Recently, investigators demonstrated associations between fine particulate matter (PM)-associated metals and adverse health effects. Residual oil fly ash (ROFA), a waste product of fossil fuel combustion from boilers, is rich in the transition metals Fe, Ni, and V, and when released as a fugitive particle, is an important contributor to ambient fine particulate air pollution. We hypothesized that a single-inhalation exposure to transition metal-rich PM will cause concentration-dependent cardiovascular toxicity in spontaneously hypertensive (SH) rats. Rats implanted with telemeters to monitor heart rate and electrocardiogram were exposed once by nose-only inhalation for 4 hours to 3.5 mg/m(3), 1.0 mg/m(3), or 0.45 mg/m(3) of a synthetic PM (dried salt solution), similar in composition to a well-studied ROFA sample consisting of Fe, Ni, and V. Exposure to the highest concentration of PM decreased T-wave amplitude and area, caused ST depression, reduced heart rate (HR), and increased nonconducted P-wave arrhythmias. These changes were accompanied by increased pulmonary inflammation, lung resistance, and vagal tone, as indicated by changes in markers of HR variability (increased root of the mean of squared differences of adjacent RR intervals [RMSSD], low frequency [LF], high frequency [HF], and decreased LF/HF), and attenuated myocardial micro-RNA (RNA segments that suppress translation by targeting messenger RNA) expression. The low and intermediate concentrations of PM had less effect on the inflammatory, HR variability, and micro-RNA endpoints, but still caused significant reductions in HR. In addition, the intermediate concentration caused ST depression and increased QRS area, whereas the low concentration increased the T-wave parameters. Thus, PM-induced cardiac dysfunction is mediated by multiple mechanisms that may be dependent on PM concentration and myocardial vulnerability (this abstract does not reflect the policy of the United States Environmental Protection Agency).

Diesel exhaust (DE) is a major contributor to traffic-related fine particulate matter (PM)(2.5). Although inroads have been made in understanding the mechanisms of PM-related health effects, DE's complex mixture of PM, gases, and volatile organics makes it difficult to determine how the constituents contribute to DE's effects. We hypothesized that exposure to particle-filtered DE (fDE; gases alone) will elicit less cardiac effects than whole DE (wDE; particles plus gases). In addition, we hypothesized that spontaneously hypertensive (SH) rats will be more sensitive to the electrocardiographic effects of DE exposure than Wistar Kyoto rats (WKY; background strain with normal blood pressure). SH and WKY rats, implanted with telemeters to monitor electrocardiogram and heart rate (HR), were exposed once for 4 h to 150 μg/m(3) or 500 μg/m(3) of wDE (gases plus PM) or fDE (gases alone) DE, or filtered air. Exposure to fDE, but not wDE, caused immediate electrocardiographic alterations in cardiac repolarization (ST depression) and atrioventricular conduction block (PR prolongation) as well as bradycardia in SH rats. Exposure to wDE, but not fDE, caused postexposure ST depression and increased sensitivity to the pulmonary C fiber agonist capsaicin in SH rats. The only notable effect of DE exposure in WKY rats was a decrease in HR. Taken together, hypertension may predispose to the potential cardiac effects of DE and components of DE may have divergent effects with some eliciting immediate irritant effects (e.g., gases), whereas others (e.g., PM) trigger delayed effects potentially via separate mechanisms.

Background: Ozone (O3) is a well-documented respiratory oxidant, but increasing epidemiological evidence points to extrapulmonary effects, including positive associations between ambient O3 concentrations and cardiovascular morbidity and mortality.Objective: With preliminary reports linking O3 exposure with changes in heart rate (HR), we investigated the hypothesis that a single inhalation exposure to O3 will cause concentration-dependent autonomic modulation of cardiac function in rats.Methods: Rats implanted with telemeters to monitor HR and cardiac electrophysiology [electrocardiography (ECG)] were exposed once by whole-body inhalation for 4 hr to 0.2 or 0.8 ppm O3 or filtered air. A separate cohort was tested for vulnerability to aconitine-induced arrhythmia 24 hr after exposure.Results: Exposure to 0.8 ppm O3 caused bradycardia, PR prolongation, ST depression, and substantial increases in atrial premature beats, sinoatrial block, and atrioventricular block, accompanied by concurrent increases in several HR variability parameters that were suggestive of increased parasympathetic tone. Low-O3 exposure failed to elicit any overt changes in autonomic tone, heart rhythm, or ECG. However, both 0.2 and 0.8 ppm O3 increased sensitivity to aconitine-induced arrhythmia formation, suggesting a latent O3-induced alteration in myocardial excitability.Conclusions: O3 exposure causes several alterations in cardiac electrophysiology that are likely mediated by modulation of autonomic input to the heart. Moreover, exposure to low O3 concentrations may cause subclinical effects that manifest only when triggered by a stressor, suggesting that the adverse health effects of ambient levels of air pollutants may be insidious and potentially underestimated.

Background: Exercise “stress” testing is a screening tool used to determine the amount of stress for which the heart can compensate before developing abnormal rhythm or ischemia, particularly in susceptible persons. Although this approach has been used to assess risk in humans exposed to air pollution, it has never been applied to rodent studies.Objective: We hypothesized that a single exposure to diesel exhaust (DE) would increase the risk of adverse cardiac events such as arrhythmia and myocardial ischemia in rats undergoing a dobutamine challenge test, which can be used to mimic exercise-like stress.Methods: Wistar-Kyoto normotensive (WKY) and spontaneously hypertensive (SH) rats implanted with radiotelemeters and a chronic intravenous catheter were whole-body exposed to 150 μg/m3 DE for 4 hr. Increasing doses of dobutamine, a β1-adrenergic agonist, were administered to conscious unrestrained rats 24 hr later to elicit the cardiac response observed during exercise while heart rate (HR) and electrocardiogram (ECG) were monitored.Results: A single exposure to DE potentiated the HR response of WKY and SH rats during dobutamine challenge and prevented HR recovery at rest. During peak challenge, DE-exposed SH rats had lower overall HR variability when compared with controls, in addition to transient ST depression. All DE-exposed animals also had increased arrhythmias.Conclusions: These results are the first evidence that rats exhibit stress-induced cardiac dysrhythmia and ischemia sensitivity comparable to humans after a single exposure to a toxic air pollutant, particularly when in the presence of underlying cardiovascular disease. Thus, exposure to low concentrations of air pollution can impair the heart’s ability to respond to stress and increase the risk of subsequent triggered dysfunction.

The binding of high-mobility group box-1 (HMGB-1) to the membrane receptor for advanced glycation end-products (mRAGE) is a key early mediator of non-infectious inflammation and its triggers include ischaemia/hypoxia. The effects of acute hypoxia on soluble RAGE (sRAGE) are unknown. Fourteen healthy adults (50 % women; 26.6±3.8 years) were assessed at baseline normoxia (T0), followed by four time-points (T90, 95, 100 and 180 min) over three hours of continuous normobaric hypoxia (NH, 4,450 m equivalent) and again 60 min after return to normoxia (T240). A 5-min exercise step test was performed during NH at T90. Plasma concentrations of HMGB-1, sRAGE VCAM-1, ICAM-1, VEGF IL-8 and IL-13 were measured using venous blood. Arterial and tissue oxygen saturations were measured using pulse oximetry (SpO2) and near-infrared spectroscopy (StO2), respectively. NH led to a significant reduction in SpO2, StO2, sRAGE and VEGF, which was compounded by exercise, before increasing to baseline values with normoxic restoration (T240). NH-exercise led to a paired increase in HMGB-1. sRAGE inversely correlated with HMGB-1 (r=-0.32; p=0.006), heart rate (r=-0.43; p=0.004) but was not linked to SpO2 or StO2. In conclusion, short-term NH leads to a fall in sRAGE and VEGF concentrations with a transient rise post NH-exercise in HMGB-1.