T2DM is one of the most common chronic diseases with increasing prevalence. Patients with T2DM have a considerably higher risk of cardiovascular morbidity and mortality. T2DM is also a risk factor for AF. Individuals with diabetes mellitus have a 40% higher risk of developing AF than that without diabetes. Atrial electrical remodeling, structural remodeling and autonomic remodeling caused by T2DM may be the pathogenesis of AF[3, 6]. Yang S et al divided 6,199,629 patients without AF into the normal fasting glucose (NFG) group, the impaired fasting glucose (IFG) group, the diabetes duration < 5 years (early T2DM) group, and the diabetes duration ≥ 5 years (late T2DM) group, followed up for 7.2 years on average, and compared the incidence of AF among the groups. The results showed that the incidence of AF increased significantly with the progression of T2DM.At the same time, with the increase of FG, the risk of AF increased significantly. This study shows that FG is a predictor of AF in patients with T2DM with a poor predictive value. It can still be used as an indicator to prevent AF in patients with T2DM. Chang SH et al divided 645,710 patients with T2DM into the two groups based on the use of metformin or not, and followed up for 13 years. Multivariate Cox regression analysis showed that metformin reduced the incidence of new-onset AF significantly (HR = 0.81, P < 0.001). Chang CY et al divided 90,880 patients with T2DM who were taking metformin into the two groups according to whether they were taking dipeptidyl peptidase-4 inhibitor (DPP4i) or not, and followed up for 3 years. They found that DPP4i users were associated with a lower risk of new-onset AF compared with non-DPP4i users (HR 0.65, P < 0.0001). Therefore, the use of metformin or DPP4ito reduce fasting glucose in patients with T2DM may reduce the incidence of new-onset AF. For patients with poor glycemic control, metformin combined with DPP4i may bring more benefit.
Inflammation is involved in the initiation of AF, and AF leads to inflammation in turn, which maintains the occurrence of AF. Inflammation leads to inflammatory infiltration, necrosis and fibrosis of cardiomyocytes, which is the basis of atrial electrical remodeling and structural remodeling, and can lead to the occurrence and maintenance of AF. Monocytes are a type of inflammatory cells, which will accumulate rapidly during inflammation and secrete monocyte chemoattractant protein-1 (MCP-1) together with vascular endothelial cells, smooth muscle cells, macrophages, and cardiomyocytes. MCP-1 induces monocytes and vascular endothelial cells to express adhesion molecules and promotes the release of inflammatory factors such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α). IL-6 can directly affect connexins resulting in gap-junction dysfunction. TNF-α can down-regulation of channel protein expression. Both caused atrial electrical remodeling. MCP-1 and intercellular adhesion molecule-1 (ICAM-1) recruit macrophages. Macrophages secrete transforming growth factor-β (TGF-β) and profibrotic cytokines, which promote the formation of myofibroblasts and lead to myocardial fibrosis[13, 14].In addition, MCP-1 binding to chemokine receptor 2 (CCR2) induced a novel transcription factor (MCP-induced protein), which caused apoptosis of cardiomyocytes and lead to structural remodeling. HDL-C can inhibit the migration and activation of monocytes, thus reducing the inflammatory.
MHR is an inflammatory marker that combines inflammation and anti- inflammatory effects, which is associated with a variety of cardiovascular diseases. Some studies have shown that MHR is a risk factor for new-onset AF and postoperative AF recurrence. Ulus T et al divided 308 elderly patients with acute coronary syndrome undergoing percutaneous coronary intervention into the group with postoperative AF (n = 54) and the group without postoperative AF (n = 254). The difference in MHR between the two groups was statistically significant (P < 0.01), and multivariate logistic regression analysis showed that MHR was an independent predictor of new-onset AF (OR = 1.102, P < 0.001). Canpolat U et al included 402 patients with AF in their study and performed cryoballoon-based catheter ablation. The patients were divided into the four groups according to their preoperative MHR quartiles. The lowest to highest quartiles of AF recurrence were 7.1%, 6.9%, 15.8% and 65% (P < 0.01). Multivariate Cox regression analysis showed that MHR was an independent predictor of postoperative AF recurrence (HR = 1.20, P < 0.001).In our study, the area under ROC curve of MHR was 0.736, the sensitivity 65.6%, and the specificity 76.2%.It showed that MHR is a predictor of AF in patients with T2DM with a great predictive value.
At present, the correlation between blood lipid and new-onset AF is still uncertain. The decrease of plasma membrane cholesterol determines the distribution of Kv1.5 subunits, and lead to a slow and progressive increase in ultra-rapid delayed rectifier K+ current (IKur).It causes the action potential duration to shorten and the conduction velocity to slow down, then causes the atrial fibrillation. This may explain the inverse association between TC and AF, as well as LDL-C and AF. Lopez FL et alfollowed up 13,969 community participants over a period of 18.7 years, and found that high levels of LDL-C and TC were associated with lower incidence of AF. Mourtzinis G et al followed 51,020 primary-care hypertensive patients without AF for 3.5 years, and AF occurred in 2,389 participants. Poisson regression analysis showed that 1.0 mmol/l increase in TC was associated with 19% lower risk of new-onset AF (95% CI 9%-28%), and 1.0 mmol/l increase in LDL-C was associated with 16% lower risk of new-onset AF (95% CI 3%-27%).Other studies[20, 22, 23] have shown the same conclusion, which including white, yellow and mixed American populations. In our study, the levels of TC and LDL-C in the AF(+) group were lower than those in the AF(-) group, and multivariate logistic regression showed that TC was a predictor for AF, but not LDL-C.
Aspirin use is recommended for secondary prevention in T2DM patients with cardiovascular disease, which significantly reduced cardiovascular disease morbidity and mortality as well as all-cause death. For primary prevention, aspirin did not bring more benefits. In this study, antiplatelet therapy can reduce the incidence of AF in patients with T2DM. This suggests that early antiplatelet therapy may prevent AF in high-risk patients with T2DM.
Finally, the combination of TC, MHR, FG, LAD and antiplatele therapy were used to performed ROC curve analysis. Its AUC was higher than that of single index. The risk of AF in patients with T2DM can be evaluated more accurately by using the combined index. It can guide our clinical practice.
There are some important limitations in our study that need to be addressed. First, this study is a retrospective study with a small sample size. However, we attempted to adjust for potential confounders by propensity score-matched method and multivariate adjustment. Second, the unknown number of undiagnosed AF is a well-known issue, and we may have underestimated the true incidence of AF in this study. Longer continuous ECG monitoring for AF screening would detect more undiagnosed cases of AF. Finally, we cannot rule out residual confounding. Therefore, a prospective study with a large sample size is still needed to find the risk factors for AF in patients with T2DM, so as to verify the consistency of the results.