Association of splenic contraction with stroke severity and diabetes mellitus in patients with acute ischemic stroke

Introduction

Stroke is the second leading cause of death and the third leading cause of death and disability combined worldwide (1). At present, the standard treatment for ischemic stroke is reperfusion therapy; however, this approach is limited owing to its narrow therapeutic time window and restricted eligibility criteria (2-5), highlighting the need for alternative management strategies (6). In this context, immunotherapy targeting neuroinflammatory responses during post-stroke damage and recovery has garnered increasing attention.

The evidence of peripheral immune system activation and neurodegeneration following stroke is well established (7-10). Lymphoid organs, including the spleen, thymus, lymph nodes, bone marrow, and gastrointestinal tract, are important contributors to these immune responses. The spleen, the largest lymphoid organ, serves as a storage site for immune cells and plays a pivotal role in the immune response to stroke. Recent insights suggest that stroke pathophysiology functions as a multi-organ network involving the brain, spleen, immune system, and circulation. Concepts such as the “cardiosplenic axis”, which describe the interplay between splenic status, hemodynamics, and prognosis in heart failure, suggest that splenic volume (SV) and function are modulated by complex mechanisms. These include not only sympathetic nerve activity but also humoral modulators (such as inflammatory cytokines and hormones) and hemodynamic changes (11-14). Following stroke, these systemic interactions precipitate the release of splenocytes from the spleen into the systemic circulation and their migration to the brain, resulting in reduced SV, a phenomenon known as splenic contraction (SC) (15-23). While SC is clinically associated with post-stroke neural injury (21,22), experimental studies provide evidence for its contribution to neurodegeneration (15-17,24-27). Specifically, in rodent models, splenectomy demonstrated a protective effect against stroke compared to non-splenectomized controls (18,25,26,28), suggesting that the spleen plays a role in exacerbating neural injury.

Based on the established relationship between stroke and SC, this study aimed to investigate the differences between patients with acute ischemic stroke with and without SC by measuring changes in SV, and to identify factors associated with SC. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1725/rc).

Methods

Study design and participants

We conducted a retrospective study of patients admitted to Jeonbuk National University Hospital with a diagnosis of acute ischemic stroke and measured their SV during admission using abdominal computed tomography (CT). All patients were Korean and had no history of splenic disease. Between November 2020 and February 2023, we screened 1,405 patients diagnosed with ischemic stroke. We included patients who had undergone abdominal CT prior to stroke and another scan within 7 days of stroke onset. To minimize age-related changes in SV, previous CT examinations were limited to those performed within 5 years before stroke onset. Of the included patients, 89 with sufficient image quality for SV measurements were selected as the final study population. SC was defined as an SV change ≤−5 cm³. Accordingly, 39 patients who met this criterion were assigned to the SC group, and 40 patients with an SV change >0 cm³ were assigned to the non-SC group. Ten patients who did not fit into either group were excluded. A flowchart showing the selection of participants for this study is presented in Figure 1. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Jeonbuk National University Hospital on June 12, 2024 (CHU 2024-05-057), and the requirement for informed consent was waived because of the retrospective nature of the study. All methods were performed in accordance with relevant journal guidelines and regulations.

Figure 1 Flowchart showing the selection of study participants. SC group: SV change ≤−5 cm³. Non-SC group: SV change >0 cm³. SV change = (post-stroke SV) − (pre-stroke SV). Pre-stroke SV: SV measured before stroke. Post-stroke SV: SV measured within 7 days after stroke. CT, computed tomography; SC, splenic contraction; SV, splenic volume.

Definitions and classification

The following clinical data were included in the analysis: age, sex, body mass index (BMI), onset-to-CT time, hypertension status, diabetes mellitus (DM) status, dyslipidemia status, atrial fibrillation (AF) status, ischemic heart disease status, congestive heart failure status, stroke history, National Institutes of Health Stroke Scale (NIHSS) scores at admission and discharge, and modified Rankin Scale (mRS) scores at 3 months after discharge. Hypertension was defined as a previous diagnosis of hypertension, persistent systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg. DM was defined as a previous diagnosis of DM, fasting blood glucose ≥126 mg/dL, or postprandial blood glucose ≥200 mg/dL within 2 h of admission. Dyslipidemia was defined as a previous diagnosis of dyslipidemia or low-density lipoprotein cholesterol ≥160 mg/dL; high-density lipoprotein cholesterol <40 mg/dL in men or <50 mg/dL in women; or triglycerides ≥175 mg/dL (29). Coronary artery disease was defined as a previous diagnosis of coronary artery disease or confirmation of angina or myocardial infarction via electrocardiography, stress myocardial perfusion imaging, exercise stress tests, echocardiography, or coronary angiography. AF was defined as a previous diagnosis of AF or confirmation of AF using electrocardiography. History of stroke was defined as a diagnosis of ischemic or hemorrhagic stroke prior to admission. Data extracted from blood tests performed after admission included total white blood cell (WBC) count, hemoglobin level, platelet count, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts (total and percentage values), D-dimer level, and hemoglobin A1c (HbA1c) level.

SV measurements

Measurements were performed using Infinitt PACS (Infinitt Healthcare Co., Seoul, South Korea). SV was directly measured and calculated from abdominal CT images. The measurements were performed by two well-trained authors (S.J.J. and Y.K.W.), with each CT measured three times, and the average value was used. In the case of discrepancies, an experienced neurologist (H.G.K.) reviewed the scans to provide a definitive interpretation. SV measurement was performed according to the method described by Prassopoulos et al. (30). As illustrated in Figure 2, the maximal width (W) was measured as the maximal diameter in the transverse section, and the maximal thickness (Th) was measured perpendicular to W, passing through the hilum. Splenic length (L) was calculated by multiplying the number of consecutive transverse CT sections by slice thickness. SV was calculated using the formula:

SV=30+0.58(W×L×Th)[1]

Figure 2 Measurement of SV in a representative case of a 64-year-old female patient. Abdominal CT scans were obtained 3 years prior to stroke onset (A,B) and 8 hours after stroke onset (C,D). Splenic measurements included maximal W (indicated by green arrows) in the transverse section (A,C) and maximal Th (indicated by red arrows) measured perpendicular to W in the section passing through the hilum (B,D). Pre-stroke measurements were: W =112.88 mm (A), Th =46.34 mm (B), and splenic L =120 mm, yielding a calculated SV of 394.07 cm³. Post-stroke measurements were: W =94.66 mm (C), Th =39.23 mm (D), and L =105 mm, yielding a calculated SV of 256.15 cm³. This represents a decrease of 137.92 cm³ in SV following stroke, consistent with stroke-induced SC. CT, computed tomography; L, length; SC, splenic contraction; SV, splenic volume; Th, thickness; W, width.

For each patient, the W and Th values were obtained from the same anatomical plane on the CT images when measuring the pre- and post-stroke SV.

Statistical analysis

First, patient demographics and laboratory findings were compared between the SC and non-SC groups. Pearson’s Chi-squared test or Fisher’s exact test was used for categorical variables, and a t-test was used for continuous variables. Second, multivariate analysis was performed to identify the independent factors associated with SC. To avoid variable selection caused by spurious correlations, only variables that showed a potential association (P<0.10) in univariate analysis were included as potential factors associated with SC in the multivariate logistic regression model. Statistical significance was set at P<0.05 (two-tailed). All statistical analyses were performed using SPSS 21.0 (IBM Corp., Armonk, NY, USA).

Results

In this study, we analyzed the demographic, clinical, and radiological characteristics of 79 patients with acute ischemic stroke (Table 1). Of these, 47 (59.5%) were male and 32 (40.5%) were female. The mean age was 75.0±10.03 years, and the mean BMI was 23.00±3.42 kg/m². The most common risk factor associated with stroke was hypertension, present in 59 patients (74.7%). This was followed by DM in 39 patients (49.4%) and dyslipidemia in 14 patients (17.7%). Other notable risk factors included AF in 21 patients (26.6%), history of stroke in 29 patients (36.7%), ischemic heart disease in six patients (7.6%), and congestive heart failure in three patients (3.8%). Stroke severity evaluated using the NIHSS score at admission was 6 [interquartile range (IQR) 3–10], the NIHSS score at discharge was 4 (IQR 2–10), and the mRS score at 3 months post-discharge was 3 (IQR 3–4). In addition, the average time from stroke onset to CT imaging was 3,602.37±2,895.23 min. Radiological analysis of the CT findings revealed that the mean SV prior to stroke was 161.84±75.83 cm³, and the mean post-stroke SV was 163.31±84.61 cm³. The average change in SV before and after stroke was 1.47±47.72 cm³.

The 79 patients were divided into the SC group (SV change ≤−5 cm³) and non-SC group (SV change >0 cm³) based on their SV change; a box-and-whisker plot visualizing the distribution of SV change values for these two groups is presented in Figure 3. The clinical and demographic characteristics of these groups were then compared (Table 2). The SC group showed a significantly higher proportion of female patients than the non-SC group (53.8% vs. 27.5%, P=0.017). In addition, the NIHSS score at admission was significantly higher in the SC group (median 7, IQR 3–12) than in the non-SC group (median 5, IQR 2–9, P=0.025). Conversely, the prevalence of DM was significantly lower in the SC group than in the non-SC group (35.9% vs. 62.5%, P=0.018). The prevalence of AF was significantly higher in the SC group (38.5% vs. 15.0%, P=0.018). Regarding laboratory findings, HbA1c levels were significantly lower in the SC group than in the non-SC group (6.03±0.94 vs. 6.96±1.68, P=0.005).

Figure 3 Box-and-whisker plot of SV change by group. The plot compares the distribution of SV change values between the non-SC group (n=40; SV change >0 cm³) and the SC group (n=39; SV change ≤−5 cm³). The horizontal line within each box indicates the median, the box represents the IQR, and the whiskers extend to 1.5 times the IQR. Outliers are indicated by black dots. IQR, interquartile range; SC, splenic contraction; SV, splenic volume.

Univariate and multivariate logistic regression analyses were performed to evaluate factors associated with SC (Table 3). In univariate analysis, female sex, NIHSS scores, DM, and AF were significantly associated with the occurrence of SC. However, in multivariate analysis, only the NIHSS score [adjusted odds ratio (aOR) 1.119, 95% confidence interval (CI): 1.001–1.252, P=0.048] and DM (aOR 0.278, 95% CI: 0.097–0.798, P=0.017) were identified as independent factors that significantly affected the occurrence of SC.

Discussion

Recent studies on the relationship between stroke and the immune system have made significant progress (7-10). However, our understanding of the mechanisms underlying this interaction is limited, highlighting the need for further studies. We selected the spleen, which is the largest lymphoid organ, as the research target to investigate the association between ischemic stroke and the immune system. The spleen allows for the quantitative evaluation of the immune response using SC. Furthermore, the impairment or removal of splenic function is associated with a relatively acceptable risk, as splenectomy has been widely performed in patients with hematological diseases and trauma (31). The well-established risks associated with splenectomy support the rationale for considering the spleen as a potential therapeutic target.

Previous animal studies have demonstrated the effects of the removal of splenic function through splenectomy on stroke. The groups that underwent splenectomy prior to ischemic stroke induction had smaller infarction volume (18,25,28), less immune cell infiltration such as microglia, macrophages, and neutrophils in brain parenchyma (18,28), lower IFNγ levels in brain parenchyma (18,25,26), and milder neurological deficits (26) compared with groups that did not undergo splenectomy. In contrast, adoptive splenocyte transfer after splenectomy eliminated the protective effects of splenectomy (26). These results suggest that the spleen plays a significant role in post-stroke immune responses, emphasizing the need for a further exploration of the relationship between the spleen and stroke.

In this study, we categorized patients with acute ischemic stroke into two groups based on the occurrence of SC and analyzed their characteristics. SC after stroke has been observed not only in animal studies (15-18) but also in clinical studies (19-23); it is caused by sympathetic nerve signaling and the release of splenocytes (27). Given these observations, several studies have investigated the effects of SC on stroke. In the present study, the NIHSS score at admission was significantly higher in the SC group than in the non-SC group. This finding is consistent with that of previous experimental studies (15-18,24-28), suggesting that SC contributes to brain damage caused by post-stroke immune responses. In a clinical study by Vahidy et al. (21), patients in the SC group presented with higher initial and mean serial NIHSS scores compared with those in the non-SC group. Nous et al. (22) reported that the SC group had higher NIHSS scores than the control group at admission and on the third day of hospitalization. Our study is concordant with these results, as the SC group showed greater neurological deficits at the time of admission (the acute phase). However, there was no significant difference in the NIHSS scores at discharge between the two groups. This pattern—where SC correlated with stroke severity at admission but not at discharge—suggests that SC’s contribution to neurological deficit may be largely confined to the acute phase. The correlation with initial severity likely reflects how sympathetic activation and subsequent splenocyte release drive immediate neuroinflammation and brain damage. Over time, however, other factors may become more influential in determining outcomes, including acute treatments such as tissue plasminogen activator, post-admission complications such as infections, or varying lengths of hospitalization. In addition, it is important to consider the potential role of the immune system not only in brain injury but also in the repair processes following stroke. Furthermore, our study showed that the mRS scores at 3 months were unrelated to post-stroke SC. These findings raise questions about whether SC affects long-term stroke severity and prognosis beyond the acute stage. Alternatively, the absence of significant correlations at later time points may represent a false negative due to our limited sample size. A larger, prospective study would be necessary to establish whether a long-term association also exists.

Moreover, there were no significant differences in the WBC and differential counts between the SC and non-SC groups. A previous clinical study showed that SC was associated with an increase in the total WBC count (19), whereas another study did not find a statistical relationship between the two (20). In addition, other clinical studies have reported an association between SC and lymphocytes, with some showing increased levels (20,23) and others showing decreased levels (22). Similarly, neutrophils have been observed to increase (19) or decrease (20,23) relative to SC. Thus, the results of WBC and differential counts in existing clinical studies, including ours, are inconsistent, which may be due to the different time points of WBC measurements. In animal experiments that clearly demonstrated the release of immune cells following SC, evaluations were performed using cell counts (17,18,24,26,28), proinflammatory cytokine/chemokine levels (15,18,24-26), and gene expression (15,16) in the spleen or brain parenchyma, which may be more sensitive and accurate indicators than blood cell counts. Similarly, in a clinical study by Vahidy et al. (21), blood pro-inflammatory cytokine levels, measured as indicators of the immune response, were significantly higher in the SC group than in the control group.

Recent research on the cardiosplenic axis highlights how hemodynamic disturbances can influence SV. In our study, AF was significantly more prevalent in the SC group (38.5% vs. 15.0%). Although AF did not remain significant in multivariate analysis, its high prevalence in the SC group aligns with the concept of the “cardiosplenic axis”, where hemodynamic disturbances and congestion are known to influence SV (11-14). This suggests that AF may serve as a marker of shared pathophysiological mechanisms—such as heightened sympathetic activity, systemic inflammation, and hemodynamic instability—rather than acting as a sole independent driver of SC (32,33).

DM is associated with a high prevalence and recurrence of stroke, poor outcomes, and a high risk of death (34-37). We found that patients with DM had a lower incidence of SC than those without DM. The absence of SC may reduce immune response-related damage during stroke, which contradicts previous findings regarding the negative effect of DM on stroke. The reason for this apparent protective effect of DM against SC is likely multifactorial. First, post-stroke SC is primarily driven by sympathetic nerve signaling (27). It is well-established that patients with long-standing DM are at high risk for developing diabetic autonomic neuropathy, which can lead to a significant impairment in autonomic nervous system control (38-41). This reduced sympathetic drive may inhibit the spleen’s ability to contract and mobilize immune cells (27,42-44) in response to the acute stress of an ischemic stroke. Second, the chronic state of DM facilitates the production of reactive oxygen species (ROS), leading to systemic oxidative stress (45). This oxidative stress can directly damage the immune system, including the splenic tissue, and impair its function (46-48).

This cumulative damage to the splenic parenchyma and microvasculature may reduce its contractile capacity, which is consistent with splenic atrophy previously observed in chronic diseases (46,48,49). However, past research on post-stroke SC has not found an association with DM (21,23). A distinguishing feature of our study was the measurement of baseline SV before stroke onset, allowing for direct comparison with post-stroke SV in the same patients. This methodology contrasts with previous studies that assessed SV after stroke and compared it with that in healthy volunteers (19,21,23). With these prior approaches, it is possible that splenic atrophy had occurred before stroke onset in patients with DM due to persistent oxidative stress (46,48,49). In such cases, patients without SC may have been misclassified as having SC, resulting in an insignificant relationship between DM and SC.

This study not only showed that SC can affect stroke severity but also demonstrated that patients with DM have a lower tendency to develop SC, which may result in a partially protective effect against stroke injury. This relationship between DM and SC is noteworthy in the context of post-stroke therapeutic interventions. Several studies have proposed therapeutic strategies targeting the spleen, such as low-dose splenic irradiation (50), sympathetic nerve inhibitors (27,42), and stem cell administration (51). Our study suggests that DM may alter the efficacy of such interventions, making it a potentially critical factor in determining the optimal treatment strategy for individual patients.

This study had some limitations. First, the study participants were restricted to patients who underwent abdominal CT at a single institution, which may not be representative of the broader population of patients with stroke. Patients who underwent abdominal CT may have had specific clinical indications such as abdominal symptoms, suspected complications, or particular risk factors that prompted imaging, whereas patients without these features would not have been included. These underlying conditions or clinical characteristics could be associated with both SC and stroke severity, potentially introducing selection bias. However, considering that none of the patients were confirmed to have known splenic disease, the impact was considered limited. In addition, because this study was conducted retrospectively, it was not feasible to control all potential confounding variables that may have affected SC and stroke severity. For instance, the study did not differentiate between various ischemic stroke subtypes such as large artery atherosclerotic, cardioembolic, or lacunar strokes, which might have confounded the findings. Autonomic and immune responses may differ substantially depending on stroke subtype, as the underlying pathophysiological mechanisms, infarct locations, and tissue injury patterns vary. Future studies should investigate whether the relationship between SC and stroke severity differs across these subtypes, as this could provide insights into the mechanisms linking sympathetic activation, splenic immune response, and neurological outcomes. Furthermore, although this study analyzed the mRS scores 3 months after discharge for stroke prognosis, long-term follow-up data beyond that time point were not obtained. Moreover, the finding regarding the inverse association between DM and SC is based on a limited cohort size of 79 patients, meaning this relationship should be considered exploratory, requiring further investigation in significantly larger, prospective multicenter studies. Therefore, a prospective cohort study with a larger sample size is required to address these limitations. Lastly, we evaluated splenic function by measuring SC using CT images; however, a more accurate evaluation of splenic function could be achieved using methods such as scintigraphy with ^99mTc-labelled, heat-altered erythrocytes (52).

Conclusions

We investigated the relationship between SC and acute ischemic stroke as well as the factors associated with SC. The SC group had significantly higher NIHSS scores at admission than the non-SC group, suggesting that SC contributes to the severity of neurological deficits in the acute phase of stroke. The presence of DM was associated with a lower incidence of post-stroke SC. This effect may be attributed to DM-associated pathophysiology, such as impaired autonomic reactivity, blunting the sympathetic stress response, or chronic oxidative stress-induced splenic dysfunction. In particular, the relationship between DM and SC warrants further investigation, as it may affect the efficacy of potential spleen-targeted therapies in patients with stroke and comorbid DM.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1725/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1725/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1725/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Jeonbuk National University Hospital on June 12, 2024 (CHU 2024-05-057), and the requirement for informed consent was waived because of the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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