Anti-Inflammatory Strategies for Plaque Stabilization after Acute Coronary Syndromes

  • Amos Baruch
  • Nicholas van Bruggen
  • Juyong Brian Kim
  • Joshua E. Lehrer-Graiwer
Vascular Biology (RS Rosenson, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Vascular Biology


Despite dramatic advances in standard of care, the risk of recurrent myocardial infarction early after an acute coronary syndrome (ACS) remains high. This period of elevated risk after a cardiovascular event is associated with an acute inflammatory response. While post-ACS inflammation correlates with the risk for recurrent events and is likely to play a causal role in this period, the precise pathophysiologic mechanisms have been unclear. Recent studies have proposed that the cardiac event itself activates the sympathetic nervous system to directly mobilize hematopoietic stem cells to differentiate into inflammatory monocytes, acutely infiltrate plaque, and lead to recurrent plaque rupture. Here, we summarize the existing and emerging evidence implicating post-ACS activation of systemic inflammation in the progression of atherosclerosis, and identify possible targets for therapeutic intervention. We highlight experimental therapies and ongoing clinical studies that will validate these targets.


Acute coronary syndrome Vulnerable plaque Inflammation Therapeutics Plaque stabilization 


Conflicts of Interest

Amos Baruch declares no conflicts of interest.

Nicholas van Bruggen declares no conflicts of interest.

Brian Kim declares no conflicts of interest.

Joshua Lehrer-Graiwer has stock options with Genentech.

A. Baruch, N van Bruggen and J Lehrer-Graiwer are employees of Genentech.

No other disclosures are required.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O'Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000;343(13):915–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Milonas C et al. Effect of angiotensin-converting enzyme inhibition on one-year mortality and frequency of repeat acute myocardial infarction in patients with acute myocardial infarction. Am J Cardiol. 2010;105:1229–34.PubMedCrossRefGoogle Scholar
  3. 3.
    Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial infarction: the Framingham study. Am J Cardiol. 1979;44(1):53–9.PubMedCrossRefGoogle Scholar
  4. 4.
    • Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, Mehran R, McPherson J, Farhat N, Marso SP, Parise H, Templin B, White R, Zhang Z, Serruys PW; PROSPECT Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364(3):226–35. This article prospectively followed the progression of plaques in patients with acute coronary syndrome (ACS) for median of 3.4 years using coronary angiography and radiofrequency intravascular ultrasound. Major finding was that the non-culprit lesions for initial ACS event were equally likely to cause major cardiovascular adverse events. These lesions were mostly angiographically mild but had characteristics of vulnerable plaque, including thin-cap fibroatheromas, large plaque burden or small luminal area.Google Scholar
  5. 5.
    Virmani R, Burke AP, Farb A. Plaque morphology in sudden coronary death. Cardiologia. 1998;43(3):267–71.Google Scholar
  6. 6.
    Kato Y, Yonetsu T, Kim S, Xing L, Lee H, McNulty I, et al. Nonculprit plaques in patients with acute coronary syndromes have more vulnerable features compared with those with non–acute coronary syndromes: a 3-vessel optical coherence tomography study. Circ Cardiovasc Imaging. 2012;5:433–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Rioufol G, Finet G, Ginon I, André-Fouët X, Rossi R, Vialle E, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002;106:804–8.PubMedCrossRefGoogle Scholar
  8. 8.
    MacNeill BD, Jang IK, Bouma BE, et al. Focal and multi-focal plaque macrophage distributions in patients with acute and stable presentations of coronary artery disease. J Am Coll Cardiol. 2004;44(5):972–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation. 2004;109:II2–10.PubMedGoogle Scholar
  10. 10.
    Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA. 1998;279(20):1643–50.PubMedCrossRefGoogle Scholar
  11. 11.
    Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005;4:977–87.PubMedCrossRefGoogle Scholar
  12. 12.
    Nissen E, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. For the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.PubMedCrossRefGoogle Scholar
  14. 14.
    Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, et al. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes. J Am Coll Cardiol. 2005;46(8):1405–10.PubMedCrossRefGoogle Scholar
  15. 15.
    Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. For the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Wilbert-Lampen U, Nickel T, Leistner D, Güthlin D, Matis T, Völker C, et al. Modified serum profiles of inflammatory and vasoconstrictive factors in patients with emotional stress-induced acute coronary syndrome during World Cup Soccer 2006. J Am Coll Cardiol. 2010;55(7):637–42.PubMedCrossRefGoogle Scholar
  17. 17.
    • Steptoe A, Wikman A, Molloy GJ, Messerli-Bürgy N, Kaski JC. Inflammation and symptoms of depression and anxiety in patients with acute coronary heart disease. Brain Behav Immun. 2012. doi:10.1016/j.bbi.2012.09.002. This study supports the concept that inflammatory cytokines and leukocytosis are related to stress and anxiety.
  18. 18.
    Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010;121(22):2437–45.PubMedCrossRefGoogle Scholar
  19. 19.
    Maekawa Y, Anzai T, Yoshikawa T, Asakura Y, Takahashi T, Ishikawa S, et al. Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction: a possible role for left ventricular remodeling. J Am Coll Cardiol. 2002;39(2):241–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Tsujioka H, Imanishi T, Ikejima H, Kuroi A, Takarada S, Tanimoto T, et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol. 2009;54(2):130–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204(12):3037–47.PubMedCrossRefGoogle Scholar
  22. 22.
    • Leuschner F, Rauch PJ, Ueno T, Gorbatov R, Marinelli B, Lee WW, et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med. 2012;209(1):123–37. The spleen hosts niches for extramedullary emergency monocytopoiesis that are important to the infarct healing process, but can also contribute to the risk of ASC recurrence in cases where the kinetics of monocyte response is altered.PubMedCrossRefGoogle Scholar
  23. 23.
    Aoki S, Nakagomi A, Asai K, Takano H, Yasutake M, Seino Y, et al. Elevated peripheral blood mononuclear cell count is an independent predictor of left ventricular remodeling in patients with acute myocardial infarction. J Cardiol. 2011;57(2):202–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Shantsila E, Lip GY. Monocytes in acute coronary syndromes. Arterioscler Thromb Vasc Biol. 2009;29(10):1433–8.PubMedCrossRefGoogle Scholar
  25. 25.
    • Rogacev KS, Cremers B, Zawada AM, Seiler S, Binder N, Ege P, et al. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol. 2012;60(16):1512–20.PubMedCrossRefGoogle Scholar
  26. 26.
    • Kashiwagi M, Imanishi T, Tsujioka H, Ikejima H, Kuroi A, Ozaki Y, et al. Association of monocyte subsets with vulnerability characteristics of coronary plaques as assessed by 64-slice multidetector computed tomography in patients with stable angina pectoris. Atherosclerosis. 2010;212(1):171–6. Strong association between circulating CD14+CD16+ monocytes and the presence of vulnerable plaques in angina patients suggests potential link between monocyte response post ACS and risk of event recurrence.PubMedCrossRefGoogle Scholar
  27. 27.
    • Imanishi T, Ikejima H, Tsujioka H, Kuroi A, Ishibashi K, Komukai K, et al. Association of monocyte subset counts with coronary fibrous cap thickness in patients with unstable angina pectoris. Atherosclerosis. 2010;212(2):628–35. Circulating CD14+CD16+CX3CR1+ monocytes were in strong correlation with reduced fibrous cap thickness as measured by intravascular optical coherence tomography (OCT) in patients admitted with unstable angina. Provides a link between monocyte response post ACS and plaque vulnerability.PubMedCrossRefGoogle Scholar
  28. 28.
    • Assmus B, Iwasaki M, Schächinger V, Roexe T, Koyanagi M, Iekushi K, et al. Acute myocardial infarction activates progenitor cells and increases Wnt signalling in the bone arrow. Eur Heart J. 2012;33(15):1911–9. AMI increases the number of CD34+ and CD133+ bone marrow cells within 7 days provides a potential link between catecholamine action following ACS and progenitor response in the bone marrow through Wnt signaling.PubMedCrossRefGoogle Scholar
  29. 29.
    Leone AM, Rutella S, Bonanno G, Abbate A, Rebuzzi AG, Giovannini S, et al. Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function. Eur Heart J. 2005;26(12):1196–204.PubMedCrossRefGoogle Scholar
  30. 30.
    Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, et al. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood. 2005;105(1):199–206.PubMedCrossRefGoogle Scholar
  31. 31.
    Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11(11):762–74.PubMedCrossRefGoogle Scholar
  32. 32.
    Combadière C, Potteaux S, Rodero M, Simon T, Pezard A, Esposito B, et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation. 2008;117(13):1649–57.PubMedCrossRefGoogle Scholar
  33. 33.
    Liaudet L, Rosenblatt-Velin N. Role of innate immunity in cardiac inflammation after myocardial infarction. Front Biosci (Schol Ed). 2013;5:86–104.CrossRefGoogle Scholar
  34. 34.
    Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339(6116):161–6.PubMedCrossRefGoogle Scholar
  35. 35.
    •• Shi C, Jia T, Mendez-Ferrer S, Hohl TM, Serbina NV, Lipuma L, et al. Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands. Immunity. 2011;34(4):590–601. Very low levels of circulating TLR ligands promote the release of bone marrow monocytes into the circulation, providing a possible mechanistic insight into the communication between remote sites of injury or inflammation and bone marrow responses.PubMedCrossRefGoogle Scholar
  36. 36.
    Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006;124(2):407–21.PubMedCrossRefGoogle Scholar
  37. 37.
    •• Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, et al. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487(7407):325–9. A provocative hypothesis of the mechanisms associated with event recurrence following acute coronary syndrome. The paper establishes the foundation for the understanding of increased CV risk in ACS patients and the potential therapeutic avenues to tackle such risk.PubMedCrossRefGoogle Scholar
  38. 38.
    Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Leuschner F, Panizzi P, Chico-Calero I, Lee WW, Ueno T, Cortez-Retamozo V, et al. Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ Res. 2010;107(11):1364–73.PubMedCrossRefGoogle Scholar
  40. 40.
    Robinette CD, Fraumeni Jr JF. Splenectomy and subsequent mortality in veterans of the 1939–45 war. Lancet. 1977;ii:127–9.CrossRefGoogle Scholar
  41. 41.
    • Gilbert J, Lekstrom-Himes J, Donaldson D, Lee Y, Hu M, Xu J, et al. MLN1202 Study Group. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. Am J Cardiol. 2011;107(6):906–11. The only clinical study to date that demonstrates the potential contribution of CCR2 to the pro-inflammatory condition in patients with CV disease.PubMedCrossRefGoogle Scholar
  42. 42.
    Hotchi J, Hoshiga M, Takeda Y, Yuki T, Fujisaka T, Ishihara T, et al. Plaque-stabilizing effect of angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker in a rabbit plaque model. J Atheroscler Thromb. 2013;20(3):257–66.PubMedCrossRefGoogle Scholar
  43. 43.
    Kuhnast SB, van der Hoorn JWA, van den Hoek AM, Havekes LM, Liau G, Jukema JW, et al. Aliskiren inhibits atherosclerosis development and improves plaque stability in APOE*3Leiden. CETP transgenic mice with or without treatment with atorvastatin. J Hypertens. 2012;30(1):107–16.PubMedCrossRefGoogle Scholar
  44. 44.
    Cipollone F, Fazia M, Iezzi A, Pini B, Cuccurullo C, Zucchelli M, et al. Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity. Circulation. 2004;109:1482–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Hoffmann C, Leitz MR, Oberdorf-Maass S, Lohse MJ, Klotz KN. Comparative pharmacology of human β-adrenergic receptor subtypes – characterization of stably transfected receptors in CHO cells. Naunyn Schmiedeberg’s Arch Pharmacol. 2004;369:151–9.CrossRefGoogle Scholar
  46. 46.
    Yonekawa K, Neidhart M, Altwegg LA, Wyss CA, Corti R, Vogl T, et al. Myeloid related proteins activate Toll-like receptor 4 in human acute coronary syndromes. Atherosclerosis. 2011;218(2):486–92.PubMedCrossRefGoogle Scholar
  47. 47.
    • Kashiwagi M, Imanishi T, Ozaki Y, Satogami K, Masuno T, Wada T, et al. Differential expression of Toll-like receptor 4 and human monocyte subsets in acute myocardial infarction. Atherosclerosis. 2012;221(1):249–53. Increased TLR4 expression levels on CD14+CD16+ monocytes at the culprit site in patients with ACS, suggesting the involvement of specific monocyte subsets in plaque destabilization.PubMedCrossRefGoogle Scholar
  48. 48.
    Methe H, Kim JO, Kofler S, Weis M, Nabauer M, Koglin J. Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation. 2005;111(20):2654–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Methe H, Brunner S, Wiegand D, Nabauer M, Koglin J, Edelman ER. Enhanced T-helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol. 2005;45(12):1939–45.PubMedCrossRefGoogle Scholar
  50. 50.
    Satoh M, Shimoda Y, Maesawa C, Akatsu T, Ishikawa Y, Minami Y, et al. Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction. Int J Cardiol. 2006;109(2):226–34.PubMedCrossRefGoogle Scholar
  51. 51.
    Liuzzo G, Angiolillo DJ, Buffon A, Rizzello V, Colizzi C, Ginnetti F, et al. Enhanced response of blood monocytes to in vitro lipopolysaccharide-challenge in patients with recurrent unstable angina. Circulation. 2001;103(18):2236–41.PubMedCrossRefGoogle Scholar
  52. 52.
    Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A. 2009;106(48):20388–93.PubMedCrossRefGoogle Scholar
  53. 53.
    Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011;123(6):594–604.PubMedCrossRefGoogle Scholar
  54. 54.
    Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86(2):515–81.PubMedCrossRefGoogle Scholar
  55. 55.
    Pasqui AL, Di Renzo M, Bova G, Maffei S, Pompella G, Auteri A, et al. Pro-inflammatory/anti-inflammatory cytokine imbalance in acute coronary syndromes. Clin Exp Med. 2006;6(1):38–44.PubMedCrossRefGoogle Scholar
  56. 56.
    Felge E et al. Modified phospholipids as anti-inflammatory compounds. Curr Opin Lipidol. 2010;21(6):525–9.CrossRefGoogle Scholar
  57. 57.
    Ridker PM et al. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162(4):597–605.PubMedCrossRefGoogle Scholar
  58. 58.
    De Palma R, Del Galdo F, Abbate G, Chiariello M, Calabró R, Forte L, et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation. 2006;113(5):640–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Gotsman I, Sharpe AH, Lichtman AH. T-cell costimulation and coinhibition in atherosclerosis. Circ Res. 2008;103(11):1220–31.PubMedCrossRefGoogle Scholar
  60. 60.
    • Zhao Z, Wu Y, Cheng M, Ji Y, Yang X, Liu P, et al. Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. Atherosclerosis. 2011;217(2):518–24. IFNg-producing Th1 cells the can also release IL-17 are implicated in ACS. This paper highlights the imbalance in T cell response following ACS, and suggests the potential involvement of pro-inflammatory T cells in the development of atherosclerotic plaque instability.PubMedCrossRefGoogle Scholar
  61. 61.
    Mor A, Luboshits G, Planer D, Keren G, George J. Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J. 2006;27(21):2530–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Liuzzo G, Kopecky SL, Frye RL, O'Fallon WM, Maseri A, Goronzy JJ, et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation. 1999;100(21):2135–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Nakajima T, Schulte S, Warrington KJ, Kopecky SL, Frye RL, Goronzy JJ, et al. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation. 2002;105(5):570–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Nakajima T, Goek O, Zhang X, Kopecky SL, Frye RL, Goronzy JJ, et al. De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes. Circ Res. 2003;93(2):106–13.PubMedCrossRefGoogle Scholar
  65. 65.
    Liuzzo G, Biasucci LM, Trotta G, Brugaletta S, Pinnelli M, Digianuario G, et al. Unusual CD4 + CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol. 2007;50(15):1450–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Dumitriu IE, Baruah P, Finlayson CJ, Loftus IM, Antunes RF, Lim P, et al. High levels of costimulatory receptors OX40 and 4-1BB characterize CD4 + CD28null T cells inpatients with acute coronary syndrome. Circ Res. 2012;110(6):857–69.PubMedCrossRefGoogle Scholar
  67. 67.
    Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost. 2009;7 Suppl 1:332–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Gómez-Guerrero C, Mallavia B, Egido J. Targeting inflammation in cardiovascular diseases. still a neglected field? Cardiovasc Ther. 2012;30(4):e189-97. doi:10.1111/j.1755-5922.2011.00274.x.
  69. 69.
    Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685–95.PubMedCrossRefGoogle Scholar
  70. 70.
    Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, Shibata N, et al. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell. 2012;151(1):138–52.PubMedCrossRefGoogle Scholar
  71. 71.
    Tabas L. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2010;10(1):36–46.PubMedGoogle Scholar
  72. 72.
    van Gils JM, Derby MC, Fernandes LR, Ramkhelawon B, Ray TD, Rayner KJ, et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol. 2012;13(2):136–43.PubMedCrossRefGoogle Scholar
  73. 73.
    Björkerud S, Björkerud B. Am J Pathol. 1996;149(2):367–80.PubMedGoogle Scholar
  74. 74.
    Saso L, Firuzi O, Miri R, Tavakkoli M. Antioxidant therapy: current status and future prospects. Curr Med Chem. 2011;25:3871–88.Google Scholar
  75. 75.
    Merched AJ, Williams E, Chan L. Macrophage-specific p53 expression plays a crucial role in atherosclerosis development and plaque remodeling. Arterioscler Thromb Vasc Biol. 2003;23(9):608–14.CrossRefGoogle Scholar
  76. 76.
    Liu J, Thewke DP, Su YR, Linton MF, Fazio S, Sinensky MS. Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice. Arterioscler Thromb Vasc Biol. 2005;25(1):174–9.PubMedGoogle Scholar
  77. 77.
    Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005;25(11):2255–64.PubMedCrossRefGoogle Scholar
  78. 78.
    Hotamisligil GS. Endoplasmic reticulum stress and atherosclerosis. Nat Med. 2010;16(4):396–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Schrijvers DM, De Meyer GR, Martinet W. Autophagy in atherosclerosis: a potential drug target for plaque stabilization. Arterioscler Thromb Vasc Biol. 2011;31(12):2787–91.Google Scholar
  80. 80.
    Ouimet M, Franklin V, Mak E, Liao X, Tabas I, Marcel YL. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 2011;13(6):655–67.PubMedCrossRefGoogle Scholar
  81. 81.
    Tardif JC, L'Allier PL, Grégoire J, Ibrahim R, McFadden G, Kostuk W, et al. A randomized controlled, phase 2 trial of the viral serpin Serp-1 in patients with acute coronary syndromes undergoing percutaneous coronary intervention. Circ Cardiovasc Interv. 2010;3(6):543–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Dong B, Zhang C, Feng JB, Zhao YX, Li SY, Yang YP, et al. Overexpression of ACE2 enhances plaque stability in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28(7):1270–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Rosenson RS, Brewer Jr HB, Davidson WS, Fayad ZA, Fuster V, Goldstein J, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012;125(15):1905–19.PubMedCrossRefGoogle Scholar
  84. 84.
    Nissen SE et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290(17):2292–300.PubMedCrossRefGoogle Scholar
  85. 85.
    Vucic E, Rosenson RS. Recombinant high-density lipoprotein formulations. Curr Atheroscler Rep. 2011;13(1):81–7.PubMedCrossRefGoogle Scholar
  86. 86.
    O'Donoghue ML, Braunwald E, White HD, Serruys P, Steg PG, Hochman J, et al. Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J. 2011;162(4):613–619.e1.PubMedCrossRefGoogle Scholar
  87. 87.
    Serruys PW, García-García HM, Buszman P, Erne P, Verheye S, Aschermann M, et al. Integrated Biomarker and Imaging Study-2 Investigators. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation. 2008;118(11):1172–82.PubMedCrossRefGoogle Scholar
  88. 88.
    Rosenson RS, Stafforini DM. Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2. J Lipid Res. 2012;53(9):1767–82.PubMedCrossRefGoogle Scholar
  89. 89.
    Verheye S. Selective clearance of macrophages in atherosclerotic plaques by autophagy. J Am Coll Cardiol. 2007;49(6): 798706–15Google Scholar
  90. 90.
    Bailey D et al. A small molecule that increases apolipoprotein a-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55(23):2580–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Grommes J et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med. 2012;185(6):628–36.PubMedCrossRefGoogle Scholar
  92. 92.
    Bhaskar V et al. Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice. Atherosclerosis. 2011;216(2):313–20.PubMedCrossRefGoogle Scholar
  93. 93.
    Arsian F et al. Treatment with OPN-305, a humanized anti-Toll-Like receptor-2 antibody, reduces myocardial ischemia/reperfusion injury in pigs. Circ Cardiovasc Interv. 2012;5(2):279–87.CrossRefGoogle Scholar
  94. 94.
    Melloni C et al. The study of LoSmapimod treatment on inflammation and InfarCtSizE (SOLSTICE): design and rationale. Am Heart J. 2012;164(5):646–53.PubMedCrossRefGoogle Scholar
  95. 95.
    Liehn EA et al. A New Monocyte chemotactic protein-1/Chemokine CC motif ligand-2 competitor limiting neointima formation and myocardial ischemia/reperfusion injury in mice. J Am Coll Cardiol. 2010;56(22):1847–57.PubMedCrossRefGoogle Scholar
  96. 96.
    Khuseyinova N et al. Predicting the risk of cardiovascular disease: where does lipoprotein-associated phospholipase A(2) fit in? Mol Diagn Ther. 2007;11(4):203–17.PubMedCrossRefGoogle Scholar
  97. 97.
    Li JS, Jaggers J, Anderson PA. The use of TP10, soluble complement receptor 1, in cardiopulmonary bypass. Expert Rev Cardiovasc Ther. 2006;4(5):649–54.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Amos Baruch
    • 1
  • Nicholas van Bruggen
    • 1
  • Juyong Brian Kim
    • 2
  • Joshua E. Lehrer-Graiwer
    • 1
  1. 1.Genentech Research and Early DevelopmentSouth San FranciscoUSA
  2. 2.Division of CardiologyStanford University Department of MedicineStanfordUSA

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