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The biology behind the atherothrombotic effects of cigarette smoke

Nature Reviews Cardiology volume 10, pages 219–230 (2013)Cite this article

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Abstract

Cigarette smoke is an aerosol that contains >4,000 chemicals, including nicotine, carbon monoxide, acrolein, and oxidant compounds. Exposure to cigarette smoke induces multiple pathological effects in the endothelium, several of which are the result of oxidative stress initiated by reactive oxygen species, reactive nitrogen species, and other oxidant constituents of cigarette smoke. Cigarette-smoke exposure interferes adversely with the control of all stages of plaque formation and development and pathological thrombus formation. The reactive oxygen species in cigarette smoke contribute to oxidative stress, upregulation of inflammatory cytokines, and endothelial dysfunction, by reducing the bioavailability of nitric oxide. Plaque formation and the development of vulnerable plaques also result from exposure to cigarette smoke via the enhancement of inflammatory processes and the activation of matrix metalloproteases. Moreover, exposure to cigarette smoke results in platelet activation, stimulation of the coagulation cascade, and impairment of anticoagulative fibrinolysis. Many cigarette-smoke-mediated prothrombotic changes are quickly reversible upon smoking cessation. Public health efforts should urgently promote our understanding of current cigarette-smoke-induced cardiovascular pathology to encourage individuals to reduce their exposure to cigarette smoke and, therefore, the detrimental consequences of associated atherothrombotic disease.

Key Points

  • A large body of literature strongly suggests that cigarette smoke unfavourably influences all major stages of atherosclerosis as well as pathological atherothrombus formation

  • Cigarette smoke contains oxidant compounds that cause oxidative stress in the endothelium, leading to endothelial dysfunction and injury, initiation of the atherosclerotic process, and subsequent formation of atherosclerotic plaques

  • Cigarette smoke promotes the development of vulnerable plaques and plaque rupture by enhancing inflammation and activating matrix metalloproteinases

  • Cigarette smoke causes platelet activation, and promotes platelet aggregation and platelet adhesion to sites of endothelial injury

  • Exposure to cigarette smoke shifts the balance of haemostasis towards thrombus formation by enhancing blood clotting and, at the same time, reducing the fibrinolytic capacity

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Figure 1: Setting the stage for atherosclerotic plaque formation.
Figure 2
Figure 3: Effects of cigarette smoke (indicated by upward arrows) on coagulatory (blue) and fibrinolytic (orange) pathways.

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References

  1. Ezzati, M., Henley, S. J., Thun, M. J. & Lopez, A. D. Role of smoking in global and regional cardiovascular mortality. Circulation 112, 489–497 (2005).

    Article  PubMed  Google Scholar 

  2. Cornel, J. H. et al. Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial. Am. Heart J. 164, 334–342e1 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Burke, A. P. et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N. Engl. J. Med. 336, 1276–1282 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Pope, C. A. III et al. Cardiovascular mortality and exposure to airborne fine particulate matter and cigarette smoke: shape of the exposure-response relationship. Circulation 120, 941–948 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Smith, C. J. & Fischer, T. H. Particulate and vapor phase constituents of cigarette mainstream smoke and risk of myocardial infarction. Atherosclerosis 158, 257–267 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Csordas, A., Wick, G., Laufer, G. & Bernhard, D. An evaluation of the clinical evidence on the role of inflammation and oxidative stress in smoking-mediated cardiovascular disease. Biomark. Insights 3, 127–139 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pryor, W. A. & Stone, K. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann. NY Acad. Sci. 686, 12–27 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Lippi, G., Franchini, M. & Targher, G. Arterial thrombus formation in cardiovascular disease. Nat. Rev. Cardiol. 8, 502–512 (2011).

    Article  PubMed  Google Scholar 

  9. Fuster, V., Moreno, P. R., Fayad, Z. A., Corti, R. & Badimon, J. J. Atherothrombosis and high-risk plaque: part I: evolving concepts. J. Am. Coll. Cardiol. 46, 937–954 (2005).

    Article  PubMed  Google Scholar 

  10. Rahman, M. M. & Laher, I. Structural and functional alteration of blood vessels caused by cigarette smoking: an overview of molecular mechanisms. Curr. Vasc. Pharmacol. 5, 276–292 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Zeiher, A. M., Schächinger, V. & Minners, J. Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation 92, 1094–1100 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Celermajer, D. S. et al. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N. Engl. J. Med. 334, 150–154 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Barua, R. S., Ambrose, J. A., Srivastava, S., DeVoe, M. C. & Eales-Reynolds, L. J. Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation 107, 2342–2347 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Jaimes, E. A., DeMaster, E. G., Tian, R. X. & Raij, L. Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation. Arterioscler. Thromb. Vasc. Biol. 24, 1031–1036 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Kayyali, U. S. et al. Upregulation of xanthine oxidase by tobacco smoke condensate in pulmonary endothelial cells. Toxicol. Appl. Pharmacol. 188, 59–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Talukder, M. A. et al. Chronic cigarette smoking causes hypertension, increased oxidative stress, impaired NO bioavailability, endothelial dysfunction, and cardiac remodeling in mice. Am. J. Physiol. Heart Circ. Physiol. 300, H388–H396 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Frey, R. S., Ushio-Fukai, M. & Malik, A. B. NADPH oxidase-dependent signalling in endothelial cells: role in physiology and pathology. Antioxid. Redox Signal. 11, 791–780 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, J. et al. The NADPH oxidase NOX4 drives cardiac differentiation: role in regulating cardiac transcription factors and MAP kinase activation. Mol. Biol. Cell 17, 3978–3988 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Takac, I., Schröder, K. & Brandes, R. P. The Nox family of NADPH oxidases: friend or foe of the vascular system? Curr. Hypertens. Rep. 14, 70–78 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Collins, T. Endothelial nuclear factor-κB and the initiation of the atherosclerotic lesion. Lab. Invest. 68, 499–508 (1993).

    CAS  PubMed  Google Scholar 

  21. Cacciola, R. R., Guarino, F. & Polosa, R. Relevance of endothelial-haemostatic dysfunction in cigarette smoking. Curr. Med. Chem. 14, 1887–1892 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Jennings, L. K. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb. Haemost. 102, 248–257 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Ruberg, F. L. & Loscalzo, J. Prothrombotic determinants of coronary atherothrombosis. Vasc. Med. 7, 289–299 (2002).

    Article  PubMed  Google Scholar 

  24. Bernhard, D. et al. Cigarette smoke metal-catalyzed protein oxidation leads to vascular endothelial cell contraction by depolymerization of microtubules. FASEB J. 19, 1096–1107 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Csordas, A. et al. Cigarette smoke extract induces prolonged endoplasmic reticulum stress and autophagic cell death in human umbilical vein endothelial cells. Cardiovasc. Res. 92, 141–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Falk, E., Shah, P. K. & Fuster, V. Coronary plaque disruption. Circulation 92, 657–671 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Glaser, R. et al. Clinical progression of incidental, asymptomatic lesions discovered during culprit vessel coronary intervention. Circulation 111, 143–149 (2005).

    Article  PubMed  Google Scholar 

  28. Wissler, R. W. New insights into the pathogenesis of atherosclerosis as revealed by PDAY. Pathobiological Determinants of Atherosclerosis in Youth. Atherosclerosis 108 (Suppl.), S3–S20 (1994).

    Article  PubMed  Google Scholar 

  29. Newby, A. C. Metalloproteinases and vulnerable atherosclerotic plaques. Trends Cardiovasc. Med. 17, 253–258 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shah, P. K. et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques: potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation 92, 1565–1569 (1995).

    CAS  PubMed  Google Scholar 

  31. Nelson, K. K. & Melendez, J. A. Mitochondrial redox control of matrix metalloproteinases. Free Radic. Biol. Med. 37, 768–784 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Perlstein, T. S. & Lee, R. T. Smoking, metalloproteinases, and vascular disease. Arterioscler. Thromb. Vasc. Biol. 26, 250–256 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Carty, C. S. et al. Nicotine and cotinine stimulate secretion of basic fibroblast growth factor and affect expression of matrix metalloproteinases in cultured human smooth muscle cells. J. Vasc. Surg. 24, 927–934 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Liu, P. Y., Chen, J. H., Li, Y. H., Wu, H. L. & Shi, G. Y. Synergistic effect of stromelysin-1 (matrix metallo-proteinase-3) promoter 5A/6A polymorphism with smoking on the onset of young acute myocardial infarction. Thromb. Haemost. 90, 132–139 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Churg, A. et al. α1-Antitrypsin suppresses TNF-α and MMP-12 production by cigarette smoke-stimulated macrophages. Am. J. Respir. Cell Mol. Biol. 37, 144–151 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Kangavari, S. et al. Smoking increases inflammation and metalloproteinase expression in human carotid atherosclerotic plaques. J. Cardiovasc. Pharmacol. Ther. 9, 291–298 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Nordskog, B. K., Blixt, A. D., Morgan, W. T., Fields, W. R. & Hellmann, G. M. Matrix-degrading and pro-inflammatory changes in human vascular endothelial cells exposed to cigarette smoke condensate. Cardiovasc. Toxicol. 3, 101–117 (2003).

    Article  PubMed  Google Scholar 

  38. Wright, J. L., Tai, H., Wang, R., Wang, X. & Churg, A. Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-α signaling. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L125–L133 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Xue, H. et al. Etanercept attenuates short-term cigarette-smoke-exposure-induced pulmonary arterial remodelling in rats by suppressing the activation of TNF-α/NF-κB signal and the activities of MMP-2 and MMP-9. Pulm. Pharmacol. Ther. 25, 208–215 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Vikman, P., Xu, C. B. & Edvinsson, L. Lipid-soluble cigarette smoking particles induce expression of inflammatory and extracellular-matrix-related genes in rat cerebral arteries. Vasc. Health Risk Manag. 5, 333–341 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. O'Toole, T. E. et al. Acrolein activates matrix metalloproteinases by increasing reactive oxygen species in macrophages. Toxicol. Appl. Pharmacol. 236, 194–201 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lamaître, V., Dabo, A. J. & D'Armiento, J. Cigarette smoke components induce matrix metalloproteinase-1 in aortic endothelial cells through inhibition of mTOR signalling. Toxicol. Sci. 123, 542–549 (2011).

    Article  CAS  Google Scholar 

  43. Oikonen, M. et al. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) in a population of young adults: Relations to cardiovascular risk markers and carotid artery intima–media thickness. The Cardiovascular Risk in Young Finns Study. Scand. J. Clin. Lab. Invest. 72, 540–546 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Raveendran, M. et al. Cigarette suppresses the expression of P4Hα and vascular collagen production. Biochem. Biophys. Res. Commun. 323, 592–598 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Jorgensen, L. N., Kallehave, F., Christensen, E., Siana, J. E. & Gottrup, F. Less collagen production in smokers. Surgery 123, 450–455 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Zhang, K. et al. Interleukin 6 destabilizes atherosclerotic plaques by downregulating prolyl-4-hydroxylase α1 via a mitogen-activated protein kinase and c-Jun pathway. Arch. Biochem. Biophys. 528, 127–133 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Bermudez, E. A., Rifai, N., Buring, J. E., Manson, J. E. & Ridker, P. M. Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women. Arterioscler. Thromb. Vasc. Biol. 22, 1668–1673 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Grundtman, C., Kreutmayer, S. B., Almanzar, G., Wick, M. C. & Wick, G. Heat shock protein 60 and immune inflammatory responses in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 960–968 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bouki, K. P. et al. Inflammatory markers and plaque morphology: an optical coherence tomography study. Int. J. Cardiol. 154, 287–292 (2012).

    Article  PubMed  Google Scholar 

  50. van der Wal, A. C., Becker, A. E., van der 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 89, 36–44 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Botti, T. P., Amin, H., Hiltscher, L. & Wissler, R. W. A comparison of the quantitation of macrophage foam cell populations and the extent of apolipoprotein E deposition in developing atherosclerotic lesions in young people: high and low serum thiocyanate groups as an indication of smoking. PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth. Atherosclerosis 124, 191–202 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Henderson, B. et al. Cigarette smoke is an endothelial stressor and leads to cell cycle arrest. Atherosclerosis 201, 298–305 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Virmani, R. et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler. Thromb. Vasc. Biol. 25, 2054–2061 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Zhu, B. Q. & Parmley, W. W. Hemodynamic and vascular effects of active and passive smoking. Am. Heart J. 130, 1270–1275 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Hung, J., Lam, J. Y., Lacoste, L. & Letchacovski, G. Cigarette smoking acutely increases platelet thrombus formation in patients with coronary artery disease taking aspirin. Circulation 92, 2432–2436 (1995).

    Article  CAS  PubMed  Google Scholar 

  56. Winniford, M. D. et al. Smoking-induced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery tone. Circulation 73, 662–667 (1986).

    Article  CAS  PubMed  Google Scholar 

  57. Wang, L. X. et al. Coronary spasm, a pathogenic trigger of vulnerable plaque rupture. Chin. Med. J. (Engl.) 124, 4071–4178 (2011).

    Google Scholar 

  58. Annex, B. H. et al. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation 91, 619–622 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Toschi, V. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95, 594–599 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Breitenstein, A., Camici, G. G. & Tanner, F. C. Tissue factor: beyond coagulation in the cardiovascular system. Clin. Sci. (Lond.) 118, 159–172 (2010).

    Article  CAS  Google Scholar 

  61. Sambola, A. et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 107, 973–977 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Li, M., Yu, D., Williams, K. J. & Liu, M. L. Tobacco smoke induces the generation of procoagulant microvesicles from human monocytes/macrophages. Arterioscler. Thromb. Vasc. Biol. 30, 1818–1824 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cirillo, P. et al. Nicotine induces tissue factor expression in cultured endothelial and smooth muscle cells. J. Thromb. Haemost. 4, 453–458 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Matetzky, S. et al. Smoking increases tissue factor expression in atherosclerotic plaques: implications for plaque thrombogenicity. Circulation 102, 602–604 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Hölschermann, H. et al. Monocyte tissue factor expression is enhanced in women who smoke and use oral contraceptives. Thromb. Haemost. 82, 1614–1620 (1999).

    Article  PubMed  Google Scholar 

  66. Heiss, C. et al. Brief secondhand smoke exposure depresses endothelial progenitor cells activity and endothelial function: sustained vascular injury and blunted nitric oxide production. J. Am. Coll. Cardiol. 51, 1760–1771 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Kreutmayer, S. B. et al. Dynamics of heat shock protein 60 in endothelial cells exposed to cigarette smoke extract. J. Mol. Cell. Cardiol. 51, 777–780 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wickenden, J. A. et al. Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. Am. J. Respir. Cell Mol. Biol. 29, 562–570 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Thaulow, E., Erikssen, J., Sandvik, L., Stormorken, H. & Cohn, P. F. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 84, 613–617 (1991).

    Article  CAS  PubMed  Google Scholar 

  71. Law, M. R. & Wald, N. J. Environmental tobacco smoke and ischemic heart disease. Prog. Cardiovasc. Dis. 46, 31–38 (2003).

    Article  PubMed  Google Scholar 

  72. Davis, J. W., Shelton, L., Eigenberg, D. A., Hignite, C. E. & Watanabe, I. S. Effects of tobacco and non-tobacco cigarette smoking on endothelium and platelets. Clin. Pharmacol. Ther. 37, 529–533 (1985).

    Article  CAS  PubMed  Google Scholar 

  73. Imaizumi, T. et al. Effect of cigarette smoking on the levels of platelet-activating factor-like lipid(s) in plasma lipoproteins. Atherosclerosis 87, 47–55 (1991).

    Article  CAS  PubMed  Google Scholar 

  74. Fusegawa, Y., Goto, S., Handa, S., Kawada, T. & Ando, Y. Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers. Thromb. Res. 93, 271–278 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Levine, P. H. An acute effect of cigarette smoking on platelet function: a possible link between smoking and arterial thrombosis. Circulation 48, 619–623 (1973).

    Article  CAS  PubMed  Google Scholar 

  76. Glynn, M. F., Mustard, J. F., Buchanan, M. R. & Murphy, E. A. Cigarette smoking and platelet aggregation. Can. Med. Assoc. J. 95, 549–553 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Caponnetto, P. et al. Circulating endothelial-coagulative activation markers after smoking cessation: a 12-month observational study. Eur. J. Clin. Invest. 41, 616–626 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Blache, D. Involvement of hydrogen and lipid peroxides in acute tobacco smoking-induced platelet hyperactivity. Am. J. Physiol. 268, H679–H685 (1995).

    CAS  PubMed  Google Scholar 

  79. Lupia, E. et al. Thrombopoietin contributes to enhanced platelet activation in cigarette smokers. Atherosclerosis 210, 314–319 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Yarlioglues, M. et al. The acute effects of passive smoking on mean platelet volume in healthy volunteers. Angiology 63, 353–357 (2012).

    Article  PubMed  Google Scholar 

  81. Sinzinger, H. & Kefalides, A. Passive smoking severely decreases platelet sensitivity to antiaggregatory prostaglandins. Lancet 2, 392–393 (1982).

    Article  CAS  PubMed  Google Scholar 

  82. Schmid, P. et al. Passive smoking and platelet thromboxane. Thromb. Res. 81, 451–460 (1996).

    Article  CAS  PubMed  Google Scholar 

  83. Tell, G. S., Grimm, R. H., Vellar, O. D. & Theodorsen, L. The relationship of white cell count, platelet count, and hematocrit to cigarette smoking in adolescents: the Oslo Youth Study. Circulation 72, 971–974 (1985).

    Article  CAS  PubMed  Google Scholar 

  84. Podrez, E. A. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat. Med. 13, 1086–1095 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Miyaura, S., Eguchi, H. & Johnston, J. M. Effect of a cigarette smoke extract on the metabolism of the proinflammatory autacoid, platelet-activating factor. Circ. Res. 70, 341–347 (1992).

    Article  CAS  PubMed  Google Scholar 

  86. Marathe, G. K., Prescott, S. M., Zimmerman, G. A. & McIntyre, T. M. Oxidized LDL contains inflammatory PAF-like phospholipids. Trends Cardiovasc. Med. 11, 139–142 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Togna, A. R., Latina, V., Orlando, R. & Togna, G. I. Cigarette smoke inhibits adenine nucleotide hydrolysis by human platelets. Platelets 19, 537–542 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Ichiki, K., Ikeda, H., Haramaki, N., Ueno, T. & Imaizumi, T. Long-term smoking impairs platelet-derived nitric oxide release. Circulation 94, 3109–3114 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. Haramaki, N. et al. Long-term smoking causes nitroglycerin resistance in platelets by depletion of intraplatelet glutathione. Arterioscler. Thromb. Vasc. Biol. 21, 1852–1856 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Takajo, Y., Ikeda, H., Haramaki, N., Murohara, T. & Imaizumi, T. Augmented oxidative stress of platelets in chronic smokers: mechanisms of impaired platelet-derived nitric oxide bioactivity and augmented platelet aggregability. J. Am. Coll. Cardiol. 38, 1320–1327 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Della Corte, A. et al. Platelet proteome in healthy volunteers who smoke. Platelets 23, 91–105 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Hennan, J. K. et al. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation 104, 820–825 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. FitzGerald, G. A., Oates, J. A. & Nowak, J. Cigarette smoking and hemostatic function. Am. Heart J. 115, 267–271 (1988).

    Article  CAS  PubMed  Google Scholar 

  94. Reinders, J. H., Brinkman, H. J., van Mourik, J. A. & de Groot, P. G. Cigarette smoke impairs endothelial cell prostacyclin production. Arteriosclerosis 6, 15–23 (1986).

    Article  CAS  PubMed  Google Scholar 

  95. Hioki, H. et al. Acute effects of cigarette smoking on platelet-dependent thrombin generation. Eur. Heart J. 22, 56–61 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Kimura, S., Nishinaga, M., Ozawa, T. & Shimada, K. Thrombin generation as an acute effect of cigarette smoking. Am. Heart J. 128, 7–11 (1994).

    Article  CAS  PubMed  Google Scholar 

  97. Renaud, S., Blache, D., Dumont, E., Thevenon, C. & Wissendanger, T. Platelet function after cigarette smoking in relation to nicotine and carbon monoxide. Clin. Pharmacol. Ther. 36, 389–395 (1984).

    Article  CAS  PubMed  Google Scholar 

  98. Watts, D. T. The effect of nicotine and smoking on the secretion of epinephrine. Ann. NY Acad. Sci. 90, 74–80 (1960).

    Article  CAS  PubMed  Google Scholar 

  99. Lande, K., Gjesdal, K., Fønstelien, E., Kjeldsen, S. E. & Eide, I. Effects of adrenaline infusion on platelet number, volume and release reaction. Thromb. Haemost. 54, 450–453 (1985).

    Article  CAS  PubMed  Google Scholar 

  100. Harding, S. A. et al. Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers. Circulation 109, 1926–1929 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Sithu, S. D. et al. Exposure to acrolein by inhalation causes platelet activation. Toxicol. Appl. Pharmacol. 248, 100–110 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Andrè, E. et al. Cigarette smoke-induced neurogenic inflammation is mediated by α,β-unsaturated aldehydes and the TRPA1 receptor in rodents. J. Clin. Invest. 118, 2574–2582 (2008).

    PubMed  PubMed Central  Google Scholar 

  103. Selley, M. L., Bartlett, M. R., McGuiness, J. A. & Ardlie, N. G. Effects of acrolein on human platelet aggregation. Chem. Biol. Interact. 76, 101–109 (1990).

    Article  CAS  PubMed  Google Scholar 

  104. Ambrose, J. A. & Barua, R. S. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J. Am. Coll. Cardiol. 43, 1731–1737 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Miller, G. J., Bauer, K. A., Cooper, J. A. & Rosenberg, R. D. Activation of the coagulant pathway in cigarette smokers. Thromb. Haemost. 79, 549–553 (1998).

    Article  CAS  PubMed  Google Scholar 

  106. Markuljak, I., Ivankova, J. & Kubisz, P. Thrombomodulin and von Willebrand factor in smokers and during smoking. Nouv. Rev. Fr. Hematol. 37, 137–139 (1995).

    CAS  PubMed  Google Scholar 

  107. Raza, S. L., Nehring, L. C., Shapiro, S. D. & Cornelius, L. A. Proteinase-activated receptor-1 regulation of macrophage elastase (MMP-12) secretion by serine proteinases. J. Biol. Chem. 275, 41243–41250 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Kwaan, H. C. Role of plasma proteins in whole blood viscosity: a brief clinical review. Clin. Hemorheol. Microcirc. 44, 167–176 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Heinrich, J., Balleisen, L., Schulte, H., Assmann, G. & van de Loo, J. Fibrinogen and factor VII in the prediction of coronary PROCAM study in healthy men. Arterioscler. Thromb. 14, 54–59 (1994).

    Article  CAS  PubMed  Google Scholar 

  110. Tuut, M. & Hense, H. W. Smoking, other risk factors and fibrinogen levels: evidence of effect modification. Ann. Epidemiol. 11, 232–238 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Hunter, K. A., Garlick, P. J., Broom, I., Anderson, S. E. & McNurlan, M. A. Effects of smoking and abstention from smoking on fibrinogen synthesis in humans. Clin. Sci. (Lond.) 100, 459–465 (2001).

    Article  CAS  Google Scholar 

  112. Stone, M. C. & Thorp, J. M. Plasma fibrinogen--a major coronary risk factor. J. R. Coll. Gen. Pract. 35, 565–569 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Tapson, V. F. The role of smoking in coagulation and thromboembolism in chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 2, 71–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Barbash, G. I. et al. Significance of smoking in patients receiving thrombolytic therapy for acute myocardial infarction: experience gleaned from the International Tissue Plasminogen Activator/Streptokinase Mortality trial. Circulation 87, 53–58 (1993).

    Article  CAS  PubMed  Google Scholar 

  115. Barbash, G. I., White, H. D., Modan, M. & Van der Werf, F. Smoking and acute myocardial infarction. Circulation 87, 1427–1428 (1993).

    Article  CAS  PubMed  Google Scholar 

  116. Kirtane, A. J. et al. Association of smoking with improved myocardial perfusion and the angiographic characterization of myocardial tissue perfusion after fibrinolytic therapy for ST-segment elevation myocardial infarction. J. Am. Coll. Cardiol. 45, 321–323 (2005).

    Article  PubMed  Google Scholar 

  117. Barua, R. S. et al. Acute cigarette smoke exposure reduces clot lysis--association between altered fibrin architecture and the response to t-PA. Thromb. Res. 126, 426–430 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Pretorius, E., Oberholzer, H. M., van der Spuy, W. J. & Meiring, J. H. Smoking and coagulation: the sticky fibrin phenomenon. Ultrastruct. Pathol. 34, 236–239 (2010).

    Article  PubMed  Google Scholar 

  119. Shacter, E., Williams, J. A., Lim, M. & Levine, R. L. Differential susceptibility of plasma proteins to oxidative modification: examination by western blot immunoassay. Free Radic. Biol. Med. 17, 429–437 (1994).

    Article  CAS  PubMed  Google Scholar 

  120. Parahuelva, M. S. et al. Nicotine modulation of factor VII activating protease (FSAP) expression in human monocytes. J. Atheroscler. Thromb. 19, 962–969 (2012).

    Article  Google Scholar 

  121. van Wersch, J. W., Vooijs, M. E. & Ubachs, J. M. Coagulation factor XIII in pregnant smokers and non-smokers. Int. J. Clin. Lab. Res. 27, 68–71 (1997).

    Article  CAS  PubMed  Google Scholar 

  122. Allen, R. A., Kluft, C. & Brommer, E. J. Effect of chronic smoking on fibrinolysis. Arteriosclerosis 5, 443–450 (1985).

    Article  CAS  PubMed  Google Scholar 

  123. Newby, D. E. et al. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation 103, 1936–1941 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Newby, D. E. et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 99, 1411–1415 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. Kaehler, J. et al. Impaired capacity for acute endogenous fibrinolysis in smokers is restored by ascorbic acid. Free Radic. Biol. Med. 44, 315–321 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Barua, R. S., Ambrose, J. A., Saha, D. C. & Eales-Reynolds, L. J. Smoking is associated with altered endothelial-derived fibrinolytic and antithrombotic factors: an in vitro demonstration. Circulation 106, 905–908 (2002).

    Article  PubMed  Google Scholar 

  127. Pellegrini, M. P., Newby, D. E., Maxwell, S. & Webb, D. J. Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man. Cardiovasc. Res. 52, 321–327 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Zidovetzki, R., Chen, P., Fisher, M., Hofman, F. M. & Faraci, F. M. Nicotine increases plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway. Stroke 30, 651–655 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Haire, W. D., Goldsmith, J. C. & Rasmussen, J. Abnormal fibrinolysis in healthy male cigarette smokers: role of plasminogen activator inhibitors. Am. J. Hematol. 31, 36–40 (1989).

    Article  CAS  PubMed  Google Scholar 

  130. Simpson, A. J., Gray, R. S., Moore, N. R. & Booth, N. A. The effects of chronic smoking on the fibrinolytic potential of plasma and platelets. Br. J. Haematol. 97, 208–13 (1997).

    Article  CAS  PubMed  Google Scholar 

  131. Margaglione, M. et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants. Arterioscler. Thromb. Vasc. Biol. 18, 562–567 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. Tzoulaki, I. et al. Relative value of inflammatory, hemostatic, and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery Study. Circulation 115, 2119–2127 (2007).

    Article  PubMed  Google Scholar 

  133. Kotani, K., Inata, A. & Araga, S. Hemorheology by microchannel method in males with metabolic syndrome. Arch. Med. Res. 38, 463–464 (2007).

    Article  PubMed  Google Scholar 

  134. Lowe, G. D., Drummond, M. M., Forbes, C. D. & Barbenel, J. C. The effects of age and cigarette-smoking on blood and plasma viscosity in men. Scott. Med. J. 25, 13–17 (1980).

    Article  CAS  PubMed  Google Scholar 

  135. Yarnell, J. W. et al. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease: the Caerphilly and Speedwell collaborative heart disease studies. Circulation 83, 836–844 (1991).

    Article  CAS  PubMed  Google Scholar 

  136. Haustein, K. O., Krause, J., Haustein, H., Rasmussen, T. & Cort, N. Effects of cigarette smoking or nicotine replacement on cardiovascular risk factors and parameters of haemorheology. J. Intern. Med. 252, 130–139 (2002).

    Article  PubMed  Google Scholar 

  137. Shimada, S. et al. High blood viscosity is closely associated with cigarette smoking and markedly reduced by smoking cessation. Circ. J. 75, 185–189 (2011).

    Article  PubMed  Google Scholar 

  138. Price, J. F. et al. Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease and coronary artery disease: Edinburgh Artery Study. Eur. Heart J. 20, 344–353 (1999).

    Article  CAS  PubMed  Google Scholar 

  139. Ernst, E. Haemorheological consequences of chronic cigarette smoking. J. Cardiovasc. Risk 2, 435–439 (1995).

    Article  CAS  PubMed  Google Scholar 

  140. Wang, X. L., Sim, A. S., Badenhop, R. F., Mccredie R. M. & Wilcken, D. E. A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxidase gene. Nat. Med. 2, 41–45 (1996).

    Article  CAS  PubMed  Google Scholar 

  141. Ragia, G. et al. Endothelial nitric oxide synthase gene polymorphisms -786T>C and 894G>T in coronary artery bypass graft surgery patients. Hum. Genomics 4, 375–383 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Dzida, G., Sobstyl, J., Pužniak A., Prystupa, A. & Mosiewicz, J. Impact of smoking status on particular genetic polymorphisms associations with cardiovascular diseases. J. Preclin. Clin. Res. 6, 31–34 (2012).

    Google Scholar 

  143. Lee, C. R. et al. NOS3 polymorphisms, cigarette smoking, and cardiovascular disease. Pharmacogenet. Genomics 16, 891–899 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Nasreen, S. et al. T-786C polymorphism in endothelial NO synthetase gene affects cerebral circulation in smokers: possible gene-environmental interaction. Arterioscler. Thromb. Vasc. Biol. 22, 605–610 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Yin, R.-X. et al. Interactions of several lipid-related gene polymorphisms and cigarette smoking on blood pressure levels. Int. J. Biol. Sci. 8, 685–696 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Sen-Banerjee, S., Siles, X. & Campos, H. Tobacco smoke modifies association between Glu-Arg192 polymorphism of human paraxonase gene and risk of myocardial infarction. Atheroscler. Thromb. Vasc. Biol. 20, 2120–2126 (2000).

    Article  CAS  Google Scholar 

  147. Frey, P. et al. Impact of smoking on cardiovascular events in patients with coronary disease receiving contemporary medical therapy (from the Treating to New Targets [TNT] and the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] trials). Am. J. Cardiol. 107, 145–150 (2011).

    Article  PubMed  Google Scholar 

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Acknowledgements

D. Bernhard is supported by the Austrian National Bank (Project 14745).

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  1. Division of Cardiovascular Surgery, University Hospital Zürich, Raemistrasse 100, Zürich, CH-8091, Switzerland

    Adam Csordas

  2. Cardiac Surgery Research Laboratory, Innsbruck Medical University, Innrain 66, 6th floor, Innsbruck, A-6020, Austria

    David Bernhard

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Csordas, A., Bernhard, D. The biology behind the atherothrombotic effects of cigarette smoke. Nat Rev Cardiol 10, 219–230 (2013). https://doi.org/10.1038/nrcardio.2013.8

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