Exposure to medium and high ambient levels of ozone causes adverse systemic inflammatory and cardiac autonomic effects

Abstract

Epidemiological evidence suggests that exposure to ozone increases cardiovascular morbidity. However, the specific biological mechanisms mediating ozone-associated cardiovascular effects are unknown. To determine whether short-term exposure to ambient levels of ozone causes changes in biomarkers of cardiovascular disease including heart rate variability (HRV), systemic inflammation, and coagulability, 26 subjects were exposed to 0, 100, and 200 ppb ozone in random order for 4 h with intermittent exercise. HRV was measured and blood samples were obtained immediately before (0 h), immediately after (4 h), and 20 h after (24 h) each exposure. Bronchoscopy with bronchoalveolar lavage (BAL) was performed 20 h after exposure. Regression modeling was used to examine dose-response trends between the endpoints and ozone exposure. Inhalation of ozone induced dose-dependent adverse changes in the frequency domains of HRV across exposures consistent with increased sympathetic tone [increase of (parameter estimate ± SE) 0.4 ± 0.2 and 0.3 ± 0.1 in low- to high-frequency domain HRV ratio per 100 ppb increase in ozone at 4 h and 24 h, respectively (P = 0.02 and P = 0.01)] and a dose-dependent increase in serum C-reactive protein (CRP) across exposures at 24 h [increase of 0.61 ± 0.24 mg/l in CRP per 100 ppb increase in ozone (P = 0.01)]. Changes in HRV and CRP did not correlate with ozone-induced local lung inflammatory responses (BAL granulocytes, IL-6, or IL-8), but changes in HRV and CRP were associated with each other after adjustment for age and ozone level. Inhalation of ozone causes adverse systemic inflammatory and cardiac autonomic effects that may contribute to the cardiovascular mortality associated with short-term exposure.

Keywords: airway inflammation; heart rate variability; inhalational exposure; ozone; systemic inflammation.

Fig. 1.

Study design. Subjects were exposed to 0, 100, and 200 ppb ozone (O₃) in random order for 4 h with intermittent exercise in a repeated measure design. Electrocardiogram recording, phlebotomy, and spirometry were obtained immediately before (0 h), immediately after (4 h), and 20 h after (24 h) each exposure. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at 24-h time point. The exposures were at least 3 wk apart to allow for recovery from previous exposure.

Fig. 2.

Change in systemic inflammatory and autonomic responses across ozone exposures. Graphs represent individual data as well as median and interquartile range of changes in inflammatory and autonomic variables across exposure (0 h to 4 h and 0 h to 24 h) to ozone at 0, 100, and 200 ppb levels. PE ± SE, parameter estimate ± SE from generalized estimating equation models of change in dependent variables for 100 ppb increase in ozone exposure; CRP, C-reactive protein; LF and HF, low and high frequency domains of heart rate variability; HRV, heart rate variability.