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No Effect of Acute Exposure to Coarse Particulate Matter Air Pollution in a Rural Location on High Density Lipoprotein Function
Abstract
Context:
High-density lipoprotein (HDL) particles perform numerous vascular-protective functions. Animal studies demonstrate that exposure to fine or ultrafine particulate matter (PM) can promote HDL dysfunction. However, the impact of PM on humans remains unknown.
Objective:
We aimed to determine the effect of exposure to coarse concentrated ambient particles (CAP) on several metrics of HDL function in healthy humans.
Methods:
Thirty-two adults (25.9 ± 6.6 years) were exposed to coarse CAP [76.2 ± 51.5 µg·m(-3)] in a rural location and filtered air (FA) for 2 h in a randomized double-blind crossover study. Venous blood collected 2- and 20-h post-exposures was measured for HDL-mediated efflux of [(3)H]-cholesterol from cells and 20-h exposures for HDL anti-oxidant capacity by a fluorescent assay and paraoxonase activity. The changes [median (first, third quartiles)] between exposures among 29 subjects with available results were compared by matched Wilcoxon tests.
Results:
HDL-mediated cholesterol efflux capacity did not differ between exposures at either time point [16.60% (15.17, 19.19) 2-h post-CAP versus 17.56% (13.43, 20.98) post-FA, p = 0.768 and 14.90% (12.47, 19.15) 20-h post-CAP versus 17.75% (13.22, 23.95) post-FA, p = 0.216]. HOI [0.26 (0.24, 0.35) versus 0.28 (0.25, 0.40), p = 0.198] and paraoxonase activity [0.54 (0.39, 0.82) versus 0.60 μmol·min(-1 )ml plasma(-1) (0.40, 0.85), p = 0.137] did not differ 20-h post-CAP versus FA, respectively.
Conclusions:
Brief inhalation of coarse PM from a rural location did not acutely impair several facets of HDL functionality. Whether coarse PM derived from urban sites, fine particles or longer term PM exposures can promote HDL dysfunction warrant future investigations.
... In view of the recent hypothesis that HDL function could be more relevant than HDL levels (at least when measured as their cholesterol content) for atheroprotection, a handful of studies have been already performed to investigate the impact of air pollution on HDL properties [24,25,[77][78][79][80][81][82][83][84]. To date, HDL ability to prevent oxidation, and to promote cholesterol efflux from macrophages and NO release from endothelial cells were investigated (Figure 4). ...
... In the first study, healthy subjects underwent the inhalation of filtered air or high levels of coarse PM from a rural source for 2 h with a double-blind crossover desi and HDL function was assessed 2 h and 20 h after inhalation. HDL-mediated choleste efflux and HDL oxidation index were not affected by coarse PM [82]. In the second stud healthy subjects were exposed to filtered air or to very high levels of PM2.5 for 2 h, fo total of 4 exposures at least 2 weeks apart. ...
... In the first study, healthy subjects underwent the inhalation of filtered air or of high levels of coarse PM from a rural source for 2 h with a double-blind crossover design and HDL function was assessed 2 h and 20 h after inhalation. HDL-mediated cholesterol efflux and HDL oxidation index were not affected by coarse PM [82]. In the second study, healthy subjects were exposed to filtered air or to very high levels of PM 2.5 for 2 h, for a total of 4 exposures at least 2 weeks apart. ...
Epidemiological studies have consistently demonstrated a positive association between exposure to air pollutants and the incidence of cardiovascular disease, with the strongest evidence for particles with a diameter < 2.5 μm (PM2.5). Therefore, air pollution has been included among the modifiable risk factor for cardiovascular outcomes as cardiovascular mortality, acute coronary syndrome, stroke, heart failure, and arrhythmias. Interestingly, the adverse effects of air pollution are more pronounced at higher levels of exposure but were also shown in countries with low levels of air pollution, indicating no apparent safe threshold. It is generally believed that exposure to air pollution in the long-term can accelerate atherosclerosis progression by promoting dyslipidemia, hypertension, and other metabolic disorders due to systemic inflammation and oxidative stress. Regarding high density lipoproteins (HDL), the impact of air pollution on plasma HDL-cholesterol levels is still debated, but there is accumulating evidence that HDL function can be impaired. In particular, the exposure to air pollution has been variably associated with a reduction in their cholesterol efflux capacity, antioxidant and anti-inflammatory potential, and ability to promote the release of nitric oxide. Further studies are needed to fully address the impact of various air pollutants on HDL functions and to elucidate the mechanisms responsible for HDL dysfunction.
... These were screened at the abstract level. All relevant epidemiological and human exposure studies as well as animal studies assessing the effects of particulate air pollution on HDL functionality were included, resulting in a total of two epidemiological [27,28], two clinical [29,30] and three animal studies [31][32][33]. Additional search strategies were also applied focusing on keywords (combinations of keywords): ("HDL" OR "high-density lipoprotein") AND ("PM" OR "particulate matter" OR "air pollution" OR "inhalation exposure"). ...
... Maiseyeu et al. were the first to investigate the effects of PM on HDL function in humans (n = 32) [29]. Their controlled exposure study showed that brief inhalation of coarse PM (76,2 ± 51,5 μg/m 3 ) from a rural source did not lead to development of HDL dysfunction as no alterations were found in HDL-cholesterol efflux capacity, HDL oxidation index or paraoxonase (PON) activity. ...
... Accordingly, in LDLR−/− mice exposed to ultrafine particles, a decreased paraoxonase activity was associated with a larger atherosclerotic lesion size [32,33]. However, other studies did not observe altered paraoxonase activity following exposure to PM [29,30]. ...
Background:
Exposure to air pollution has been associated with adverse effects on human health, and ultimately increased morbidity and mortality. This is predominantly due to hazardous effects on the cardiovascular system. Exposure to particulate matter (PM) is considered to be responsible for the most severe effects.
Main body:
Here we summarize current knowledge from existing epidemiological, clinical and animal studies on the influence of PM exposure on high-density lipoprotein (HDL) functionality and the potential initiation and progression of atherosclerosis. We highlight experimental studies that bring support to the causality and point to possible mechanistic links. Recent studies indicate that the functional properties of HDL are more important than the levels per se. Fine (PM2.5-0.1) and ultrafine (UFP) PM are composed of chemicals as well as biological elements that are redox-active and may trigger pro-inflammatory responses. Experimental studies indicate that these properties and responses may promote HDL dysfunction via oxidative pathways. By affecting protein and lipid components of the HDL particle, its anti-atherosclerotic characteristics including cholesterol efflux capacity, as well as other anti-oxidative and anti-inflammatory features might be impaired.
Conclusion:
Current literature suggests that PM promotes HDL dysfunction via oxidative pathways. However, as relatively few studies so far have evaluated the impact of particulate air pollution on HDL functionality, more human epidemiological as well as experimental studies are needed to strengthen any possible causal relationship and determine any relevance to atherosclerosis.
... Epidemiologic studies suggest that PM 2.5 -mediated increases in low-density lipoproteins (LDL) and reductions in high-density lipoproteins (HDL) cause the CV burden 5,[9][10][11][12][13] . While low HDL levels are linked to CV risk, specific anti-atherosclerotic functions of HDL, namely the ability of HDL to off-load cholesterol from macrophages (measured as cholesterol efflux capacity, CEC) predict both prevalent and incident CV events [14][15][16][17][18][19] . Myeloperoxidase (MPO), a heme-enzyme, together with a host of other systemic inflammatory responses are elevated with PM 2.5 exposure 3,20,21 . ...
... Converging epidemiological and experimental evidence highlights that CEC, rather than HDL levels per se, is the critical HDL-facilitated process responsible for protecting against CV events 14,15 . However, few studies have evaluated the impact of air pollutants on HDL function [16][17][18][19] . Animals exposed to high PM levels developed a blunted HDL anti-oxidant capacity 16,17 . ...
... In our prior study, acute exposure to concentrated PM 2.5 prompted a similar response in a subset of adults 18 . As far as we are aware, the lack of impact on CEC following a 2-hour exposure to coarse PM is the only previous study to evaluate the effect of any air pollutant on this endpoint 19 . This makes our current findings -that ambient PM 2.5 levels and not 24-hour personal PM 2.5 were independently associated with a reduction in CEC over subacute time periods -both novel and clinically relevant. ...
Fine particulate matter (PM2.5) air pollution and environmental temperatures influence cardiovascular morbidity and mortality. Recent evidence suggests that several air pollutants can promote dyslipidemia; however, the impact of ambient PM2.5 and temperature on high-density lipoprotein (HDL) function remains unclear. We hypothesized that daily exposures to higher levels of ambient PM2.5 and colder outdoor temperatures would impair HDL functionality. Lipoproteins, serum cholesterol efflux capacity (CEC), and HDL oxidation markers were measured twice in 50 healthy adults (age 32.1 ± 9.6 years) living in southeast Michigan and associated with ambient and personal-level exposures using mixed models. Although previous 7-day mean outdoor temperature (4.4 ± 9.8°C) and PM2.5 levels (9.1 ± 1.8 µg/m³) were low, higher ambient PM2.5 exposures (per 10 µg/m³) were associated with significant increases in the total cholesterol-to-HDL-C ratio (rolling average lag days 1 and 2) as well as reductions in CEC by −1.93% (lag day 5, p = 0.022) and −1.62% (lag day 6, p = 0.032). Colder outdoor temperatures (per 10°C) were also associated with decreases in CEC from −0.62 to −0.63% (rolling average lag days 5 and 7, p = 0.027 and 0.028). Previous 24-hour personal-level PM2.5 and temperature exposures did not impact outcomes, nor were any exposures associated with changes in HDL-oxidation metrics. In conclusion, we provide the first evidence that ambient PM2.5 (even at low levels) and outdoor temperatures may influence serum CEC, a critical antiatherosclerotic HDL function.
... Few studies have evaluated the impact of air pollution on HDL functionality. Mixed results have been reported in response to a brief 2-hour controlled exposure to concentrated PM. 16,17 Recently, we demonstrated that acute exposures to low levels of ambient PM 2.5 were associated with significant impairments in HDL function (measured as HDL-CEC). 6 However, previous studies have focused on the impact of a single air pollutant (eg, PM 2.5 ) and were conducted in locations with relatively good air quality or in controlled experimental settings. ...
... We speculated that larger coarse PM from rural sources might be less toxic in this regard or the brief time frame of exposure was insufficient to elicit HDL dysfunction. 16 Studies in vivo showed that systemic lipid peroxidation provoked by PM 2.5 and UFPs exposures could convert normal HDL into a dysfunctional form with impaired anti-inflammatory capacity. 3-5 A recent in vitro study reported that normal HDL could inhibit the harmful effects of diesel exhaust particles on endothelial cells and macrophages, whereas dysfunction HDL further promoted, rather than inhibited, diesel exhaust particle-induced oxidation. ...
Objective—
We aimed to assess whether exposure to higher levels of ambient air pollution impairs HDL (high-density lipoprotein) function and to elucidate the underlying biological mechanisms potentially involved.
Approach and Results—
In the Beijing AIRCHD study (Air Pollution and Cardiovascular Dysfunction in Healthy Adults), 73 healthy adults (23.3±5.4 years) were followed-up with 4 repeated study visits in 2014 to 2016. During each visit, ambient air pollution concentrations, HDL function metrics, and parameters of inflammation and oxidative stress were measured. Average daily concentrations of ambient particulate matter in diameter <2.5 μm were 62.9 µg/m ³ (8.1–331.0 µg/m ³ ). We observed significant decreases in HDL cholesterol efflux capacity of 2.3% (95% CI, −4.3 to −0.3) to 5.0% (95% CI, −7.6 to −2.4) associated with interquartile range increases in moving average concentrations of particulate matter in diameter <2.5 μm and traffic-related air pollutants (black carbon, nitrogen dioxide, and carbon monoxide) during the 1 to 7 days before each participant’s clinic visit. Higher ambient air pollutant levels were also associated with significant reductions in circulating HDL cholesterol and apoA-I (apolipoprotein A-I), as well as elevations in HDL oxidation index, oxidized LDL (low-density lipoprotein), malondialdehyde, and high-sensitivity C-reactive protein.
Conclusions—
Higher ambient air pollution concentrations were associated with impairments in HDL functionality, potentially because of systemic inflammation and oxidative stress. These novel findings further our understanding of the mechanisms whereby air pollutants promote cardiometabolic disorders.
... Therefore, the HOI serves as an instrumental measure of HDL anti-oxidant and anti-inflammatory capacities. This assay has shown to be quite sensitive and reproducible in previous studies [34,35,37] and similar assays have been employed to demonstrate impairment of HDL functionality in patients with [26,27,29]. We hypothesized that assessment of HDL antioxidant protection could be affected by small degrees of hemolysis that might occur during processing of blood samples. ...
... To our knowledge, this is the first report about the modifying effects of PM 2.5 exposure on HDL functionality in humans. Interestingly, we have reported that 2-hour exposures to rural coarse PM (PM 2.5-10 ) does not induce changes in HOI or HDL-mediated cholesterol efflux [37], which suggests the higher CV toxicity of urban PM 2.5 , as far as the ability to induce functional changes in plasma HDL. ...
Background
Exposures to ambient particulate matter (PM) are associated with increased morbidity and mortality. PM2.5 (<2.5 μm) and ozone exposures have been shown to associate with carotid intima media thickness in humans. Animal studies support a causal relationship between air pollution and atherosclerosis and identified adverse PM effects on HDL functionality.We aimed to determine whether brief exposures to PM2.5 and/or ozone could induce effects on HDL anti-oxidant and anti-inflammatory capacity in humans. Methods
Subjects were exposed to fine concentrated ambient fine particles (CAP) with PM2.5 targeted at 150 μg/m3, ozone targeted at 240 μg/m3(120 ppb), PM2.5 plus ozone targeted at similar concentrations, and filtered air (FA) for 2 h, on 4 different occasions, at least two weeks apart, in a randomized, crossover study. Blood was obtained before exposures (baseline), 1 h after and 20 h after exposures. Plasma HDL anti-oxidant/anti-inflammatory capacity and paraoxonase activity were determined. HDL anti-oxidant/anti-inflammatory capacity was assessed by a cell-free fluorescent assay and expressed in units of a HDL oxidant index (HOI). Changes in HOI (ΔHOI) were calculated as the difference in HOI from baseline to 1 h after or 20 h after exposures. ResultsThere was a trend towards bigger ΔHOI between PM2.5 and FA 1 h after exposures (p = 0.18) but not 20 h after. This trend became significant (p <0.05) when baseline HOI was lower (<1.5 or <2.0), indicating decreased HDL anti-oxidant/anti-inflammatory capacity shortly after the exposures. There were no significant effects of ozone alone or in combination with PM2.5 on the change in HOI at both time points. The change in HOI due to PM2.5 showed a positive trend with particle mass concentration (p = 0.078) and significantly associated with the slope of systolic blood pressure during exposures (p = 0.005). Conclusions
Brief exposures to concentrated PM2.5 elicited swift effects on HDL anti-oxidant/anti-inflammatory functionality, which could indicate a potential mechanism for how particulate air pollution induces harmful cardiovascular effects.
... In the current study, there was no signi cant difference between the three departments regarding APO-A serum levels. This was withMaiseyeu et al. (2014) results that showed that PM exposure did not lead to HDL dysfunction. However, results ofMathew et al. (2018) showed that exposure to even low levels of PM 2.5 (0.091 ± 0.018 mg/m 3 ) for a short period of time were linked to HDL dysfunction. ...
Background
Workers in wastewater treatment plant (WWTPs) are at high risk of developing various infections and cardiovascular diseases (CVD).
Aims
of the study were estimation of the concentrations of 16 EPA priority polycyclic aromatic hydrocarbons (PAHs) and particulate matters (PM) with different sizes in air of WWTP, and prediction of CVDs to evaluate the potential risk of developing CVDs in the WWTP workers due to their occupational exposures, in addition to identification of the CVDs` risky work tasks. Methodology: PM concentrations, and wind rose plots for meteorological data, were monitored for 24 months. Estimation of the individual PAHs in suspended particulate matter samples and identification of sources were done. Cross-sectional study was done on 142 male workers from WWTP. All participants were subjected to occupational and medical questionnaire, electrocardiogram (ECG), and measurement of blood pressure. Serum APO-A, APO-B, APO-E, and Lipoprotein α (Lpα) were estimated for all participants.
Results
The annual mean concentrations of PM (PM1, PM2.5, PM10 and TSP) were lower than Egyptian limit. EPA 16 PAHs were detected in all samples, lower molecular weight PAHs were the most predominant PAHs. The most predominant wind direction was from North-West; as the selected WWPT is placed downwind to the surrounding areas. Fifty percent of the workers were complaining of dyspnea. About 30.9% of the workers were found to be hypertensive; the majority of them were from the operator department. ECG abnormalities were found in 18.3% of the workers mainly among operators (23.95%). Ventricular extra systole was the highest prevalent detected ECG abnormality followed by left ventricular enlargement. APO-B and APO-B/APO-A ratio were significantly higher in operator workers compared to the administrators and laboratory workers. While, APO-E was significantly lower in operator workers compared to the administrators and laboratory workers.
Conclusion
PM2.5 and PM1 and PAH exposure maybe associated with potential risk of developing CVD in the exposed WWTP workers. The main sources of PAHs in the WWTP could be the fuel used for the machines in the operator department, as the treatment process occurs in the WWTP contribute to high concentrations of PM and its PAHs, but the most contributed sources were found to be from the surrounding areas. The use of APO-B or APO-B/APO-A holds a promising biomarkers for evaluating cardiovascular disease risk.
... The HDL isolation was performed using the modified method of Maiseyeu et al. (Maiseyeu et al., 2014). Briefly, the density of the human plasma was adjusted to 1.22 gms/ml using potassium bromide (KBr) and centrifuged at a speed of 450,000 x g for 3 hrs at 4 C and a top layer containing all lipoproteins was collected. ...
Lipopolysaccharide (LPS), cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but doesn’t involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knock-out mice (StabDKO) and Stab1KO, but not Stab2KO showed significantly enhanced systemic inflammatory cytokine production and early death compared to WT mice. Stab1KO is not significantly different from Stab DKO in circulatory LPS clearance, LPS uptake and endocytosis by LSEC and cytokine production. These data indicate that a) Stab1 receptor, primarily, facilitates the proactive clearance of LPS, and limits TLR4 mediated inflammation and b) TLR4 and Stab1 are functionally opposing LPS receptors. These findings suggest that endotoxemia can be controlled by optimizing LPS clearance by Stab1.
... The HDL isolation was performed using the modified method of Maiseyeu et al. (Maiseyeu et al., 2014). Briefly, the density of the human plasma was adjusted to 1.22 gms/ml using potassium bromide (KBr) and centrifuged at a speed of 450,000 x g for 3 hrs at 4 C and a top layer containing all lipoproteins was collected. ...
Lipopolysaccharides (LPS), remnants of Gram-negative bacterial cell membranes, cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanism(s). We discovered that LPS clearance through LSEC involves endocytosis via Stabilin scavenger receptors (Stab-1 and -2) through lysosomal inactivation. We determined that LPS was lower in the circulation of wild-type (WT) mice than Stab-1 and -2 KO mice, and endocytic uptake was higher in LSEC from WT than in Stab-1 and -2 KO. Stab-1 and -2 KO showed enhanced systemic inflammatory cytokine production and early death compared to WT mice when exposed to LPS. Although LSEC expresses innate immune mediator TLR4, LPS clearance does not use this functional TLR4 system. These data suggest that Stabilin receptors facilitate the proactive clearance of LPS, and control TLR4 mediated inflammation. The findings suggest a means of minimizing endotoxemia by optimizing Stabilin-dependent systemic LPS clearance.
... The collected fraction was resolved by chromatographic separation on the Superose 6 column (100/300 GL, GE Healthcare) as previously described. 21 Eluted HDL fractions were collected and sterile-filtered before use. HDL was identified by PAGE electrophoresis where it runs alongside recombinant ApoA-I (Sigma SRP6410). ...
Here, we report a nanoparticle-based probe that affords facile cell labeling with cholesterol in cholesterol efflux (CE) assays. This probe, called ezFlux, was optimized through a screening of multiple nanoformulations engineered with a Förster resonance energy transfer (FRET) reporter. The physicochemical- and bio-similarity of ezFlux to standard semi-synthetic acetylated low-density lipoprotein (acLDL) was confirmed by testing uptake in macrophages, the intracellular route of degradation, and performance in CE assays. A single-step fast self-assembly fabrication makes ezFlux an attractive alternative to acLDL. We also show that CE testing using ezFlux is significantly cheaper than that performed using commercial kits or acLDL. Additionally, we analyze clinical trials that measure CE and show that ezFlux has a place in many research and clinical laboratories worldwide that use CE to assess cellular and lipoprotein function.
... 16,17 Exposures to both fine and ultrafine particulate matter (PM) have been associated with development of dysfunctional HDL and reduced HDL anti-inflammatory capacity in some (but not all) experimental studies. [18][19][20][21] The association between ambient air pollution and HDL-C, HDL-P, and HDL particle size has not been well studied. ...
Objective:
The relationship between air pollution and cardiovascular disease may be explained by changes in high-density lipoprotein (HDL).
Approach and results:
We examined the cross-sectional relationship between air pollution and both HDL cholesterol and HDL particle number in the MESA Air study (Multi-Ethnic Study of Atherosclerosis Air Pollution). Study participants were 6654 white, black, Hispanic, and Chinese men and women aged 45 to 84 years. We estimated individual residential ambient fine particulate pollution exposure (PM2.5) and black carbon concentrations using a fine-scale likelihood-based spatiotemporal model and cohort-specific monitoring. Exposure periods were averaged to 12 months, 3 months, and 2 weeks prior to examination. HDL cholesterol and HDL particle number were measured in the year 2000 using the cholesterol oxidase method and nuclear magnetic resonance spectroscopy, respectively. We used multivariable linear regression to examine the relationship between air pollution exposure and HDL measures. A 0.7×10(-)(6) m(-)(1) higher exposure to black carbon (a marker of traffic-related pollution) averaged over a 1-year period was significantly associated with a lower HDL cholesterol (-1.68 mg/dL; 95% confidence interval, -2.86 to -0.50) and approached significance with HDL particle number (-0.55 mg/dL; 95% confidence interval, -1.13 to 0.03). In the 3-month averaging time period, a 5 μg/m(3) higher PM2.5 was associated with lower HDL particle number (-0.64 μmol/L; 95% confidence interval, -1.01 to -0.26), but not HDL cholesterol (-0.05 mg/dL; 95% confidence interval, -0.82 to 0.71).
Conclusions:
These data are consistent with the hypothesis that exposure to air pollution is adversely associated with measures of HDL.
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... The HDL isolation was performed as described previously by us (30). In brief, the density of the human plasma was adjusted to 1.22 g/ml using potassium bromide and ultracentrifuged at 450,000 3 g for 3 h at 4˚C. ...
During Gram-negative bacterial infections, excessive LPS induces inflammation and sepsis via action on immune cells. However, the bulk of LPS can be cleared from circulation by the liver. Liver clearance is thought to be a slow process mediated exclusively by phagocytic resident macrophages, Kupffer cells (KC). However, we discovered that LPS disappears rapidly from the circulation, with a half-life of 2-4 min in mice, and liver eliminates about three quarters of LPS from blood circulation. Using microscopic techniques, we found that ∼75% of fluor-tagged LPS in liver became associated with liver sinusoidal endothelial cells (LSEC) and only ∼25% with KC. Notably, the ratio of LSEC-KC-associated LPS remained unchanged 45 min after infusion, indicating that LSEC independently processes the LPS. Most interestingly, results of kinetic analysis of LPS bioactivity, using modified limulus amebocyte lysate assay, suggest that recombinant factor C, an LPS binding protein, competitively inhibits high-density lipoprotein (HDL)-mediated LPS association with LSEC early in the process. Supporting the previous notion, 3 min postinfusion, 75% of infused fluorescently tagged LPS-HDL complex associates with LSEC, suggesting that HDL facilitates LPS clearance. These results lead us to propose a new paradigm of LSEC and HDL in clearing LPS with a potential to avoid inflammation during sepsis.
Background:
Exposure to air pollution increases cardiovascular morbidity and mortality. Preventing chronic cardiovascular diseases caused by air pollution relies on detecting the early effects of pollutants on the risk of cardiovascular disease development, which is limited by the lack of sensitive biomarkers. We have previously identified promising biomarkers in experimental animals but comparable evidence in humans is lacking.
Methods:
Air pollution is substantially worse in Beijing than in Los Angeles. We collected urine and blood samples from 26 nonsmoking, healthy adult residents of Los Angeles (mean age, 23.8 years; 14 women) before, during, and after spending 10 weeks in Beijing during the summers of 2014 and 2015. We assessed a panel of circulating biomarkers indicative of lipid peroxidation and inflammation. Personal exposure to polycyclic aromatic hydrocarbons (PAHs), a group of combustion-originated air pollutants, was assessed by urinary PAH metabolite levels.
Results:
Urinary concentrations of 4 PAH metabolites were 176% (95% CI, 103% to 276%) to 800% (95% CI, 509% to 1780%) greater in Beijing than in Los Angeles. Concentrations of 6 lipid peroxidation biomarkers were also increased in Beijing, among which 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 9- and 13-hydroxyoctadecadienoic acid levels reached statistical significance (false discovery rate <5%), but not 8-isoprostane (20.8%; 95% CI, -5.0% to 53.6%). The antioxidative activities of paraoxonase (-9.8%; 95% CI, -14.0% to -5.3%) and arylesterase (-14.5%; 95% CI, -22.3% to -5.8%) were lower and proinflammatory C-reactive protein (101%; 95% CI, 3.3% to 291%) and fibrinogen (48.3%; 95% CI, 4.9% to 110%) concentrations were higher in Beijing. Changes in all these biomarkers were reversed, at least partially, after study participants returned to Los Angeles. Changes in most outcomes were associated with urinary PAH metabolites (P<0.05).
Conclusions:
Traveling from a less-polluted to a more-polluted city induces systemic pro-oxidative and proinflammatory effects. Changes in the levels of 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 9- and 13-hydroxyoctadecadienoic acid as well as paraoxonase and arylesterase activities in the blood, in association with exposures to PAH metabolites, might have important implications in preventive medicine as indicators of increased cardiovascular risk caused by air pollution exposure.
The goals of the experiments described herein involve determining in real time the size, concentration enrichment, and chemical composition of coarse-mode (> 2.5 mu m) and fine-mode (< 2.5 mu m) particles within the nonconcentrated and concentrated flows of a coarse particle concentrator used for human exposure studies. The coarse particle concentrator was intended to concentrate ambient particles in the PM(10-2.5) size range before sending them into a human exposure chamber. The aerodynamic size and chemical composition of particles in the upstream and downstream flows of the concentrator were monitored with an aerosol time-of-flight mass spectrometer (ATOFMS) for fixed time intervals over the course of three days. Based on the ATOFMS results, it was found that there was no change in the composition of the ten major particle types observed in the upstream and downstream flows of the concentrator under normal operating conditions. Furthermore, no new particle types were detected downstream that were not detected upstream of the concentrator. A characterization of the aerosol chemical composition and its dependence on sampling conditions is also discussed. Aerosol size distributions were measured with three aerodynamic particle-sizing (APS) instruments sampling simultaneously from different regions of the concentrator. The APS size distributions were used to scale ATOFMS data and measure the ambient concentration factors for the coarse particle concentrator and the exposure chamber. The average concentration factor (ratio of inlet number concentration to the outlet number concentration) for the particle concentrator was 60 +/- 17 for the 2.5-7.2 mu m size range before dilution and transport to the exposure chamber. It was observed that not only were coarse particles being concentrated but fine (< 2.5 mu m) particles were being concentrated as well, with concentration factors ranging from 2-46 for aerodynamic particle sizes from 0.54-2.5 mu m.
Fine particulate matter (PM2.5) has been linked to cardiovascular disease, possibly via accelerated atherosclerosis. We examined associations between the progression of the intima-medial thickness (IMT) of the common carotid artery, as an indicator of atherosclerosis, and long-term PM2.5 concentrations in participants from the Multi-Ethnic Study of Atherosclerosis (MESA).
MESA, a prospective cohort study, enrolled 6,814 participants at the baseline exam (2000-2002), with 5,660 (83%) of those participants completing two ultrasound examinations between 2000 and 2005 (mean follow-up: 2.5 years). PM2.5 was estimated over the year preceding baseline and between ultrasounds using a spatio-temporal model. Cross-sectional and longitudinal associations were examined using mixed models adjusted for confounders including age, sex, race/ethnicity, smoking, and socio-economic indicators. Among 5,362 participants (5% of participants had missing data) with a mean annual progression of 14 µm/y, 2.5 µg/m(3) higher levels of residential PM2.5 during the follow-up period were associated with 5.0 µm/y (95% CI 2.6 to 7.4 µm/y) greater IMT progressions among persons in the same metropolitan area. Although significant associations were not found with IMT progression without adjustment for metropolitan area (0.4 µm/y [95% CI -0.4 to 1.2 µm/y] per 2.5 µg/m(3)), all of the six areas showed positive associations. Greater reductions in PM2.5 over follow-up for a fixed baseline PM2.5 were also associated with slowed IMT progression (-2.8 µm/y [95% CI -1.6 to -3.9 µm/y] per 1 µg/m(3) reduction). Study limitations include the use of a surrogate measure of atherosclerosis, some loss to follow-up, and the lack of estimates for air pollution concentrations prior to 1999.
This early analysis from MESA suggests that higher long-term PM2.5 concentrations are associated with increased IMT progression and that greater reductions in PM2.5 are related to slower IMT progression. These findings, even over a relatively short follow-up period, add to the limited literature on air pollution and the progression of atherosclerotic processes in humans. If confirmed by future analyses of the full 10 years of follow-up in this cohort, these findings will help to explain associations between long-term PM2.5 concentrations and clinical cardiovascular events. Please see later in the article for the Editors' Summary.
Background- Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular diseases. The redox-active ultrafine particles promote vascular oxidative stress and inflammatory responses. We hypothesized that UFP modulated lipid metabolism and anti-oxidant capacity of high density lipoprotein (HDL) with an implication in atherosclerotic lesion size. Methods and Results- Fat-fed LDL Receptor-null (LDLR-/-) mice were exposed to filtered air (FA) or UFP for 10 weeks with or without administering an apolipoprotein A-I mimetic peptide, D-4F. LDLR-null mice exposed to UFP developed reduced plasma HDL level (p < 0.01), paraoxonase (PON) activity (p < 0.01), and HDL anti-oxidant capacity (p < 0.05), but increased LDL oxidation, free oxidized fatty acids, triglycerides, serum Amyloid A (SAA) (p < 0.05) and TNF-α (p<0.05), accompanied by a 62% increase in atherosclerotic lesion ratio of the en face aortic staining and a 220% increase in cross-sectional lesion area of aortic sinus (p < 0.001). D-4F administration significantly attenuated these changes. Conclusions- UFP exposure promoted pro-atherogenic lipid metabolism and reduced HDL anti-oxidant capacity in fat-fed LDLR-null mice, associated with a greater atherosclerotic lesion size compared to FA exposed animals. D-4F attenuated UFP-mediated pro-atherogenic effects, suggesting the role of lipid oxidation underlying UFP-mediated atherosclerosis.
Plasma high-density lipoprotein cholesterol(HDL-C) levels do not predict functionality and composition of high-density lipoprotein(HDL). Traditionally, keeping levels of low-density lipoprotein cholesterol(LDL-C) down and HDL-C up have been the goal of patients to prevent atherosclerosis that can lead to coronary vascular disease(CVD). People think about the HDL present in their cholesterol test, but not about its functional capability.
Up to 65% of cardiovascular death cannot be prevented by putative LDL-C lowering agents. It well explains the strong interest in HDL increasing strategies. However, recent studies have questioned the good in using drugs to increase level of HDL. While raising HDL is a theoretically attractive target, the optimal approach remains uncertain. The attention has turned to the quality, rather than the quantity, of HDL-C. An alternative to elevations in HDL involves strategies to enhance HDL functionality.
The situation poses an opportunity for clinical chemists to take the lead in the development and validation of such biomarkers. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport (RCT). The functions of HDL that have recently attracted attention include anti-inflammatory and anti-oxidant activities. High antioxidant and anti-inflammatory activities of HDL are associated with protection from CVD.
This review addresses the current state of knowledge regarding assays of HDL functions and their relationship to CVD. HDL as a therapeutic target is the new frontier with huge potential for positive public health implications.
High-density lipoprotein (HDL) is a major carrier of cholesterol in the blood. Unlike other lipoproteins, physiological functions of HDL influence the cardiovascular system in favorable ways except when HDL is modified pathologically. The cardioprotective mechanism of HDL is mainly based on reverse cholesterol transport, but there has been an emerging interest in the anti-inflammatory and antioxidant roles of HDL. These latter activities of HDL are compromised in many pathological states associated with inflammation. Further, abnormal HDL can become proinflammatory contributing to oxidative damage. In this paper, we discuss the functional heterogeneity of HDL, how alterations in these particles in inflammatory states result in loss of both antioxidant activity and reverse cholesterol transport in relation to atherosclerosis, and the need for assays to predict its functionality.
In air pollution epidemiology, there is a growing interest in estimating the health effects of coarse particulate matter (PM)
with aerodynamic diameter between 2.5 and 10 μm. Coarse PM concentrations can exhibit considerable spatial heterogeneity because the particles travel shorter distances
and do not remain suspended in the atmosphere for an extended period of time. In this paper, we develop a modeling approach
for estimating the short-term effects of air pollution in time series analysis when the ambient concentrations vary spatially
within the study region. Specifically, our approach quantifies the error in the exposure variable by characterizing, on any
given day, the disagreement in ambient concentrations measured across monitoring stations. This is accomplished by viewing
monitor-level measurements as error-prone repeated measurements of the unobserved population average exposure. Inference is
carried out in a Bayesian framework to fully account for uncertainty in the estimation of model parameters. Finally, by using
different exposure indicators, we investigate the sensitivity of the association between coarse PM and daily hospital admissions
based on a recent national multisite time series analysis. Among Medicare enrollees from 59 US counties between the period
1999 and 2005, we find a consistent positive association between coarse PM and same-day admission for cardiovascular diseases.
A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk.
In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-β-1 HDL subclass that participates in macrophage cholesterol efflux.
We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions.
High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden.
We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B-depleted serum from the study participants.
The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins.
Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.).
Particle biokinetics is important in hazard identification and characterization of inhaled particles. Such studies intend to convert external to internal exposure or biologically effective dose, and may help to set limits in that way. Here we focus on the biokinetics of inhaled nanometer sized particles in comparison to micrometer sized ones.
The presented approach ranges from inhaled particle deposition probability and retention in the respiratory tract to biokinetics and clearance of particles out of the respiratory tract. Particle transport into the blood circulation (translocation), towards secondary target organs and tissues (accumulation), and out of the body (clearance) is considered. The macroscopically assessed amount of particles in the respiratory tract and secondary target organs provides dose estimates for toxicological studies on the level of the whole organism. Complementary, microscopic analyses at the individual particle level provide detailed information about which cells and subcellular components are the target of inhaled particles. These studies contribute to shed light on mechanisms and modes of action eventually leading to adverse health effects by inhaled nanoparticles.
We review current methods for macroscopic and microscopic analyses of particle deposition, retention and clearance. Existing macroscopic knowledge on particle biokinetics and microscopic views on particle organ interactions are discussed comparing nanometer and micrometer sized particles. We emphasize the importance for quantitative analyses and the use of particle doses derived from real world exposures.
The relationship of fine particulate matter < 2.5 microm in diameter (PM(2.5)) air pollution with mortality and cardiovascular disease is well established, with more recent long-term studies reporting larger effect sizes than earlier long-term studies. Some studies have suggested the coarse fraction, particles between 2.5 and 10 microm (PM(10-2.5)), may also be important. With respect to mortality and cardiovascular events, questions remain regarding the relative strength of effect sizes for chronic exposure to fine and coarse particles.
We examined the relationship of chronic PM(2.5) and PM(10-2.5) exposures with all-cause mortality and fatal and nonfatal incident coronary heart disease (CHD), adjusting for time-varying covariates.
The current study included women from the Nurses' Health Study living in metropolitan areas of the northeastern and midwestern United States. Follow-up was from 1992 to 2002. We used geographic information systems-based spatial smoothing models to estimate monthly exposures at each participant's residence.
We found increased risk of all-cause mortality [hazard ratio (HR), 1.26; 95% confidence interval (CI), 1.02-1.54] and fatal CHD (HR = 2.02; 95% CI, 1.07-3.78) associated with each 10-microg/m(3) increase in annual PM(2.5) exposure. The association between fatal CHD and PM(10-2.5) was weaker.
Our findings contribute to growing evidence that chronic PM(2.5) exposure is associated with risk of all-cause and cardiovascular mortality.
Although many studies have examined the effects of air pollution on mortality, data limitations have resulted in fewer studies of both particulate matter with an aerodynamic diameter of <or= 2.5 microm (PM(2.5); fine particles) and of coarse particles (particles with an aerodynamic diameter > 2.5 and < 10 microm; PM coarse). We conducted a national, multicity time-series study of the acute effect of PM(2.5) and PM coarse on the increased risk of death for all causes, cardiovascular disease (CVD), myocardial infarction (MI), stroke, and respiratory mortality for the years 1999-2005.
We applied a city- and season-specific Poisson regression in 112 U.S. cities to examine the association of mean (day of death and previous day) PM(2.5) and PM coarse with daily deaths. We combined the city-specific estimates using a random effects approach, in total, by season and by region.
We found a 0.98% increase [95% confidence interval (CI), 0.75-1.22] in total mortality, a 0.85% increase (95% CI, 0.46-1.24) in CVD, a 1.18% increase (95% CI, 0.48-1.89) in MI, a 1.78% increase (95% CI, 0.96-2.62) in stroke, and a 1.68% increase (95% CI, 1.04-2.33) in respiratory deaths for a 10-microg/m(3) increase in 2-day averaged PM(2.5). The effects were higher in spring. For PM coarse, we found significant but smaller increases for all causes analyzed.
We conclude that our analysis showed an increased risk of mortality for all and specific causes associated with PM(2.5), and the risks are higher than what was previously observed for PM(10). In addition, coarse particles are also associated with more deaths.
Studies on health effects of airborne particulate matter (PM) have traditionally focused on particles <10 microm in diameter (PM10) or particles <2.5 microm in diameter (PM2.5). The coarse fraction of PM10, particles >2.5 microm, has only been studied recently. These particles have different sources and composition compared with PM2.5. This paper is based on a systematic review of studies that have analysed fine and coarse PM jointly and examines the epidemiological evidence for effects of coarse particles on health. Time series studies relating ambient PM to mortality have in some places provided evidence of an independent effect of coarse PM on daily mortality, but in most urban areas, the evidence is stronger for fine particles. The few long-term studies of effects of coarse PM on survival do not provide any evidence of association. In studies of chronic obstructive pulmonary disease, asthma and respiratory admissions, coarse PM has a stronger or as strong short-term effect as fine PM, suggesting that coarse PM may lead to adverse responses in the lungs triggering processes leading to hospital admissions. There is also support for an association between coarse PM and cardiovascular admissions. It is concluded that special consideration should be given to studying and regulating coarse particles separately from fine particles.
Health risks of fine particulate matter of 2.5 microm or less in aerodynamic diameter (PM2.5) have been studied extensively over the last decade. Evidence concerning the health risks of the coarse fraction of greater than 2.5 microm and 10 microm or less in aerodynamic diameter (PM10-2.5) is limited.
To estimate risk of hospital admissions for cardiovascular and respiratory diseases associated with PM10-2.5 exposure, controlling for PM2.5.
Using a database assembled for 108 US counties with daily cardiovascular and respiratory disease admission rates, temperature and dew-point temperature, and PM10-2.5 and PM2.5 concentrations were calculated with monitoring data as an exposure surrogate from January 1, 1999, through December 31, 2005. Admission rates were constructed from the Medicare National Claims History Files, for a study population of approximately 12 million Medicare enrollees living on average 9 miles (14.4 km) from collocated pairs of PM10 and PM2.5 monitors.
Daily counts of county-wide emergency hospital admissions for primary diagnoses of cardiovascular or respiratory disease.
There were 3.7 million cardiovascular disease and 1.4 million respiratory disease admissions. A 10-microg/m3 increase in PM10-2.5 was associated with a 0.36% (95% posterior interval [PI], 0.05% to 0.68%) increase in cardiovascular disease admissions on the same day. However, when adjusted for PM2.5, the association was no longer statistically significant (0.25%; 95% PI, -0.11% to 0.60%). A 10-microg/m3 increase in PM10-2.5 was associated with a nonstatistically significant unadjusted 0.33% (95% PI, -0.21% to 0.86%) increase in respiratory disease admissions and with a 0.26% (95% PI, -0.32% to 0.84%) increase in respiratory disease admissions when adjusted for PM2.5. The unadjusted associations of PM2.5 with cardiovascular and respiratory disease admissions were 0.71% (95% PI, 0.45%-0.96%) for same-day exposure and 0.44% (95% PI, 0.06% to 0.82%) for exposure 2 days before hospital admission.
After adjustment for PM2.5, there were no statistically significant associations between coarse particulates and hospital admissions for cardiovascular and respiratory diseases.
We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima–media thickness, 442 patients with angiograph ically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B–depleted serum from the study participants. Results The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima–media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P = 0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P = 0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins. Conclusions Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima–media thickness and the likeli hood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.)
Objective:
To evaluate whether exposure to air pollutants induces oxidative modifications of plasma lipoproteins, resulting in alteration of the protective capacities of high-density lipoproteins (HDLs).
Approach and results:
We exposed apolipoprotein E-deficient mice to diesel exhaust (DE) at ≈ 250 µg/m(3) for 2 weeks, filtered air (FA) for 2 weeks, or DE for 2 weeks, followed by FA for 1 week (DE+FA). DE led to enhanced lipid peroxidation in the brochoalveolar lavage fluid that was accompanied by effects on HDL functionality. HDL antioxidant capacity was assessed by an assay that evaluated the ability of HDL to inhibit low-density lipoprotein oxidation estimated by 2',7'-dichlorofluorescein fluorescence. HDL from DE-exposed mice exhibited 23,053 ± 2844 relative fluorescence units, higher than FA-exposed mice (10,282 ± 1135 relative fluorescence units, P<0.001) but similar to the HDL from DE+FA-exposed mice (22,448 ± 3115 relative fluorescence units). DE effects on HDL antioxidant capacity were negatively correlated with paraoxonase enzymatic activity, but positively correlated with levels of plasma 8-isoprostanes, 12-hydroxyeicosatetraenoic acid, 13-hydroxyoctadecadienoic acid, liver malondialdehyde, and accompanied by perturbed HDL anti-inflammatory capacity and activation of the 5-lipoxygenase pathway in the liver.
Conclusions:
DE emissions induced systemic pro-oxidant effects that led to the development of dysfunctional HDL. This may be one of the mechanisms by which air pollution contributes to enhanced atherosclerosis.
Objective:
Diminished cholesterol efflux activity of apolipoprotein B (apoB)-depleted serum is associated with prevalent coronary artery disease, but its prognostic value for incident cardiovascular events is unclear. We investigated the relationship of cholesterol efflux activity with both prevalent coronary artery disease and incident development of major adverse cardiovascular events (death, myocardial infarction, or stroke).
Approach and results:
Cholesterol efflux activity from free cholesterol-enriched macrophages was measured in 2 case-control cohorts: (1) an angiographic cohort (n=1150) comprising stable subjects undergoing elective diagnostic coronary angiography and (2) an outpatient cohort (n=577). Analysis of media from cholesterol efflux assays revealed that the high-density lipoprotein fraction (1.063<d<1.21) contained only a minority (≈ 40%) of [(14)C]cholesterol released, with the majority found within the lipoprotein particle-depleted fraction, where ≈ 60% was recovered after apolipoprotein A1 immunoprecipitation. Albumin immunoprecipitation recovered another ≈ 30% of radiolabeled cholesterol within this fraction. Enhanced cholesterol efflux activity from ATP-binding cassette transporter A1-stimulated macrophages was associated with reduced risk of prevalent coronary artery disease in unadjusted models within both cohorts; however, the inverse risk relationship remained significant after adjustment for traditional coronary artery disease risk factors only within the outpatient cohort. Surprisingly, higher cholesterol efflux activity was associated with increase in prospective (3 years) risk of myocardial infarction/stroke (adjusted hazard ratio, 2.19; 95% confidence interval, 1.02-4.74) and major adverse cardiovascular events (adjusted hazard ratio, 1.85; 95% confidence interval, 1.11-3.06).
Conclusions:
Heightened cholesterol efflux to apoB-depleted serum was paradoxically associated with increased prospective risk for myocardial infarction, stroke, and death. The majority of released radiolabeled cholesterol from macrophages in cholesterol efflux activity assays does not reside within a high-density lipoprotein particle.
This paper presents the development and laboratory characterization of a prototype slit nozzle virtual impactor that can be used to concentrate coarse particles. A variety of physical design and flow parameters were evaluated including different acceleration and collection slit nozzles and Reynolds numbers (Re). Performance parameters investigated include concentration factor (CF), cutpoint, collection efficiency, minor-to-total flow ratio, and particle losses.Investigation of the effect of the different parameters on the overall performance of the virtual impactor made it possible to optimize its design. For a flow rate of 11.4 LPM/cm length of the acceleration slit, Re of 2520, and a 5% minor-to-total-flow ratio (r), the corresponding size cut-off (d50) was . Under these conditions the CF is approximately 17 and remains constant for particles larger than . Also for these conditions the pressure drop in both the minor and major flows were water) and water), respectively, and average particle losses were <10%. Finally, separation and concentration of the coarse particles occurred without any significant distortion of their size distribution making this system suitable for inhalation toxicological studies.
Levels of high-density lipoprotein (HDL) cholesterol are generally inversely associated with the risk for the development of atherosclerosis. The mechanism by which HDL imparts protection from the initiation and progression of occlusive vascular disease is complex and multifactorial. The major anti-atherosclerotic effect of HDL is felt to be reverse cholesterol transport. HDL has been demonstrated to scavenge cholesterol from the peripheral vasculature with transport to the liver, where is it excreted in the biliary system. However, HDL exhibits multiple other physiologic effects that may play a role in the reduced risk for atherosclerosis. HDL has been demonstrated to exhibit beneficial effects on platelet function, endothelial function, coagulation parameters, inflammation, and interactions with triglyceride-rich lipoproteins. Increasing amounts of clinical and experimental data have shown that HDL cholesterol has significant antioxidant effect that may significantly contribute to protection from atherosclerosis.
This study examined an anti-inflammatory property of high-density lipoprotein (HDL) in subjects with acute coronary syndrome (ACS) and stable coronary artery disease (CAD) compared with control subjects.
HDL has anti-inflammatory properties in vitro, but its relationship to coronary disease in humans is unclear. The high-density lipoprotein inflammatory index (HII) measures the ability of HDL to mitigate oxidation of low-density lipoprotein; this function may be impaired in ACS and/or CAD.
We measured HII in 193 patients undergoing angiography for symptoms of CAD. Control subjects (n = 99) had no angiographic CAD, chronic CAD subjects (n = 51) had ≥ 70% vessel stenosis, and ACS subjects (n = 43) had ≥ 20% vessel stenosis and ischemia or infarction. We also examined HII in a cohort of healthy subjects randomly assigned to a statin or placebo.
Subjects who had ACS had higher HII (less antioxidative capacity) compared with controls (1.57 vs. 1.17, p = 0.005) or those with chronic CAD (1.57 vs. 1.11, p = 0.006). HII was not different in subjects with stable CAD compared with controls. Furthermore, those subjects with higher HII were more likely to have ACS than no CAD (quartile 4 vs. 1, odds ratio [OR]: 1.74, p = 0.008). In a multivariate logistic regression model, HII was associated with ACS after adjusting for traditional cardiac risk factors (OR: 3.8, p = 0.003). There was a small improvement in HII after statin therapy compared with placebo (-14%, p = 0.03).
HDL has less anti-inflammatory capacity as assessed by HII in the setting of ACS compared with controls or subjects with chronic CAD.
To investigate acute changes in circulating lipids after exposure to relatively high levels of particulate matter through welding.
Using a repeated measures panel study, lipid levels before and after welding and personal exposures to fine particulate matter (PM2.5) were measured in 36 male welders over 63 exposure and/or control days.
There was a trend toward decrease in HDL (-2.3 mg/dL, P = 0.08) 18 hours after welding. This effect became significant (-2.6 mg/dL, P = 0.05) after adjustment for possible confounders. The effect was strongest (-4.3 mg/dL, P = 0.02) among welders who did not weld the day before the study. There were no significant changes in other lipids associated with welding or PM2.5 exposure.
Welding exposure was associated with an acute decrease in circulating HDL, which may relate to the inflammatory and proatherosclerotic effects of fine particle exposure.
High-density lipoprotein (HDL) has many protective activities against atherosclerosis, including its role in reverse cholesterol transport, and its antioxidant, anti-inflammatory, and endothelial cell maintenance functions. However, all HDL is not functionally equivalent. The authors of recent studies have shown that infection, inflammation, diabetes, and coronary artery disease are associated with dysfunctional HDL. HDL can lose its protective activities through a variety of mechanisms, including, but not limited to, altered protein composition, oxidative protein modification mediated by the enzyme myeloperoxidase, and lipid modification. Studies in which the authors used bacterial endotoxin in humans and mice have directly demonstrated changes in HDL composition, loss of HDL's cholesterol acceptor activity, and decreased hepatic processing and secretion of cholesterol. Although a routine clinical assay for dysfunctional HDL is not currently available, the development of such an assay would be beneficial for a better understanding of the role that dysfunctional HDL plays as a risk factor for coronary artery disease and for the determination of how various drug therapies effect HDL functionality.
In 2004, the first American Heart Association scientific statement on "Air Pollution and Cardiovascular Disease" concluded that exposure to particulate matter (PM) air pollution contributes to cardiovascular morbidity and mortality. In the interim, numerous studies have expanded our understanding of this association and further elucidated the physiological and molecular mechanisms involved. The main objective of this updated American Heart Association scientific statement is to provide a comprehensive review of the new evidence linking PM exposure with cardiovascular disease, with a specific focus on highlighting the clinical implications for researchers and healthcare providers. The writing group also sought to provide expert consensus opinions on many aspects of the current state of science and updated suggestions for areas of future research. On the basis of the findings of this review, several new conclusions were reached, including the following: Exposure to PM <2.5 microm in diameter (PM(2.5)) over a few hours to weeks can trigger cardiovascular disease-related mortality and nonfatal events; longer-term exposure (eg, a few years) increases the risk for cardiovascular mortality to an even greater extent than exposures over a few days and reduces life expectancy within more highly exposed segments of the population by several months to a few years; reductions in PM levels are associated with decreases in cardiovascular mortality within a time frame as short as a few years; and many credible pathological mechanisms have been elucidated that lend biological plausibility to these findings. It is the opinion of the writing group that the overall evidence is consistent with a causal relationship between PM(2.5) exposure and cardiovascular morbidity and mortality. This body of evidence has grown and been strengthened substantially since the first American Heart Association scientific statement was published. Finally, PM(2.5) exposure is deemed a modifiable factor that contributes to cardiovascular morbidity and mortality.
Fine particulate matter air pollution plus ozone impairs vascular function and raises diastolic blood pressure. We aimed to determine the mechanism and air pollutant responsible. The effects of pollution on heart rate variability, blood pressure, biomarkers, and brachial flow-mediated dilatation were determined in 2 randomized, double-blind, crossover studies. In Ann Arbor, 50 subjects were exposed to fine particles (150 microg/m(3)) plus ozone (120 parts per billion) for 2 hours on 3 occasions with pretreatments of an endothelin antagonist (Bosentan, 250 mg), antioxidant (Vitamin C, 2 g), or placebo. In Toronto, 31 subjects were exposed to 4 different conditions (particles plus ozone, particles, ozone, and filtered air). In Toronto, diastolic blood pressure significantly increased (2.9 and 3.6 mm Hg) only during particle-containing exposures in association with particulate matter concentration and reductions in heart rate variability. Flow-mediated dilatation significantly decreased (2.0% and 2.9%) only 24 hours after particle-containing exposures in association with particulate matter concentration and increases in blood tumor necrosis factor alpha. In Ann Arbor, diastolic blood pressure significantly similarly increased during all of the exposures (2.5 to 4.0 mm Hg), a response not mitigated by pretreatments. Flow-mediated dilatation remained unaltered. Particulate matter, not ozone, was responsible for increasing diastolic blood pressure during air pollution inhalation, most plausibly by instigating acute autonomic imbalance. Only particles from urban Toronto additionally impaired endothelial function, likely via slower proinflammatory pathways. Our findings demonstrate credible mechanisms whereby fine particulate matter could trigger acute cardiovascular events and that aspects of exposure location may be an important determinant of the health consequences.
Paraoxonase-1 (PON1) is an HDL-associated protein of 354 amino acids with a molecular mass of 43 000 Da. It is synthesized in the liver, and in serum it is almost exclusively associated with HDL. PON1 has been reported to be an important contributor to the antioxidant and anti-inflammatory activities of HDL. PON1 impedes oxidative modification of LDL. PON1 serum activity is related to systemic lipid peroxidation stress and prospective cardiovascular risk. In this review, we discuss the relationship between PON1 activity and atherosclerotic diseases and various factors modulating PON1 activity including genes, age, lifestyle factors and medical conditions. Finally, evidence that pharmacological agents may affect PON1 activity is summarized.
There is increasing evidence from both animal and human studies linking low PON1 activity to an increased likelihood of cardiovascular diseases. Two prospective studies reported a significantly lower incidence of major cardiovascular events in participants with the highest systemic PON1 activity, compared with those with the lowest activity.
PON1 is a potentially antiatherogenic HDL-associated enzyme that protects LDL from oxidative modification. Enhancing PON1 activity could be an important target for future pharmacological agents aimed at decreasing cardiovascular risk.
Epidemiological studies have reported that elevated levels of particulate air pollution in urban communities are associated with increases in attacks of asthma based on evidence from hospital admissions and emergency department visits. Principal pathologic features of chronic airway diseases, like asthma, are airway inflammation and mucous hypersecretion with excessive amounts of luminal mucus and increased numbers of mucus-secreting cells in regions of the respiratory tract that normally have few or no mucous cells (ie, mucous cell metaplasia). The overall goal of the present project was to understand the adverse effects of urban air fine particulate matter (PM2.5; < or = 2.5 pm in aerodynamic diameter)* on normal airways and airways compromised with airway inflammation and excess mucus. Our project was specifically designed to (1) examine the chemical and physical characteristics of PM2.5 and other airborne pollutants in the outdoor air of a local Detroit community with a high incidence of childhood asthma; (2) determine the effects of this community-based PM2.5 on the airway epithelium in normal rats and rats compromised with preexisting hypersecretory airway diseases (ie, animal models of human allergic airway disease--asthma and chronic bronchitis); and (3) identify the chemical or physical components of PM2.5 that are responsible for PM2.5 -induced airway inflammation and epithelial alterations in these animal models. Two animal models of airway disease were used to examine the effects of PM2.5 exposure on preexisting hypersecretory airways: neutrophilic airway inflammation induced by endotoxin challenge in F344 rats and eosinophilic airway inflammation induced by ovalbumin (OVA) challenge in BN rats. A mobile air monitoring and exposure laboratory equipped with inhalation exposure chambers for animal toxicology studies, air pollution monitors, and particulate collection devices was used in this investigation. The mobile laboratory was parked in a community in southwestern Detroit during the summer months when particulate air pollution is usually high (July and September 2000). We monitored the outdoor air pollution in this community daily, and exposed normal and compromised rats to concentrated PM2.5 from this local urban atmosphere. Rats in the inhalation studies were exposed for 1 day or for 4 or 5 consecutive days (10 hours/day) to either filtered air (controls) or concentrated ambient particles (CAPs) delivered by a Harvard ambient fine particle concentrator. Rats were killed 24 hours after the end of the exposure. Biochemical, morphometric, and molecular techniques were used to identify airway epithelial and inflammatory responses to CAPs. Lung lobes were also either intratracheally lavaged with saline to determine cellular composition and protein in bronchoalveolar lavage fluid (BALF) or removed for analysis by inductively coupled plasma-mass spectrometry (ICPMS) to detect retention of ambient PM2.5--derived trace elements. The Harvard concentrator effectively concentrated the fine ambient particles from this urban atmosphere (10-30 times) without significantly changing the major physicochemical features of the atmospheric particles. Daily CAPs mass concentrations during the 10-hour exposure period (0800-1800) in July ranged from 16 to 895 microg/m3 and in September ranged from 81 to 755 microg/m3. In general, chemical characteristics of ambient particles were conserved through the concentrator into the exposure chamber. Single or repeated exposures to CAPs did not cause adverse effects in the nasal or pulmonary airways of healthy F344 or BN rats. In addition, CAPs-related toxicity was not observed in F344 rats pretreated with bacterial endotoxin. Variable airway responses to CAPs exposure were observed in BN rats with preexisting allergic airway disease induced by OVA sensitization and challenge. Only OVA-challenged BN rats exposed to CAPs for 5 consecutive days in September 2000 had significant increases in airway mucosubstances and pulmonary inflammation compared to saline-challenged/air-exposed control rats. OVA-challenged BN rats that were repeatedly exposed to CAPs in July 2000 had only minor CAPs-related effects. In only the September 5-day exposure protocol, PM2.5 trace elements of anthropogenic origin (La, V, and S) were recovered from the lung tissues of CAPs-exposed rats. Recovery of these specific trace elements was greatest in rats with OVA-induced allergic airway disease. Additional laboratory experiments using intratracheal instillations of ambient PM2.5 samples were performed to identify bioactive agents in the CAPs to which rats had been exposed in the inhalation exposure component. Because the most pronounced effects of CAPs inhalation were found in BN rats with OVA-induced allergic airways exposed in September, we used ambient PM2.5 samples that were collected on 2 days during the September CAPs inhalation exposures to use for instillation. Ambient PM2.5 samples were collected, fractionated into soluble and insoluble species, and then compared with each other and with total PM2.5 for their effects in healthy BN rats and those with OVA-induced allergic airway disease. Intratracheal instillation of the insoluble fraction of PM2.5 caused mild neutrophilic inflammation in the lungs of healthy rats. However, total PM2.5 or the soluble or insoluble fractions instilled in rats with OVA-induced airway inflammation did not enhance the inflammation or the airway epithelial remodeling that was evident in some of the BN rats exposed to CAPs by inhalation. Therefore, the results from this instillation component did not suggest what fractions of the CAPs may have been responsible for enhancing OVA-induced airway mucosubstances and pulmonary inflammation observed in the inhalation exposure component. In summary, inhaled CAPs-related pulmonary alterations in the affected OVA-challenged rats appeared to be related to the chemical composition, rather than the mass concentration, to which the animals were exposed. Results of the trace element analysis in the lungs of CAPs-exposed BN rats exposed in September suggested that air particles derived from identified local combustion sources were preferentially retained in allergic airways. These results demonstrate that short-term exposures to CAPs from this southwestern Detroit community caused variable responses in laboratory rats and suggest that adverse biological responses to ambient PM2.5 may be associated more closely with local sources of particles and weather patterns than with particle mass.
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.
Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks/significance
- X-M Li
- Wh Tang
- Mk Mosior
Effects of inhaled urban air particulates on normal and hypersecretory airways in rats
- J R Harkema
- G J Keeler
- J G Wagner
Fine particulate air pollution and the progression of carotid intimamedia thickness: A prospective cohort study from the Multi-Ethnic Study of Atherosclerosis and Air Pollution
- References Adar
- S D Sheppard
- L Vedal
- S Polak
- J F Samspon
- Diez Roux
- A V Budoff
- M Jacobs
- D R Barr
- R G Watson
- K Kaufman
0.39, 0.82) versus 0.60 µmol·min −1 ·ml plasma −1 (0.40, 0.85), p=0.137] did not differ 20-hours
post-CAP versus FA, respectively.
References
Adar SD, Sheppard L, Vedal S, Polak JF, Samspon PD, Diez Roux AV, Budoff M, Jacobs DR, Barr
RG, Watson K, Kaufman JD. Fine particulate air pollution and the progression of carotid intimamedia thickness: A prospective cohort study from the Multi-Ethnic Study of Atherosclerosis and
Air Pollution. PLOS Med. 2013; 10:e1001430. [PubMed: 23637576]
Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress
- J A Araujo
- B Barajas
- M Leinman
- X Wang
- B J Bennett
- K W Gong
- M Navab
- J Harkema
- C Sioutas
- A J Lusis
- A E Nel
Araujo JA, Barajas B, Leinman M, Wang X, Bennett BJ, Gong KW, Navab M, Harkema J, Sioutas C,
Lusis AJ, Nel AE. Ambient particulate pollutants in the ultrafine range promote early
atherosclerosis and systemic oxidative stress. Circ Res. 2008; 102:589-596. [PubMed: 18202315]
Particulate matter air pollution and cardiovascular disease. An update to the scientific statement from the
- R D Brook
- S Rajagopalan
- C A Pope
- Iii
- J R Brook
- A Bhatnagar
- A Diez-Roux
- F Holguin
- Y Hong
- R V Luepker
- M Mittleman
- A Peters
- D Siscovich
- S C Smith
- L Whitsel
- J D Kaufman
Brook RD, Rajagopalan S, Pope CA III, Brook JR, Bhatnagar A, Diez-Roux A, Holguin F, Hong Y,
Luepker RV, Mittleman M, Peters A, Siscovich D, Smith SC Jr, Whitsel L, Kaufman JD. Particulate
matter air pollution and cardiovascular disease. An update to the scientific statement from the
American Heart Association. Circulation. 2010; 121:2331-2378. [PubMed: 20458016]
MA: Health Effects Institute
- J R Harkema
- G J Keeler
- J G Wagner
- M Morishita
- E Timm
- J Hotchkiss
Harkema, JR.; Keeler, GJ.; Wagner, JG.; Morishita, M.; Timm, E.; Hotchkiss, J., et al. Health Effects
Institute Research Report 120. Boston MA: Health Effects Institute; 2004. Effects of inhaled urban
air particulates on normal and hypersecretory airways in rats.
Ambient ultrafine particles alter lipid metabolism and HDL anti-oxidant capacity in LDLR-null mice
- R Li
- M Navan
- P Pakbin
- Z Ning
- K Navab
- G Hough
- T E Morgan
- C E Finch
- J A Araujo
- A M Fogelman
- C Sioiutas
- T Hsiai
Li R, Navan M, Pakbin P, Ning Z, Navab K, Hough G, Morgan TE, Finch CE, Araujo JA, Fogelman
AM, Sioiutas C, Hsiai T. Ambient ultrafine particles alter lipid metabolism and HDL anti-oxidant
capacity in LDLR-null mice. J Lipid Res. 2013 (A); 54:1608-1615. [PubMed: 23564731]
Paradoxical Association of Enhanced Cholesterol Efflux With Increased Incident Cardiovascular Risks
- X-M Li
- Wjw Tamg
- M K Mosior
- Y Huang
- Y Wu
- W Matter
- V Gao
- D Schmitt
- J A Didonato
- E A Fisher
- J D Smith
- S L Hazen
Li X-M, Tamg WJW, Mosior MK, Huang Y, Wu Y, Matter W, Gao V, Schmitt D, DiDonato JA,
Fisher EA, Smith JD, Hazen SL. Paradoxical Association of Enhanced Cholesterol Efflux With
Increased Incident Cardiovascular Risks. Arterioscl Thromb Vasc Biol. 2013 (B); 33:1696-1701.
2013. [PubMed: 23520163]
Diesel exhaust induces systemic lipid peroxidation and development of dysfunctional pro-oxidant and pro-inflammatory high-density lipoprotein
- F Yin
- A Lawal
- J Pciks
- J R Fox
- T Larson
- Navab
- A M Fogelman
- M E Rosenfeld
- J A Araujo
Yin F, Lawal A, Pciks J, Fox JR, Larson T, Navab, Fogelman AM, Rosenfeld ME, Araujo JA. Diesel
exhaust induces systemic lipid peroxidation and development of dysfunctional pro-oxidant and
pro-inflammatory high-density lipoprotein. Arterioscler Thromb Vasc Biol. 2013; 33:1153-1161.
[PubMed: 23559632]
Particulate matter air pollution and cardiovascular disease. An update to the scientific statement from the
- R D Brook
- S Rajagopalan
- C A Pope
- Iii