In this latest study based on the Southern Chinese cohort, we used the mediation model to check whether CRP and AST act as mediators in the association between DM and MI. Both CRP and AST are significantly related to MI, and DM has a highly significant direct impact on MI risk. The results show that most of the effects of DM are mediated through CRP and AST, and this indirect effect of CRP and AST accounts for about two-thirds of the risk of MI caused by DM.
Advanced statistical models may be important for accurately assessing the impact of multifactorial diseases, including the interactions between diseases and the regulatory effects of intermediate mediators on diseases. Mediation analysis is a promising method, which has been widely used in social science research and psychological research in the past, and can be used to determine possible mechanisms that mediate influencing factors-disease associations. It can flexibly explain the extent to which the influence of independent variables on the results can be mediated by potential potential intermediaries. It can also assess potential biases caused by exposure-mediation interactions, which are difficult to resolve with traditional methods. Serum CRP and AST values are independent predictors of mortality in patients with MI and have predictive value for the occurrence of MI. However, there are limited studies on the relationship between CRP and AST and MI patients after stratification by DM status (yes/no). Previous studies have showed that the increase in CRP value at admission is a risk sign of MI in DM patients, and the relationship between AST and MI has always been concerned. In the current study, CRP value and AST value are predictors of MI in diabetic and non-diabetic patients. In addition, our research further illustrates the mediating effect of CRP and AST between DM and MI.
CRP is mainly secreted by the liver and responds very quickly to infections, inflammatory diseases and tissue ischemia. The influence of inflammation on cardiovascular events has always been a key issue in clinical research. In the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), it was found that treatment with canakinumab (a monoclonal antibody that selectively neutralizes interleukin-1β) resulted in fewer cardiovascular events than placebo, patients with the greatest decrease in CRP levels experienced the greatest decrease in major cardiovascular events, and our study also found that the CRP value of no-MI patients is lower than that of MI patients, indicating that CRP may be the target of this benefit. A cross-sectional study showed that AST was positively correlated with the risk and severity of early coronary heart disease, suggesting that these enzymes can be used as surrogate markers of cardiovascular risk. Studies have shown that AST is related to the risk of myocardial infarction, the reduction of AST level can reduce the initial infarct size and fundamentally change the inflammatory response pattern of damaged myocardium. The results of this study are the same as ours, AST is positively correlated with the risk of MI.
We found that DM, CRP, and AST have a significant correlation in MI risk, which is consistent with the mediating effect of CRP and AST between DM and MI. However, we also found that creatinine is also significantly related to the risk of MI. Although the chance of discovery cannot be ruled out, a previous study found that compared with DM patients with increased serum creatinine during follow-up, DM patients with increased serum creatinine The risk of MI is increased, and this result is consistent with our findings. However, we did not find that creatinine has a mediating effect between DM and MI. This may be because creatinine affects the occurrence of MI risk through other channels, and ethnic differences also have a certain impact on the results. The results of the correlation analysis between TG and MI risk are also consistent with previously reported, that the increase in serum TG level causes an increase in MI risk, but we also found that there was no significant difference in TG levels between MI and no-MI patients (P > 0.05), and TG had no mediating effect between DM and MI.
AST plays the main mediating effect in the DM-MI association, and the DM-MI mediating effect mediated by CRP only accounts for 7.69%. Although the DM-MI association is not mainly mediated by CRP, it can significantly enhance the mediating effect of AST in the presence of CRP, which is reflected by the synergy of CRP and AST in the risk of DM-MI. The mechanism by which DM increases the risk of MI is still unknown. It may be through inflammation to increase the risk of MI. This is due to the high expression of CRP leading to greater inflammation and the myocardial inflammation induced by AST. A previous report supports our view, which shows that high expression of inflammatory factors in diabetic patients is significantly associated with an increased risk of MI.
To our knowledge, this is the first study to use mediation analysis to study the mechanism of DM-induced MI in a case-control study. The advantage of our research lies in the use of intermediary analysis beyond traditional analysis, which can provide more causal explanations for the interaction between disease and disease for specific hypotheses, and mediation analysis is a powerful tool to disentangle direct and indirect effects, which can provide insights on mechanisms. The existence of chain intermediary explains the interaction between the factors that affect the disease, which is more comprehensive for the discovery of the mechanism. We performed coronary angiography on all participants to avoid misclassification of asymptomatic CAD and other heart diseases that may show symptoms similar to MI (such as pericarditis and cardiomyopathy).
There are several limitations to this study. First, we only studied some biochemical indicators and traditional cardiovascular risk factors, and smoking and drinking status are self-reported, which may be misclassified due to memory errors, and exposure through passive smoking is not included in the model, which may affect the results to a certain extent. Therefore, the influence of unmeasured mediator-outcome confounding factors or the interaction between exposure factors and intermediary can not be ruled out. These may play a role effect in the research. Some other influencing factors (such as obesity, environmental factors, eating habits, etc.) may also affect the development of DM-MI in the same direction, which would result in changes in the degree of direct effect and indirect effects. CRP and AST only represent part of the mediating effects, which may include more complex mediating effects and unresearched regulatory effects. Therefore, it may overestimate the mediating effect of CRP and AST on the association of DM-MI, and the discovery of more mediators associated with DM-MI is of great significance for improving the predictive ability of CRP and AST and as a reference for the treatment of diseases. Finally, the study mainly included individuals of Han ethnicity in South China, so it is not clear whether these findings can be generalized to other populations.