Serum desmosine levels are associated with the size of ruptured cerebral aneurysms in patients with aneurysmal subarachnoid hemorrhage

Serum desmosine levels are associated with the size of ruptured cerebral aneurysms in patients with aneurysmal subarachnoid hemorrhage | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Serum desmosine levels are associated with the size of ruptured cerebral aneurysms in patients with aneurysmal subarachnoid hemorrhage Peter Csecsei, Agnes Bogdan, Tihamer Molnar, Laszlo Zavori, Attila Schwarcz, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5660763/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Aneurysmal subarachnoid hemorrhage (aSAH) is a disease associated with high mortality, caused by the rupture of a cerebral aneurysm. Decision-support scoring systems used for managing unruptured aneurysms (UIAs) include only radiological parameters related to the size and configuration of the aneurysm, without incorporating blood-based markers. Our aim is to identify a serum marker that shows a correlation with aneurysm size in patients with ruptured aneurysms. Methods Arterial blood samples were collected from patients who experienced aSAH within 24 hours of the ictus, and serum desmosine levels were determined using ELISA. The morphological parameters of the aneurysms were assessed during 3D DSA. A favorable outcome was defined as a 3-month mRS score of 0–3. Results The study included 135 aSAH patients and 25 controls. (i) The desmosine level in serum collected within 24 hours after aneurysm rupture in patients with aSAH was significantly higher compared to the serum level in the control group (aSAH: 0.737 ng/mL [IQR: 0.401–1.214], vs. control: 0.365 ng/mL [IQR: 0.251–0.531], p < 0.001), (ii) examining the size of ruptured aneurysms, patients with aneurysms larger than 7 mm had significantly higher serum desmosine levels than those with aneurysms smaller than 7 mm, (iii) in the group with aneurysms smaller than 7 mm, serum desmosine levels correlated with the aneurysm neck width and the size ratio. Conclusion Serum desmosine shows a strong correlation with the size of ruptured aneurysms in aSAH patients. aneurysmal subarachnoid hemorrhage size of cerebral aneurysm desmosine size ratio Figures Figure 1 Figure 2 Figure 3 Introduction Aneurysmal subarachnoid hemorrhage (aSAH), although its mortality rate shows a decreasing trend [ 1 ], is still considered a serious condition. aSAH places a significant burden on society, with an estimated incidence of 6 to 8 cases per 100,000 people per year, and morbidity remains high [ 2 ]. For these reasons, treating rupture-prone aneurysms before they bleed is critically important. Current treatment options, such as microsurgical clipping and endovascular coiling, carry specific risks, which should be carefully considered in decisions regarding unruptured aneurysms. Several risk factors have been associated with rupture, including smoking, hypertension, certain aneurysmal morphological features (e.g. aneurysm size, daughter sacs, aspect ratio, size ratio), family history, and ethnicity [ 3 ]. Based on these, decision-support scoring systems (e.g., PHASES, UIATS) have been developed [ 4 – 5 ] to guide clinical decisions regarding treatment. In all of these scoring systems, the size and location of the aneurysm are important parameters; however, only one of them (UIATS) considers derived parameters (aspect ratio, size ratio), which are crucial for characterizing the aneurysm. The size and morphological characteristics of the aneurysm (AR, SR) are important risk factors for rupture [ 6 ]. Moreover, in certain locations, smaller aneurysms also carry a higher risk of rupture [ 6 ]. The aneurysm neck width and the SR have been proven to be independent risk factors for rupture status [ 7 – 8 ]. None of the predictive scores include a blood-measurable biomarker that could provide insights into the size or risk status of an aneurysm. Desmosine and isodesmosine are two pyridinium amino acids that act as positional isomers, functioning as crosslinking molecules to bind polymeric amino acid chains into elastin's three-dimensional network [ 9 ]. During the degradation of elastin-containing tissues, such as in pulmonary emphysema [ 10 ], COPD [ 11 ], or abdominal aortic aneurysm [ 12 ], desmosine can appear in the urine, sputum [ 9 ]and blood. A positive association has been found between plasma desmosine levels and the degree of aortic dilation in patients with Marfan syndrome [ 13 ]. Moreover, a small-scale study observed higher plasma desmosine levels in acute stroke patients compared to the control group [ 14 ]. A study by Nakagawa et al demonstrated a significantly higher concentration of soluble human elastin fragments in the lumen of ruptured intracranial aneurysms compared to nonruptured ones [ 15 ]. In addition, elastin degradation is considered to play an important role in the development of cerebral aneurysms [ 16 ]. Based on this, it can be hypothesized that desmosine may play a role in the formation of cerebral aneurysms, during potential rupture and may also be correlated with the size of the aneurysm. The main objective of our current study is to investigate the correlation between serum desmosine levels and clinical as well as aneurysm morphological parameters, in patients with aSAH. Methods Study design and subjects In this single-center, prospective study, a total of 174 patients were screened between February 2021 and April 2024. Of these, 135 patients met the inclusion criteria, which were as follows: (i) subarachnoid hemorrhage caused by a ruptured aneurysm, (ii) age 18 years or older, (iii) signed informed consent by the patient or their legal representative. Fourty-nine patients were excluded for the following reasons: missing biomarker data (n = 5), malignancies (n = 3), COPD or other lung diseases (n = 2), liver and/or kidney diseases (n = 5), confirmed abdominal aortic aneurysm or aneurysm in other parts of the body (n = 4), immunological disease (6), loss of follow-up (n = 6), non-traumatic cause of SAH/AVM (n = 5) and multiple cerebral aneurysm on DSA (13). As a control group, we selected 25 healthy, non-smoking, age- and sex-matched individuals who had undergone cranial CT/MR angiography for other reasons and abdominal ultrasound, and who had previously been treated for mild post-COVID symptoms. The clinical management of patients adhered to the guidelines set by the Neurocritical Care Society [ 17 ] and the American Heart Association [ 18 ]. The patients underwent endovascular aneurysm treatment within 24 hours of rupture and were placed under intensive care unit observation, where all patients received oral nimodipine and intravenous hydration with 0.9% saline, with additional fluids as necessary to maintain euvolemia. After admission we recorded significant comorbidities, smoking, and diabetes. The diagnosis of SAH was confirmed either by the admission CT scan or by the presence of xanthochromia in the lumbar puncture if the initial CT scan was inconclusive. A venous blood sample was collected within 24 hours of admission as part of the routine clinical evaluation. Neuroradiological grading was performed using the modified Fisher scale, which categorizes the amount of subarachnoid blood on the initial CT scan as none, diffuse thin, localized thin, diffuse thick, or localized thick, along with the presence of intraventricular hemorrhage (IVH), intracerebral hemorrhage, and hydrocephalus [ 19 ]. The World Federation of Neurological Societies (WFNS) score was used for clinical group classification [ 20 ]. Delayed cerebral ischemia was diagnosed based on established guidelines [ 21 ]. A favorable outcome for 3 month was considered a modified Rankin scale score of 0–3, which was assessed 90 days (± 5 days) after the ictus, either in an outpatient setting or via phone, with the assistance of an independent, trained evaluator. Definition of aneurysm morphological parameters For each patient, digital subtraction angiography (DSA) images and three-dimensional (3D) reconstructions during treatment were obtained using the Philips Allura Xper FD 20/15 system. During this process, we determined the number of aneurysms, their location, aneurysm size, neck diameter, parent artery diameter, aspect ratio (AR), and size ratio (SR) [ 22 ]. Aneurysm size was defined as the maximum distance of the dome from the aneurysm neck plane. Aspect ratio (AR) was calculated from the maximum perpendicular height of the aneurysm divided by the average neck diameter of the aneurysm. Size ratio (SR) was calculated from the maximum aneurysm height divided by the mean vessel diameter of all branches associated with the aneurysm. For each patient, two independent neuroradiologists performed the measurements, and the average value was used for subsequent statistical analysis. In our study the aneurysms were divided into six location groups: internal carotid artery (ICA), middle cerebral artery (MCA), anterior communicating artery (Acom), posterior communicating artery (Pcom), anterior cerebral artery (ACA) and vertebrobasilar (vertebral artery, basilar artery, posterior inferior cerebral artery and superior cerebellar artery). For the size-based categorization of aneurysms, we used the thresholds defined by the PHASES score [ 4 ]. Based on this, we classified aneurysms into groups of less than 7 mm, 7–9.9 mm, and 10–19.9 mm. (There were no aneurysms larger than 20 mm in the cohort.) Biomarker measurements Arterial blood samples were taken from patients with subarachnoid hemorrhage confirmed by native CT within 24 hours after the ictus. The samples were centrifuged at 4000 rpm for 10 minutes, after which the serum was separated and stored at -80 degrees Celsius until analysis. For the desmosine measurement a human desmosine ELISA kit was used (Cusabio, CSB-E12871h). Reagents and serum samples were prepared according to the Manufacturer’s instructions. Solutions were brought to room temperature 30 min before use. Biotinylated anti-desmosine antibody and HRP-avidin were diluted by the provided diluents (100-fold dilution). Standards were prepared from a stock solution by serial dilutions (10 ng/ml desmosine, 5 ng/ml, 2.5 ng/ml, 1.25 ng/ml, 0.625 ng/ml, 0.312 ng/ml, 0.156 ng/ml), sample diluent served as blank (standard zero, 0 ng/ml desmosine). Samples were thawed on ice. 100 µl of standards and samples were added to each well, and the plate was incubated for 2h at 37°C. After the incubation the liquid was removed from each well, and 100 µl of biotinylated anti-desmosine antibody was added. Following incubation (1h, 37°C) the antibody was aspirated and the wells were washed (3x200 µl washing buffer). HRP-avidin was added to the wells (100 µl), and the plate was incubated for 1h at 37°C. After aspiration of the HRP-avidin, the wells were washed (5x200 µl washing buffer), then 90 µl TMB Substrate was added to each well, followed by incubation (25 min, 37°C). The reaction was stopped by adding 50 µl Stop solution to each well, then the plate was read at 450 nm. The standard curve was plotted by four parameter logistic (4-PL) curve-fit, and the results were blank corrected (vagy blank correction was applied). Preliminary experiment was performed with a few samples at various dilutions (2-fold, 5-fold, 10-fold and 20-fold) and without dilution. Based on the results of that measurement the samples were used without dilution for the experiment. Statistical analysis All analyses were conducted with SPSS® Statistics version 25 (IBM Corporation, Armonk, NY, USA) and GraphPad Prism 9 software (GraphPad Software, San Diego, USA). Continuous variables are reported as mean ± SD or median with interquartile range, whereas categorical variables are reported as number and percentage. Differences between groups were assessed using unpaired t tests, analysis of variance, Kruskal-Wallis tests, or chi-squared tests, as appropriate. Correlations were assessed using Spearman’s correlation. The accuracy of desmosine in predicting size of aneurysm was evaluated by receiver operating characteristic curves, and the data are presented as the area under the curve (AUC). Results Patients characteristics A total of 135 patients were included in the analysis, with a mean age of 58.4 ± 12.4 years, and nearly three-quarters (73%) were female. The median WFNS score at admission was 2 (IQR: 1–4). The rate of favorable outcomes at 3 months (mRS 0–3) was 56%. The median size of aneurysms detected on DSA was 7 mm (IQR: 5–10.7). The most common aneurysm location was the Acom (31%), followed by the MCA at 24%. In the patient group (n = 135), the serum desmosine level was 0.737 ng/mL (IQR: 0.401–1.214), while in the control group (n = 25), it was 0.365 ng/mL (IQR: 0.251–0.531), p < 0.001, Fig. 1 . No significant differences were observed in the age (years) distribution (aSAH: 58.4 ± 12.4 vs. control: 53.3 ± 8, p = 0.074) or gender distribution (aSAH: 73% vs. control: 66.7%, p = 0.366) between the patient group and the control group. The detailed parameters of the cohort are shown in Table 1 . Variable Total < 7 mm 7 mm< P-value Number of patients, n 135 69 66 N/A age, years, mean ± SD 58.4 ± 12.4 57 ± 13 59 ± 12 0.360 female, n (%) 99 (73) 52 (75) 47 (73) 0.518 Hypertension, n (%) 71 (53) 37 (54) 34 (53) 0.544 Smoking, n (%) 46 (34) 23 (37) 23 (38) 0.491 Diabetes, n (%) 14 (9) 7 (9.5) 7 (8.5) 0.584 WFNS, median (IQR) 2 (1–4) 2 (1–4) 2.5 (1–5) 0.364 mFisher score, median (IQR) 3 (2–4) 3 (2–3) 3 (2–4) 0.344 3-month mRS score, median (IQR) 3 (2–5) 2 (1–4) 4 (2–5) 0.003 3-month mRS (0–3), n (%) 75 (56) 48 (70) 27 (41) 0.004 Delayed cerebral ischemia, n (%) 25 (19) 13 (19) 12 (18) 0.482 Extraventricular drainage, n (%) 60 (44) 26 (37) 34 (52) 0.092 Mechanical ventillation, n (%) 64 (47) 24 (35) 40 (61) 0.008 creatinine a , µmol/L, median (IQR) 60 (48–71) 59 (47–77) 61 (49–70) 0.677 CRP a , mg/L, median (IQR) 17 (5–59) 16 (5–45) 14 (3–77) 0.745 WBC a , G/L, median (IQR) 10 (8–13) 10.6 (8–13) 10 (9–12) Size of aneurysm, mm, median (IQR) 7 (5-10.7) 5 (4–6) 10.8 (9–13) < 0.001 Neck width, mm, median (IQR) 3.3 (2.4-4) 2.6 (2.2–3.3) 3.7 (3.3–4.8) < 0.001 Aspect ratio, median (IQR) 1.7 (1.4–2.2) 1.52 (1.2–2.1) 1.8 (1.5–2.3) 0.022 Size ratio, median (IQR) 3.8 (2.6-5) 2.72 (1.9–3.9) 4.42 (3.7–5.5) < 0.001 Daughter sac, n (%) 54 (44) 22 (32) 32 (55) 0.018 Location of ruptured aneurysm, n (%) 0.003 ICA 6 (4.8) 2 (3.3) 4 (6.8) MCA 33 (24) 9 (13.1) 25 (37.3) Acom 42 (31.2) 31 (44.3) 9 (13.6) Pcom 20 (14.4) 10 (14.8) 10 (15.3) ACA 3 (2.4) 2 (3.3) 1 (1.7) Vertebrobasilar 31 (23.2) 15 (21.3) 17 (25.4) serum desmosine, ng/mL, median (IQR) 0.64 (0.37–1.12) 0.503 (0.285–0.740) 1.196 (0.714–1.665) < 0.001 serum desmosine, ng/mL, mean ± SD 0.932 0.588 ± 0.46 1.281 ± 0.78 < 0.001 a on admission; WFNS: World Federation os Neurological Societies score; IQR: interquartile range; SD: standard deviation; mRS: modified Rankin scale; CRP: C-reactive protein; WBC: white blood count; ICA: internal carotid artery; MCA: middle cerebral artery; Acom: anterior communicating artery; Pcom: posterior communicating artery; ACA: anterior cerebral artery Relationship between serum desmosine levels and aneurysm morphology Within 24 hours after rupture, the serum desmosine level was significantly higher in patients with aneurysms larger than 7 mm compared to those with aneurysms smaller than 7 mm (p < 0.001). No significant difference in serum desmosine levels was observed between patients with aneurysms sized 7-9.9 mm and those with aneurysms larger than 9.9 mm, as shown in Fig. 2 . We examined the correlation between aneurysm morphological data and serum desmosine levels for aneurysms smaller than 7 mm and those larger than 7 mm. We found that aneurysm size showed a positive correlation with serum desmosine levels in both groups (Spearman rho, 0.327 and 0.287, respectively), while the size ratio and aneurysm neck diameter only showed a negative correlation with serum desmosine levels in aneurysms smaller than 7 mm (Spearman rho, -0.336 and − 0.326, respectively). Age, admission WFNS score, CRP, and creatinine levels showed no correlation with serum desmosine levels, Table 2 . The area under the curve of serum desmosine to differentiate between the large (7 mm ) ruptured aneurysms on DSA was 0.804 (95% CI 0.723 to 0.884), p < 0.001, Fig. 3 . The cut-off value was determined to be 0.533 ng/mL, with a sensitivity of 81.7% and a specificity of 60.3%. Table 2 The correlation of serum desmosine with clinical variables and aneurysm morphological parameters. ρ , Spearman’s rho, CRP, C-reactive protein, WFNS score, World Federation of Neurological Societies score. < 7 mm (n = 69) 7 mm< (n = 66) Variable ρ p -value ρ p -value Size of aneurysm 0.327 0.009 0.287 0.026 Size ratio -0.336 0.008 -0.006 0.966 Aspect ratio 0.145 0.266 0.046 0.731 Neck width -0.326 0.01 -0.202 0.132 CRP -0.003 0.450 -0.111 0.450 Creatinine 0.024 0.856 -0.029 0.838 Age 0.229 0.071 -0.116 0.380 WFNS score 0.037 0.775 -0.047 0.721 mRS score (3 month) -0.078 0.544 0.009 0.948 Discussion In this study, we found the following results: (i) The desmosine level in serum collected within 24 hours after aneurysm rupture in patients with aSAH was significantly higher compared to the serum level in the control group, (ii) examining the size of ruptured aneurysms, patients with aneurysms larger than 7 mm had significantly higher serum desmosine levels than those with aneurysms smaller than 7 mm, (iii) in the group with aneurysms smaller than 7 mm, serum desmosine levels correlated with the aneurysm neck width and the size ratio. We hypothesize that the higher serum desmosine levels observed in patients who experienced subarachnoid hemorrhage, compared to the control group, can be attributed to the breakdown of elastin released from the damaged aneurysm tissue during the rupture. Since patients with comorbidities known to increase desmosine levels (e.g., COPD, abdominal aortic aneurysm, [ 10 – 12 ] etc.) were excluded from the study, the difference observed between the two groups is presumed to be associated with the rupture of the aneurysm. The outcomes differed significantly between the two groups (7 mm > vs. 7 mm <), suggesting the possibility that the difference in desmosine levels between the groups might be due to the outcomes. However, serum desmosine levels showed no correlation with clinical (WFNS) or radiological (mFisher score) scales, nor with 3-month outcomes, and no association was observed with outcomes within the individual groups either. In our cohort, the significantly worse outcomes observed in patients with larger aneurysms (> 7 mm) can be partially explained by the higher prevalence of MCA (middle cerebral artery) aneurysms in this group. This is associated with an increased need for EVD (external ventricular drainage), which is known to elevate the risk of unfavorable outcomes [ 23 ]. Aneurysm size itself is also associated with outcomes in cases of aSAH [ 24 ]. Plasma desmosine concentrations correlated with the maximal abdominal aortic aneurysm (AAA) diameter and log plasma desmosine concentration was associated with increased likelihood of an AAA event (death, rupture or urgent repair) in a recent, large study with AAA patients [ 12 ]. According to the study, measuring plasma desmosine levels could be a useful additional biomarker in the therapeutic decision-making process [ 12 ]. Although this study [ 12 ] determined levels from plasma, the levels measured in serum in our study are comparable to the concentrations observed in both the control and patient groups. Considering the abdominal aortic aneurysm, it typically comprises a larger tissue mass than the aneurysms observed in our study. However, the similarity in concentrations can be attributed to the fact that we investigated patients with ruptured aneurysms. It is assumed that rupture involves more significant elastin degradation and consequently a greater increase in desmosine levels compared to stable aneurysms. Nakagawa et al found that mean of plasma concentration of serum soluble human elastin fragments was significantly higher in ruptured aneurysms than unruptured aneurysms [ 15 ], which is also supports our findings that significantly greater elastin degradation can be measured during aneurysm rupture compared to stable aneurysms. The results of other studies also support our findings, suggesting that desmosine appears to be more specific to vascular elastin breakdown rather than lung elastin degradation [ 12 , 25 ]. In our current study, we excluded individuals with COPD or other chronic lung diseases, but we did not exclude smokers, given that smoking is a known risk factor for aSAH. However, we found no correlation between smoking and serum desmosine levels or aneurysm size, which aligns with previous large-scale studies conducted on patients with abdominal aortic aneurysms [ 12 ]. Although in this study we measured serum desmosine levels at only one time point which is a limitation, a [ 12 ] previous study involving measurements at multiple time points indicate that its levels are relatively stable. This reduces the significance of this limitation in our study. An other study plasma desmosine concentrations predict clinical outcomes in patients with acute myocardial infarction (AMI), demonstrating its potential role as a prognostic marker in AMI [ 26 ]. Results from other studies examining role in desmosine in various diseases [ 27 – 29 ] suggest that desmosine predominantly reflects elastin degradation in the vascular tissue of the vascular system, likely to be caused by vascular tissue inflammation or atherosclerosis. In our study, we observed an inverse correlation between serum desmosine levels and both the neck width of the ruptured aneurysm and the size ratio in patients with aneurysms smaller than 7 mm. Kashiwazaki et al [ 30 ], in a large-scale study, found that the size ratio, and not the absolute size, may highly predict the risk of rupture in small unruptured intracranial aneurysms. Our finding that desmosine levels correlate with the size ratio in aneurysms smaller than 7 mm strongly suggests the possibility that, if confirmed in studies with larger sample sizes, this could lead to the identification of a serum biomarker capable of influencing treatment strategies. It is important to acknowledge that the shape and size of aneurysms can change following rupture [ 31 ]; therefore, our findings are not fully applicable to unruptured aneurysms (UIAs). Another reason why our results need to be reproduced in patients with UIAs is that in unruptured aneurysms, elastin degradation is likely a much slower process, whereas in ruptured cases, the acute vascular wall disruption may lead to a significantly greater release of elastin degradation products. Thus, desmosine appears in measurable amounts in the serum of patients with ruptured aneurysms, whereas in the case of stable UIAs, lower concentrations are expected due to the prolonged release of desmosine, although there is currently no evidence to support this. Our study has several limitations. Blood samples were collected only during the acute period, so we do not know the kinetics of desmosine levels in later stages. Additionally, the control group consisted of individuals without aneurysms or other comorbidities that could affect desmosine levels, preventing us from making comparisons between cohorts of patients with ruptured (aSAH) and unruptured (UIA) aneurysms. In summary, serum desmosine levels show a strong correlation with the size and size ratio (SR) of ruptured aneurysms in patients with aSAH. Further studies are needed to determine whether serum desmosine could serve as a relevant biomarker for aneurysm size in unruptured cerebral aneurysms and whether it could play a role in therapeutic decision-making. Declarations Acknowledgements We would like to thank all the patients who contributed to our study by participating, as well as all colleagues in the team who are involved in data collection, serum measurements, and statistical data analysis. Author Contribution PC and AB contributed to the conception and design of the study. PC, TM, GL and LZ contributed to the acquisition and analysis of samples and data. PC and LZ drafted a significant portion of the manuscript. AB performed the laboratory measurements and validations. TM and AS provided supervision of the study. All authors interpreted the data, reviewed the manuscript, and approved the final version. Funding This work was supported in part by National Laboratory for Translational Neuroscience (TINL) RRF-2.3.1-21-2022-00011 project and hungarian NRDI Fund (NKFI-FK-146159). Data Availability Data supporting the fndings of this study are available upon reasonable request. Conflict of Interest The authors declare no competing interests. Ethics approval and consent statement Study was approved by the Hungarian Medical Research Council (BM/29883-1/2023). All procedures were performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. Informed Consent Statement Informed consent was obtained from all subjects involved in the study. References Bugazia S, Boshnaf M, Sreenivasan A et al (2024) 278: Subarachnoid hemorrhage mortality trends in U.S. patients with circulatory disease (1999–2020). 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Front Cardiovasc Med 9:992388 Rabinovich RA, Miller BE, Wrobel K et al (2016) Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD. Eur Respir J 47:1365–1373 Huang JT, Kuzmanova E, Dicker AJ et al (2020) Serum desmosine is associated with long-term all-cause and cardiovascular mortality in bronchiectasis. Am J Respir Crit Care Med 202:897–899 Iskandar Z, Mordi I, Huang JTJ et al (2019) Plasma desmosine, an elastin degradation product, predicts outcomes in at-risk populations. J Am Coll Cardiol 73(Suppl_1):1805 Kashiwazaki D, Kuroda S, Sapporo SAH, Study Group (2013) Size ratio can highly predict rupture risk in intracranial small (< 5 mm) aneurysms. Stroke 44(8):2169–2173 Chien A, Sayre J, Viñuela F (2011) Comparative morphological analysis of the geometry of ruptured and unruptured aneurysms. Neurosurgery 69:349–356 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5660763","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":391895029,"identity":"86c37a10-8ce0-4c09-bfc2-3aeae483b1f4","order_by":0,"name":"Peter Csecsei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYPACCSBmbHzAwHCAFC1sjM0GpGgBAjYGNgmitPD3Hz748UeFRR6/fHNbNU/NHTl+BuaHj27gc9GNtGRpnjMSxZJtjG23eY49M5ZsYDM2zsGjxUCCx4yZsU0iccMxkBa2w4kbDvCwSePVwn/+G+PPfxKJ+4Fainn+EaOFIYeNgbcBaAsbYxszbxsRWoB+MZbmOSZRLHEssVlybt9hY8lmAn4BhtjDjz9q6vL4m48//PDm22E5fvbmh4/xaYGBBBDBxAMimYlQDtfC+INI1aNgFIyCUTCyAAB+30pKpdA9AgAAAABJRU5ErkJggg==","orcid":"","institution":"University of Pecs","correspondingAuthor":true,"prefix":"","firstName":"Peter","middleName":"","lastName":"Csecsei","suffix":""},{"id":391895030,"identity":"fb33ce53-75e6-4ace-8502-71adae2ac121","order_by":1,"name":"Agnes Bogdan","email":"","orcid":"","institution":"University of Pecs","correspondingAuthor":false,"prefix":"","firstName":"Agnes","middleName":"","lastName":"Bogdan","suffix":""},{"id":391895031,"identity":"7f39b0b7-dfc6-44fa-90f6-81f8333aa0df","order_by":2,"name":"Tihamer Molnar","email":"","orcid":"","institution":"University of Pecs","correspondingAuthor":false,"prefix":"","firstName":"Tihamer","middleName":"","lastName":"Molnar","suffix":""},{"id":391895032,"identity":"9e782949-3d8c-4673-a13a-424fdf03a9d5","order_by":3,"name":"Laszlo Zavori","email":"","orcid":"","institution":"Saudi German Hospital","correspondingAuthor":false,"prefix":"","firstName":"Laszlo","middleName":"","lastName":"Zavori","suffix":""},{"id":391895033,"identity":"3bcb76bf-6936-4d3d-bf0c-a6cb8cbc4bea","order_by":4,"name":"Attila Schwarcz","email":"","orcid":"","institution":"University of Pecs","correspondingAuthor":false,"prefix":"","firstName":"Attila","middleName":"","lastName":"Schwarcz","suffix":""},{"id":391895034,"identity":"5429b4f2-84b6-454e-86ae-c8cc94a1eba4","order_by":5,"name":"Gabor Lenzser","email":"","orcid":"","institution":"University of Pecs","correspondingAuthor":false,"prefix":"","firstName":"Gabor","middleName":"","lastName":"Lenzser","suffix":""}],"badges":[],"createdAt":"2024-12-17 10:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5660763/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5660763/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":72290691,"identity":"81295b90-f5bf-40f8-8375-3d9aca76a84a","added_by":"auto","created_at":"2024-12-24 17:24:09","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38623,"visible":true,"origin":"","legend":"\u003cp\u003eSerum desmosine levels in the patient group (n=135) and the control group (n=25). Ctrl, control, ***, p\u0026lt;0.001\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5660763/v1/ef7777010f30d00a9f85c985.jpeg"},{"id":72290697,"identity":"3247bc2e-f4e0-477c-b356-e8e9b84340ad","added_by":"auto","created_at":"2024-12-24 17:24:09","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":142233,"visible":true,"origin":"","legend":"\u003cp\u003eSerum desmosine levels collected 24 hours after rupture, categorized by the size of the aneurysm measured on 3D-DSA. The size-based categorization of aneurysms is based on the PHASES score [4] classification. ns: non-significant; number of aneurysms in each group: \u0026lt;7 mm (n=69), 7-9.9 mm (n=25), 10-19.9 mm (n=41).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5660763/v1/a318d3ce837d862c64df4fa7.jpeg"},{"id":72290700,"identity":"0515b77a-0eda-4c58-b65d-a93aab5a68e0","added_by":"auto","created_at":"2024-12-24 17:24:09","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":107012,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve for serum desmosine levels in detecting aneurysms larger than 7 mm. The best cut-off value was 0.533 ng/mL with the sensitivity and specificity of 81.7% and 60.3% respectively.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5660763/v1/629e3245d96f5767fb693554.jpeg"},{"id":75240674,"identity":"d7453624-fc7f-454e-b3d8-569326b09b87","added_by":"auto","created_at":"2025-02-01 20:16:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1102678,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5660763/v1/9700101d-61b6-4d19-b4a8-34ebbdf564e2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Serum desmosine levels are associated with the size of ruptured cerebral aneurysms in patients with aneurysmal subarachnoid hemorrhage","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAneurysmal subarachnoid hemorrhage (aSAH), although its mortality rate shows a decreasing trend [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], is still considered a serious condition. aSAH places a significant burden on society, with an estimated incidence of 6 to 8 cases per 100,000 people per year, and morbidity remains high [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For these reasons, treating rupture-prone aneurysms before they bleed is critically important. Current treatment options, such as microsurgical clipping and endovascular coiling, carry specific risks, which should be carefully considered in decisions regarding unruptured aneurysms.\u003c/p\u003e \u003cp\u003eSeveral risk factors have been associated with rupture, including smoking, hypertension, certain aneurysmal morphological features (e.g. aneurysm size, daughter sacs, aspect ratio, size ratio), family history, and ethnicity [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Based on these, decision-support scoring systems (e.g., PHASES, UIATS) have been developed [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] to guide clinical decisions regarding treatment. In all of these scoring systems, the size and location of the aneurysm are important parameters; however, only one of them (UIATS) considers derived parameters (aspect ratio, size ratio), which are crucial for characterizing the aneurysm. The size and morphological characteristics of the aneurysm (AR, SR) are important risk factors for rupture [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Moreover, in certain locations, smaller aneurysms also carry a higher risk of rupture [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The aneurysm neck width and the SR have been proven to be independent risk factors for rupture status [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. None of the predictive scores include a blood-measurable biomarker that could provide insights into the size or risk status of an aneurysm. Desmosine and isodesmosine are two pyridinium amino acids that act as positional isomers, functioning as crosslinking molecules to bind polymeric amino acid chains into elastin's three-dimensional network [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. During the degradation of elastin-containing tissues, such as in pulmonary emphysema [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], COPD [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], or abdominal aortic aneurysm [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], desmosine can appear in the urine, sputum [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]and blood. A positive association has been found between plasma desmosine levels and the degree of aortic dilation in patients with Marfan syndrome [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Moreover, a small-scale study observed higher plasma desmosine levels in acute stroke patients compared to the control group [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A study by Nakagawa et al demonstrated a significantly higher concentration of soluble human elastin fragments in the lumen of ruptured intracranial aneurysms compared to nonruptured ones [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In addition, elastin degradation is considered to play an important role in the development of cerebral aneurysms [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Based on this, it can be hypothesized that desmosine may play a role in the formation of cerebral aneurysms, during potential rupture and may also be correlated with the size of the aneurysm. The main objective of our current study is to investigate the correlation between serum desmosine levels and clinical as well as aneurysm morphological parameters, in patients with aSAH.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and subjects\u003c/h2\u003e \u003cp\u003eIn this single-center, prospective study, a total of 174 patients were screened between February 2021 and April 2024. Of these, 135 patients met the inclusion criteria, which were as follows: (i) subarachnoid hemorrhage caused by a ruptured aneurysm, (ii) age 18 years or older, (iii) signed informed consent by the patient or their legal representative. Fourty-nine patients were excluded for the following reasons: missing biomarker data (n\u0026thinsp;=\u0026thinsp;5), malignancies (n\u0026thinsp;=\u0026thinsp;3), COPD or other lung diseases (n\u0026thinsp;=\u0026thinsp;2), liver and/or kidney diseases (n\u0026thinsp;=\u0026thinsp;5), confirmed abdominal aortic aneurysm or aneurysm in other parts of the body (n\u0026thinsp;=\u0026thinsp;4), immunological disease (6), loss of follow-up (n\u0026thinsp;=\u0026thinsp;6), non-traumatic cause of SAH/AVM (n\u0026thinsp;=\u0026thinsp;5) and multiple cerebral aneurysm on DSA (13). As a control group, we selected 25 healthy, non-smoking, age- and sex-matched individuals who had undergone cranial CT/MR angiography for other reasons and abdominal ultrasound, and who had previously been treated for mild post-COVID symptoms.\u003c/p\u003e \u003cp\u003eThe clinical management of patients adhered to the guidelines set by the Neurocritical Care Society [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and the American Heart Association [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The patients underwent endovascular aneurysm treatment within 24 hours of rupture and were placed under intensive care unit observation, where all patients received oral nimodipine and intravenous hydration with 0.9% saline, with additional fluids as necessary to maintain euvolemia. After admission we recorded significant comorbidities, smoking, and diabetes.\u003c/p\u003e \u003cp\u003eThe diagnosis of SAH was confirmed either by the admission CT scan or by the presence of xanthochromia in the lumbar puncture if the initial CT scan was inconclusive. A venous blood sample was collected within 24 hours of admission as part of the routine clinical evaluation. Neuroradiological grading was performed using the modified Fisher scale, which categorizes the amount of subarachnoid blood on the initial CT scan as none, diffuse thin, localized thin, diffuse thick, or localized thick, along with the presence of intraventricular hemorrhage (IVH), intracerebral hemorrhage, and hydrocephalus [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The World Federation of Neurological Societies (WFNS) score was used for clinical group classification [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Delayed cerebral ischemia was diagnosed based on established guidelines [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A favorable outcome for 3 month was considered a modified Rankin scale score of 0\u0026ndash;3, which was assessed 90 days (\u0026plusmn;\u0026thinsp;5 days) after the ictus, either in an outpatient setting or via phone, with the assistance of an independent, trained evaluator.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDefinition of aneurysm morphological parameters\u003c/h3\u003e\n\u003cp\u003eFor each patient, digital subtraction angiography (DSA) images and three-dimensional (3D) reconstructions during treatment were obtained using the Philips Allura Xper FD 20/15 system. During this process, we determined the number of aneurysms, their location, aneurysm size, neck diameter, parent artery diameter, aspect ratio (AR), and size ratio (SR) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Aneurysm size was defined as the maximum distance of the dome from the aneurysm neck plane. Aspect ratio (AR) was calculated from the maximum perpendicular height of the aneurysm divided by the average neck diameter of the aneurysm. Size ratio (SR) was calculated from the maximum aneurysm height divided by the mean vessel diameter of all branches associated with the aneurysm. For each patient, two independent neuroradiologists performed the measurements, and the average value was used for subsequent statistical analysis. In our study the aneurysms were divided into six location groups: internal carotid artery (ICA), middle cerebral artery (MCA), anterior communicating artery (Acom), posterior communicating artery (Pcom), anterior cerebral artery (ACA) and vertebrobasilar (vertebral artery, basilar artery, posterior inferior cerebral artery and superior cerebellar artery). For the size-based categorization of aneurysms, we used the thresholds defined by the PHASES score [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Based on this, we classified aneurysms into groups of less than 7 mm, 7\u0026ndash;9.9 mm, and 10\u0026ndash;19.9 mm. (There were no aneurysms larger than 20 mm in the cohort.)\u003c/p\u003e\n\u003ch3\u003eBiomarker measurements\u003c/h3\u003e\n\u003cp\u003eArterial blood samples were taken from patients with subarachnoid hemorrhage confirmed by native CT within 24 hours after the ictus. The samples were centrifuged at 4000 rpm for 10 minutes, after which the serum was separated and stored at -80 degrees Celsius until analysis. For the desmosine measurement a human desmosine ELISA kit was used (Cusabio, CSB-E12871h). Reagents and serum samples were prepared according to the Manufacturer\u0026rsquo;s instructions. Solutions were brought to room temperature 30 min before use. Biotinylated anti-desmosine antibody and HRP-avidin were diluted by the provided diluents (100-fold dilution). Standards were prepared from a stock solution by serial dilutions (10 ng/ml desmosine, 5 ng/ml, 2.5 ng/ml, 1.25 ng/ml, 0.625 ng/ml, 0.312 ng/ml, 0.156 ng/ml), sample diluent served as blank (standard zero, 0 ng/ml desmosine). Samples were thawed on ice. 100 \u0026micro;l of standards and samples were added to each well, and the plate was incubated for 2h at 37\u0026deg;C. After the incubation the liquid was removed from each well, and 100 \u0026micro;l of biotinylated anti-desmosine antibody was added. Following incubation (1h, 37\u0026deg;C) the antibody was aspirated and the wells were washed (3x200 \u0026micro;l washing buffer). HRP-avidin was added to the wells (100 \u0026micro;l), and the plate was incubated for 1h at 37\u0026deg;C. After aspiration of the HRP-avidin, the wells were washed (5x200 \u0026micro;l washing buffer), then 90 \u0026micro;l TMB Substrate was added to each well, followed by incubation (25 min, 37\u0026deg;C). The reaction was stopped by adding 50 \u0026micro;l Stop solution to each well, then the plate was read at 450 nm. The standard curve was plotted by four parameter logistic (4-PL) curve-fit, and the results were blank corrected (vagy blank correction was applied). Preliminary experiment was performed with a few samples at various dilutions (2-fold, 5-fold, 10-fold and 20-fold) and without dilution. Based on the results of that measurement the samples were used without dilution for the experiment.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll analyses were conducted with SPSS\u0026reg; Statistics version 25 (IBM Corporation, Armonk, NY, USA) and GraphPad Prism 9 software (GraphPad Software, San Diego, USA). Continuous variables are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median with interquartile range, whereas categorical variables are reported as number and percentage. Differences between groups were assessed using unpaired t tests, analysis of variance, Kruskal-Wallis tests, or chi-squared tests, as appropriate. Correlations were assessed using Spearman\u0026rsquo;s correlation. The accuracy of desmosine in predicting size of aneurysm was evaluated by receiver operating characteristic curves, and the data are presented as the area under the curve (AUC).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatients characteristics\u003c/h2\u003e \u003cp\u003eA total of 135 patients were included in the analysis, with a mean age of 58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4 years, and nearly three-quarters (73%) were female. The median WFNS score at admission was 2 (IQR: 1\u0026ndash;4). The rate of favorable outcomes at 3 months (mRS 0\u0026ndash;3) was 56%. The median size of aneurysms detected on DSA was 7 mm (IQR: 5\u0026ndash;10.7). The most common aneurysm location was the Acom (31%), followed by the MCA at 24%. In the patient group (n\u0026thinsp;=\u0026thinsp;135), the serum desmosine level was 0.737 ng/mL (IQR: 0.401\u0026ndash;1.214), while in the control group (n\u0026thinsp;=\u0026thinsp;25), it was 0.365 ng/mL (IQR: 0.251\u0026ndash;0.531), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. No significant differences were observed in the age (years) distribution (aSAH: 58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4 vs. control: 53.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8, p\u0026thinsp;=\u0026thinsp;0.074) or gender distribution (aSAH: 73% vs. control: 66.7%, p\u0026thinsp;=\u0026thinsp;0.366) between the patient group and the control group. The detailed parameters of the cohort are shown in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;7 mm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 mm\u0026lt;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eage, years, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.360\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.518\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.544\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.491\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (8.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.584\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWFNS, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.5 (1\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.364\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emFisher score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (2\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.344\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3-month mRS score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3-month mRS (0\u0026ndash;3), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelayed cerebral ischemia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.482\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtraventricular drainage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventillation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40 (61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecreatinine\u003csup\u003ea\u003c/sup\u003e, \u0026micro;mol/L, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (48\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (47\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (49\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.677\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003csup\u003ea\u003c/sup\u003e, mg/L, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (5\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (5\u0026ndash;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (3\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.745\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC\u003csup\u003ea\u003c/sup\u003e, G/L, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (8\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.6 (8\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (9\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of aneurysm, mm, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (5-10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (4\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.8 (9\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeck width, mm, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.3 (2.4-4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.6 (2.2\u0026ndash;3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.7 (3.3\u0026ndash;4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspect ratio, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.7 (1.4\u0026ndash;2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.52 (1.2\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.8 (1.5\u0026ndash;2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize ratio, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.8 (2.6-5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.72 (1.9\u0026ndash;3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.42 (3.7\u0026ndash;5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaughter sac, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation of ruptured aneurysm, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (37.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (31.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (44.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePcom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (14.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (15.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVertebrobasilar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (23.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (21.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (25.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eserum desmosine, ng/mL, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.64 (0.37\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.503 (0.285\u0026ndash;0.740)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.196 (0.714\u0026ndash;1.665)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eserum desmosine, ng/mL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.932\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.588\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.281\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e on admission; WFNS: World Federation os Neurological Societies score; IQR: interquartile range; SD: standard deviation; mRS: modified Rankin scale; CRP: C-reactive protein; WBC: white blood count; ICA: internal carotid artery; MCA: middle cerebral artery; Acom: anterior communicating artery; Pcom: posterior communicating artery; ACA: anterior cerebral artery\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRelationship between serum desmosine levels and aneurysm morphology\u003c/h3\u003e\n\u003cp\u003eWithin 24 hours after rupture, the serum desmosine level was significantly higher in patients with aneurysms larger than 7 mm compared to those with aneurysms smaller than 7 mm (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No significant difference in serum desmosine levels was observed between patients with aneurysms sized 7-9.9 mm and those with aneurysms larger than 9.9 mm, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe examined the correlation between aneurysm morphological data and serum desmosine levels for aneurysms smaller than 7 mm and those larger than 7 mm. We found that aneurysm size showed a positive correlation with serum desmosine levels in both groups (Spearman rho, 0.327 and 0.287, respectively), while the size ratio and aneurysm neck diameter only showed a negative correlation with serum desmosine levels in aneurysms smaller than 7 mm (Spearman rho, -0.336 and \u0026minus;\u0026thinsp;0.326, respectively). Age, admission WFNS score, CRP, and creatinine levels showed no correlation with serum desmosine levels, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe area under the curve of serum desmosine to differentiate between the large (7 mm \u0026lt;) and small (7 mm\u0026gt;) ruptured aneurysms on DSA was 0.804 (95% CI 0.723 to 0.884), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The cut-off value was determined to be 0.533 ng/mL, with a sensitivity of 81.7% and a specificity of 60.3%.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe correlation of serum desmosine with clinical variables and aneurysm morphological parameters. \u003cem\u003eρ\u003c/em\u003e, Spearman\u0026rsquo;s rho, CRP, C-reactive protein, WFNS score, World Federation of Neurological Societies score.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;7 mm (n\u0026thinsp;=\u0026thinsp;69)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e7 mm\u0026lt; (n\u0026thinsp;=\u0026thinsp;66)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eρ\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eρ\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of aneurysm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.327\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.287\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSize ratio\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-0.336\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.966\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAspect ratio\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.145\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.266\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.046\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.731\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeck width\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-0.326\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.202\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.132\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRP\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.450\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.111\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.450\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCreatinine\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.024\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.856\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.029\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.838\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.229\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.071\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.116\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.380\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWFNS score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.037\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.775\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.047\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.721\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003emRS score (3 month)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-0.078\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.544\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.948\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we found the following results: (i) The desmosine level in serum collected within 24 hours after aneurysm rupture in patients with aSAH was significantly higher compared to the serum level in the control group, (ii) examining the size of ruptured aneurysms, patients with aneurysms larger than 7 mm had significantly higher serum desmosine levels than those with aneurysms smaller than 7 mm, (iii) in the group with aneurysms smaller than 7 mm, serum desmosine levels correlated with the aneurysm neck width and the size ratio. We hypothesize that the higher serum desmosine levels observed in patients who experienced subarachnoid hemorrhage, compared to the control group, can be attributed to the breakdown of elastin released from the damaged aneurysm tissue during the rupture. Since patients with comorbidities known to increase desmosine levels (e.g., COPD, abdominal aortic aneurysm, [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] etc.) were excluded from the study, the difference observed between the two groups is presumed to be associated with the rupture of the aneurysm. The outcomes differed significantly between the two groups (7 mm\u0026thinsp;\u0026gt;\u0026thinsp;vs. 7 mm \u0026lt;), suggesting the possibility that the difference in desmosine levels between the groups might be due to the outcomes. However, serum desmosine levels showed no correlation with clinical (WFNS) or radiological (mFisher score) scales, nor with 3-month outcomes, and no association was observed with outcomes within the individual groups either. In our cohort, the significantly worse outcomes observed in patients with larger aneurysms (\u0026gt;\u0026thinsp;7 mm) can be partially explained by the higher prevalence of MCA (middle cerebral artery) aneurysms in this group. This is associated with an increased need for EVD (external ventricular drainage), which is known to elevate the risk of unfavorable outcomes [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Aneurysm size itself is also associated with outcomes in cases of aSAH [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Plasma desmosine concentrations correlated with the maximal abdominal aortic aneurysm (AAA) diameter and log plasma desmosine concentration was associated with increased likelihood of an AAA event (death, rupture or urgent repair) in a recent, large study with AAA patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. According to the study, measuring plasma desmosine levels could be a useful additional biomarker in the therapeutic decision-making process [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although this study [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] determined levels from plasma, the levels measured in serum in our study are comparable to the concentrations observed in both the control and patient groups. Considering the abdominal aortic aneurysm, it typically comprises a larger tissue mass than the aneurysms observed in our study. However, the similarity in concentrations can be attributed to the fact that we investigated patients with ruptured aneurysms. It is assumed that rupture involves more significant elastin degradation and consequently a greater increase in desmosine levels compared to stable aneurysms. Nakagawa et al found that mean of plasma concentration of serum soluble human elastin fragments was significantly higher in ruptured aneurysms than unruptured aneurysms [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], which is also supports our findings that significantly greater elastin degradation can be measured during aneurysm rupture compared to stable aneurysms. The results of other studies also support our findings, suggesting that desmosine appears to be more specific to vascular elastin breakdown rather than lung elastin degradation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In our current study, we excluded individuals with COPD or other chronic lung diseases, but we did not exclude smokers, given that smoking is a known risk factor for aSAH. However, we found no correlation between smoking and serum desmosine levels or aneurysm size, which aligns with previous large-scale studies conducted on patients with abdominal aortic aneurysms [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although in this study we measured serum desmosine levels at only one time point which is a limitation, a [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] previous study involving measurements at multiple time points indicate that its levels are relatively stable. This reduces the significance of this limitation in our study. An other study plasma desmosine concentrations predict clinical outcomes in patients with acute myocardial infarction (AMI), demonstrating its potential role as a prognostic marker in AMI [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Results from other studies examining role in desmosine in various diseases [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] suggest that desmosine predominantly reflects elastin degradation in the vascular tissue of the vascular system, likely to be caused by vascular tissue inflammation or atherosclerosis. In our study, we observed an inverse correlation between serum desmosine levels and both the neck width of the ruptured aneurysm and the size ratio in patients with aneurysms smaller than 7 mm. Kashiwazaki et al [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], in a large-scale study, found that the size ratio, and not the absolute size, may highly predict the risk of rupture in small unruptured intracranial aneurysms. Our finding that desmosine levels correlate with the size ratio in aneurysms smaller than 7 mm strongly suggests the possibility that, if confirmed in studies with larger sample sizes, this could lead to the identification of a serum biomarker capable of influencing treatment strategies. It is important to acknowledge that the shape and size of aneurysms can change following rupture [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]; therefore, our findings are not fully applicable to unruptured aneurysms (UIAs). Another reason why our results need to be reproduced in patients with UIAs is that in unruptured aneurysms, elastin degradation is likely a much slower process, whereas in ruptured cases, the acute vascular wall disruption may lead to a significantly greater release of elastin degradation products. Thus, desmosine appears in measurable amounts in the serum of patients with ruptured aneurysms, whereas in the case of stable UIAs, lower concentrations are expected due to the prolonged release of desmosine, although there is currently no evidence to support this. Our study has several limitations. Blood samples were collected only during the acute period, so we do not know the kinetics of desmosine levels in later stages. Additionally, the control group consisted of individuals without aneurysms or other comorbidities that could affect desmosine levels, preventing us from making comparisons between cohorts of patients with ruptured (aSAH) and unruptured (UIA) aneurysms.\u003c/p\u003e \u003cp\u003eIn summary, serum desmosine levels show a strong correlation with the size and size ratio (SR) of ruptured aneurysms in patients with aSAH. Further studies are needed to determine whether serum desmosine could serve as a relevant biomarker for aneurysm size in unruptured cerebral aneurysms and whether it could play a role in therapeutic decision-making.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e We would like to thank all the patients who contributed to our study by participating, as well as all colleagues in the team who are involved in data collection, serum measurements, and statistical data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u0026nbsp; PC and AB contributed to the conception and design of the study. PC, TM, GL and LZ contributed to the acquisition and analysis of samples and data. PC and LZ drafted a significant portion of the manuscript. AB performed the laboratory measurements and validations. TM and AS provided supervision of the study. All authors interpreted the data, reviewed the manuscript, and approved the final version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e This work was supported in part by National Laboratory for Translational Neuroscience (TINL)\u003cbr\u003e\u0026nbsp;RRF-2.3.1-21-2022-00011 project and hungarian NRDI Fund (NKFI-FK-146159).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e Data supporting the fndings of this study are available upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy was approved by the Hungarian Medical Research Council (BM/29883-1/2023). All procedures were performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement\u003c/strong\u003e Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBugazia S, Boshnaf M, Sreenivasan A et al (2024) 278: Subarachnoid hemorrhage mortality trends in U.S. patients with circulatory disease (1999\u0026ndash;2020). Crit Care Med 52(1):S114\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVlak MH, Algra A, Brandenburg R et al (2011) Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. 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RSC Adv 12(49):31769\u0026ndash;31777\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakagawa D, Zanaty M, Hudson J et al (2018) Plasma soluble human elastin fragments as an intra-aneurysmal localized biomarker for ruptured intracranial aneurysm. J Am Heart Assoc 7(17):e010051\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJung KH (2018) New pathophysiological considerations on cerebral aneurysms. Neurointervention 13(2):73\u0026ndash;83\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDiringer MN, Bleck TP, Claude Hemphill J et al (2011) Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the neurocritical care society\u0026rsquo;s multidisciplinary consensus conference. Neurocrit Care 15:211\u0026ndash;240\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConnolly ES Jr, Rabinstein AA, Carhuapoma JR et al (2012) Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 43(6):1711\u0026ndash;1737\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClaassen J, Bernardini GL, Kreiter K et al (2001) Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 32:2012\u0026ndash;2020\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrake CG (1988) Report of World Federation of Neurological Surgeons Committee on a universal subarachnoid hemorrhage scale. J Neurosurg 68:985\u0026ndash;986\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVergouwen MD, Vermeulen M, van Gijn J et al (2010) Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 41:2391\u0026ndash;2395\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMocco J, Brown RD Jr, Torner JC et al (2018) Aneurysm morphology and prediction of rupture: an international study of unruptured intracranial aneurysms analysis. Neurosurgery 82(4):491\u0026ndash;496\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG\u0026ouml;ttsche J, Piffko A, Pantel TF et al (2022) Aneurysm location affects clinical course and mortality in patients with subarachnoid hemorrhage. Front Neurol 13:846066\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShiue I, Arima H, Hankey GJ et al (2011) Location and size of ruptured intracranial aneurysm and serious clinical outcomes early after subarachnoid hemorrhage: a population-based study in Australasia. Cerebrovasc Dis 31(6):573\u0026ndash;579\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChalmers JD, Moffitt KL, Suarez-Cuartin G et al (2017) Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis. Am J Respir Crit Care Med 195:1384\u0026ndash;1393\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAli K, Israr MZ, Ng LL et al (2022) Plasma desmosine for prediction of outcomes after acute myocardial infarction. Front Cardiovasc Med 9:992388\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRabinovich RA, Miller BE, Wrobel K et al (2016) Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD. Eur Respir J 47:1365\u0026ndash;1373\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang JT, Kuzmanova E, Dicker AJ et al (2020) Serum desmosine is associated with long-term all-cause and cardiovascular mortality in bronchiectasis. Am J Respir Crit Care Med 202:897\u0026ndash;899\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIskandar Z, Mordi I, Huang JTJ et al (2019) Plasma desmosine, an elastin degradation product, predicts outcomes in at-risk populations. J Am Coll Cardiol 73(Suppl_1):1805\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKashiwazaki D, Kuroda S, Sapporo SAH, Study Group (2013) Size ratio can highly predict rupture risk in intracranial small (\u0026lt;\u0026thinsp;5 mm) aneurysms. Stroke 44(8):2169\u0026ndash;2173\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChien A, Sayre J, Vi\u0026ntilde;uela F (2011) Comparative morphological analysis of the geometry of ruptured and unruptured aneurysms. Neurosurgery 69:349\u0026ndash;356\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"aneurysmal subarachnoid hemorrhage, size of cerebral aneurysm, desmosine, size ratio","lastPublishedDoi":"10.21203/rs.3.rs-5660763/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5660763/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cb\u003eIntroduction\u003c/b\u003e Aneurysmal subarachnoid hemorrhage (aSAH) is a disease associated with high mortality, caused by the rupture of a cerebral aneurysm. Decision-support scoring systems used for managing unruptured aneurysms (UIAs) include only radiological parameters related to the size and configuration of the aneurysm, without incorporating blood-based markers. Our aim is to identify a serum marker that shows a correlation with aneurysm size in patients with ruptured aneurysms.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods\u003c/b\u003e Arterial blood samples were collected from patients who experienced aSAH within 24 hours of the ictus, and serum desmosine levels were determined using ELISA. The morphological parameters of the aneurysms were assessed during 3D DSA. A favorable outcome was defined as a 3-month mRS score of 0\u0026ndash;3.\u003c/p\u003e \u003cp\u003e \u003cb\u003eResults\u003c/b\u003e The study included 135 aSAH patients and 25 controls. (i) The desmosine level in serum collected within 24 hours after aneurysm rupture in patients with aSAH was significantly higher compared to the serum level in the control group (aSAH: 0.737 ng/mL [IQR: 0.401\u0026ndash;1.214], vs. control: 0.365 ng/mL [IQR: 0.251\u0026ndash;0.531], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), (ii) examining the size of ruptured aneurysms, patients with aneurysms larger than 7 mm had significantly higher serum desmosine levels than those with aneurysms smaller than 7 mm, (iii) in the group with aneurysms smaller than 7 mm, serum desmosine levels correlated with the aneurysm neck width and the size ratio.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusion\u003c/b\u003e Serum desmosine shows a strong correlation with the size of ruptured aneurysms in aSAH patients.\u003c/p\u003e","manuscriptTitle":"Serum desmosine levels are associated with the size of ruptured cerebral aneurysms in patients with aneurysmal subarachnoid hemorrhage","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-24 17:24:04","doi":"10.21203/rs.3.rs-5660763/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b670c191-bff2-460c-8319-cba80bdaa034","owner":[],"postedDate":"December 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-01T20:08:21+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-24 17:24:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5660763","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5660763","identity":"rs-5660763","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}