Grantee Research Project Results
Michael T. Kleinman1, Robert Kloner2, and Boris Simkohovich2
1University of California–Irvine, Irvine, CA; 2The Heart Institute of the Good
Samaritan Hospital, Los Angeles, CA
EPA Grant Number: RD831952
Cardiovascular disease is the leading cause of death among men and women in the United States. Epidemiologic studies have clearly shown that there are increased cardiopulmonary deaths in cities that are the most polluted versus those that are less polluted. There is a dearth of data regarding the basic science of how particulate matter causes development of and triggering of cardiovascular disease, that have involved studies in animal models. Animal models of pulmonary hypertension, bronchitis, asthma, and cardiovascular disease, but not emphysema alone, appear to exhibit greater susceptibility to the toxic effects of pollution. However few studies have assessed details regarding susceptibility of aged and diseased hearts to adverse cardiovascular effects of pollutants. The goals of this study are to test two main hypotheses. First, that exposure to ultrafine (< 0.18 micrometer) particles typical of polluted ambient air causes physiologic and pathologic damage to hearts by direct routes (not involving the lung) and by indirect mechanisms due to effects of particles on the respiratory system. Second, that difference in susceptibility will be conferred by differences in genetic expression between sensitive populations. We will use the well established model of isolated working hearts that are normal (young adult versus senescent hearts), hypertrophied (hearts from spontaneously hypertensive rats) or that had been subjected to myocardial infarction due to proximal coronary artery occlusion to test for direct effects of administered ultrafine ambient particles. We will examine the effects of chronic inhalation exposure to polluted ambient air to determine whether adverse effects with respect to physiology and pathology and the differential susceptibility of different aged and hypertensive individuals can be explained by differences in gene expression of young adult rats, aged rats, rats with genetic spontaneous hypertension and rats that have been subjected to myocardial infarction. By identifying genes that appear to confer susceptibility, we hope to identify possible treatments to mitigate pollutant effects. If physiologic, pathologic and/or genetic alterations develop in either Specific Aims 1 or 2 above then we will test the hypothesis that these deleterious processes can be blocked or prevented with (a) beta blockers and (b) oxygen radical scavenging agents administered prior to exposure. This study will try to better elucidate the mechanisms by which air pollutants affect the cardiovascular system, resulting in increased morbidity and mortality, and will seek to define factors which lead to differential susceptibility for certain groups and individuals. This multidisciplinary, collaborative research program will use innovative models and model systems and state-of-the-art technologies to examine the role of ultrafine particles in the development or aggravation of heart disease in susceptible populations.