How Can We Protect Susceptible Individuals from the Adverse Cardiovascular Effects of Air Pollution?

Air pollution is thought to be responsible for 7 million premature deaths worldwide each year, with the majority of deaths resulting from cardiovascular disease (1, 2). During the last 10 years, key mechanisms have emerged that link exposure to air pollution with the onset, progression, and clinical manifestations of cardiovascular disease (3). However, few studies have addressed whether these adverse effects of exposure to air pollution can be diminished or prevented. As such, our guidance to vulnerable individuals or those with established cardiovascular disease is based on expert consensus, rather than the results of rigorous clinical trials.

Chamber studies that permit controlled exposures to air pollutants under carefully regulated conditions have been invaluable in advancing our understanding of the health effects of air pollution in man. Even brief exposures to diesel exhaust at concentrations encountered in heavy traffic promote vasoconstriction (4), impair vasodilatation (5), and increase arterial stiffness (6). These effects are thought to occur as a consequence of millions of nanoparticles that penetrate deep into the lung and deliver reactive chemicals, instigating oxidative stress and inflammation (7). Indeed, removing nanoparticles from diesel exhaust through filtration prevents these cardiovascular effects (8). Although preventing exposure is clearly preferable, how can we identify and protect those at greatest risk of harm now? Can we harness our understanding of the pathophysiological effects of exposure to air pollution to design preventative strategies that limit their harmful effects?

In this issue of the Journal, Sack and colleagues (pp. 1000–1007) evaluate whether the use of antioxidant supplementation with ascorbate and N-acetylcysteine before exposure to diesel exhaust can prevent adverse vascular effects in a small, randomized, placebo-controlled clinical trial (9). They observe that exposure to diesel exhaust resulted in acute vasoconstriction in men and women without cardiovascular disease. Interestingly, these effects were more marked in individuals with variant alleles of the type 1 angiotensin II receptor (AGTR1), suggesting the adverse vascular effects of exposure to diesel exhaust may be mediated through the renin–angiotensin system. Perhaps surprisingly, antioxidant pretreatment not only did not prevent this effect but also appeared to augment the acute vasoconstrictor effects of exposure to diesel exhaust.

Unfortunately, seemingly paradoxical findings are not uncommon in studies of antioxidant supplementation, and there are a number of plausible explanations. First, in individuals without vitamin C deficiency, the absorption of high-dose oral ascorbate is limited, and supplementation may not significantly increase antioxidant levels in the vasculature. Limited bioavailability is unlikely to be the only explanation, as even direct intra-arterial infusions of vitamin C do not consistently reverse the endothelial dysfunction associated with cigarette smoking (10). There is some evidence that vitamin C supplementation can exert prooxidant effects (11) and impair vasodilatation to endothelial-derived hyperpolarizing factor (12). Together, these observations provide a plausible explanation for the enhanced vasoconstriction associated with antioxidant supplementation in the present study. Second, despite the evidence from cell and animal studies that air pollution induces oxidative stress, there remains little direct evidence to support this hypothesis in man. It is possible that the other mechanisms, such as activation of the autonomic nervous system or translocation of nanoparticles into the circulation, may account for the adverse cardiovascular effects of vehicle emissions.

Human exposure studies have made a major contribution to our understanding of the adverse health effects of air pollution. The contribution by Sack and colleagues is an important addition, and one of the few randomized controlled studies to evaluate the effectiveness of an intervention in modifying the effects of exposure (9). The study was well designed and included an exposure to filtered air and a matched placebo control. It seems unlikely, therefore, that the investigators have missed an important beneficial effect of ascorbate and N-acetylcysteine. Interestingly, studies in animals have shown that several therapies can attenuate the cardiovascular actions of exposures to particulate air pollutants, including statins (13), inhibitors of the renin-angiotensin system (14), endothelin receptor antagonists (15), β-blockers, and capsaicin receptor (TRVP1) antagonists (16). Whether use of these therapies will modulate the effects of air pollution on the cardiovascular system in man is not known.

A novel aspect of the study by Sack and colleagues was the use of stratification based on common variants of genes involved in oxidative stress, the renin-angiotensin system, and nociception (9). Although there was no difference in the vascular effects of exposure to diesel exhaust in individuals with variants in the glutathione-S-transferase (GSTM1) gene, those with the AC/CC allele in the AGTR1 or the CC/CT allele for the TRPV1 gene had more marked vasoconstriction than those individuals without. Although the study was underpowered to formally identify effect modification by these genetic variants, this approach has the potential to provide novel mechanistic insight and identify susceptible individuals. Observational studies support the concept that elderly individuals or those with preexisting cardiovascular disease are more susceptible to air pollution, although it has been challenging to demonstrate this in controlled exposure studies, as these groups already have marked vascular dysfunction before exposure (17, 18). The current study by Sack and colleagues suggests an alternative approach to identifying susceptibility may be possible, but these observations need to be verified in larger studies with interventions targeting the renin angiotensin-system and alveolar nociceptive sensory receptors (9).

Although determining whether preventative strategies in susceptible individuals are likely to be effective is undoubtedly important, this research also serves to highlight that our environment is an important and modifiable risk factor for cardiovascular disease. Addressing the complex societal and political barriers to limiting our emissions is challenging, and in many countries, especially developing countries with large urban populations, air pollution is escalating to previously unseen levels. At present, the best the scientific community can do is support regulations that limit important sources of air pollution and pragmatic policies that aim to reduce risk through traffic restrictions, and provide advice to vulnerable individuals to minimize exposure during major air pollution episodes.