A large number of epidemiologic studies showed an association between short-term exposure to increased particulate air pollution and CVD morbidity and mortality (Brook et al. 2004
; Craig et al. 2008
). However, the mechanisms responsible for such an association have not been fully identified. Previous studies suggested several promising underlying mechanisms, including cardiac autonomic impairment as measured by lower heart rate variability (Creason et al. 2001
; Gold et al. 2000
, Liao et al. 1999
; Pope et al. 1999
). Other studies indicated that impaired cardiac autonomic control may lower the threshold for arrhythmia (Huikuri et al. 2001
), and that ECG-detected ectopy, especially that of ventricular origin, may predict cardiovascular disease mortality (Engel et al, 2007
; Rautaharju et al, 2006a
). Because many publications repeatedly reported an association between acute PM exposure and lower HRV, it was postulated that an acute increase in ambient PM concentration may imbalance sympathetic and parasympathetic nervous control of the heart and thereby decrease threshold for ectopy. Through such PM-mediated decreases, short-term acute PM exposure may thereby trigger the onset of clinical cardiac events. In our study, data on the PM exposures, the HRV measures, and ectopy measures were presented. However, since ectopy is an exclusion criterion for our HRV measures, it was not possible to assess this hypothesis directly in this population. Instead, the associations of PM exposure with ectopy (this paper) and HRV (to be published else where), were assessed, respectively.
Among the post-menopausal women participating in the WHI clinical trials, a significant, direct association was found between acute exposure to ambient PM2.5 and PM10 and ventricular ectopy among current smokers that gives some credence to this hypothesis. This study, however, did not find significant associations between acute PM exposure and ventricular ectopy among non-smokers, acute PM exposure and supaventricular ectopy, or chronic PM exposure and ectopy.
This is the first study to demonstrate such an association in a large, non-patient, geographically diverse, female population not selected on the basis of having an ICD (). The study thereby broadens the scope of the extant literature in the area, which to date, has been based on a handful of small, overlapping, single-city studies of majority-male, patient populations with ICD or Holter ECG assessed potential role of ventricular arrhythmogenesis in PM-mediated cardiovascular risk (Peters et al 2000
; Rich et al. 2004
; Vedal et al. 2004
; Dockery et al. 2005a
; Ebelt et al. 2005
; Berger et al. 2006
; Sarnat et al. 2006
; Metzger et al. 2007
). Our findings are nonetheless consistent with those previously described in several of these populations, although as a group, the WHI CT participants were clearly much less vulnerable to ventricular tachyarrhythmia than those in . If our findings are confirmed by others, the confirmation would provide support for the hypothesized role of autonomic imbalance and ventricular arrhythmogenesis in PM-mediated cardiovascular risk.
Human studies of the PM-ventricular arrhythmia association
It should be noted that this study has several limitations that may affect interpretation of its findings. First, it is an ancillary study of participants in the WHI clinical trial. As such, women in it were randomized to estrogen ± progestin treatment, calcium / vitamin D supplementation, and / or dietary modification. Although randomized, these exposures may have affected measures of both ectopy and smoking status. However, it is of interest that adjustment of treatment arm did not change the pattern of association in our data. Similarly, the participants selected to participate in the WHI clinical trials may not be representative of the general female population. This is evidenced by lower current smoking rate in this population (6%) as compared to the US female population (about 18%).
Second, ectopy was measured from resting, standard 12-lead ECG which were only 10 sec in duration. The presence and temporal distribution of ectopy are highly variable and dependent on circadian rhythms, physical activity, as well as on other environmental and clinical conditions. Clinically, the standard duration used to evaluate ectopy is 24 hr, which was not feasible in this large-scale, population-based study. However, it is important to note that a standard 12-lead ECG only captures an extremely small window of cardiac rhythm, and is insensitive for detecting ectopy among relatively healthy populations especially when its frequency is low or varies diurnally. Despite such insensitivity, it has been argued that when the purpose is to identify participants at risk with relatively high specificity, short ECG recordings serve this epidemiologic objective reliably. Indeed, ectopy frequent enough to be captured by short recordings may carry more prognostic significance than ectopy infrequent enough to require long recordings to capture it (Abdalla et al. 1987
; Evenson et al. 2000
; Ruberman et al. 1981;1981b
). The insensitivity of the ECG may have nevertheless biased the observed association between acute PM exposure and ventricular ectopy towards the null. It is also possible that the frequency of ectopy among smokers is higher than that among non-smokers, which may lead to even lower sensitivity of detection among non-smokers. This may help explain why an association between PM and ectopy among non-smokers was not found.
was not directly measured in the personal breathing space of participants. Instead, it was spatially interpolated at each participant’s geocoded address, raising questions about its validity as a surrogate of personal exposure or biological exposure. To overcome this particular limitation, the reliability and accuracy of address geocoding (Whitsel 2004
), and spatial interpolations (Liao et al. 2006
) was carefully established. The advantages of our spatial correlation based PM estimation over traditional area averages was previously discussed (Liao et al. 2006
). Finally, data on the chemical components of the ambient particles were not available. Therefore, one can only implicate the involvement of both PM10
concentrations, but can not elucidate the specific chemical components responsible for their adverse effects.
In this study, a significant effect modification by current smoking status in the acute PM exposure-ventricular ectopy relationship was shown. Our finding is consistent with that from the American Cancer Society-Cancer Prevention II (ACS-CPII) study, which also found that PM exposures were more strongly associated with mortality from dysrhythmias and cardiac arrest among current than former or never smokers (Pope et al. 2004
). Such effect modification is biologically relevant, for several reasons. It is well-known that smoking increases vulnerability to various adverse health conditions, as illustrated by e.g. ACS-CPII. Our data are suggestive of a higher vulnerability to PM effects among smokers. It is also likely that current smoking is related to higher frequency of ectopy, and by extension, higher chance of detection by the standard 12-lead ECG. These arguments provide plausible explanations as to why observed associations between acute PM exposures and ventricular ectopy in non-smokers lacked significance in this context, if not others.
The present data show that the subacute exposures (Lag30
) and chronic exposures (Lag365
) are not significantly associated with ectopy. Moreover, when simultaneously controlled for subacute and chronic exposures into the analyses, the association between acute exposures (Lag0
) and ectopy remained similar. Such a lack of chronic effects, similar to our previous findings (Liao et al. 2006
), support our hypothesis that PM effects on cardiac autonomic control are in general acute. Studies are needed to examine the actual time course of PM effects.
Finally, multiple statistical models were utilized in our analyses. Given the biological plausibility, our a priori hypothesized short-term acute effect (e.g. Lag0 and Lag1 effects), data were not adjusted for multiple testing in our main findings. As such, it was not possible to fully exclude the possibility of significant findings by chance. However, it is very unlikely that “the chance findings” just occurred among those to be most vulnerable and on the exposure windows that are believed to be the most important time period for PM action. For the interested readers, Bonferroni correction was performed on OR of PM2.5 effect on ventricular ectopy among current smokers (OR=2, 95% CI 1.32, 3.03, ). After correction for 30 tests performed in , the Bonferroni-corrected OR remained significant (OR=1.36, 95% 1.03 to 3.89). It can be argued that this application of Bonferroni correction is over-conservative; that is, variuos studies showed that PM exerted more adverse health effects at lag1 and lag0 than at other lags. Therefore, the number of tests need to be adjusted for need to be smaller than 30 used in the above example. For all of the above reasons it was decided to present the main results without adjusting for multiple testing.
In summary, acute exposure to ambient PM2.5 and PM10 is directly associated with higher odds of ventricular ectopy among smokers, suggesting that they are more vulnerable to the arrhythmogenic effects of PM. These and other published data support the proposed role of autonomic imbalance and ventricular arrhythmogenesis in PM-mediated cardiovascular risk.