Associations Of Plasma Cytokines With The Heart Rate Variability And Risk Of Acute Coronary Syndrome

Objective:Along with economic growth and industrialization, one of the major causes of air pollution is the combustion of coal, gasoline and other fossil fuels, which can induce inflammation and cause adverse health effects, such as decreased heart rate variability and increasing risk of cardiovascular diseases (CVD). Cytokines as important inflammatory biomarkers play an essential role in the path-physiology of adverse health effects and acute coronary syndrome (ACS). Therefore, our goal in this study was to assess relationships between plasma cytokines and alteration in HRV in coke oven workers and risk of ACS, respectively.Methods:In the discovery stage,280cytokines were measured quantitatively in small samples including8coke oven workers,12ACS patients and16controls with solid-phase protein microarrays.4top cytokines were validated in568coke oven workers and5top cytokines were validated in two independent sets of case-control studies using enzyme-linked immunosorbent assays (ELISA). In568coke workers, the concentrations of12urinary OH-PAHs were determined with gas chromatograph-mass spectrometer, urinary creatinine was determined using a Randox Daytona fully automated clinical chemistry analyzer and HRV indices by Holter monitor. The trend for plasma cytokines and OH-PAHs, HRV indices were tested by multiple linear regression models or generalized linear models and the association of plasma cytokines with risk of acute coronary syndrome with binary logistic regression and Meta analysis.Results:Among a number of notable findings, the plasma levels of23cytokines in the coke oven workers were significantly higher than those in the controls, and4top cytokines were validated in568coke oven workers. Even when considering potential confounders, we found positive dose-dependent trends between CRP and the concentrations of1-hydroxypyrene,1,2-hydroxynaphthalene,2-hydroxyfluorene,1-,2-hydroxyphenanthrene,3-hydroxyphenanthrene,9-hydroxyphenanthrene and total OH-PAHs (P trend<0.05for all); ALCAM and the concentrations of1-hydroxypyrene,1-hydroxynaphthalene,2-,3-hydroxyphenanthrene,9-hydroxyphenanthrene and total OH-PAHs (P trend<0.05for all); While inverse dose-dependent trends were found between BDNF and1-hydroxypyrene,1-hydroxynaphthalene,2-hydroxyfluorene,9-hydroxyfluorene,4-,9-hydroxyphenanthrene and total OH-PAHs (P trend<0.05for all). After adjustment for potential confounders, an inverse relationship between plasma cytokines and HRV indices including SDNN, rMSSD, LF and TP (P<0.05). Additionally, we found that the plasma levels of15cytokines in the ACS patients were significantly higher than those in the controls, and5top cytokines were validated in two independent sets of case-control studies. The results of logistic regression analysis showed that high expressions of CRP, OPN and CCL23were significantly associated with the increased risk of ACS and lower expressions of BDNF significantly were associated with increased risk of ACS, which was consistent with the results of Meta analysis of two independent case-control studies. Moreover, when the four biomarkers (CRP, OPN, CCL23and BDNF) were incorporated into a model (as expanded model) with established risk factors, the difference related to the area under the curve (AUC), net reclassification index (NRI) and integrated discrimination index (IDI) between the basic and expanded models was calculated, the AUCs of basic models were significantly improved after adding4cytokines (C statistic with biomarkers vs. without biomarkers:0.902vs.0.986, P＜0.0001;0.836vs.0.980, P<0.0001); furthermore, it is of interest to observe the contributions of the4cytokines to the improvement in NRI and IDI compared with basic models (P＜0.0001).Conclusion:Our findings represent positive associations between OH-PAHs and CRP and ALCAM, respectively, and an inverse association of OH-PAHs with BDNF; Moreover, these polycyclic aromatic hydrocarbons-associated cytokines were associated with decrease in HRV, which suggested that plasma cytokines play a crucial role in regulating environmental factor-induced adverse health effect. Lower BDNF and higher CRP, OPN and CCL23were associated with an increase in risk of ACS, which may indicate that the pathological processes leading to ACS would induce characteristic changes in the concentrations of plasma cytokines, generating detectable disease-specific molecular phenotypes which may be promising biomarkers.