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Abstract
Ambient particulate matter (PM) exposure is linked to cardiovascular events and death, especially among individuals with heart disease. A model of toxic cardiomyopathy was developed in Spontaneously Hypertensive Heart Failure (SHHF) rats to explore potential mechanisms. Rats were infused with isoproterenol (ISO; 2.5 mg/kg/day subcutaneous [sc]), a β-adrenergic agonist, for 28 days and subsequently exposed to PM by inhalation. ISO induced tachycardia and hypotension throughout treatment followed by postinfusion decrements in heart rate, contractility, and blood pressures (systolic, diastolic, pulse), and fibrotic cardiomyopathy. Changes in heart rate and heart rate variability (HRV) 17 days after ISO cessation indicated parasympathetic dominance with concomitantly altered ventilation. Rats were subsequently exposed to filtered air or Harvard Particle 12 (HP12) (12 mg/m3)—a metal-rich oil combustion-derived PM—at 18 and 19 days (4 h/day) after ISO infusion via nose-only inhalation to determine if cardio-impaired rats were more responsive to the effects of PM exposure. Inhalation of PM among ISO-pretreated rats significantly increased pulmonary lactate dehydrogenase, serum high-density lipoprotein (HDL) cholesterol, and heart-to-body mass ratio. PM exposure increased the number of ISO-pretreated rats that experienced bradyarrhythmic events, which occurred concomitantly with acute alterations of HRV. PM, however, did not significantly affect mean HRV in the ISO- or saline-pretreated groups. In summary, subchronic ISO treatment elicited some pathophysiologic and histopathological features of heart failure, including cardiomyopathy. The enhanced sensitivity to PM exposure in SHHF rats with ISO-accelerated cardiomyopathy suggests that this model may be useful for elucidating the mechanisms by which PM exposure exacerbates heart disease.
Acknowledgments
The authors acknowledge Judy Richards for her analysis of serum, plasma, and lavage fluid, and Dr. Christopher Gordon, Dr. Jan Dye, Dr. Urmila Kodavanti, Dr. Gary Hatch, and Dr. Mary Jane Selgrade of the US EPA and Dr. Matthew Campen of Lovelace Respiratory Research Institute for their review of the manuscript. The authors also would like to dedicate this paper to the many contributions of W. Penn Watkinson to the field of air pollution toxicology.
Disclaimer: This paper has been reviewed and approved for release by the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency. Approval does not signify that the contents necessarily reflect the views and policies of the US EPA, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
Declaration of interest
Alex Carll was supported by US EPA/UNC-CH: EPA CR83323601. The authors alone are responsible for the content and writing of the paper.