This longitudinal study showed that increased levels of particulate air pollution are associated with significant changes in ECG repolarization parameters reflecting myocardial substrate and vulnerability. The analyzed repolarization parameters showed different pollutant-specific responses, although some of the measured particulate pollutants were highly correlated. In association with ACP, PM2.5
, and OC concentrations for the whole 0–23-hr period before the recording, an increase in QTc could be seen, which was significant especially for OC. T-wave amplitude showed a significant decrease with UFP, ACP, PM2.5
, and EC concentrations measured during 0–5 hr (only borderline for EC) and during 0–23 hr before the recording (significant only for UFPs and ACPs). Consistently with this finding, T-wave complexity, a computerized measure of repolarization morphology, increased significantly in association with PM2.5
concentrations in the same time interval. The variability of T-wave complexity also showed an immediate borderline increase with PM2.5
concentrations measured during the 0–5 and the 0–23-hr time interval before the ECG and a significant increase in association with OC and EC concentrations during the whole 24 hr before recording the ECG. The observed inhomogeneous reaction to the air pollution mix for the analyzed repolarization parameters might point toward different actions of air pollution components on the complex repolarization process (Brook et al. 2004
Previous studies on the daily variation of particulate air pollution and heart rate variability in elderly subjects showed an increase in heart rate (Liao et al. 2004
; Peters et al. 1999
; Pope et al. 1999
) and a decrease in heart rate variability (Creason et al. 2001
; Gold et al. 2000
; Liao et al. 1999
; Pope et al. 1999
) associated with particulate air pollution. Animal data support the concept that the autonomic nervous system may be a target for the adverse effects of air pollution. Rats exposed to fuel oil fly ash, a known contributor to PM2.5
, developed an inflammation in the lung and also showed signs of inflammatory response in the heart (Killingsworth et al. 1997
). Instillation of residual oil fly ash caused cardiac arrhythmias in rats with preexisting pulmonary inflammation (Watkinson et al. 1998
). T-wave alternans, a marker of myocardial vulnerability and electrical instability, increases in dogs with inhalation of residual oil fly ash (Godleski et al. 2000
). Exposure to concentrated air particles induced an increase of the high- and low-frequency domains of the heart rate variability in healthy dogs (Godleski et al. 2000
). All of these findings suggest that inhaled particles may affect the balance between the sympathetic and parasympathetic control of the heart, and promote a stress response that potentially leads to arrhythmias.
This study demonstrates that air pollution also affects the other two components of the “cardiac death triangle,” the myocardial substrate and myocardial vulnerability, assessed by repolarization parameters. Abnormalities in repolarization morphology, described by the fairly novel measurement of T-wave complexity and T-wave amplitude, reflect the status of the myocardial substrate and were previously found to be associated with an increased risk of cardiac events in a cohort of healthy subjects (Kors et al. 1998
; Okin et al. 2002
) and in postinfarction patients (Zabel et al. 1998
) in studies unrelated to the field of air pollution. Our findings indicate that abnormalities in repolarization duration and morphology occur in response to an increased level of air pollution reflecting its short-term influence on the myocardium. Such changes might predispose to arrhythmic events. The risk of an arrhythmic event is further enhanced by the observed increased vulnerability of the myocardium (measured by the variability of T-wave complexity). Further evidence for this interpretation was collected by a study in patients with implanted cardioverter defibrillators, where increases in levels of ambient particles have been associated with increases in arrhythmia frequency (Peters et al. 2000
). Also, Riediker et al. (2004)
found a strong increase of ventricular and supraventricular ectopic beats with higher PM2.5
in-vehicle measurements in young, healthy, nonsmoking male highway patrol troopers.
In the study presented here, most of the changes in repolarization due to elevated air pollution (UFPs, ACPs, PM2.5
, OC, EC) started immediately. A decrease in heart rate variability with an increase in PM2.5
was analyzed in Pope et al. (1999)
for the same day and the previous day. Gold et al. (2000)
also showed immediate effects for PM2.5
concentrations during 0–3 hr before the testing, which is consistent with our findings 0–5 hr before the recording. Peters et al. (2000)
found an association between cardiac arrhythmia and a 2-day lag for PM2.5
, CO, and NO2
. Pekkanen et al. (2002)
showed an association between ACPs and ST-segment depression in the ECG on the 2-day lag. These findings lead to the hypothesis that the immediate effects in T-wave morphology and heart rate variability might lead 2 days later to a manifestation expressing in ST-segment depression or cardiac arrhythmia.
Particulate matter is a complex mixture containing many different components including metallic compounds such as iron, zinc, copper, vanadium, and nickel, which are potent inducers of physiologic effects in animals and humans (Campen et al. 2002
; Evangelou and Kalfakakou 1993
). Direct effects on the cardiovascular system, blood, and lung receptors, as well as indirect effects mediated through pulmonary oxidative stress and inflammatory responses, have been observed. The direct effects may occur via agents such as soluble constituents of PM2.5
or possibly UFPs that cross the pulmonary epithelium into the circulation. They might be an explanation for the quick cardiovascular responses within a few hours, as seen, for example, for the repolarization and T-wave morphometry changes in this study. Mechanisms under discussion (Brook et al. 2004
; Schulz et al., in press) include a dysfunction of the autonomic nervous system in response to direct reflexes from receptors in the lung, a cardiac malfunction due to ischemic responses in the myocardium, and/or altered ion channel functions in the myocardial cells. Complicating our understanding even more is the fact that different chemicals released from deposited particles are able to induce different ion channel reactions (Graff et al. 2004
). The observed change in QT interval and T-wave morphology might be indicative of changes in ion channel functions, but the understanding of the complex biologic pathways is still very limited. In contrast, responses within several hours or days after the inhalation of particles may possibly occur via pulmonary oxidative stress and systemic inflammation. These reactions are able to trigger endothelial dysfunction and a procoagulatory state with thrombus formation and promotion of atherosclerotic lesions.
It is conceivable that the combined effect of transient increases in blood coagulability (Seaton et al. 1995
), an acute-phase response (Ernst and Resch 1993
; Ridker et al. 2000
), an increase in blood viscosity (Peters et al. 1997
), and a change in myocardial substrate and vulnerability, as suggested in this study, could precipitate adverse cardiac events, especially in susceptible individuals.
Strength and limitations.
Our longitudinal study with multiple observations per subject has the advantage of an almost complete follow-up in all 56 participants for 6 months, with each subject being his own control. To assure the quality of the ECGs, all nurses were trained carefully and frequently checked by the quality assurance officer in terms of electrode placement as well as skin preparation. Because the ECG parameters differ from person to person (age, sex, genetics, physiology, pathophysiology, therapy), the confounder model included an indicator variable for each subject and thus indirectly adjusted for the interperson differences and medication use of the participants. Ischemic heart disease patients are of particular interest because their cardiovascular disease might make them particularly sensitive to the effects of air pollution episodes, and these patients are particularly prone to die from cardiac and arrhythmic death. The often high use of different medications in these patients is expected to bias the estimates toward the null and thus only leads to an underestimation of the effects. For subgroup analyses of different medication groups, the sample size and thus the statistical power were unfortunately too small.
We chose to focus on T-wave complexity and amplitude in addition to the QTc interval to evaluate changes in repolarization morphology and duration as more reliable descriptors of repolarization changes than QT duration. Accumulating evidence indicates that principal component analysis of the T-wave provides a better quantitative assessment of the complexity of repolarization than other ECG parameters and is becoming a useful tool in noninvasive ECG diagnostics (Okin et al. 2002
). The medical relevance of the observed changes in the analyzed ECG parameters might be small, but the results of this study will nevertheless help to understand the different pathways and mechanisms of the “cardiac death triangle” that lead from ambient air pollution to adverse cardiac events.
Misclassification of air pollution exposure is another potential source of bias especially in time-series studies (Zeger et al. 2000
). Factors such as wind direction, climatic conditions, long-range transport, and distances from sources affect personal exposure patterns to pollutants from ambient sources. But any exposure misclassification would be expected to be nondifferential and thus to bias the estimates toward the null.