To the best of our knowledge, the current prospective cohort study is the first to report positive and non-linear associations of long-term exposure to O3 with incident hypertension, elevated SBP, DBP, PP and MAP among the general employed population in a highly polluted area. Compared with the Q1 of O3 concentrations, the HRs of hypertension for the Q2 to Q4 were 1.77 (95% CI: 1.34, 2.36), 2.06 (95% CI: 1.42, 3.00), and 3.43 (95% CI: 2.46, 4.79), respectively. SBP, PP and MAP significantly increased by 2.49–2.88, 2.03–2.14, and 1.04–1.39 mmHg with ozone concentrations of Q2–Q4 compared to ozone concentrations at Q1, while DBP increased modestly by 0.65 mmHg only at ozone concentrations of Q2. The robustness of our findings was confirmed by the consistent results when one or both of two air pollutants (PM2.5 and NO2) were added to the models and those who reported doctor-diagnosed incident hypertension during the follow-up were excluded. Stratification analyses indicated that the long-term impacts of O3 exposure persisted regardless of sex, age and BMI, while males, overweight and obese individuals were more vulnerable. These findings might improve the current understanding of the role of O3 exposure in the occurrence of hypertension and blood pressure modulation.
Although the relationship between ambient pollutants and blood pressure or hypertension has been enormously investigated, the impacts of long-term exposure to O3 on hypertension were much less addressed [4, 39, 40]. Prior to our study, several cross-sectional studies reported inconsistent relationships of long-term exposure to O3 with prevalent hypertension, however, its association with incident hypertension was seldom investigated [10, 39]. One prospective cohort study in black women found that every 6.7 ppb increment of O3 exposure was associated with a 9% (HR: 1.09; 95% CI: 1.00, 1.18) higher risk of incident hypertension based on the single-pollutant model with adjustment for potential covariates. However, the estimated HR attenuated to non-significance (HR: 0.94; 95% CI: 0.94, 1.15) once another pollutant (NO2 and PM2.5) was further added to the model, leaving the relationship still unsolved [15]. Another longitudinal study among African American with a high (56%) prevalence of hypertension failed to observe any significant association of 1-year O3 concentrations (RR: 0.91; 95% CI: 0.77, 1.08) or 3-year O3 concentrations (RR: 0.93; 95% CI: 0.84, 1.02) with incident hypertension [13]. It is important to note that these studies assessed the ozone exposure levels of the study subjects' residential addresses. Given the diurnal pattern of O3 concentrations, i.e., higher concentrations during the day and lower concentrations at night [17, 18], the studies above may have misestimated the ozone levels that caused adverse health effects on the study subjects. Moreover, the low levels of ozone exposure and small study sample sizes may have reduced the power of the aforementioned longitudinal studies, resulting in the failure to detect any positive associations between O3 exposure and the development of hypertension. Our study, which restricted the participants to working adults, with a large sample size, prospective design and high levels of O3 exposure, found a positive association of 3-year exposure to ozone at workplace with incident hypertension. The results remained consistent and statistically significant when we applied two-pollutant models by adding PM2.5 and NO2. Our findings not only confirmed the overall positive association between O3 exposure and the risk of incident hypertension, but also indicated that this association was robust against other air pollutants.
Although blood pressure levels are a better measure of the health risks associated with blood pressure than hypertensive status, only a few studies have evaluated the effect of long-term O3 exposure on blood pressure levels and the results were inclusive [14, 39]. Moreover, the longitudinal effects of long-term ozone exposure on blood pressure indicators have been rarely documented [39]. The aforementioned prospective study in highly hypertensive African Americans, due to the smaller variation in O3 exposure (IQR = 0.7 ppb) and sample size (n = 4,105), detected only marginal and non-clinically relevant effect of 3-year O3 concentrations on blood pressure indicators, e.g., SBP, DBP, MAP increased by 0.20 (95% CI: 0.001, 0.39), 0.14 (95% CI: 0.03, 0.25) and 0.16 (95% CI: 0.04, 0.29) mmHg for every interquartile increment in O3 concentrations, while the increment of PP was non-significant (0.05 (95% CI: −0.11, 0.20) mmHg). The impact of long-term ozone exposure on blood pressure remains to be clarified. Nevertheless, the current study, with much large sample size and greater variation in ozone exposure, detected considerable significant increases in SBP, DBP, MAP and PP, which may not only contribute to a more profound understanding of the effects of ozone exposure on blood pressure indicators, but may also have potential clinical relevance.
Notably, we observed the most substantial increases in SBP, where the increments were 2.88 (95% CI: 2.00, 3.77), 2.49 (95% CI: 1.36, 3.61), and 2.61 (95% CI: 1.64, 3.58) mmHg higher for the second to fourth quartile, respectively, compared with the first quartile of O3 exposure concentrations; whereas the least substantial increases were observed in DBP, suggesting that long-term exposure to O3 impacts SBP more than DBP. Higher SBP has been consistently associated with increased CVD risk after adjustment for or stratification by DBP, whereas the results about the association between higher DBP and CVD risk are inconsistent after adjustment for or stratification by SBP [41–44]. High SBP has been a vital contributor to death at the global level [1]. Therefore, our findings suggest that the adverse effects of long-term exposure to ozone on blood pressure may contribute to deleterious cardiovascular outcomes or death.
Though a few positive findings regarding the effects of long-term ozone exposure on elevated SBP, DBP and MAP, no significant findings have been reported regarding the relationship between long-term ozone exposure and elevated PP [10, 13, 14]. Determined by the compliance of arteries and the timing and intensity of arterial wave reflections, PP is usually considered as an indicator of arterial stiffness [45]. The current finding, by reporting for the first time a significant effect of long-term ozone exposure on elevated PP, may suggest that arterial stiffness is involved in the blood pressure regulation induced by long-term O3 exposure, in contrast to previous studies that reported positive correlations between short-term or long-term O3 exposure and SBP, DBP and MAP, and smaller or non-significant correlations with several indices of arterial stiffness (including carotid-femoral pulse wave velocity, anterior pressure wave amplitude and augmentation index) [10, 13, 46–48]. Our study provides evidence of a positive relationship between long-term O3 exposure and elevated SBP, MAP, and PP, which may improve the current understanding of the role of long-term ozone exposure in the regulation of blood pressure and the development of cardiometabolic diseases.
Even though previous studies have mostly assumed a linear relationship [11–15], the detailed shape of the relationship between O3 exposure and the risk of hypertension remains a key question that has not been addressed. With a wide range of O3 exposure concentrations in our study (35.43 to 50.96 ppb), using generalized additive mixed models, this study revealed a non-linear relationship between O3 exposure levels and incident hypertension, where the risk of hypertension increased slowly from 35.43 to 44.09 ppb, while it was at almost a stable level within 44.09 to 47.07 ppb, and then elevated sharply when the concentrations were greater than 47.07 ppb. Previously, mixed results have been found regarding the relationship between O3 exposure and cardiovascular outcomes. For example, several recent large cohort studies in the US and China showed that long-term exposure to O3 was positively and monotonically related to cardiovascular mortality [5, 49, 50], whereas null or even negative associations were also reported in cohorts from France, Denmark, and the UK [51–53]. Since hypertension is one of the most important risk factors for various cardiovascular outcomes, the non-linear shape of the relationship between O3 exposure and hypertension might indicate the presence of non-linear associations between O3 exposure and other cardiovascular outcomes.
The prospective nature may be the key strength of the current study. By conducting the large-scale, population-based cohort study, we, for the first time worldwide, quantify the impacts of long-term exposure to O3 on incident hypertension and blood pressure among the general employed population in a highly polluted area. Second, we focused our study on the working population and estimated their daytime ozone exposure levels, i.e., workplace ozone exposure levels, rather than nighttime ozone exposure levels, i.e., residential ozone exposure levels. Considering the diurnal pattern of ozone concentration, with higher concentration in the daytime and a lower concentration at night [17, 18], O3 exposure at daytime address is what causes health risks. By using workplace O3 exposure, we might have controlled exposure measurement bias and improved the power of the study. Third, instead of assuming the linear relationship between ozone exposure and hypertension, we transformed the ozone exposure concentrations to a four-level categorical variable based on their quartiles, and also utilized the GAMMs to detect a non-linear relationship between ozone exposure and hypertension and blood pressure indicators, which is vital for a more detailed understanding of the hypertensive effects of ozone exposure and provides new perspectives for future studies on the health effects of ambient pollutants. Fourth, only the urban population was included in this study to ensure the reliability of the results. Given the different sources and components of ambient pollutants in urban and rural areas [54], as well as the differences in factors affecting hypertension and susceptibility to hypertension in urban and rural populations [55], the inclusion of both urban and rural populations in the study may introduce additional confounding, thus reducing the power of the study and the reliability of the results. Finally, we included the highly prevalent cardiometabolic risk behaviors in contemporary society, i.e., sleep deprivation and being sedentary, as covariates, and also included personal mask-wearing and air purifier use in the model, which had never been considered in previous studies.
Nevertheless, our findings must be interpreted with caution due to several limitations. We did not collect information on or adjust for some factors affecting blood pressure, such as salt intake and dietary patterns, resulting in a confounding bias in the results. Moreover, as in most previous epidemiological studies, we could not account for the geographic mobility of the population during the follow-up period.