We conducted a retrospective cohort study of 292,091 subjects to investigate the causal relationship between air pollutant exposure and the incidence of PAD. The results of the analysis demonstrated several important findings. First, exposure to SO2 and NO2 was significantly associated with an increased risk of PAD in the general population. Second, particulate matters such as PM2.5, and PM10 were not significantly associated with the incidence of PAD.
The first mechanism is a thrombogenic effect caused by platelet activation. Animal study results showed that fossil fuel exhaust particulates are directly translocated into the blood circulation through alveolar capillary trigger platelet activation and cause arterial thrombosis (12). This mechanism resulted in the same results in humans. The experimental subjects composed of volunteers who had developed thrombosis with rapid platelet aggregation (13). Thrombosis due to platelet activation induces CVDs including PAD. The second mechanism is inflammation. Inflammation is a risk factor for PAD. When exposed to fossil fuel exhaust air pollutants such as SO2 or NO2, the inhaled air particulates directly stimulate the macrophages or alveolar epithelium inside the lungs, causing inflammation. Inflammation occurs when cells stimulated by SO2 or NO2 produce reactive oxygen species (ROS), resulting in oxidative stress (14). Oxidative stress activates transcription factors such as nuclear factor–kappaB, which express pro-inflammatory mediators, cytokines, and chemokines (15). Inflammation is indirectly induced by fossil fuel exhaust particulates aggravating the disease in patients with chronic respiratory diseases such as asthma, COPD, and interstitial lung disease, which causes generalized inflammation. The third mechanism is the induction of hypertension, a well-known risk factor for CVD. Inhaled air pollution can downregulate nitric oxide synthase and affect autonomic nervous system dysfunction (16). These events result in vasoconstriction and hypertension, which persist for up to 1 day (17). In addition, the incidence of PAD is increased by mechanisms such as atherosclerosis or atherosclerotic plaque instability inducing plaque rupture (18).
Previous studies confirming the correlation between the existing CVD incidence and air pollution revealed that PM causes coronary artery disease (CAD), but there was no correlation in the incidence of PAD (19, 20). PAD and CAD showed different results depending on air pollution type, and among the mechanisms that affect the cardiovascular system, those that directly affect the heart are important. These mechanisms were applied only to CAD incidence and not PAD incidence among the PM exposure effects. The first mechanism is that PM directly affects cardiomyocytes. Exposure of the alveolar epithelium to PM increases ROS production (14). Excessive increases in ROS cause cardiomyocyte cell damage (21). PM-induced peroxide production affects calcium regulation in the Na–Ca exchange channel (22). This increases the concentration of cytosolic calcium and reduces cardiac contractility, leading to cardiac hypertrophy. Second, PM influences autonomic nervous system regulation, causing heart rate variability, which induces arrhythmia (23, 24). The activation of the sympathetic drive increases the incidence of cardiac arrhythmia and the risk of cardiovascular morbidity, including cardiac muscle remodeling and heart failure.
The main advantage of this study is that it analyzed real-world data. Its follow-up period was long. Previous CVD-related studies limited the period of air pollution exposure, so there is a limit to confirming how it affects daily life, but this study included a follow-up period of more than 4 years. Second, existing studies were conducted in places where the concentrations of air pollution were relatively low. Cities in Europe and North America may have underestimated the impact of air pollution on CVD, as their air pollution levels were not as high as those in Asian metropolitan cities (1). However, this study was conducted in cities where the degree of air pollution was much higher than those previously studied. Third, we adjusted the socioeconomic status (SES) data during the analysis process. SES is an important variable because it affects the risk factors for PAD, and there may be differences in the use of air purification facilities, such as indoor air cleaners, depending on SES (25).
This study also has some limitations. First, for a more practical analysis, outdoor and indoor air pollution analyses should be performed simultaneously. Indoor and outdoor air pollution have different types or concentrations of particulates, and people are exposed to indoor air pollution as long as outdoor air pollution. Second, among the risk factors for PAD, smoking history is an important confounding factor, but there were no related data. Race is also a risk factor for PAD, but the results of this study are limited to Asian populations.