The most common complication of AF is thromboembolism, especially IS [6]. AF-related IS has high rates of mortality and disability. Because of the combination of high morbidity with a low diagnosis rate for cardiogenic stroke, it is of great significance to accurately identify high-risk patients and provide timely treatment to prevent the occurrence of IS in patients with AF. Currently, there is no risk model that can accurately predict IS in patients with AF. A large sample cohort study showed that the C-statistic of CHA2DS2-VASc score was 0.68, with only moderate predictive capacity [21]. Therefore, the present study explored the risk factors for IS in patients with NVAF in Xinjiang and provided the basis for further clinical treatment. First, multivariate logistic regression analysis showed that LDL-C/HDL-C > 1.22, smoking, BMI ≥ 24 kg/m2 and CHA2DS2-VASc score were independent risk factors for IS in patients with NVAF. Second, principal component regression analysis showed that LDL-C/HDL-C, age, smoking, drinking, hypertension and LDL-C were risk factors for IS in NVAF patients.
In this study, high LDL-C/HDL-C was found to be an independent risk factor for IS after adjusting for age and other related factors, indicating that high LDL-C/HDL-C may influence the progression of IS through particular pathways. The potential mechanism of the positive correlation between LDL-C/HDL-C and IS in NVAF patients remains unclear; however, there are several possible mechanisms that could explain this phenomenon. First, LDL-C/HDL-C indicates the proportions of atherosclerotic and anti-atherosclerotic lipoproteins, thus offering improved power for predicting the development of atherosclerosis. High LDL-C/HDL-C may indicate vulnerability to atherosclerotic plaques, which are prone to plaque rupture and thrombosis and eventually lead to IS. Okuzumi A et al. [22] indicated that high LDL-C/HDL-C was significantly correlated the vulnerability of aortic plaque in patients with IS. Second, LDL-C/HDL-C may be closely related to inflammation because HDL-C has anti-inflammatory and antioxidant properties [23], and LDL-C may be correlated with inflammation [24]. The high LDL-C/HDL-C ratio may be due to an increase in inflammatory components, a decrease in the anti-inflammatory and antioxidative components reflected in the denominator, or both. Pinto A et al. [25] observed that inflammatory markers, including TNF-α, IL-6 and von Willebrand factor (vWF), were predictors of new-onset IS in patients with chronic NVAF. vWF aggravates ischaemic injury by promoting thrombosis in the injured vessels, a finding that provides a new target for antithrombotic therapy [26-27]. Inflammation has been confirmed to be associated with left atrial thrombosis in AF patients [28]. Previous studies have found that inflammatory biomarkers are significantly associated with left atrium or left atrial appendage thrombus outcomes in AF patients [29]. In conclusion, LDL-C/HDL-C may cause IS in NVAF patients by promoting atherosclerosis and left atrial or left atrial appendage thrombosis.
Studies have found that smoking affects serum lipid metabolism, increasing the level of LDL-C while decreasing HDL-C [30-31]. After smoking cessation, LDL-C levels remain unchanged, while HDL-C levels increased [32]. Nicotine and oxygen free radicals in tobacco cause or aggravate vascular endothelial dysfunction, atherosclerosis and hypercoagulability through a variety of mechanisms [33-35]. These factors can promote thrombosis. Previous studies have shown that smoking increases the risk of thromboembolism or death in AF patients [36-37]. Incorporating smoking as a risk factor for IS in CHADS2 and CHA2DS2-VASc scores could better predict the risk of IS in male patients [38]. Weight gain increases the LDL-C concentration and decreases the level of HDL-C [39-40]. With increases in BMI, serum lipids and blood viscosity increase significantly, leading to thromboembolism and IS [41]. The present study found that an increase in BMI is an important risk factor for IS in NVAF patients. Previous studies have shown that BMI is negatively correlated with IS in AF patients [42], which is contrary to the results of the present study. At present, the relationship between obesity and IS remains controversial [42-43]. Large sample, multicentre and prospective studies are needed to further explore the relationship between BMI and serum lipids and the influence of this relationship on adverse event outcomes in AF patients. In conclusion, smoking and BMI can increase the LDL/HDL ratio, which may lead to an increased risk of IS in NVAF patients by promoting atherosclerosis and cardiogenic thromboembolism.
Age is a risk factors for IS in AF patients. Previous studies have shown that AF is a disease of ageing, and with increasing age, the incidence of AF and stroke increases [5, 44]. With increasing age, LDL-C and HDL-C show an upward trend [45]. However, other research reached different or opposing conclusions [46]. There is a close relationship between serum lipids and age, but conclusions differ among research studies, possibly due to age, geographical and ethnic differences in study populations. Moderate drinking can increase HDL-C and decrease LDL-C levels [47], which seems to be beneficial for reducing the risk of cardiovascular disease. However, the effects of drinking on IS are multifaceted and complex. Alcohol intake is a risk factor for thromboembolism, which may offset the protective effect of serum lipids through unknown mechanisms. Studies have found that long-term drinking can cause vascular haemodynamic changes, altered blood viscosity, and enhanced platelet aggregation, which subsequently promote the occurrence of IS [48]. The Stroke Prevention in Atrial Fibrillation (SPAF) I-III trials found that the incidence of IS in patients with AF who regularly drank a small amount of alcohol was lower than that in patients who did not drink alcohol [49]. In contrast, heavy drinking was related to a higher risk of IS [50]. Patients with hypertension have increased LDL-C levels [51] and normal or reduced levels of HDL-C [51-52]. It has been shown that statins can reduce blood pressure when they are taken for lipid-lowering therapy [53], indicating that hypertension is closely related to dyslipidaemia. Hypertension is closely related to stroke, and active and effective control of blood pressure can reduce the incidence of IS [54]. Anti-hypertensive treatment can therefore reduce the incidence of stroke in hypertension patients [55]. In terms of mechanisms, hypertension can cause vascular haemodynamic changes, leading to atherosclerosis, and stenosis of the lumen, and can affect the blood supply of brain tissue [56]. At the same time, hypertension can promote the remodelling of left atrial structure and function and eventually lead to atrial fibrosis and electrical activity changes [57]. These changes, together with local or systemic inflammatory reactions, lead to local thrombosis or atherosclerotic thrombosis in the left atrium [57]. In conclusion, age, alcohol consumption, hypertension and serum lipid levels are closely related, and IS also closely related to these factors, which can lead to the occurrence of IS through the effects of lipoproteins and other mechanisms (as mentioned above).
The results show that the PC1 had the highest contribution (17.27%), and the LDL-C/HDL-C and HDL-C had the highest loads. HDL-C was negatively correlated with IS, and LDL-C/HDL-C was positively correlated with IS. The contribution rate of PC2 was 14.25%, and the factor loads of smoking and drinking were the highest, suggesting that bad living habits are among the risk factors for IS in AF patients. The contribution rate of PC4 was 12.49%. LDL-C and age had the highest factor loads, and they were positively correlated with IS. PC5 had the lowest contribution rate (10.78%), and hypertension was the factor with the highest load, suggesting that blood pressure is the factor that influences IS in AF patients. These results suggest that in clinical practice, in addition to the use of the classic CHA2DS2-VASc score to assess the risk of AF stroke, blood lipid-related parameters should be considered, as well as poor living habits and other factors. Blood lipid-related parameters include LDL-C/HDL-C, which comprehensively considers the impact of blood lipids on stroke and is a better indicator than either measure alone.
In summary, the findings of present study demonstrated that LDL-C/HDL-C, smoking, BMI, age, alcohol consumption, LDL-C and hypertension were risk factors for IS in NVAF patients. LDL-C/HDL-C is the main risk factor, which manifests that LDL-C/HDL-C may help identify AF individuals who are at high risk of IS and who may benefit from lipid-lowering therapy. Recent studies have found that the correct and continuous use of statins may reduce the risk of cardiogenic stroke recurrence, which is consistent with the findings of this study [58]. In clinical practice, AF patients often have various diseases, such as hypertension, diabetes, and coronary atherosclerotic heart disease, which create challenges for medical staff in the overall management of AF. In addition to focusing on the CHA2DS2-VASc score, factors such as blood lipid levels, smoking and drinking should be considered in AF patients, comprehensive health education should be provided, interventions for unhealthy lifestyles should be strengthened, and comprehensive management measures should be formulated to reduce the incidence rate and harm of IS. Wańkowicz P et al. [59] found that anticoagulant therapy alone cannot effectively prevent the occurrence of IS in NVAF patients. They believe that statins can be used for the secondary prevention of IS, and AF patients should improve their lifestyles.