al. Coronary plaque disruption. Circulation 1995; 92: 657-671.
• 13 Narula J. et al. Arithmetic of vulnerable plaques for noninvasive imaging. Nat Clin Pract Cardiovasc Med 2008; 5 (Suppl. 02) S2-10.
• 14 Kolodgie FD. et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol 2001; 16: 285-292.
• 15 Virmani R. et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 1262-1275.
• 16 Cheruvu PK. et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. J Am Coll Cardiol 2007; 50: 940-949.
• 17 Wang JC. et al. Coronary artery spatial distribution of acute myocardial infarction occlusions. Circulation 2004; 110: 278-284.
• 18 Waxman S. et al. Detection and treatment of vulnerable plaques and vulnerable patients: novel approaches to prevention of coronary events. Circulation 2006; 114: 2390-2411.
• 19 Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983; 50: 127-134.
• 20 Yla-Herttuala S. et al. Glycosaminoglycans and apolipoproteins B and A-I in human aortas. Chemical and immunological analysis of lesion-free aortas from children and adults. Arteriosclerosis 1987; 7: 333-340.
• 21 Yla-Herttuala S. et al. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest 1989; 84: 1086-1095.
• 22 Stary HC. et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995; 92: 1355-1374.
• 23 Sluimer JC. et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol 2008; 51: 1258-1265.
• 24 Barger AC. et al. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 1984; 310: 175-177.
• 25 Kolodgie FD. et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003; 349: 2316-2325.
• 26 Kubo T. et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007; 50: 933-939.
• 27 Kolodgie FD. et al. Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 2000; 157: 1259-1268.
• 28 Motoyama S. et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009; 54: 49-57.
• 29 Pasterkamp G. et al. Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox. J Am Coll Cardiol 1998; 32: 655-662.
• 30 Nicholls SJ. et al. Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling: a pooled analysis of 5 intravascular ultrasound trials. J Am Coll Cardiol 2008; 52: 255-262.
• 31 Getz GS, Reardon CA. Diet and murine atherosclerosis. Arterioscler Thromb Vasc Biol 2006; 26: 242-249.
• 32 Jackson CL. et al. Assessment of unstable atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2007; 27: 714-720.
• 33 Schwartz SM. et al. Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol 2007; 27: 705-713.
• 34 Paigen B. et al. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 1987; 68: 231-240.
• 35 Plump AS. et al. Severe hypercholesterolemia and atherosclerosis in apolipopro- tein E-deficient mice created by homologous recombination in ES cells. Cell 1992; 71: 343-353.
• 36 Zhang SH. et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992; 258: 468-471.
• 37 Ishibashi S. et al. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 1994; 93: 1885-1893.
• 38 Suo J. et al. Hemodynamic shear stresses in the mouse aortas: implications for atherogenesis. Arterioscler Thromb Vasc Biol 2007; 27: 346-351.
• 39 Hu W. et al. Atherosclerotic lesions in the common coronary arteries of ApoE knockout mice. Cardiovasc Pathol 2005; 14: 120-125.
• 40 Rosenfeld ME. et al. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol 2000; 20: 2587-2592.
• 41 Rosenfeld ME. et al. Animal models of spontaneous plaque rupture: the holy grail of experimental atherosclerosis research. Curr Atheroscler Rep 2002; 4: 238-242.
• 42 Johnson JL, Jackson CL. Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse. Atherosclerosis 2001; 154: 399-406.
• 43 Heeneman S. et al. Control of atherosclerotic plaque vulnerability: insights from transgenic mice. Front Biosci. 2008; 13: 6289-6313.
• 44 Bentzon JF, Falk E. Atherosclerotic lesions in mouse and man: is it the same disease?. Curr Opin Lipidol 2010; 21: 434-440.
• 45 Shiomi M, Ito T. The Watanabe heritable hyperlipidemic (WHHL) rabbit, its characteristics and history of development: a tribute to the late Dr. Yoshio Watanabe. Atherosclerosis 2009; 207: 1-7.
• 46 Brasen JH. et al. Extracellular superoxide dismutase inhibits in-stent restenosis and accelerates endothelial recovery in stented atherosclerotic WHHL rabbit aorta. J Am Col Cardiol 2007; 50: 2249-2253.
• 47 Rosenfeld ME. et al. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis 1990; 10: 336-349.
• 48 Gerrity RG. et al. Dietary induced atherogenesis in swine. Am J Pathol 1979; 95: 775-792.
• 49 Granada JF. et al. Porcine models of coronary atherosclerosis and vulnerable plaque for imaging and interventional research. EuroIntervention 2009; 5: 140-148.
• 50 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6: 508-519.
• 51 Tedgui A, Mallat Z. Cytokines in atherosclerosis: Pathogenic and regulatory pathways. Physiol Rev 2006; 86: 515-581.
• 52 Martinez FO. et al. Alternative Activation of Macrophages: An Immunologic Functional Perspective. Annu Rev Immunol 2008; 27: 451-483.
• 53 Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8: 958-969.
• 54 Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005; 85: 1-31.
• 55 Bouhlel MA, Derudas B, Rigamonti E. et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 2007; 6: 137-143.
• 56 Boyle JJ, Harrington HA, Piper E. et al. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 2009; 174: 1097-1108.
• 57 Rigamonti E, Chinetti-Gbaguidi G, Staels B. Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men. Arterioscler Thromb Vasc Biol 2008; 28: 1050-1059.
• 58 Jandeleit-Dahm KAM, Calkin A, Tikellis C. et al. Direct antiatherosclerotic effects of PPAR agonists. Curr Opin Lipidology 2009; 20: 24-29.
• 59 Shibata N, Glass CK. Regulation of macrophage function in inflammation and atherosclerosis. J Lipid Res 2009; 50: S277-S281.
• 60 Teupser D. et al. Effect of Macrophage Overexpression of Murine Liver X Receptor-alpha (LXR-alpha) on Atherosclerosis in LDL-Receptor Deficient Mice. Arte- rioscler Thromb Vasc Biol 2008; 28: 2009-2015.
• 61 Odegaard JI. et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007; 447: 1116-1120.
• 62 Mallat Z. et al. Inhibition of transforming growth factor-p signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res 2001; 89: 930-934.
• 63 Gojova A. et al. Specific abrogation of transforming growth factor-Bsignaling in T cells alters atherosclerotic lesion size and composition in mice. Blood 2003; 102: 4052-4058.
• 64 Cipollone F. et al. Increased expression of transforming growth factor-p1 as a stabilizing factor in human atherosclerotic plaques. Stroke 2004; 35: 2253-2257.
• 65 Potteaux S. et al. Leukocyte-derived interleukin 10 is required for protection against atherosclerosis in low-density lipoprotein receptor knockout mice. Arte- rioscler Thromb Vasc Biol 2004; 24: 1474-1478.
• 66 Braunersreuther V. et al. Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2007; 27: 373-379.
• 67 Potteaux S. et al. Role of bone marrow-derived CC-chemokine receptor 5 in the development of atherosclerosis of low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol 2006; 26: 1858-1863.
• 68 Greaves DR. et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2001; 21: 923-929.
• 69 Cheng C. et al. Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J Clin Invest 2007; 117: 616-626.
• 70 Ionita MG. et al. High levels of myeloid-related protein 14 in human atherosclerotic plaques correlate with the characteristics of rupture-prone lesions. Arte- rioscler Thromb Vasc Biol 2009; 29: 1220-1227.
• 71 Bot I. et al. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation 2007; 115: 2516-2525.
• 72 Zernecke A. et al. Macrophage migration inhibitory factor in cardiovascular disease. Circulation 2008; 117: 1594-1602.
• 73 Bernhagen J. et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 2007; 13: 587-596.
• 74 De Kleijn DP. et al. Local atherosclerotic plaques are a source of prognostic biomarkers for adverse cardiovascular events. Arterioscler Thromb Vasc Biol 2010; 30: 612-619.
• 75 Ylâ-Herttuala S. et al. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci USA 1991; 88: 5252-5256.
• 76 Rutanen J. et al. Vascular endothelial growth factor-D expression in human atherosclerotic lesions. Cardiovasc Res 2003; 59: 971-979.
• 77 Celletti FL. et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med 2001; 7: 425-429.
• 78 Roy H. et al. VEGF-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, NF-kB, and RAGE in atherosclerotic lesions of diabetic Watanabe heritable hyperlipidemic rabbits. FASEB J 2006; 20: 2159-2161.
• 79 Lucerna M. et al. Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment. Blood 2007; 109: 122-129.
• 80 Leppânen P. et al. Gene transfers of VEGF-A, VEGF-B, VEGF-C and VEGF-D have no effects on atherosclerosis in hypercholesterolemic low-density lipoprotein-re- ceptor/apolipoprotein B48-deficient mice. Circulation 2005; 112: 1347-1352.
• 81 Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc Res 2006; 69: 614-624.
• 82 Sluijter JPG. et al. Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions - A study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms. Stroke 2006; 37: 235-239.
• 83 Newby AC. Metalloproteinases and vulnerable atherosclerotic plaques. Trends Cardiovasc Med 2007; 17: 253-258.
• 84 Khallou-Laschet J. et al. Macrophage plasticity in experimental atherosclerosis. PLoS ONE 2010; 5: e8852.
• 85 Mantovani A. et al. Macrophage diversity and polarization in atherosclerosis: A question of balance. Artherioscler Thromb Vasc Biol 2009; 29: 1419-1423.
• 86 von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007; 100: 27-40.
• 87 Huo Y. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 9: 61-67.
• 88 Koenen RR. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 2009; 15: 97-103.
• 89 Afek A. et al. Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice. Microvasc Res 2009; 77: 364-369.
• 90 Kraaijeveld AO. et al. CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms. Circulation 2007; 116: 1931-1941.
• 91 Chan MY. et al. Hypercoagulable states in cardiovascular disease. Circulation 2008; 118: 2286-2297.
• 92 Seehaus S. et al. Hypercoagulability inhibits monocyte transendothelial migration through protease-activated receptor-1-, phospholipase-cp-, phosphoi- nositide 3-kinase-, and nitric oxide-dependent signaling in monocytes and promotes plaque stability. Circulation 2009; 120: 774-784.
• 93 Herrmann J, Lerman A. The endothelium - the cardiovascular health barometer. Herz 2008; 33: 343-353.
• 94 Lavi S. et al. Segmental coronary endothelial dysfunction in patients with minimal atherosclerosis is associated with necrotic core plaques. Heart 2009; 95: 1525-1530.
• 95 Rong JX. et al. Arterial injury by cholesterol oxidation products causes endothelial dysfunction and arterial wall cholesterol accumulation. Arterioscler Thromb Vasc Biol 1998; 18: 1885-1894.
• 96 Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 2006; 113: 1708-1714.
• 97 Naruse K. et al. Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium dependent relaxation. Arterioscler Thromb 1994; 14: 746-752.
• 98 Wang BY. et al. Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit. J Am Coll Cardiol 1994; 23: 452-458.
• 99 Suwaidi JA. et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000; 101: 948-954.
• 100 Schachinger V. et al. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101: 1899-1906.
• 101 Halcox JP. et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002; 106: 653-658.
• 102 Shaw JA. et al. Diurnal variation in endothelium-dependent vasodilatation is not apparent in coronary artery disease. Circulation 2001; 103: 806-812.
• 103 Zerrouk A. et al. Role of endothelium in the endothelin-1-mediated potentiation of the norepinephrine response in the aorta of hypertensive rats. J Hypertension 1997; 15: 1101-1111.
• 104 Schafer A. et al. Reduced vascular NO bioavailability in diabetes increases platelet activation in vivo. Arterioscler Thromb Vasc Biol 2004; 24: 1720-1726.
• 105 Marcus AJ. et al. Role of CD39 (NTPDase-1) in thromboregulation, cerebroprotection, and cardioprotection. Semin Thromb Hemost 2005; 31: 234-246.
• 106 Hoffmeister HM. et al. Endothelial tissue-type plasminogen activator release in coronary heart disease: Transient reduction in endothelial fibrinolytic reserve in patients with unstable angina pectoris or acute myocardial infarction. J Am Coll Cardiol 1998; 31: 547-551.
• 107 Miller DL. et al. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression. J Leukocyte Biol 1998; 63: 373-379.
• 108 Gertz SD, Roberts WC. Hemodynamic shear force in rupture of coronary arterial atherosclerotic plaques. Am J Cardiol 1990; 66: 1368-1372.
• 109 Belkhiri A. et al. Increased expression of activated matrix metalloproteinase-2 by human endothelial cells after sublethal H2O2 exposure. Lab Invest 1997; 77: 533-539.
• 110 Taraboletti G. et al. Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol 2002; 160: 673-680.
• 111 Sugiyama S. et al. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler Thromb Vasc Biol 2004; 24: 1309-1314.
• 112 Tricot O. et al. Relation between endothelial cell apoptosis and blood flow direction in human atherosclerotic plaques. Circulation 2000; 101: 2450-2453.
• 113 Sumi T. et al. Disturbed blood flow induces erosive injury to smooth muscle cell- rich neointima and promotes thrombus formation in rabbit femoral artery. J Thromb Haemost 2010; 8: 1394-1402.
• 114 Sluimer JC, Daemen MJAP.. Novel concept in atherogenesis: Angiogenesis and hypoxia in atherosclerosis. J Pathol 2009; 218: 7-29.
• 115 Sluimer JC. et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions: relevance of compromised structural integrity for intraplaque microvascular leakage. J Am Coll Cardiol 2009; 53: 1517-1527.
• 116 Langheinrich AC. et al. Correlation of vasa vasorum neovascularization and plaque progression in aortas of apolipoprotein E (-/-)/low-density lipoprotein (-/-) double knockout mice. Arterioscler Thromb Vasc Biol 2006; 26: 347-352.
• 117 Galili O, Herrmann J, Woodrum J. et al. Adventitial vasa vasorum heterogeneity among different vascular beds. J Vasc Surg 2004; 40: 529-535.
• 118 Heistad DD, Armstrong ML, Marcus ML. Hyperemia of the aortic wall in atherosclerotic monkeys. Circ Res 1981; 48: 669-675.
• 119 Herrmann J. et al. Coronary vasa vasorum neovascularization precedes epicar- dial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res 2001; 51: 762-766.
• 120 Khurana R. et al. Angiogenesis-dependent and independent phases of intimal hyperplasia. Circulation 2004; 110: 2436-2443.
• 121 Virmani R. et al. Atherosclerotic Plaque Progression and Vulnerability to Rupture Angiogenesis as a Source of Intraplaque Hemorrhage. Arterioscler Thromb Vasc Biol 2005; 25: 2054-2061.
• 122 Moulton KS. et al. Angiogenesis inhibitors endostatin or TNP-470 reduce inti- mal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 1999; 99: 1726-1732.
• 123 Jain RK. et al. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nat Clin Pract Cardiovasc Med 2007; 4: 491-502.
• 124 Daher IN, Yeh ET. Vascular complications of selected cancer therapies. Nat Clin Pract Cardiovasc Med 2008; 5: 797-805.
• 125 Asahara T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-967.
• 126 Simper D. et al. Smooth muscle progenitor cells in human blood. Circulation 2002; 106: 1199-1204.
• 127 Sata M. et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002; 8: 403-409.
• 128 Foteinos G. et al. Rapid endothelial turnover in atherosclerosis-prone areas coincides with stem cell repair in apolipoprotein E-deficient mice. Circulation 2008; 117: 1856-1863.
• 129 Vasa M. et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89: E1-7.
• 130 Hill JM. et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593-600.
• 131 Werner N. et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005; 353: 999-1007.
• 132 Zoll J. et al. Role of human smooth muscle cell progenitors in atherosclerotic plaque development and composition. Cardiovasc Res 2008; 77: 471-480.
• 133 Güven H. et al. The number of endothelial progenitor cell colonies in the blood is increased in patients with angiographically significant coronary artery disease. J Am Coll Cardiol 2006; 48: 1579-1587.
• 134 Hristov M. et al. Reduced numbers of circulating endothelial progenitor cells in patients with coronary artery disease associated with long-term statin treatment. Atherosclerosis 2007; 192: 413-420.
• 135 Timmermans F. et al. Endothelial progenitor cells: Identity defined?. J Cell Mol Med 2009; 13: 87-102.
• 136 Sirker AA. et al. Vascular progenitor cells and translational research: the role of endothelial and smooth muscle progenitor cells in endogenous arterial remodelling in the adult. Clin Sci (Lond) 2009; 116: 283-299.
• 137 Prokopi M. et al. Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures. Blood 2009; 114: 723-732.
• 138 Bentzon JF. et al. Smooth muscle cells in atherosclerosis originate from the local vessel wall and not circulating progenitor cells in apoE knockout mice. Arte- rioscler Thromb Vasc Biol 2006; 26: 2696-2702.
• 139 Bentzon JF. et al. Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice. Circulation 2007; 116: 2053-2061.
• 140 Hagensen MK. et al. Circulating endothelial progenitor cells do not contribute to plaque endothelium in murine atherosclerosis. Circulation 2010; 121: 898-905.
• 141 Schroder K. et al. NADPH oxidase Nox2 is required for hypoxia-induced mobilization of endothelial progenitor cells. Circ Res 2009; 105: 537-544.
• 142 Sofi F. et al. Adherence to Mediterranean diet and health status: meta-analysis. Br Med J 2008; 337: a1344.
• 143 Thies F. et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 2003; 361: 477-485.
• 144 Hu MY. et al. Comparison of lycopene and fluvastatin effects on atherosclerosis induced by a high-fat diet in rabbits. Nutrition 2008; 24: 1030-1038.
• 145 Song L. et al. Quercetin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells through extracellular signal-regulated kinase. Arch Biochem Biophys 2001; 391: 72-78.
• 146 Romero M. et al. Quercetin inhibits vascular superoxide production induced by endothelin-1: Role of NADPH oxidase, uncoupled eNOS and PKC. Atherosclerosis 2009; 202: 58-67.
• 147 Xia X. et al. An anthocyanin-rich extract from black rice enhances atherosclerotic plaque stabilization in apolipoprotein E-deficient mice. J Nutr 2006; 136: 2220-2225.
• 148 Hartung D. et al. Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy. J Nucl Med 2005; 46: 2051-2056.
• 149 Naruszewicz M. et al. Chronic intake of potato chips in humans increases the production of reactive oxygen radicals by leukocytes and increases plasma C-reactive protein: a pilot study. Am J Clin Nutr 2009; 89: 773-777. Erratum in: Am J Clin Nutr 2009; 89: 1951
• 150 The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J Am Med Assoc 2002; 288: 2015-2022.
• 151 Teo KK. et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study. Lancet 2006; 368: 647-658.
• 152 Weisz G. et al. Impact of smoking status on outcomes of primary coronary intervention for acute myocardial infarction–the smoker’s paradox revisited. Am Heart J 2005; 150: 358-364.
• 153 Metz L, Waters DD. Implications of cigarette smoking for the management of patients with acute coronary syndromes. Prog Cardiovasc Dis 2003; 46: 1-9.
• 154 Wang TJ. et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 2006; 355: 2631-2639.
• 155 Ridker PM. 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: 2195-2207.
• 156 Calabro P. et al. CRP and the risk of atherosclerotic events. Semin Immunopath- ol 2009; 31: 79-94.
• 157 Emerging Risk Factors Collaboration. Kaptoge S. et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132-140.
• 158 Trion A. et al. No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-leiden/human C-reactive protein transgenic mice. Arterioscler Thromb Vasc Biol 2005; 25: 1635-1640.
• 159 Bisoendial RJ. et al. C-reactive protein and atherogenesis: from fatty streak to clinical event. Atherosclerosis 2007; 195: e10-8.
• 160 Kraaijeveld AO. et al. Chemokines and atherosclerotic plaque progression: towards therapeutic targeting? Review. Curr Pharm Des 2007; 13: 1039-1052.
• 161 Inokubo Y. et al. Plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 are increased in the coronary circulation in patients with acute coronary syndrome. Am Heart J 2001; 141: 211-217.
• 162 Kanse SM. et al. Factor VII-activating protease (FSAP): vascular functions and role in atherosclerosis, Review. Thromb Haemost 2008; 99: 286-289.
• 163 Naruko T. et al. Increased expression and plasma levels of myeloperoxidase are closely related to the presence of angiographically-detected complex lesion morphology in unstable angina. Heart 2010; 96: 1716-1722. Erratum in: Heart 2010 96 2044 2045.
• 164 Verhoeven BA. et al. Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design. Eur J Epidemiol 2004; 19: 1127-1133.
• 165 Marenberg ME. et al. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330: 1041-1046.
• 166 Jukema JW. et al. The Asp9 Asn mutation in the lipoprotein lipase gene is associated with increased progression of coronary atherosclerosis. REGRESS Study Group, Interuniversity Cardiology Institute, Utrecht, The Netherlands. Regression Growth Evaluation Statin Study. Circulation 1996; 94: 1913-1918.
• 167 Kuivenhoven JA. et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med 1998; 338: 86-93.
• 168 Monraats PS. et al. Genetic inflammatory factors predict restenosis after percutaneous coronary interventions. Circulation 2005; 112: 2417-2425.
• 169 Roy H. et al. Molecular genetics of atherosclerosis. Hum Genet 2009; 125: 467-491.
• 170 Samani NJ. et al. Genomewide association analysis of coronary artery disease. N Engl J Med 2007; 357: 443-453.
• 171 Turunen MP. et al. Epigenetics and atherosclerosis. Biochim Biophys Acta 2009; 1790: 886-891.
• 172 Pons ED. et al. Epigenetic histone acetylation modifiers in vascular remodelling: new targets for therapy in cardiovascular disease. Eur Heart J 2009; 30: 266-277.
• 173 Hoffmann U. et al. Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by multidetector computed tomography. J Am Coll Cardiol 2006; 47: 1655-1662.
• 174 Nishioka H. et al. Impact of HMG-CoA reductase inhibitors for non-treated coronary segments. Osaka City Med J 2004; 50: 61-68.
• 175 Kawasaki M. et al. In vivo quantitative tissue characterization of human coronary arterial plaques by use of integrated backscatter intravascular ultrasound and comparison with angioscopic findings. Circulation 2002; 105: 2487-2492.
• 176 Takano M. et al. Changes in coronary plaque color and morphology by lipidlowering therapy with atorvastatin: serial evaluation by coronary angioscopy. J Am Coll Cardiol 2003; 42: 680-686.
• 177 von Birgelen C. et al. Plaque distribution and vascular remodeling of ruptured and nonruptured coronary plaques in the same vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol 2001; 37: 1864-1870.
• 178 Nadkarni SK. et al. Measurement of collagen and smooth muscle cell content in atherosclerotic plaques using polarization-sensitive optical coherence tomography. J Am Coll Cardiol 2007; 49: 1474-1481.
• 179 Garcia-Garcia HM. et al. Virtual histology and remodeling index allow in vivo identification of allegedly high risk coronary plaques in patients with acute coronary syndromes: a three vessel intravascular ultrasound radiofrequency data analysis. Eurointervention 2006; 2: 338-344.
• 180 Wu JC, Ylâ-Herttuala S. Human gene therapy and imaging: cardiology. Eur J Nucl Med Mol Imaging 2005; 32: S346-S357.
• 181 Ambrose JA, Martinez EE. A new paradigm for plaque stabilization. Circulation 2002; 105: 2000-2004.
• 182 Brown G. et al. Regression of coronary artery disease as a result of intensive lipidlowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990; 323: 1289-1298.
• 183 Watts GF. et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet 1992; 339: 563-569.
• 184 Libby P, Aikawa M. Mechanisms of plaque stabilization with statins. Am J Cardiol 2003; 91: 4B-8B.
• 185 Crisby M. et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001; 103: 926-933.
• 186 Cortellaro M. et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost 2002; 88: 41-47.
• 187 Tuomisto TT. et al. Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor. Cardiovasc Res 2008; 78: 175-184.
• 188 Schartl M. et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation 2001; 104: 387-392.
• 189 Kawasaki M. et al. Volumetric quantitative analysis of tissue characteristics of coronary plaques after statin therapy using three-dimensional integrated backscatter intravascular ultrasound. J Am Coll Cardiol 2005; 45: 1946-1953.
• 190 Nissen SE. Effect of intensive lipid lowering on progression of coronary atherosclerosis: evidence for an early benefit from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. Am J Cardiol 2005; 96: 61F-68F.
• 191 Cannon CP. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495-1504.
• 192 Patti G. et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007; 49: 1272-1278.
• 193 Yusuf S. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
• 194 Wiviott SD. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
• 195 Wallentin L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
• 196 Olsson G. et al. Long-term treatment with metoprolol after myocardial infarction: effect on 3 year mortality and morbidity. J Am Coll Cardiol 1985; 5: 1428-1437.
• 197 Sipahi I. et al. Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 2007; 147: 10-18.
• 198 Dol F. et al. Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 2001; 38: 395-405.
• 199 Yusuf S. et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 145-153.
• 200 Yusuf S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547-1559.
• 201 Digby JE. et al. Nicotinic acid and the prevention of coronary artery disease. Curr Opin Lipidol 2009; 20: 321-326.
• 202 Lee JM. et al. Effects of high-dose modified-release nicotinic acid on athero-sclerosis and vascular function: a randomized, placebo-controlled, magnetic res-onance imaging study. J Am Coll Cardiol 2009; 54: 1787-1794.
• 203 Taylor AJ. et al. Extended-release niacin or ezetimibe and carotid intima-mediathickness. N Engl J Med 2009; 361: 2113-2122.
• 204 Shah PK. et al. High-dose recombinant apolipoprotein A-I(milano) mobilizestissue cholesterol and rapidly reduces plaque lipid and macrophage content inapolipoprotein e-deficient mice. Potential implications for acute plaque stabili-zation. Circulation 2001; 103: 3047-3050.
• 205 Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Die-tary supplementation with n-3 polyunsaturated fatty acids and vitamin E aftermyocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354: 447-455.
• 206 Jandeleit-Dahm KA. et al. Direct antiatherosclerotic effects of PPAR agonists. Curr Opin Lipidol 2009; 20: 24-29.
• 207 Meisner F. et al. Effect of rosiglitazone treatment on plaque inflammation andcollagen content in nondiabetic patients: data from a randomized placebo-con-trolled trial. Arterioscler Thromb Vasc Biol 2006; 26: 845-850.
• 208 Home PD. et al. Rosiglitazone evaluated for cardiovascular outcomes in oralagent combination therapy for type 2 diabetes (RECORD): a multicentre, rando-mised, open-label trial. Lancet 2009; 373: 2125-2135.
• 209 Nissen SE. et al. STRADIVARIUS Investigators. Effect of rimonabant on pro-gression of atherosclerosis in patients with abdominal obesity and coronary ar-tery disease: the STRADIVARIUS randomized controlled trial. JAMA 2008; 299: 1547-1560
• 210 Nissen SE. et al. ILLUSTRATE Investigators. Effect of torcetrapib on the progres-sion of coronary atherosclerosis. N Engl J Med 2007; 356: 1304-1316.
• 211 Häkkinen T. et al. Lipoprotein-associated phospholipase A2, platelet-activatingfactor acetylhydrolase, is expressed by macrophages in human and rabbit athero-sclerotic lesions. Arterioscler Thromb Vasc Biol 1999; 19: 2909-2917.
• 212 Wilensky RL. et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008; 14: 1059-1066.
• 213 Serruys PW. et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008; 118: 1172-1182.
• 214 De Nooijer R. et al. Lesional overexpression of matrix metalloproteinase-9 promotes intraplaque hemorrhage in advanced lesions but not at earlier stages of atherogenesis. Arterioscler Thromb Vasc Biol 2006; 26: 340-346.
• 215 Sukhova GK. et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2003; 111: 897-906.
• 216 Bea F. et al. Melagatran reduces advanced atherosclerotic lesion size and may promote plaque stability in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26: 2787-2792.
• 217 Koenen RR, Weber C. Therapeutic targeting of chemokine interactions in atherosclerosis. Nat Rev Drug Discov 2009; 9: 141-153.
• 218 Gulick RM. et al. MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008; 359: 1429-1441.
• 219 Binder CJ. et al. Innate and acquired immunity in atherogenesis. Nat Med 2002; 8: 1218-1226.
• 220 Nilsson J. et al. Immunomodulation of atherosclerosis: implications for vaccine development. Arterioscler Thromb Vasc Biol 2005; 25: 18-28.
• 221 Ludewig B. et al. Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model. Proc Natl Acad Sci USA 2000; 97: 12752-12757.
• 222 Menges M. et al. Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity. J Exp Med 2002; 195: 15-21.