Clinical features of ischemic stroke in patients with nonvalvular atrial fibrillation combined with intracranial atherosclerotic stenosis

Abstract Background Nonvalvular atrial fibrillation (NVAF) and intracranial atherosclerotic stenosis (ICAS) are major causes of ischemic stroke. Relatively few studies have focused on the risk factors and clinical features of ischemic stroke caused by NVAF combined with ICAS. Method We retrospectively evaluated NVAF and/or ICAS in patients with acute ischemic stroke admitted within 72 h after stroke. All patients with acute ischemic stroke underwent diffusion‐weighted magnetic resonance imaging (DWI), magnetic resonance angiography (MRA), computed tomography angiography (CTA), and/or digital subtraction angiography (DSA). NVAF was detected by routine electrocardiogram or 24‐h Holter examination, Doppler echocardiography, and contrast echocardiography of the right heart. Results Among the 635 enrolled patients, NVAF, ICAS, and NVAF+ICAS were diagnosed in 170 (26.77%), 255 (40.16%), and 210 (33.07%) patients, respectively. Patients in the NVAF+ICAS group were older (p < .001), specifically aged ≥75 years (p < .001). The admission time of the NVAF+ICAS group was shorter (p < .001) than that of the ICAS group. The admission NIHSS score of the NVAF group was higher than that of the NVAF+ICAS group (p < .001). HsCRP, NTpro‐BNP, and LEVF levels were significantly different among the three groups (p < .001). NVAF+ICAS ischemic stroke occurred mainly in the right hemisphere (52.4%). Conclusion NVAF with ICAS ischemic stroke is more likely to occur in older patients. Infarctions occurred mainly in the right cerebral hemisphere. Neurological deficits in NVAF are more severe than those in NVAF combined with ICAS and in simple ICAS ischemic strokes. HsCRP, LEVF, andNTpro‐BNP seem to be closely associated with NVAF+ICAS ischemic stroke.


INTRODUCTION
Ischemic stroke is the main cause of death and disability among adults and has become a major public health concern worldwide (Katan & Luft, 2018). In recent years, China has observed and increased stroke burden. A previous study reported on the prevalence of stroke in China between 2013 and 2019. In most provinces of China, the prevalence of stroke continues to increase annually, and the weighted prevalence of stroke is higher for male sex, older age, and residence in rural and northeast areas (Tu et al., 2022). Patients with cardioembolism usually present with severe neurological deficits and recurrent strokes.
Atrial fibrillation (AF), especially nonvalvular atrial fibrillation (NVAF), is associated with more than half of all cardioembolisms and early neurological deterioration (Ogata & Yasaka, 2007). Numerous studies have explored the risk factors and pathogenesis of ischemic stroke due to NVAF Kim et al., 2015;Matsumoto et al., 2013). However, not all ischemic strokes with NVAF are related to cardioembolism; the occurrence of ischemic stroke in patients share many modifiable and nonmodifiable risk factors, and there are also some important differences in clinical practice Sun et al., 2018). Some patients with ischemic stroke with NVAF also present cerebral atherosclerosis (Abolbashari, 2022;Sun et al., 2018). Clinical observations have shown that most patients with cerebral atherosclerosis have intracranial atherosclerotic stenosis (ICAS) in Asia, especially in China (Niu et al., 2014). The interaction mechanism between NVAF and ICAS in the occurrence and development of ischemic stroke remains unclear; therefore, the pathogenesis, treatment options, and prevention strategies for ischemic stroke are complicated by the coexistence of NVAF and ICAS.
Clinical studies have reported high-risk factors for ischemic strokes caused by NVAF or ICAS, and their overlapping factors include age, hypertension, diabetes, dyslipidemia, homocysteine levels, and metabolic syndrome Wang et al., 2017). However, most of these results indicated a positive correlation between multiple risk factors and ischemic stroke. Only a few studies have reported the differences in the risk factors and related mechanisms of NVAF combined with cerebral atherosclerosis, and sound scientific evidence is still lacking. In this study, we retrospectively analyzed patients with ischemic stroke with first NVAF combined with ICAS and sought to identify the relevant risk factors and mechanisms to provide meaningful references for further prevention and treatment.

Patients
We retrospectively studied patients with first-ever ischemic stroke  (Men et al., 2013;NCEP, 2002). Clinical data from the following imaging modalities were also collected: magnetic resonance imaging (MRI) with MRA, CTA or DSA, carotid duplex ultrasonography, electrocardiography or 24-h electrocardiography (Holter), Doppler echocardiography and contrast echocardiography of the right heart (within the next 3 days after stroke). Fasting (no caloric intake for at least 8 h) venous blood samples were collected within 24 h of admission. The laboratory tests included homocysteine (Hcy), high-sensitivity C-reactive protein The exclusion criteria were as follows: (1)  incomplete records and loss to follow-up.

Clinical data and assessments
Patients with AF were characterized by a history of AF or an episode of AF lasting more than 30 s. Electrocardiography or 24-h electrocardiography (Holter) showed absolutely irregular RR intervals F I G U R E 1 Study patients selection. and no discernible or distinct P waves lasting for at least 30 s (the frequency was between 350 and 600 beats per minute) (Chen et al., 2018). Patients with ICAS with significant intracranial stenosis (those with ≥50% stenosis or occlusion) were characterized by duplex imaging or arteriography according to the methods

Statistical analysis
Data from selected patients were compared among the three groups. Normally distributed numerical variables are expressed as mean ± standard deviation, nonnormally distributed numerical variables are expressed as medians (interquartile ranges), and categorical variables are expressed as percentages. T-test and the Kruskal-Wallis test were used for independent normally and nonnormally distributed continuous variables, respectively, while the χ 2 or Fisher's exact test was used to analyze the relationships between categorical variables.
The risk factors that were significant in the one-way analysis were determined by multifactor logistic regression, and the odds ratio (OR) and 95% confidence interval (95% CI) were used to estimate the risk of each factor. p < .05 was considered statistically significant. All statistical analyses were performed using the SPSS software, version 26.0.

Ethics statement
This study was approved by the local Ethics Committee of the affiliated Hospital of Weifang Medical University. The written or oral informed consent for this study was obtained from the patients or their family members. The research ethics approval number was wyfy-2022-ky-202.

Baseline characteristics of patients with strokes of different etiologies
As shown in Table 1

Infarction location in strokes of different etiologies
The locations of the infarct areas are presented in Tables 3 and 4.

Multivariate logistic regression analysis of the three groups
Multifactor logistic regression analysis showed that age (OR = 0.809,    Hcy = homocysteine; HsCRP = hypersensitive C-reactive protein; WBC = white blood cell; PLT = platelet count; RBC = red blood cell; Hb = hemoglobin; HbAlc = glycohemoglobin A1c; UA = uric acid; FIB = fibrinogen; NTpro-BNP = N-terminal pro-B-type natriuretic peptide; LEVF = left ventricular ejection fraction; TC = total cholesterol; TG = triglycerides; HDL-C = high-density lipid cholesterol; LDL-C = low-density lipid cholesterol; NVAF = nonvalvular atrial fibrillation; ICAS = intracranial atherosclerotic stenosis. Inflammation plays a crucial role in the pathogenesis of ischemic stroke. The HsCRP level is positively correlated with the severity of ischemic stroke as an inflammatory factor (Swastini et al., 2019). We also found that HsCRP levels were higher in the NVAF and NVAF+ICAS groups than in the ICAS group. Our data agree with those of previous TA B L E 4 Infarction location in stroke of different etiologies. only changes the heart structure and remodels atrial systolic function (He et al., 2018), but also activates renin-angiotensin aldosterone to downregulate LEVF. We hypothesized that NVAF did not play a primary role in the NVAF+ICAS infarct mechanism. These factors, either alone or in combination, affect the occurrence of strokes of different etiologies.

Distribution of infarct areas
Currently, there is controversy regarding the hemispheric distributions in ICAS ischemic stroke. However, reports have suggested that ICAS with an artery-to-artery embolism mechanism principally occurs in the left cerebral hemisphere, the hypoperfusion mechanism occurs F I G U R E 3 NVAF patient. A 78-year-old male was admitted 3.5 h after stroke and he was a NVAF patient. A+B: DWI, C: FLAIR, D: MRA. Multiple infarct in the right cerebral hemisphere. No obvious atherosclerotic stenosis in MRA.
in the right cerebral hemisphere, and the infarction volume in the right hemisphere is commonly larger than that in the left (Fink et al., 2002;Naess et al., 2006;Rastogi et al., 2015;Rodriguez Hernandez et al., 2003). We found that the infarction foci were located in the left cerebral hemisphere in most ICAS groups (Figure 4), and this pathogenesis was primarily artery-to-artery embolism. It is noteworthy that the different geometries of the aortic arch branches may affect CE laterality.
Some studies have shown that NVAF is more common in the right cerebral hemisphere (Figure 3), which is inconsistent with reports that CE ischemic stroke is symmetrically distributed in both hemispheres (Elsaid et al., 2020;Naess et al., 2006;Rastogi et al., 2015;Rodriguez Hernandez et al., 2003). Our results showed that the proportions of the left and right cerebral hemispheres in the NVAF group were equivalent.
The proportion of patients with right hemispheric infarction was higher in the NVAF+ICAS group ( Figure 2). This may be explained by the pathogenesis of CE and intracranial hypoperfusion. Further prospective studies are needed to understand the laterality of the hemispheric distribution, explore the infarct distribution pattern, and speculate on the pathogenesis of ischemic stroke.
Moreover, Hcy has been reported to be an independent risk factor for ischemic stroke, and can promote the formation of atherosclerosis by mediating the inflammatory response. It was closely correlated with AF. However, there were no significant differences in Hcy levels among the three groups, suggesting that Hcy might be a risk factor. There is no consensus on the relationship between uric acid and ischemic stroke.
Some studies believe that uric acid is a major risk factor for ischemic stroke (Verdecchia et al., 2000) and that patients with AF are more susceptible to coexisting with hyperuricemia than the general population (Nyrnes et al., 2014). Nevertheless, other studies (Lee et al., 2009) believed that uric acid was a protective factor with the prognosis of ischemic stroke. Our study did not find a correlation between uric acid and ischemic stroke. This still required to expand the sample size for verification and further analysis.
However, our study has some limitations. First, catheter angiography is considered the standard reference for stenosis detection. MRA is not adequate to replace conventional angiography and is less precise. Second, owning to time and equipment limitations, we did not further explore the subtypes of topographic patterns or the mechanism of NVAF combined with ICAS ischemic stroke. Additionally, bias is inevitable in retrospective studies. First, we enrolled the NVAF and/or ICAS ischemic stroke-specific populations in our hospital. It was based on data from a single referral center, potentially resulting in selection bias, admission rate bias, or attenuation of statistical power in the analysis of patients with stroke. Thus, our results may not apply to the general stroke population. However, this could have clinical implications, because few studies have attempted to clarify the clinical features of ischemic stroke in patients with NVAF combined with ICAS. Second, this was a retrospective study, the sample size and information collection were relatively insufficient, and there were regional limitations and a long recruitment period, which may have introduced information bias. Finally, although we included risk factors as comprehensively as possible, there may be other confounding factors that we did not consider, which may have confounded the bias.
In conclusion, our findings suggest that ischemic stroke caused by NVAF combined with ICAS is responsible for most strokes in older patients. The right cerebral hemisphere is the main location of stroke lesions. Neurological deficits in the NVAF group were the most severe type of ischemic stroke among the three groups. The HsCRP, LEVF, and NTpro-BNP biomarkers are of great significance in evaluating patient prognosis.

CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflict of interest.

DATA AVAILABILITY STATEMENT
All data are available.