INSTRUMENTO HALPERN – POST

It is still unclear why some subjects develop cardiovascular diseases or suffer from an MI due to certain triggers while others do not. Heavy physical exertion (Albert et al., 2000; Mittleman et al., 1993), extreme anger (Mittleman et al., 1995) and cocaine or marijuana use (Mittleman et al., 1999; Mittleman et al., 2001) have been reported as causes for an acute MI. Also, environmental stimuli such as second hand tobacco smoke (Barnoya et al., 2005) noise (Babisch, 2006), meteorology (Medina-Ramon et al., 2006; Medina-Ramon et al., 2007; Morabito et al., 2005; Sarna et al., 1977) and air pollution (Lanki et al., 2006; Peters et al., 2001a) are associated with an increased risk for adverse cardiovascular events. It is conceivable that individuals with special characteristics react in a more pronounced way to environmental factors than others. A generally higher level of inflammatory markers, and/or a higher variation in inflammation might represent one possible explanation.

A higher variation was seen in patients with elevated HbA1c and self reported type 2 diabetes. It is plausible, but speculative, that these subgroups also show a stronger reaction to environmental factors, e.g. a more pronounced inflammatory response.

5.3.1 Air pollution and hs-CRP

The current analyses are focused on the association between hs-CRP and air pollution as environmental parameter. Hs-CRP has been one of the first acute phase reactants to be examined in association with air pollution in literature. Increased concentrations have been shown during an air pollution episode in Germany in healthy men (Peters et al., 2001b) and for ambient PM10

levels currently present in Europe (Seaton et al., 1999). Additionally, in a panel of coronary heart disease patients, an increase in hs-CRP above the 90th percentile was found in association with ambient particles with a lag of two days (Ruckerl et al. 2006) (Appendix IV). The AIRGENE dataset did not show any associations between the measured air pollutants such as PNC, PM2.5,

PM10 or gaseous pollutants and hs-CRP; however IL-6 and fibrinogen concentrations were

elevated in association with increased ambient particles (Ruckerl et al., 2007) (Appendix III). A possible explanation for the lack of association between hs-CRP and air pollution in these data

might be the widespread intake of statins in the AIRGENE population. It has been shown that statins reduce CRP through inhibition of its hepatic synthesis (Arnaud et al., 2005). IL-6, which is produced upstream to the production of CRP in the liver, is not affected by this compound. Also, fibrinogen has been implicated to be reduced by fibrates but not statins (Rosenson et al., 2001). This study, in line with many others (Albert et al., 2001a; Dubowsky et al., 2006; Ridker et al., 2001; Rosenson et al., 2003), showed a clear negative association between statin intake and hs- CRP concentrations (Peters et al., 2007). It can be hypothesised that the intake of statins attenuates the impact of environmental parameters and might therefore, in addition to recommended guidelines, be beneficial in certain particularly susceptible subgroups to avoid adverse cardiovascular effects of environmental stimuli. Zeka et al. (2006) reported evidence for a greater effect of black carbon on inflammatory markers among non-users of statins. However, more research in this area is clearly needed.

5.3.2 Possible biological mechanisms

The exact mechanisms linking the inhalation of ambient air particles to an acute exacerbation of cardiovascular disease are not completely understood (Brook et al., 2004). Increased concentrations of hs-CRP are known to predict cardiovascular events in healthy subjects (Pepys et al., 2003) and alveolar inflammation induced by particles may either directly or via oxidative stress lead to systemic inflammation with increased levels of blood coagulability, progression of atherosclerosis, and destabilization or even rupture of vulnerable plaques, resulting in acute ischemic events (Brook et al., 2004; Peters et al., 1997; Pope et al., 2004; Seaton et al., 1995; Seaton et al., 1999). Hs-CRP, even at lower than medically relevant concentrations, can be considered as a sensitive marker reflecting systemic inflammation caused by particles.

In this dataset, in addition to a higher mean concentration in hs-CRP a higher variation in certain subgroups was found (Ruckerl et al., 2007 Appendix II) which might be one possible link for the reported associations between air pollution and adverse cardiovascular outcomes. Persistently elevated concentrations as well as acute changes in concentrations of inflammatory markers have

been associated with an increased risk of cardiovascular events in cohort studies (Koenig et al., 1999; Ridker et al., 1997).

MI patients were selected for this study, as it has been shown that individuals with certain diseases, such as diabetes and MI, have an enhanced susceptibility for air pollution related conditions, possibly due to a disease induced increased inflammatory burden (Bateson et al., 2004; Brook et al., 2008; Goldberg et al., 2001; Zanobetti et al., 2001). In this dataset, mean hs- CRP concentrations were not significantly higher in diabetic patients, but a higher variation was seen compared to non-diabetics. Furthermore, subjects with increased HbA1c (≥6.5%) showed

higher hs-CRP concentrations and higher variation.

Recent analyses demonstrate that diabetics seem to react especially strongly to environmental stimuli such as air pollution. O’Neill et al. (2007) report a positive association between air pollution and markers of inflammation in a panel of diabetic patients. Dubowsky et al. (2006) found that patients with diabetes, obese and especially individuals with metabolic syndrome showed stronger associations between air pollution and hs-CRP than subjects without any of these conditions. Results were similar for IL-6 (Dubowsky et al., 2006). However, the number of individuals was very limited in their analyses. In the AIRGENE dataset, analyses of effect modification showed that for fibrinogen associations were slightly higher and almost significant for the exposure to PM10 for patients with elevated HbA1c levels compared to patients with

HbA1c levels below 6.5%.

The biological mechanisms that apply to the association between air pollution and atherogenesis could also promote the development of diabetes. Insulin resistance, the main biological pathway that causes type 2 diabetes, is triggered by oxidative stress and proinflammatory mediators at the cellular and transduction level. Likewise, autonomic nervous system imbalance and impaired endothelial function can also lead to blunted insulin action. Air pollution is capable of causing such physiological responses (Brook et al., 2008). However, these hypotheses are still highly

speculative and more research on parameters that make a person especially prone to cardiovascular disease is needed.

Hypothesised mechanisms also differ regarding different size fractions of ambient particles. PM10

is suggested to affect the upper bronchi and therefore lead to an inflammation in the lung, whereas the smaller particles potentially transfer into the blood and start a systemic inflammatory response. According to Geiser (2002), UFP are rapidly translocated into the blood. It is therefore possible that the delay that has been observed in a previous study on hs-CRP and air pollution (Ruckerl et al., 2006) is due to the time needed to initiate the acute-phase response after a fast UFP translocation.