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Published ahead of print on October 11, 2007, doi:10.1164/rccm.200704-632OC
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American Journal of Respiratory and Critical Care Medicine Vol 177. pp. 419-425, (2008)
© 2008 American Thoracic Society
doi: 10.1164/rccm.200704-632OC

Original Article

Indoor Particles Affect Vascular Function in the Aged

An Air Filtration–based Intervention Study

Elvira Vaclavik Bräuner1, Lykke Forchhammer1, Peter Møller1, Lars Barregard2, Lars Gunnarsen3, Alireza Afshari3, Peter Wåhlin4, Marianne Glasius4, Lars Ove Dragsted5, Samar Basu6, Ole Raaschou-Nielsen7 and Steffen Loft1

1 Institute of Public Health, Department of Environmental Health, Copenhagen, Denmark; 2 Department of Occupational and Environmental Medicine, Sahlgrenska University Hospital and Academy, Gothenburg, Sweden; 3 Danish Building Research Institute, Hørsholm, Denmark; 4 Department of Atmospheric Environment, National Environmental Research Institute, Roskilde, Denmark; 5 The National Food Institute, Danish Technical University, Lyngby, and Institute of Human Nutrition, Faculty of Life Sciences, Frederiksberg, Denmark; 6 Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala, Sweden; and 7 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark

Correspondence and request for reprints should be addressed to Steffen Loft, M.D., D.M.Sc., Institute of Public Health, Department of Environmental and Occupational Health, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark. E-mail: s.loft{at}pubhealth.ku.dk


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Exposure to particulate matter is associated with risk of cardiovascular events, possibly through endothelial dysfunction, and indoor air may be most important.

Objectives: We investigated effects of controlled exposure to indoor air particles on microvascular function (MVF) as the primary endpoint and biomarkers of inflammation and oxidative stress as secondary endpoints in a healthy elderly population.

Methods: A total of 21 nonsmoking couples participated in a randomized, double-blind, crossover study with two consecutive 48-hour exposures to either particle-filtered or nonfiltered air (2,533–4,058 and 7,718–12,988 particles/cm3, respectively) in their homes.

Measurements and Main Results: MVF was assessed noninvasively by measuring digital peripheral artery tone after arm ischemia. Secondary endpoints included hemoglobin, red blood cells, platelet count, coagulation factors, P-selectin, plasma amyloid A, C-reactive protein, fibrinogen, IL-6, tumor necrosis factor-{alpha}, protein oxidation measured as 2-aminoadipic semialdehyde in plasma, urinary 8-iso-prostaglandin F2{alpha}, and blood pressure. Indoor air filtration significantly improved MVF by 8.1% (95% confidence interval, 0.4–16.3%), and the particulate matter (diameter < 2.5 µm) mass of the indoor particles was more important than the total number concentration (10–700 nm) for these effects. MVF was significantly associated with personal exposure to iron, potassium, copper, zinc, arsenic, and lead in the fine fraction. After Bonferroni correction, none of the secondary biomarkers changed significantly.

Conclusions: Reduction of particle exposure by filtration of recirculated indoor air for only 48 hours improved MVF in healthy elderly citizens, suggesting that this may be a feasible way of reducing the risk of cardiovascular disease.

Key Words: atherosclerosis • biomarkers • cardiovascular disease • indoor air pollution • inflammation



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Increased cardiovascular risk is associated with exposure to air pollution.

What This Study Adds to the Field
Particles in indoor air affect endothelial function in elderly subjects. A significant improvement was shown after reduction of particles in the indoor air achieved by air filtration in their homes.

 
Short-term and chronic exposure to ambient levels of particulate matter (PM) is associated with increased morbidity and mortality related to respiratory and cardiovascular disease (1, 2).

Biological mechanisms of action of PM are believed to involve altered pulmonary inflammation, cardiac autonomic function, endothelial dysfunction, systemic inflammation, oxidative stress, and altered balance between blood clotting and fibrinolysis, with small particles being more potent per unit mass than larger particles due to their higher surface area and reactivity (3–5). Traffic-related PM may be particularly relevant, as indicated by risk of cardiovascular events shortly after exposure in traffic (6). These particles may also penetrate indoors, and previous studies have described increased mortality associated with a residential address close to major roads with dense traffic as well as acute mortality associated with source allocation (7, 8).

Abnormal endothelial function (EF) is a strong predictor of adverse cardiovascular outcomes (9, 10) and widely recognized in patients with atherosclerosis and its risk factors (11, 12). Inhalation of high concentrations of diesel exhaust particles has recently been shown to impair two important and complementary aspects of vascular functions in healthy humans: the regulation of vascular tone and fibrinolysis (13).

A number of personal monitoring studies have found that biomarkers related to cardiovascular diseases show stronger association with personal exposure than with ambient levels (14, 15). This indicates that the exposure to particles generated indoors could cause an additional increase in adverse effects. However, studies of the health effects of indoor air on healthy humans are lacking. In addition, most of the mechanistic evidence comes from experimental human or animal studies with high levels of exposure, or from observational panel studies with associated difficulties in exposure assessment and control of confounders. Indoor penetration of ambient air particles is variable, and there are many indoor sources, such as cooking, candles, human activity, heating appliances, and environmental tobacco smoke (15, 16). This underlines the importance of understanding details of indoor PM levels, and there is a specific need to study this in the elderly, as they appear to have elevated susceptibility (17) and have the largest attributable risk related to indoor PM, as they spend more time indoors (18).

The primary aim of this study was to use controlled exposure to real-life indoor air particles to delineate the relationship between intervention and microvascular function (MVF), as a measure of EF in a healthy population of 42 elderly volunteers. We used two consecutive 48-hour periods in each private home, and an intervention was achieved by using high-efficiency particle air (HEPA) filters during one of these periods. Changes in peripheral artery tone due to enhanced flow after arm ischemia was used to assess MVF as the a priori–defined primary endpoint. Secondary endpoints in terms of blood pressure, hematological parameters, markers of inflammation, and hemostasis, as well as lipid and protein oxidation products, were included to elucidate potential mechanisms of action.


   METHODS
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Further details of all methods are available in the extended METHODS in the online supplement.

Study Population and Design
A total of 21 couples, aged 60–75 (median, 67) years and mean body mass index of 25 (SD, 3.24), were recruited, and one female was later excluded. All participants were healthy nonsmokers, and each was his/her own control, excluding confounding by factors that are stable within an individual over time but vary between participants.

The project design was a double-blind crossover intervention with randomized order of 48-hour exposure to recirculated particle-filtered and nonfiltered indoor air in the volunteer's homes located in Copenhagen in proximity (<350 m) to major roads (>10,000 vehicles/24 h). Two filter units (Airshower; Airsonett AB, Ängelholm, Sweden), running continuously with airflow of 540 m3/hour, sound level less than 35 dB, and filter exhaust height of 2.15 m, were placed in the bedroom and living room of each apartment during the study period (either with or without a HEPA filter, according to scenario; see Figure E2 in the online supplement). When the HEPA filter was removed, filtration efficiency of the unit was less than 10%, with unchanged noise, airflow, and appearance. The air pollution monitoring equipment was always positioned at the furthest point diagonally away from the filter.

The size distribution and number concentration (NC) of particles (10–700 nm) in each residence were continuously monitored. Particle samples were collected using Dichotomous Stacked Filter Units (University of Hertfortshire, Hatfield, UK) (19), as fine (diameter < 2.5 µm [PM2.5]) and coarse (10–2.5 µm diameter [PM10–2.5]) fractions. Particle mass was determined gravimetrically, and elemental composition was determined using a proton-induced X-ray emission method (20).

Blood and spot-urine was sampled on the morning after each 48-hour scenario, and, to avoid problems due to diurnal variation, each scenario started at the same time of morning. For the duration of the study, we asked participants to stay indoors (equivalent to 92–94% of time) and keep windows closed.

The study was approved by the local ethics committee and in accordance with the Declaration of Helsinki. All participants gave written, informed consent before inclusion.

Primary Endpoint
Vascular function.
MVF was measured immediately before blood sampling and noninvasively using reactive hyperemia–peripheral arterial tonometry (RH-PAT), as previously described in detail (21–23). This technique uses finger-mountable pneumatic sensors (Endo-PAT 2000; Itamar Medical Ltd., Cesaria, Israel) specifically designed to continuously record the digital arterial pulse wave amplitude. A blood pressure cuff was placed above the elbow of the right arm for hyperemia testing, while the left arm served as a control. The plethysmographic finger probes were placed on the index fingers of both hands. The test consisted of three stages: baseline, brachial arterial occlusion, and a postocclusion recording of the induced reactive hyperemia response. Data was digitally stored as pulse wave tracings from both hands and an MVF score describing the extent of hyperemia was computed using an automated algorithm in an operator independent manner.

Secondary Endpoints
Hematological measurements, markers of inflammation, hemostasis, and oxidative stress.
We measured hemoglobin, red blood cells, fibrinogen, platelets, coagulation factors (II + VII + X), C-reactive protein (CRP), IL-6, tumor necrosis factor (TNF)-{alpha}, plasma amyloid A, 2-aminoapidic semialdehyde, and urinary 8-iso-prostaglandin F2{alpha} (8-iso-PGF2{alpha}).

Statistical Analysis
Due to three missing data points for the MVF score and one missing blood sample, we used mixed-effect model repeated measures analysis to investigate the effect of intervention on the primary and secondary outcome variables. Partner cluster and participant nested in partner cluster were included as random factor variables to account for interindividual variation and the effects of partners living at the same address. Exposure in terms of filtration status was included as a fixed categorical explanatory variable. Gender was included as a categorical variable, and age, body mass index, and indoor temperature as continuous variables. We investigated dose–response relationships related to the total NC, area and volume of particles, as well as mass concentration of PM2.5 and PM10–2.5 up to blood sampling. These were analyzed in single-exposure models and in a multiple-component, backward stepwise selection procedure. Similarly, the mass concentration of each element analyzed in the PM2.5 and PM10–2.5 fractions were analyzed with and without adjustment for mass concentration of the fraction. The significance threshold was P less than 0.05 in all analyses.


   RESULTS
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Exposure Characterization
Table 1 summarizes indoor levels of PM characteristics and NO2 during the two different exposure scenarios. The HEPA filter placed in homes effectively removed ultrafine, fine, and coarse particles, whereas levels of NO2 were unaltered. Filtration mean efficacy within each apartment was uniform: 59.8% (bedroom) and 61.2% (living area), and this was not significantly correlated with NCurban background, maximum traffic density within a 100-m radius, room volume, or carpeting coverage (see Table E1). Figure 1 depicts NC10–700 nm, Area10–700 nm, and Volume10–700 nm of particles with and without filtration of the air in one of the included homes. Occasional peaks could be related to candle burning and cooking. The average change in NC10–700 nm over the entire study period within the included apartments is presented in the online supplement (Figure E1); peaks were not related to rush hour traffic, but rather to indoor activities. The concentrations of the elements in the indoor fine fraction of particles (PM2.5) per indoor air unit of nonfiltered and particle-filtered indoor air are presented in the online supplement (Table E2). There was a relatively high concentration of sulfur, consistent with substantial penetration from outdoor air originating from long-range transport, and this fraction was also relatively rich in metals. All concentrations were substantially reduced by HEPA filtration. With the exception of chromium, antimony, arsenic, and chlorine, the concentrations of all the elements within the PM2.5 fraction of indoor air were significantly correlated with Area10–700 nm and Volume10–700 nm of particles (Table E3).


Figure 1
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  		Figure 1. Number concentration (NC10–700 nm; black line), Area10–700 nm; (red line), and Volume10–700 nm; (blue line) of particles during 48 hours without and 48 hours with filtration of the indoor air in one of the included homes. Peaks in NC10–700 nm (asterisks) occurred during candle burning and cooking, as indicated.

 

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  		TABLE 1. GEOMETRIC MEAN AND 95% CONFIDENCE INTERVAL OF INDOOR CONCENTRATIONS OF PARTICULATE MATTER NUMBER CONCENTRATION10–700 nm, AREA10–700 nm, VOLUME10–700 nm, PARTICULATE MATTER MASS, INDOOR NO2, RELATIVE HUMIDITY, AND TEMPERATURE

 
Biomarkers and Function Tests
MVF score, hematological parameters, oxidative products, and markers of inflammation and hemostasis are presented in Table 2 according to exposure scenario.


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  		TABLE 2. GEOMETRIC MEAN AND 95% CONFIDENCE INTERVAL OF MICROVASCULAR FUNCTION AND BIOMARKERS ACCORDING TO FILTRATION SCENARIO AND RELATIONSHIP BETWEEN BIOMARKERS AND INTERVENTION FILTRATION IN THE HOMES OF 41 ELDERLY SUBJECTS

 
Primary endpoint.
Three pulse wave tracings of RH-PAT were not recorded due to instrument failure. The MVF score was significantly improved by 8.1% (95% confidence interval [CI], 0.4–16.3%; P = 0.03) during air filtration, as assessed in the mixed-effects model with inclusion of filtration as a categorical variable (Table 2). The MVF score was significantly and inversely associated with mass concentration of PM2.5 and NC10–700 nm during both scenarios in the single-exposure models, whereas PM10–2.5, Area10–70 nm, and Volume10–700 nm were not significant predictors (Table 3). After applying a backward stepwise selection approach and the stepwise exclusion of exposure variables: PM10–2.5 mass, Volume10–700 nm, NC10–700 nm, and Area10–70 0nm, only PM2.5 mass was a significant predictor of MVF score in the reduced model. Of the elements in PM2.5 fraction, we found that iron, copper, potassium, zinc, lead, and arsenic were all significantly and inversely associated with MVF score. When these single-element associations were adjusted for the mass concentration of the PM2.5 fraction, we found that only potassium was significantly and independently associated with MVF score (Table E2). There was no effect of exposure on the baseline peripheral arterial tone amplitude in either the ischemic or control arm.


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  		TABLE 3. THE RELATIONSHIP BETWEEN THE MICROVASCULAR FUNCTION SCORE AND CONTINUOUS PARAMETERS OF EXPOSURE MEASURED WITH AND WITHOUT FILTRATION OF THE INDOOR HOME AIR

 
Secondary endpoints.
Filtration of the indoor air was significantly associated with an increase in hemoglobin concentration in the blood (Table 2). None of the other biomarkers was significantly associated with exposure as categorical or continuous variables. However, an association between NC10–700 nm and 8-iso-PGF2{alpha} was borderline significant (P = 0.055), and a doubling in NC10–700nm corresponded to a 4.31 (95% CI, –0.09 to 8.91) % increase. After Bonferroni correction, none of the secondary endpoints changed significantly in accordance with exposure as either a continuous or categorical variable. None of these secondary endpoints correlated with MVF score (P >= 0.099).

NO2 was not a significant predictor when included in the above models of primary and secondary endpoints (P >= 0.20). The intake of medication with antiinflammatory properties had no significant effects on the predictive value of exposure on these endpoints and was not significantly associated with any of the markers studied here (P >= 0.79). Finally, the order of randomization had no affect on the parameters studied.


   DISCUSSION
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
EF constitutes an independent predictor of cardiovascular events (24, 25), and the clinical implications of endothelial dysfunction and the association between endothelial cell dysfunction and cardiac events are well established (26, 27). There have been a number of studies showing associations between improved EF after interventions of increased exercise (28), smoking cessation (29), and weight reduction (30). In this study, we investigated the effects of intervention using HEPA filtration of indoor air particles for 48 hours. Our main finding was a significant improvement in MVF demonstrated by an increased flow-mediated vasoresponse after reduction of indoor air particles, most likely indicating a general improvement in EF.

A recent experimental study including 30 young healthy volunteers was the first to demonstrate that inhalation of diesel emission in high doses (300 µg/m3) could impair vasomotor responses to both endothelium-dependent (acetylcholine and bradykinin) and endothelium-independent (sodium nitroprusside) vasodilators (13). Moreover, this group showed that endothelium-dependent vasodilatation occurring in the presence of mild systemic inflammation was persistent 24 hours after the same exposure in 15 volunteers (31). We found an effect on MVF at a 10-times lower exposure level in an elderly population, which may be more susceptible. Indeed, EF measured in connection with previous exposure studies was only negatively associated with ambient levels of PM2.5 and sulfate and/or black carbon among diabetics, who are particularly susceptible, and diabetes enhances vulnerability to particulate air pollution–associated impairment in vascular reactivity and EF (32). Moreover, EF measured as acetylcholine-induced vasodilatation in aorta segments 1 hour after systemic administration of diesel exhaust particles was only reduced in hyperlipidemic apolipoprotein E knockout mice, whereas there was a tendency toward enhanced vasodilatation in wild-type mice, and no effect on endothelium-independent vasodilatation in any type of mouse (33). Thus, EF appears to be negatively affected by exposure to particulate air pollution in susceptible individuals, and this could provide part of a mechanistic link to acute cardiovascular events as well as progression of atherosclerosis.

Digital MVF was defined as our primary endpoint because this functional measure reflects coronary EF and can be considered a more specific predictor of cardiovascular risk than the secondary biomarkers that were included to elucidate potential mechanisms. The method has been validated in clinical settings (23, 34, 35), but ours is the first group to use it in relation to the effects of air pollution. The portable, user-independent, automated, and noninvasive equipment allowed us to study the most relevant exposure in terms of indoor air within the homes of elderly volunteers. In another experimental study using this technique, we included 29 young, healthy volunteers and found that the MVF score geometric mean was higher (2.14; 95% CI, 2.08–2.19), reflecting the general consensus that aging increases susceptibility. In a study of patients referred for coronary angiography, those showing endothelial dysfunction had an average MVF score of 1.27, whereas patients without coronary endothelial dysfunction had an average MVF score of 1.78 (34), which is comparable to our healthy, elderly volunteers. Endothelium-independent vasodilatation assessed by the peripheral artery tone response to nitroglycerin was similar in the two groups in that study (34). These data support the application of RH-PAT as a convenient, noninvasive measure of EF.

An assessment of endothelium-independent vasodilation using PAT to measure the hyperemic response to sublingual nitroglycerine would have clarified the mechanism by which particulate filtration improved MVF in our study. This was not performed, as the administration of nitroglycerine in the home environment posed unacceptable risks of adverse effects to the elderly study participants. Previous studies have suggested a role for oxidative stress and reduced nitric oxide bioavailability in mediating adverse vascular effects of PM (13, 31). As the digital hyperemic response is largely dependent on nitric oxide (35), we believe that the improvement in MVF after particle filtration in our study represents a generalized improvement in EF.

Limitations to the use of MVF score for EF assessment include the limited data on associations with outcomes and other risk factors such as smoking, hypertension, and hypercholesterolemia.

We attempted to address the mechanisms of the association between MVF and particle exposure by means of biomarkers as secondary endpoints. There was a borderline significant (P = 0.055) association between particle NC10–700 nm and excretion of free 8-iso-PGF2{alpha}, a major F2-isoprostane, although this was far from significant after Bonferroni correction. The F2-isoprostanes are formed from arachidonic acid through nonenzymatic, free radical–catalyzed reaction, and are reliable markers of lipid peroxidation in a variety of conditions, including acute and chronic inflammatory conditions (36). Excretion of free 8-iso-PGF2{alpha} was elevated in cigarette smokers (37) and in subjects after high-dose exposure to woodsmoke (38), and has been shown to be associated with coronary artery disease (39). We have previously found correlations between lipid and protein oxidation products in plasma and personal exposure to black carbon in PM2.5 in individuals living in Copenhagen (40). However, in the present study, we found no effect of particle exposure on protein oxidation assessed by plasma protein 2-aminoapidic semialdehyde, although this lack of effect may have been due to the use of heparinized plasma, which is not ideal for the measurement.

The biomarkers related to inflammation responses and coagulation (IL-6, TNF-{alpha}), the acute-phase reactants (fibrinogen, CRP, and serum amyloid A), as well as coagulation factors II, VII, and X showed no sign of effect. Previously, experimental exposure to concentrated ambient air particles at mean concentrations of 120 µg/m3 caused increased fibrinogen levels among 15 volunteers (41). In another study including 13 healthy subjects exposed to woodsmoke particles at 280 µg/m3, serum amyloid A as well as factor VIII in plasma and the factor VIII/von Willebrand factor ratio were significantly increased, whereas IL-6, TNF-{alpha}, CRP, and fibrinogen showed no increase (38). High exposure to diesel emission at 300 µg/m3 caused diminished fibrinolytic capacity in other studies, whereas the plasma concentration of IL-6, TNF-{alpha}, von Willebrand factor activity, prothrombin fragments, CRP, and fibrinogen were unaltered, despite reduced EF (13, 42). A recent study showed some association between ambient PM levels and global coagulation function, whereas fibrinogen was unaffected (43). In other panel studies, CRP levels have been found to be associated with ambient or personal PM exposure (44–46). Accordingly, acute-phase reactants, such as CRP, fibrinogen, and amyloid A in plasma, may respond at relatively high levels of particle exposure, whereas cytokine levels in plasma do not seem to be sensitive for the detection of inflammatory responses in this respect. Moreover, there are no obvious associations between biomarkers of inflammation or oxidative stress and MVF. In accordance with this observation, we found no sign of correlations in the present study. The recent finding of association between expression of adhesion molecules on leukocytes or in plasma and ambient levels of PM in observational panel studies suggest these as promising biomarkers for experimental exposure studies, (46–48), although we found no effect on P-selectin in the present study. We found that PM exposure was significantly associated with a decrease in hemoglobin, without Bonferroni correction, which is in agreement with earlier results (49); however, in another previous study, we observed a positive association with exposure to black smoke among young women (40). Our results may suggest that some component of PM causes sequestration of red blood cells in the circulation, but the effect on hemoglobin may also be due to chance, considering the large number of secondary endpoints.

Indoor air contains a mixture of PM from both indoor and outdoor sources with various chemical species and trace elements. We analyzed size distribution and elemental composition of particles within the PM2.5 and PM10–2.5 fractions in both scenarios and found that PM2.5 mass was the only remaining independent predictor of the MVF score in the reduced multiexposure model, indicating that the indoor fine particle mass, rather than numbers or surface area of particles, are important for the effect on EF. However, this may be due to the fact that indoor sources, such as cooking and candle burning, contributed substantially to indoor NC, whereas vehicle emissions probably contributed less. Of the elements in the PM2.5 fraction, we found significant associations between individual increases in iron, copper, potassium, zinc, lead, and arsenic concentrations and reduced MVF score, whereas other elements, including the transition metals, vanadium, titanium, chromium, and nickel, had no effects. Iron and copper are typical elements associated with brake dust from vehicles, and their presence indoors may be due to penetration (20). Transition metals, including iron and copper, catalyze the formation of reactive oxygen species via Haber-Weiss reactions (50), which may explain the effects observed for iron and copper. However, the associations between the metals and the MVF score were not independent of the PM2.5 mass, and we found no clear associations between the MVF score and markers of oxidative stress, as discussed previously here. Only potassium showed an independent association with the MVF score. Potassium is a typical element associated with particles generated from the burning of biomass and smoking (51, 52), and indoor penetration of ambient particles from biomass burning, including long-range transport, and/or penetration of environmental tobacco smoke from neighboring apartments, may have contributed to the effect on MVF. A relatively high level of indoor sulfur in the PM2.5 fraction, which correlated with the urban background levels (Table E3), suggests substantial penetration of long-range transported particles. These findings are in keeping with a recent source apportionment study in Copenhagen, which showed associations between daily cardiovascular-related admissions and daily urban background concentrations of secondary sulfate-rich particles and biomass particles in PM10 (53). Unfortunately, we could not address contributions from elemental carbon or organic compounds directly in the present study.

NO2 was not a significant predictor of any of the endpoints, and this result was expected, as the filtration of recirculated indoor air had no effects on NO2 levels. Furthermore, the intake of minor medications had no effect on our results, which was also expected, as these medications were constant within these individuals throughout the study, and each individual was his/her own control.

The effects we show in this study were measured after a 48-hour intervention. It is possible that the effects occurred much earlier, and it may also be speculated that further improvement may occur after prolonged intervention by 6 months to 1 year, and that this could result in further reduction in cardiovascular risk in this healthy, elderly age group.

Conclusions
The results of this study indicate that reduction of particles in recirculated indoor air by filtration significantly improves MVF in a healthy, nonsmoking, elderly population. The improvement could not be ascribed to significant reductions in inflammation or oxidative stress by means of biomarkers. Indoor air sources differ from outdoor air and indoor PM2.5 mass, rather than total numbers or surface area of particles had the most important association with MVF. Indoor air filtration represents a feasible means of reducing cardiovascular risk and suggests long-term and large-scale studies with cardiovascular events as endpoints.


   Acknowledgments
 
The authors thank Janne Kjærsgaard for expert assistance with blood sampling, Betty Bügel Mogensen for NO2 measurements, Britta Krath for analysis of 2-aminoapidic semialdehyde, and technicians at National Environmental Research Institute and Danish Building Research Institute for technical assistance.


   FOOTNOTES
 
Supported by contract no. 513943 from the Danish National Research Councils, Denmark Velux Foundation, Denmark Environmental Cancer Risk, Nutrition and Individual Susceptibility, European Union 6th Framework Program, Priority 5: "Food Quality and Safety."

Current affiliation for M.G.: Department of Chemistry, University of Aarhus, Aarhus, Denmark.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200704-632OC on October 11, 2007

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form April 26, 2007; accepted in final form October 11, 2007


   REFERENCES
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Pope CA, Dockery DW. Health effects of fine particulate air pollution: lines that connect. J Air Waste Manag Assoc 2006;56:709–742.[Medline]
  2. Miller KA, Siscovick DS, Sheppard L, Shepherd K, Sullivan JH, Anderson GL, Kaufman JD. Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med 2007;356:447–458.[Abstract/Free Full Text]
  3. Schlesinger RB, Kunzli N, Hidy GM, Gotschi T, Jerrett M. The health relevance of ambient particulate matter characteristics: coherence of toxicological and epidemiological inferences. Inhal Toxicol 2006;18:95–125.[CrossRef][Medline]
  4. Donaldson K, Mills N, MacNee W, Robinson S, Newby D. Role of inflammation in cardiopulmonary health effects of PM. Toxicol Appl Pharmacol 2005;207:483–488.[CrossRef][Medline]
  5. Mills NL, Amin N, Robinson SD, Anand A, Davies J, Patel D, de la Fuente JM, Cassee FR, Boon NA, MacNee W, et al. Do inhaled carbon nanoparticles translocate directly into the circulation in humans? Am J Respir Crit Care Med 2006;173:426–431.[Abstract/Free Full Text]
  6. Peters A, von Klot S, Heier M, Trentinaglia I, Hörmann A, Wichmann HE, Löwel H; Cooperative Health Research in the Region of Augsburg Study Group. Exposure to traffic and the onset of myocardial infarction. N Engl J Med 2004;351:1721–1730.[Abstract/Free Full Text]
  7. Laden F, Neas LM, Dockery DW, Schwartz J. Association of fine particulate matter from different sources with daily mortality in six US cities. Environ Health Perspect 2000;108:941–947.[Medline]
  8. Hoek G, Brunekreef B, Goldbohm S, Fischer P, van den Brandt PA. Association between mortality and indicators of traffic-related air pollution in The Netherlands: a cohort study. Lancet 2002;360:1203–1209.[CrossRef][Medline]
  9. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation 2005;111:363–368.[Free Full Text]
  10. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:2673–2678.[Abstract/Free Full Text]
  11. Newby DE, Wright RA, Labinjoh C, Ludlam CA, Fox KA, Boon NA, Webb DJ. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 1999;99:1411–1415.[Abstract/Free Full Text]
  12. Newby DE, McLeod AL, Uren NG, Flint L, Ludlam CA, Webb DJ, Fox KA, Boon NA. Impaired Coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation 2001;103:1936–1941.[Abstract/Free Full Text]
  13. Mills NL, Törnqvist H, Robinson SD, Gonzalez M, Darnley K, MacNee W, Boon NA, Donaldson K, Blomberg A, Sandström T, et al. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation 2005;112:3930–3936.[Abstract/Free Full Text]
  14. Vinzents PS, Møller P, Sørensen M, Knudsen LE, Hertel O, Jensen FP, Schibye B, Loft S. Personal exposure to ultrafine particles and oxidative DNA damage. Environ Health Perspect 2005;113:1485–1490.[Medline]
  15. Lanki T, Ahokas A, Alm S, Janssen NA, Hoek G, de Hartog JJ, Brunekreef B, Pekkanen J. Determinants of personal and indoor PM2.5 and absorbance among elderly subjects with coronary heart disease. J Expo Sci Environ Epidemiol 2007;17:124–133.[CrossRef][Medline]
  16. Polidori A, Turpin B, Meng QY, Lee JH, Weisel C, Morandi M, Colome S, Stock T, Winer A, Zhang J, et al. Fine organic particulate matter dominates indoor-generated PM2.5 in RIOPA homes. J Expo Sci Environ Epidemiol 2006;16:321–331.[CrossRef][Medline]
  17. Forastiere F, Stafoggia M, Picciotto S, Bellander T, D'Ippoliti D, Lanki T, von Klot S, Nyberg F, Paatero P, Peters A, et al. A case-crossover analysis of out-of-hospital coronary deaths and air pollution in Rome, Italy. Am J Respir Crit Care Med 2005;172:1549–1555.[Abstract/Free Full Text]
  18. Simoni M, Jaakkola MS, Carrozzi L, Baldacci S, Di Pede F, Viegi G. Indoor air pollution and respiratory health in the elderly. Eur Respir J Suppl 2003;40:15s–20s.[Medline]
  19. Luhana L, Mao H, Sokhi, RS. Laboratory and field evaluation of UH Dichotomous Stacked Filter Units. Hatfield, UK: University of Hertfordshire Printing Office; 2001. Saphire Report Publication No. (EVK4)2001-00192.
  20. Wåhlin P, Berkowicz R, Palmgren F. Characterisation of traffic-generated particulate matter in Copenhagen. Atmos Environ 2006;40:2151–2159.
  21. Kuvin JT, Karas RH. Clinical utility of endothelial function testing: ready for prime time? Circulation 2003;107:3243–3247.[Free Full Text]
  22. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, Karas RH, Udelson JE. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J 2003;146:168–174.[CrossRef][Medline]
  23. Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST, Lerman A. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol 2003;41:1761–1768.[Abstract/Free Full Text]
  24. Schachinger V, Zeiher AM. Atherosclerosis-associated endothelial dysfunction. Z Kardiol 2000; 89(suppl 9):IX/70–IX/74.[CrossRef]
  25. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002;106:653–658.[Abstract/Free Full Text]
  26. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003;42:1149–1160.[Abstract/Free Full Text]
  27. Stocker R, Keaney JF Jr. New insights on oxidative stress in the artery wall. J Thromb Haemost 2005;3:1825–1834.[CrossRef][Medline]
  28. Walther C, Gielen S, Hambrecht R. The effect of exercise training on endothelial function in cardiovascular disease in humans. Exerc Sport Sci Rev 2004;32:129–134.[CrossRef][Medline]
  29. Morita K, Tsukamoto T, Naya M, Noriyasu K, Inubushi M, Shiga T, Katoh C, Kuge Y, Tsutsui H, Tamaki N. Smoking cessation normalizes coronary endothelial vasomotor response assessed with 15O-water and PET in healthy young smokers. J Nucl Med 2006;47:1914–1920.[Abstract/Free Full Text]
  30. Mather KJ, Steinberg HO, Baron AD. Weight loss and endothelial function in obesity. Diabetes Care 2003;26:1927–1928.[Free Full Text]
  31. Törnqvist H, Mills NL, Gonzalez M, Miller MR, Robinson SD, Megson IL, MacNee W, Donaldson K, Söderberg S, Newby DE, et al. Persistent endothelial dysfunction following diesel exhaust inhalation in man. Am J Respir Crit Care Med 2007;176:395–400.[Abstract/Free Full Text]
  32. O'Neill MS, Veves A, Zanobetti A, Sarnat JA, Gold DR, Economides PA, Horton ES, Schwartz J. Diabetes enhances vulnerability to particulate air pollution–associated impairment in vascular reactivity and endothelial function. Circulation 2005;111:2913–2920.[Abstract/Free Full Text]
  33. Hansen CS, Sheykhzade M, Moller P, Folkmann JK, Amtorp O, Jonassen T, Loft S. Diesel exhaust particles induce endothelial dysfunction in apoE–/– mice. Toxicol Appl Pharmacol 2007;219:24–32.[CrossRef][Medline]
  34. Bonetti PO, Pumper GM, Higano ST, Holmes DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 2004;44:2137–2141.[Abstract/Free Full Text]
  35. Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P. Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol 2006;101:545–548.[Abstract/Free Full Text]
  36. Basu S, Whiteman M, Mattey DL, Halliwell B. Raised levels of F2-isoprostanes and prostaglandin F{alpha} in different rheumatic diseases. Ann Rheum Dis 2001;60:627–631.[Abstract/Free Full Text]
  37. Helmersson J, Larsson A, Vessby B, Basu S. Active smoking and a history of smoking are associated with enhanced prostaglandin F{alpha}, interleukin-6 and F2-isoprostane formation in elderly men. Atherosclerosis 2005;181:201–207.[CrossRef][Medline]
  38. Barregard L, Sällsten G, Gustafson P, Andersson L, Johansson L, Basu S, Stigendal L. Experimental exposure to wood-smoke particles in healthy humans: effects on markers of inflammation, coagulation, and lipid peroxidation. Inhal Toxicol 2006;18:845–853.[CrossRef][Medline]
  39. Wang B, Pan J, Wang L, Zhu H, Yu R, Zou Y. Associations of plasma 8-isoprostane levels with the presence and extent of coronary stenosis in patients with coronary artery disease. Atherosclerosis 2006;184:425–430.[CrossRef][Medline]
  40. Sørensen M, Daneshvar B, Hansen M, Dragsted LO, Hertel O, Knudsen L, Loft S. Personal PM2.5 exposure and markers of oxidative stress in blood. Environ Health Perspect 2003;111:161–166.[Medline]
  41. Ghio AJ, Hall A, Bassett MA, Cascio WE, Devlin RB. Exposure to concentrated ambient air particles alters hematologic indices in humans. Inhal Toxicol 2003;15:1465–1478.[Medline]
  42. Blomberg A, Tornqvist H, Desmyter L, Deneys V, Hermans C. Exposure to diesel exhaust nanoparticles does not induce blood hypercoagulability in an at-risk population. J Thromb Haemost 2005;3:2103–2105.[CrossRef][Medline]
  43. Baccarelli A, Zanobetti A, Martinelli I, Grillo P, Hou L, Giacomini S, Bonzini M, Lanzani G, Mannucci PM, Bertazzi PA, et al. Effects of exposure to air pollution on blood coagulation. J Thromb Haemost 2007;5:252–260.[CrossRef][Medline]
  44. Seaton A, MacNee W, Donaldson K, Godden D. Particulate air pollution and acute health effects. Lancet 1995;345:176–178.[CrossRef][Medline]
  45. Riediker M, Cascio WE, Griggs TR, Herbst MC, Bromberg PA, Neas L, Williams RW, Devlin RB. Particulate matter exposure in cars is associated with cardiovascular effects in healthy young men. Am J Respir Crit Care Med 2004;169:934–940.[Abstract/Free Full Text]
  46. Rückerl R, Ibald-Mulli A, Koenig W, Schneider A, Woelke G, Cyrys J, Heinrich J, Marder V, Frampton M, Wichmann HE, et al. Air pollution and markers of inflammation and coagulation in patients with coronary heart disease. Am J Respir Crit Care Med 2006;173:432–441.[Abstract/Free Full Text]
  47. Frampton MW, Stewart JC, Oberdörster G, Morrow PE, Chalupa D, Pietropaoli AP, Frasier LM, Speers DM, Cox C, Huang LS, et al. Inhalation of ultrafine particles alters blood leukocyte expression of adhesion molecules in humans. Environ Health Perspect 2006;114:51–58.[Medline]
  48. O'Neill MS, Veves A, Sarnat JA, Zanobetti A, Gold DR, Economides PA, Horton ES, Schwartz J. Air pollution and inflammation in type 2 diabetes: a mechanism for susceptibility. Occup Environ Med 2007;64:373–379.[Abstract/Free Full Text]
  49. Seaton A, Soutar A, Crawford V, Elton R, McNerlan S, Cherrie J, Watt M, Agius R, Stout R. Particulate air pollution and the blood. Thorax 1999;54:1027–1032.[Abstract/Free Full Text]
  50. Risom L, Møller P, Loft S. Oxidative stress–induced DNA damage by particulate air pollution. Mutat Res 2005;592:119–137.[Medline]
  51. Naeher LP, Brauer M, Lipsett M, Zelikoff JT, Simpson CD, Koenig JQ, Smith KR. Woodsmoke health effects: a review. Inhal Toxicol 2007;19:67–106.[Medline]
  52. Molnár P, Gustafson P, Johannesson S, Boman J, Barregård L, Sällsten G. Domestic wood burning and PM2.5 trace elements: personal exposures, indoor and outdoor levels. Atmos Environ 2005;39:2643–2653.
  53. Andersen ZJ, Wahlin P, Raaschou-Nielsen O, Scheike T, Loft S. Ambient particle source apportionment and daily hospital admissions among children and elderly in Copenhagen. J Expo Sci Environ Epidemiol [Epub ahead of print 2007 May 9].

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