Air pollutants are being increasingly linked to extrapulmonary multi-organ effects. Specifically, recent studies associate air pollutants with brain disorders including psychiatric conditions, neuroinflammation and chronic diseases. Current evidence of the linkages between neuropsychiatric conditions and chronic peripheral immune and metabolic diseases provides insights on the potential role of the neuroendocrine system in mediating neural and systemic effects of inhaled pollutants (reactive particulates and gases). Autonomically-driven stress responses, involving sympathetic-adrenal-medullary and hypothalamus-pituitary-adrenal axes regulate cellular physiological processes through adrenal-derived hormones and diverse receptor systems. Recent experimental evidence demonstrates the contribution of the very stress system responding to non-chemical stressors, in mediating systemic and neural effects of reactive air pollutants. The assessment of how respiratory encounter of air pollutants induce lung and peripheral responses through brain and neuroendocrine system, and how the impairment of these stress pathways could be linked to chronic diseases will improve understanding of the causes of individual variations in susceptibility and the contribution of habituation/learning and resiliency. This review highlights effects of air pollution in the respiratory tract that impact the brain and neuroendocrine system, including the role of autonomic sensory nervous system in triggering neural stress response, the likely contribution of translocated nano particles or metal components, and biological mediators released systemically in causing effects remote to the respiratory tract. The perspective on the use of systems approaches that incorporate multiple chemical and non-chemical stressors, including environmental, physiological and psychosocial, with the assessment of interactive neural mechanisms and peripheral networks are emphasized.

ADVERTISEMENT RETURN TO ISSUEPREVViewpointNEXTComplex Air Pollution Mixtures Formed by Irradiation of Hydrocarbons Elicit an Array of Toxicological ResponsesM. Ian Gilmour*M. Ian GilmourNational Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United States*Phone: +1-919-541-0015; e-mail: [email protected]More by M. Ian Gilmourhttp://orcid.org/0000-0002-3070-6704, Jonathan D. KrugJonathan D. KrugNational Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United StatesMore by Jonathan D. Krughttp://orcid.org/0000-0002-7045-7650, Stephen H. GavettStephen H. GavettNational Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United StatesMore by Stephen H. Gavett, Mehdi HazariMehdi HazariNational Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United StatesMore by Mehdi Hazarihttp://orcid.org/0000-0003-0280-9690, David M. DeMariniDavid M. DeMariniNational Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United StatesMore by David M. DeMarinihttp://orcid.org/0000-0001-8357-7988, and Daniel L. CostaDaniel L. CostaAir in a Changing Environment National Program, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United StatesMore by Daniel L. CostaCite this: Environ. Sci. Technol. 2018, 52, 5, 2429–2431Publication Date (Web):February 22, 2018Publication History Received9 February 2018Published online22 February 2018Published inissue 6 March 2018https://pubs.acs.org/doi/10.1021/acs.est.7b04857https://doi.org/10.1021/acs.est.7b04857newsACS PublicationsCopyright © 2018 U.S. Government. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views2124Altmetric-Citations5LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (1 MB) Get e-AlertscloseSUBJECTS:Air pollution,Atmospheric chemistry,Environmental pollution,Gases,Particulate matter Get e-Alerts

Air pollutant exposures are linked to cardiopulmonary diseases, diabetes, metabolic syndrome, neurobehavioral conditions, and reproductive abnormalities. Significant effort is invested in understanding how pollutants encountered by the lung might induce effects in distant organs. The role of circulating mediators has been predicted; however, their origin and identity have not been confirmed. New evidence has emerged which implicates the role of neuroendocrine sympathetic-adrenal-medullary (SAM) and hypothalamic-pituitary-adrenal (HPA) stress axes in mediating a wide array of systemic and pulmonary effects. Our recent studies using ozone exposure as a prototypical air pollutant demonstrate that increases in circulating adrenal-derived stress hormones (epinephrine and cortisol/corticosterone) contribute to lung injury/inflammation and metabolic effects in the liver, pancreas, adipose, and muscle tissues. When stress hormones are depleted by adrenalectomy in rats, most ozone effects including lung injury/inflammation are diminished. Animals treated with antagonists for adrenergic and glucocorticoid receptors show inhibition of the pulmonary and systemic effects of ozone, whereas treatment with agonists restore and exacerbate the ozone-induced injury/inflammation phenotype, implying the role of neuroendocrine activation. The neuroendocrine system is critical for normal homeostasis and allostatic activation; however, chronic exposure to stressors may lead to increases in allostatic load. The emerging mechanisms by which circulating mediators are released and are responsible for producing multiorgan effects of air pollutants insists upon a paradigm shift in the field of air pollution and health. Moreover, since these neuroendocrine responses are linked to both chemical and nonchemical stressors, the interactive influence of air pollutants, lifestyle, and environmental factors requires further study.

Air pollution has a compelling history in the development of human cultures. Fossil fuels opened a new human cultural chapter of extraordinary technical and economic growth while bringing about noxious and unhealthful combustion byproducts to breathe. Toxicology saw its birth in the modern world with demonstrating the potential harmful effects of breathing smoke in its various forms. The empirical nature of toxicology provided insights and underpinnings to epidemiological studies providing biological plausibility and relative risk attributions. As toxicology evolves with its sister sciences, there will be gains in fundamental understandings of susceptibility and potential long-term risks of air pollution with revelation of potential interventions and remedies for those affected.

From climate change to hydraulic fracturing, and from drinking water safety to wildfires, environmental challenges are changing. The United States has made substantial environmental protection progress based on media-specific and single pollutant risk-based frameworks. However, today's environmental problems are increasingly complex and new scientific approaches and tools are needed to achieve sustainable solutions to protect the environment and public health. In this article, we present examples of today's environmental challenges and offer an integrated systems approach to address them. We provide a strategic framework and recommendations for advancing the application of science for protecting the environment and public health. We posit that addressing 21st century challenges requires transdisciplinary and systems approaches, new data sources, and stakeholder partnerships. To address these challenges, we outline a process driven by problem formulation with the following steps: a) formulate the problem holistically, b) gather and synthesize diverse information, c) develop and assess options, and d) implement sustainable solutions. This process will require new skills and education in systems science, with an emphasis on science translation. A systems-based approach can transcend media- and receptor-specific bounds, integrate diverse information, and recognize the inextricable link between ecology and human health.

Exposure of adult male and female DBA/2 mice to 3100 ppm benzene for 4 hr significantly increased the frequency of sister chromatid exchanges in bone marrow cells of both sexes, inhibited marrow cellular proliferation (but only in male mice), and did not significantly increase the frequency of chromosomal aberrations in either sex. Phenobarbital pre- treatment synergistically interacted with benzene exposure to further increase sister chromatid exchanges in female mice, induce greater inhibition of cellular proliferation in male mice, and induce a significant level of chromatid-type chromosomal aberrations in both sexes. During the second day after exposure to benzene there was increased inhibition of cellular prolifer- ation in male mice and both new DNA damage and persistence of old DNA damage in female mice. The differences in both the type and magnitude of the response of bone marrow cellular populations, as determined by different cytogenetic end points in male and female DBA/2 mice exposed to benzene or to phenobarbital and benzene, suggest not only that a metabolite of benzene is responsible for the observed effects, but that dif- ferent metabolites may be involved in different end points. The extensive use of benzene in industry and local commerce has resulted in both a large degree of human exposure and a considerable potential for environmental contamination (1). Acute exposure to benzene produces a dose-dependent de- pression of the central nervous system, whereas chronic expo-

Seven million premature deaths occur annually due to air pollution worldwide, of which approximate to 80% are attributed to exacerbation of cardiovascular disease (CVD), necessitating greater attention to understanding the causes of susceptibility to air pollution in this sector of population. We used rat models of CVD with or without obesity and compared them to healthy strains to examine the risk factors of ozone-induced lung injury and inflammation. We examined functional, biochemical and molecular changes in several organs to evaluate how physiological factors as well as compensatory antioxidant reserves modulate processes by which ozone injury is influenced by underlying disease. In this study, we highlight key findings of this series of reports. We show that underlying cardiopulmonary insufficiency in genetically predisposed rats appears to increase the effective ozone dose; thus dosimetry is one factor contributing to exacerbated ozone effects. We further show that antioxidant reserve in airway lining fluid modulates ozone-induced damage such that strains with the least antioxidant reserve incur the greatest injury. And finally, we show that the inflammatory response to ozone is governed by a cluster of genes involved in regulating cytokine release, trafficking of inflammatory cells and processes related to cellular apoptosis and growth. All such processes are influenced not only by ozone dosimetry and the lung antioxidant milieu but also by the strain-specific genetic factors. In using a comprehensive systems biology research approach, our data reveal key risk factors for - and strategies to reduce risk of - air pollution mortality among those with CVD.

This chapter examines the practical application of lung function tests that are or can be used in laboratory animals that provide analogues of clinical pulmonary function tests conducted on humans. Attention is given to the theory behind how changes in lung volume and flow occur and the techniques used to measure these changes in animals. With that knowledge, the various lung function tests and their usefulness in describing normal and abnormal lung function are discussed. The interpretation of functional changes detected in animals after experimental intervention remains predicated on our knowledge and experience in human pulmonary medicine yet also serves to illuminate and refine our understanding of normal and altered lung function in all mammals, including humans.

Abstract To elucidate key factors of host susceptibility to air pollution, healthy and cardiovascular (CV)-compromised rats were exposed to air or ozone (O3) at 0.25, 0.5, or 1.0 ppm for 4 h. We hypothesized that rat strains with the least cardiac reserve would be most prone to develop significant health effects. Using flow whole body plethysmography (FWBP), ventilatory responses in healthy 3-month-old male rats [i.e. Wistar–Kyoto (WKY), Wistar (WIS), and Sprague–Dawley (SD) strains] were compared with hypertensive [i.e. spontaneously hypertensive (SH), fawn-hooded-hypertensive (FHH), and SH-stroke-prone (SHSP)] strains and obese [i.e. SH-heart failure-prone (SHHF) and JCR:LA-cp, atherosclerosis-prone (JCR)] strains. SH were slower to acclimate to the FWBP chambers. At 0-h post-air-exposure, SHSP and SHHF exhibited hyperpnea, indicative of cardiopulmonary insufficiency. At 0-h-post-O3, all but one strain showed significant concentration-dependent decreases in minute volume [MV = tidal volume (TV) × breathing frequency]. Comparing air with 1.0 ppm responses, MV declined 20–27% in healthy, 21–42% in hypertensive, and 33% in JCR rats, but was unchanged in SHHF rats. Penh increased significantly in all strains, with disproportionate increases in “responder” WKY and FHH strains. By 20 h, most changes had resolved, although Penh remained elevated in WKY, SH, and SHSP. Based on the effective dose estimates (O3 ppm × h × MV), the most CV-compromised (SHSP and SHHF) strains received significantly greater O3 lung deposition (25% and 40%, respectively). Data support epidemiologic associations that individuals with cardiopulmonary insufficiency are at greater risk for urban pollutant exposure due, in part, to enhanced lung deposition and exacerbation of hypoxia and pathophysiologic processes of heart failure.

The Clean Air Act (CAA) is responsible for dramatically improving United States air quality over the last 40 years. The scientific community has served as the backbone of that improvement. Experimental sciences, animal toxicology and controlled human exposures, have played valuable roles in deciphering the mechanisms of air pollution-related health effects and in some cases clearly demonstrating the overt health effects that result from exposure to air pollutants. However, at times the research community is unaware of how their contributions to science are used to inform policy decisions in the context of the National Ambient Air Quality Standards (NAAQS). Within this chapter, researchers will gain a better understanding of the legislative history and requirements of the CAA. Additionally, the chapter will detail how the U.S. Environmental Protection Agency evaluates the scientific evidence that forms the basis of each NAAQS along with the resulting steps taken to inform policy decisions. The chapter will conclude with a discussion of the uncertainties that still shape air quality policy, the shift that has taken within the air pollution research community towards the examination of multipollutant exposures, and the potential future of air quality policy.

Context: Air pollution exposure affects autonomic function, heart rate, blood pressure and left ventricular function. While the mechanism for these effects is uncertain, several studies have reported that air pollution exposure modifies activity of the carotid body, the major organ that senses changes in arterial oxygen and carbon dioxide levels, and elicits downstream changes in autonomic control and cardiac function.Objective: We hypothesized that exposure to acrolein, an unsaturated aldehyde and mucosal irritant found in cigarette smoke and diesel exhaust, would activate the carotid body chemoreceptor response and lead to secondary cardiovascular responses in rats.Materials and methods: Spontaneously hypertensive (SH) rats were exposed once for 3 h to 3 ppm acrolein gas or filtered air in whole body plethysmograph chambers. To determine if the carotid body mediated acrolein-induced cardiovascular responses, rats were pretreated with an inhibitor of cystathionine gamma-lyase (CSE), an enzyme essential for carotid body signal transduction.Results: Acrolein exposure induced several cardiovascular effects. Systolic, diastolic and mean arterial blood pressure increased during exposure, while cardiac contractility decreased 1 day after exposure. The cardiovascular effects were associated with decreases in pO(2), breathing frequency and expiratory time, and increases in sympathetic tone during exposure followed by parasympathetic dominance after exposure. The CSE inhibitor prevented the cardiovascular effects of acrolein exposure.Discussion and conclusion: Pretreatment with the CSE inhibitor prevented the cardiovascular effects of acrolein, suggesting that the cardiovascular responses with acrolein may be mediated by carotid body-triggered changes in autonomic tone. (This abstract does not reflect EPA policy.)

Acute exposure to ambient fine particulate matter (PM2.5) is tied to cardiovascular morbidity and mortality, especially among those with prior cardiac injury. The mechanisms and pathophysiological events precipitating these outcomes remain poorly understood but may involve inflammation, oxidative stress, arrhythmia and autonomic nervous system imbalance. Cardiomyopathy results from cardiac injury, is the leading cause of heart failure, and can be induced in heart failure-prone rats through sub-chronic infusion of isoproterenol (ISO). To test whether cardiomyopathy confers susceptibility to inhaled PM2.5 and can elucidate potential mechanisms, we investigated the cardiophysiologic, ventilatory, inflammatory and oxidative effects of a single nose-only inhalation of a metal-rich PM2.5 (580 µg/m(3), 4 h) in ISO-pretreated (35 days × 1.0 mg/kg/day sc) rats. During the 5 days post-treatment, ISO-treated rats had decreased HR and BP and increased pre-ejection period (PEP, an inverse correlate of contractility) relative to saline-treated rats. Before inhalation exposure, ISO-pretreated rats had increased PR and ventricular repolarization time (QT) and heterogeneity (Tp-Te). Relative to clean air, PM2.5 further prolonged PR-interval and decreased systolic BP during inhalation exposure; increased tidal volume, expiratory time, heart rate variability (HRV) parameters of parasympathetic tone and atrioventricular block arrhythmias over the hours post-exposure; increased pulmonary neutrophils, macrophages and total antioxidant status one day post-exposure; and decreased pulmonary glutathione peroxidase 8 weeks after exposure, with all effects occurring exclusively in ISO-pretreated rats but not saline-pretreated rats. Ultimately, our findings indicate that cardiomyopathy confers susceptibility to the oxidative, inflammatory, ventilatory, autonomic and arrhythmogenic effects of acute PM2.5 inhalation.

Individuals with cardiovascular and metabolic diseases (CVD) are shown to be more susceptible to adverse health effects of pollutants. Rodent models of CVD are used for examining susceptibility variations. CVD models developed by selective inbreeding are shown to represent the etiology of human disease and metabolic dysfunction. The goal of this article was to review the origin and the pathobiological features of rat models of varying CVD with or without metabolic syndrome and healthy laboratory rat strains to allow better interpretation of the data regarding their susceptibility to air pollutant exposures. Age-matched healthy Sprague-Dawley (SD), Wistar (WIS) and Wistar Kyoto (WKY), and CVD-prone spontaneously hypertensive (SH), Fawn-Hooded hypertensive (FHH), SH stroke-prone (SHSP), SHHF/Mcc heart failure obese (SHHF) and insulin-resistant JCR:LA-cp obese (JCR) rat models were considered for this study. The genetics and the underlying pathologies differ between these models. Normalized heart weights correlated with underlying cardiac disease while wide differences exist in the number of white blood cells and platelets within healthy strains and those with CVD. High plasma fibrinogen and low angiotensin converting enzyme activity in FHH might relate to kidney disease and associated hypertension. However, other obese strains with known kidney lesions do not exhibit decreases in ACE activity. The increased activated partial thromboplastin time only in SHSP correlates with their hemorrhagic stroke susceptibility. Increases plasma lipid peroxidation in JCR might reflect their susceptibility to acquire atherosclerosis. These underlying pathologies involving CVD and metabolic dysfunction are critical in interpretation of findings related to susceptibility variations of air pollution health effects.

The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure dependent on the type and severity of disease. Healthy male 12-14-week-old Wistar Kyoto (WKY), Wistar (WS) and Sprague Dawley (SD); and CVD-compromised spontaneously hypertensive (SH), Fawn-Hooded hypertensive (FHH), stroke-prone spontaneously hypertensive (SHSP), obese spontaneously hypertensive heart failure (SHHF) and obese JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0ppm ozone for 4h; pulmonary injury and inflammation were analyzed immediately following (0-h) or 20-h later. Baseline bronchoalveolar lavage fluid (BALF) protein was higher in CVD strains except for FHH when compared to healthy. Ozone-induced increases in protein and inflammation were concentration-dependent within each strain but the degree of response varied from strain to strain and with time. Among healthy rats, SD were least affected. Among CVD strains, lean rats were more susceptible to protein leakage from ozone than obese rats. Ozone caused least neutrophilic inflammation in SH and SHHF while SHSP and FHH were most affected. BALF neutrophils and protein were poorly correlated when considering the entire dataset (r=0.55). The baseline and ozone-induced increases in cytokine mRNA varied markedly between strains and did not correlate with inflammation. These data illustrate that the degree of ozone-induced lung injury/inflammation response is likely influenced by both genetic and physiological factors that govern the nature of cardiovascular compromise in CVD models.

Short-term exposure to air pollutants has been linked to acute cardiovascular morbidity and mortality. Even in the absence of overt signs or symptoms, pollutants can cause subtle disruptions to internal compensatory mechanisms, which maintain homeostatic balance in response to various environmental and physiological stressors. We hypothesized that a single exposure to acrolein, a ubiquitous gaseous air pollutant, would decrease the sensitivity of baroreflex (BRS), which maintains blood pressure by altering heart rate (HR), modify cardiac electrophysiological properties and increase arrhythmia in rats. Wistar–Kyoto normotensive (WKY) and spontaneously hypertensive (SH) rats implanted with radiotelemeters and a chronic jugular vein catheter were tested for BRS using phenylephrine and sodium nitroprusside 2 days before and 1 h after whole-body exposure to 3 ppm acrolein (3 h). HR and electrocardiogram (ECG) were continuously monitored for the detection of arrhythmia in the pre-exposure, exposure and post-exposure periods. Whole-body plethysmography was used to continuously monitor ventilation in conscious animals. SH rats had higher blood pressure, lower BRS and increased frequency of AV block as evidence by non-conducted p-waves when compared with WKY rats. A single exposure to acrolein caused a decrease in BRS and increased incidence of arrhythmia in both WKY and SH rats. There were minimal ECG differences between the strains, whereas only SH rats experienced irregular breathing during acrolein. These results demonstrate that acrolein causes immediate cardiovascular reflexive dysfunction and persistent arrhythmia in both normal and hypertensive animals. As such, homeostatic imbalance may be one mechanism by which air pollution increases risk 24 h after exposure, particularly in people with underlying cardiovascular disease.

Climate change and global public health is a growing concern among the pulmonary care community. The Turkish Thoracic Society and the American Thoracic Society held special sessions during their 2013 annual conferences to discuss the impact of climate change on the environment and public health. These sessions are summarized in this review to illustrate the global consequences of climate change. Climate and its impact on air pollution and the relative incidence, timing and length of allergens in the atmosphere (pollen and allergen season) are presented. The influence of climate change on housing, indoor air quality and public health is discussed, along with how climate change is uniquely affecting low resource countries due to the process of desertification and its impact on water and food. The European and Caribbean perspectives of climate change on human vulnerability and adaption strategies are discussed, along with how federal and global policies might be implemented to mitigate the effects of climate change.

Exposure to air pollution increases the risk of cardiovascular morbidity and mortality, especially in susceptible populations. Despite increased risk, adverse responses are often delayed and require additional stress tests to reveal latent effects of exposure. The goal of this study was to use an episode of "transient hypoxia" as an extrinsic stressor to uncover latent susceptibility to environmental pollutants in a rodent model of hypertension. We hypothesized that exposure to acrolein, an unsaturated aldehyde and mucosal irritant found in cigarette smoke, diesel exhaust, and power plant emissions, would increase cardiopulmonary sensitivity to hypoxia, particularly in hypertensive rats. Spontaneously hypertensive and Wistar Kyoto (normotensive) rats, implanted with radiotelemeters, were exposed once for 3h to 3 ppm acrolein gas or filtered air in whole-body plethysmograph chambers and challenged with a 10% oxygen atmosphere (10min) 24h later. Acrolein exposure increased heart rate, blood pressure, breathing frequency, and minute volume in hypertensive rats and also increased the heart rate variability parameter LF, suggesting a potential role for increased sympathetic tone. Normotensive rats only had increased blood pressure during acrolein exposure. The hypoxia stress test after acrolein exposure revealed increased diastolic blood pressure only in hypertensive rats and increased minute volume and expiratory time only in normotensive rats. These results suggest that hypertension confers exaggerated sensitivity to air pollution and that the hypoxia stress test is a novel tool to reveal the potential latent effects of air pollution exposure.

Cardiac disease exacerbation is associated with short-term exposure to vehicular emissions. Diesel exhaust (DE) might impair cardiac performance in part through perturbing efferent sympathetic and parasympathetic autonomic nervous system (ANS) input to the heart. We hypothesized that acute changes in ANS balance mediate decreased cardiac performance upon DE inhalation. Young adult heart failure-prone rats were implanted with radiotelemeters to measure heart rate (HR), HR variability (HRV), blood pressure (BP), core body temperature, and pre-ejection period (PEP, a contractility index). Animals pretreated with sympathetic antagonist (atenolol), parasympathetic antagonist (atropine), or saline were exposed to DE (500 µg/m(3) fine particulate matter, 4h) or filtered air and then treadmill exercise challenged. At 1 day postexposure, separate rats were catheterized for left ventricular pressure (LVP), contractility, and lusitropy and assessed for autonomic influence using the sympathoagonist dobutamine and surgical vagotomy. During DE exposure, atenolol inhibited increases in HR, BP, and contractility, but not body temperature, suggesting a role for sympathetic dominance. During treadmill recovery at 4h post-DE exposure, HR and HRV indicated parasympathetic dominance in saline- and atenolol-pretreated groups that atropine inhibited. Conversely, at treadmill recovery 21h post-DE exposure, HRV and PEP indicated sympathetic dominance and subsequently diminished contractility that only atenolol inhibited. LVP at 1 day postexposure indicated that DE impaired contractility and lusitropy while abolishing parasympathetic-regulated cardiac responses to dobutamine. This is the first evidence that air pollutant inhalation both causes time-dependent oscillations between sympathetic and parasympathetic dominance and decreases cardiac performance via aberrant sympathetic dominance.

Acute air pollutant inhalation is linked to adverse cardiac events and death, and hospitalizations for heart failure. Diesel engine exhaust (DE) is a major air pollutant suspected to exacerbate preexisting cardiac conditions, in part, through autonomic and electrophysiologic disturbance of normal cardiac function. To explore this putative mechanism, we examined cardiophysiologic responses to DE inhalation in a model of aged heart failure-prone rats without signs or symptoms of overt heart failure. We hypothesized that acute DE exposure would alter heart rhythm, cardiac electrophysiology, and ventricular performance and dimensions consistent with autonomic imbalance while increasing biochemical markers of toxicity. Spontaneously hypertensive heart failure rats (16 months) were exposed once to whole DE (4h, target PM(2.5) concentration: 500 µg/m(3)) or filtered air. DE increased multiple heart rate variability (HRV) parameters during exposure. In the 4h after exposure, DE increased cardiac output, left ventricular volume (end diastolic and systolic), stroke volume, HRV, and atrioventricular block arrhythmias while increasing electrocardiographic measures of ventricular repolarization (i.e., ST and T amplitudes, ST area, T-peak to T-end duration). DE did not affect heart rate relative to air. Changes in HRV positively correlated with postexposure changes in bradyarrhythmia frequency, repolarization, and echocardiographic parameters. At 24h postexposure, DE-exposed rats had increased serum C-reactive protein and pulmonary eosinophils. This study demonstrates that cardiac effects of DE inhalation are likely to occur through changes in autonomic balance associated with modulation of cardiac electrophysiology and mechanical function and may offer insights into the adverse health effects of traffic-related air pollutants.