Grantee Research Project Results
2003 Progress Report: Coronary Effects of Combustion-Source Particulate Matter
EPA Grant Number: R830839Title: Coronary Effects of Combustion-Source Particulate Matter
Investigators: Campen, Matthew J. , McDonald, Jacob D. , Reed, Matthew D.
Institution: Lovelace Biomedical & Environmental Research Institute
EPA Project Officer: Chung, Serena
Project Period: April 21, 2003 through April 20, 2006 (Extended to March 31, 2007)
Project Period Covered by this Report: April 21, 2003 through April 20, 2004
Project Amount: $1,018,920
RFA: Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms (2002) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air , Human Health
Objective:
Ambient levels of particulate matter (PM) air pollution within attainment of current National Ambient Air Quality Standards have been associated with cardiovascular morbidity and mortality in many epidemiological studies. Although a causal relationship between PM and cardiovascular morbidity is implicated, a concrete mechanism has not yet been demonstrated. A recent report demonstrated systemic vasoconstriction following inhalation of environmentally relevant levels of combined PM and ozone, whereas other evidence has specifically linked myocardial infarction with acute PM exposure. Therefore, the primary objective of this research project is to examine the in vivo and ex vivo effects of particles on coronary artery physiology. We hypothesize that PM could adversely affect cardiac function in two ways:
- directly, via soluble constituents of PM that access the circulation and alter vascular physiology, which may disrupt dilatory responses or lead to vasospasm and myocardial infarction;
- and indirectly by PM-induced inflammation that impairs the basic function of the cardiopulmonary system and potentially releases vasoactive cytokines into the circulation.
The overall objective of this research project is to investigate indices of risk for vasospastic sudden cardiac death and alterations in coronary artery physiology incurred by exposure to combustion-source (diesel exhaust) particles and associated gaseous co-pollutants in a murine model of coronary vascular disease.
A model of atherosclerosis, the ApoE-/- knockout mouse, will be used to investigate the susceptibility conferred by a compromised coronary vasculature; this model later will be coupled with a model of acute pulmonary inflammation to examine the added impact of ventilatory impairment. In Specific Objective 1, ApoE-/- and their genetic background, C57BL/6J, mice will be exposed to two levels of diesel engine exhaust (DE) for 6 hours per day for 4 days. Various proposed mechanisms of cardiac effects will be examined in vivo during and after PM exposure, including electrocardiographic changes (measured by telemetry) to assess myocardial repolarization anomalies, heart rate variability to identify alterations in autonomic tone, and pulmonary function tests to quantify PM-induced deficits in ventilatory capacity. Pulmonary inflammation (induced by ozone exposure) will be used to examine the cardiac impact of pre-existing ventilatory defects during exposure to DE. In Specific Objective 2, we will assess the effect of bioavailable PM on coronary artery physiology using state-of-the-art ex vivo video microscopic edge-detection myography. Vessels from exposed and naïve mice will be used to compare the relative pathophysiologic contributions of bioavailable PM versus endogenous circulating mediators. In Specific Objective 3, we will implement a novel inhalation exposure system that enables separation of DE PM and gaseous phase components to identify putative toxic drivers of cardiac responses. Mice will be exposed as in Specific Objective 1 to gaseous and particulate phases to determine respective health impact of either portion.
We expect that bioavailable PM components will lead to anomalies in cardiac conduction related to alterations in coronary physiology and that these adverse effects will be exacerbated by pre-existing pulmonary inflammation. Through this research project, we will develop a novel approach for identifying components of air pollution that impair coronary physiology. Results will help identify vulnerability incurred by coronary artery disease, as well as characterize the relative health impact of gaseous and particle phases of DE.
Progress Summary:
To date we have conducted diesel exposures of four main groups: C57BL/6J and ApoE-/- mice on either high fat or normal diet. The high fat ApoE mice exhibited profound atherosclerotic manifestations after 16 weeks of the diet, and preliminary evidence suggests that they were the only group susceptible to diesel exhaust (as indicated by changes in heart rate). Pulmonary function tests were equivocal, and some pulmonary inflammation was evident only at the highest concentration exposure (5 mg/m3). We have digitally collected ECG data for each animal continuously throughout all exposures; this amount of data analysis will require some time before it is completed.
We also have begun the isolated vascular portion of the study. We have had little trouble isolating coronaries from mice, although we started with mesenteric vessels for training purposes. Diesel exposure has been conducted by exposing the saline via an impinger prior to isolating the vessel. Vasoactive assays are then conducted in the presence of either a nonexposed or diesel–exposed saline. The chemical analysis of the saline post-exposure reveals concentrations of aldehydes and alkanes. Our preliminary findings suggest a heightened constrictor response to endothelin when in the presence of diesel components.
Future Activities:
We will investigate the impact of particles versus gases from the whole exhaust of diesel combustion. With the vascular assay, we will confirm results with individual components observed in the diesel-saline mixture (e.g., acetaldehyde). Furthermore, we will validate the method of ex vivo exposures by specifically looking for levels of alkanes and aldehydes in the serum of a separate cohort of exposed animal.
Journal Articles:
No journal articles submitted with this report: View all 22 publications for this projectSupplemental Keywords:
transition metals, ozone, exposure risk, health effects, bioavailability, sensitive populations, toxics, particulates, acute cardiovascular effects, airborne urban contaminants, cardiopulmonary effects, inhaled pollutants, particulate exposure,, RFA, Scientific Discipline, Health, Air, TREATMENT/CONTROL, particulate matter, Air Pollution Control, Health Risk Assessment, air toxics, Risk Assessments, Incineration/Combustion, copollutant exposures, elderly adults, health effects, atmospheric particulate matter, airway epithelial cells, cardiopulmonary responses, fine particles, combustion-related pollutants, stratospheric ozone, acute cardiovascular effects, acute lung injury, vascoconstriction, combustion emissions, air pollution, susceptible subpopulations, cardiac arrest, chronic health effects, lung inflammation, oxidant gas, particulate exposure, cardiopulmonary effects, Acute health effects, inhaled, cardiovascular morbifity, cardiopulmonary, cardiotoxicity, concentrated particulate matter, acute exposure, airborne urban contaminants, cardiovascular disease, exposure assessmentProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.