Progress in Cardiovascular Diseases 53 (2011) 369 378 www.onlinepcd.

com

Progress of Ambient Air Pollution and Cardiovascular Disease Research in Asia

Ta-Chen Sua , Szu-Ying Chenb,c , Chang-Chuan Chanc,
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan b Department of Anesthesiology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan c Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan
a

Abstract

Asian countries are with deteriorating air quality accompanying the rapid economic and social development of the past decades, and the potential health impacts of air pollution have been noticed by researchers in the region. We reviewed the scientific literature on air pollution and cardiovascular diseases (CVD) published by Asian researchers in English since the 1980s to determine whether the findings in Europe and North America can be extrapolated to Asia. Epidemiological studies show that short-term particulate matter pollution is a strong predictor for CVD morbidity and mortality and suggestive on cerebrovascular morbidity and mortality in newly developed countries in Asia. Multicountry epidemiological studies are needed to fully appreciate the extent of air pollution on CVD in Asia, especially less developed Asian countries. New cohort studies should be initiated to improve our understanding of particulate matter's toxicological pathways, long-term exposure effects, and gene-environment interaction on CVD among the Asian population. (Prog Cardiovasc Dis 2011;53:369-378) 2011 Elsevier Inc. All rights reserved.
Cardiovascular disease; Air pollution; Epidemiology; Panel study; Asia

Keywords:

Background: A knowledge gap in environmental cardiology Cardiovascular disease (CVD) is the leading cause of mortality and a major health burden in developed countries and has the same profile in many Asian countries, such as China and India.1 Cardiovascular diseases, cerebrovascular diseases, and cancers are the top 3 causes of death over the past 2 decades in China and Taiwan.2,3 The increasing rate of CVD morbidity and mortality, in particular, has become a major focus of public health policies and epidemiological studies among

The work reported was done from National Taiwan University. Address reprint requests to Chang-Chuan Chan, ScD, Professor, Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Rm. 722, 17 Xu-Zhou Road, Taipei 100, Taiwan. E-mail address: ccchan@ntu.edu.tw (C.-C. Chan).

Asian countries. The causes of CVD are very complex, and disease susceptibility is closely associated with both genetic traits and environmental factors. Environmental cardiology is gaining recognition as an important field to uncover environmental risk factors for CVD and providing useful medical knowledge for both public health practitioners and clinicians in their management of a rising epidemic of CVD worldwide. Environmental epidemiological and panel studies are the 2 most frequently used research types to investigate the relation between air pollution and CVD in environmental cardiology. Numerous epidemiological studies have consistently reported that ambient air pollution, especially particulate matters (PM), is associated with cardiovascular morbidity and mortality in North America and Europe.4-9 The World Health Organization (WHO) published an air quality guideline in 2005, providing detailed information on health riskassociated air pollutants including PM. The American Heart Association (AHA) has also issued 2

0033-0620/$ see front matter 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2010.12.007

369

370

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378

scientific statements on PM air pollution and AHA = American Heart CVD to medical comAssociation munities in 2004 and ADS = Asian dust storms 2010.4,10 Most cardiologists in BP = blood pressure Asia, however, are still CAVI = cardio-ankle vascular not fully aware of such index new findings and have CHF = congestive heart not yet linked ambient failure air pollution to CVD in their clinical practice. CO = carbon monoxide Such a knowledge gap CVD = cardiovascular disease is due, in part, to relatively less research on HF = high frequency this important issue in HRV = heart rate variability the region than the IQR = interquartile range United States and Europe. For example, less LF = low frequency than 10% of studies in NO2 = nitrogen dioxide the 426 references in the AHA Scientific StateO3 = ozone ment of 2010 are from PAPA = Public Health and Asia.4 This is an intriguAir Pollution in Asia ing phenomenon conPM = particulate matters sidering the rapidly worsening air pollution PM10 = particulate matters in many countries in with diameter b10 m Asia. In past decades, PM2.5 = particulate matters Asian countries experiwith diameter b2.5 m enced enormous ecoSDNN = standard deviation of nomic and social normal-beat to normal-beat development, as well as intervals an accompanying rapid increase in industrializaSO2 = sulfur dioxide tion, urbanization, and SPM = suspended particulate motorization. As a rematters sult, some of the highest TSP = total suspended levels of outdoor air particles pollution in the world are found in Asian cities, UFP = ultrafine particle and the health impact of VOC = volatile organic air pollution in this recompound gion has been already estimated to be substanWHO = World Health Organization tial. The WHO cautioned that urban air pollution might contribute to approximately 800,000 deaths and 6.4 million lost lifeyears worldwide in 2000, with two thirds of these losses occurring in rapidly developing Asian countries.11 There is an urgent need to fill the knowledge gap of our understanding of the impact of air pollution on health in Asia, now the region with the worst air pollution in the world. In this article, we will summarize existing evidence associating ambient air pollution with CVD and cerebro-

Abbreviations and Acronyms

A short description of time series, case crossover and panel study Times-series analysis is a statistical approach used to examine associations between air pollution levels (usually daily concentrations measured at fixed monitoring sites) and changes in morbidity or mortality of cardiopulmonary diseases for a study population in several cities or even an entire country over a period (usually several years). It can also be applied to analyze associations between personal air pollution exposures (usually hourly concentrations measured by either fixed monitoring sites or personal samplers) and changes in individual's physiologic functions (eg, blood pressure, heart rate, and heart rate variability) for a group of people (usually in tens to hundreds) over a period (usually days to months). Such analysis can be readily performed in standard statistical packages. Case-crossover is a statistical approach used to examine acute effects (eg, increases in daily mortality or morbidity) of air pollution episodes (eg, dust storm days or unusual high pollution days) for a population (usually the patients covered by the service of hospitals or all residents in cities or entire country) over a period time (usually years). For each study subject, this approach defines the onset time of their illness or death as case periods and the matched time before or after their case periods as the control periods. This method can be regarded as a variant of the traditional case-control design, and hence, conditional logistic regressions can be used to estimate the odds ratios for the study population. Because both case and control components are from the same individuals, the case-crossover design has the advantage of eliminating individual's confounding factors (eg, age, sex, and education level). Panel study is a commonly used study design to investigate the mechanisms of air pollution effects on humans by collecting pollution (usually in seconds to hours) and pathophysiologic data (eg, continuously monitored blood pressure or heart rate variability or periodically measured biomarkers in urine or blood) for a group of study subjects (eg, children, adults, elderly people or patients) and following them up for a period (usually days to months). The collected data can be readily analyzed by either time-series or mixed-effects regression models.

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378

371

vascular diseases in this region. We will also provide an Asian perspective on whether previous study results in the West can be directly extrapolated to our understanding of air pollution on CVD in Asia, which has different spectra of air pollution, population structure, and disease pattern from those in Europe and North America.

Air pollution and exposure in Asia Air pollution in Asia is composed of a mixture of pollutants, including particles and gases emitted in large quantities from many different combustion sources, including cars and industries. Air quality in Asia has deteriorated significantly in recent decades because of rapid industrialization, urbanization, and motorization. According to average air quality levels between 2000 and 2003 summarized by the Clean Air Initiative Network (Fig 1),12 most Asian cities cannot comply with the WHO air quality guidelines or the US Environmental Protection Agency standards; exceptions are cities in more developed countries such as Singapore, Taiwan, and Japan. Several Asian cities in China, India, and Vietnam have the highest levels of outdoor air pollution in the world.

In addition to comparatively higher air pollution levels, Asian countries have specific emission sources that are different from those in the West. Two-stroke vehicles, combustion of lower-quality fuels, and open burning of biomass and solid waste materials together contribute to a larger portion of emissions in many Asian countries. Traffic emission in South Asia is especially different from that in Europe or North America, having the largest motorcycle fleet in the world, under-regulated emission standards of vehicles, and high contents of aromatic hydrocarbons and sulfur in gasoline and diesel oils. The 2-stroke engines of motorcycles are an especially important source of volatile organic compounds (VOCs), carbon monoxide (CO), Nitrogen Oxide (NOx), and PM in Taiwan with 20 million motorcycles. Exposure becomes even worse because of frequent traffic congestion in Asian countries such as China, India, Indonesia, Pakistan, the Philippines, and Thailand. The burning of biomass, including rice straw and garbage as well as forest fire, is also an important emitted source of urban air pollution in South and Southeast Asia. Large cities in this region are often surrounded by agricultural land, and the open burning of agricultural waste may also contribute directly to urban air pollution. The products of biomass burning include CO,

Fig 1. The average ambient air pollution levels in Asian cities between 2000 and 2003. Data from Clean Air Initiative-Asia Network, 2003.

372

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378

carbon dioxide, nitrogen, methane, nonmethane hydrocarbons, methyl chloride, and PM in various size classes.13 In addition, anecdotal emissions from manufacturing mishap can also contribute significant exposures to residents in industrial areas.14 Long-range transported air pollution, such as Asian dust storms (ADS) in north Asia and forest fires in South Asia, account for additional exposure to the residents in the affected countries, such as China, Japan, Korea, Taiwan, Indonesia, Malaysia, Thailand, Singapore, and Vietnam.15

The transitions of population structure, lifestyle, and disease pattern in Asia According to the United Nations, the high-density population in Asia presents a closer exposure to air pollution emissions than their Western counterparts. Asian countries are increasingly urbanized; from 30% to 50% of the population, nearly twice that in North America, live in urban areas now.16 Residents of Asian cities are likely to have higher exposures to air pollution than those in Western nations because of their proximity to the pollution sources of industries, roads, and farms.17 The patterns of morbidity and mortality are also changing in Asian countries, with a transition of lifestyle and diet from a traditional way to a Western pattern and universal increase in life expectancy. Aging is a general demographic trend, with the exception of a still relatively young population in India and Indonesia. A growing consumption of high-fat and high-carbohydrate food among people is occurring because of the rapid expansion of fast-food restaurant chains in the region. People also become more inactive in their daily life because of increasing motorized transport and farming. The prevalence of cancers, CVD, and other noncommunicable diseases are becoming leading causes of diseases and deaths in the region in the past 2 decades.18 Air pollution may interact with such transition in population structure, lifestyle, and disease pattern and, hence, enhance the negative health impacts.

blood pressure (BP) change.19 We do not intend to review all of these studies in this article. Instead, we will focus on epidemiological studies that present key findings about short-term outdoor air pollution effects on CVD morbidity and mortality and those that elucidate the pathophysiologic mechanisms of cardiovascular effects by air pollution in general and PM in specific. Among these studies, time-series and case-crossover designs were commonly used. The time-series design highlights the important component of repeated measurement or longitudinal data in the environmental study. In the case-crossover design, each individual's exposure just before the immediate adverse health event was defined as case component and compared with the same individual's exposure at a referent time (control component).This design is a powerful tool in the evaluation of the association between short-term air pollution exposure and the risk of an immediate adverse health event. Time-invariant confounders are controlled by making within-subject comparisons. In addition, the panel study is also applied to assess the short-term association between air pollution and health outcomes by repeatedly observing the same respondents over time. The panel study is readily appreciated and understood by many practitioners than the longitudinal models. Table 1 summarizes the strength of evidence for cardiovascular and cerebrovascular effects of particulate and gaseous pollutants from all Asian studies reviewed in this article. Current findings for the associations of various cardiovascular and cerebrovascular outcomes and air pollution in Asia are discussed in further detail below. Hospital admissions and emergency department visits for CVD Epidemiological studies consistently demonstrate the effect of short-term air pollution on cardiovascular hospitalization in several Asian countries, including Taiwan, South Korea, Japan, Hong Kong, and China. A time-series study conducted in Seoul, South Korea, found that hospital admission for ischemic heart disease was associated significantly with air pollutants of PM with diameter b10 m (PM10), ozone (O3), CO, nitrogen dioxide (NO2), and sulfur dioxide (SO2).20 It was reported that NO2 and PM10 were associated with daily hospital emergency visits for angina, coronary insufficiency, and myocardial infarction in Tokyo, Japan.21 Studies in Taiwan also showed an excess of emergency department visits for CVD with PM with diameter b2.5 m (PM2.5), PM10, NO2, CO, and O3.22,23 Associations between congestive heart failure (CHF) hospitalization and PM, O3, NO2, and CO were also observed.24,25 One recent report in Taipei found an increase in hospital admission for myocardial infarction with increases in O3 and NO2 concentrations in both warm and cool days.26 Two timeseries studies in Hong Kong showed significant associations between hospital admissions for CVD and air

Evidence for air pollution on cardiovascular effects in Asia More than 400 original epidemiological studies from Asia on health impacts of outdoor air pollution have been published in peer-reviewed English journals since the 1980s; however, more than half of these studies addressed the effects of air pollution on respiratory outcomes. Only about 50 studies evaluated cardiovascular outcomes to short-term air pollution exposure. Of these, nearly 75% were conducted in 4 Asian countries, Japan, South Korea, Taiwan, China, and Hong Kong (China). Only one publication evaluates 1-year air pollution exposure on

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378 Table 1 Summary of evidence for cardiovascular effects of particulate and gaseous pollutants from epidemiological studies in Asia Cardiovascular Outcomes (No. of Studies) Hospital admission for CVD (14) Mortality of CVD (15) Hospital admission for cerebrovascular disease (3) Mortality for cerebrovascular disease (2) Systemic inflammation and thrombosis (2) HRV (5) Cardiac contractility (1) BP (4) Aortic pulse wave velocity (1) TSP +++ + PM10 +++ +++ + + + + + PM2.5 + + + ++ + + + UFPs SO2 +++ +++ + + ++ ++ + + NO2 +++ +++ + + + + + + CO ++ + + + + + O3 +++ ++ + + VOCs +

373

ADS + + +

+ + +

The symbol + represents strength of the evidence based on the number and/or quality, as well as the consistency, of the relevant studies. +++ indicates the strong consistence of overall epidemiological evidence. ++ indicates the moderate consistence of overall epidemiological evidence. + indicates inconsistent or weak epidemiological evidence. Blank indicates lack of evidence.

pollutants of PM10, NO2, O3, and SO2.24,27 There is one study showing that cardiovascular hospital admissions were associated with gaseous pollutants (SO2 and NO2), particularly more evident in the cool season (from November to April) in Shanghai, China.28 These studies confirm the association between increases in cardiovascular hospitalization and short-term PM and gaseous pollutant exposures of less than 1 week. Mortality of CVD An increasing number of epidemiological studies have been independently conducted in several Asian countries, including South Korea, Japan, China, and Taiwan, to document excess risks of daily cardiovascular mortality by short-term air pollution. In South Korea, a study demonstrated that air pollutants of PM10, CO, NO2, SO2, and O3 increased excess mortality in general and for patients with CHF particularly.29 Another study in South Korea showed that PM10 was associated with increases of 4.4% and 6.3% in cardiovascular and cerebrovascular diseases, respectively.30 Multicity studies demonstrated the positive associations between suspended PM (SPM) and cardiovascular mortality in Japan.31,32 Another study in Tokyo, Japan, also found that myocardial infarction deaths were associated with an increased SPM concentrations.33 Studies in China demonstrated an excess risk for cardiovascular mortality by SO2 and total suspended particles (TSP).34,35 There was a significant decline of 2.0% in deaths from CVD after reducing sulfur content in fuel oil in Hong Kong since 1990.36 A study showed cardiovascular mortality was significantly associated with traffic-related air pollutants of NO2 and VOCs including propane, isobutane, and benzene in Taiwan.37 The Public Health and Air Pollution in Asia (PAPA) studies,38-42 which were conducted in Hong Kong, Shanghai, and Wuhan, China, and Bangkok, Thailand, are the first coordinated multicity analyses of air pollution and daily mortality in Asia. These 5 studies provide a

relatively consistent picture of PM's impact on acute cardiovascular mortality in several large metropolitan areas in Asia. The Hong Kong study found significant associations of NO2, SO2, PM10, and O3 with cardiovascular mortality, which was more significant in areas with middle or high social deprivation.38 The Shanghai and Wuhan studies found that PM10, SO2, NO2, and O3 increased cardiovascular mortality.39,40 In Shanghai, the pollution effects were even more evident in the cool season and among females, the elderly, and low educational residents.39 The Bangkok study showed an excess risk for cardiovascular mortality by PM10, with higher risks for subjects older than 65 years.41 This multicity study concluded that a 10-mg/m3 increase in PM10 level was associated with a 0.27% to 1.9% increase in daily rates of cardiovascular mortality.42 It should be mentioned that the effects of the 4 pollutants, PM10, SO2, NO2 and O3, tended to be equal or greater than those identified in studies conducted in the multicity studies in the United States, which have consistently demonstrated the positive associations between short-term PM exposure and cardiovascular mortality ranging from 0.47% to 0.85% per 10 mg/m3 of PM2.5 at a lag 0 to 1 day.43,44 Mortality and hospital admissions for cerebrovascular diseases European studies showed that cerebrovascular diseases were significantly related to short-term exposure to NO2 and PM10.45-47 Acute exposure of PM10, SO2, NO2 and CO was significantly associated with hospital admission for ischemic stroke in 9 US cities.48 Asian studies, however, showed inconsistent associations between air pollution and cerebrovascular diseases. In Seoul, South Korea, SPM, SO2, NO2, CO, and O3 were significantly associated with daily mortality of ischemic stroke in different time lags, but such associations were not observed in hemorrhagic stroke.49 One study in Japan found that PM with diameter b7 m (PM7) increased the

374

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378

risk of death because of intracranial hemorrhage but was not associated with death because of ischemic stroke.50 However, the study in Taiwan found that PM10 and NO2 were significantly associated with admissions for both hemorrhagic and ischemic stroke on warm days.51 The estimated relative risks were 1.54 (95% confidence interval, 1.31-1.81) and 1.56 (95% confidence interval, 1.32-1.84) for primary intracerebral hemorrhage for each interquartile range (IQR) increase in PM10 and NO2. Another study in Taiwan found that O3 lagged 0 day, CO lagged 2 days, and PM2.5 and PM10 lagged 3 days and were significantly associated with increased emergency admissions for cerebrovascular diseases in single-pollutant models but not multipollutant models.52 A Hong Kong study, however, showed negative associations between air pollution and cerebrovascular disease.24 Cerebrovascular disease is one of the leading causes of mortality, especially for East Asian populations, accounting for 10% to 16% of total deaths. The proportions of cerebral hemorrhage, small artery lacunar infarct, and intracranial atherosclerosis are more common in Asian populations than in white populations. There is prominent ethnic difference in cerebrovascular disease between Asian and white populations and diverse impact of air pollution on cerebrovascular diseases among different populations. The findings of the Asian epidemiological studies indicate further investigation is still needed to confirm whether cerebrovascular diseases can be affected by air pollution to the same degree as CVDs. Epidemiological studies on transboundary air pollution Both naturally occurring forest fires and dust storms and man-made coal-fired power plant and biomass burning emit large amounts of SO2, NOx, VOCs, PM, CO, organics, and heavy metals and all contribute to transboundary air pollution in Asia. Among these emission sources, smoke haze caused by land and forest fires seems to be the most common problem in South Asia. Between April and November of 1997, a widespread forest fire in Indonesia threw a blanket of thick, smoky haze over a large portion of Southeast Asia. A time-series study showed persons older than 65 years with previous hospital admissions for cardiorespiratory disease were significantly more likely to be rehospitalized during this event in 1997 than the prefire years of 1995 or 1996.53 Another important cause of transboundary air pollution in the region is the ADS, which originate from the Gobi desert areas in China and Mongolia and affect air quality in China, Hong Kong, Taiwan, South Korea, Japan, and even North America.54 The highest frequency of ADS occurrence is observed during spring (March-May). During ADS events, finer dust particles can be lifted up as high as 1 to 3 km into the atmosphere, remaining for a period of 5 to 10 days, during which they are transported over large distances up to 5000 to 10,000 km, and hence cause air pollution in

the downwind areas. A significant increase in emergency visits for CVD was observed for the 39 high Asian dust events from 1995 to 2002 in Taiwan.55 However, some studies in Taiwan also provided weak evidence that the ADS events are associated with CVD. Two time-series studies estimated the effects of dust storms were increases of 3.65% and 2.59% in excess risks for circulatory and CVD admissions in Taiwan; however, these effects were not statistically significant.56,57 Another time-series study observed a statistically significant association between ADS events and daily intracerebral hemorrhagic admissions 3 days after the event,58 a positive but nonsignificant association with ischemic stroke. A study in South Korea also provided positive but nonstatistically significant evidence that cardiovascular mortality was associated with ADS events during 1995 to 1998.59 Systematic inflammation and thrombosis An increasing number of both human exposure and toxicological studies in Europe and North America have elucidated the effects of PM on systematic inflammation and thrombosis, including multiple biomarkers such as cytokines, tumor necrosis factor-a, highly sensitive C-reactive protein, and coagulation factors,60-62 which are thought to participate in the pathophysiologic mechanisms of atherosclerosis. However, few such evaluations of inflammatory biomarkers response to air pollution were conducted in Asia, except for a few in Taiwan. A study on 23 patients with coronary heart disease and 26 patients with 2 or more cardiovascular risk factors revealed that high air pollution days with PM10 concentration greater than 100 mg/m3 during 8 to 18 hours could increase in plasma levels of plasminogen activator inhibitor-1 compared with that in low PM10 days.63 One panel study on 76 healthy and young adults in Taiwan demonstrated that PM10, PM2.5, and PM components of sulfate and nitrate were associated with increases in highly sensitive Creactive protein, fibrinogen, and plasminogen activator inhibitor-1.64 In this study, 8-hydroxy-2-deoxyguanosine, an oxidative stress marker, was also observed in association with PM fraction size and components.64 Heart rate variability Heart rate variability (HRV) is a noninvasive method and widely used to investigate cardiovascular autonomic control. Heart rate variability can be analyzed in time domain (eg, standard deviation of normal-beat to normalbeat intervals [SDNN] and square root of the mean squared successive normal-beat to normal-beat interval differences [RMSSD]) and frequency domain (eg, high frequency [HF], low frequency [LF], ratio of LF to HF [LF/HF]). Reduced HRV has been demonstrated to be a predictor of increased cardiovascular morbidity and mortality.65,66 A panel study in Taiwan showed with 1to 4-hour moving average number concentration of

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378

375

submicrometer particles with a size range of 0.02 to 1 m (NC0.02-1) was associated with decreases in both time- and frequency-domain HRV indices in 9 healthy subjects.67 This is the first study to examine the effects of personal exposure to ultrafine particles (UFPs) on HRV. Another Taiwanese study also observed an HRV reduction with 1.49% to 4.88% decreases in SDNN and 2.73% to 8.25% decreases in square root of the mean squared successive NN interval differences for an IQR of PM with diameters between 0.3 and 1.0 m (PM0.3-1) in cardiac and hypertensive populations.68 However, neither PM with diameters between 1.0 and 2.5 m (PM1.0-2.5) nor PM with diameters between 2.5 and 10 m (PM2.5-10) replicated the effects of PM0.3-1. The other panel study in Taiwan further found that, in addition to PM2.5, the components of PM2.5, such as sulfate and organic carbon, were associated with HRV reduction in 46 patients with risk for CVD.69 A panel study showed that decreases in SDNN and LF HRV indices in 83 cardiovascular patients were associated with NO2 but not with PM10, CO, O3, or SO2 exposure in Taiwan.70 One Korean study shows that subjects with metabolic syndrome had significant decreases in SDNN and HF with the CO exposure for 25 to 48 hours preceding the HRV measurements.71 Cardiac contractility There are only limited epidemiological studies that demonstrate the associations between air pollutants and cardiac contractility, in part, because of the difficulties in invasive surgical instrumentation of human beings that measure real-time hemodynamic change with short-term air pollution exposure. A population-based study found that the pulse pressure, a surrogate indicator of cardiac stroke volume, narrowed by SO2, CO, O3, PM10, and NO2 at 1- to 3-day lags, indicating a decrease in cardiac contractility with short-term air pollution exposure.72 This study provided some information that cardiac contractility might be altered after short-term air pollution exposure. However, more comprehensive studies are necessary to elucidate potential hemodynamic changes in response to short-term air pollution exposure. Blood pressure A panel study in Taiwan found that with 1 to 3 hour of NC0.02-1 exposure, systolic and diastolic BP significantly increased in 10 patients with lung function impairment.73 A Taiwan population-based study on 7578 subjects observed that short-term PM10 exposure was associated with slightly elevated systolic BP and that elevated O3 was associated with elevated diastolic BP.74 Regarding longterm air pollution exposure, one recent study in Taiwan found that increased 1-year-averaged particulate air pollutants of PM10, PM2.5, O3, and NO2 were associated with elevated systolic and diastolic BP.19 One communitybased study on 10,459 Korean subjects also found that

PM10 concentrations were associated with BP with a lag of 0 to 2 days in warm season, and BP was significantly associated with SO2 and O3 in cold season.75 Epidemiological studies in North America and Europe reported inverse associations between PM and BP.76,77 Apparently, there are discrepancies between air pollution and BP among studies in Asian and non-Asian studies. Aortic pulse wave velocity Cardio-ankle vascular index (CAVI), an index of aortic pulse wave velocity, can represent the change in vascular tone and is associated with coronary atherosclerosis and left ventricular function in patients with ischemic heart disease.78 One recent panel study in Taiwan reported that an IQR increase in personal exposure to O3 and PM1.0-2.5 was associated with a 4.8% and 2.5% increase in CAVI but not with HRV change among young, healthy mail carriers.79 This study indicates that vascular function may be more sensitive to air pollutants than the autonomic balance and CAVI can be used as a new marker of cardiovascular effects by urban air pollution.80 Conclusions and recommendations Epidemiological studies conducted in Asia show that short-term outdoor air pollution, especially PM, influences cardiovascular morbidity and mortality. These studies were conducted primarily in the countries with electronically available air pollution data such as Taiwan, Japan, Hong Kong, and South Korea. This may bias our current understanding of air pollution effects toward more urbanized, motorized, Westernized, and economically developed Asian countries, which encompass only a small proportion of the total Asian population (0.3 of 3 billion populations in the region). The associations between CVD mortality, as well as morbidity, and important sources of air pollution, such as industrial, agricultural, and 2-stroke mobile sources, as well as transboundary pollution have not been sufficiently studied yet in many Asian countries. There still is the need to conduct more epidemiological research to fill the knowledge gap of our understanding of the extent of health impacts and the physical-biologic mechanism of air pollution on health in the region. Asian cohort studies are also needed to improve our understanding of population susceptibility and pollution diversity. More collaborative research is especially needed to elucidate short-term and long-term air pollution effects on cardiovascular morbidity and mortality. The success of such research requires Asian health and environmental scientists to build up collaborative multidisciplinary teams of investigators and that governments throughout Asia commit adequate long-term resources to this important public health issue. The following priority research issues should be fully addressed in future studies.

376

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378

Research needs in the future Hemodynamic changes by air pollution The AHA scientific statements in 2004 and 2010 proposed several subclinical pathophysiologic responses of the cardiovascular system to PM exposure, including systemic inflammation and thrombosis, oxidative stress, increase in BP, vascular dysfunction and atherosclerosis, and a decrease in HRV4,10; however, some physiologic response to air pollution, such as BP and HRV changes, are inconclusive in several studies. Additional panel studies will need to determine if these parameters are a physiologic response to underlying hemodynamic change with air pollution exposure or real risk factors linking air pollution to CVD. Multicity studies across Asian countries Although an increasing number of published studies on air pollution effects on CVDs in Asia have grown exponentially in the last 2 decades, more coordinated, multicity time series will be needed to show the robust and consistent results in the United States and Europe. The effects of PM constituents The emission sources in Asia are much different from those in the West; therefore, the compositions of particulate in Asia may be quite different from those in Europe or North America. Limited studies have addressed the compositions of particulate pollutants and their associated health effects. More studies are needed to evaluate PM constituents and their relationship to cardiovascular effects and clinical outcomes. Long-term air pollution effects Although, several cohort studies in Europe and North America have reported the associations of long-term PM concentrations with cardiovascular mortality and subclinical outcomes of such as BP and atherosclerosis,5,80,81 little information is available on the long-term air pollution effect on either cardiovascular morbidity or mortality in Asia. More cohort studies are needed in Asian populations to estimate effects of long-term exposure on mortality and life expectancy. Gene-environmental interaction and pharmacobiologic response The impact of gene-environmental interaction on urban air pollution has gained more attention in recent studies in Europe and the United States. Fibrinogen genetic polymorphism is reported to modify physiologic response to environmental inflammatory stimuli of ambient PM exposure.62 Hemochromatosis genotype is also found to modify PM's effects on cardiac autonomic function.82 On the other hand, PM's effects on HRV among high-risk

population, such as patients with clinical diagnosis of CHF, can be shielded by modern cardioprotective therapy.83 Because genetic diversity and medication patterns among patients with CVD vary widely among Asian populations, detailed information of subject's disease status and medication need to be considered in future studies of the cardiovascular effects of urban air pollution in Asia. Acknowledgments This study is supported by a grant from National Science Council, Taiwan (NSC97-2923-1-002-001-MY4). References
1. Reddy KS: Cardiovascular disease in non-Western countries. N Engl J Med 2004;350:2438-2440. 2. He J, Gu D, Wu X, et al: Major causes of death among men and women in China. N Engl J Med 2005;353:1124-1134. 3. Department of Health: Vital statistics. Taiwan, R.O.C. Taipei: Department of Health, Executive Yuan, Taiwan; 2009. Available at: http://www.doh.gov.tw/CHT2006/DM/DM2_2_p02.aspx?class_ no=440&now_fod_list_no=11397&level_no=-1&doc_no=76512. Accessed September 15, 2010. 4. Brook RD, Rajagopalan S, Pope CA, et al: American Heart Association council on epidemiology and prevention, council on the kidney in cardiovascular disease, and council on nutrition, physical activity and metabolism. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010;121:2331-2378. 5. Pope CA III, Burnett RT, Thurston GD, et al: Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 2004;109:71-77. 6. Miller KA, Siscovick DS, Sheppard L, et al: Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med 2007;356:447-458. 7. Pope CA 3rd, Muhlestein JB, May HT, et al: Ischemic heart disease events triggered by short-term exposure to fine particulate air pollution. Circulation 2006;114:2443-2448. 8. Puett RC, Hart JE, Yanosky JD, et al: Chronic fine and coarse particulate exposure, mortality, and coronary heart disease in the Nurses' Health Study. Environ Health Perspect 2009;117: 1697-1701. 9. Bhatnagar A: Environmental cardiology: studying mechanistic links between pollution and heart disease. Circ Res 2006;99:692-705. 10. Brook RD, Franklin B, Cascio W, et al: Air pollution and cardiovascular disease. A statement for healthcare professionals from the expert panel on population and prevention science of the American Heart Association. Circulation 2004;109:2655-2671. 11. World Health Organization: The World Health Report 2002. Reducing risks, promoting healthy life. Geneva: WHO; 2002. Available at: http://www.who.int/whr/2002/en/whr02_en.pdf. Accessed September 15, 2010. 12. Huizenga C, Ajero M, Fabian H: Benchmarking urban air quality management in Asian cities. Presented at 13th World Clean Air and Environmental Protection Congress and Exhibition, London, UK, August 22; 2004. 13. Koppmann R, Czapiewski KV, Reid JS: A review of biomass burning emissions, part I: gaseous emissions of carbon monoxide, methane, volatile organic compounds, and nitrogen containing compounds. Atmos Chem Phys Discuss 2005;5:10455-10516.

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378 14. Harrison RM: Source of air pollution. In: Chan M, Danzon M, editors. Air Quality Guidelines. Global Update 2005. Copenhagen: WHO; 2005. p. 9-30. Available at: http://www.euro.who.int/__data/ assets/pdf_file/0005/78638/E90038.pdf. Accessed September 15, 2010. 15. Stockholm Environment Institute: Urban air pollution in Asia. Foundation Course on Air Quality Management in Asia. Sweden: Stockholm; 2008. 16. United Nations: World urbanization prospects: the 2009 revision. United Nations: Department of Economic and Social Affairs; 2009. 17. Janssen N, Mehta S: Human exposure to air pollution. In: Chan M, Danzon M, editors. Air Quality Guidelines. Global Update 2005. Copenhagen: WHO; 2005. p. 61-85. Available at: http://www.euro. who.int/__data/assets/pdf_file/0005/78638/E90038.pdf. Accessed September 15, 2010. 18. Abdul Ghaffar A, Reddy KS, Singhi M: Burden of non-communicable diseases in South Asia. Br Med J 2004;328:807-810. 19. Chuang KJ, Yan YH, Chiu SY, et al: Long-term air pollution exposure and risk factors for cardiovascular diseases among the elderly in Taiwan. Occup Environ Med 2010;68:64-68. 20. Lee JT, Kim H, Cho YS, et al: Air pollution and hospital admissions for ischemic heart diseases among individuals 64+ years of age residing in Seoul, Korea. Arch Environ Health 2003; 58:617-623. 21. Ye F, Piver WT, Ando M, et al: Effects of temperature and air pollutants on cardiovascular and respiratory diseases for males and females older than 65 years of age in Tokyo, July and August 19801995. Environ Health Perspect 2001;109:355-359. 22. Chang CC, Tsai SS, Ho SC, et al: Air pollution and hospital admissions for cardiovascular disease in Taipei, Taiwan. Environ Res 2005;98:114-119. 23. Yang CY, Chen YS, Yang CH, et al: Relationship between ambient air pollution and hospital admissions for cardiovascular diseases in Kaohsiung, Taiwan. J Toxicol Environ Health A 2004; 67:483-493. 24. Wong TW, Lau TS, Yu TS, et al: Air pollution and hospital admissions for respiratory and cardiovascular diseases in Hong Kong. Occup Environ Med 1999;56:679-683. 25. Yang CY: Air pollution and hospital admissions for congestive heart failure in a subtropical city: Taipei, Taiwan. J Toxicol Environ Health A 2008;71:1085-1090. 26. Hsieh YL, Yang YH, Wu TN, et al: Air pollution and hospital admissions for myocardial infarction in a subtropical city: Taipei, Taiwan. J Toxicol Environ Health A 2010;73:757-765. 27. Wong CM, Atkinson RW, Anderson HR, et al: A tale of two cities: effects of air pollution on hospital admissions in Hong Kong and London compared. Environ Health Perspect 2002;110:67-77. 28. Chen R, Chu C, Tan J, et al: Ambient air pollution and hospital admission in Shanghai, China. J Hazard Mater 2010;18:234-240. 29. Kwon HJ, Cho SH, Nyberg F, et al: Effects of ambient air pollution on daily mortality in a cohort of patients with congestive heart failure. Epidemiology 2001;12:413-419. 30. Kim H, Kim Y, Hong YC: The lag-effect pattern in the relationship of particulate air pollution to daily mortality in Seoul, Korea. Int J Biometeorol 2003;48:25-30. 31. Omori T, Fujimoto G, Yoshimura I, et al: Effects of particulate matter on daily mortality in 13 Japanese cities. J Epidemiol 2003;13: 314-322. 32. Iwai K, Mizuno S, Miyasaka Y, et al: Correlation between suspended particles in the environmental air and causes of disease among inhabitants: cross-sectional studies using the vital statistics and air pollution data in Japan. Environ Res 2005;99:106-117. 33. Murakami Y, Ono M: Myocardial infarction deaths after high level exposure to particulate matter. J Epidemiol Community Health 2006; 60:262-266.

377

34. Venners SA, Wang B, Xu Z, et al: Particulate matter, sulfur dioxide, and daily mortality in Chongqing, China. Environ Health Perspect 2003;111:562-567. 35. Xu Z, Yu D, Jing L, et al: Air pollution and daily mortality in Shenyang, China. Arch Environ Health 2000;55:115-120. 36. Hedley AJ, Wong CM, Thach TQ, et al: Cardiorespiratory and all-cause mortality after restrictions on sulphur content of fuel in Hong Kong: an intervention study. Lancet 2002;360:1646-1652. 37. Tsai DH, Wang JL, Chuang KJ, et al: Traffic-related air pollution and cardiovascular mortality in central Taiwan. Sci Total Environ 2010; 408:1818-1823. 38. Wong CM, Ou CQ, Chan KP, et al: The Effects of Air Pollution on Mortality in Socially Deprived Urban Areas in Hong Kong, China. Environ Health Perspect 2008;116:1189-1194. 39. Kan H, London SJ, Chen G, et al: Season, sex, age, and education as modifiers of the effects of outdoor air pollution on daily mortality in Shanghai, China: The Public Health and Air Pollution in Asia (PAPA) Study. Environ Health Perspect 2008;116: 1183-1188. 40. Qian Z, He Q, Lin HM, et al: High temperatures enhanced acute mortality effects of ambient particle pollution in the oven city of Wuhan, China. Environ Health Perspect 2008;116: 1172-1178. 41. Vichit-Vadakan M, Vajanapoom N, Ostro B: The Public Health and Air Pollution in Asia (PAPA) Project: estimating the mortality effects of particulate matter in Bangkok, Thailand. Environ Health Perspect 2008;116:1179-1182. 42. Wong CM, Vichit-Vadakan N, Kan H, et al: Public Health and Air Pollution in Asia (PAPA): a multicity study of short-term effects of air pollution on mortality. Environ Health Perspect 2008;116: 1195-1202. 43. Franklin M, Zeka A, Schwartz J: Association between PM2.5 and allcause and specific-cause mortality in 27 US communities. J Expo Sci Environ Epidemiol 2007;17:279-287. 44. Zanobetti A, Schwartz J: The effect of fine and coarse particulate air pollution on mortality: a national analysis. Environ Health Perspect 2009;117:1-40. 45. Ponka A, Virtanen M: Low-level air pollution and hospital admissions for cardiac and cerebrovascular diseases in Helsinki. Am J Public Health 1996;86:1273-1280. 46. Ballester F, Tenias JM, Perez-Hoyos S: Air pollution and emergency hospital admissions for cardiovascular diseases in Valencia, Spain. J Epidemiol Community Health 2001;55:57-65. 47. Wordley J, Walters S, Ayres JG: Short term variations in hospital admissions and mortality and particulate air pollution. Occup Environ Med 1997;54:108-116. 48. Wellenius GA, Schwartz J, Mittleman MA: Air pollution and hospital admissions for ischemic and hemorrhagic stroke among medicare beneficiaries. Stroke 2005;36:2549-2553. 49. Hong YC, Lee JT, Kim H, et al: Air pollution: a new risk factor in ischemic stroke mortality. Stroke 2002;33:2165-2169. 50. Yamazaki S, Nitta H, Ono M, et al: Intracerebral haemorrhage associated with hourly concentration of ambient particulate matter: case-crossover analysis. Occup Environ Med 2007;64:17-24. 51. Tsai SS, Goggins WB, Chiu HF, et al: Evidence for an association between air pollution and daily stroke admissions in Kaohsiung, Taiwan. Stroke 2003;34:2612-2616. 52. Chan CC, Chuang KJ, Chien LC, et al: Urban air pollution and emergency admissions for cerebrovascular diseases in Taipei, Taiwan. Eur Heart J 2006;27:1238-1244. 53. Mott JA, Mannino DM, Alverson CJ, et al: Cardiorespiratory hospitalizations associated with smoke exposure during the 1997, Southeast Asian forest fires. Int J Hyg Environ Health 2005;208: 75-85. 54. Husar RB, Tratt DM, Schichtel BA, et al: Asian dust events of April 1998. Geophys Res 2001;106:18316-18330.

378

T.-C. Su et al. / Progress in Cardiovascular Diseases 53 (2011) 369378 71. Min JY, Paek D, Cho SI, et al: Exposure to environmental carbon monoxide may have a greater negative effect on cardiac autonomic function in people with metabolic syndrome. Sci Total Environ 2009; 407:4807-4811. 72. Chen SY, Lin YL, Chan CC: The effects of short-term air pollution exposure on pulse pressure changes in non-smoking adults. Presented at 2010 Joint Conference of the International Society of Exposure Science (ISES) and the International Society of Environmental Epidemiology (ISEE), Seoul, Korea, August 31; 2010. 73. Chuang KJ, Chan CC, Shiao GM, et al: Associations between submicrometer particles exposures and blood pressure and heart rate in patients with lung function impairments. J Occup Environ Med 2005;47:1093-1098. 74. Chuang KJ, Yan YH, Cheng TJ: Effect of air pollution on blood pressure, blood lipids, and blood sugar: a population-based approach. J Occup Environ Med 2010;52:258-262. 75. Choi JH, Xu QS, Park SY, et al: Seasonal variation of effect of air pollution on blood pressure. J Epidemiol Community Health 2007; 61:314-318. 76. Ebelt ST, Wilson WE, Brauer M: Exposure to ambient and nonambient components of particulate matter: a comparison of health effects. Epidemiology 2005;16:396-405. 77. Ibald-Mulli A, Timonen KL, Peters A, et al: Effects of particulate air pollution on blood pressure and heart rate in subjects with cardiovascular disease: a multicenter approach. Environ Health Perspect 2004;112:269-277. 78. Miyoshi T, Doi M, Hirohata S, et al: Cardio-ankle vascular index is independently associated with the severity of coronary atherosclerosis and left ventricular function in patients with ischemic heart disease. J Atheroscler Thromb 2010;17:249-258. 79. Wu CF, Kuo IC, Su TC, et al: Effects of personal exposure to particulate matter and ozone on arterial stiffness and heart rate variability in healthy adults. Am J of Epidemiol 2010;171: 1299-1309. 80. Hoffmann B, Moebus S, Kroger K, et al: Residential exposure to urban pollution, ankle-brachial index, and peripheral arterial disease. Epidemiology 2009;20:280-288. 81. Laden F, Schwartz J, Speizer FE, et al: Reduction in fine particulate air pollution and mortality: extended follow-up of the Harvard Six Cities study. Am J Respir Crit Care Med 2006;173: 667-672. 82. Park SK, O'Neill MS, Wright RO, et al: HFE genotype, particulate air pollution, and heart rate variability: a gene-environment interaction. Circulation 2006;114:2798-2805. 83. Barclay JL, Miller BG, Dick S, et al: A panel study of air pollution in subjects with heart failure: negative results in treated patients. Occup Environ Med 2009;66:325-334.

55. Chan CC, Chuang KJ, Chen WJ, et al: Increasing cardiopulmonary emergency visits by long-range transported Asian dust storms in Taiwan. Environ Res 2008;106:393-400. 56. Chen YS, Sheen PC, Chen ER, et al: Effects of Asian dust storm events on daily mortality in Taipei, Taiwan. Environ Res 2004;95:151-155. 57. Chen YS, Yang CY: Effects of Asian dust storm events on daily hospital admissions for cardiovascular disease in Taipei, Taiwan. J Toxicol Environ Health 2005;68:1457-1464. 58. Yang CY, Chen YS, Chiu HF, et al: Effects of Asian dust storm events on daily stroke admissions in Taipei, Taiwan. Environ Res 2005;99:79-84. 59. Kwon HJ, Cho SH, Chun Y, et al: Effects of the Asian dust events on daily mortality in Seoul, Korea. Environ Res 2002;90:1-5. 60. Pope CA, Hansen ML, Long RW, et al: Ambient particulate air pollution, heart rate variability, and blood markers of inflammation in a panel of elderly subjects. Environ Health Perspect 2004;112:339-345. 61. Liao D, Heiss G, Chinchilli VM, et al: Association of criteria pollutants with plasma hemostatic/inflammatory markers: a population-based study. J Expo Sci Environ Epidemiol 2005;15:319-328. 62. Peters A, Greven S, Heid I, et al: Fibrinogen genes modify the fibrinogen response to ambient particulate matter. Am J Respir Crit Care Med 2009;179:484-491. 63. Su TC, Chan CC, Liau CS, et al: Urban air pollution increases plasma activator inhibitor-1 and fibrinogen levels in susceptible patients. Eur J Cardiovasc Prev Rehabil 2006;13:849-852. 64. Chuang KJ, Chan CC, Su TC, et al: The effect of urban air pollution on inflammation, oxidative stress, coagulation, and autonomic dysfunction in young adults. Am J Respir Crit Care Med 2007; 176:370-376. 65. Sandercock GRH, Brodie DA: The role of heart rate variability in prognosis for different modes of death in chronic heart failure. Pacing Clin Electrophysiol 2006;29:892-904. 66. Chen PS, Tan AY: Autonomic nerve activity and atrial fibrillation. Heart Rhythm 2007;4:S61-S64. 67. Chan CC, Chuang KJ, Shiao GM, et al: Personal exposure to submicrometer particles and heart rate variability in human subjects. Environ Health Perspect 2004;112:1063-1067. 68. Chuang KJ, Chan CC, Chen NT, et al: Effects of particle size fractions on reducing heart rate variability in cardiac and hypertensive patients. Environ Health Perspect 2005;113:1693-1697. 69. Chuang KJ, Chan CC, Su TC, et al: Associations between particulate sulfate and organic carbon exposures and heart rate variability in patients with or at risk for cardiovascular diseases. J Occup Environ Med 2007;49:610-617. 70. Chan CC, Chuang KJ, Su TC, et al: Association between nitrogen dioxide and heart rate variability in a susceptible population. Eur J Cardiovas Prev and Rehabil 2005;12:580-586.