As cardiologists know to their cost, the course of coronary artery disease is highly unpredictable. Although the disease accounts for about 20% of all deaths in developed countries and high levels of morbidity, in most cases the disease is clinically silent. Autopsy studies reveal that more than half of all people over the age of 60 and over a quarter of adults under this age have coronary artery disease. Even when this is manifest as angina, the annual event rate is only about 3%. When adverse events occur, however, they usually do so without apparent cause and without warning. About half of the deaths due to coronary artery disease are sudden and, of these, half are due to plaque rupture and intracoronary thrombosis.¹ In the remainder, although severe coronary artery disease is often present, no evidence of thrombus is found at autopsy and the cause of death is believed to be arrhythmic. If most adult residents of the western world are walking around with coronary artery disease, what are the factors that determine whether, on any given day, the disease remains silent or presents with an acute coronary syndrome or sudden arrhythmic death? Could external environmental factors increase the chances of plaque rupture or arrhythmia? If so, what are the mechanisms?

AIR POLLUTION AND CORONARY ARTERY DISEASE

Of the environmental factors examined, air pollution has become a prime suspect. While modern levels of particulate and gaseous pollutants are far lower than those of the 1950s, they continue to be related to daily total and cardiovascular mortality rates.² A large number of papers from independent researchers in geographically and climatically distinct regions of the world have shown a consistent association between daily levels of pollution and cardiovascular mortality and morbidity including strokes, arrhythmia, and myocardial infarction. The effect size appears small; an increase of 10 μg/m³ in fine particulate pollution is associated with an increase of less than 1% in daily cardiovascular mortality (mean 24 hour levels in urban areas are usually about 20 μg/m³ but can approach 100). On an individual level, this is an effect much smaller than smoking but, because it is an ever present stimulus to the entire population, the number of deaths attributable to this effect may be very large indeed.

Two areas of research into coronary artery disease have begun to shed light on the mechanisms by which air pollution might result in adverse cardiac events. Pulmonary inflammation as a result of air pollutant exposure might give rise to a systemic cytokine mediated inflammatory response. Atherosclerosis is an inflammatory disease and there is no doubt that there is a relationship between levels of inflammation and cardiovascular risk. An increase in C reactive protein (CRP) levels is predictive of cardiovascular risk in subjects with coronary artery disease and in apparently healthy subjects with or without conventional risk factors.³ Possible mechanisms include effects on plaque stability, endothelial function, platelet activation, and coagulation. A second mechanism by which airborne pollution might lead to adverse cardiac events is via adverse effects on cardiac autonomic control, either as a result of airway receptor stimulation or as an indirect consequence of an inflammatory response. There are robust data linking high levels of sympathetic tone and low levels of vagal control—as assessed by measurement of baroreflex sensitivity, heart rate variability and catecholamine levels—to mortality and the occurrence of arrhythmia in patients with heart failure, survivors of myocardial infarction, and even in healthy volunteer groups.^4–6 There is also convincing evidence to suggest that this relationship is causal. Numerous animal studies have shown that sympathetic tone increases and vagal tone reduces the susceptibility to ventricular fibrillation.^7–9

In keeping with these inflammatory and autonomic hypotheses, observational studies have found that there are associations between daily levels of particulate pollution and markers of both inflammation and heart rate variability (HRV). Levels of CRP and plasma viscosity increased during an episode of pollution in Germany in 1985 that was also associated with a dramatic increase in hospital admissions for cardiac events.¹⁰ During the same episode heart rates were increased, suggesting an increase in sympathetic nervous activity and/or vagal withdrawal. Subsequently, small panel studies from Boston,¹¹ Baltimore,¹² and Utah¹³ supported this interpretation, finding that HRV was reduced during particulate pollution episodes. More recently, larger studies from Mexico¹⁴ and from Utah¹⁵ have shown that high frequency (vagal) components of HRV vary inversely with levels of particulate matter less than 2.5 μm in diameter (PM_2.5), particularly in at risk subjects with hypertension. A human challenge study has also shown that experimental exposure to concentrated ambient particles results in reduced HRV.¹⁶

Two new papers that further investigate the relationship between ambient pollutant concentrations and HRV are published in this issue of Thorax.^17,18 Once again they are small studies with fewer than 40 subjects in each case. What new information do these papers provide? Schwartz and colleagues¹⁷ working in Boston examined the effect of locally measured pollutants on HRV and confirmed the results of their earlier study, showing an inverse association between the preceding 24 hour average PM_2.5 and high frequency HRV indices of cardiac vagal control such as r-MSSD. A weaker effect on SDNN, a measure of total variability that includes non-autonomic influences, was observed. In a sophisticated analysis they found that the effects of black carbon were slightly greater in magnitude than those of PM_2.5, and that these effects were present in all individuals studied although they were strongest in the three subjects with a previous myocardial infarction. The study is perhaps best viewed as hypothesis generating, but it does suggest that traffic related particles exert even more powerful adverse effects on cardiac autonomic control than PM_2.5 which, in Boston, is composed predominantly of long range transported sulphates probably derived from industrial emissions. This result accords with a recent report that implicates exposure to traffic as a trigger of myocardial infarction.¹⁹ It is also consistent with the hypothesis that subjects with coronary artery disease are at particular risk from the adverse effects of air pollution.

In contrast, Sullivan and colleagues¹⁸ working in Seattle found no association between 1, 4 or 24 hour outdoor or indoor exposure to particulate matter and any frequency or time domain measure of HRV in 24 elderly individuals monitored over 10 day periods. These results are in disagreement with previous published work. Publication bias cannot be excluded as an explanation for the absence of previous negative studies, but could there be methodological or other features of this study that might explain the negative results? Unlike most previous reports, the measurement of particulates was performed at each individual’s home rather than at a local monitoring station. However, this should be viewed as a major strength of the study and it is hard to see how this could have been responsible for anything other than increasing the strength of any association with HRV values. The study was performed on the western coast of the United States and the authors speculate that the particulate pollution in this region may differ in its composition from that of previous studies in other areas. There is evidence that the toxicity of particulate pollution is related to the content of reactive metal species and sulphates. The particles in Seattle may have contained lower levels of these toxic components than those from regions such as Boston and Baltimore, although no information on this is given in the paper. A more likely explanation, however, may lie in the combination of low PM values and the small range of concentrations encountered. It is possible that there were simply too few periods of high exposure to cause any detectable effects on HRV and this, in turn, is probably a reflection of the short 10 day study periods. A further factor could be the inclusion of 21 patients with cardiovascular disease in the study, a large proportion of whom were on drugs such as β blockers and ACE inhibitors known to increase HRV and preserve vagal tone under conditions of stress.²⁰

The relationship between air pollution and both autonomic control and inflammation clearly requires further study. There is, however, a key piece of evidence missing in both of these mechanistic theories. Paradoxically, the prognostic value of both HRV and CRP is established for medium and long term associations but not for short term effects over hours or days. Unless it can be shown that changes in these markers precede adverse events within an appropriate time scale, the significance of reports of changes in response to day to day fluctuations in pollutant levels must remain in doubt. On biological grounds both mechanisms appear plausible. An inflammatory cytokine response resulting in a rise in CRP occurs within hours in response to infection, inflammation, and tissue damage—events that occur frequently throughout life. Similarly, sympathetic and cardiac vagal activities vary constantly in response to reflex stimuli, emotion, exertion and, of course, inflammation and infection. Support for the concept also comes from the recent reports that CRP varies markedly over time in patients with coronary artery disease,²¹ even when clinical infective episodes are excluded, and from the finding that acute respiratory and urinary tract infections are associated with a transient increase in the risk of a stroke and myocardial infarction.²² In addition, a small study of patients with heart failure showed that cases of sudden death were preceded by intra-individual increases in CRP and falls in HRV.²³ As the American Heart Association has recognised in their recent statement, further research on the relationship between air pollution, autonomic control, inflammation, and adverse cardiac events is required.² Funding bodies should be aware of this new field that has been termed “environmental cardiology”. The results of research could be of immediate value to people with coronary disease—and this includes most of us!