Insular cortex Hounsfield units predict postoperative neurocardiogenic injury in patients with aneurysmal subarachnoid hemorrhage

Abstract Objective Our study aims to investigate the association between the Hounsfield unit (Hu) value of the insular cortex (IC) during emergency admission and the subsequent occurrence of post‐operative neurocardiogenic injury (NCI) among patients afflicted with aneurysmal subarachnoid hemorrhage (aSAH). Methods Patients baseline characteristics were juxtaposed between those with and without NCI. The significant variables were incorporated into a multivariable stepwise logistic regression model. Receiver operating characteristic (ROC) curves were drafted for each significant variable, yielding cutoff values and the area under the curve (AUC). Subgroup and sensitivity analyses were performed to assess the predictive performance across various cohorts and ascertain result stability. Propensity score matching (PSM) was ultimately employed to redress any baseline characteristic disparities. Results Patients displaying a right IC Hu value surpassing 28.65 exhibited an escalated risk of postoperative NCI upon confounder adjustment (p < 0.001). The ROC curve eloquently manifested the predictive capacity of right IC Hu in relation to NCI (AUC = 0.650, 95%CI, 0.591–0.709, p < 0.001). Further subgroup analysis revealed significant interactions between right IC Hu and factors such as age, history of heart disease, and Graeb 5–12 score. Sensitivity analysis further upheld the results' significant (p = 0.002). The discrepancy in NCI incidence between the two groups, both prior (p < 0.002) and post (p = 0.039) PSM, exhibited statistical significance. After PSM implementation, the likelihood of NCI displayed an ascending trend with increasing right IC Hu values, from the Hu1 cohort onward, receding post the Hu4 cohort. Conclusion This study definitively establishes an elevated right IC Hu value in the early stages of emergency admission as an autonomous predictor for ensuing NCI subsequent to aSAH.


Introduction
2][3][4] A discernible towards diminished incidence is intricately linked to public health interventions and lifestyle adaptations. 5Capitalizing ª 2023 The Authors.Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
on the progressive advancements in cerebrovascular surgical diagnostics and therapeutics, the previously formidable case fatality rate of aSAH, hovering around 40%, has witnessed substantial reduction. 6However, a considerable cohort of patients may present an extensive array of postoperative complications due to underlying pathophysiologic mechanisms. 7,8ontemporary investigations pertaining to the sequela of aSAH have predominantly concentrated on the realm of delayed cerebral ischemia (DCI). 9,10As scientific exploration delves deeper into the intricate interplay between the brain and the heart, cardiac complications have gained prominence within the aSAH domain.][16] Antecedent research has illuminated the indispensable role of the insular cortex (IC) within the central automatic network in regulating of the cardiovascular system. 17,180][21][22][23][24] Thus, impairment of the IC could potentially contribute to the genesis of NCI subsequent to aSAH.Furthermore, the severity of aSAH appears to correlate positively with the magnitude of NCI. 21apid processing of perfusion and diffusion (RAPID), an image post-processing software, has the capacity to automatically assess the Alberta Stroke Program Early CT score (ASPECTS) through computation of mean Hounsfield unit (Hu) values within the middle cerebral artery (MCA) territory. 1,25Hounsfield units (Hu) represent a quantitative density metric employed by radiologists for interpreting CT images. 26Previous researches have elucidated the prognostic significance of Hu values concerning DCI and clinical outcomes among aSAH patients. 27,28Nevertheless, studies on the potential correlation between IC Hu values and cardiac events in aSAH patients remain limited.
In the pursuit of discerning whether the Hu values can function as robust indicators of cardiac injury, facilitating judicious preemptive monitoring and intervention, our study endeavors to scrutinize the conceivable interrelation between IC Hu values upon admission and the manifestation of NCI in patients with aSAH.

Study design and population
Patients diagnosed with aSAH and who underwent assessment of cardiac enzymes and echocardiography within a 72-h window from the onset of bleeding were deemed eligible for participation in this single-center, retrospective, observational study, carried out at Beijing Tiantan Hospital spanning the period from January 2019 to September 2022, as illustrated in Fig. 1.Within this study framework, patients afflicted with aSAH were diagnosed employing cranial computed tomography (CT), lumbar puncture, CT angiography (CTA), or digital subtraction angiography (DSA).The stipulated inclusion criteria encompassed: (1)  Approval from the Institutional Review Board at Beijing Tiantan hospital, specifically under reference KY 2021-008-01, was duly secured prior to the initiation of this study.Informed consent conscientiously obtained from all individual participants or their legally authorized representatives.The research was conducted in strict accordance with the principles in the Declaration of Helsinki.It is noteworthy that the management of all patients adhered diligently to established guidelines. 5,29

Clinical data collection
We extracted patient data during the acute phase from our electrical medical records, encompassing: (

Imaging acquisition and radiological data
The image dataset underwent processing via the RAPID post-processing software, meticulously designed for ischemic penumbra identification. 30Furthermore, the ASPECTS scoring system was employed for an intricate early infarct analysis. 31ASPECTS predominantly encompasses two CT tiers: the basal ganglia and the body of the lateral ventricle.Distinct colorations are employed to demarcate distribution zones for each branch of the MCA, vividly visible in Fig. 2. Utilizing RAPID ASPECTS, mean CT values for MCA distribution regions can be automatically computed, enabling ASPECT score assessment within the specific IC region of interest (ROI) designated for this study.

Outcome assessment
The primary objective of our research is to ascertain the frequency of postoperative NCI.NCI was delineated by one or more of the subsequent criteria: (1) elevated serum myocardial enzyme levels: cardiac troponin I > 1.0 ng/mL; creatine kinase myocardial isoenzyme >1%; (2) aberrant echocardiography presentation: abnormal ventricular wall motion.The aforementioned presentation may be accompanied by brain natriuretic peptide >100 pg/mL, and conceivable electrocardiographic alterations such as T-wave inversion and QT-interval prolongation.4]32,33

Statistical analysis
Prior to analysis, the distribution pattern of each continuous variable underwent assessment via visual examination using Q-Q plots or histograms, and numerically through the Shapiro-Wilk test.Additionally, the equivalence of variance between two random groups was evaluated using Levene's test.Variables that exhibited a near-normal distribution and comparable variances were subjected to independent t-tests or ANOVA tests, with results presented as mean AE standard deviation (SD).Conversely, variables failing to meet these assumptions were subject to the Mann-Whitney U-test, with outcomes presented as medians along with interquartile ranges (IQR).Categorical variables were scrutinized using the chi-squared test or Fisher's exact test, depending on anticipated frequencies.
Subsequently, risk factors associated with NCI, having attained a p-value < 0.05 during univariable analysis, were subjected to multivariable logistic regression.This step aimed to rectify confounding biases and ascertain the independent impact of each variable on the outcome.Results were expressed as odds ratios (ORs) accompanied by 95% confidence intervals (95% CIs).These findings were then visualized via a graphical representation illustrating adjusted predicted probabilities concerning NCI occurrence in individual patients, correlated against the principal independent predictor, namely the right IC Hu.
A receiver operating curve (ROC) analysis was performed to determine the threshold mean CT Hu value, subsequently establishing the area under the curve (AUC) as an indicator of each factor's predictive potential.Additionally, subgroup analyses, depicted through forest plots, were executed to explore the predictive efficacy of right IC Hu in subpopulations exhibiting distinct characteristics from the overall cohort.Given the Hu value representation within the MCA regions as reflected in ASPECTS, a supplementary analysis was pursued, excluding cases of MCA aneurysms.This was carried out to ascertain whether elevated right IC Hu remained an independent predictor in aSAH patients with aneurysms situated in alternate regions.
To delve deeper into relationship between the admission right IC Hu and in-hospital NCI complications, the study partitioned the population based on a predetermined cutoff value for right IC Hu.Measures were taken to address potential confounding biases arising from baseline characteristic imbalances through propensity score matching (PSM), utilizing a match tolerance of 0.02 and a 1:1 ratio.The incidence of in-hospital NCI complications was treated as a binary variable in the matched pairs and evaluated via the chi-squared test.Lastly, the range of right Hu values was divided into quartiles and median intervals.The changing trend in the likelihood of NCI occurrence with increasing Hu intervals was depicted through a bar line chart.

Relationship between right IC Hu and admission time, relationship between NCI and admission time
The right IC Hu for patients admitted within 24, 48, and 72 h from aSAH onset were 28.9, 28.7, and 28.9, respectively.None of the patients admitted within these time frames experienced postoperative NCI.There were no significant differences observed in either right IC Hu (p = 0.482) or NCI (p = 0.487) between the groups (Fig. 3).

Association of right IC Hu at admission with NCI
Table 2 illustrates the outcomes of executing stepwise multivariable logistic regression analyses, founded upon significant variables recognized in the univariable regression.Ultimately, a total of six variables manifested in the multivariable output: age, history of cardiac ailments, Graeb score ranging from 5 to 12, acute hydrocephalus, right IC Hu, and endovascular intervention.These factors exhibited independent predictability concerning the incidence of NCI in postoperative scenarios.Figure 4 elaborates upon the adjusted correlation between the right IC Hu and the probability of NCI.
The research employed the ROC curve to ascertain the optimal threshold value for the right IC Hu, which materialized as 28.65, as determined by the selection of the

Subgroup and sensitivity analysis of the association between right IC Hu and NCI
In Fig. 6, the subgroup analysis unveils a compelling interplay wherein the right IC Hu exhibit noteworthy correlations with age, a history of heart disease, and Graeb scores ranging from 5 to 12.The influence of the right IC Hu on the prevalence of NCI manifests more prominently within the cohort of patients with Graeb 5-12, in stark contrast to those with Graeb 0-4 (p for interaction = 0.008).Analogous findings reverberate within the subgroups of patients with a history of heart disease (p for interaction = 0.018) and varying age strata (p for interaction = 0.035).Conversely, other subgroupings, including those encompassing acute hydrocephalus and treatment modalities, fail to manifest any discernible nexus.
Upon subjecting the analysis to a sensitivity evaluation that excludes cases involving aneurysms in the MCA zone, the outcomes remain notably unaltered.The prognostic potency of the right IC Hu concerning postoperative NCI endures its stability.Even when instances involving MCA aneurysms are excluded, the cohort comprising aSAH patients persistently showcases heightened susceptibility to postoperative NCI with the escalating right IC Hu values (p = 0.002) (Table 3).

Association of right IC Hu with NCI after PSM
The disparity in NCI incidence between the two groups exhibited statistical significance both prior to (p < 0.001) and subsequent to (p = 0.039) PSM.Notably, a significant variance was discerned among groups with mFS grade 3-4 following PSM (p < 0.001) (Table S1).The special baseline characteristics of the patients with postoperative NCI was listed, as well as the subcategories of each NCI, as detailed in Table S2.
To illustrate the outcomes of PSM, a bar chart was crafted, partitioning the respective values of right IC Hu into four intervals (Hu 1 -Hu 4 ) based on quartiles and medians, both before and after the matching procedure (Fig. 7).Pre-PSM, the likelihood of NCI escalation was concomitant with augmented right IC Hu values, originating from the Hu

Discussion
Our study explores the correlation between IC Hu values and cardiovascular events in aSAH.Employing both multivariable logistic regression and propensity score matching techniques, we meticulously accounted for confounding variables within our sample.Our analyses unveiled a notable association between elevated right IC Hu values, particularly those surpassing a specified threshold, and the frequent occurrence of postoperative myocardial injury among emergent aSAH patients (Fig. S1).Meanwhile, this correlation is independent of the type of intervention and usual risk factors.In a subgroup analysis, we ascertained that the interplay between right IC Hu values and intraventricular hemorrhage wielded a substantial influence on NCI.
While the ASPECTS remains a dependable and uncomplicated scoring system for appraising early ischemic changes within the distribution zones of the MCA, it is crucial to acknowledge the potential variability in interpretations due to divergent levels of expertise among non-contrast CT observers. 34In contrast, the RAPID ASPECTS system harnesses validated machine-learning algorithms to autonomously identify cerebral regions and compute scores, thereby enabling swift and more harmonious assessment for thrombectomy eligibility (j = 0.9), surpassing the concordance of human readers (j = 0.57 and j = 0.56). 31rior investigative trajectories focusing on the predictive potential of CT Hu values for DCI and clinical outcomes predominantly centered on average Hu values within specific hemorrhage tiers. 27,28,35In contradistinction, the Hu value derived from the RAPID ASPECTS software furnishes objective imaging metrics for each distinct zone, facilitating a nuanced evaluation of complications or prognosis.This approach circumvents the inherent subjective bias that could manifest when experts choose the CT plane, rendering it an advanced stride.Remarkably, this marks the inaugural clinical application of mean insular CT Hu value extracted from the RAPID ASPECTS in the realm of aSAH patients management.
The intricate configuration of neural networks presumably exhibits variations contingent upon definitions, specifically reliant on the distinct autonomic outcome measures.][38] Extensive research has delved into the mechanisms through which IC impairment may precipitate cardiac injury.Among these, Michiaki Nagai's exploration of Takotsubo syndrome, a transient cardiomyopathy triggered by acute emotional or physical stress, stands prominent. 18Earlier studies have substantiated the notion that the cardiovascular system finds governance within the central automatic network (CAN), comprising the IC, anterior cingulate gyrus, and amygdala. 17Normally, the CAN maintains a dynamic equilibrium between the sympathetic nervous system (SNS) and the parasympathetic nervous system under physiological conditions.Disruption to either facet of the CAN disturbs the balance of automatic function. 39 preceding study has demonstrated that inactivation of the right hemisphere led to an elevation in heart rate and blood pressure's high-frequency components, while left hemisphere inactivation yielded the converse, especially notable in drug-refractory epilepsy patients. 19By bilaterally stimulating the IC, Oppenheimer SM discovered that right IC stimulation induced tachycardia and pressor effects, whereas left IC stimulation elicited bradycardia and depressor effects. 20Ayano Osawa proposed that damage to the right insular cortex, possibly inducing heightened sympathetic nervous system activity, played a role in CAN dysregulation, myocardial injury, escalated brain natriuretic peptide levels, and the incidence of Takotsubo cardiomyopathy. 40Consequently, human right IC stimulation escalated sympathetic cardiovascular tone, while left IC stimulation more frequently elevated parasympathetic activity.The exacerbated SNS activity stemming from right IC stimulation might underlie myocardial necrosis.This form of cardiotoxicity following aSAH manifests electrocardiographic alterations, abnormal ventricular wall motion, cardiac insufficiency, and elevated serum myocardial enzyme levels. 21Our study highlights that solely the Hu value of the right IC exerts an independent impact on NCI, whereas the left IC Hu value does not exhibit such influence according to univariable analysis.These findings intimate that autonomic control of cardiac activity is lateralized, likely predominantly mediated by the right-sided IC.Nonetheless, through both univariable and multivariable regression analyses, it was observed that the left IC Hu value bore correlation with other variables.Thus,  significant influences of the left IC on the cardiovascular system should not be dismissed.
Upon the occurrence of aSAH, the stimulation of the right IC by blood may indeed be the instigator of sympathetic overactivation, mirroring a comparable phenomenon.Subsequent to aSAH, left ventricular systolic dysfunction correlates with regular myocardial perfusion juxtaposed with abnormal augmentation in sympathetic activity. 23In situations of unaltered myocardial perfusion, catecholamines released from sympathetic terminals provoke myocardial necrosis, its extent intricately linked to the severity of aSAH. 21Furthermore, a discernible association surfaces between right-hemispheric IC strokes and sinus tachycardia, escalated plasma levels of norepinephrine, augmented blood pressure, diminished heart rate variability, electrocardiographic abnormalities, and amplified mortality. 38It has been posited that instances of right MCA infarction ensuing vasospasm post aSAH impede IC functionality, consequentially inducing heightened sympathetic cardiovascular tone and the cardiac ramifications of the stroke. 37,38,41ur research employed myocardial enzymes as pivotal indicator for prognostic discernment.3][44] Additionally, some researchers have alluded to the concurrence of IC impairment due to stroke with elevated troponin concentrations. 45,46Scheitz, J.F. and colleagues delineated that augmented cardiac troponin T levels were independently correlated with heightened stroke severity (p = 0.04) and IC involvement (p < 0.001). 45These findings collectively buttress the assertion that troponin release and IC injury subsequent to aSAH stand as pivotal cues for NCI.
An intriguing phenomenon emerged: the interplay between Graeb 5-12 and the right IC Hu value impacting NCI.Within subgroups, patients with acute hydrocephalus exhibited a notable positive predictive effect on outcomes associated with higher right IC Hu values.In instances of intracerebral hemorrhage, QTc prolongation on ECG seemed associated with IC involvement, the presence of intraventricular blood, and hydrocephalus. 47Explorations of structural connectivity in brain networks unveiled significant discrepancies in regional network measures, including IC in hydrocephalus groups, compared to controls. 48Building on these pertinent findings, we scrutinized cases involving intraventricular hemorrhage or acute hydrocephalus, leading to relevant speculations.Our hypothesis posited that the proximity between the lateral ventricle and IC could exacerbate stimulation and extrusion to IC in aSAH patients facing intraventricular hemorrhage or acute hydrocephalus.
A representative case was chosen, featuring 78-year-old female with aSAH and diagnosed NCI (Fig. S2).This patient, devoid of heart disease history, encountered NCI on the fifth post aneurysm clipping day.A CTA unveiled an anterior communicating artery (AcoA) aneurysm.Her right insular Hu value reached 29.8, contrasting with the contralateral value of 27.9, as indicated by preoperative RAPID-ASPECTS within 24 h post-aneurysmal rupture onset.Upon experiencing symptoms like chest tightness, breathlessness, and dyspnea on the fifth day post-surgery, laboratory tests unveiled elevated CK-MB levels.Echocardiography further disclosed abnormal left ventricular wall motion and reduced apical motion.Swiftly, a brain-heart combined treatment approach was instituted, and collaborative consultation determined NCI.Subsequent steps encompassed intensive care, oxygen therapy, sedation, fluid intake management, ventricular rate control, and myocardial ischemia reduction.Post-symptom stabilization, cerebral CT, CTA, and CTP scans detected no rebleeding or hypoperfusion.Ultimately, the patient's condition ameliorated, and cardiac indicators normalized.Hence, meticulous focus on the ICU's ECG monitoring and timely postoperative echocardiography, along with cardiac biomarker assessment around the fifth postoperation day, especially in the IC region indicated by the preoperative emergency CT-ASPECTS, becomes imperative.These measures, anticipate cardiac function shifts, thereby enhancing postoperative functional prognosis.
Nevertheless, our study bears limitations.First, it is a retrospective, single-center, observational case-control study, susceptible to recall bias and constrained by a modest sample size.Nonetheless, it is worth noting that this study represents, to the best of our knowledge, the largest cohort of aSAH cases focused on IC Hu values and NCI.Therefore, future prospects necessitate largescale, prospective, multicenter studies to authenticate our findings.Second, despite controlling key clinical baselines, potential confounders might persist, necessitating refined designs in future studies to mitigate biases.Third, our analysis centered solely on Hu values from one region, prompting future studies to encompass supplementary imaging indicators for a more comprehensive analysis.Finally, while these differences were statistically significant, the small differences in IC Hu values between the two groups is valid.We posit that this subtle variance might be attributed to the ensuing factors: (1) Unlike the relatively confined cerebral parenchymal hemorrhage, aSAH manifests in a more dispersed manner, with the ROI encompassing the insula presenting a diminutive expanse at the level of the basal ganglia on CT scans.Consequently, the amplitude of Hu value fluctuations within the insula ROI due to multifaceted pathological determinants could be restricted; (2) The precision of the right IC Hu value in prognosticating NCI was utilized to ascertain the threshold for prediction (right IC Hu > 28.65).Given the variable spectrum of the right IC Hu values in our dataset, a larger and heterogeneous populace would be requisite to authenticate these findings in subsequent investigations.

Conclusion
The study unveiled the early elevation of right insular cortex CT Hu value following emergency admission as an independent predictor of neurocardiogenic injury post aSAH.This CT density-based prognostication for clinical cardiac complications could substantially inform perioperative management.

Figure 1 .
Figure 1.Flow chart showing inclusion/exclusion of patients.

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Jia et al.Insular cortex Hu predicts post-op neurocardiogenic injury after aneurysmal subarachnoid hemorrhage maximal Youden index.Pursuant to this threshold, it was ascertained that patients exceeding this right IC Hu value were predisposed to NCI development.Moreover, Fig. 5 portrays the area under the ROC curve accompanied by a 95%CI, along with p-values corresponding to all independent predictors.The outcomes underscored that the right IC Hu stood as the most robust predictor (right IC Hu>28.65,AUC = 0.650, 95%CI, 0.591-0.709,p < 0.001).

Figure 3 .
Figure 3. (A) Relationship between right IC Hu and admission time.(B) Relationship between NCI and admission time.

Figure 4 .
Figure 4.The association of right IC Hu with the probability of NCI.There is an increase in the likelihood of NCI with increase of right IC Hu (adjusted for age, history of heart disease, Graeb 5-12, acute hydrocephalus, treatment modality).

Figure 5 .
Figure 5.Comparison of AUC values of right IC Hu (F) and other preoperative independent risk factors (A-E).

Figure 6 .
Figure 6.Subgroup analysis of the association between right IC Hu and neurocardiogenic injury.

Figure 7 .
Figure 7.The relationship between right IC Hu and the probability of NCI before PSM (A) and after PSM (B): A line connecting the midpoints of the top edge of each of the four bars chart was added to generate a bar line chart, with the respective interquartile range of Hu as the horizontal axis and the probability of NCI for each interval of Hu as the vertical axis.

Table 1 .
Baseline characteristics of patients with aSAH according to NCI.
a Unit of measurement: mm.ª 2023 The Authors.Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Table 2 .
Multivariable analysis of the relationship between the variables and NCI for cases after operation.

Table 3 .
Sensitivity analysis after removal of MCA aneurysm cases.