Coronary Effects of Combustion-Source Particulate MatterEPA Grant Number: R830839
Title: Coronary Effects of Combustion-Source Particulate Matter
Investigators: Campen, Matthew J. , McDonald, Jacob D. , Reed, Matthew D.
Institution: Lovelace Respiratory Research Institute
EPA Project Officer: Chung, Serena
Project Period: April 21, 2003 through April 20, 2006 (Extended to March 31, 2007)
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 , Health Effects
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. While 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, while other evidence has specifically linked myocardial infarction with acute PM exposure. Therefore, the primary objective of this proposal will be to examine the in vivo and in vitro effects of particles on coronary artery function. The working hypothesis is that PM can adversely affect cardiac function in two ways: 1) directly, via soluble constituents of PM that access the circulation and alter vascular physiology, potentially disrupting dilatory responses or even leading to vasospasm and myocardial infarction, and 2) indirectly by PM-induced inflammation that impairs the basic function of the cardiopulmonary system, i.e., gas exchange, and thus predisposes the myocardium to hypoxemic conduction anomalies. Therefore, this study will 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-/- lipoprotein knockout mouse, will be used to investigate the susceptibility conferred by a compromised coronary vasculature; this model will later be coupled with a model of acute pulmonary inflammation to examine the added impact of ventilatory impairment. In Specific Aim 1, ApoE-/- and their genetic background, C57BL/6J, mice will be exposed to two levels of diesel engine exhaust (DE) for 6 h/dx4 d. 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 will be induced by ozone exposure to examine the impact of pre-existing ventilatory defects on cardiac outcomes during exposure to DE. In Specific Aim 2, the effect of bioavailable PM on coronary artery physiology will be assessed using in vitro microscopic video 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. Lastly, in Specific Aim 3, a novel inhalation exposure system that enables separation of DE PM and gaseous phase components will be implemented to identify putative toxic drivers of cardiac responses. Mice will be exposed as in Specific Aim 1 to gaseous and particulate phases to determine respective health impact of either portion.
It is anticipated that bioavailable PM components will lead to anomalies in coronary vascular function, and that these adverse effects will be exacerbated by pre-existing vascular disease and pulmonary inflammation. Through these studies 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.