STATE-OF-THE-ART PAPER
From *The Heart Institute, Good Samaritan Hospital, Los Angeles, California;
Division of Cardiovascular Medicine, Keck School of Medicine, University of
Southern California, Los Angeles, California; and the Department of Community
and Environmental Medicine, University of California Irvine, Irvine, California. This
study was supported by U.S. Environmental Protection Agency (USEPA) STAR
Grant No. RD-83195201 and the Gwladys and John Zurlo Charitable Foundation.
Manuscript received January 14, 2008; revised manuscript received May 14, 2008,
accepted May 19, 2008.
720
Simkhovich et al.
Air Pollution and Cardiovascular Injury
Abbreviations
and Acronyms
AD aerodynamic
diameter
Simkhovich et al.
Air Pollution and Cardiovascular Injury
721
722
Simkhovich et al.
Air Pollution and Cardiovascular Injury
Figure 1
Simkhovich et al.
Air Pollution and Cardiovascular Injury
723
Pathophysiological Mechanisms of Lung- and Circulation-Mediated Cardiovascular Toxicity of Particulate Air Pollutants
Inhaled ambient air particles increase production of reactive oxygen species (ROS) in the airways and lung alveoli and stimulate local inflammatory reaction in the lungs.
The ROS and pro-inflammatory cytokines released into the blood stream affect autonomic cardiac control (heart rate, heart rate variability, and cardiac contractility),
blood pressure, vascular tone and reactivity, blood coagulability, and progression of atherosclerosis. Ultrafine particles may translocate into the circulation and induce
oxidative stress and pro-inflammatory changes directly in the cardiac muscle and vasculature. Lung- and circulation-mediated and direct pathophysiological mechanisms
exacerbate myocardial ischemia and increase cardiovascular mortality. CRP C-reactive protein; IL interleukin; TNF tumor necrosis factor. Figure illustration by Rob
Flewell.
in increased oxidative stress in the heart and was accompanied by increased HRV 30 min after the exposure. The
antioxidant N-acetyl cysteine prevented both the accumulation of oxidants and changes in the HRV caused by
UAPs. Both the beta-1 adrenergic antagonist (atenolol)
and the muscarinic receptor antagonist (glycopyrrolate)
given before the instillation of UAPs prevented oxidative
stress caused by particulate pollutants. These results were
also confirmed with inhalation exposure to CAPs. The
authors concluded that particulate pollutants caused oxidative stress via changes in autonomic signaling, and
724
Simkhovich et al.
Air Pollution and Cardiovascular Injury
Simkhovich et al.
Air Pollution and Cardiovascular Injury
725
37. Poloniecki JD, Atkinson RW, de Leon AP, Anderson RH. Daily time
series for cardiovascular hospital admissions and previous days air
pollution in London, UK. Occup Environ Med 1997;54:535 40.
38. Peters A, Dockery DW, Muller JE, Mittleman MA. Increased
particulate air pollution and the triggering of myocardial infarction.
Circulation 2001;103:2810 5.
39. Pope CA III, Muhlestein JB, May HT, Rehlund DG, Anderson JL,
Horne BD. Ischemic heart disease events triggered by short-term
exposure to fine particulate air pollution. Circulation 2006;114:
2443 8.
40. Devlin RB, Ghio AJ, Kehrk H, Sanders G, Cascio W. Elderly humans
exposed to concentrated air pollution particles have decreased heart
rate variability. Eur Respir J 2003;21:76S 80S.
41. Zanobetti A, Schwartz J. Cardiovascular damage by air borne particles:
are diabetics more susceptible? Epidemiology 2002;13:588 92.
42. ONeill MS, Veves A, Zanobetti A, et al. Diabetes enhances vulnerability to particulate air pollution-associated impairment in vascular
reactivity and endothelial function. Circulation 2005;111:291320.
43. Pope CA III, Hansen ML, Long RW, et al. Ambient particulate air
pollution, heart rate variability, and blood markers of inflammation in
a panel of elderly subjects. Environ Health Perspect 2004;112:339 45.
44. Mills NL, Trnqvist H, Gonzalez MC, et al. Ischemic and thrombotic
effects of dilute diesel-exhaust inhalation in men with coronary heart
disease. New Eng J Med 2007;357:1075 82.
45. Campen MJ, Nolan JP, Schladweiler MC, Kodavanti UP, Coasta DL,
Watkinson WP. Cardiac and thermoregulatory effects of instilled
particulate matter-associated transition metals in healthy and
cardiopulmonary-compromised rats. J Toxicol Environ Health Part A
2002;65:161531.
46. Lam CW, James JT, McCluskey R, Arepalli S, Hunter RL. A review
of carbon nanotube toxicity and assessment of potential occupational
and environmental health risks. Crit Rev Toxicol 2006;36:189 217.
47. Ruidavets JB, Cournot M, Cassadou S, Giroux M, Meybeck M,
Ferrieres J. Ozone air pollution is associated with acute myocardial
infarction. Circulation 2005;111:5639.
48. Sunyer J, Ballester F, Le Tertre A, et al. The association of daily
sulfur dioxide air pollution levels with hospital admissions for
cardiovascular diseases in Europe (the Aphea-II study). Eur Heart J
2003;24:752 60.
49. Kleinman MT, Davidson DM, Vandagriff RB, Caiozzo VJ, Whittenberger JL. Effects of short-term exposure to carbon monoxide in
subjects with coronary artery disease. Arch Environ Health 1989;44:
3619.
50. Gold DR, Litonjua A, Schwartz J, et al. Ambient pollution and heart
rate variability. Circulation 2000;101:126773.
51. Pope CA III, Dockery DW, Kanner RE, Villegas GM. Oxygen
saturation, pulse rate, and particulate air pollution. A daily time-series
panel study. Am J Respir Crit Care Med 1999;159:36572.
52. Pope CA, Verrier RL, Lovett EG, et al. Heart rate variability
associated with particulate air pollution. Am Heart J 1999;138:804 7.
53. Tsuji H, Larson MG, Venditti FJ, et al. Impact of reduced heart rate
variability on risk for cardiac events. The Framingham heart study.
Circulation 1996;94:2850 5.
54. Zanobetti A, Canner MJ, Stone PH, et al. Ambient air pollution and
blood pressure in cardiac rehabilitation patients. Circulation 2004;110:
2184 9.
55. Ibald-Mulli A, Stieber J, Wichmann H-E, Koenig W, Peters A.
Effects of air pollution on blood pressure: a population-based approach. Am J Public Health 2001;91:5717.
56. Brook RD, Brook JR, Urch B, Vincent R, Rajagopalan S, Silverman F.
Inhalation of fine particulate air pollution and ozone causes acute
arterial vasoconstriction in healthy adults. Circulation 2002;105:
1534 6.
57. Nemmar A, Hoet PHM, Dinsdale D, Vermylen J, Hoylaerts MF,
Nemery B. Diesel exhaust particles in lung acutely enhance experimental peripheral thrombosis. Circulation 2003;107:1202 8.
58. Mutlu GM, Green D, Bellmeyer A, et al. Ambient particulate matter
accelerates coagulation via an IL-6-dependent pathway. J Clin Invest
2007;117:2952 61.
59. Peters A, Dring A, Wichmann H-E, Koenig W. Increased plasma
viscosity during an air pollution episode: a link to mortality? Lancet
1997:15827.
60. Baccarelli A, Zanobetti A, Martinelli I, et al. Effects of exposure to air
pollutants on blood coagulation. J Thromb Haemost 2007;5:250 1.
726
Simkhovich et al.
Air Pollution and Cardiovascular Injury
61. Sun Q, Wang A, Jun X, et al. Long-term air pollution exposure and
acceleration of atherosclerosis and vascular inflammation in an animal
model. JAMA 2005;294:300310.
62. Araujo JA, Barajas B, Kleinman MT, et al. Ambient particulate
pollutants in the ultrafine range promote early atherosclerosis and
systemic oxidative stress. Cir Res 2008;102:589 96.
63. Suwa T, Hogg JC, Quinlan KB, Ohgami A, Vincent R, van Eeden SF.
Particulate air pollution induces progression of atherosclerosis. J Am
Coll Cardiol 2002;39:935 42.
64. Ghio AJ, Kim C, Devlin RB. Concentrated ambient air particle induce
mild pulmonary inflammation in healthy human volunteers. Am J
Respirat Crit Care Med 2000;162:981 8.
65. Donaldson K, Stone V. Current hypotheses on the mechanisms of
toxicity of ultrafine particles. Ann Ist Super Sanita 2003;39:40510.
66. Li XY, Brown DM, Smith SC, MacNee W, Donaldson K. Short-term
inflammatory responses following intratracheal instillation of fine and
ultrafine carbon black in rats. Inhal Toxicol 1999;11:709 31.
67. Schins PF, Lightbody JH, Borm PJA, Shi T, Donaldson K, Stone V.
Inflammatory effects of coarse and fine particulate matter in relation to
chemical and biological constituents. Toxicol Appl Pharmacol 2004;
195:111.
68. Dick CAJ, Singh P, Daniels M, Evansky P, Becker S, Gilmour MI.
Murine pulmonary inflammatory responses following instillation of
size-fractioned ambient particulate matter. J Toxicol Environ Health
Part A 2003;66:2193207.
69. Ghio AJ, Devlin RB. Inflammatory lung injury after bronchial
instillation of air pollution particles. Am J Respirat Crit Care Med
2001;164:704 8.
70. Wellenius GA, Coull BA, Godleski JJ, et al. Inhalation of concentrated ambient air particles exacerbates myocardial ischemia in conscious dogs. Environ Health Perspect 2003;111:402 8.
71. Kodavanti UP, Moyer CF, Ledbetter AD, et al. Inhaled environmental combustion particles cause myocardial injury in the Wystar Kyoto
rat. Toxicol Sci 2003;71:237 45.
72. Cozzi E, Hazarika S, Stallings HW, et al. Ultrafine particulate matter
exposure augments ischemia-reperfusion injury in mice. Am J Physiol
Heart Circ Physiol 2006;291:H894 903.
73. Peters A, Frhlich M, Dring A, et al. Particulate air pollution is
associated with an acute phase response in men. Eur Heart J 2001;22:
1198 204.
74. Ruckert R, Greven S, Ljungman P, et al. Air pollution and inflammation (interleukin-6, C-reactive protein, fibrinogen) in myocardial
infarction survivors. Environ Health Perspect 2007;115:1072 80.
75. Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive
marker of inflammation, predicts future risk of coronary heart disease
in initially healthy middle-aged men: results from the MONICA
(Monitoring Trends and Determinants in Cardiovascular Disease)
Augsburg Cohort Study. Circulation 1999;99:237 42.
76. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of
C-reactive protein and low-density lipoprotein cholesterol levels in the
prediction of first cardiovascular events. N Eng J Med 2002;347:155765.
77. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor.
Circulation 2004;109:II210.
78. Libby P. Current concepts in the pathogenesis of the acute coronary
syndromes. Circulation 2001;104:36572.
79. Nemmar A, Hoet PHM, Vanquickenborne B, et al. Passage of inhaled
particles into the blood circulation in humans. Circulation 2002;105:
411 4.