In this study we investigated the effects of acute exposure to ambient AP from an industrial source on cardiac autonomic function, as described by changes in HRV. We found small but statistically significant associations between exposure to ambient AP at a site near a steel plant and reductions in both time and frequency domain components of HRV. The associations between exposure sites and HRV appear to be related to the statistically significant pollutant exposure contrast between the two sites, as similar associations were seen in models of the effects of individual pollutant exposures on HRV. Associations between increasing levels of AP and the time domain showed a consistent inverse relationship, HRV decreasing as pollutant levels increased. A similar pattern of associations between AP and the frequency domain was seen although this may be more challenging to interpret.
An initial report of the effects of ambient AP near the steel plant on cardiovascular outcomes showed that pulse rate (PR) was slightly but significantly elevated (approximately 1.5 bpm) at the plant site [19]. Liu et al. [19] described significant elevations in PR in response to IQR increases in SO2 (IQR = 2.9 ppb), NO2 (IQR = 5.0 ppb) and CO (IQR = 0.2 ppb). In the current investigation of the effects of ambient AP near the steel plant on autonomic function, we also showed a small but significant elevation in HR at the Bayview site, when compared to the College site (approximately 2 bpm; Fig. 1) and small but consistently significant associations between individual pollutants and HR (Table 3). While we saw no association between IQR changes in O3 and HR, Liu et al. [19] did report a significant inverse association. The difference in this finding, as well as the additional finding of significant associations between HR and IQR changes in NO, NOx and UFP concentrations in this study may be related to the difference in the sensitivity and recording duration for HR. In the Liu et al. [19] report, PR was derived from the PR recorded during pulse oximetry at a different time point than the HR in the current analysis, which was determined from an ambulatory electrocardiogram. In addition, participant specific AP exposure estimates were based on slightly different exposure times than those used by Liu and colleagues [19]. Finally, we might expect some small differences in results due to the subtle differences in the mixed effects models used for data analysis, and the number of participant records available for analysis for each variable and at each time point. In our analysis IQR increases of most of the measured pollutants (excluding O3) were significantly positively associated with HR and significantly negatively associated with the time domain of HRV. Increased HR and decreased HRV are hallmarks of increased sympathetic input [22].
The effects of exposure to ambient AP from industrial sites on HRV in healthy young populations have not been extensively studied, and the effects seen in other studies of AP mixtures or single pollutants show a high degree of heterogeneity, with few points of consensus. For example, in two similar crossover studies of the effects of traffic related AP exposure on HRV parameters, Weichenthal et al. [15, 17] found different patterns of effects. In a 2011 study of urban cyclists Weichenthal et al. [15] found that HF power was significantly reduced when cycling in high traffic areas, and HRV was inversely associated with IQR increases in UFP concentrations [15]. The reported reductions in HRV in response to increasing pollutant levels in Weichenthal et al. [15] support the findings of the current study. In 2014 Weichenthal et al. [17] reported that HRV was affected by traffic related AP in a population of female cyclists, but the results were unexpected in the context of the 2011 study [15, 17]. Specifically, ozone was associated with significant increases in SDNN and LF/HF ratio, and more surprisingly UFPs were associated with a significant increase in SDNN [17]. Additionally, regional background AP levels appeared to be modifying autonomic nervous system sensitivity to short term traffic pollution exposures, suggesting that an individual’s background AP exposures may modulate acute responses to traffic-related AP [17]. The consistent inverse associations we report in this study are not supported by the findings of the Weichenthal et al. 2014 [17] study. In another study of healthy young commuters, Nyhan et al. [16] found that exposure to particulate matter was associated with significant reductions in the time domain of HRV. This finding was stronger in physically active commuters (cyclists and pedestrians) but also was true for more sedentary commuters (bus and train) [16]. These findings support the findings of the current study, which showed significant reduction in the time domain of HRV associated with IQR increases in PM2.5.
Other studies have investigated the effects of controlled exposures to components of AP on HRV in healthy subjects. In controlled exposures of healthy young volunteers to carbon UFP, significant positive associations between UFP and HRV parameters were reported [13]. The pattern of effects suggested that peripheral nervous system tone was elevated following exposure to low levels of UFP, but not at higher concentrations [13]. In our study, when the associations between HRV parameters and IQR changes in UFP were tested, we saw significant inverse associations with some measures, and all trends were consistently inverse, suggesting an increase in sympathetic tone. Controlled exposure to concentrated ambient particles [14] was positively associated with the frequency domain of HRV, and these changes were larger following co-exposure to particles and O3. Individual pollutants may interact in ambient pollutant mixtures to enhance or alter the autonomic effects of AP.
In future analyses it may be important to consider interactions between pollutants or to generate multi-pollutant models to better test the associations between AP and autonomic effects. We tested the degree of correlation between individual pollutants irrespective of site, and found that most pollutants were significantly positively correlated with one another. We found consistent, moderate to strong, positive correlations between the Nitrogen oxides and also SO2 (Additional file 1: Table S1). This, taken with our findings of consistent inverse associations between these individual pollutants and HRV, suggests that the high degree of correlation between individual pollutants may contribute to the consistency of the effect. It may be important to investigate the effects of controlled exposure to individual pollutants and specific mixtures to tease out which pollutants are primarily responsible for the effects on HRV. However, if we consider our site-specific analysis as a method to investigate the effects of pollutant mixtures on HRV, the pollutant mixture at the Bayview site was associated with significant reductions in HRV when compared to the mixture at the College site. We also took a second multipollutant approach, by testing the associations between IQR changes in the Air Quality Health Index (AQHI) and HRV parameters. The AQHI is a health information tool, calculated from ambient O3, NO2, and PM2.5 [23]. It is used to communicate the health risks of AP to the public. Previous studies [2, 24–27], however, also have used the AQHI as a unique 3 pollutant summary of AP, and tested its associations with health effects, including asthma [25, 26] and cardiovascular outcomes [2, 24]. In our study the AQHI was not significantly associated with changes in any of the HRV parameters tested (Additional file 2: Table S2). A detailed description of the AQHI and the results can be found in the table and legend for Additional file 2: Table S2.
Healthy younger individuals have been followed in two different panel studies of ambient AP effects in Taiwan [28, 29]. Chuang et al. [28] reported consistent inverse associations between ambient AP levels and both time and frequency domains of HRV. These results were similar to the results of the current study, although some of the patterns of effect differed. Chuang et al. [28] also reported associations between AP and elevated blood levels of biomarkers of oxidative stress, suggesting that oxidative stress may be involved in the altered autonomic function. In mail carriers in Taiwan, IQR changes in PM2.5 were not significantly associated with changes in HRV [29]. The lack of significant associations reported by Wu et al. [29] are especially surprising in light of the much higher exposure experienced by the mail carriers (PM2.5 IQR = 52) when compared to the exposures in the current study (IQR = 9), where we reported significant inverse associations. It is possible that the lack of significant associations in the mail carriers study [29] was related to a lack of exposure contrast, since no crossover to a different exposure scenario was completed, and background exposures may have been similar or higher. Taken together, the results of the current study with results from other studies in healthy younger study populations [13–17, 28, 29] appear to show that depending on pollutants, exposure metric, and timeline the effects of AP on autonomic nervous system function can show slightly different patterns of effects; however throughout all the studies, the overall message appears to be that exposure to AP can alter cardiac autonomic balance in the absence of other disease states or risk factors.
When we examined the associations between LF power and site alone or LF power and individual pollutants, LF showed significant inverse associations. The inputs which might influence changes in LF power are less clearly defined than those for HF power or the ratio of LF:HF. Changes in HF power are consistently linked to changes in parasympathetic input [8, 9, 22]. Some researchers therefore have hypothesized that changes in LF power might be evidence of sympathetic effects [22], while others suggest that such change represents both sympathetic and parasympathetic activity [9] but there is no clear consensus, and it is difficult to interpret the individual findings with respect to LF power. Other studies of healthy younger volunteers have reported significant changes in LF power [14, 28], in the absence of effects on other components of the frequency domain of HRV. While reductions in HF were linked to pollutant and particulate matter exposure in diabetics [30], the elderly [31] and individuals with a history of hypertension or ischemic heart disease [31], this was not seen in healthy young volunteers [30]. These findings seem to point to a difference in the response to pollutant exposure of the frequency domain. LF power appears to be inversely associated with increasing AP in healthy young study participants in this study and others [14, 28], while AP exposure in members of vulnerable populations has been associated with changes in HF power [30, 31].
The associations between AP and HRV reported in this study were small. This may be related to the study population, who were a group of healthy and relatively young volunteers, rather than members of susceptible populations. The changes in HRV were statistically significant and followed consistent patterns of effect, especially within the time domain of HRV. The consistent patterns of association suggest that these effects represent real changes in autonomic function in response to changing AP rather than spurious associations. Ambient AP levels in this study were consistent with generally low Canadian ambient AP levels [32], and therefore are relevant to Canadians. Additionally, the outdoor exposure location close to the steel plant was adjacent to a residential neighbourhood; therefore, ambient AP exposures at the Bayview site reflected real world ambient AP exposure. It is possible that, had pollutant levels been higher, and the exposure contrast been greater, a larger effect of proximity to the industrial site, and of pollutant exposure, on autonomic nervous system function could have been recorded. That said, our statistically significant findings at relatively low levels of pollution, and with a small exposure contrast between study sites, provide us with important information about the autonomic effects of small changes in AP when AP levels are low. The crossover design of the study was a great strength, allowing us to contrast the health effects of exposure to AP near a steel plant and at a site farther from the plant. In the crossover design participants act as their own controls, reducing the potential for confounding by time-invariant individual characteristics such as age, sex, social status, residential air quality, and medical history. Some bias may have been introduced into the study due to the nature of the crossover design. It was not possible to blind the study participants or study team to the exposure arm, as the exposure was location specific, and the Bayview site was within view of the steel plant. The analysis of associations with individual pollutant levels, however, which pooled all pollutant exposures by participant irrespective of site, would have mitigated some of the bias introduced by the site dependence of the primary study design. The Sault Ste Marie Crossover study as a whole was a randomized controlled crossover study where the exposure conditions were not artificial, but rather were real world exposures, and therefore the significant results that this study has yielded may be generalizable to the Canadian population.
The results of our study, taken together with other studies, indicate that the patterns of changes in autonomic function associated with exposure to AP may differ between young healthy individuals and vulnerable individuals. Reductions in HF power are linked to pollutant and particulate matter exposure in diabetics [30] and the elderly [31], while this study, as well as Fakhri et al. [14] and Chuang et al. [28] reported few associations between AP and HF power, but significant inverse associations with LF power, all in healthy, younger populations. Despite the less clear pattern of significant associations with the frequency domain of HRV, HR and the time domain of HRV showed consistent significant inverse associations with changes in HRV. This is indicative of either reduced parasympathetic activation or enhanced sympathetic activation [22]. Increased sympathetic activation could be indicative of increased systemic stress, and would have wide ranging physiological consequences. Recent animal studies have shown that hypothalamic-pituitary axis and the autonomic nervous system may be activated by inhaled particulate and/or gaseous AP [33, 34]. Recent studies have pointed for a role of increased sympathetic activity in the health effects of AP [4, 34], however these alterations in autonomic function may be a direct mechanism of the health effects of ambient AP, or they may be a secondary effect of activation of oxidative stress pathways [4, 28].