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Effect Of Atherosclerosis On The Relationship Between Atrial Fibrillation And Ischemic Stroke Incidence Among Patients On Hemodialysis – Scientific Reports – Renal.PlatoHealth.ai

Main findings

A lack of a consistent association between AF and new-onset CI in patients undergoing HD was reported by a previous small-sample study; therefore, in the present study, we attempted to identify the association between AF and new-onset ischemic stroke using a nationwide database. Similar to the findings in patients not undergoing HD, the presence of AF was closely associated with new-onset ischemic stroke in Japanese patients undergoing HD, even after adjusting for confounding variables. Another important new finding of this study was that the association between AF and CI was attenuated with an increasing number of atherosclerotic complications, although not statistically significant. This finding does not support our hypothesis that atherothrombotic CI, rather than cardiogenic cerebral embolism, plays a primary role in the development of ischemic stroke in patients with AF on HD.

AF and new-onset ischemic stroke

This nationwide large-sample study showed that as in patients not undergoing HD, the presence of AF was closely associated with new-onset ischemic stroke in Japanese patients on HD. However, an important point to discuss is the difference in the magnitude of the impact of AF on ischemic stroke between patients on HD and those not on HD. Two previous community studies that did not include patients undergoing dialysis reported a much higher risk of ischemic stroke in patients with AF than that in patients with AF in the present study. In the Framingham study, the incidence of stroke was estimated to be approximately 25/1000 participants/year in patients with AF, which was 4.8 times higher than the incidence rate of approximately 5/1000 participants/year in patients without AF11. A community study conducted in Taiwan reported that in patients with AF, the incidence of ischemic stroke of 37.7/1000 participants/year was 8.3 times higher than that in patients without AF (4.5/1000 participants/year)17. In the present study, the incidence rates were 49.1/1000 patients/year in patients with AF and 31.9/1000 patients/year in patients without AF; the rate was 1.5 times higher in patients with AF than that in patients without AF who were on HD. These findings show that the relative risk for ischemic stroke in patients with or without AF was lower in those not undergoing HD than that in those undergoing HD. This phenomenon has been confirmed in previous studies15,18. The difference was the higher incidence of stroke in patients without AF who were on HD than that in patients with AF who were on HD. The incidence rate of CI was high, even in patients without AF, which was probably due to advanced atherosclerotic lesions. These findings are supported by those of previous studies18,19. In patients undergoing dialysis, CI due to thromboembolism caused by AF is not as common as it is in patients not undergoing dialysis, and atherothrombotic CI may be more common than CI due to thromboembolism. These findings suggest that cardiogenic thromboembolism may not be the main cause of CI in patients with AF undergoing HD compared with that in healthy participants. This may explain the lack of ample evidence on anticoagulation with warfarin is effective in preventing the onset of CI16.

Effect of atherosclerotic disease on the relationship between AF and ischemic stroke

If atherosclerotic disease and not thromboembolism is the main cause of ischemic stroke, the impact of AF on new-onset stroke may differ according to the severity of atherosclerosis. After excluding patients with pre-existing cerebrovascular disease, we analyzed the incidence of stroke according to the presence of AF under conditions stratified by the severity of atherosclerotic disease according to the presence of coronary artery disease and peripheral artery disease. The attenuation of the odds ratio from 1.57 to 1.04 parallelly with an increase in the number of atherosclerotic diseases from 0 to 2 was confirmed; however, the P-value of this interaction was 0.34, indicating no significant effect of atherosclerosis on ischemic stroke. In patients with severe atherosclerosis, we could not conclude that atherosclerotic disease, rather than cardiogenic thromboembolism, might be the primary cause, even if complicated by AF; further investigation is essential to confirm this possibility.

Risk factors for de novo ischemic stroke

In the present study, independent of the traditional risk factors and AF, older age, diabetes mellitus, smoking, blood pressure, atherosclerotic disease, malnutrition, and inflammatory markers were closely associated with ischemic stroke. Malnutrition-inflammation-atherosclerosis (MIA) syndrome20 is often observed in patients on HD. The retention of uremic toxins, dysregulation of glucose metabolism, hypertension, dyslipidemia, hyperuricemia, and infection can lead to increased levels of proinflammatory cytokines, consequently increasing serum CRP levels21. This persistent low-grade inflammation potentially plays an important role in the accelerated progression of atherosclerosis through an increase in the number of cellular adhesion molecules expressed on the surface of vascular endothelial cells, which can induce endothelial dysfunction22. Patients on HD with ischemic lesions evaluated using brain computed tomography or magnetic resonance imaging show higher CRP levels than those with hemorrhagic stroke or normal imaging results23.

The inverse relationship between BMI and ischemic stroke indicates that malnutrition is a risk factor for CI. As intradialytic weight gain may be a marker of malnutrition due to appetite loss, it is theoretically reasonable that a negative association between malnutrition and BMI exists. In addition to low-grade inflammation, low appetite due to azotemia, increased catabolism, decreased nutrient and calorie intake due to dietary restriction, and nutrient loss during HD24 are often observed and cause malnutrition in patients on HD; therefore, malnutrition is highly prevalent among these patients25. The mechanism by which malnutrition contributes to ischemic stroke involves the antioxidant role of albumin26, which consequently plays a role in the progression of atherosclerosis. Hypoalbuminemia was shown to be associated with coronary artery narrowing in patients with end-stage kidney disease27. Low BMI and hypoalbuminemia have been reported to be independent risk factors for stroke in Japanese patients on HD28.

Clinical implications

While not statistically significant, the association between AF and new-onset ischemic stroke weakened with an increase in the severity of the atherosclerotic disease. This finding implies that the balance between the risks and benefits of anticoagulant therapy in preventing thromboembolism varies depending on the atherosclerotic disease. For example, in patients with AF on dialysis complicated by coronary artery disease or peripheral arterial lesions, the risk of bleeding complications may be higher than the thromboembolic preventive effect of warfarin. This may be partly explained by the regular use of antiplatelet agents in patients with comorbid atherosclerotic disease. An increased risk of bleeding complications has been reported with concomitant anticoagulation therapy in patients on oral antiplatelet agents29. The use of anticoagulation for preventing thromboembolism in patients with AF on HD remains unclear because the results of the relevant randomized controlled studies have not yet been reported. Randomized controlled studies in selected patients with no history of atherosclerotic disease may be required to confirm the benefits of anticoagulation in these patients.

Strengths

The present study has several strengths. First, the findings of the association between AF and stroke obtained in this study are precise and generalizable because the analysis was based on nationwide data with a large sample size. Second, consideration of DAGs which included hemodialysis-specific confounding factors such as ultrafiltration rate and MIA syndrome minimized bias in the analysis of the association between AF and stroke.

Limitations

First, the diagnostic criteria for AF were confirmed using a single resting 12-lead ECG; however, we were unable to identify the subtype of AF (paroxysmal, persistent, or chronic). Thus, the number of patients on HD with AF, especially those with paroxysmal AF, may be underestimated. The prevalence of AF reported in this study was lower than that previously reported9. Thus, the possibility that patients who suffered CI in the absence of AF had paroxysmal AF could not be ruled out. However, currently, in a clinical setting, accurate identification of paroxysmal AF using any routine examination technique is difficult. In addition, the JRDR registry was unable to collect the data on the duration of AF, which is reported to be useful for stroke risk stratification among patients with non-kidney disease30.

Second, information regarding the use of anticoagulants was not available. The effectiveness of anticoagulants in preventing thromboembolism in patients with AF on HD remains unclear. However, warfarin is routinely used in Japan, where DOACs are not available, based on CHADS2 scores31. Warfarin users could be included in the analysis population of the present study. A previous study suggested that warfarin is useful in preventing CI in patients undergoing dialysis19. A part of the reason for the smaller risk of CI associated with AF than that in the general population can be because patients with AF included warfarin users.

Third, we could not distinguish between the three types of CI (atherothrombotic CI, cardiogenic cerebral embolism, and lacunar infarction) using our survey database. Thus, as shown in many studies, CI in patients with AF may not necessarily be due to a cardiogenic cerebral embolism. This may have caused a bias in the results. However, this bias is always inherent to studies using large volumes of survey data, such as the present study. We believe that the present study is unlikely to contain a particularly strong bias compared with other similar studies.