Cholesterol crystals piercing the arterial plaque and intima trigger local and systemic inflammation

Published:March 17, 2010DOI:https://doi.org/10.1016/j.jacl.2010.03.003

      Abstract

      The response to arterial wall injury is an inflammatory process, which over time becomes integral to the development of atherosclerosis and subsequent plaque instability. However, the underlying injurious agent, critical to this process, has not received much attention. In this review, a model of plaque rupture is hypothesized with two stages of inflammatory activity. In stage I (cholesterol crystal-induced cell injury and apoptosis), intracellular cholesterol crystals induce foam cell apoptosis, setting up a vicious cycle by signaling more macrophages, resulting in accumulation of extra cellular lipids. This local inflammation eventually leads to the formation of a semi-liquid, lipid-rich necrotic core of a vulnerable plaque. In stage II (cholesterol crystal-induced arterial wall injury), the saturated lipid core is now primed for crystallization, which can manifest as a clinical syndrome with a systemic inflammation response. Cholesterol crystallization is the trigger that causes core expansion, leading to intimal injury. We recently demonstrated that when cholesterol crystallizes from a liquid to a solid state, it undergoes volume expansion, which can tear the plaque cap. This observation of cholesterol crystals perforating the cap and intimal surface was made in the plaques of patients who died with acute coronary syndrome. We have also demonstrated that several agents (ie, statins, aspirin, and ethanol) can dissolve cholesterol crystals and may be exerting their immediate benefits by this direct mechanism. Also, because recent studies have demonstrated that high-sensitivity C-reactive protein may be a reliable marker in selecting patients for statin therapy, it could reflect the presence of intimal injury by cholesterol crystals. This was demonstrated in an atherosclerotic rabbit model. Therefore, we propose that cholesterol crystallization could help explain in part both local and systemic inflammation associated with atherosclerosis.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Journal of Clinical Lipidology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kumar
        • Abbas
        • Fausto
        Robbins and Cotran Pathologic Basis of Disease.
        Acute and Chronic Inflammation. 7th ed. Saunders Elsevier, Philadelphia2005 (47–85)
        • Virchow R.
        Cellular Pathology as Based Upon Physiological and Pathological Histology (translated by Frank Chance from the 2nd German Edition).
        John Churchill, London1860 (360)
        • Ross R.
        Atherosclerosis-an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Libby P.
        Inflammation in atherosclerosis.
        Nature. 2002; 420: 868-874
        • Small D.M.
        George Lyman Duff memorial lecture. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry.
        Arterioscler Thromb Vasc Biol. 1988; 8: 103-129
        • Abela G.S.
        • Aziz K.
        Cholesterol crystals cause mechanical damage to biological membranes: a proposed mechanism of plaque rupture and erosion leading to arterial thrombosis.
        Clin Cardiol. 2005; 28: 413-420
        • Abela G.S.
        • Aziz K.
        Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events: a novel insight into plaque rupture by scanning electron microscopy.
        Scanning. 2006; 28: 1-10
        • Lundber B.
        Chemical composition and physical state of lipid deposits in atherosclerosis.
        Atherosclerosis. 1985; 56: 93-110
        • Abela G.S.
        • Aziz K.
        • Vedre A.
        • Pathak D.
        • Talbott J.D.
        • Joyce DeJong J.
        Effect of cholesterol crystals on plaques and intima in arteries of patients with acute coronary and cerebrovascular syndromes.
        Am J Cardiol. 2009; 103: 959-968
        • Ridker P.M.
        • Hennekens C.H.
        • Buring J.E.
        • Rifai N.
        C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
        N Engl J Med. 2000; 342: 836-843
        • Wong N.D.
        • Gransar H.
        • Narula J.
        • et al.
        Myeloperoxidase, subclinical atherosclerosis, and cardiovascular disease events.
        JACC Cardiovasc Imaging. 2009; 2: 1093-1099
        • Currie C.J.
        • Poole C.D.
        • Conway P.
        Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality.
        Heart. 2008; 94: 457-462
        • Sabatine M.S.
        • Morrow D.A.
        • Jablonski K.A.
        • et al.
        PEACE Investigators. Prognostic significance of the centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease.
        Circulation. 2007; 115: 1528-1536
        • Ridker P.M.
        • Cannon C.P.
        • Morrow D.
        • et al.
        Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-Reactive protein levels and outcomes after statin therapy.
        N Engl J Med. 2005; 352: 20-28
        • Ridker P.
        • Rifai N.
        • Rose L.
        • Buring J.E.
        • Cook N.R.
        Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.
        N Engl J Med. 2002; 347: 1557-1565
        • Koenig W.
        • Twardella D.
        • Brenner H.
        • Rothenbacher D.
        Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function and hemodynamic stress (KAROLA).
        Artheroscler Thromb Vasc Biol. 2006; 26: 1586-1593
        • Ridker P.M.
        • Danielson E.
        • Fonseca F.A.
        • 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
        • Kinlay S.
        • Egido J.
        Inflammatory biomarkers in stable atherosclerosis.
        Am J Cardiol. 2006; (2P-8P): 98
        • Fichtlscherer S.
        • Heeschen C.
        • Zeiher A.M.
        Inflammatory markers and coronary artery disease.
        Curr Op Pharmacol. 2004; 4: 124-131
        • Schwartz G.G.
        • Olsson A.G.
        • Ezekowitz M.G.
        • et al.
        Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study.
        JAMA. 2001; 285: 1711-1718
        • Serruys P.W.
        • de Feyter P.
        • Macaya C.
        • et al.
        Lescol Intervention Prevention Study (LIPS) Investigators. Lescol Intervention Prevention Study (LIPS) Investigators. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
        JAMA. 2002; 287: 3215-3222
        • de Lemos J.A.
        • Blazing M.A.
        • Wiviott S.D.
        • et al.
        A to Z Investigators. Early intensive vs. a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
        JAMA. 2004; 292: 1307-1316
        • Fonarow G.C.
        • Wright R.S.
        • Spencer F.A.
        • et al.
        National Registry of Myocardial Infarction 4 Investigators. Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality.
        Am J Cardiol. 2005; 96: 611-616
        • Fernández-Jarne E.
        • Martínez-Losa E.
        • Serrano-Martínez M.
        • et al.
        Type of alcoholic beverage and first acute myocardial infarction: a case-control study in a Mediterranean country.
        Clin Cardiol. 2003; 26: 313-318
        • O'Keefe J.H.
        • Bybee K.A.
        • Lavie C.J.
        Alcohol and cardiovascular health: the razor-sharp double–edged sword.
        J Am Coll Cardiol. 2007; 50: 1009-1014
        • Di Castelnuovo A.
        • Rotondo S.
        • Iacoviello L.
        • Benedetta Donati M.
        • de Gaetano G.
        Meta-analysis of wine and beer consumption in relation to vascular risk.
        Circulation. 2002; 105: 2836-2844
        • Baigent C.
        • Blackwell L.
        • Collins R.
        • et al.
        • Antithrombotic Trialists' (ATT) Collaboration
        Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials.
        Lancet. 2009; 373: 1849-1860
        • Collins R.
        • Peto R.
        • Baigent C.
        • Sleight P.
        Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction.
        N Engl J Med. 1997; 336: 847-860
        • Abela G.S.
        • Aziz K.
        • Huang R.
        • DeJong J.
        Statins inhibit cholesterol crystallization and prevent perforation of biological membranes and intima in human coronary arteries of patients with acute coronary syndrome.
        J Am Coll Cardiol. 2007; 49 (A358)
        • Vedre A.
        • Aziz K.
        • Huang R.
        • Abela G.S.
        Aspirin prevents cholesterol crystallization: a potential mechanism of plaque stabilization.
        J Am Coll Cardiol. 2008; 51 (A318)
        • Kibe A.
        • Holzbach R.T.
        • LaRusso N.F.
        • Mao S.J.
        Inhibition of cholesterol crystal formation by apolipoproteins in supersaturated model bile.
        Science. 1984; 225: 514-516
        • Jialal I.
        • Miguelino E.
        • Griffen S.C.
        • Devaraj S.
        Concomitant reduction of low-density lipoprotein-cholesterol and biomarkers of inflammation with low-dose simvastatin therapy in patients with type 1 diabetes.
        J Clin Endocrinol Metab. 2007; 92: 3136-3140
        • Albert M.A.
        • Glynn R.J.
        • Ridker P.M.
        Alcohol consumption and plasma concentration of C-reactive protein.
        Circulation. 2003; 107: 443-447
        • Ridker P.M.
        • Cushman M.
        • Stampfer M.J.
        • Tracy R.P.
        • Hennekens C.H.
        Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.
        N Engl J Med. 1997; 336: 973-979
        • Multiple Risk Factor Intervention Trial Research Group
        Multiple risk factor intervention trial. Risk factor changes and mortality results.
        JAMA. 1982; 248: 1465-1477
        • Scandinavian Simvastatin Survival Study Group
        Randomized trial of cholesterol lowering in 4444 participants with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
        Lancet. 1994; 344: 1383-1389
        • Heart Protection Study Collaborative Group
        Cost effectiveness of simvastatin in people at different levels of vascular disease risk: economic analysis of a randomized trial in 20 536 individuals.
        Lancet. 2005; 365: 1779-1785
        • Lipid Research Clinic Program
        The Lipid Research Clinics Coronary Primary Prevention Trial results, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering.
        JAMA. 1984; 251: 365-374
        • Shepherd J.
        • Cobbe S.M.
        • Ford I.
        • et al.
        Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
        N Engl J Med. 1995; 333: 1301-1307
        • Sacks F.M.
        • Pfeffer M.A.
        • Moye L.A.
        • et al.
        The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators.
        N Engl J Med. 1996; 335: 1001-1009
        • Downs J.R.
        • Clearfield M.
        • Weis S.
        • et al.
        Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
        JAMA. 1998; 279: 1615-1622
        • Davies M.J.
        • Thomas A.C.
        Plaque fissuring: the cause of acute myocardial infarction causing sudden ischaemic death, and crecendo angina.
        Br Heart J. 1985; 53: 363-373
        • Schaar J.A.
        • Muller J.E.
        • Falk E.
        • et al.
        Terminology for high-risk and vulnerable coronary artery plaques.
        Eur Heart J. 2004; 25: 1077-1082
        • Muller J.E.
        • Abela G.S.
        • Nesto R.W.
        • Toffler G.H.
        Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier.
        J Am Coll Cardiol. 1994; 23: 809-813
      1. Stone GW and PROSPECT Investigators. Providing regional observations to study predictors of events in the coronary tree (The PROSPECT Trial). Presented at: Transcatheter Cardiovascular Therapeutics Conference. San Francisco, CA, USA, September 10, 2009

        • Lamarche B.
        • Tchernof A.
        • Moorjani S.
        • et al.
        Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study.
        Circulation. 1997; 95: 69-75
        • Chan L.
        • Dresel H.A.
        Genetic factors influencing lipoprotein structure: implications for atherosclerosis.
        Lab Invest. 1990; 62: 522-537
        • Hurt-Camejo E.
        • Camejo G.
        • Rosengren B.
        • López F.
        • Wiklund O.
        • Bondjers G.
        Differential uptake of proteoglycan-selected subfractions of low density lipoprotein by human macrophages.
        J Lipid Res. 1990; 31: 1387-1398
        • Khalil M.F.
        • Wagner W.D.
        • Goldberg I.J.
        Molecular interactions leading to lipoprotein retention and the initiation of atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2004; 24: 2211-2218
        • Brown M.S.
        • Goldstein J.L.
        A receptor-mediated pathway for cholesterol homeostasis.
        Science 1986. 1986; 232: 34-47
        • Guyton J.R.
        • Klemp K.F.
        Development of the lipid-rich core in human atherosclerosis.
        Athero Thromb Vasc Biol. 1996; 16: 4-11
      2. Duewell P, Kono H, Bauernfeind F, et al. NLRP3 Inflamasomes are required for atherogenesis and activated by cholesterol crystals that form early in disease. Nature. [In Press].

        • Kellner-Weibel G.
        • Jerome W.G.
        • et al.
        Effect of intracellular free cholesterol accumulation on macrophage viability: a model for foam cell death.
        Arterioscler Thromb Vasc Biol. 1998; 18: 423-431
        • Geng Y.-J.
        • Phillips J.E.
        • Mason R.P.
        • Casscells S.W.
        Cholesterol crystallization and macrophage apoptosis: implication for atherosclerotic plaque instability and rupture.
        Biochem Pharm. 2003; 66: 1485-1492
        • Kolodgie F.D.
        • Gold H.K.
        • Burke A.P.
        • et al.
        Intraplaque hemorrhage and progression of coronary atheroma.
        N Engl J Med. 2003; 349: 2316-2325
        • Levy A.P.
        • Moreno P.R.
        Intraplaque hemorrhage.
        Curr Mol Med. 2006; 6: 479-488
        • Barger A.C.
        • Beeuwkes 3rd, R.
        Rupture of coronary vas vasorum as a trigger of acute myocardial infarction.
        Am J Cardiol. 1990; 66: 41G-43G
        • Abela G.S.
        • Maheshwari A.
        • Kantipudi S.C.
        Atherosclerotic vascular disease as a systemic process.
        in: Abela G.S. Peripheral Vascular Disease: Basic Diagnostic and Therapeutic Approaches. Lippincott, New York2004: 23-36
        • Nair P.N.
        • Sjögren U.
        • Sundqvist G.
        Cholesterol crystals as an etiological factor in on-resolving chronic inflammation: an experimental study in guinea pigs.
        Eur J Oral Sci. 1998; 106: 644-650
        • Vedre A.
        • Pathak D.R.
        • Crimp M.
        • Lum C.
        • Koochesfahani M.
        • Abela G.S.
        Physical factors that trigger cholesterol crystallization leading to plaque rupture.
        Atherosclerosis. 2009; 203: 89-96
        • Bogren H.
        • Larson K.
        An X-ray-Diffraction study of crystalline cholesterol in some pathological deposits in man.
        Bio Biophys Acta. 1963; 75: 65-69
        • Gerber Y.
        • Jacobsen S.J.
        • Killian J.M.
        • Weston S.A.
        • Roger V.L.
        Seasonability and daily weather conditions in relation to myocardial infarction and sudden cardiac death in Olmsted County, Minnesota, 1979 to 2002.
        J Am Coll Cardiol. 2006; 48: 287-292
        • Mittleman M.A.
        • Maclure M.
        • Tofler G.H.
        • Sherwood J.B.
        • Goldberg R.J.
        • Muller J.E.
        Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion.
        N Engl J Med. 1993; 329: 1677-1683
        • Abela G.S.
        The role of cholesterol crystals in myocardial infarction and stroke: a review.
        Clin Lipidol. 2010; 5: 57-69
        • Arbustini E.
        • Dal Bello B.
        • Morbini P.
        • et al.
        Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction.
        Heart. 1999; 82: 269-272
        • Aziz K.
        • Berger K.
        • Claycombe K.
        • Huang R.
        • Patel R.
        • Abela G.S.
        Non-invasive detection and localization of vulnerable plaque and arterial thrombosis using CTA/PET.
        Circulation. 2008; 117: 2061-2070
        • Patel R.
        • Vedre A.
        • Rubinstein J.
        • Shamoun F.
        • Tamhane U.
        • Abela G.S.
        Cholesterol lowering inhibits crystal formation with associated plaque disruption, thrombosis and inflammation.
        Atherosclerosis. 2009; 10 (P156)
        • Morrow D.A.
        • Rifai N.
        • Antman E.M.
        • et al.
        C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy.
        J Am Coll Cardiol. 1998; 31: 1460-1465
        • Heeschen C.
        • Hamm C.W.
        • Bruemmer J.
        • Simoons M.L.
        Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE investigators. Chimeric c7E3 AntiPlatelet therapy in unstable angina refractory to standard treatment trial.
        J Am Coll Cardiol. 2000; 35: 1535-1542
        • Lindahl B.
        • Toss H.
        • Siegbahn A.
        • Venge P.
        • Wallentin L.
        Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during instability in coronary artery disease.
        N Engl J Med. 2000; 343: 1139-1147
        • Mueller C.
        • Buettner H.J.
        • Hodgson J.M.
        • Marsch S.
        • Perruchoud A.P.
        • Roskamm H.
        • Neumann F.J.
        Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients.
        Circulation. 2002; 105: 1412-1415
        • Lendon C.L.
        • Born G.V.R.
        • Richardson P.D.
        Atherosclerotic plaque caps are locally weakened when macrophages density is increased.
        Atherosclerosis. 1991; 87: 87-90
        • Galis Z.S.
        • Sukhova G.K.
        • Lark M.W.
        • Libby P.
        Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.
        J Clin Invest. 1994; 94: 2493-2503
        • Rossi A.
        • Franceschini L.
        • Fusaro M.
        • et al.
        Carotid atherosclerotic plaque instability in patients with acute myocardial infarction.
        Int J Cardiol. 2006; 111: 263-266
        • Rioufol G.
        • Finet G.
        • Ginon I.
        • et al.
        Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study.
        Circulation. 2002; 106: 804-808
        • Ueda Y.
        • Oyabu J.
        • Okada K.
        • Murakawa T.
        • Hirayama A.
        • Kodama K.
        Angioscopically-determined extent of coronary atherosclerosis is associated with severity of acute coronary syndrome.
        J Invasive Cardiol. 2006; 18: 220-225
        • Lutgens E.
        • van Suylen R.-J.
        • Faber B.C.
        • et al.
        Atherosclerotic plaque rupture: local or systemic process?.
        Arterioscler Thromb Vasc Biol. 2003; 23: 2123-2130
        • Tanaka A.
        • Shimada K.
        • Sano T.
        • et al.
        Multiple plaque rupture and C-reactive protein in acute myocardial infarction.
        J Am Coll Cardiol. 2005; 45: 1594-1599
        • Shamoun F.
        • Tamhane U.
        • Vedre A.
        • Abela G.S.
        Cholesterol crystals disrupt atherosclerotic plaques in several arterial beds.
        Vascular Med. 2009; 14 (P172)
        • Epstein S.E.
        • Zhu J.
        • Najafi A.H.
        • Burnett M.S.
        Insights into the role of infection in atherogenesis and in plaque rupture.
        Circulation. 2009; 119: 3133-3141
        • Park E.K.
        • Jung H.S.
        • Yang H.I.
        • Yoo M.C.
        • Kim C.
        • Kim K.S.
        Optimized THP-1 differentiation is required for the detection of responses to weak stimuli.
        Inflamm Res. 2007; 56: 45-50
        • LaRosa J.C.
        • Grundy S.M.
        • Waters D.D.
        • et al.
        Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
        N Engl J Med. 2005; 352: 1425-1435
        • Mao G.
        • Chen D.
        • Handa H.
        • Dong W.
        • Kurth D.G.
        • Möhwald H.
        Deposition and aggregation of aspirin molecules on a phospholipid bilayer patter.
        Langmuir. 2005; 21: 578-585
        • Amarenco P.
        • Bogousslavsky J.
        • Callahan 3rd, A.
        • et al.
        The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack.
        N Engl J Med. 2006; 355: 549-559
        • Maranhão R.C.
        • Tavares E.R.
        • Padoveze A.F.
        • Valduga C.J.
        • Rodrigues D.G.
        • Pereira M.D.
        Paclitaxel associated with cholesterol-rich nanoemulsions promotes atherosclerotic regression in the rabbit.
        Atherosclerosis. 2008; 197: 959-966
        • Klintworth G.K.
        Advances in the molecular genetics of corneal dystrophies.
        Am J Ophthal. 1999; 128: 747-754
        • Barchiesi B.J.
        • Eckel R.H.
        • Ellis P.P.
        The cornea and disorders of lipid metabolism.
        Surv Opthal. 1991; 36: 1-22
        • Martinon F.
        • Pétrilli V.
        • Mayor A.
        • Tardivel A.
        • Tschopp J.
        Gout-associated uric acid crystals activate the NALP3 inflammasome.
        Nature. 2006; 440: 237-241
        • Garrod E.
        The incidence of alkaptonuria: a study in chemical individuality.
        Lancet. 1902; 2: 1616-1620
        • Phornphutkul C.
        • Introne W.J.
        • Perry M.B.
        • et al.
        Natural history of alkaptonuria.
        N Engl J Med. 2002; 347: 2111-2121