Association of Abdominal Volume Index with Asymptomatic Intracranial Arterial Stenosis in Rural Chinese Adults: A Population-Based Study

Intracranial atherosclerotic stenosis (ICAS) is a leading cause of clinical stroke worldwide, especially among Asian populations [1]. Furthermore, ICAS has been linked with a substantial risk of recurrent stroke despite aggressive medical treatments [2]. Prior to the occurrence of clinical stroke, ICAS can be asymptomatic for an extended period. Therefore, identifying clinically manageable risk factors for asymptomatic ICAS (aICAS) would facilitate early interventions to target these factors, thereby reducing the risk and burden of clinical stroke.

Previous studies have linked adiposity, especially visceral and abdominal fat, with ischemic stroke [3‒5]. Traditionally, body mass index (BMI) has been widely employed in routine clinical practice as a measure of obesity. However, BMI fails to provide information about the regional distribution of adiposity, an important factor for predicting the risk of stroke [6]. To address this limitation, abdominal volume index (AVI), which utilizes both waist circumference (WC) and hip circumference (HC) to indirectly reflect visceral fat content by assessing the overall abdominal volume, has been proposed [7]. Several studies have indicated that AVI is associated with hypertension, impaired glucose tolerance, diabetes mellitus (DM), and metabolic syndrome [7‒10]. AVI has also been correlated with subclinical carotid atherosclerosis [11]. However, the relationship between AVI and aICAS remains to be clarified.

Therefore, in this community-based cross-sectional study, we aimed to investigate the association of AVI with aICAS among a rural population in China while taking into account the severity and burden of aICAS. We also tested possible interactions of AVI with demographics and vascular risk factors (e.g., age, sex, hypertension, and DM) on aICAS. Our hypothesis is that a greater AVI may be associated with aICAS and that AVI may interact with vascular risk factors (e.g., hypertension) to increase the likelihood of aICAS.

This was a population-based cross-sectional study. The study participants were from the Rose asymptomatic IntraCranial Artery Stenosis (RICAS) study, as previously described in detail [12, 13]. In brief, a total of 2,474 rural residents who living in Kongcun Town, Pingyin County, Shandong, China, were enrolled from October 2017 to November 2017. The main inclusion criteria of RICAS study were as follows: (1) aged ≥40 years and (2) no history of clinical stroke or transient ischemic attack. Participants who were unable to complete questionnaire, provide blood samples, or complete examinations for the diagnosis of ICAS were excluded in RICAS study. All participants underwent a standardized questionnaire survey, laboratory tests, physical examinations, and transcranial Doppler (TCD) ultrasound examination. Subsequently, 204 participants who were screened positive for aICAS in TCD further underwent brain magnetic resonance imaging and magnetic resonance angiography (MRA) examinations for the diagnosis of ICAS. The exclusion criteria in this study were as follows: (1) unable to complete questionnaires (n = 163); (2) unable to provide blood samples (n = 106); (3) unable to complete TCD (n = 143); (4) unable to complete magnetic resonance imaging and MRA (n = 35); (5) missing data or abnormal values on body weight or height (n = 30); and (6) abnormal WC values (n = 3). Abnormal values on body weight or height or WC mean the value of weight (kg), height (cm), or WC (cm) is <10. Thus, the final analytical sample for this study consisted of 1,994 participants. Figure 1 shows the flowchart of the study participants.

In October–November 2017, the trained medical personnel conducted face-to-face interviews and physical examinations to collect demographic and clinical information following a structured questionnaire, as previously documented [12]. BMI was determined by dividing body weight (kg) by the square of height (m²). Obesity was defined as BMI ≥28.0 kg/m² according to the national guidelines for Chinese adults [14]. After an overnight fast, fasting venous blood samples were obtained in the morning to assess high-sensitivity C-reactive protein (hsCRP), lipid parameters, and blood glucose. The definitions for hypertension, DM, dyslipidemia, smoking, and alcohol drinking were fully described elsewhere [13, 15, 16]. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, the use of antihypertensive drugs, or self-reported hypertension. DM was defined as fasting plasma glucose ≥7.0 mmol/L, current use of blood glucose-lowering agents, or self-reported diabetes. Dyslipidemia was defined as total cholesterol ≥6.20 mmol/L, triglyceride ≥1.8 mmol/L, high-density lipoprotein cholesterol <1.11 mmol/L, low-density lipoprotein cholesterol ≥3.36 mmol/L, the use of lipid-lowering agents, or self-reported hyperlipidemia.

The protocols for assessing aICAS have been extensively described in previous studies [12, 17]. In brief, the initial evaluation of aICAS involved TCD examinations, followed by a diagnostic confirmation utilizing MRA. The MRA findings were interpreted by a neurologist specialized in stroke and a clinical neuroradiologist, adhering to the criteria established by the Warfarin-Aspirin Symptomatic Intracranial Disease Study [18]. The degree of the most stenotic lesions (i.e., stenosis <50%, 50%–69%, 70%–99%, and occlusion) was measured and recorded in various vessel segments, including the intracranial internal carotid artery, middle cerebral artery, anterior cerebral artery, vertebral artery, posterior cerebral artery in both hemispheres, and the basilar artery. Mild aICAS was defined as stenotic lesions <50% in the analyzed vessels, while moderate-to-severe aICAS was characterized by the detection of at least one examined artery with stenotic lesion ≥50%. This classification is consistent with clinical cutoffs for aICAS frequently used in the literature [19‒21].

IBM SPSS Statistics v.27.0 (IBM Corp., Armonk, NY, USA) for Windows was used for all statistical analyses. Characteristics of study participants were presented as median (interquartile range) for continuous variables with skewed distributions and frequency (%) for categorical variables. We compared baseline characteristics of the study participants by aICAS status (absence vs. presence) using the Mann-Whitney U test for continuous variables and the chi-square test for categorical variables. Multivariate logistic regression analysis was conducted to estimate the odds ratio (OR) and 95% confidence interval (CI) of aICAS or mild and moderate-to-severe aICAS associated with AVI. AVI was analyzed as both a continuous variable and a categorical variable (tertiles). We reported the main results from two models: model 1 was adjusted for age and sex and model 2 was further adjusted for dyslipidemia, hypertension, DM, smoking, alcohol drinking, and hsCRP. We examined interactions of AVI with demographic and vascular risk factors (i.e., age, sex, hypertension, DM, and dyslipidemia) on aICAS because these factors might potentially modify the association of AVI with aICAS [7, 10, 17]. When a statistically significant interaction was detected, further stratified analysis was performed to assess the direction and magnitude of the interaction. A two-tailed p value <0.05 was considered statistically significant.

Of the 1,994 participants, the median age was 56 (interquartile range, 49–65) years, 52.11% were women, and 146 (7.32%) were diagnosed with aICAS at baseline. Participants with aICAS were older, more likely to be women, and had higher proportions of hypertension, DM, dyslipidemia, and obesity. AVI and hsCRP were higher in participants with aICAS than those without aICAS (Table 1). Notably, there was a lower proportion of alcohol drinking in people with aICAS than those without (p = 0.044, Table 1). However, when controlling for potential confounders, alcohol drinking was not significantly associated with overall aICAS (p = 0.660) and mild aICAS (p = 0.780) or moderate-to-severe aICAS (p = 0.763), neither with single moderate-to-severe aICAS (p = 0.731) nor multiple moderate-to-severe aICAS (p = 0.965) (data not shown).

A higher AVI (upper vs. lower tertile) was independently associated with aICAS (OR = 2.12; 95% CI: 1.33–3.38; p = 0.002, Table 2) and moderate-to-severe aICAS (OR = 3.52; 95% CI: 1.83–6.76; p < 0.001, Table 3), after adjusting for age, sex, smoking, alcohol drinking, hypertension, DM, dyslipidemia, and hsCRP. AVI was not significantly associated with mild aICAS (Table 3). When analyzing the association of AVI with the number of moderate-to-severe aICAS, AVI was significantly associated with single and multiple moderate-to-severe aICAS (p for linear trend = 0.008 and 0.005, respectively) (Table 4).

We detected a statistically significant interaction of AVI with hypertension on the likelihood of aICAS (p for interaction = 0.011). Stratified analysis by hypertension showed a significantly independent association between AVI and aICAS in participants with hypertension (upper vs. lower tertile of AVI: OR = 2.90; 95% CI: 1.65–5.10; p < 0.001) but not in those without hypertension (Fig. 2). There was no statistical interaction of AVI with age, sex, DM, and dyslipidemia on aICAS (for all interactions, p > 0.10, data not shown).

In this community-based study, we found that an increased AVI was independently associated with an increased likelihood of aICAS, especially in people with hypertension, in a rural Chinese population. Furthermore, a higher AVI was associated with increased likelihoods of moderate-to-severe aICAS and multiple moderate-to-severe aICAS. Our community-based study provides evidence for the first time that AVI is associated with aICAS independent of a range of potential confounding factors.

The AVI is considered to reflect abdominal obesity (central obesity) and indirectly indicate visceral fat volume (visceral obesity). Previous studies suggested that an elevated AVI was linked to hypertension, DM, and the metabolic syndrome [7, 9, 10, 22]. A clinical-based Spanish study of 789 patients indicated that AVI was positively related to subclinical carotid atherosclerosis [11]. Previous studies showed that visceral adiposity could secrete pro-inflammatory cytokines and adipokines, which may possibly induce endothelial dysfunction and vascular stiffness, as well as result in increased atherosclerosis [23‒25]. This may partly explain the association between AVI and subclinical carotid atherosclerosis.

However, the relationship between AVI and aICAS in the general population has not yet been investigated so far. Our population-based study suggests that visceral obesity may be involved in aICAS. The potential mechanism underlying the association between high AVI and aICAS can be explained as follows. First, a higher AVI indicates an increased proportion of visceral adipose tissue, which is known to produce numerous adipokines, most of which are considered pro-inflammatory. Additionally, an inequilibrium between pro-inflammatory and anti-inflammatory adipokines may contribute to insulin resistance and endothelial dysfunction, and thus, leading to the onset of aICAS [26, 27].

A mendelian randomization study indicated that approximately 10% of the observed effect of abdominal obesity on ischemic stroke was mediated by blood pressure [28]. In line with this previous study, we revealed an important interaction of AVI with hypertension on aICAS such that a greater AVI was independently associated with aICAS among people with hypertension but not in those without. This suggests an important role of hypertension in the association between AVI and aICAS. Chronic hypertension affects endothelial function, promotes inflammation, and eventually leads to atherosclerosis and aICAS [17, 29, 30]. Thus, it is plausible that higher AVI, a surrogate for abdominal obesity and visceral obesity, may be linked with aICAS in people with hypertension, possibly due to the combined effects of endothelial dysfunction and inflammation.

Notably, we found that a higher AVI may be a useful marker for the presence and numerical burden of moderate-to-severe aICAS. This is in line with the previous report suggesting that abdominal obesity was correlated with the presence and severity of coronary artery disease [31]. A greater number of intracranial arteries affected with moderate-to-severe stenosis often indicates a higher risk of stroke or other vascular events. Therefore, these findings indicate that AVI might serve as a convenient and cost-effective anthropometric index for evaluating the presence, severity, and burden of aICAS in a rural population of China, where widespread TCD screening is not feasible and the available assessment methods for aICAS remain limited.

To the best of our knowledge, this is the first community-based study to investigate the association between AVI and aICAS in a rural Chinese population. Moreover, integrating the screening TCD examination with MRA assessments could improve diagnostic precision for the presence and severity of aICAS. Our study also has limitations. Initially, due to cross-sectional nature of the study, we were unable to establish a causal relationship between AVI and aICAS. Additionally, TCD is still operator dependent and may not be as accurate as other imaging measurements such as MRA or angiography in assessing the presence of aICAS. Furthermore, the recruitment of study participants was confined to a single rural region and Han Chinese people; caution is needed for external generalizability.

This population-based study found that AVI was independently associated with the presence, severity, and burden of aICAS, especially among people with hypertension. Future prospective cohort studies are warranted to establish the potential causal relationships of AVI with subsequent occurrence and progression of aICAS, which will facilitate preventive and therapeutic interventions to prevent ICAS and its clinical consequences such as stroke.

We are very grateful to all the study participants and the staff at the Shandong Provincial Hospital.

The RICAS study was approved by the Ethics Committee of Shandong Provincial Hospital, Shandong University (No.2017566). All participants provided written informed consent. This study was conducted in accordance with the principles expressed in the Declaration of Helsinki. The RICAS study was registered in the Chinese Clinical Trial Registry (registration no. ChiCTR1800017197).

The authors have no conflicts of interest to declare.

This study was supported by the grants from the Jinan Science and Technology Bureau [201704101], the Department of Science and Technology of Shandong Province [ZR2017MH114, ZR2020QH109, ZR2022QH382, and ZR2022LSW010], and the National Natural Science Foundation of China [81971128 and 82201477]. C Qiu received grants from the Swedish Research Council [2017-05819 and 2020-01574] and the Swedish Foundation for International Cooperation in Research and Higher Education [CH2019-8320], Stockholm, Sweden. The funding agency had no role in the study design, the data collection and analysis, the writing of this article, and in the decision to submit the work for publication.

Q.S., and Q.W. contributed to the conception of the study. Q.W., X.Y., and M.L. contributed to data collection. Q.W., X.Y., Z.Y., X.H., J.Y., X.M., and X.W. contributed to data analysis and interpretation. Q.W. drafted the manuscript. C.Q. and Q.S. critically revised the manuscript. All authors approved the final version of the manuscript.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants. But data are available from the corresponding author upon reasonable request.