Systemic immune-inflammation index is associated with cardiac complications following acute ischemic stroke: A retrospective single-center study

Background: Stroke-induced heart syndrome is a feared complication of ischemic stroke, that is commonly encountered and has a strong association with unfavorable prognosis. More research is needed to explore underlying mechanisms and inform clinical decision making. This study aims to explore the relationship between the early systemic immune-inflammation (SII) index and the cardiac complications after acute ischemic stroke. Methods: Consecutive patients with acute ischemic stroke were prospectively collected from January 2020 to August 2022 and retrospectively analyzed. We included subjects who presented within 24 hours after symptom onset and were free of detectable infections or cancer on admission. SII index [(neutrophils × platelets/ lymphocytes)/1000] was calculated from laboratory data at admission. Results: A total of 121 patients were included in our study, of which 24 (19.8 %) developed cardiac complications within 14 days following acute ischemic stroke. The SII level was found higher in patients with stroke-heart syndrome ( p < .001), which was an independent predictor of stroke-heart syndrome (adjusted odds ratio 5.089, p = .002). Conclusion: New-onset cardiovascular complications diagnosed following a stroke are very common and are associated with early SII index.


Introduction
Stroke, a leading cause of disability and mortality worldwide, has brought huge personal and social burden.Patients with stroke have a high risk of new-onset cardiovascular complications, the incidence of severe cardiovascular complications following stroke is approximately 20 % in previous study [1,2].Varying cardiac disturbances appearing after stroke, summarized as stroke-heart syndrome (SHS), include both functional and structural alterations [2].Impaired cardiovascular function can worsen the pre-existing cerebral ischemia and cause a new secondary brain injury.A new cardiac complication is an independent risk factor for poor prognosis in stroke patients [3], early detection of cardiovascular dysfunctions following stroke has become paramount.
Inflammation and immunology have been demonstrated to play a central role in the pathogenesis of stroke [4,5].Systemic immune-inflammation (SII) index, an inflammatory index combining peripheral neutrophils, lymphocytes, and platelet counts, was evaluated as an independent predictor of for developing incident cancer [6,7].More recently, SII index was shown to predict functional outcome in acute ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage [8][9][10], while SII index is a novel biomarker of systemic inflammatory response underexplored in stroke-heart syndrome.The aim of this study is to explore the relationship between SII index and cardiac complications following ischemic stroke, as well as to note the importance of inflammation and immunology in brain-heart interaction.

Patient population
We prospectively collected a consecutive series of patients with acute ischemic stroke admitted to the Department of Neurology of People's Hospital of Zhengzhou University between January 2020 and August 2022.MRI was performed to confirm the presence of acute ischemic stroke.Eligible patients who met the following criteria were recruited as the training cohort: (i) age ≥18 years; (ii) diagnosis of acute ischemic stroke within 24 hours from symptom onset or the last time seen well; and (iii) magnetic resonance imaging (MRI) performed within 24 hours after stroke.Patients with any of the following characteristics were excluded: (i) participants with a history of hematologic disease, malignant tumor, or presenting detectable infections; (ii) newly diagnosed heart disease within one month; (iii) any type of brain injury including brain hemorrhage, tumor, encephalitis, and others; (iv) loss to follow-up (Fig. 1).Demographic information and clinical history were collected including age, sex, and comorbid conditions such as the history of hypertension, diabetes mellitus, previous stroke.

Study design
Peripheral complete blood samples were obtained within 24 hours after ischemic stroke onset in all participants.Neutrophil-lymphocyte ratio (NLR) was computed by dividing the absolute neutrophil counts by the absolute lymphocyte counts.The SII index was defined as follows [10]: SII (10 9 /L) = [(platelet counts × neutrophil counts / lymphocyte counts)/1000] [10].The National Institutes of Health Stroke Scale (NIHSS) was used for risk stratification in this study.ECG, ultrasound, and cardiac enzyme testing were conducted at least twice during hospitalization and would be repeated if necessary.Newly diagnosed cardiovascular complications include dynamic changes on ECG, abnormalities on cardiac enzymes, acute coronary syndrome, arrhythmias, left ventricular dysfunction, heart failure, and even cardiovascular deaths within 14days following stroke [1,2].Any new cardiac complications were diagnosed by professional cardiologists finally.

Statistical analysis
Kolmogorov-Smirnov test was used to figure out the data distribution.Continuous variables with normal distributions were shown as the mean ± SD while other variables were presented as the median with interquartile range.Student t-test or the Mann-Whitney test was used for continuous variables, and Chi-square analysis or the Fisher exact test for categorical variables.Logistic regression was used to identify laboratory predictors of SHS.Receiver operating characteristic (ROC) analysis was performed to assess the ability of SII index to distinguish between patients with or not cardiac complications.Youden's index was calculated to determine optimal test cut-offs.A p-value of <0.05 was considered statistically significant unless otherwise indicated.

Clinical characteristics of the patients
Fourteen patients with acute ischemic stroke were excluded from the study because of active infections before hospital admissions or hematological disorders.A total of 121 patients (m/w ratio, 1.18 and mean age, 63.8 ± 12.9 years) were admitted to our analysis.The baseline clinical characteristics of patients are shown in Table 1.Of these 121, 24 (19.8 %) developed SHS within 14 days following the event, including acute myocardial infarction (3/24, 12.5 %), dynamic changes on ECG (5/24, 20.8 %), and abnormalities on cardiac enzymes (16/24, 66.7 %).A subgroup analysis for different cardiac complications is presented in Supplementary Table 1.

Multivariable analysis for association factors of SHS in patients with stroke
Potential predictors of SHS were considered in univariable and multivariable logistic regression models.The variables statistically significantly associated with cardiac complications (Table 2) were included in a multivariate logistic regression model.After adjusting for baseline differences in age, gender, hypertension, diabetes mellitus, and NIHSS in multivariable logistic regression, neutrophil count, lymphocyte count, NLR, and SII index predicted cardiac complications   following stroke (all p<.05,Table 3).However, SII index had the highest odds ratio (OR) of 5.089 (95 % CI 1.981-15.74,p=.002,Table 3)

Receiver operating characteristic curve analysis
Finally, this study explored the ability of SII index to distinguish between patients with or without stroke-heart syndrome.The optimal cutoff for SII index was 0.857, whereby those with SII index above this level would be likely to develop cardiac complications following acute ischemic stroke (Youden's index = 0.502, sensitivity 66.67 %, specificity 83.51 %), with the area under the curve at 0.767 (95 % CI 0.644-0.889;p<.001, Fig. 2).After covariate adjustment, the multivariable SII model demonstrated significant improvement in distinguishing between patients with or without SHS (AUC = 0.822, 95 % CI 0.719-0.925,P <.001, Fig. 2).

Discussions
A considerable body of evidence indicates that peripheral immunity is associated with the risk of neurological diseases, for example, primary central nervous system lymphoma [11], depression [12], Parkinson's disease [13,14], and dementia [15,16].It has become increasingly clear that stroke is a disease not exclusively limited to the central nervous system [17], systemic inflammation is common after stroke and contributes to feared complications.Highly damage-associated molecular patterns and immunogenic cellular components are released from the brain into the systemic circulation after stroke, which activate and recruit peripheral immune cells to ischemic brain regions [18].The inflammatory reactions following acute stroke occur rapidly and typify a highly intricate interaction between the resident cells in the brain and those in the peripheral immune systems [19], which activate both toxic and protective inflammatory processes after stroke (Fig. 3).Peripheral sterile inflammatory response following ischemic stroke is usually accompanied by neutrophils activation [20,21], lymphocytes apoptosis [22,23], and platelet dysfunctions [24,25].Our study also demonstrated for the first time that elevated neutrophils and decreased lymphocytes were associated with the development of SHS in ischemic stroke.The SII index may serve as a superior tool to NLR given the strong interaction between thrombosis and inflammation [9].In this study, admission SII index independently predicted development of SHS and suggested a potential role for early inflammatory responses in driving SHS after ischemic stroke.
Accumulating studies now generally identify the existence of a bidirectional interaction between the brain and the heart [26].The stroke-associated cardiac dysfunction is summarized as stroke-heart syndrome [2,3].The SHS can be classified into five major categories [1]: 1) ischemic and non-ischemic myocardial injury with elevated cardiac biomarkers, which can be asymptomatic or symptomatic; 2) acute myocardial infarction and other acute coronary syndromes following stroke; 3) left ventricular dysfunction and heart failure; 4) arrhythmia and electrocardiographic changes; 5) cardiac death.Our study indicated that about 20 % of patients develop SHS within 14 days following acute ischemic stroke.The main mechanisms involved in the stroke-heart syndrome include pre-existing heart diseases and risk factors primarily involved in the stroke [2,27].Additionally, stroke and subsequent strong mental stress lead to the dysregulation within the central autonomic network, which promotes microvascular dysfunction and myocardial necrosis [28].Furthermore, ischemic stroke significantly increases macrophage infiltration into the heart, increases macrophage-associated inflammatory cytokine levels and finally induces cardiac fibrosis and hypertrophy [29].Recent evidence also suggested that the hypothalamic-pituitary-adrenal axis [26], microRNAs [30,31], and gut microbiome [32,33] play a key role in the brain-heart interaction after stroke.As cardiac complications following stroke are associated with a poor functional prognosis [3] and are the second leading cause of post-stroke death in the first few weeks [34], there is a necessity for potential targets for the prevention and treatment of cardiac complications following stroke.While approaches such as ECG and cardiac enzymes exist to diagnose patients actively experiencing cardiac complications, we lack objective methods to predict their development prior to onset.Our study demonstrates SII index is a novel and noninvasive biomarker that help identify patients at high risk of developing cardiac complications following stroke and guide early management.
Nevertheless, there are several limitations of this study.(1) This is a single-center retrospective study.(2) The association between SII index and functional outcome is not established.(3) Participants in our study were mainly elderly, which may limit the generalization to other populations.(4) Patients in this study have relatively mild conditions, which may underestimate the impact of SII index on SHS.(5)A long-time follow-up is needed to fully assess the exact incidence of cardiac complications following stroke.

Conclusions
Increasing findings have suggested that immunity and inflammation play crucial roles in atherogenesis, our current results also found that high SII index suggests a potential role for early inflammatory responses in driving cardiac complications following stroke.SII index may become a useful and readily available tool for monitoring and predicting brainheart syndrome.

Fig. 3 .
Fig. 3. Role of Immune and Inflammatory Mechanisms in SHS.

Table 1
Baseline characteristics of patient with and without SHS.

Table 2
Univariate logistic regression analysis of admission laboratory values to predict stroke-heart syndrome.

Table 3
Multivariable logistic regression analysis of admission laboratory values as predictors of stroke-heart syndrome.