- Email: [email protected]
Increased risk of carotid atherosclerosis for long-term exposure to indoor coal-burning pollution in rural area, Hebei Province, China
Journal Pre-proof Increased risk of carotid atherosclerosis for long-term exposure to indoor coal-burning pollution in rural area, Hebei Province, China Yaxian Pang, Boyuan Zhang, Dongmei Xing, Jinmei Shang, Fengge Chen, Hui Kang, Chen Chu, Binghua Li, Juan Wang, Lixiao Zhou, Xuan Su, Bin Han, Jie Ning, Peiyuan Li, Shitao Ma, Dong Su, Rong Zhang, Yujie Niu PII:
S0269-7491(19)33573-0
DOI:
https://doi.org/10.1016/j.envpol.2019.113320
Reference:
ENPO 113320
To appear in:
Environmental Pollution
Received Date: 8 July 2019 Revised Date:
12 August 2019
Accepted Date: 27 September 2019
Please cite this article as: Pang, Y., Zhang, B., Xing, D., Shang, J., Chen, F., Kang, H., Chu, C., Li, B., Wang, J., Zhou, L., Su, X., Han, B., Ning, J., Li, P., Ma, S., Su, D., Zhang, R., Niu, Y., Increased risk of carotid atherosclerosis for long-term exposure to indoor coal-burning pollution in rural area, Hebei Province, China, Environmental Pollution (2019), doi: https://doi.org/10.1016/j.envpol.2019.113320. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
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Increased risk of carotid atherosclerosis for long-term exposure to indoor Coal-burning pollution in rural area, Hebei Province, China
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Yaxian Panga, Boyuan Zhanga, Dongmei Xingb, Jinmei Shangb, Fengge Chenc, Hui Kangd,
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Chen Chua, Binghua Lid, Juan Wangb, Lixiao Zhoua, Xuan Sua, Bin Hana, Jie Ninga, Peiyuan
＜
Lia, Shitao Mad, Dong Sud, Rong Zhanga,e*, Yujie Niud,e*
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a Department of Toxicology, School of Public Health, Hebei Medical University,
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Shijiazhuang 050017, PR China. b Department of internal Medicine-Cardiovascular, Nangong Jinan Great Wall Hospital, Nangong 051800, PR China.
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c Shijiazhuang Center for Disease Control and Prevention, Shijiazhuang 050000, PR China.
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d Deportment occupational Health and Environmental Health, School of Public Health, Hebei
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Medical University, Shijiazhuang 050017, PR China e Hebei Key Laboratory of Environment and Human Health, Shijiazhuang 050017, PR China.
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* Corresponding authors
18
CORRESPONDENCE:
Rong Zhang
19
Dept. Toxicology
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Hebei Medical University
21
361 Zhongshan east Rd.
22
Shijiazhuang, Hebei 050017
23
fax: 86-311-86265605
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Email: [email protected]
2＜
Abstract
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Smoky coal burning is a predominant manner for heating and cooking in most rural areas,
28
China. Air pollution is associated with the risk of atherosclerosis, however, the link between
29
indoor air pollution induced by smoky coal burning and atherosclerosis is not very clear.
30
Therefore, we designed a cross-sectional study to evaluate the association of long-term
31
exposure to smoky coal burning pollutants with the risk of atherosclerosis. 426 and 326
32
participants were recruited from Nangong, China and assigned as the coal exposure and
33
control group according to their heating and cooking way, respectively. The indoor air quality
34
(PM2.5, CO, SO2) was monitored. The association between coal burning exposure and the
35
prevalence of atherosclerosis was evaluated by unconditional logistic regression analysis,
3＜
adjusted for confounding factors. The inflammatory cytokines mRNAs (IL-8, SAA1, TNF-α,
37
CRP) expression in whole blood were examined by qPCR. People in the coal exposure group
38
had a higher risk of carotid atherosclerosis compared with the control (risk ratio [RR], 1.434;
39
95% confidence interval [95%CI], 1.063 to 1.934; P=0.018). The association was stronger in
40
smokers, drinkers and younger (<45 years old) individuals. The elevation of IL-8 (0.24,
41
95%CI, 0.06-0.58; P<0.05), CRP (0.37, 95%CI, 0.05-0.70; P<0.05), TNF-α (0.41, 95%CI,
42
0.14-0.67; P<0.01) mRNAs expression in whole blood positively were related with coal
43
exposure. Our results suggested long-term exposure to smoky coal burning emissions could
44
increase the risk of carotid atherosclerosis. The potential mechanism might relate that coal
45
burning emissions exposure induced inflammatory cytokines elevation which had adverse
4＜
effects on atherosclerotic plaque, and then promoted the development of atherosclerosis.
47 48 49 50
Capsule: Long-term exposure to coal combustion could increase the risk of carotid
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atherosclerosis: a cross-sectional study in rural area, China.
52
Key Words:
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inflammatory cytokines.
54 55
smoky coal burning; carotid atherosclerosis; indoor air pollution;
5＜
1. Introduction
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The Global Burden of Disease 2015 study identified household air pollution from solid
58
fuel use (coal, wood, charcoal, dung, and agricultural residues) as the eighth contributors to
59
global disability-adjusted life-years (DALYs), which induced 85.6 million people lost health-
＜0
life-years (Forouzanfar et al. 2016). There was usually bulk-burning smoky coal burning for
＜1
heating in winter in the rural areas of northern China (Li et al. 2018; Li et al. 2019; Seow et al.
＜2
2016). The smoky coal-burning can produce fine particulate matter (PM), carbon monoxide
＜3
(CO), sulfur oxide (SO2), nitrogen dioxide (NO2), polyromantic hydrocarbons (PAHs) which
＜4
bring about problems of environment (Secrest et al. 2017), especially the high levels of indoor
＜5
air pollution (Ni et al. 2016; Seow et al. 2016).
＜＜
Previous studies demonstrated that coal burning for cooking and heating contributed to
＜7
the excess all-cause mortality, especially respiratory diseases (asthma, chronic obstructive
＜8
pulmonary disease and lung cancer)(Chan et al. 2019; Seow et al. 2014) and cardiovascular
＜9
diseases (ischemic heart disease, myocardial infarction, stroke ) (Kim et al. 2016). The toxic
70
emissions produced by the solid fuels including coal have been recognized as contributors to
71
the increasing risk of cardiovascular disease (Mitter et al. 2016). Evidence suggested coal
72
burning was associated with increased risks of supraventricular premature beat, premature
73
ventricular contraction and ventricular tachycardia (Feng et al. 2019).
74
Carotid atherosclerosis is a form of chronic vascular inflammation, and a leading cause of
75
acute coronary syndrome and loss of productive life years (Libby et al. 2011; Soeki et al.
7＜
2016). The rural population detection rate of carotid atherosclerotic lesions was 76.3% in
77
Shanxi province, China, which were comparable to the rate the national population (Li et al.
78
2016). Recent study identified ambient air pollution was a contributor to the acceleration of
79
atherosclerosis (Wang et al. 2019). Long-term exposure to the indoor pollutants caused by
80
biomass fuels (such as wood and straw) was associated with an increasing risk of
81
atherosclerotic plaques (Painschab et al. 2013). Pollutants from biomass burning mainly
82
included PM (mostly composed of organic carbon), volatile organic compounds (VOCs), CO
83
and PAHs (Chen et al. 2017). However, the primary emissions produced by coal burning were
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characterized by SO2, and harmful elements (e.g. F, Hg, As) apart from the toxic pollutants
85
PM, VOCs, CO, PAHs
(Krumal et al. 2019).The different components of pollutants
8＜
emitted by the two fuels could contribute to different health effects. Though literature
87
demonstrated that coal burning was associated with excess cardiovascular mortality (Yu et al.
88
2018), the evidences of association between indoor air pollution by coal combustion and
89
atherosclerosis still limited. Finding the association between coal-burning indoor and the risk
90
of atherosclerosis could provide a clue to prevent the high prevalence of carotid
91
atherosclerotic lesions and cardiovascular disease.
92
The study of mechanism could provide strong evidences of causality between diseases
93
and exposure. Studies had demonstrated that carotid atherosclerosis was a chronic
94
inflammatory disease (Fredman et al. 2017; MY Wu et al. 2017). Inflammatory responses
95
play a crucial role in beginning with endothelial dysfunction and continue in each stage of the
9＜
atherosclerotic development (Ramji et al. 2015). C-reactive protein (CRP) and amyloid A
97
(SAA), usually served as markers of systemic inflammation, had been found increase in
98
patients with atherosclerosis and used to predict the risk of the disease cardiovascular events
99
(Rifai et al. 1999). SAA was also a participant in the early atherosclerotic development (Getz
100
et al. 2016). Interleukin (IL)-8 was a chemokine produced at inflammatory sites, which
101
promoted the development of carotid atherosclerosis .Tumor necrosis factor (TNF)-α was an
102
inflammatory cytokine, symbolized by the activation of M1 macrophages, which involved in
103
plaque destabilization and rupture (Soeki et al. 2016; Stancel et al. 2016; MY Wu et al. 2017).
104
PM and gaseous air pollutants (SO2, CO) released by coal combustion could induce
105
inflammatory events (Lawal 2017; XM Wu et al. 2017). Therefore, it was hypothesis that coal
10＜
burning triggered the inflammatory reactions and then developed the initiation and progress of
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carotid atherosclerosis.
108
In the present study, we designed a cross-sectional study based on a Rural Health Project
109
(RHP), which help the local residents to check up health and conducted in the Jinan Great
110
Wall Hospital, in Nangong County, Hebei Province, North China. The local rural dwellers
111
mainly cook and heat the rooms with traditional open-fire stove and the smoky coal is used as
112
the mainly fuel. In contrast, city dwellers cook mainly with clean fuels (e.g. natural gas and
113
electricity) and the heating method is predominantly central heating in winter. Here, we
114
enrolled the local long-term residents with or without smoky coal for cooking and heating.
115
The association of carotid atherosclerosis with coal burning was evaluated. Our study could
11＜
provide the evidences to explain atherosclerosis etiology, at least partly, and to make the
117
public policy for limiting the coal combustion and turning to the clean energy.
118
2. Methods
119
2.1 Study design and setting
120
We designed a geospatial, population-based cross-sectional study. This study protocol
121
was approved by the Institutional Review Board of Hebei Medical University. All participants
122
provided written informed consent at enrollment. We collected the information of the
123
participants in the RHP from November, 2018 to January, 2019. The inclusion criteria were as
124
follows: 1. Age ranging from 25 to 80 years old; 2. Not suffering from coronary heart disease,
125
stroke, diabetes, kidney diseases, tumor, and surgery. The participants who had incomplete
12＜
information for covariates were excluded. We issued questionnaires to the participants
127
enrolled in the present study. The questionnaire included items about cigarette smoking,
128
alcohol consumption, dietary, cooking and heating methods.
129
For coal burning exposure group, smoky coal combustion was used to heat and cook in
130
the living rooms in winter and never changed these methods of heating and cooking. The total
131
exposure time was equal to age and about 3 months per year in winter. Central heating and
132
cooking with clean fuels (gas and electricity) were enrolled in the control group. The
133
diagnosis of carotid atherosclerosis is according to the carotid ultrasound results: the carotid
134
artery intima-media thickness>1.5 mm or focal wall thickening that protruded into the
135
lumen >0.5 mm or >50% was defined as atherosclerosis (Stein et al. 2008). The height, body
13＜
weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), cholesterol and
137
triglyceride were examined and recorded. All the procedures for measuring followed the
138
standardized guidelines. The flow chart of this study is shown in Figure 1. A total of 752
139
people (426 for the coal exposure group; 326 for the control group) who had a health
140
check-up and met the inclusion and exclusion criteria during November, 2018 to January,
141
2019 were recruited in the final analysis. To clarify the association between coal burning and
142
the prevalence of atherosclerosis, we also collected the blood samples (two milliliters EDTA
143
anticoagulation blood from each participant), which were used for mRNA analysis.
144
2.2 Indoor air quality monitoring
145
During January 26 to 31, 2019, six households using coal burning for heating and six
14＜
households using central heating were randomly selected to monitor indoor air quality,
147
respectively. The averages of air quality from six households in each group represented the
148
overall indoor pollution (Chen et al. 2017; Huang et al. 2017).The concentrations of PM2.5,
149
SO2, and CO in the living room were measured. An aerosol detector DUSTTRAKTM
150
II-Model 8530 (TSI Instrument, Shoreview, MN) was used to monitor the concentrations of
151
indoor PM2.5. The indoor concentration of CO was measured by portable automatic carbon
152
monoxide monitor (JXC-3810A; Beijing Jinxincheng Technology Co., Ltd, China) according
153
to the manufacturer’s protocols. Atmospheric sampler (TW-2000, Qingdao Tuowei Intelligent
154
Instrument Co., Ltd. China) was used to collect the air samples at the air flow of 5 L/min for
155
24h which then was analyzed for SO2 concentration by the method of Formaldehyde Buffer
15＜
Solution Absorption-Pararosaniline Spectrophotometry according to the manufacturer’s
157
protocols. All the air quality monitors were located in the center of the living rooms in the
158
non-coal burning group whereas 1 meter from the coal-stove in the coal-burning group. There
159
were 0.5 meters from the wall, and 1 meter from the window and door. The height was 1
1＜0
meter. Sampling for 24 hours continuously, and then calculated the average concentration per
1＜1
hour (1-h average concentration). The protocols were according to Technical Specifications
1＜2
for Monitoring of Indoor Air Quality (State Environmental Protection Administration of
1＜3
China, 2004).
1＜4
2.3 mRNA analysis
1＜5
We measured expression of IL-8, CRP, TNF-α and SAA1 mRNAs, which were related to
1＜＜
the pathogenesis of atherosclerosis. Briefly, total RNA was extracted using an RNApure
1＜7
Blood Kit (CWBIO) immediately from whole blood according to the manufacturer’s
1＜8
protocols and stored at −80°C. Complementary DNA was synthesized by M-MLV reverse
1＜9
transcription (Promega, USA) using total RNA. The RT reaction was conducted at 65°C for 5
170
minutes, followed by 60 minutes at 45°C and 5 minutes at 70°C. Then, the products were
171
stored at −20°C for later use. The RT mixtures were then subjected to qPCR reactions. The
172
qPCR analysis and data collection were performed on a LineGene9600 qPCR system. The
173
reaction conditions were as follows: 10 minutes at 95 °C, then 45 cycles were performed
174
( each cycle was at 95 °C for 30 seconds), annealing temperatures of 60 °C for 45 seconds
175
and then 72 °C for 30 seconds. The relative expression of each gene of interest was
17＜
normalized to the relative expression of GAPDH. The data were analyzed using the 2-△△Ct.
177
2.4 Statistical analysis
178
Descriptive analyses were used to evaluate the demographic characteristics. Univariate
179
analyses were used to test the differences of the sex, age, BMI, SBP, DBP, cholesterol,
180
triglyceride and life characteristics between the two groups, respectively. The Student's t-test
181
or Mann-Whitney U test (if the variables were not normality or homogeneity) were used to
182
test continuous variables, and categorical variables were analyzed by the chi-squared test. We
183
applied unconditional logistic regression models to evaluate the association between coal
184
exposure and carotid atherosclerosis, and multiple linear regressions models were used to
185
analyze the expression of IL-8, CRP, TNF-α, SAA1 mRNAs. Model 1 was not adjusted by
18＜
any variable. Model 2 was adjusted by variables including age, sex, BMI, SBP, DBP,
187
cholesterol and triglyceride. Model 3 was adjusted by all the variables in model 2 plus
188
lifestyles (smoking status, alcohol drinking status and dietary). We recognized model 3 as the
189
primary model of interest after compared (Table S1). The inclusion of covariates were based
190
on univariate analysis to select the statistically significant factors (P
191
analysis by smoking, drinking status and age and interaction analysis were used to eliminate
192
the effects of confounding factors. Subgroup analyses were conducted through stratification
193
by age (≤45, 45-65, >65 years), sex (male or female), smoking, and drinking (yes or no).
194
Body mass index (BMI) was calculated by weight divided by height square. In addition,
195
sensitivity analyses were conducted to further evaluate the confounding factors. Sensitivity
19＜
analysis was used to adjust for job, education and family history.
197
0.05). Specified
All analyses were performed using software IBM SPSS Statistics 22, and the statistical
198
significance was set at P 0.05 based on a two-tailed calculation.
199
3. Results
200
3.1 The characteristics of the participants
201
The characteristics of the enrolled population were shown in Table 1. The average ages
202
were 55.64±10.13 and 53.32±12.5 years old In the coal-burning and control group,
203
respectively. And the average SBPs were 142.82±19.85 and 138.12±18.58 mmHg, in the two
204
groups, respectively. Compared with the control, the average age and SBP were statistically
205
higher in the coal burning exposure group (P 0.05). Among the total of 426 in coal burning
20＜
exposure group, there was 259 people (60.8%) suffering from the carotid atherosclerosis,
207
whereas 172 in 326 people (52.8%) from the control group. The prevalence of carotid
208
atherosclerosis in the coal exposure group was statistically higher than that in the control
209
group (P 0.05). There were no significant differences in sex, BMI, cholesterol, triglyceride,
210
smoking, drinking status and diet habits between the control and coal burning exposure
211
groups.
212
3.2 Multivariate analyses for the risk factors of atherosclerosis
213
Smoking, age and drinking are major confounders for atherosclerosis developing. Therefore
214
the stratification was used to test for differences in atherosclerosis. The coal burning group
215
had higher prevalence of atherosclerosis than that in the control group among smokers
21＜
(P=0.006) but not found difference among non-smokers. Among people less than 45 years old,
217
the coal burning exposure had higher prevalence of atherosclerosis compared with the control
218
group (P=0.006). The coal burning group had higher prevalence of atherosclerosis than that in
219
the control group among drinkers (P=0.012) but not among non-drinkers. However, there
220
were no interactions between coal exposure and smoking (P=0.121), drinking (P=0.051) as
221
well as age (P=0.289), respectively (Table 2). Generally, smokers tend to alcohol uses
222
compared with nonsmokers. We tested the interaction between smoking and drinking to
223
identify whether the effect from alcohol uses was independent or due to the effect of smoking.
224
After analyzed by logistic regression, the interaction effect of smoking*drinking statistical
225
value was 0.288, and P-value was 0.591. This data suggested that the effect from alcohol uses
22＜
was independent (Table S2).
227
Fig.2 presented the association of coal burning exposure with the risk of carotid
228
atherosclerosis events after adjusting for sex, age, smoking, alcohol drinking, BMI, SBP, DBP,
229
cholesterol, triglyceride and dietary. People in the coal exposure group had a 43.4% higher
230
risk of carotid atherosclerosis compared with the control group (risk ratio [RR], 1.434; 95%
231
confidence interval [95%CI], 1.063 to 1.934; P=0.018). After stratified by smoking, in the
232
smoking people, the risk of carotid atherosclerosis was 111.8% higher in the coal exposure
233
group than that in the control group (RR, 2.118; 95%CI, 1.093 to 4.106), and the trend
234
remained significant (P =0.026). The drinking-specific analysis showed that the risk of
235
carotid atherosclerosis in the coal exposure group was higher than that in the control group
23＜
(RR, 2.380; 95%CI, 1.253 to 4.522; P=0.008). People less than 45 years old in the coal
237
exposure group were proneness to carotid atherosclerosis than those in the control group (RR,
238
4.206; 95%CI, 1.512 to 11.700; P=0.006). A similar but non-significant association was
239
observed in other sub-groups.
240
3.3 The levels of indoor air pollutants
241
Fig.3 showed the mean concentrations of PM2.5, CO and SO2 in the coal exposure group
242
were higher significantly than those in the control group, respectively (all P <0.05). During
243
the monitoring time, in the coal burning exposure group, the median (minimum-maximum)
244
concentrations of PM2.5, CO, and SO2 were 87.0 (77-112) µg/m3, 7.2 (4.3-8.7) mg/m3,
245
191.5 (125.0-320.0) µg/m3, whereas, 17.5 (12-15) µg/m3, 0.80 (0.70-1.20) mg/m3, 26.0
24＜
(19.0-35.0) µg/m3 in the control group, respectively.
247
3.4 The mRNAs expression of IL-8, CRP, TNF-α, SAA1 in whole blood
248
The IL-8, CRP, TNF-α, SAA1 mRNAs levels in whole blood were statistically higher in
249
the coal exposure group than those in the control group, respectively (P <0.05) Table 3 .
250
Compared with the control, the levels of IL-8, CRP, TNF-α, SAA1 mRNAs in the coal
251
burning group were 1.47-, 1.31-, 1.24- and 1.27-fold increases, respectively.
252
3.5 The multiple regression analysis for the mRNAs expression of inflammatory cytokines
253
The multiple regression analysis of age, BMI, smoking, alcohol drinking, DBP, SBP and
254
coal exposure on mRNAs expression of inflammatory cytokines was shown in Table 4. There
255
was a statistical association between coal burning exposure and the expression of IL-8, CRP
25＜
and TNF-α mRNAs (P<0.05). No significant associations were observed between other
257
factors and the mRNAs expression.
258
3.6 Sensitivity analyses
259 2＜0
Sensitivity analyses did not produce substantively different results, in which there was little change in point estimates in models adjusted for job and education levels (Table S1).
2＜1 2＜2
Discussion
2＜3
In recent years, there are mounting studies exploring the long-term effects of exposure to
2＜4
air pollution on cardiovascular diseases. A recent findings indicated each 10 µg/m3 increment
2＜5
of PM2.5 concentration could increase 11% risk of hypertension (hazard ratio, 1.11; 95% CI,
2＜＜
1.05-1.17) (Huang et al. 2019). SO2 and CO could increase the risk of cardiovascular diseases
2＜7
(Liu et al. 2018), which are in line with the results in the present study. In the present study,
2＜8
our data showed that indoor air pollutants (PM2.5, CO, SO2) had a very high concentration in
2＜9
coal burning rooms compared with the control, which positive associated with the increased
270
risk of carotid atherosclerosis. A previous study suggested the accumulation of primary
271
emissions by coal combustion was responsible for the increasing air pollution in winter (Xie
272
et al. 2019), which might be a major contributor to the cardiovascular disease. In animal study,
273
emissions induced by coal burning contributed to the progression of atherosclerosis (Chen et
274
al. 2013). In the present study, our data indicated that coal burning increase 43.4% (RR: 1.434,
275
95CI%:1.063-1.934) risk of carotid atherosclerosis.
27＜
The previous studies identified long-term exposure to air pollutants could accelerate the
277
progression of atherosclerosis (Duan et al. 2019; Tonne et al. 2017). PM2.5 and gaseous
278
pollutants contributed to the progression of atherosclerosis (Bai et al. 2016; Wang et al. 2019).
279
However, the various sources of air pollutants, such as traffic exhaust, industrial emission and
280
coal combustion, induced the different adverse health effects. A 1 µg/m3 rise in PM2.5
281
increased 1% carotid intima media thickness (CIMT) (Tonne et al. 2017). In the present study,
282
we found 73.13 µg/m3 of PM2.5 increased in the coal burning indoors contrast to the non-coal
283
burning, which might be the reason to explain in the higher prevalence of atherosclerosis in
284
the coal burning group, at least partly.
285
Additionally, smoking and alcohol use were usually recognized as atherosclerosis risk
28＜
factors (Britton et al. 2017; Erhardt 2009). In the present study, we found a stronger
287
association between coal burning and atherosclerosis progression in smokers and drinkers,
288
suggesting coal burning pollutants as synergistic factors with cigarette and alcohol use.
289
However, previous study found that traffic-related air pollution could increase the risk of
290
atherosclerosis in never smoker (RR=1.10, 95%CI, 1.03 to 1.17) and non-alcohol users RR
291
=1.09, 95%CI, 1.01 to 1.17
292
literature and the present study might contribute to the different sources of air pollutants.
293
Previous epidemiologic studies (Mackinnon et al. 2004; Olmastroni et al. 2019) demonstrated
294
that there had been higher risk of atherosclerosis in the aged. Interestingly, our data suggested
295
that long-term exposed to pollutants derived from coal burning could increase the risk of
29＜
atherosclerosis among individuals younger than 45 years old. Our findings are consistent with
297
the conclusion of the Heinz Nixdorf Recall (HNR) Study, which confirmed that the
298
association between PM2.5 and atherosclerosis was stronger in younger (<60 years old) (RR,
299
5.9; 95%CI, 3.0 to 9.0) (Bauer et al. 2010). A recent epidemiological study (Andersson et al.
300
2018) reported that cardiovascular disease incidence tended to increase among younger
301
individuals (aged 18 to 50 years old) in the past 2 decades, owing to the obesity, poor diet,
302
and physical inactivity but air pollution analysis was absent. In the present study, coal
303
combustion-derived pollutants could increase the risk of atherosclerosis in younger, which
304
might partly explain the reasons that the trend of cardiovascular diseases incidence was
305
increasing in young population.
(Wang et al. 2016). The conflict conclusion between the
30＜
Consisted with the previous study (Yu et al. 2019), levels of cytokines in whole blood of
307
coal burning group were significantly increased which symbolized systemic inflammation and
308
then involved in the pathophysiology of carotid atherosclerosis. The increases of TNF-α, IL-6,
309
IL-8 and CRP in serum had been shown to be triggered the initiation and progress of
310
atherosclerosis (Ramji et al. 2015; Soeki et al. 2016; De Buck et al. 2016). In the present
311
study, a strong positive association between coal burning exposure and the TNF-α, IL-8, and
312
CRP mRNAs expression had been confirmed. In animals experiment, coal burning emissions
313
also strongly associated with the elevation of airway and serum inflammatory cytokines levels
314
(Gasparotto et al. 2018; Yu et al. 2019). After adjusted for important confounders, including
315
sex, age, BMI, smoking, and drinking habit, multiple linear regression analyses still showed a
31＜
positive association between coal burning exposure and elevation of inflammatory cytokines
317
levels. Another study reported that long-term exposure to traffic-related air pollution
318
increased the levels of serum inflammatory cytokines in children (Gruzieva et al. 2017).
319
Systematic inflammatory cytokines had adverse effects on atherosclerotic plaque through the
320
injury of endothelial function, and then promoted the development of atherosclerosis (Bai et
321
al. 2016).
322
This study had apparent advantages. First, to our knowledge, it is first time to evaluate
323
the association between coal burning exposure and the risk of carotid atherosclerosis. Second,
324
the study was based on population, which enhanced the evidence of coal burning emissions
325
associated with atherosclerosis. Third, the link of inflammatory markers with coal exposure
32＜
could provide strong evidences of causality between diseases and exposure.
327
This study also had some limitations. First, the cross-sectional study provided the weak
328
evidences of causality compared with the cohort study. Therefore, we will conduct a cohort
329
study to evaluate the association of coal burning and atherosclerosis. Second, the indoor air
330
pollutants were measured in those which households were randomly selected but not the
331
personal environmental parameters. Third, the unmeasured covariate data (e.g. outdoor air
332
pollution exposure levels) might be the confounding factors. Fourthly, the overall association
333
between coal exposure and atherosclerosis relevance was driven by subgroup of smokers and
334
young adults whose population sizes were small compared to the rest of the population. These
335
findings need follow-up study to confirm because of our small size population, but our results
33＜
could provide a clue to a certain extent.
337
In summary, the study showed that long-term exposure to the indoor air pollutants
338
derived from smoky coal combustion for heating and cooking could increase the risk of
339
atherosclerosis and systemic inflammation among rural residents in north of China.
340
Inflammatory cytokines partly provided a potential mechanism of the association between
341
coal exposure and the risk of atherosclerosis. To the extent, our findings provided an
342
epidemiological evidence of the association between long term exposure to coal combustion
343
pollutants and carotid atherosclerosis, especially among the smokers, drinkers and the young
344
people but need follow-up study in large size population. In view of the present findings, we
345
recommend measures to reduce household air pollution from coal burning by switching to
34＜
cleaner fuel options.
347 348 349
Competing interests The authors declare that they have no competing interests.
350
Acknowledgements
351
This work is supported by National Key R&D Program of China (2016YFC0900604),
352
National Natural Science Foundation of China (91643108, 81573190), National Natural
353
Science Foundation of Hebei Province of China (H2015206326) and National Natural
354
Science Foundation of Education Department of Hebei Province of China (ZD2015008).
355
35＜
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Figure legends Fig.1 The selection process of the participants in this study.
Fig.2 Adjusted risk ratios for carotid atherosclerosis (95% confidence interval [CI]) in different subgroups. Data were adjusted for sex, age, smoking status, alcohol drinking status, BMI, SBP, DBP, cholesterol, triglyceride and dietary. Unconditional logistic regression analyses were used to find the differences. Differences were considered significant when P < 0.05.
Fig.3 The 1-h average concentrations of indoor air pollutants in the two groups. PM2.5, particulate matter with aerodynamic diameter less than 2.5 µm; SO2, sulfur oxide; CO, carbon monoxide. Data were represented by median (minimum-maximum) and analyzed by Mann-Whitney U test (n=6).*P＜0.05.
Tables Table 1 Demographic characteristics of the participants
Variables Carotid atherosclerosis, n (%) Yes No Sex, n (%) Male Female Age(years, mean ±SD ) BMI (kg/m2, mean ±SD) SBP (mmHg, mean ±SD) DBP (mmHg, mean ±SD) CHOL(mmol/L, mean ±SD) Triglyceride(mmol/L, mean ±SD) Smoking, n (%) Yes No Drinking, n (%) Yes No Diet, n (%) Bland Sweet Heavy Greasy
Coal exposure group(n=426)
Control group(n=326)
259(60.8) 167(39.2)
172(52.8) 154(47.2)
4.880
0.027a
198(46.5) 228(53.5) 55.64±10.13 26.95±3.62 142.82±19.85 82.08±11.59 4.97±1.02 1.70±1.15
152(46.6) 174(53.4) 53.32±12.5 26.73±3.62 138.12±18.58 80.90±11.15 5.10±1.12 1.85±1.27
0.002
0.968a
-2.730 -0.843 -3.306 -1.401 1.700 1.629
0.007b 0.399b 0.001b 0.162b 0.090b 0.104b
115(27.0) 311(73.0)
72(22.1) 254(77.9)
2.380
0.123a
314(73.7) 112(26.3)
234(71.8) 92(28.2)
0.348
0.555a
223(52.3) 25(5.9) 175(41.1) 3(0.7)
196(60.1) 11(3.4) 114(35.0) 5(1.5)
7.393
0.060a
Statistics P-value
BMI: body mass index calculated by weight/height2; SBP: systolic blood pressure; DBP: diastolic blood pressure; CHOL: serum total cholesterol; aChi square test was used to compare values from both groups.bt-test was used to compare values from both groups. Differences were considered significant when P < 0.05.
Table 2
Prevalence of carotid atherosclerosis stratified by smoking, drinking, age Control group(n=326)
Parameters
Coal-exposed group(n=426)
Atherosclerosis yes
Smoking, n (%) Yes No Age, n (%) ＜45 45-65 >65 Drinking, n (%) Yes No
Atherosclerosis
P-value
Pinteraction
0.121b
no
yes
no
31 141
41 113
73 186
42 125
0.006a 0.304a
14
64
21
32
0.006a
111
81
161
122
0.842a
47
9
77
13
0.789a
43
49
72
40
0.012a
129
105
187
127
0.300a
0.051b
0.289b
Stratified by smoking status, drinking status and age. a Chi square test was used to compare values from both groups. b interaction effect of coal exposure and smoking, drinking, age was analyzed. Differences were considered significant when P < 0.05
Table 3 The IL-8, CRP, TNF-α and SAA1 mRNA levels in whole blood mRNA
Coal exposure
Control group
group (n=426)
(n=326)
Statistics
P-value
IL-8
1.008±0.770
0.684±0.506
-2.525
0.013
CRP
1.600±1.012
1.222±0.411
-2.444
0.016
TNF-α
1.952±0.757
1.573±0.563
-2.899
0.005
SAA1
1.551±1.017
1.224±0.404
-2.131
0.035
t-test was used to compare values from both groups. Differences were considered significant when P < 0.05.
Table 4 Multiple regression analysis (regression coefficient and 95% CI) of age, BMI, smoking, alcohol drinking, coal exposure and gene expression Parameters Coal exposure
IL-8
CRP
TNF-α
SAA1
0.24(0.06-0.58)
0.37(0.050.70)*
0.41(0.14-0.67)**
0.25(-0.06-0.56)
Age
-0.24(-0.51-0.03)
-0.00(-0.33-0.33)
-0.30(-0.57-0.02)
-0.20(-0.52-0.12)
BMI
0.01(-0.00-0.02)
0.00(-0.05-0.05)
-0.00(-0.04-0.04)
0.04(-0.04-0.09)
SBP
0.01(-0.03-0.00)
0.00(-0.01-0.02)
0.00(-0.01-0.01)
0.03(-0.01-0.02)
DBP
-0.01(-0.03- 0.05)
-0.00(-0.02-0.02)
-0.00(-0.02-0.01)
-0.03(-0.05-0.01)
Smoking
-0.07(-0.40- 0.27)
0.05(-0.36-0.46)
-0.07(-0.40-0.27)
0.26(-0.13-0.66)
Drinking
-0.14(-0.41- 0.14)
-0.01(-0.35-0.33)
0.20(-0.08-0.48)
-0.09(-0.05-0.01)
*P＜0.05; **P＜0.01
HIGHLIGHTS 1. Smoky coal burning exposure could increase the risk of carotid atherosclerosis. 2. The indoor air pollutants levels in coal burning room far exceeded the control. 3. The inflammatory cytokines levels elevated in participants of coal exposure group.
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
S0269-7491(19)33573-0
DOI:
https://doi.org/10.1016/j.envpol.2019.113320
Reference:
ENPO 113320
To appear in:
Environmental Pollution
Received Date: 8 July 2019 Revised Date:
12 August 2019
Accepted Date: 27 September 2019
Please cite this article as: Pang, Y., Zhang, B., Xing, D., Shang, J., Chen, F., Kang, H., Chu, C., Li, B., Wang, J., Zhou, L., Su, X., Han, B., Ning, J., Li, P., Ma, S., Su, D., Zhang, R., Niu, Y., Increased risk of carotid atherosclerosis for long-term exposure to indoor coal-burning pollution in rural area, Hebei Province, China, Environmental Pollution (2019), doi: https://doi.org/10.1016/j.envpol.2019.113320. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
1 2 3
Increased risk of carotid atherosclerosis for long-term exposure to indoor Coal-burning pollution in rural area, Hebei Province, China
4
Yaxian Panga, Boyuan Zhanga, Dongmei Xingb, Jinmei Shangb, Fengge Chenc, Hui Kangd,
5
Chen Chua, Binghua Lid, Juan Wangb, Lixiao Zhoua, Xuan Sua, Bin Hana, Jie Ninga, Peiyuan
＜
Lia, Shitao Mad, Dong Sud, Rong Zhanga,e*, Yujie Niud,e*
7
a Department of Toxicology, School of Public Health, Hebei Medical University,
8 9 10
Shijiazhuang 050017, PR China. b Department of internal Medicine-Cardiovascular, Nangong Jinan Great Wall Hospital, Nangong 051800, PR China.
11
c Shijiazhuang Center for Disease Control and Prevention, Shijiazhuang 050000, PR China.
12
d Deportment occupational Health and Environmental Health, School of Public Health, Hebei
13 14 15
Medical University, Shijiazhuang 050017, PR China e Hebei Key Laboratory of Environment and Human Health, Shijiazhuang 050017, PR China.
1＜ 17
* Corresponding authors
18
CORRESPONDENCE:
Rong Zhang
19
Dept. Toxicology
20
Hebei Medical University
21
361 Zhongshan east Rd.
22
Shijiazhuang, Hebei 050017
23
fax: 86-311-86265605
24 25
Email: [email protected]
2＜
Abstract
27
Smoky coal burning is a predominant manner for heating and cooking in most rural areas,
28
China. Air pollution is associated with the risk of atherosclerosis, however, the link between
29
indoor air pollution induced by smoky coal burning and atherosclerosis is not very clear.
30
Therefore, we designed a cross-sectional study to evaluate the association of long-term
31
exposure to smoky coal burning pollutants with the risk of atherosclerosis. 426 and 326
32
participants were recruited from Nangong, China and assigned as the coal exposure and
33
control group according to their heating and cooking way, respectively. The indoor air quality
34
(PM2.5, CO, SO2) was monitored. The association between coal burning exposure and the
35
prevalence of atherosclerosis was evaluated by unconditional logistic regression analysis,
3＜
adjusted for confounding factors. The inflammatory cytokines mRNAs (IL-8, SAA1, TNF-α,
37
CRP) expression in whole blood were examined by qPCR. People in the coal exposure group
38
had a higher risk of carotid atherosclerosis compared with the control (risk ratio [RR], 1.434;
39
95% confidence interval [95%CI], 1.063 to 1.934; P=0.018). The association was stronger in
40
smokers, drinkers and younger (<45 years old) individuals. The elevation of IL-8 (0.24,
41
95%CI, 0.06-0.58; P<0.05), CRP (0.37, 95%CI, 0.05-0.70; P<0.05), TNF-α (0.41, 95%CI,
42
0.14-0.67; P<0.01) mRNAs expression in whole blood positively were related with coal
43
exposure. Our results suggested long-term exposure to smoky coal burning emissions could
44
increase the risk of carotid atherosclerosis. The potential mechanism might relate that coal
45
burning emissions exposure induced inflammatory cytokines elevation which had adverse
4＜
effects on atherosclerotic plaque, and then promoted the development of atherosclerosis.
47 48 49 50
Capsule: Long-term exposure to coal combustion could increase the risk of carotid
51
atherosclerosis: a cross-sectional study in rural area, China.
52
Key Words:
53
inflammatory cytokines.
54 55
smoky coal burning; carotid atherosclerosis; indoor air pollution;
5＜
1. Introduction
57
The Global Burden of Disease 2015 study identified household air pollution from solid
58
fuel use (coal, wood, charcoal, dung, and agricultural residues) as the eighth contributors to
59
global disability-adjusted life-years (DALYs), which induced 85.6 million people lost health-
＜0
life-years (Forouzanfar et al. 2016). There was usually bulk-burning smoky coal burning for
＜1
heating in winter in the rural areas of northern China (Li et al. 2018; Li et al. 2019; Seow et al.
＜2
2016). The smoky coal-burning can produce fine particulate matter (PM), carbon monoxide
＜3
(CO), sulfur oxide (SO2), nitrogen dioxide (NO2), polyromantic hydrocarbons (PAHs) which
＜4
bring about problems of environment (Secrest et al. 2017), especially the high levels of indoor
＜5
air pollution (Ni et al. 2016; Seow et al. 2016).
＜＜
Previous studies demonstrated that coal burning for cooking and heating contributed to
＜7
the excess all-cause mortality, especially respiratory diseases (asthma, chronic obstructive
＜8
pulmonary disease and lung cancer)(Chan et al. 2019; Seow et al. 2014) and cardiovascular
＜9
diseases (ischemic heart disease, myocardial infarction, stroke ) (Kim et al. 2016). The toxic
70
emissions produced by the solid fuels including coal have been recognized as contributors to
71
the increasing risk of cardiovascular disease (Mitter et al. 2016). Evidence suggested coal
72
burning was associated with increased risks of supraventricular premature beat, premature
73
ventricular contraction and ventricular tachycardia (Feng et al. 2019).
74
Carotid atherosclerosis is a form of chronic vascular inflammation, and a leading cause of
75
acute coronary syndrome and loss of productive life years (Libby et al. 2011; Soeki et al.
7＜
2016). The rural population detection rate of carotid atherosclerotic lesions was 76.3% in
77
Shanxi province, China, which were comparable to the rate the national population (Li et al.
78
2016). Recent study identified ambient air pollution was a contributor to the acceleration of
79
atherosclerosis (Wang et al. 2019). Long-term exposure to the indoor pollutants caused by
80
biomass fuels (such as wood and straw) was associated with an increasing risk of
81
atherosclerotic plaques (Painschab et al. 2013). Pollutants from biomass burning mainly
82
included PM (mostly composed of organic carbon), volatile organic compounds (VOCs), CO
83
and PAHs (Chen et al. 2017). However, the primary emissions produced by coal burning were
84
characterized by SO2, and harmful elements (e.g. F, Hg, As) apart from the toxic pollutants
85
PM, VOCs, CO, PAHs
(Krumal et al. 2019).The different components of pollutants
8＜
emitted by the two fuels could contribute to different health effects. Though literature
87
demonstrated that coal burning was associated with excess cardiovascular mortality (Yu et al.
88
2018), the evidences of association between indoor air pollution by coal combustion and
89
atherosclerosis still limited. Finding the association between coal-burning indoor and the risk
90
of atherosclerosis could provide a clue to prevent the high prevalence of carotid
91
atherosclerotic lesions and cardiovascular disease.
92
The study of mechanism could provide strong evidences of causality between diseases
93
and exposure. Studies had demonstrated that carotid atherosclerosis was a chronic
94
inflammatory disease (Fredman et al. 2017; MY Wu et al. 2017). Inflammatory responses
95
play a crucial role in beginning with endothelial dysfunction and continue in each stage of the
9＜
atherosclerotic development (Ramji et al. 2015). C-reactive protein (CRP) and amyloid A
97
(SAA), usually served as markers of systemic inflammation, had been found increase in
98
patients with atherosclerosis and used to predict the risk of the disease cardiovascular events
99
(Rifai et al. 1999). SAA was also a participant in the early atherosclerotic development (Getz
100
et al. 2016). Interleukin (IL)-8 was a chemokine produced at inflammatory sites, which
101
promoted the development of carotid atherosclerosis .Tumor necrosis factor (TNF)-α was an
102
inflammatory cytokine, symbolized by the activation of M1 macrophages, which involved in
103
plaque destabilization and rupture (Soeki et al. 2016; Stancel et al. 2016; MY Wu et al. 2017).
104
PM and gaseous air pollutants (SO2, CO) released by coal combustion could induce
105
inflammatory events (Lawal 2017; XM Wu et al. 2017). Therefore, it was hypothesis that coal
10＜
burning triggered the inflammatory reactions and then developed the initiation and progress of
107
carotid atherosclerosis.
108
In the present study, we designed a cross-sectional study based on a Rural Health Project
109
(RHP), which help the local residents to check up health and conducted in the Jinan Great
110
Wall Hospital, in Nangong County, Hebei Province, North China. The local rural dwellers
111
mainly cook and heat the rooms with traditional open-fire stove and the smoky coal is used as
112
the mainly fuel. In contrast, city dwellers cook mainly with clean fuels (e.g. natural gas and
113
electricity) and the heating method is predominantly central heating in winter. Here, we
114
enrolled the local long-term residents with or without smoky coal for cooking and heating.
115
The association of carotid atherosclerosis with coal burning was evaluated. Our study could
11＜
provide the evidences to explain atherosclerosis etiology, at least partly, and to make the
117
public policy for limiting the coal combustion and turning to the clean energy.
118
2. Methods
119
2.1 Study design and setting
120
We designed a geospatial, population-based cross-sectional study. This study protocol
121
was approved by the Institutional Review Board of Hebei Medical University. All participants
122
provided written informed consent at enrollment. We collected the information of the
123
participants in the RHP from November, 2018 to January, 2019. The inclusion criteria were as
124
follows: 1. Age ranging from 25 to 80 years old; 2. Not suffering from coronary heart disease,
125
stroke, diabetes, kidney diseases, tumor, and surgery. The participants who had incomplete
12＜
information for covariates were excluded. We issued questionnaires to the participants
127
enrolled in the present study. The questionnaire included items about cigarette smoking,
128
alcohol consumption, dietary, cooking and heating methods.
129
For coal burning exposure group, smoky coal combustion was used to heat and cook in
130
the living rooms in winter and never changed these methods of heating and cooking. The total
131
exposure time was equal to age and about 3 months per year in winter. Central heating and
132
cooking with clean fuels (gas and electricity) were enrolled in the control group. The
133
diagnosis of carotid atherosclerosis is according to the carotid ultrasound results: the carotid
134
artery intima-media thickness>1.5 mm or focal wall thickening that protruded into the
135
lumen >0.5 mm or >50% was defined as atherosclerosis (Stein et al. 2008). The height, body
13＜
weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), cholesterol and
137
triglyceride were examined and recorded. All the procedures for measuring followed the
138
standardized guidelines. The flow chart of this study is shown in Figure 1. A total of 752
139
people (426 for the coal exposure group; 326 for the control group) who had a health
140
check-up and met the inclusion and exclusion criteria during November, 2018 to January,
141
2019 were recruited in the final analysis. To clarify the association between coal burning and
142
the prevalence of atherosclerosis, we also collected the blood samples (two milliliters EDTA
143
anticoagulation blood from each participant), which were used for mRNA analysis.
144
2.2 Indoor air quality monitoring
145
During January 26 to 31, 2019, six households using coal burning for heating and six
14＜
households using central heating were randomly selected to monitor indoor air quality,
147
respectively. The averages of air quality from six households in each group represented the
148
overall indoor pollution (Chen et al. 2017; Huang et al. 2017).The concentrations of PM2.5,
149
SO2, and CO in the living room were measured. An aerosol detector DUSTTRAKTM
150
II-Model 8530 (TSI Instrument, Shoreview, MN) was used to monitor the concentrations of
151
indoor PM2.5. The indoor concentration of CO was measured by portable automatic carbon
152
monoxide monitor (JXC-3810A; Beijing Jinxincheng Technology Co., Ltd, China) according
153
to the manufacturer’s protocols. Atmospheric sampler (TW-2000, Qingdao Tuowei Intelligent
154
Instrument Co., Ltd. China) was used to collect the air samples at the air flow of 5 L/min for
155
24h which then was analyzed for SO2 concentration by the method of Formaldehyde Buffer
15＜
Solution Absorption-Pararosaniline Spectrophotometry according to the manufacturer’s
157
protocols. All the air quality monitors were located in the center of the living rooms in the
158
non-coal burning group whereas 1 meter from the coal-stove in the coal-burning group. There
159
were 0.5 meters from the wall, and 1 meter from the window and door. The height was 1
1＜0
meter. Sampling for 24 hours continuously, and then calculated the average concentration per
1＜1
hour (1-h average concentration). The protocols were according to Technical Specifications
1＜2
for Monitoring of Indoor Air Quality (State Environmental Protection Administration of
1＜3
China, 2004).
1＜4
2.3 mRNA analysis
1＜5
We measured expression of IL-8, CRP, TNF-α and SAA1 mRNAs, which were related to
1＜＜
the pathogenesis of atherosclerosis. Briefly, total RNA was extracted using an RNApure
1＜7
Blood Kit (CWBIO) immediately from whole blood according to the manufacturer’s
1＜8
protocols and stored at −80°C. Complementary DNA was synthesized by M-MLV reverse
1＜9
transcription (Promega, USA) using total RNA. The RT reaction was conducted at 65°C for 5
170
minutes, followed by 60 minutes at 45°C and 5 minutes at 70°C. Then, the products were
171
stored at −20°C for later use. The RT mixtures were then subjected to qPCR reactions. The
172
qPCR analysis and data collection were performed on a LineGene9600 qPCR system. The
173
reaction conditions were as follows: 10 minutes at 95 °C, then 45 cycles were performed
174
( each cycle was at 95 °C for 30 seconds), annealing temperatures of 60 °C for 45 seconds
175
and then 72 °C for 30 seconds. The relative expression of each gene of interest was
17＜
normalized to the relative expression of GAPDH. The data were analyzed using the 2-△△Ct.
177
2.4 Statistical analysis
178
Descriptive analyses were used to evaluate the demographic characteristics. Univariate
179
analyses were used to test the differences of the sex, age, BMI, SBP, DBP, cholesterol,
180
triglyceride and life characteristics between the two groups, respectively. The Student's t-test
181
or Mann-Whitney U test (if the variables were not normality or homogeneity) were used to
182
test continuous variables, and categorical variables were analyzed by the chi-squared test. We
183
applied unconditional logistic regression models to evaluate the association between coal
184
exposure and carotid atherosclerosis, and multiple linear regressions models were used to
185
analyze the expression of IL-8, CRP, TNF-α, SAA1 mRNAs. Model 1 was not adjusted by
18＜
any variable. Model 2 was adjusted by variables including age, sex, BMI, SBP, DBP,
187
cholesterol and triglyceride. Model 3 was adjusted by all the variables in model 2 plus
188
lifestyles (smoking status, alcohol drinking status and dietary). We recognized model 3 as the
189
primary model of interest after compared (Table S1). The inclusion of covariates were based
190
on univariate analysis to select the statistically significant factors (P
191
analysis by smoking, drinking status and age and interaction analysis were used to eliminate
192
the effects of confounding factors. Subgroup analyses were conducted through stratification
193
by age (≤45, 45-65, >65 years), sex (male or female), smoking, and drinking (yes or no).
194
Body mass index (BMI) was calculated by weight divided by height square. In addition,
195
sensitivity analyses were conducted to further evaluate the confounding factors. Sensitivity
19＜
analysis was used to adjust for job, education and family history.
197
0.05). Specified
All analyses were performed using software IBM SPSS Statistics 22, and the statistical
198
significance was set at P 0.05 based on a two-tailed calculation.
199
3. Results
200
3.1 The characteristics of the participants
201
The characteristics of the enrolled population were shown in Table 1. The average ages
202
were 55.64±10.13 and 53.32±12.5 years old In the coal-burning and control group,
203
respectively. And the average SBPs were 142.82±19.85 and 138.12±18.58 mmHg, in the two
204
groups, respectively. Compared with the control, the average age and SBP were statistically
205
higher in the coal burning exposure group (P 0.05). Among the total of 426 in coal burning
20＜
exposure group, there was 259 people (60.8%) suffering from the carotid atherosclerosis,
207
whereas 172 in 326 people (52.8%) from the control group. The prevalence of carotid
208
atherosclerosis in the coal exposure group was statistically higher than that in the control
209
group (P 0.05). There were no significant differences in sex, BMI, cholesterol, triglyceride,
210
smoking, drinking status and diet habits between the control and coal burning exposure
211
groups.
212
3.2 Multivariate analyses for the risk factors of atherosclerosis
213
Smoking, age and drinking are major confounders for atherosclerosis developing. Therefore
214
the stratification was used to test for differences in atherosclerosis. The coal burning group
215
had higher prevalence of atherosclerosis than that in the control group among smokers
21＜
(P=0.006) but not found difference among non-smokers. Among people less than 45 years old,
217
the coal burning exposure had higher prevalence of atherosclerosis compared with the control
218
group (P=0.006). The coal burning group had higher prevalence of atherosclerosis than that in
219
the control group among drinkers (P=0.012) but not among non-drinkers. However, there
220
were no interactions between coal exposure and smoking (P=0.121), drinking (P=0.051) as
221
well as age (P=0.289), respectively (Table 2). Generally, smokers tend to alcohol uses
222
compared with nonsmokers. We tested the interaction between smoking and drinking to
223
identify whether the effect from alcohol uses was independent or due to the effect of smoking.
224
After analyzed by logistic regression, the interaction effect of smoking*drinking statistical
225
value was 0.288, and P-value was 0.591. This data suggested that the effect from alcohol uses
22＜
was independent (Table S2).
227
Fig.2 presented the association of coal burning exposure with the risk of carotid
228
atherosclerosis events after adjusting for sex, age, smoking, alcohol drinking, BMI, SBP, DBP,
229
cholesterol, triglyceride and dietary. People in the coal exposure group had a 43.4% higher
230
risk of carotid atherosclerosis compared with the control group (risk ratio [RR], 1.434; 95%
231
confidence interval [95%CI], 1.063 to 1.934; P=0.018). After stratified by smoking, in the
232
smoking people, the risk of carotid atherosclerosis was 111.8% higher in the coal exposure
233
group than that in the control group (RR, 2.118; 95%CI, 1.093 to 4.106), and the trend
234
remained significant (P =0.026). The drinking-specific analysis showed that the risk of
235
carotid atherosclerosis in the coal exposure group was higher than that in the control group
23＜
(RR, 2.380; 95%CI, 1.253 to 4.522; P=0.008). People less than 45 years old in the coal
237
exposure group were proneness to carotid atherosclerosis than those in the control group (RR,
238
4.206; 95%CI, 1.512 to 11.700; P=0.006). A similar but non-significant association was
239
observed in other sub-groups.
240
3.3 The levels of indoor air pollutants
241
Fig.3 showed the mean concentrations of PM2.5, CO and SO2 in the coal exposure group
242
were higher significantly than those in the control group, respectively (all P <0.05). During
243
the monitoring time, in the coal burning exposure group, the median (minimum-maximum)
244
concentrations of PM2.5, CO, and SO2 were 87.0 (77-112) µg/m3, 7.2 (4.3-8.7) mg/m3,
245
191.5 (125.0-320.0) µg/m3, whereas, 17.5 (12-15) µg/m3, 0.80 (0.70-1.20) mg/m3, 26.0
24＜
(19.0-35.0) µg/m3 in the control group, respectively.
247
3.4 The mRNAs expression of IL-8, CRP, TNF-α, SAA1 in whole blood
248
The IL-8, CRP, TNF-α, SAA1 mRNAs levels in whole blood were statistically higher in
249
the coal exposure group than those in the control group, respectively (P <0.05) Table 3 .
250
Compared with the control, the levels of IL-8, CRP, TNF-α, SAA1 mRNAs in the coal
251
burning group were 1.47-, 1.31-, 1.24- and 1.27-fold increases, respectively.
252
3.5 The multiple regression analysis for the mRNAs expression of inflammatory cytokines
253
The multiple regression analysis of age, BMI, smoking, alcohol drinking, DBP, SBP and
254
coal exposure on mRNAs expression of inflammatory cytokines was shown in Table 4. There
255
was a statistical association between coal burning exposure and the expression of IL-8, CRP
25＜
and TNF-α mRNAs (P<0.05). No significant associations were observed between other
257
factors and the mRNAs expression.
258
3.6 Sensitivity analyses
259 2＜0
Sensitivity analyses did not produce substantively different results, in which there was little change in point estimates in models adjusted for job and education levels (Table S1).
2＜1 2＜2
Discussion
2＜3
In recent years, there are mounting studies exploring the long-term effects of exposure to
2＜4
air pollution on cardiovascular diseases. A recent findings indicated each 10 µg/m3 increment
2＜5
of PM2.5 concentration could increase 11% risk of hypertension (hazard ratio, 1.11; 95% CI,
2＜＜
1.05-1.17) (Huang et al. 2019). SO2 and CO could increase the risk of cardiovascular diseases
2＜7
(Liu et al. 2018), which are in line with the results in the present study. In the present study,
2＜8
our data showed that indoor air pollutants (PM2.5, CO, SO2) had a very high concentration in
2＜9
coal burning rooms compared with the control, which positive associated with the increased
270
risk of carotid atherosclerosis. A previous study suggested the accumulation of primary
271
emissions by coal combustion was responsible for the increasing air pollution in winter (Xie
272
et al. 2019), which might be a major contributor to the cardiovascular disease. In animal study,
273
emissions induced by coal burning contributed to the progression of atherosclerosis (Chen et
274
al. 2013). In the present study, our data indicated that coal burning increase 43.4% (RR: 1.434,
275
95CI%:1.063-1.934) risk of carotid atherosclerosis.
27＜
The previous studies identified long-term exposure to air pollutants could accelerate the
277
progression of atherosclerosis (Duan et al. 2019; Tonne et al. 2017). PM2.5 and gaseous
278
pollutants contributed to the progression of atherosclerosis (Bai et al. 2016; Wang et al. 2019).
279
However, the various sources of air pollutants, such as traffic exhaust, industrial emission and
280
coal combustion, induced the different adverse health effects. A 1 µg/m3 rise in PM2.5
281
increased 1% carotid intima media thickness (CIMT) (Tonne et al. 2017). In the present study,
282
we found 73.13 µg/m3 of PM2.5 increased in the coal burning indoors contrast to the non-coal
283
burning, which might be the reason to explain in the higher prevalence of atherosclerosis in
284
the coal burning group, at least partly.
285
Additionally, smoking and alcohol use were usually recognized as atherosclerosis risk
28＜
factors (Britton et al. 2017; Erhardt 2009). In the present study, we found a stronger
287
association between coal burning and atherosclerosis progression in smokers and drinkers,
288
suggesting coal burning pollutants as synergistic factors with cigarette and alcohol use.
289
However, previous study found that traffic-related air pollution could increase the risk of
290
atherosclerosis in never smoker (RR=1.10, 95%CI, 1.03 to 1.17) and non-alcohol users RR
291
=1.09, 95%CI, 1.01 to 1.17
292
literature and the present study might contribute to the different sources of air pollutants.
293
Previous epidemiologic studies (Mackinnon et al. 2004; Olmastroni et al. 2019) demonstrated
294
that there had been higher risk of atherosclerosis in the aged. Interestingly, our data suggested
295
that long-term exposed to pollutants derived from coal burning could increase the risk of
29＜
atherosclerosis among individuals younger than 45 years old. Our findings are consistent with
297
the conclusion of the Heinz Nixdorf Recall (HNR) Study, which confirmed that the
298
association between PM2.5 and atherosclerosis was stronger in younger (<60 years old) (RR,
299
5.9; 95%CI, 3.0 to 9.0) (Bauer et al. 2010). A recent epidemiological study (Andersson et al.
300
2018) reported that cardiovascular disease incidence tended to increase among younger
301
individuals (aged 18 to 50 years old) in the past 2 decades, owing to the obesity, poor diet,
302
and physical inactivity but air pollution analysis was absent. In the present study, coal
303
combustion-derived pollutants could increase the risk of atherosclerosis in younger, which
304
might partly explain the reasons that the trend of cardiovascular diseases incidence was
305
increasing in young population.
(Wang et al. 2016). The conflict conclusion between the
30＜
Consisted with the previous study (Yu et al. 2019), levels of cytokines in whole blood of
307
coal burning group were significantly increased which symbolized systemic inflammation and
308
then involved in the pathophysiology of carotid atherosclerosis. The increases of TNF-α, IL-6,
309
IL-8 and CRP in serum had been shown to be triggered the initiation and progress of
310
atherosclerosis (Ramji et al. 2015; Soeki et al. 2016; De Buck et al. 2016). In the present
311
study, a strong positive association between coal burning exposure and the TNF-α, IL-8, and
312
CRP mRNAs expression had been confirmed. In animals experiment, coal burning emissions
313
also strongly associated with the elevation of airway and serum inflammatory cytokines levels
314
(Gasparotto et al. 2018; Yu et al. 2019). After adjusted for important confounders, including
315
sex, age, BMI, smoking, and drinking habit, multiple linear regression analyses still showed a
31＜
positive association between coal burning exposure and elevation of inflammatory cytokines
317
levels. Another study reported that long-term exposure to traffic-related air pollution
318
increased the levels of serum inflammatory cytokines in children (Gruzieva et al. 2017).
319
Systematic inflammatory cytokines had adverse effects on atherosclerotic plaque through the
320
injury of endothelial function, and then promoted the development of atherosclerosis (Bai et
321
al. 2016).
322
This study had apparent advantages. First, to our knowledge, it is first time to evaluate
323
the association between coal burning exposure and the risk of carotid atherosclerosis. Second,
324
the study was based on population, which enhanced the evidence of coal burning emissions
325
associated with atherosclerosis. Third, the link of inflammatory markers with coal exposure
32＜
could provide strong evidences of causality between diseases and exposure.
327
This study also had some limitations. First, the cross-sectional study provided the weak
328
evidences of causality compared with the cohort study. Therefore, we will conduct a cohort
329
study to evaluate the association of coal burning and atherosclerosis. Second, the indoor air
330
pollutants were measured in those which households were randomly selected but not the
331
personal environmental parameters. Third, the unmeasured covariate data (e.g. outdoor air
332
pollution exposure levels) might be the confounding factors. Fourthly, the overall association
333
between coal exposure and atherosclerosis relevance was driven by subgroup of smokers and
334
young adults whose population sizes were small compared to the rest of the population. These
335
findings need follow-up study to confirm because of our small size population, but our results
33＜
could provide a clue to a certain extent.
337
In summary, the study showed that long-term exposure to the indoor air pollutants
338
derived from smoky coal combustion for heating and cooking could increase the risk of
339
atherosclerosis and systemic inflammation among rural residents in north of China.
340
Inflammatory cytokines partly provided a potential mechanism of the association between
341
coal exposure and the risk of atherosclerosis. To the extent, our findings provided an
342
epidemiological evidence of the association between long term exposure to coal combustion
343
pollutants and carotid atherosclerosis, especially among the smokers, drinkers and the young
344
people but need follow-up study in large size population. In view of the present findings, we
345
recommend measures to reduce household air pollution from coal burning by switching to
34＜
cleaner fuel options.
347 348 349
Competing interests The authors declare that they have no competing interests.
350
Acknowledgements
351
This work is supported by National Key R&D Program of China (2016YFC0900604),
352
National Natural Science Foundation of China (91643108, 81573190), National Natural
353
Science Foundation of Hebei Province of China (H2015206326) and National Natural
354
Science Foundation of Education Department of Hebei Province of China (ZD2015008).
355
35＜
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Figure legends Fig.1 The selection process of the participants in this study.
Fig.2 Adjusted risk ratios for carotid atherosclerosis (95% confidence interval [CI]) in different subgroups. Data were adjusted for sex, age, smoking status, alcohol drinking status, BMI, SBP, DBP, cholesterol, triglyceride and dietary. Unconditional logistic regression analyses were used to find the differences. Differences were considered significant when P < 0.05.
Fig.3 The 1-h average concentrations of indoor air pollutants in the two groups. PM2.5, particulate matter with aerodynamic diameter less than 2.5 µm; SO2, sulfur oxide; CO, carbon monoxide. Data were represented by median (minimum-maximum) and analyzed by Mann-Whitney U test (n=6).*P＜0.05.
Tables Table 1 Demographic characteristics of the participants
Variables Carotid atherosclerosis, n (%) Yes No Sex, n (%) Male Female Age(years, mean ±SD ) BMI (kg/m2, mean ±SD) SBP (mmHg, mean ±SD) DBP (mmHg, mean ±SD) CHOL(mmol/L, mean ±SD) Triglyceride(mmol/L, mean ±SD) Smoking, n (%) Yes No Drinking, n (%) Yes No Diet, n (%) Bland Sweet Heavy Greasy
Coal exposure group(n=426)
Control group(n=326)
259(60.8) 167(39.2)
172(52.8) 154(47.2)
4.880
0.027a
198(46.5) 228(53.5) 55.64±10.13 26.95±3.62 142.82±19.85 82.08±11.59 4.97±1.02 1.70±1.15
152(46.6) 174(53.4) 53.32±12.5 26.73±3.62 138.12±18.58 80.90±11.15 5.10±1.12 1.85±1.27
0.002
0.968a
-2.730 -0.843 -3.306 -1.401 1.700 1.629
0.007b 0.399b 0.001b 0.162b 0.090b 0.104b
115(27.0) 311(73.0)
72(22.1) 254(77.9)
2.380
0.123a
314(73.7) 112(26.3)
234(71.8) 92(28.2)
0.348
0.555a
223(52.3) 25(5.9) 175(41.1) 3(0.7)
196(60.1) 11(3.4) 114(35.0) 5(1.5)
7.393
0.060a
Statistics P-value
BMI: body mass index calculated by weight/height2; SBP: systolic blood pressure; DBP: diastolic blood pressure; CHOL: serum total cholesterol; aChi square test was used to compare values from both groups.bt-test was used to compare values from both groups. Differences were considered significant when P < 0.05.
Table 2
Prevalence of carotid atherosclerosis stratified by smoking, drinking, age Control group(n=326)
Parameters
Coal-exposed group(n=426)
Atherosclerosis yes
Smoking, n (%) Yes No Age, n (%) ＜45 45-65 >65 Drinking, n (%) Yes No
Atherosclerosis
P-value
Pinteraction
0.121b
no
yes
no
31 141
41 113
73 186
42 125
0.006a 0.304a
14
64
21
32
0.006a
111
81
161
122
0.842a
47
9
77
13
0.789a
43
49
72
40
0.012a
129
105
187
127
0.300a
0.051b
0.289b
Stratified by smoking status, drinking status and age. a Chi square test was used to compare values from both groups. b interaction effect of coal exposure and smoking, drinking, age was analyzed. Differences were considered significant when P < 0.05
Table 3 The IL-8, CRP, TNF-α and SAA1 mRNA levels in whole blood mRNA
Coal exposure
Control group
group (n=426)
(n=326)
Statistics
P-value
IL-8
1.008±0.770
0.684±0.506
-2.525
0.013
CRP
1.600±1.012
1.222±0.411
-2.444
0.016
TNF-α
1.952±0.757
1.573±0.563
-2.899
0.005
SAA1
1.551±1.017
1.224±0.404
-2.131
0.035
t-test was used to compare values from both groups. Differences were considered significant when P < 0.05.
Table 4 Multiple regression analysis (regression coefficient and 95% CI) of age, BMI, smoking, alcohol drinking, coal exposure and gene expression Parameters Coal exposure
IL-8
CRP
TNF-α
SAA1
0.24(0.06-0.58)
0.37(0.050.70)*
0.41(0.14-0.67)**
0.25(-0.06-0.56)
Age
-0.24(-0.51-0.03)
-0.00(-0.33-0.33)
-0.30(-0.57-0.02)
-0.20(-0.52-0.12)
BMI
0.01(-0.00-0.02)
0.00(-0.05-0.05)
-0.00(-0.04-0.04)
0.04(-0.04-0.09)
SBP
0.01(-0.03-0.00)
0.00(-0.01-0.02)
0.00(-0.01-0.01)
0.03(-0.01-0.02)
DBP
-0.01(-0.03- 0.05)
-0.00(-0.02-0.02)
-0.00(-0.02-0.01)
-0.03(-0.05-0.01)
Smoking
-0.07(-0.40- 0.27)
0.05(-0.36-0.46)
-0.07(-0.40-0.27)
0.26(-0.13-0.66)
Drinking
-0.14(-0.41- 0.14)
-0.01(-0.35-0.33)
0.20(-0.08-0.48)
-0.09(-0.05-0.01)
*P＜0.05; **P＜0.01
HIGHLIGHTS 1. Smoky coal burning exposure could increase the risk of carotid atherosclerosis. 2. The indoor air pollutants levels in coal burning room far exceeded the control. 3. The inflammatory cytokines levels elevated in participants of coal exposure group.
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: