Environmentally persistent free radicals compromise left ventricular function during ischemia/reperfusion injury

Abstract

Increases in airborne particulate matter (PM) are linked to increased mortality from myocardial ischemia. PM contains environmentally persistent free radicals (EPFRs) that form as halogenated hydrocarbons chemisorb to transition metal oxide-coated particles, and are capable of sustained redox cycling. We hypothesized that exposure to the EPFR DCB230 would increase cardiac vulnerability to subsequent myocardial ischemia-reperfusion (MI/R) injury. Rats were exposed to DCB230 or vehicle via nose-only inhalation (230 μg max/day) over 30 min/day for 7 days. MI/R or sham MI/R (sham) was initiated 24 h after the final exposure. Following 1 or 7 days of reperfusion, left ventricular (LV) function was assessed and infarct size measured. In vehicle-exposed rats, MI/R injury did not significantly reduce cardiac output (CO), stroke volume (SV), stroke work (SW), end-diastolic volume (EDV), or end-systolic volume (ESV) after 1 day of reperfusion, despite significant reductions in end-systolic pressure (ESP). Preload-recruitable SW (PRSW; contractility) was elevated, presumably to maintain LV function. MI/R 1-day rats exposed to DCB230 also had similarly reduced ESP. Compared with vehicle controls, CO, SV, and SW were significantly reduced in DCB230-exposed MI/R 1-day rats; moreover, PRSW did not increase. DCB230's effects on LV function dissipated within 8 days of exposure. These data show that inhalation of EPFRs can exacerbate the deficits in LV function produced by subsequent MI/R injury. Infarct size was not different between the MI/R groups. We conclude that inhalation of EPFRs can compromise cardiac function during MI/R injury and may help to explain the link between PM and MI/R-related mortality.

Keywords: cardiac toxicity; particulate matter; pressure volume; rat.

Fig. 1.

Inhalational exposure to DCB230 does not affect infarct size. A: representative cardiac section from a vehicle-exposed myocardial ischemia/reperfusion injury 1-day (MI/R 1d) rat showing how the area at risk (AAR) for MI/R injury and area of necrosis (AON) were determined. B: the AAR was consistent between all groups receiving MI/R injury. Additionally, no significant difference in AON was measured between exposure groups at either MI/R 1d or MI/R 7-day (7d) time periods. In this and all figures, n = 10/group except the MI/R 7d vehicle group where n = 9. LV, left ventricle.

Fig. 2.

Effects of inhaled DCB230 and MI/R on heart rate (HR) (A), mean arterial blood pressure (MABP) (B), LV volumes (C), and LV pressures (D). Rats were exposed (20 min/day for 7 days) by nose-only inhalation to either DCB230 (230 μg max/day) or vehicle. Twenty-four hours after the final exposure, rats underwent sham or MI/R surgery followed by 1 or 7 days of reperfusion (MI/R 1d and MI/R 7d, respectively) before assessing ventricular function. A: exposure to DCB230 or MI/R did not markedly affect HR, except for the significant differences in HR between the DCB230- and vehicle-exposed rats in the MI/R 1d and MI/R 7d groups. B: MABP in DCB230-exposed rats at MI/R 1d was significantly lower than in DCB230-exposed sham rats, but was not different than baseline in the MI/R 7d group. C: inhalational exposure to DCB230 reduced baseline cardiac end-diastolic volume (EDV) and end-systolic volume in (ESV) sham rats, although this effect dissipated within 8 days of the final exposure (MI/R 7d). D: neither DCB230 nor MI/R injury significantly affected end-diastolic pressure (EDP); however, MI/R acutely decreased end-systolic pressure (ESP) in both exposure groups at the 1 day time point. Lower case letters indicated the following: a, P < 0.05 vs. vehicle-exposed sham; b, P < 0.05 vs. exposure-matched sham; c, P < 0.05 vs. exposure-matched MI/R 1d.

Fig. 3.

Effects of DCB230 and MI/R injury on LV systolic function. Prior inhalational exposure to DCB230 produced significant reductions in cardiac output (CO) (A), stroke volume (SV) (B), and stroke work (SW) at the MI/R 1d time point (C); preload-recruitable stroke work (PRSW) was significantly elevated compared with sham controls at the MI/R 1d time point in vehicle-exposed, but not those exposed to DCB230 (D). Lower case letters indicated the following: a, P < 0.05 vs. vehicle-exposed sham; b, P < 0.05 vs. exposure-matched sham; c, P < 0.05 vs. exposure-matched MI/R 1d.

Fig. 4.

Effects of DCB230 and MI/R injury on LV diastolic function and ejection fraction (EF%). A: prior inhalational exposure to DCB230 significantly increased the end-diastolic pressure-volume relationship (EDPVR) in sham and MI/R 1d rats; however, this effect dissipated by the MI/R 7d time point. B: no significant changes to the isovolumetric relaxation constant, Tau, were caused by either DCB230 exposure or MI/R injury. C: Prior inhalational exposure to DCB230 had no effect on LV EF%. Additionally, no significant change in EF% was elicited by MI/R 1d injury, although EF% significantly declined in both exposure groups by the MI/R 7d time point. Lower case letters indicated the following: a, P < 0.05 vs. vehicle-exposed sham; c, P < 0.05 vs. exposure-matched MI/R 1d.