Air pollution and adverse cardiac remodeling: clinical effects and basic mechanisms

Recent studies have suggested a link between inhaled particulate matter exposure in urban areas and susceptibility to cardiovascular events; however, the precise mechanisms remain to be determined. To test the hypothesis that subchronic exposure to environmentally relevant particulate matter, even at low concentrations, potentiates atherosclerosis and alters vasomotor tone in a susceptible disease model. Between July 21, 2004, and January 12, 2005, 28 apolipoprotein E-/- (apoE-/-) mice were, based on randomized assignments, fed with normal chow or high-fat chow and exposed to concentrated ambient particles of less than 2.5 microm (PM2.5) or filtered air (FA) in Tuxedo, NY, for 6 hours per day, 5 days per week for a total of 6 months. Composite atherosclerotic plaque in the thoracic and abdominal aorta and vasomotor tone changes. In the high-fat chow group, the mean (SD) composite plaque area of PM2.5 vs FA was 41.5% (9.8%) vs 26.2% (8.6%), respectively (P<.001); and in the normal chow group, the composite plaque area was 19.2% (13.1%) vs 13.2% (8.1%), respectively (P = .15). Lipid content in the aortic arch measured by oil red-O staining revealed a 1.5-fold increase in mice fed the high-fat chow and exposed to PM2.5 vs FA (30.0 [8.2] vs 20.0 [7.0]; 95% confidence interval [CI], 1.21-1.83; P = .02). Vasoconstrictor responses to phenylephrine and serotonin challenge in the thoracic aorta of mice fed high-fat chow and exposed to PM2.5 were exaggerated compared with exposure to FA (mean [SE], 134.2% [5.2%] vs 100.9% [2.9%], for phenylephrine, and 156.0% [5.6%] vs 125.1% [7.5%], for serotonin; both P = .03); relaxation to the endothelium-dependent agonist acetylcholine was attenuated (mean [SE] of half-maximal dose for dilation, 8.9 [0.2] x 10(-8) vs 4.3 [0.1] x 10(-8), respectively; P = .04). Mice fed high-fat chow and exposed to PM2.5 demonstrated marked increases in macrophage infiltration, expression of the inducible isoform of nitric oxide synthase, increased generation of reactive oxygen species, and greater immunostaining for the protein nitration product 3-nitrotyrosine (all P<.001). In an apoE-/- mouse model, long-term exposure to low concentration of PM2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis.

Whether local exposure to major roadways adversely affects lung-function growth during the period of rapid lung development that takes place between 10 and 18 years of age is unknown. This study investigated the association between residential exposure to traffic and 8-year lung-function growth. In this prospective study, 3677 children (mean age 10 years [SD 0.44]) participated from 12 southern California communities that represent a wide range in regional air quality. Children were followed up for 8 years, with yearly lung-function measurements recorded. For each child, we identified several indicators of residential exposure to traffic from large roads. Regression analysis was used to establish whether 8-year growth in lung function was associated with local traffic exposure, and whether local traffic effects were independent of regional air quality. Children who lived within 500 m of a freeway (motorway) had substantial deficits in 8-year growth of forced expiratory volume in 1 s (FEV(1), -81 mL, p=0.01 [95% CI -143 to -18]) and maximum midexpiratory flow rate (MMEF, -127 mL/s, p=0.03 [-243 to -11), compared with children who lived at least 1500 m from a freeway. Joint models showed that both local exposure to freeways and regional air pollution had detrimental, and independent, effects on lung-function growth. Pronounced deficits in attained lung function at age 18 years were recorded for those living within 500 m of a freeway, with mean percent-predicted 97.0% for FEV1 (p=0.013, relative to >1500 m [95% CI 94.6-99.4]) and 93.4% for MMEF (p=0.006 [95% CI 89.1-97.7]). Local exposure to traffic on a freeway has adverse effects on children's lung development, which are independent of regional air quality, and which could result in important deficits in attained lung function in later life.

Air pollution is associated with significant adverse health effects, including increased cardiovascular morbidity and mortality. Exposure to particulate matter with an aerodynamic diameter of <2.5 microm (PM(2.5)) increases ischemic cardiovascular events and promotes atherosclerosis. Moreover, there is increasing evidence that the smallest pollutant particles pose the greatest danger because of their high content of organic chemicals and prooxidative potential. To test this hypothesis, we compared the proatherogenic effects of ambient particles of <0.18 microm (ultrafine particles) with particles of <2.5 microm in genetically susceptible (apolipoprotein E-deficient) mice. These animals were exposed to concentrated ultrafine particles, concentrated particles of <2.5 microm, or filtered air in a mobile animal facility close to a Los Angeles freeway. Ultrafine particle-exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM(2.5) or filtered air. Exposure to ultrafine particles also resulted in an inhibition of the antiinflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress as evidenced by a significant increase in hepatic malondialdehyde levels and upregulation of Nrf2-regulated antioxidant genes. We conclude that ultrafine particles concentrate the proatherogenic effects of ambient PM and may constitute a significant cardiovascular risk factor.