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Semin Neurol 2006; 26(1): 075-087
DOI: 10.1055/s-2006-933311
Published 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

How and When Do We Alter Inflammatory Mechanisms in Stroke? Will It Help?

Thomas J. DeGraba1 , 2 , 3
  • 1Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
  • 2Department of Neurology, National Naval Medical Center, Bethesda, Maryland
  • 3Comprehensive Neuroscience Program, Henry M. Jackson Foundation, Rockville, Maryland
Further Information

Publication History

Publication Date:
15 February 2006 (online)

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ABSTRACT

The emerging recognition of atherosclerosis as primarily a chronic inflammatory process opens new possibilities to the treatment options that can reduce the risk of atherothrombotic stroke. The question is, “How do we alter the inflammatory mechanisms in atherosclerosis and will it reduce the risk of stroke?” Investigation into the fundamental pathophysiological mechanisms involved in the initiation, formation, and activation of atherosclerotic plaques is critical if we are to successfully employ pharmacotherapeutic strategies to reduce stroke risk. This article will review the key inflammatory elements associated with atherosclerosis and atherothrombotic stroke, identify potential inflammatory markers associated with the increased risk of stroke, review the effects of currently available medications that may have a beneficial impact on atherosclerosis and stroke, and briefly explore potential future strategies for reducing inflammation.

KEYWORDS

Inflammation - atherosclerosis - stroke - lymphocyte - CRP - biomarker - prevention

REFERENCES

  • 1 Libby P, Ridker P M, Maseri A. Inflammation and atherosclerosis.  Circulation. 2002;  105 1135-1143
    CrossrefPubMedGoogle Scholar
  • 2 DeGraba T J. The role of inflammation in atherosclerosis.  Semin Neurosurg. 2002;  13 203-216
    PubMedGoogle Scholar
  • 3 Pearson T A, Mensah G A, Alexander R W et al.. Markers of inflammation and cardiovascular disease: application to clinical and public health practice-a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association.  Circulation. 2003;  107 499-511
    CrossrefPubMedGoogle Scholar
  • 4 DeGraba T J, Sirén A-L, Penix L et al.. Increased endothelial expression of intercellular adhesion molecule-1 (ICAM-1) in symptomatic vs asymptomatic human atherosclerotic plaque.  Stroke. 1998;  29 1405-1410
    PubMedGoogle Scholar
  • 5 Jander S, Sitzer M, Schumann R et al.. Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization.  Stroke. 1998;  29 1625-1630
    PubMedGoogle Scholar
  • 6 Ross R. Atherosclerosis: an inflammatory disease [review].  N Engl J Med. 1999;  340 115-126
    CrossrefPubMedGoogle Scholar
  • 7 Nadareishvili Z G, Ruetzler C, Szekely B, LaBiche R, DeGraba T J. CD40-CD154 receptor ligand interaction in Chlamydia pneumoniae positive carotid atherosclerotic plaque.  Neurology. 2001;  56 A462
    PubMedGoogle Scholar
  • 8 Schonbeck U, Libby P. CD40 signaling and plaque instability.  Circ Res. 2001;  89 1092-1103
    CrossrefPubMedGoogle Scholar
  • 9 Lutgens E, Daemen M J. CD40-CD40L interactions in atherosclerosis.  Trends Cardiovasc Med. 2002;  12 27-32
    CrossrefPubMedGoogle Scholar
  • 10 Bevilacqua M P, Pober J S, Majeau G R, Cotran R S, Gimbrone Jr R A. Interleukin-1 (IL-1) induces biosynthesis and cell surface expression of pro-coagulant activity in human vascular endothelial cells.  J Exp Med. 1984;  160 618-623
    CrossrefPubMedGoogle Scholar
  • 11 Nawroth P P, Handley D A, Esmon C T, Stern D M. Interleukin-1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity.  Proc Natl Acad Sci USA. 1986;  83 3460-3464
    PubMedGoogle Scholar
  • 12 Nawroth P P, Stern D M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor.  J Exp Med. 1986;  163 740-745
    CrossrefPubMedGoogle Scholar
  • 13 Curry A J, Portig I, Goodall J C, Kirkpatrick P J, Gaston J S. T lymphocyte lines isolated from atheromatous plaque contain cells capable of responding to Chlamydia antigens.  Clin Exp Immunol. 2000;  121 261-269
    CrossrefPubMedGoogle Scholar
  • 14 de Boer O J, Hirsch F, van der Wal A C, van der Loos C M, Das P K, Becker A E. Costimulatory molecules in human atherosclerotic plaque: an indication of antigen specific T-lymphocyte activation.  Atherosclerosis. 1997;  133 227-234
    CrossrefPubMedGoogle Scholar
  • 15 van der Wal A C, Becker A E, van de Loos C M, Das P K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology.  Circulation. 1994;  89 36-44
    PubMedGoogle Scholar
  • 16 Rupprecht H J, Blankenberg S, Bickel C for the AtheroGene Investigators et al. Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease.  Circulation. 2001;  104 25-31
    PubMedGoogle Scholar
  • 17 Fernandez-Castelo S, Arzt E S, Pesce A et al.. Angiotension-2 regulates interferon-gamma production.  J Interferon Res. 1987;  7 261-268
    PubMedGoogle Scholar
  • 18 Kazama K, Anrather J, Zhou P et al.. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals.  Circ Res. 2004;  95 1019-1026
    CrossrefPubMedGoogle Scholar
  • 19 Roberts W L, Moulton L, Law T C et al.. Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications-part 2.  Clin Chem. 2001;  47 418-425
    PubMedGoogle Scholar
  • 20 Folsom A R, Aleksic N, Catellier D, Juneja H S, Wu K K. C-reactive protein and incident coronary heart disease in the Atherosclerotic Risk in Communities (ARIC) study.  Am Heart J. 2002;  144 233-238
    CrossrefPubMedGoogle Scholar
  • 21 Ridker P M, 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
    CrossrefPubMedGoogle Scholar
  • 22 Albert M A, Glynn R J, Ridker P M. Plasma concentration of C-reactive protein and the calculated Framingham Coronary Heart Disease Risk Score.  Circulation. 2003;  108 161-165
    CrossrefPubMedGoogle Scholar
  • 23 Rost N S, Wolf P A, Kase C S et al.. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study.  Stroke. 2001;  32 2575-2579
    CrossrefPubMedGoogle Scholar
  • 24 Ridker P M, Buring J E, Cook N S, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events.  Circulation. 2003;  107 391-397
    CrossrefPubMedGoogle Scholar
  • 25 Kinlay S, Schwartz G G, Olsson A G for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL Study.  Circulation. 2003;  108 1560-1566
    CrossrefPubMedGoogle Scholar
  • 26 Schwartz G G, Olsson A G, Ezekowitz M D for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study: a randomized controlled study.  JAMA. 2001;  285 1711-1718
    CrossrefPubMedGoogle Scholar
  • 27 Cannon C P, Braunwald E, McCabe C H for the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;  350 1495-1504
    CrossrefPubMedGoogle Scholar
  • 28 Libby P, Ridker P M. Inflammation and atherosclerosis: role of C-reactive protein in risk management.  Am J Med. 2004;  116(suppl 6A) 9S-16S
    CrossrefPubMedGoogle Scholar
  • 29 Schonbeck U, Varo N, Libby P, Buring J, Ridker P M. Soluble CD40L and cardiovascular risk in women.  Circulation. 2001;  104 2266-2268
    CrossrefPubMedGoogle Scholar
  • 30 Garlichs C D, Kozina S, Fateh-Moghadam S et al.. Upregulation of CD40-CD40 ligand (CD154) in patients with acute cerebral ischemia.  Stroke. 2003;  34 1412-1418
    CrossrefPubMedGoogle Scholar
  • 31 Heeschen C, Dimmeler S, Hamm C W for the CAPTURE Study Investigators et al. Soluble CD40 ligand in acute coronary syndromes.  N Engl J Med. 2003;  348 1104-1111
    CrossrefPubMedGoogle Scholar
  • 32 Mallat Z, Corbaz A, Scoazec A et al.. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability.  Circulation. 2001;  104 1598-1603
    PubMedGoogle Scholar
  • 33 Blankenberg S, Luc G, Ducimetiere P for the PRIME Study group et al. Interleukin-18 and the risk of coronary heart disease in European men: the prospective epidemiological study of myocardial infarction (PRIME).  Circulation. 2003;  108 2453-2459
    CrossrefPubMedGoogle Scholar
  • 34 Pradhan A D, Rifai N, Ridker P M. Soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and the development of symptomatic peripheral arterial disease in men.  Circulation. 2002;  106 820-825
    CrossrefPubMedGoogle Scholar
  • 35 Noji Y, Kajinami K, Kawashiri M A et al.. Circulating matrix metalloproteinases and their inhibitors in premature coronary atherosclerosis.  Clin Chem Lab Med. 2001;  39 380-384
    CrossrefPubMedGoogle Scholar
  • 36 Tayebjee M H, Nadar S, Blann A D, Gareth Beevers D, MacFadyen R J, Lip G Y. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).  Am J Hypertens. 2004;  17 764-769
    PubMedGoogle Scholar
  • 37 Worrall B B, Azhar S, Nyquist P A, Ackerman R H, Hamm T L, DeGraba T J. Interleukin-1 receptor antagonist gene polymorphisms in carotid atherosclerosis.  Stroke. 2003;  34 790-793
    CrossrefPubMedGoogle Scholar
  • 38 Ridker P M, Rifai N, Stampfer M J, Hennekens C H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.  Circulation. 2000;  101 1767-1772
    CrossrefPubMedGoogle Scholar
  • 39 Jerrard-Dunne P, Sitzer M, Risley P et al.. Interleukin-6 promoter polymorphism modulates the effects of heavy alcohol consumption on early carotid artery atherosclerosis: the Carotid Atherosclerosis Progression Study (CAPS).  Stroke. 2003;  34 402-407
    CrossrefPubMedGoogle Scholar
  • 40 Conway D S, Buggins P, Hughes E, Lip G Y. Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation.  Am Heart J. 2004;  148 462-466
    CrossrefPubMedGoogle Scholar
  • 41 Pola R, Flex A, Gaetani E, Flore R, Serricchio M, Pola P. Synergistic effect of -174G/C polymorphism of the interleukin-6 promoter and 469 E/K polymorphism of the intercellular adhesion molecule-1 gene in Italian patients with history of ischemic stroke.  Stroke. 2003;  34 881-885
    CrossrefPubMedGoogle Scholar
  • 42 Flex A, Gaetani E, Papaleo P et al.. Proinflammatory genetic profiles in subjects with history of ischemic stroke.  Stroke. 2004;  35 2270-2275
    CrossrefPubMedGoogle Scholar
  • 43 Cipollone F, Toniato E, Martinotti S for the Identification of New Elements of Plaque Stability (INES) Study Group et al. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke.  JAMA. 2004;  291 2221-2228
    CrossrefPubMedGoogle Scholar
  • 44 Aikawa M, Libby P. Atherosclerotic plaque inflammation: the final frontier?.  Can J Cardiol. 2004;  20 631-634
    PubMedGoogle Scholar
  • 45 Mason J C. Statins and their role in vascular protection.  Clin Sci (Lond). 2003;  105 251-266
    PubMedGoogle Scholar
  • 46 Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents?.  Circulation. 2004;  109(suppl 1) 18-26
    PubMedGoogle Scholar
  • 47 Edelberg J M, Christie P D, Rosenberg R D. Regulation of vascular bed-specific prothrombotic potential.  Circ Res. 2001;  89 117-124
    CrossrefPubMedGoogle Scholar
  • 48 Crisby M, Nordin-Frederiksson G, Shah P K, Yano J, Zhu J, Nilsson J. 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
    PubMedGoogle Scholar
  • 49 Cannon C P, Braunwald E, McCabe C H for the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;  350 1495-1504
    CrossrefPubMedGoogle Scholar
  • 50 Youssef S, Stuve O, Patarroyo J C et al.. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.  Nature. 2002;  420 78-84
    CrossrefPubMedGoogle Scholar
  • 51 Horne B D, Muhlestein J B, Carlquist J F for the Intermountain Heart Collaborative (IHC) Study Group et al. Statin therapy interacts with cytomegalovirus seropositivity and high C-reactive protein in reducing mortality among patients with angiographically significant coronary disease.  Circulation. 2003;  107 258-263
    CrossrefPubMedGoogle Scholar
  • 52 Ridker P M, Rifai N, Clearfield M for the Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.  N Engl J Med. 2001;  344 1959-1965
    CrossrefPubMedGoogle Scholar
  • 53 Blake G J, Ridker P M, Kuntz K M. Potential cost effectiveness of C-reactive protein screening followed by targeted statin therapy for the primary prevention of cardiovascular disease among patients without overt hyperlipidemia.  Am J Med. 2003;  114 485-494
    CrossrefPubMedGoogle Scholar
  • 54 Shao J, Nangaku M, Miyata T et al.. Imbalance of T-cell subsets in angiotensin II infused hypertensive rats with kidney injury.  Hypertension. 2003;  42 31-38
    CrossrefPubMedGoogle Scholar
  • 55 HOPE Study Investigators . Effects of an ANG-converting-enzyme inhibitor, Ramipril, on cardiovascular events in high-risk patients.  N Engl J Med. 2000;  342 145-153
    CrossrefPubMedGoogle Scholar
  • 56 Cipollone F, Fazia M, Iezzi A 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 1482-1488
    CrossrefPubMedGoogle Scholar
  • 57 Gage J R, Fonarow G, Hamilton M et al.. Beta blocker and angiotensin converting enzyme inhibitor therapy is associated with decreased Th1/Th2 cytokine ratio and inflammatory cytokine production in patients with chronic heart failure.  Neuroimmunomodulation. 2004;  11 173-180
    CrossrefPubMedGoogle Scholar
  • 58 Ohtsuka T, Hamada M, Hiasa G et al.. Effect of beta blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy.  J Am Coll Cardiol. 2001;  37 412-417
    CrossrefPubMedGoogle Scholar
  • 59 Beattie M S, Shlipak M G, Liu H, Browner W S, Schiller N B, Whooley M A. C-reactive protein and ischemia in users and nonusers of β-blockers and statins: data from the Heart and Soul Study.  Circulation. 2003;  107 245-250
    CrossrefPubMedGoogle Scholar
  • 60 Nannizzi-Alaimo L, Alves V L, Phillips D R. Inhibitory effects of glycoprotein IIb/IIIa antagonist and aspirin on the release of soluble CD40 ligand during platelet stimulation.  Circulation. 2003;  107 1123-1128
    CrossrefPubMedGoogle Scholar
  • 61 Hermann A, Rauch B H, Braun M et al.. Platelet CD40 ligand (CD40L)-subcellular localization, regulation of expression, and inhibition by clopidogrel.  Platelets. 2001;  12 74-82
    CrossrefPubMedGoogle Scholar
  • 62 Weyrich A S, Denis MM, Kuhlmann-Eyre JR. Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates.  Circulation. 2005;  111 633-642
    CrossrefPubMedGoogle Scholar
  • 63 Ridker P M, Cook N R, Lee I et al.. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.  N Engl J Med. 2005;  352 1293-1304
    CrossrefPubMedGoogle Scholar
  • 64 Chu K, Jeong S, Jung K et al.. Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death.  J Cereb Blood Flow Metab. 2004;  24 926-933
    PubMedGoogle Scholar
  • 65 Cipollone F, Tonaiato E, Martinotti S et al.. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke.  JAMA. 2004;  291 2221-2228
    CrossrefPubMedGoogle Scholar
  • 66 Cipollone F, Fazia M, Iezzi A et al.. Balance between PGD synthase and PGE synthase is a major determinant of atherosclerotic plaque instability in humans.  Arterioscler Thromb Vasc Biol. 2004;  24 1259-1265
    PubMedGoogle Scholar
  • 67 Weiner H L. Oral tolerance: immune mechanisms and treatment of autoimmune diseases.  Immunol Today. 1997;  18 335-343
    CrossrefPubMedGoogle Scholar
  • 68 Frenkel D, Huang Z, Maron R et al.. Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells.  J Immunol. 2003;  171 6549-6555
    PubMedGoogle Scholar
  • 69 Takeda H, Spatz M, Ruetzler C, McCarron R, Becker K, Hallenbeck J. Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats.  Stroke. 2002;  33 2156-2164
    CrossrefPubMedGoogle Scholar
  • 70 Maron R, Sukhova G, Faria A et al.. Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice.  Circulation. 2002;  106 1708-1715
    CrossrefPubMedGoogle Scholar
  • 71 Binder C J, Horkko S, Dewan A et al.. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL.  Nat Med. 2003;  9 736-743
    PubMedGoogle Scholar
  • 72 Boekholdt S M, Agema WRP, Peters RJG et al.. Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events.  Circulation. 2003;  107 2416-2421
    CrossrefPubMedGoogle Scholar
  • 73 Momiyama Y, Hirano R, Taniguchi H, Nakamura H, Ohsuzu F. Effects of interleukin-1 Gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection.  J Am Coll Cardiol. 2001;  38 712-717
    CrossrefPubMedGoogle Scholar

Thomas J DeGrabaM.D. 

National Naval Medical Center, Neurology Department, Building 9, 2nd Deck, 8901 Wisconsin Avenue, Bethesda, MD 20889-5600

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