Apolipoprotein E (ApoE) is an important apolipoprotein in plasma that plays a key role in regulating lipoprotein metabolism. It is involved in lipid metabolism, oxidative stress, neuroimmune regulation, and inflammatory responses.1,2 There are three alleles of the human APOE gene, which can form six genotypes,3 thus forming a genetic polymorphism. Some of these genotypes may be susceptibility genotypes for hyperlipoproteinemia and arteriosclerosis.4,5 There are three ApoE genotypic categories: protective genotypes (ɛ2/ɛ2 and ɛ2/ɛ3), high-risk genotypes (ɛ3/ɛ4 and ɛ4/ɛ4), and others (ɛ2/ɛ4 and ɛ3/ɛ3).6–8

Atrial fibrillation (AF) is the most common type of arrhythmia. The mechanism of AF is complex, and previous studies have found that AF is closely related to dyslipidemia, excess weight or obesity, diabetes, metabolic syndrome, advanced age, smoking,9,10 hypertension, and various cardiovascular diseases.11 Analysis of a randomized controlled trial performed in the USA revealed that lower levels of low-density lipoprotein (LDL) and total cholesterol were associated with a higher incidence of AF.12 Other studies have shown that ApoE can promote the degradation of chylomicrons, LDL, and very low-density lipoprotein (VLDL) by binding to the low-density lipoprotein receptor (LDLR) and the liver ApoE receptor. We therefore hypothesized that ApoE may increase the risk of AF by degrading LDL.13,14 ApoE is involved in and has significant effects on all aspects of blood lipid metabolism, including the synthesis, secretion, transport, and metabolism of lipoproteins.15 Therefore, there is likely to be a correlation between ApoE and the occurrence of AF.

Additionally, inflammatory mediators, including high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, tumor necrosis factor-alpha (TNF-α), and transforming growth factor beta (TGF-β), are closely related to the occurrence and development of all AF types.16–18 Myocardial biopsies in healthy individuals and AF patients have demonstrated that the irreversibility of AF is associated with myocardial remodeling due to persistent inflammatory infiltration in cardiomyocytes.19 While ApoE has anti-inflammatory and antioxidative effects, ApoEɛ4 has a strong proinflammatory effect20 and activates nuclear factor-kappa B (NF-κB), which is involved in atrial remodeling.21

These data support the hypothesis that ApoE is associated with AF. This study was designed to examine the relationship between ApoE genetic polymorphisms and AF and to explore the relationship between ApoE genotype, phenotype, and AF.

ApoE, primarily expressed in the liver and brain, is an indispensable lipoprotein for physiological functions. Its most important function is to act as a ligand for the LDLR. Upon binding to the LDLR, ApoE enters liver cells, where it alters lipid metabolism and regulates lipid levels in the blood and brain.

Dyslipidemia is a recognized risk factor for atherosclerosis, and the incidence and severity of atherosclerosis are associated with the risk of AF.22 Previous studies concluded that high levels of LDL cholesterol are associated with a low risk of AF.23–25 However, other studies have shown no relationship between LDL and the occurrence of AF.22 In this study, univariate analysis showed that LDL was higher in the AF group than in the control group, and subsequent logistic regression analysis also showed that LDL was a risk factor for AF. Nevertheless, Alonso et al.26 concluded that total cholesterol is not related to the occurrence of AF, while other studies have suggested that it is associated with a low risk of AF.23–25 Our results showed no correlation between total cholesterol and AF. Generally speaking, although there is some controversy concerning the relationship between blood lipids and AF, it cannot be denied that ApoE may participate in the occurrence of AF by regulating blood lipids.

The slight effect of ApoE on blood lipid levels may not fully explain the effect of ApoE genetic polymorphisms on AF, because the development of AF is the result of many factors. This suggests that ApoE may have other biological functions and be involved in the occurrence of this disorder through other mechanisms.

Studies26,27 have reported that the occurrence and persistence of AF may be related to electrical and structural remodeling caused by electromechanical feedback associated with increased atrial diameter. In the current study, LAD in the AF group was greater than in the control group, and logistic regression analysis also showed that LAD was a risk factor for AF. Additional studies have found that ApoE has anti-inflammatory and antioxidant effects, and the order of these effects is ApoE2>ApoE3>ApoE4.28,29 The ApoEɛ4 allele lacks the anti-inflammatory properties of ApoEɛ2 and ApoEɛ3, but has a strong proinflammatory effect,27,30 which can lead to electrical and structural remodeling of the myocardium. This is supported by the higher hs-CRP levels in the AF group than in the control group in our study, as shown in Table 7. The mechanism may be as follows: ApoEɛ4 can activate NF-κB, resulting in the expression of monocyte chemoattractant protein-1 (MCP-1), TNF-α, IL-1β, IL-10, and other inflammatory mediators.16 MCP-1 can induce cardiomyocytes to express inflammatory cytokines including IL-1, IL-6, and TNF-α, causing negative cardiac inotropic effects, impairing cardiac function, and leading to myocardial structural remodeling.31,32 TNF-α may increase Ca2+ concentrations in cardiac myocytes,33 and downregulating L-type calcium channels leads to the shortening of action potential duration and the effective refractory period, and the formation of multiple reentry loops. At the same time, overloaded Ca2+ can activate calcium-activating proteins, leading to atrial contractile dysfunction through the degradation of cardiac troponin and other cardiac contractile proteins.34 This then results in atrial interstitial fibrosis, further leading to abnormal intra-atrial impulse conduction and atrial electrical remodeling. Taken together, these data support a correlation between AF and ApoE.

Many studies have shown that serum CRP is involved in the chemotaxis and activation of leukocytes and is an important marker of inflammatory responses.35 Chung et al.36 measured plasma CRP levels in 131 patients with atrial arrhythmias and 71 controls. They found for the first time that CRP was significantly increased in arrhythmias, confirming that inflammation may play an important role in the pathological mechanism of AF. At the same time, levels of plasma inflammatory markers are correlated with the burden of AF. CRP levels are significantly higher in patients with persistent AF than in patients with paroxysmal AF and normal controls. Our data also showed that plasma hs-CRP levels were significantly higher in the AF group than in the control group, indicating once again that CRP can be used as a marker of inflammation in AF and that inflammation plays an important role in the occurrence of AF.

Our results showed that there were no significant differences in gender, height, weight, smoking status, hypertension, type 2 diabetes, or coronary heart disease between the AF and control groups (p>0.05). However, we did observe significant differences in age, BMI, LAD, and LVEF. These findings suggest that older age, higher BMI, greater LAD, and lower LVEF increase the chance of AF. Advanced age is an independent risk factor for AF.23,37 Individuals with high BMI values may have high levels of body fat, which increases the prevalence of AF. Some studies have suggested that obesity is a risk factor for AF, and obese patients do in fact have a higher incidence and prevalence of AF, their disease is more serious, and it progresses faster.24 Obesity may increase the risk of AF through chronic inflammation caused by adipose factors. Taken together, our results suggested that ApoE may affect the occurrence of AF by regulating blood lipids and body mass. A greater LAD and low LVEF were mostly accompanied by myocardial electrical remodeling, structural remodeling, and fibrosis. These factors can easily lead to AF. In turn, the occurrence of AF will further increase LAD and decrease LVEF.

Six phenotypes, ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4 and ɛ4/ɛ4, were detected in 113 ApoE-genotyped subjects. The ɛ3/ɛ3 phenotype had the highest frequency, ɛ3/ɛ4 had the second highest frequency, and ɛ2/ɛ2 had the lowest frequency. ApoE genotypes can be divided into protective (ɛ2/ɛ2 and ɛ2/ɛ3), high-risk (ɛ3/ɛ4 and ɛ4/ɛ4), and others (ɛ2/ɛ4 and ɛ3/ɛ3). The risk of coronary heart disease, Alzheimer's disease, and stroke is average in patients with the ApoEɛ3 phenotype, lower for those with the ApoEɛ2 phenotype, and highest for those with the ApoEɛ4 phenotype. In this study, we found that the protective, high risk, and other genotypes accounted for 14.1%, 24.8%, and 61.1% of the sample, respectively. We also found that the distribution of the ApoE3 type accounted for 61.1% of the total, which is roughly consistent with previously published accounts.37 The high-risk ApoE4 genotypes accounted for 24.8% of the total. In this study, the ɛ3/ɛ3 genotype was significantly less frequent, while the ɛ3/ɛ4 and ɛ4/ɛ4 genotypes were significantly more frequent, in the AF group. The risk of AF in patients with ApoE4 (ɛ3/ɛ4, ɛ4/ɛ4) was the highest of all genotypic groups.

Finally, we found that penetrance of the ApoE4 phenotype was significantly higher in the AF group than in the control group. This may be related to the strong proinflammatory effect of the ɛ4 allele, which may be involved in the development of AF through the inflammatory pathway.14,16,38 Regression analysis of AF-related factors showed that the ApoE4 phenotype is an AF risk factor. ApoE4, as a risk phenotype, is likely to promote obesity, increased body fat content, and cardiovascular disease in patients with AF.39 Moreover, the role of ApoE4 in AF may be explained through the mechanisms of oxidative stress and inflammation.

Although the mechanistic relationship between ApoE polymorphisms and AF is not completely understood, in the context of the previous literature, our results suggested that AF is affected to some extent by ApoE polymorphisms, particularly ApoE4, as ApoE4 was more closely correlated with AF. Additionally, among related factors, we also found that older patients and those with hypertension, greater LAD, and lower LVEF had higher incidences of atrial arrhythmias. To help prevent cardiovascular events, attention should be paid to interventions for atrial arrhythmias at the genetic and molecular level, to reduce the occurrence of atrial arrhythmias and their serious complications.

Future research directions include further exploration of the role of ApoE2 in AF, including the use of multi-regional population studies and improving long-term patient follow-up.

This project was funded by the High-level Health Personnel “Six One Project” Top Talent Scientific Research Project of Jiangsu Province (LGY2017065), the Science and Technology Bureau of Lianyungang City (SH1618).

The data that support the findings of this study are available from The Second People's Hospital of Lianyungang, Jiangsu, China.

This study was approved by the institutional review board of the Second People's Hospital of Lianyungang Ethics Committee (no. L1618). All participants provided written informed consent.

The authors have no conflicts of interest to declare.