Environmental factors in cardiovascular disease

Key Points

  • Environmental exposure, over which the individual has little control, can have an important role in the development and severity of cardiovascular disease (CVD)

  • The WHO has identified air pollution as the world's largest single environmental-health risk, and 80% of deaths related to outdoor air pollution result from ischaemic heart disease and stroke

  • Metals such as lead, cadmium, and arsenic—listed among the WHO's top 10 environmental chemicals of concern—also mediate the development and progression of CVD

  • Exposure to fine particulate matter, a major component in urban air pollution, is associated with mortality and cardiovascular risk, even at concentrations below current US and EU regulatory standards

  • Effects occur via pathways known to affect cardiovascular risk, including changes in blood pressure, lipids, vascular function, and atherosclerosis

  • With the widespread prevalence of exposure, policy interventions that reduce environmental pollution can have substantial beneficial effects on cardiovascular health for populations around the world

Abstract

Environmental exposure is an important but underappreciated risk factor contributing to the development and severity of cardiovascular disease (CVD). The heart and vascular system are highly vulnerable to a number of environmental agents—ambient air pollution and the metals arsenic, cadmium, and lead are widespread and the most-extensively studied. Like traditional risk factors, such as smoking and diabetes mellitus, these exposures advance disease and mortality via augmentation or initiation of pathophysiological processes associated with CVD, including blood-pressure control, carbohydrate and lipid metabolism, vascular function, and atherogenesis. Although residence in highly polluted areas is associated with high levels of cardiovascular risk, adverse effects on cardiovascular health also occur at exposure levels below current regulatory standards. Considering the widespread prevalence of exposure, even modest contributions to CVD risk can have a substantial effect on population health. Evidence-based clinical and public-health strategies aimed at reducing environmental exposures from current levels could substantially lower the burden of CVD-related death and disability worldwide.

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Figure 1: A framework for the characterization of the effects of environmental factors in cardiovascular disease.
Figure 2: Size categorization of airborne pollutants.
Figure 3: Cardiovascular effects and proposed mechanisms of chronic exposure to traffic-related air pollution.
Figure 4: Cardiovascular effects and proposed mechanisms of acute exposure to traffic-related air pollution.
Figure 5: Possible mechanisms for the cardiovascular effects of exposure to arsenic.

References

  1. 1

    World Health Organization. Global status report on noncommunicable diseases 2010 [online], (2011).

  2. 2

    Lim, S. S. et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2224–2260 (2012).

  3. 3

    Bhatnagar, A. Cardiovascular pathophysiology of environmental pollutants. Am. J. Physiol. Heart Circ. Physiol. 286, H479–H485 (2004).

  4. 4

    Brook, R. D. et al. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 121, 2331–2378 (2010).

  5. 5

    Csordas, A. & Bernhard, D. The biology behind the atherothrombotic effects of cigarette smoke. Nat. Rev. Cardiol. 10, 219–230 (2013).

  6. 6

    World Health Organization. Ambient (outdoor) air quality and health [online], (2014).

  7. 7

    Wong, E. On scale of 0 to 500, Beijing's air quality tops 'crazy bad' at 755. The New York Times, A16 (12 Jan 2013).

  8. 8

    Krzyzanowski, M. et al. Air pollution in mega-cities. Curr. Env. Health Rep. 1, 185–191 (2014).

  9. 9

    United States Environmental Protection Agency. Our nation's air-status and trends through 2010 [online], (2012).

  10. 10

    Kam, W., Liacos, J. W., Schauer, J. J., Delfino, R. J. & Sioutas, C. Size-segregated composition of particulate matter (PM) in major roadways and surface streets. Atmos. Environ. 55, 90–97 (2012).

  11. 11

    World Health Organization. Burden of disease from household air pollution for 2012 [online], (2014).

  12. 12

    Rom, W. N., Boushey, H. & Caplan, A. Experimental human exposure to air pollutants is essential to understand adverse health effects. Am. J. Respir. Cell Mol. Biol. 49, 691–696 (2013).

  13. 13

    Ramsay, S. E. et al. Inequalities in heart failure in older men: prospective associations between socioeconomic measures and heart failure incidence in a 10-year follow-up study. Eur. Heart J. 35, 442–447 (2014).

  14. 14

    Romieu, I. et al. Multicity study of air pollution and mortality in Latin America (the ESCALA study). Res. Rep. Health Eff. Inst. 171, 5–86 (2012).

  15. 15

    Dockery, D. W. et al. An association between air pollution and mortality in six U. S. cities. N. Engl. J. Med. 329, 1753–1759 (1993).

  16. 16

    Pope, C. A. 3rd. et al. Particulate air pollution as a predictor of mortality in a prospective-study of U. S. adults. Am. J. Respir. Crit. Care Med. 151, 669–674 (1995).

  17. 17

    Laden, F., Schwartz, J., Speizer, F. E. & Dockery, D. W. Reduction in fine particulate air pollution and mortality: extended follow-up of the Harvard Six Cities study. Am. J. Respir. Crit. Care Med. 173, 667–672 (2006).

  18. 18

    Pope, C. A. 3rd et al. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 109, 71–77 (2004).

  19. 19

    Hoek, G. et al. Long-term air pollution exposure and cardio- respiratory mortality: a review. Environ. Health 12, 43 (2013).

  20. 20

    Zhang, L. W. et al. Long-term exposure to high particulate matter pollution and cardiovascular mortality: a 12-year cohort study in four cities in northern China. Environ. Int. 62, 41–47 (2014).

  21. 21

    Pun, V. C. et al. Differential effects of source-specific particulate matter on emergency hospitalizations for ischemic heart disease in Hong Kong. Environ. Health Perspect. 122, 391–396 (2014).

  22. 22

    Beelen, R. et al. Effects of long-term exposure to air pollution on natural-cause mortality: an analysis of 22 European cohorts within the multicentre ESCAPE project. Lancet 383, 785–795 (2014).

  23. 23

    Lepeule, J., Laden, F., Dockery, D. & Schwartz, J. Chronic exposure to fine particles and mortality: an extended follow-up of the Harvard Six Cities study from 1974 to 2009. Environ. Health Perspect. 120, 965–970 (2012).

  24. 24

    Miller, K. A. et al. Long-term exposure to air pollution and incidence of cardiovascular events in women. N. Engl. J. Med. 356, 447–458 (2007).

  25. 25

    Cesaroni, G. et al. Long term exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE Project. BMJ 348, f7412 (2014).

  26. 26

    Atkinson, R. W. et al. Long-term exposure to outdoor air pollution and incidence of cardiovascular diseases. Epidemiology 24, 44–53 (2013).

  27. 27

    Lipsett, M. J. et al. Long-term exposure to air pollution and cardiorespiratory disease in the California teachers study cohort. Am. J. Respir. Crit. Care Med. 184, 828–835 (2011).

  28. 28

    Crouse, D. L. et al. Risk of nonaccidental and cardiovascular mortality in relation to long-term exposure to low concentrations of fine particulate matter: a Canadian national-level cohort study. Environ. Health Perspect. 120, 708–714 (2012).

  29. 29

    Hart, J. E., Chiuve, S. E., Laden, F. & Albert, C. M. Roadway proximity and risk of sudden cardiac death in women. Circulation 130, 1474–1482 (2014).

  30. 30

    Madrigano, J. et al. Long-term exposure to PM2.5 and incidence of acute myocardial infarction. Environ. Health Perspect. 121, 192–196 (2013).

  31. 31

    Hart, J. E., Rimm, E. B., Rexrode, K. M. & Laden, F. Changes in traffic exposure and the risk of incident myocardial infarction and all-cause mortality. Epidemiology 24, 734–742 (2013).

  32. 32

    Koton, S. et al. Cumulative exposure to particulate matter air pollution and long-term post-myocardial infarction outcomes. Prev. Med. 57, 339–344 (2013).

  33. 33

    Wilker, E. H. et al. Residential proximity to high-traffic roadways and poststroke mortality. J. Stroke Cerebrovasc. Dis. 22, e366–e372 (2013).

  34. 34

    Eze, I. C. et al. Long-term air pollution exposure and diabetes in a population-based Swiss cohort. Environ. Int. 70, 95–105 (2014).

  35. 35

    Jerrett, M. et al. Traffic-related air pollution and obesity formation in children: a longitudinal, multilevel analysis. Environ. Health 13, 49 (2014).

  36. 36

    Pearson, J. F., Bachireddy, C., Shyamprasad, S., Goldfine, A. B. & Brownstein, J. S. Association between fine particulate matter and diabetes prevalence in the U. S. Diabetes Care 33, 2196–2201 (2010).

  37. 37

    Krämer, U. et al. Traffic-related air pollution and incident type 2 diabetes: results from the SALIA cohort study. Environ. Health Perspect. 118, 1273–1279 (2010).

  38. 38

    Chen, H. et al. Risk of incident diabetes in relation to long-term exposure to fine particulate matter in Ontario, Canada. Environ. Health Perspect. 121, 804–810 (2013).

  39. 39

    Wang, Y. et al. Long-term exposure to ambient air pollution and serum leptin in older adults: results from the MOBILIZE Boston study. J. Occup. Environ. Med. 56, e73–e77 (2014).

  40. 40

    Baja, E. S. et al. Traffic-related air pollution and QT interval: modification by diabetes, obesity, and oxidative stress gene polymorphisms in the normative aging study. Environ. Health Perspect. 118, 840–846 (2010).

  41. 41

    Park, S. K. et al. Particulate air pollution, metabolic syndrome, and heart rate variability: the multi-ethnic study of atherosclerosis (MESA). Environ. Health Perspect. 118, 1406–1411 (2010).

  42. 42

    Rückerl, R. et al. Associations between ambient air pollution and blood markers of inflammation and coagulation/fibrinolysis in susceptible populations. Environ. Int. 70, 32–49 (2014).

  43. 43

    Pascal, M. et al. Short-term impacts of particulate matter (PM10, PM10–2.5, PM2.5) on mortality in nine French cities. Atmos. Environ. 95, 175–184 (2014).

  44. 44

    Meister, K., Johansson, C. & Forsberg, B. Estimated short-term effects of coarse particles on daily mortality in Stockholm, Sweden. Environ. Health Perspect. 120, 431–436 (2012).

  45. 45

    Atkinson, R. W., Kang, S., Anderson, H. R., Mills, I. C. & Walton, H. A. Epidemiological time series studies of PM2.5 and daily mortality and hospital admissions: a systematic review and meta-analysis. Thorax 69, 660–665 (2014).

  46. 46

    Wang, Y., Eliot, M. N. & Wellenius, G. A. Short-term changes in ambient particulate matter and risk of stroke: a systematic review and meta-analysis. J. Am. Heart Assoc. 3, e000983 (2014).

  47. 47

    Adar, S. D., Filigrana, P. A., Clements, N. & Peel, J. L. Ambient coarse particulate matter and human health: a systematic review and meta-analysis. Curr. Environ. Health Rep. 1, 258–274 (2014).

  48. 48

    Wellenius, G. A., Bateson, T. F., Mittleman, M. A. & Schwartz, J. Particulate air pollution and the rate of hospitalization for congestive heart failure among Medicare beneficiaries in Pittsburgh, Pennsylvania. Am. J. Epidemiol. 161, 1030–1036 (2005).

  49. 49

    Milojevic, A. et al. Short-term effects of air pollution on a range of cardiovascular events in England and Wales: case-crossover analysis of the MINAP database, hospital admissions and mortality. Heart 100, 1093–1098 (2014).

  50. 50

    Zanobetti, A., Dominici, F., Wang, Y. & Schwartz, J. D. A national case-crossover analysis of the short-term effect of PM2.5 on hospitalizations and mortality in subjects with diabetes and neurological disorders. Environ. Health 13, 38 (2014).

  51. 51

    Mustafic, H. et al. Main air pollutants and myocardial infarction a systematic review and meta-analysis. JAMA 307, 713–721 (2012).

  52. 52

    Nawrot, T. S., Perez, L., Künzli, N., Munters, E. & Nemery, B. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet 377, 732–740 (2011).

  53. 53

    Wellenius, G. A. et al. Ambient air pollution and the risk of acute ischemic stroke. Arch. Intern. Med. 172, 229–234 (2012).

  54. 54

    Andersen, Z. J. et al. Association between short-term exposure to ultrafine particles and hospital admissions for stroke in Copenhagen, Denmark. Eur. Heart J. 31, 2034–2040 (2010).

  55. 55

    Gardner, B. et al. Ambient fine particulate air pollution triggers ST-elevation myocardial infarction, but not non-ST elevation myocardial infarction: a case-crossover study. Part. Fibre Toxicol. 11, 1 (2014).

  56. 56

    Dominici, F. et al. Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases. JAMA 295, 1127–1134 (2006).

  57. 57

    Stafoggia, M. et al. Short-term associations between fine and coarse particulate matter and hospitalizations in southern europe: results from the MED-PARTICLES project. Environ. Health Perspect. 121, 1026–1033 (2013).

  58. 58

    Guo, Y. et al. The relationship between particulate air pollution and emergency hospital visits for hypertension in Beijing, China. Sci. Total Environ. 408, 4446–4450 (2010).

  59. 59

    Xie, W. et al. Relationship between fine particulate air pollution and ischaemic heart disease morbidity and mortality. Heart 101, 257–263 (2015).

  60. 60

    Rosenthal, F. S. et al. Association of ozone and particulate air pollution with out-of-hospital cardiac arrest in Helsinki, Finland: evidence for two different etiologies. J. Expo. Sci. Environ. Epidemiol. 23, 281–288 (2013).

  61. 61

    Teng, T. H. et al. A systematic review of air pollution and incidence of out-of-hospital cardiac arrest. J. Epidemiol. Community Health 68, 37–43 (2014).

  62. 62

    Peters, A. et al. Triggering of acute myocardial infarction by different means of transportation. Eur. J. Prev. Cardiol. 20, 750–758 (2013).

  63. 63

    Sørensen, M. et al. Long-term exposure to traffic-related air pollution associated with blood pressure and self-reported hypertension in a Danish cohort. Environ. Health Perspect. 120, 418–424 (2012).

  64. 64

    Louwies, T. et al. Blood pressure changes in association with black carbon exposure in a panel of healthy adults are independent of retinal microcirculation. Environ. Int. 75, 81–86 (2015).

  65. 65

    Schwartz, J. et al. Association between long-term exposure to traffic particles and blood pressure in the Veterans Administration Normative Aging Study. Occup. Environ. Med. 69, 422–427 (2012).

  66. 66

    Fuks, K. B. et al. Arterial blood pressure and long-term exposure to traffic-related air pollution: an analysis in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Environ. Health Perspect. 122, 896–905 (2014).

  67. 67

    Delfino, R. J. et al. Traffic-related air pollution and blood pressure in elderly subjects with coronary artery disease. Epidemiology 21, 396–404 (2010).

  68. 68

    Foraster, M. et al. Association of long-term exposure to traffic-related air pollution with blood pressure and hypertension in an adult population-based cohort in Spain (the REGICOR Study). Environ. Health Perspect. 122, 404–411 (2014).

  69. 69

    Kirwa, K. et al. Residential proximity to major roadways and prevalent hypertension among postmenopausal women: results from the Women's Health Initiative San Diego Cohort. J. Am. Heart Assoc. 3, e000727 (2014).

  70. 70

    Chen, H. et al. Spatial association between ambient fine particulate matter and incident hypertension. Circulation 129, 562–569 (2014).

  71. 71

    Coogan, P. F. et al. Air pollution and incidence of hypertension and diabetes mellitus in black women living in Los Angeles. Circulation 125, 767–772 (2012).

  72. 72

    Cosselman, K. E. et al. Blood pressure response to controlled diesel exhaust exposure in human subjects. Hypertension 59, 943–948 (2012).

  73. 73

    Bellavia, A. et al. DNA hypomethylation, ambient particulate matter, and increased blood pressure: findings from controlled human exposure experiments. J. Am. Heart Assoc. 2, e000212 (2013).

  74. 74

    Auchincloss, A. H. et al. Associations between recent exposure to ambient fine particulate matter and blood pressure in the Multi-ethnic Study of Atherosclerosis (MESA). Environ. Health Perspect. 116, 486–491 (2008).

  75. 75

    Brook, R. D. et al. Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location. Environ. Health Perspect. 122, 624–630 (2014).

  76. 76

    van den Hooven, E. H. et al. Air pollution, blood pressure, and the risk of hypertensive complications during pregnancy the generation R study. Hypertension 57, 406–412 (2011).

  77. 77

    Xu, X. H., Hu, H., Ha, S. & Roth, J. Ambient air pollution and hypertensive disorder of pregnancy. J. Epidemiol. Community Health 68, 13–20 (2014).

  78. 78

    Vinikoor-Imler, L. C., Gray, S. C., Edwards, S. E. & Miranda, M. L. The effects of exposure to particulate matter and neighbourhood deprivation on gestational hypertension. Paediatr. Perinat. Epidemiol. 26, 91–100 (2012).

  79. 79

    Dadvand, P. et al. Particulate air pollution and preeclampsia: a source-based analysis. Occup. Environ. Med. 71, 570–577 (2014).

  80. 80

    Pedersen, M. et al. Ambient air pollution and pregnancy-induced hypertensive disorders: a systematic review and meta-analysis. Hypertension 64, 494–500 (2014).

  81. 81

    Hampel, R. et al. Short-term impact of ambient air pollution and air temperature on blood pressure among pregnant women. Epidemiology 22, 671–679 (2011).

  82. 82

    Stieb, D. M., Chen, L., Eshoul, M. & Judek, S. Ambient air pollution, birth weight and preterm birth: a systematic review and meta-analysis. Environ. Res. 117, 100–111 (2012).

  83. 83

    Gorr, M. W. et al. Early life exposure to air pollution induces adult cardiac dysfunction. Am. J. Physiol. Heart Circ. Physiol. 307, H1353–H1360 (2014).

  84. 84

    Wilker, E. H. et al. Relation of long-term exposure to air pollution to brachial artery flow-mediated dilation and reactive hyperemia. Am. J. Cardiol. 113, 2057–2063 (2014).

  85. 85

    Krishnan, R. M. et al. Vascular responses to long- and short-term exposure to fine particulate matter: MESA Air (Multi-Ethnic Study of Atherosclerosisi and Air Pollution). J. Am. Coll. Cardiol. 60, 2158–2166 (2012).

  86. 86

    Barath, S. et al. Impaired vascular function after exposure to diesel exhaust generated at urban transient running conditions. Part. Fibre Toxicol. 7, 19 (2010).

  87. 87

    Peretz, A. et al. Diesel exhaust inhalation elicits acute vasoconstriction in vivo. Environ. Health Perspect. 116, 937–942 (2008).

  88. 88

    Adar, S. D. et al. Air Pollution and the microvasculature: a cross-sectional assessment of in vivo retinal images in the population-based multi-ethnic study of atherosclerosis (MESA). PLoS Med. 7, e1000372 (2010).

  89. 89

    Louwies, T., Panis, L. I., Kicinski, M., De Boever, P. & Nawrot, T. S. Retinal microvascular responses to short-term changes in particulate air pollution in healthy adults. Environ. Health Perspect. 121, 1011–1016 (2013).

  90. 90

    Zanobetti, A. et al. T-wave alternans, air pollution and traffic in high-risk subjects. Am. J. Cardiol. 104, 665–670 (2009).

  91. 91

    Cakmak, S. et al. Metal composition of fine particulate air pollution and acute changes in cardiorespiratory physiology. Environ. Pollut. 189, 208–214 (2014).

  92. 92

    Lee, M. S. et al. Oxidative stress and systemic inflammation as modifiers of cardiac autonomic responses to particulate air pollution. Int. J. Cardiol. 176, 166–170 (2014).

  93. 93

    Anderson, H. R. et al. Air pollution and activation of implantable cardioverter defibrillators in London. Epidemiology 21, 405–413 (2010).

  94. 94

    Bunch, T. J. et al. Atrial fibrillation hospitalization is not increased with short-term elevations in exposure to fine particulate air pollution. Pacing Clin. Electrophysiol. 34, 1475–1479 (2011).

  95. 95

    Langrish, J. P. et al. Controlled exposures to air pollutants and risk of cardiac arrhythmia. Environ. Health Perspect. 122, 747–753 (2014).

  96. 96

    Wold, L. E. et al. Cardiovascular remodeling in response to long-term exposure to fine particulate matter air pollution. Circ. Heart Fail. 5, 452–461 (2012).

  97. 97

    Kawut, S. M. et al. Right ventricular structure is associated with the risk of heart failure and cardiovascular death: the Multi-Ethnic Study of Atherosclerosis (MESA)—right ventricle study. Circulation 126, 1681–1688 (2012).

  98. 98

    Leary, P. J. et al. Traffic-related air pollution and the right ventricle. The multi-ethnic study of atherosclerosis. Am. J. Respir. Crit. Care Med. 189, 1093–1100 (2014).

  99. 99

    Van Hee, V. C. et al. Exposure to traffic and left ventricular mass and function: the Multi-Ethnic Study of Atherosclerosis. Am. J. Respir. Crit. Care Med. 179, 827–834 (2009).

  100. 100

    Heckbert, S. R. et al. Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: the Multiethnic Study of Atherosclerosis. J. Am. Coll. Cardiol. 48, 2285–2292 (2006).

  101. 101

    Yin, F. et al. Diesel exhaust induces systemic lipid peroxidation and development of dysfunctional pro-oxidant and pro-inflammatory high-density lipoprotein. Arterioscler. Thromb. Vasc. Biol. 33, 1153–1161 (2013).

  102. 102

    Quan, C. L., Sun, Q. H., Lippmann, M. & Chen, L. C. Comparative effects of inhaled diesel exhaust and ambient fine particles on inflammation, atherosclerosis, and vascular dysfunction. Inhal. Toxicol. 22, 738–753 (2010).

  103. 103

    Miller, M. R. et al. Diesel exhaust particulate increases the size and complexity of lesions in atherosclerotic mice. Part. Fibre Toxicol. 10, 61 (2013).

  104. 104

    Sun, Q. H. et al. Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model. JAMA 294, 3003–3010 (2005).

  105. 105

    Bai, N. et al. Changes in atherosclerotic plaques induced by inhalation of diesel exhaust. Atherosclerosis 216, 299–306 (2011).

  106. 106

    Campen, M. J. et al. Inhaled diesel emissions alter atherosclerotic plaque composition in ApoE(−/−) mice. Toxicol. Appl. Pharmacol. 242, 310–317 (2010).

  107. 107

    Bauer, M. et al. Urban particulate matter air pollution is associated with subclinical atherosclerosis: results from the HNR (Heinz Nixdorf Recall) study. J. Am. Coll. Cardiol. 56, 1803–1808 (2010).

  108. 108

    Künzli, N. et al. Investigating air pollution and atherosclerosis in humans: concepts and outlook. Prog. Cardiovasc. Dis. 53, 334–343 (2011).

  109. 109

    Wilker, E. H. et al. Long-term exposure to black carbon and carotid intima-media thickness: the normative aging study. Environ. Health Perspect. 121, 1061–1067 (2013).

  110. 110

    Lambrechtsen, J. et al. The relation between coronary artery calcification in asymptomatic subjects and both traditional risk factors and living in the city centre: a DanRisk substudy. J. Intern. Med. 271, 444–450 (2012).

  111. 111

    Newby, D. E. et al. Expert position paper on air pollution and cardiovascular disease. Eur Heart J. 36, 83–93b (2015).

  112. 112

    Langrish, J. P. et al. Cardiovascular effects of particulate air pollution exposure: time course and underlying mechanisms. J. Intern. Med. 272, 224–239 (2012).

  113. 113

    Gill, E. A. et al. Air pollution and cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. Prog. Cardiovasc. Dis. 53, 353–360 (2011).

  114. 114

    Cherng, T. W., Campen, M. J., Knuckles, T. L., Gonzalez Bosc, L. & Kanagy, N. L. Impairment of coronary endothelial cell ET(B) receptor function after short-term inhalation exposure to whole diesel emissions. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R640–R647 (2009).

  115. 115

    Rodríguez-Pascual, F., Busnadiego, O., Lagares, D. & Lamas, S. Role of endothelin in the cardiovascular system. Pharmacol. Res. 63, 463–472 (2011).

  116. 116

    Roy, A. et al. The cardiopulmonary effects of ambient air pollution and mechanistic pathways: a comparative hierarchical pathway analysis. PLoS ONE 9, e114913 (2014).

  117. 117

    Pourazar, J. et al. Diesel exhaust activates redox-sensitive transcription factors and kinases in human airways. Am. J. Physiol. Lung Cell. Mol. Physiol. 289, L724–L730 (2005).

  118. 118

    Lucking, A. J. et al. Diesel exhaust inhalation increases thrombus formation in man. Eur. Heart J. 29, 3043–3051 (2008).

  119. 119

    Rückerl, R. et al. Associations between ambient air pollution and blood markers of inflammation and coagulation/fibrinolysis in susceptible populations. Environ. Int. 70, 32–49 (2014).

  120. 120

    Harrison, N. A., Cooper, E., Voon, V., Miles, K. & Critchley, H. D. Central autonomic network mediates cardiovascular responses to acute inflammation: relevance to increased cardiovascular risk in depression? Brain Behav. Immun. 31, 189–196 (2013).

  121. 121

    Huang, W. et al. Inflammatory and oxidative stress responses of healthy young adults to changes in air quality during the Beijing Olympics. Am. J. Respir. Crit. Care Med. 186, 1150–1159 (2012).

  122. 122

    Krishnan, R. M. et al. A randomized cross-over study of inhalation of diesel exhaust, hematological indices, and endothelial markers in humans. Part. Fibre Toxicol. 10, 7 (2013).

  123. 123

    Montezano, A. C. & Touyz, R. M. Reactive oxygen species, vascular Noxs, and hypertension: focus on translational and clinical research. Antioxid. Redox Signal. 20, 164–182 (2014).

  124. 124

    Langrish, J. P. et al. Altered nitric oxide bioavailability contributes to diesel exhaust inhalation-induced cardiovascular dysfunction in man. J. Am. Heart Assoc. 2, e004309 (2013).

  125. 125

    Gandhi, S. K., Rich, D. Q., Ohman-Strickland, P. A., Kipen, H. M. & Gow, A. Plasma nitrite is an indicator of acute changes in ambient air pollutant concentrations. Inhal. Toxicol. 26, 426–434 (2014).

  126. 126

    Bind, M. A. et al. Air pollution and gene-specific methylation in the Normative Aging Study: association, effect modification, and mediation analysis. Epigenetics 9, 448–458 (2014).

  127. 127

    Baccarelli, A. et al. Low blood DNA methylation determines higher risk and mortality from ischemic heart disease and stroke among elderly individuals. Circulation 119, E281 (2009).

  128. 128

    Baccarelli, A., Rienstra, M. & Benjamin, E. J. Cardiovascular epigenetics basic concepts and results from animal and human studies. Circ. Cardiovasc. Genet. 3, 567–573 (2010).

  129. 129

    Chiuve, S. E. et al. Adherence to a low-risk, healthy lifestyle and risk of sudden cardiac death among women. JAMA 306, 62–69 (2011).

  130. 130

    Yang, G. H. et al. Rapid health transition in China, 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet 381, 1987–2015 (2013).

  131. 131

    Weichenthal, S. et al. A randomized double-blind crossover study of indoor air filtration and acute changes in cardiorespiratory health in a First Nations community. Indoor Air 23, 175–184 (2013).

  132. 132

    Allen, R. W. et al. An air filter intervention study of endothelial function among healthy adults in a woodsmoke-impacted community. Am. J. Respir. Crit. Care Med. 183, 1222–1230 (2011).

  133. 133

    Langrish, J. P. et al. Beneficial cardiovascular effects of reducing exposure to particulate air pollution with a simple facemask. Part. Fibre Toxicol. 6, 8 (2009).

  134. 134

    Pope, C. A. 3rd, Ezzati, M. & Dockery, D. W. Fine-particulate air pollution and life expectancy in the United States. N. Engl. J. Med. 360, 376–386 (2009).

  135. 135

    Rich, D. Q. et al. Association between changes in air pollution levels during the Beijing Olympics and biomarkers of inflammation and thrombosis in healthy young adults. JAMA 307, 2068–2078 (2012).

  136. 136

    Kipen, H. et al. Measurement of inflammation and oxidative stress following drastic changes in air pollution during the Beijing Olympics: a panel study approach. Ann. NY Acad. Sci. 1203, 160–167 (2010).

  137. 137

    Pope, C. A. 3rd 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).

  138. 138

    Correia, A. W. et al. Effect of air pollution control on life expectancy in the United States: an analysis of 545 U. S. counties for the period from 2000 to 2007. Epidemiology 24, 23–31 (2013).

  139. 139

    Moon, K., Guallar, E. & Navas-Acien, A. Arsenic exposure and cardiovascular disease: an updated systematic review. Curr. Atheroscler. Rep. 14, 542–555 (2012).

  140. 140

    Tellez-Plaza, M., Jones, M. R., Dominguez-Lucas, A., Guallar, E. & Navas-Acien, A. Cadmium exposure and clinical cardiovascular disease: a systematic review. Curr. Atheroscler. Rep. 15, 356 (2013).

  141. 141

    Navas-Acien, A., Guallar, E., Silbergeld, E. K. & Rothenberg, S. J. Lead exposure and cardiovascular disease—a systematic review. Environ. Health Perspect. 115, 472–482 (2007).

  142. 142

    Prozialeck, W. C. et al. The vascular system as a target of metal toxicity. Toxicol. Sci. 102, 207–218 (2008).

  143. 143

    Tyrrell, J. et al. High urinary tungsten concentration is associated with stroke in the National Health and Nutrition Examination Survey 1999–2010. PLoS ONE 8, e77546 (2013).

  144. 144

    Navas-Acien, A. et al. Metals in urine and peripheral arterial disease. Environ. Health Perspect. 113, 164–169 (2005).

  145. 145

    Agency for Toxic Substances & Disease Registry (ATSDR). Prority List of Hazardous Substances [online], (2013).

  146. 146

    Naujokas, M. F. et al. The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environ. Health Perspect. 121, 295–302 (2013).

  147. 147

    Schmidt, C. W. Low-dose arsenic: in search of a risk threshold. Environ. Health Perspect. 122, A130–A134 (2014).

  148. 148

    Navas-Acien, A. & Nachman, K. E. Public health responses to arsenic in rice and other foods. JAMA Intern. Med. 173, 1395–1396 (2013).

  149. 149

    Schmidt, C. W. In search of “just right”: the challenge of regulating arsenic in rice. Environ. Health Perspect. 123, A16–A19 (2015).

  150. 150

    Davis, M. A. et al. Rice consumption and urinary arsenic concentrations in U. S. children. Environ. Health Perspect. 120, 1418–1424 (2012).

  151. 151

    Maull, E. A. et al. Evaluation of the association between arsenic and diabetes: a National Toxicology Program workshop review. Environ. Health Perspect. 120, 1658–1670 (2012).

  152. 152

    Fowler, B. A., Chou, C.-H. S., Jones, R. L. & Chen, C. J. in Handbook on the Toxicology of Metals 3rd edn Ch. 19 (eds Nordberg, G. F., Fowler, B. A., Nordberg, M. & Friberg, L.) 367–406 (Elsevier, 2007).

  153. 153

    Navas-Acien, A., Francesconi, K. A., Silbergeld, E. K. & Guallar, E. Seafood intake and urine concentrations of total arsenic, dimethylarsinate and arsenobetaine in the US population. Environ. Res. 111, 110–118 (2011).

  154. 154

    United States Environmental Protection Agency (EPA). SBAR Panel #14—national primary drinking water regulations; arsenic and clarifications to compliance and new source contaminants monitoring [online], (2001).

  155. 155

    Thomas, D. J., Styblo, M. & Lin, S. The cellular metabolism and systemic toxicity of arsenic. Toxicol. Appl. Pharmacol. 176, 127–144 (2001).

  156. 156

    Vahter, M. Mechanisms of arsenic biotransformation. Toxicology 181–182, 211–217 (2002).

  157. 157

    Steinmaus, C. et al. Arsenic methylation and bladder cancer risk in case–control studies in Argentina and the United States. J. Occup. Environ. Med. 48, 478–488 (2006).

  158. 158

    Hsueh, Y. M. et al. Serum beta-carotene level, arsenic methylation capability, and incidence of skin cancer. Cancer Epidemiol. Biomarkers Prev. 6, 589–596 (1997).

  159. 159

    Chen, Y. et al. Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study. BMJ 342, d2431 (2011).

  160. 160

    Wu, M. M. et al. Effect of plasma homocysteine level and urinary monomethylarsonic acid on the risk of arsenic-associated carotid atherosclerosis. Toxicol. Appl. Pharmacol. 216, 168–175 (2006).

  161. 161

    Kuo, C. C. et al. Arsenic exposure, arsenic metabolism, and incident diabetes in the strong heart study. Diabetes Care 38, 620–627 (2015).

  162. 162

    Gribble, M. O. et al. Body composition and arsenic metabolism: a cross-sectional analysis in the Strong Heart Study. Environ. Health 12, 107 (2013).

  163. 163

    Stýblo, M., Drobná, Z., Jaspers, I., Lin, S. & Thomas, D. J. The role of biomethylation in toxicity and carcinogenicity of arsenic: a research update. Environ. Health Perspect. 110 (Suppl. 5), 767–771 (2002).

  164. 164

    Agency for Toxic Substances & Disease Registry (ATSDR). Toxicological Profile for Arsenic [online] (2007).

  165. 165

    Hall, M. N. & Gamble, M. V. Nutritional manipulation of one-carbon metabolism: effects on arsenic methylation and toxicity. J. Toxicol. 2012, 595307 (2012).

  166. 166

    Chiou, H. Y. et al. Dose-response relationship between prevalence of cerebrovascular disease and ingested inorganic arsenic. Stroke 28, 1717–1723 (1997).

  167. 167

    Tseng, C. H. et al. Long-term arsenic exposure and ischemic heart disease in arseniasis-hyperendemic villages in Taiwan. Toxicol. Lett. 137, 15–21 (2003).

  168. 168

    Yuan, Y. et al. Acute myocardial infarction mortality in comparison with lung and bladder cancer mortality in arsenic-exposed region II of Chile from 1950 to 2000. Am. J. Epidemiol. 166, 1381–1391 (2007).

  169. 169

    Hertz-Picciotto, I., Arrighi, H. M. & Hu, S. W. Does arsenic exposure increase the risk for circulatory disease? Am. J. Epidemiol. 151, 174–181 (2000).

  170. 170

    Navas-Acien, A. et al. Arsenic exposure and cardiovascular disease: a systematic review of the epidemiologic evidence. Am. J. Epidemiol. 162, 1037–1049 (2005).

  171. 171

    Moon, K. A. et al. Association between exposure to low to moderate arsenic levels and incident cardiovascular disease. A prospective cohort study. Ann. Intern. Med. 159, 649–659 (2013).

  172. 172

    James, K. A. et al. Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ. Health Perspect. 123, 128–134 (2014).

  173. 173

    Sidhu, M. S. et al. Mechanisms of action for arsenic in cardiovascular toxicity and implications for risk assessment. Toxicology 331, 78–99 (2015).

  174. 174

    Tsuji, J. S., Perez, V., Garry, M. R. & Alexander, D. D. Association of low-level arsenic exposure in drinking water with cardiovascular disease: a systematic review and risk assessment. Toxicology 323, 78–94 (2014).

  175. 175

    Abhyankar, L. N., Jones, M. R., Guallar, E. & Navas-Acien, A. Arsenic Exposure and hypertension: a systematic review. Environ. Health Perspect. 120, 494–500 (2012).

  176. 176

    Wu, F., Molinaro, P. & Chen, Y. Arsenic exposure and subclinical endpoints of cardiovascular diseases. Curr. Environ. Health Rep. 1, 148–162 (2014).

  177. 177

    Wang, C. H. et al. Arsenic-induced QT dispersion is associated with atherosclerotic diseases and predicts long-term cardiovascular mortality in subjects with previous exposure to arsenic: a 17-year follow-up study. Cardiovasc. Toxicol. 10, 17–26 (2010).

  178. 178

    Mordukhovich, I. et al. Association between low-level environmental arsenic exposure and QT interval duration in a general population study. Am. J. Epidemiol. 170, 739–746 (2009).

  179. 179

    Kuo, C. C., Moon, K., Thayer, K. A. & Navas-Acien, A. Environmental chemicals and type 2 diabetes: an updated systematic review of the epidemiologic evidence. Curr. Diab. Rep. 13, 831–849 (2013).

  180. 180

    Zheng, L. et al. Arsenic and chronic kidney disease: a systematic review. Curr. Environ. Health Rep. 1, 192–207 (2014).

  181. 181

    Zheng, L. Y. et al. Urine arsenic and prevalent albuminuria: evidence from a population-based study. Am. J. Kidney Dis. 61, 385–394 (2013).

  182. 182

    Bunderson, M. et al. Arsenic exposure exacerbates atherosclerotic plaque formation and increases nitrotyrosine and leukotriene biosynthesis. Toxicol. Appl. Pharmacol. 201, 32–39 (2004).

  183. 183

    Srivastava, S. et al. Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE−/− mice. Toxicol. Appl. Pharmacol. 241, 90–100 (2009).

  184. 184

    Chen, Y. et al. Arsenic exposure from drinking water, arsenic methylation capacity, and carotid intima-media thickness in Bangladesh. Am. J. Epidemiol. 178, 372–381 (2013).

  185. 185

    Wang, Y. H. et al. Effects of arsenic exposure and genetic polymorphisms of p53, glutathione S-transferase M1, T1, and P1 on the risk of carotid atherosclerosis in Taiwan. Atherosclerosis 192, 305–312 (2007).

  186. 186

    Liu, S. et al. Arsenic induces diabetic effects through β-cell dysfunction and increased gluconeogenesis in mice. Sci. Rep. 4, 6894 (2014).

  187. 187

    Paul, D. S., Walton, F. S., Saunders, R. J. & Stýblo, M. Characterization of the impaired glucose homeostasis produced in C57BL/6 mice by chronic exposure to arsenic and high-fat diet. Environ. Health Perspect. 119, 1104–1109 (2011).

  188. 188

    Barchowsky, A., Dudek, E. J., Treadwell, M. D. & Wetterhahn, K. E. Arsenic induces oxidant stress and NF-κB activation in cultured aortic endothelial cells. Free Radic. Biol. Med. 21, 783–790 (1996).

  189. 189

    States, J. C., Srivastava, S., Chen, Y. & Barchowsky, A. Arsenic and cardiovascular disease. Toxicol. Sci. 107, 312–323 (2009).

  190. 190

    Kumagai, Y. & Pi, J. Molecular basis for arsenic-induced alteration in nitric oxide production and oxidative stress: implication of endothelial dysfunction. Toxicol. Appl. Pharmacol. 198, 450–457 (2004).

  191. 191

    Chen, Y. et al. Arsenic exposure from drinking water and QT-interval prolongation: results from the Health Effects of Arsenic Longitudinal Study. Environ. Health Perspect. 121, 427–432 (2013).

  192. 192

    Mumford, J. L. et al. Chronic arsenic exposure and cardiac repolarization abnormalities with QT interval prolongation in a population-based study. Environ. Health Perspect. 115, 690–694 (2007).

  193. 193

    Koestler, D. C., Avissar-Whiting, M., Houseman, E. A., Karagas, M. R. & Marsit, C. J. Differential DNA methylation in umbilical cord blood of infants exposed to low levels of arsenic in utero. Environ. Health Perspect. 121, 971–977 (2013).

  194. 194

    Reichard, J. F., Schnekenburger, M. & Puga, A. Long term low-dose arsenic exposure induces loss of DNA methylation. Biochem. Biophys. Res. Commun. 352, 188–192 (2007).

  195. 195

    Bailey, K. A. & Fry, R. C. Arsenic-associated changes to the epigenome: what are the functional consequences? Curr. Environ. Health Rep. 1, 22–34 (2014).

  196. 196

    States, J. C. et al. Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis. PLoS ONE 7, e38713 (2012).

  197. 197

    Martin, E. et al. Metabolomic characteristics of arsenic-associated diabetes in a prospective cohort in Chihuahua, Mexico. Toxicol. Sci. 144, 338–346 (2015).

  198. 198

    Agency for Toxic Substances & Disease Registry (ATSDR). Toxicological Profile for Cadmium [online], (2012).

  199. 199

    Nordberg, G. F., Nogawa, K., Nordberg, M. & Friberg, L. in Handbook on the Toxicology of Metals 3rd edn Ch. 23 (eds Nordberg, G. F., Fowler, B. A., Nordberg, M. & Friberg, L.) 445–486 (Elsevier, 2007).

  200. 200

    Fransson, M. N., Barregard, L., Sallsten, G., Akerstrom, M. & Johanson, G. Physiologically-based toxicokinetic model for cadmium using Markov-chain Monte Carlo analysis of concentrations in blood, urine, and kidney cortex from living kidney donors. Toxicol. Sci. 141, 365–376 (2014).

  201. 201

    Tellez-Plaza, M. et al. Cadmium exposure and all-cause and cardiovascular mortality in the U. S. general population. Environ. Health Perspect. 120, 1017–1022 (2012).

  202. 202

    Peters, J. L., Perlstein, T. S., Perry, M. J., McNeely, E. & Weuve, J. Cadmium exposure in association with history of stroke and heart failure. Environ. Res. 110, 199–206 (2010).

  203. 203

    Menke, A., Muntner, P., Silbergeld, E. K., Platz, E. A. & Guallar, E. Cadmium levels in urine and mortality among U.S. adults. Environ. Health Perspect. 117, 190–196 (2009).

  204. 204

    Tellez-Plaza, M. et al. Cadmium exposure and incident cardiovascular disease. Epidemiology 24, 421–429 (2013).

  205. 205

    Messner, B. et al. Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. Arterioscler. Thromb. Vasc. Biol. 29, 1392–1398 (2009).

  206. 206

    Fagerberg, B. et al. Cadmium exposure and atherosclerotic carotid plaques—results from the Malmö diet and Cancer study. Environ. Res. 136, 67–74 (2015).

  207. 207

    Tellez-Plaza, M., Navas-Acien, A., Crainiceanu, C. M., Sharrett, A. R. & Guallar, E. Cadmium and peripheral arterial disease: gender differences in the 1999–2004 US National Health and Nutrition Examination Survey. Am. J. Epidemiol. 172, 671–681 (2010).

  208. 208

    Myong, J. P., Kim, H. R., Jang, T. W., Lee, H. E. & Koo, J. W. Association between blood cadmium levels and 10-year coronary heart disease risk in the general Korean population: the Korean National Health and Nutrition Examination Survey 2008–2010. PLoS ONE 9, e111909 (2014).

  209. 209

    Tellez-Plaza, M., Navas-Acien, A., Crainiceanu, C. M. & Guallar, E. Cadmium exposure and hypertension in the 1999–2004 National Health and Nutrition Examination Survey (NHANES). Environ. Health Perspect. 116, 51–56 (2008).

  210. 210

    Chung, S. et al. Blood lead and cadmium levels and renal function in Korean adults. Clin. Exp. Nephrol. 18, 726–734 (2014).

  211. 211

    Messner, B. & Bernhard, D. Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance. Biometals 23, 811–822 (2010).

  212. 212

    Cuypers, A. et al. Cadmium stress: an oxidative challenge. Biometals 23, 927–940 (2010).

  213. 213

    Choong, G., Liu, Y. & Templeton, D. M. Interplay of calcium and cadmium in mediating cadmium toxicity. Chem. Biol. Interact. 211, 54–65 (2014).

  214. 214

    Woods, J. M. et al. Direct antiangiogenic actions of cadmium on human vascular endothelial cells. Toxicol. In Vitro 22, 643–651 (2008).

  215. 215

    Almenara, C. C. et al. Chronic cadmium treatment promotes oxidative stress and endothelial damage in isolated rat aorta. PLoS ONE 8, e68418 (2013).

  216. 216

    Donpunha, W. et al. Protective effect of ascorbic acid on cadmium-induced hypertension and vascular dysfunction in mice. Biometals 24, 105–115 (2011).

  217. 217

    Peters, J. L., Fabian, M. P. & Levy, J. I. Combined impact of lead, cadmium, polychlorinated biphenyls and non-chemical risk factors on blood pressure in NHANES. Environ. Res. 132, 93–99 (2014).

  218. 218

    Hellström, L. et al. Cadmium exposure and end-stage renal disease. Am. J. Kidney Dis. 38, 1001–1008 (2001).

  219. 219

    Navas-Acien, A. et al. Blood cadmium and lead and chronic kidney disease in US adults: a joint analysis. Am. J. Epidemiol. 170, 1156–1164 (2009).

  220. 220

    Weaver, V. M. et al. Associations of low-level urine cadmium with kidney function in lead workers. Occup. Environ. Med. 68, 250–256 (2011).

  221. 221

    Akesson, A. et al. Tubular and glomerular kidney effects in Swedish women with low environmental cadmium exposure. Environ. Health Perspect. 113, 1627–1631 (2005).

  222. 222

    Skerfving, S. & Bergdahl, I. A. in Handbook on the Toxicology of Metals 3rd edn Ch. 31 (eds Nordberg, G. F., Fowler, B. A., Nordberg, M. & Friberg, L.) 599–643 (Elsevier, 2007).

  223. 223

    Flegal, A. R. & Smith, D. R. Lead levels in preindustrial humans. N. Engl. J. Med. 326, 1293–1294 (1992).

  224. 224

    Apostolou, A. et al. Secondhand tobacco smoke: a source of lead exposure in US children and adolescents. Am. J. Public Health 102, 714–722 (2012).

  225. 225

    Hu, H., Shih, R., Rothenberg, S. & Schwartz, B. S. The epidemiology of lead toxicity in adults: measuring dose and consideration of other methodologic issues. Environ. Health Perspect. 115, 455–462 (2007).

  226. 226

    Menke, A., Muntner, P., Batuman, V., Silbergeld, E. K. & Guallar, E. Blood lead below 0.48 μmol/L (10 μg/dL) and mortality among US adults. Circulation 114, 1388–1394 (2006).

  227. 227

    Weisskopf, M. G. et al. A prospective study of bone lead concentration and death from all causes, cardiovascular diseases, and cancer in the Department of Veterans Affairs Normative Aging Study. Circulation 120, 1056–1064 (2009).

  228. 228

    Jain, N. B. et al. Lead levels and ischemic heart disease in a prospective study of middle-aged and elderly men: the VA Normative Aging Study. Environ. Health Perspect. 115, 871–875 (2007).

  229. 229

    Muntner, P., Menke, A., DeSalvo, K. B., Rabito, F. A. & Batuman, V. Continued decline in blood lead levels among adults in the United States: the National Health and Nutrition Examination Surveys. Arch. Intern. Med. 165, 2155–2161 (2005).

  230. 230

    Navas-Acien, A. et al. Lead, cadmium, smoking, and increased risk of peripheral arterial disease. Circulation 109, 3196–3201 (2004).

  231. 231

    Vaziri, N. D. Mechanisms of lead-induced hypertension and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 295, H454–H465 (2008).

  232. 232

    Kern, M. & Audesirk, G. Stimulatory and inhibitory effects of inorganic lead on calcineurin. Toxicology 150, 171–178 (2000).

  233. 233

    Zhang, L. F., Peng, S. Q. & Wang, S. Decreased aortic contractile reaction to 5-hydroxytryptamine in rats with long-term hypertension induced by lead (Pb(2+)) exposure. Toxicol. Lett. 186, 78–83 (2009).

  234. 234

    Lin, J. L., Lin-Tan, D. T., Hsu, K. H. & Yu, C. C. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N. Engl. J. Med. 348, 277–286 (2003).

  235. 235

    Hanna, C. W. et al. DNA methylation changes in whole blood is associated with exposure to the environmental contaminants, mercury, lead, cadmium and bisphenol A, in women undergoing ovarian stimulation for IVF. Hum. Reprod. 27, 1401–1410 (2012).

  236. 236

    Tajuddin, S. M. et al. Genetic and non-genetic predictors of LINE-1 methylation in leukocyte DNA. Environ. Health Perspect. 121, 650–656 (2013).

  237. 237

    Wright, R. O. et al. Biomarkers of lead exposure and DNA methylation within retrotransposons. Environ. Health Perspect. 118, 790–795 (2010).

  238. 238

    Li, C., Yang, X., Xu, M., Zhang, J. & Sun, N. Epigenetic marker (LINE-1 promoter) methylation level was associated with occupational lead exposure. Clin. Toxicol. (Phila.) 51, 225–229 (2013).

  239. 239

    Bollati, V. et al. Exposure to metal-rich particulate matter modifies the expression of candidate microRNAs in peripheral blood leukocytes. Environ. Health Perspect. 118, 763–768 (2010).

  240. 240

    Pirkle, J. L. et al. The decline in blood lead levels in the United States. The National Health and Nutrition Examination Surveys (NHANES). JAMA 272, 284–291 (1994).

  241. 241

    Tellez-Plaza, M. et al. Reduction in cadmium exposure in the United States population, 1988–2008: the contribution of declining smoking rates. Environ. Health Perspect. 120, 204–209 (2012).

  242. 242

    Lamas, G. A. et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA 309, 1241–1250 (2013).

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Cosselman, K., Navas-Acien, A. & Kaufman, J. Environmental factors in cardiovascular disease. Nat Rev Cardiol 12, 627–642 (2015). https://doi.org/10.1038/nrcardio.2015.152

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