This is the first study of controlled human exposures to elemental carbon UFP, using a comprehensive set of ECG parameters that describe autonomic regulation of the heart, myocardial substrate, and vulnerability. ECG monitoring was chosen to elucidate cardiac effects of UFP based on the concept that electrical signals of the heart might be affected by air pollution through either indirect or direct mechanistic pathways (Utell et al., 2002
; Zareba et al., 2001
). As expected, young healthy subjects did not show dramatic changes in the studied ECG parameters, but some interesting trends were observed.
Exposure to 10 µg/m3 UFP at rest was associated with some, mostly non-significant, changes in ECG parameters. These changes indicate an increase in parasympathetic tone, which is most likely also responsible for the trend toward ST elevation and blunted QTc shortening. Increased variability of T-wave complexity after exposure to UFP could also be attributed to an enhanced parasympathetic response. The heavy breathing associated with exercise physiologically increases parasympathetic modulation of the heart, and this response seems to be exaggerated by UFP exposure.
Interestingly, similar findings have been reported in other clinical studies of relatively young, healthy subjects. Gong Jr. et al. (2003)
studied healthy subjects and subjects with mild asthma exposed to concentrated ambient fine particles (at a concentration of 174 µg/m3
). They observed an air pollution-related increase in parasympathetic measures of autonomic regulation of the heart. This group found similar effects following exposures of healthy and asthmatic subjects to concentrated ambient ultrafine particles (Gong Jr. et al., 2008
). Riediker et al. (2004)
studied highway patrol officers during work shifts, and found that exposure to PM2.5
in their vehicles was associated with increased HRV parameters the next morning, indicating increased vagal tone. In contrast, elderly subjects showed reduced HRV in response to exposure to concentrated ambient fine particles (Devlin et al., 2003
), indicating a loss of vagal control.
In the second protocol, the impact of exercise was seen on most ECG variables. As with exposures at rest, the parasympa-thetic measures of HRV increased during exposure at the lower UFP level (10 µg/m3) but not the higher UFP level (25 µg/m3). This finding may indicate that low-level exposure to UFP triggers some increase in parasympathetic tone, while higher concentrations might lead to a more balanced effect on both the sympathetic and parasympathetic systems. Recovery from exercise showed a blunted response of the parasympathetic system (measured by normalized units of HF components) after exposure to UFP in comparison to air exposure. This diminished vagal response was not observed 3.5 hours later.
Epidemiological and panel studies have shown effects of air pollution on HRV. Gold et al. (2000)
found a reduction in parasympathetic (vagal) tone in elderly subjects associated with exposure to outdoor air particles. Adar et al. (2007)
also found evidence for reduced parasympathetic tone in elderly subjects associated with 24-hour exposures to PM2.5
, black carbon, and UFP (particle number). Pope 3rd et al. (1999)
measured HRV parameters and levels of PM10
and found that elevations of PM10
were associated with increased heart rate and decreased HRV. Chuang et al. (2007)
reported reduced HRV in association with ambient sulfate and ozone levels in healthy subjects. Baccarelli et al. (2008)
found that heart rate variability was reduced in association with exposures to PM2.5
in elderly men, with the effects most pronounced in men with specific susceptibility genotypes and reduced dietary intake of vitamins B6 and B12 and methio-nine. Exposure to coarse particles (PM10–2.5
) also appears to affect HRV in elderly people (Lipsett et al., 2006
). In contrast, exposure to diesel exhaust containing 200 µg/m3
of PM for 2 hours at rest did not induce significant changes in autonomic control of the heart (Peretz et al., 2008
Animal studies also indicate that concentrated ambient particles induce HRV changes in autonomic regulation of the heart, including a decrease in parasympathetic modulation (Wellenius et al., 2002
). On the other hand, rats exposed to on-road aerosols showed increased high-frequency power and decreased vago-sympathetic balance (Elder et al., 2007
). Our observations indicate that some effect of UFP on parameters of HRV, reflecting control of the heart by the autonomic nervous system, is present in healthy subjects, although the exact mechanism for these changes is not yet understood.
The repolarization changes in response to UFP exposure with exercise could have a complex mechanism, which remains to be elucidated. Blunted response of vagal modulation on the sinus node does not fully explain the observed blunted response of QTc duration after UFP exposure. It is known that heart rate (sinus node function under the influence of the autonomic nervous system) provides only a partial explanation for changes in QT duration (Merri et al., 1993
). Possibly, UFP have an additional effect on repolarization either through a direct effect of the autonomic nervous system on ventricular myocardium (apart from that on the sinus node) or by directly affecting ion channel function in ventricular myocardium through a yet unknown mechanism (Utell et al., 2002
The reduction in QT duration with concomitant increase in T- wave amplitude after UFP exposure provides evidence that repolarization is affected by air pollution. These preliminary findings require confirmation in further studies in groups likely to demonstrate more pronounced effects (for example, elderly and coronary disease patients).
Lengthening of the QTc interval predisposes to an increased potential for arrhythmias. However, shortening of repolarization is known to be caused by hypoxia and ischemia, and to be arrhythmogenic (Safi et al., 2001
). Calcium, potassium, and chloride channels may contribute significantly to shortening of the action potential duration. For example, the action potential shortening by chloride current activation may perpetuate re-entry by shortening the refractory period. The other possible explanation for observed QT shortening may be the result of cardiac myocyte functional responses to subtle changes in systemic vascular tone. These changes, in turn, may be related to increased endothelin production and/or reduced NO release by endothelium in response to particles. Alternatively, UFP may gain access to pulmonary capillary blood, where they could be transported to the heart and cause direct effects on membrane ion channel function.
Slight ST segment changes in studied young subjects should not be considered as measures of ischemic burden. Rather, the ST segment reflects the plateau phase of repolarization of the myocardium, with several ion channels operating that might be vulnerable to air pollution. Brugada syndrome is an example of an arrhythmogenic disorder manifested by ST segment elevation caused by abnormal kinetics of ion channels involved in the repolarization process (Antzelevitch, 2001
Evidence for air pollution effects on cardiac repolarization comes from a panel study in Erfurt, Germany (Henneberger et al., 2005
). Fifty-six male patients with coronary artery disease showed significant increases in QT duration in response to exposure to organic carbon; significant decreases in T-wave amplitude with exposure to ultrafine, accumulation mode, and PM2.5
particles; and a significant increase in T-wave complexity in association with PM2.5
particles for the 24 hours before the ECG recordings.
Limitations of the studies we report here include the use of laboratory-generated elemental carbon UFP, which do not contain metal, organic compounds, and other chemical species present in ambient UFP. Our findings could therefore underestimate the cardiovascular effects of ambient ultrafine particles. A limited number of subjects were included in each tested protocol (six males and six females in each). However, carefully designed protocols with multiple randomized exposures to pure air and UFP at different concentrations, with individuals serving as their own controls, are strengths of the studies. We used sophisticated measures of electrical activity of the heart including novel digital Holter technology and novel parameters quantifying T-wave morphology and repolarization variability, in addition to HRV and ST segment Holter parameters. These sensitive parameters are increasingly used in studies aiming to detect subtle changes in myocardial electrical activity. For the majority of the analyses, we standardized recording conditions (5 minutes supine) to diminish the influence of confounding factors (change in body position, activity, meals, stress) known to affect studied ECG parameters. We also analyzed whole 24-hour recordings for HRV parameters, which yielded results similar to those based on multiple 5-minute segments.
The mass concentrations of carbon UFP used in this study, 10 and 25 µg/m3, are representative of ambient mass concentrations in US cities, are below the current US 24-hour National Ambient Air Quality Standard for PM2.5 of 35 µg/m3, and are about 10-fold lower than mass concentrations used in human clinical studies of concentrated fine particles. The particle numbers are higher than those generally found in ambient air, although particle number concentrations in traffic on major highways may reach or exceed these numbers. Thus, the particle concentrations used in these studies are relevant to real-world UFP exposures.
In summary, transient exposure to ultrafine carbon particles in concentrations of 10–25 µg/m3
does not cause marked changes in ECG-derived parameters in young healthy subjects. However, trends are observed indicating that some subjects might be susceptible to such exposures, with responses involving autonomic modulation of the heart and repolarization of the ventricular myocardium. It is highly likely that individuals with compromised health status (or possibly genetic predisposition) might show significant changes in studied ECG parameters, reflecting mechanistic pathways for the cardiovascular effects of air pollution. Our findings in these studies of laboratory-generated ultrafine carbon particles, together with those using concentrated ambient particle exposures (Devlin et al., 2003
; Gong Jr. et al., 2003
; Gong Jr. et al., 2008
), suggest that, in young healthy subjects, ambient levels of ultrafine and fine particles do not have substantial effects on the electrical activity of the heart and its central regulation.