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Impact of serum omentin-1 concentrations on functional outcome among acute intracerebral hemorrhage patients
Clinica Chimica Acta 503 (2020) 169–174
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Impact of serum omentin-1 concentrations on functional outcome among acute intracerebral hemorrhage patients
T
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Guo-Hai Zhanga, , Zhe-Hao Yea, Hao-Jie Guana, Mi Guob, Xin-Xiang Zhouc, Yu-Yu Xud a
Department of Neurosurgery, The Shengzhou Hospital of Traditional Chinese Medicine, 208 Yiyuan Road, Shengzhou 312400, Zhejiang Province, China Department of Neurosurgery, The Shengzhou People’s Hospital, 666 Dangui Road, Shengzhou 312400, Zhejiang Province, China c Department of Neurology, The Shengzhou People’s Hospital, 666 Dangui Road, Shengzhou 312400, Zhejiang Province, China d Department of Neurology, The Shengzhou Hospital of Traditional Chinese Medicine, 208 Yiyuan Road, Shengzhou 312400, Zhejiang Province, China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Intracerebral hemorrhage Omentin-1 Prognosis
Background: Reduced serum omentin-1 concentrations might be related to an increased risk for poor functional outcome after acute ischemic stroke. We intended to explore whether serum omentin-1 could be a promising prognostic biomarker for acute intracerebral hemorrhage. Methods: A total of 104 consecutive patients with hemorrhagic stroke underwent 90-day follow-up. The modified Rankin scale score > 2 was evaluated as worse prognosis. A multivariable logistic model was conFig.d for assessing the relationship between serum omentin-1 concentrations and functional outcome. Results: Serum omentin-1 concentrations, with the median value of 147.9 ng/ml (interquartile range, 114.7–199.8 ng/ml), were substantially declined with rising modified Rankin scale scores (P < 0.001). Serum omentin-1 concentrations < 147.9 ng/ml was independently related to higher risk of 90-day worse prognosis (odds ratio, 3.789; 95% confidence interval, 1.819–8.608; P = 0.018). Under receiver operating characteristic curve, an optimal value of serum omentin-1 concentrations was selected as 179.7 ng/ml, which yielded 0.88 sensitivity value and 0.70 specificity value for discriminating patients at risk of 90-day worse prognosis (area under curve, 0.82; 95% confidence interval, 0.73–0.89). Conclusions: Lower serum omentin-1 concentrations are closely associated with poor functional outcome after hemorrhagic stroke, substantializing serum omentin-1 as a potential prognostic biomarker for acute intracerebral hemorrhage.
1. Introduction Spontaneous intracerebral hemorrhage (ICH) is one of the commonest causes of death and long-term disability worldwide [1–3]. ICH score, Glasgow coma scale (GCS) score and hematoma volume were often recorded to assess the severity and prognosis of ICH [4–6]. In recent decades, researchers have paid more attention to identification of prognostic biomarkers, because early prediction of prognosis can aid in the modification of therapeutic strategies and further improvement of stroke outcomes [7–9]. Omentin has been identified as a new adipokine, which is originally derived from the omental adipose tissue and exerts anti-inflammatory, anti-oxidative and anti-apoptotic effects [10,11]. It has two isoforms as follows: omentin-1 and omentin-2, among which omentin-1 was the predominant form in the human blood [12]. Omentin-1 is associated with obesity, metabolic syndrome, diabetes and hypertension [13–15]. Recently, a decreased concentration of
serum omentin-1 was suggested as a biomarker for stroke risk, severity and functional outcome among ischemic stroke patients [16–18]. 2. Materials and methods 2.1. Patients From December 2015 to December 2018, all first-ever spontaneous ICH patients at our hospital were consecutively enrolled in this prospective and observational study. We required that all patients be admitted within 24 h after symptom onset of stroke. The exclusion criteria were (1) age < 18 y; (2) bleedings due to underlying vascular lesions, venous sinus thrombosis, infarction or tumors; (3) a surgical procedure; and (4) other diseases such as autoimmune diseases, severe infection, pregnancy or known malignancies. This study conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the
Abbreviations: CT, computerized tomography; ICH, intracerebral hemorrhage; GCS, Glasgow coma scale ⁎ Corresponding author. E-mail address: [email protected] (G.-H. Zhang). https://doi.org/10.1016/j.cca.2020.01.026 Received 6 January 2020; Received in revised form 19 January 2020; Accepted 24 January 2020 Available online 25 January 2020 0009-8981/ © 2020 Elsevier B.V. All rights reserved.
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total of 104 spontaneous ICH patients constituted such a group of study cases, who included 57 males and 47 females as well as were aged from 45 to 89 y (median, 66.5 y; interquartile range, 57–76 y), body mass index ranged from 19.2 to 28.4 kg/m2 (median, 24.8 kg/m2; interquartile range, 23.6–26.6 kg/m2). In total, 53 patients were cigarette smoker and 40 patients consumed alcohol. Medical histories included hypertension (76 cases), diabetes mellitus (31 cases), hyperlipidemia (38 cases), congestive heart failure (7 cases), coronary artery disease (10 cases) and chronic kidney disease (8 cases). Some patients underwent pre-stroke specific drug therapies as follows: statin (28 cases), antiplatelet agents (23 cases) and anticoagulants (12 cases). Patients were admitted from 0.8 to 24.0 h (median, 8.5 h; interquartile range, 3.5 to 12.6 h) and their peripheral blood was collected from 1.7 to 26.1 h (median, 11.6 h; interquartile range, 5.2–14.8 h). As regards stroke severity, the median values of GCS scores and ICH scores were 15 (range, 4–15; interquartile range, 12–15) and 1 (range, 0–5; interquartile range, 0–2) respectively. We also recorded some radiological parameters, namely hematoma location (lobar hematoma, 25 cases; infratentorial hemorrhage, 14 cases), the presence of intraventricular bleeding (26 cases), subarachnoidal extension of hematoma (6 cases) and hematoma volume (range, 2–47 ml; median, 12 ml; interquartile range, 6–22 ml). The median values of systolic arterial pressure and diastolic arterial pressure were 172 mmHg (range, 125–216 mmHg; interquartile range, 160–187 mmHg) and 101 mmHg (range, 70–114 mmHg; interquartile range, 92–108 mmHg) respectively.
Institutional Review Board of our hospital. Written informed consent was acquired from their immediate family members. 2.2. Baseline data collection Demographic characteristics (age, gender and body mass index), lifestyle parameters (smoking and alcohol consumption), medical histories (hypertension, diabetes mellitus, hyperlipidemia, congestive heart failure, coronary artery disease and chronic kidney disease) and pre-stroke treatment (statin, antiplatelet agents and anticoagulants) were collected upon admission via in-person interviews with the patients or their family members. Both Glasgow coma scale (GCS) score and ICH score were utilized to evaluate stroke severity at admission [4,6]. Radiological parameters included hematoma location (lobar or infratentorial), the presence of intraventricular bleeding, subarachnoidal extension of hematoma and hematoma volume measured based on ABC/2 method [19]. A poor functional outcome was defined as a combination of major disability and death during the 90-day follow-up period after stroke onset. Major disability was referred to as a score of 3–5 on the modified Rankin scale. A score of 6 on the modified Rankin scale indicated death [20]. 2.3. Immune analysis Blood samples were obtained at hospital admission. After 30 min of clotting, the serum was separated and then stored at −80 °C until assayed. Serum omentin-1 concentrations were gauged using an enzymelinked immunosorbent assay kit (Immuno-Biological Laboratories CO., Ltd., Gunma, Japan) according to the manufacturer’s instructions. A standard curve was plotted, from which the omentin-1 concentrations of unknown samples were estimated. Every 3 months, samples were in duplicate analyzed by the same laboratory technician blinded to the characteristics and functional outcome of the study participants.
3.2. Serum omentin-1 concentrations and stroke severity Among ICH patients, serum omentin-1 concentrations range from 43.8 to 338.9 ng/ml, with the median value of 147.9 ng/ml (interquartile range, 114.8–199.8 ng/ml). Patients were stratified into two groups according to the median value of serum omentin-1 concentrations (namely, < 147.9 ng/ml and > 147.9 ng/ml). Afterwards, the demographic, clinical, and biochemical parameters were compared between the two groups (Table 1). When compared to patients with serum omentin-1 concentrations above 147.9 ng/ml, those with serum omentin-1 concentrations below 147.9 ng/ml exhibited the significantly lower GCS scores, ICH scores and hematoma volumes, as well as had the substantial lower percentage of intraventricular bleedings. There were no significant differences between the 2 groups in term of age, gender, body mass index and other variables listed in Table 1. Also, serum omentin-1 was a continuous variable, and its correlations with the preceding hemorrhagic severity, namely GCS scores, ICH scores, hematoma volumes and intraventricular bleeding, were displayed in Fig. 1.
2.4. Statistical analysis Count (percentage) and median with interquartile range were applied for reporting the results of categorical and continuous variables respectively. Comparisons were done using the Mann-Whitney U test, χ2 test or Kruskal-Wallis H test as appropriate. Patients were dichotomized according to median value of serum omentin-1 concentrations, which was thereby identified as a categorical variable. Using Spearman’s correlation coefficients, we assessed relationship between other variables and serum ometin-1, as a continuous variable. The binary logistic regression model was conFig.d to determine correlation of serum omentin-1 concentrations with functional outcome. Significant variables in univariate analyses were incorporated in the multivariate model and adjusted odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated for describing association. Receiver operating characteristic (ROC) curve was plotted to assess the prognostic predictive accuracy of serum omentin-1 concentrations and the area under the curve (AUC) was estimated. Statistics was completed with the Statistical Package for the Social Sciences ver. 20.0 (IBM). A P < 0.05 was considered statistically significant.
3.3. Serum omentin-1 concentrations and functional outcome At 90 days after the onset of stroke, 5, 15, 26, 17, 15, 8 and 18 patients had modified Rankin scale 0, 1, 2, 3, 4, 5 and 6 respectively. Therefore, the proportion of patients suffering from a poor outcome was 55.8% (58/104). Circulating omentin-1 concentrations were significantly lower in patients with the development of a poor outcome than in other remainders (132.4 (103.4–162.4) vs. 200.7 (141.4–237.7) ng/ml, P < 0.001). Just as displayed in Fig. 2, serum omentin-1 concentrations were remarkably decreased with increasing modified Rankin scale scores (P < 0.001). In Table 2, as compared with the patients without a poor outcome, the patients with a poor outcome tended to be older, and have higher ICH scores, lower GCS scores and larger hematoma volumes; more patients with a poor outcome had infratentorial hemorrhage or intraventricular bleedings; blood glucose concentrations and serum C-reactive protein concentrations were significantly higher in patients who experienced a poor outcome than in those developing a good prognosis; moreover, patients with a poor outcome exhibited the higher proportion of serum omentin-1 concentrations below 147.9 ng/ml than those with a good prognosis. When
3. Results 3.1. Patient characteristics During the study period, a total of 137 first-ever spontaneous ICH patients admitted within 24 h after symptom onset of stroke were firstly assessed. Afterwards, we excluded 2 patients aged < 18 y, 15 patients with intracerebral bleedings due to underlying vascular lesions, venous sinus thrombosis, infarction or tumors, 5 patients undergoing a surgical procedure and 11 patients with other diseases such as autoimmune diseases, severe infection, pregnancy or known malignancies. At last, a 170
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Table 1 Baseline characteristics according to median value of serum omentin-1 levels among intracerebral hemorrhage patients. Parameters
< 147.9 ng/ml
< 147.9 ng/ml
P-Value
Number Gender (male/female) Age (y) Body mass index (kg/m2) Smoking (yes/no) Drinking (yes/no) History of hypertension (yes/no) History of diabetes (yes/no) History of hyperlipidemia (yes/no) History of congestive heart failure (yes/no) History of coronary artery disease (yes/no) History of chronic kidney disease (yes/no) Pre-stroke statin treatment (yes/no) Pre-stroke usage of antiplatelet agents (yes/no) Pre-stroke usage of anticoagulants (yes/no) Time from onset to admission (h) Time from onset to blood-collection (h) Glasgow coma scale score Intracerebral hemorrhage score Hematoma volume (ml) Lobar hemorrhage (yes/no) Infratentorial hemorrhage (yes/no) Subarachnoidal extension of hematoma (yes/no) Intraventricular extension of hematoma (yes/no) Systolic arterial pressure (mmHg) Diastolic arterial pressure (mmHg) Blood glucose level (mmol/l) Serum C-reactive protein level (mg/l) Blood white blood cell count (×109/l)
52 26/26 70 (58–80) 25.0 (23.6–26.4) 28/24 22/30 40/12 17/35 20/32 6/46 5/47 3/49 13/39 11/41 5/47 8.9 (3.3–15.9) 11.6 (4.5–18.4) 12 (11–15) 1 (1–2) 15 (8–30) 11/41 6/46 5/47 18/34 172 (157–188) 102 (96–107) 14.1 (11.3–17.8) 13.4 (11.8–16.2) 8.8 (6.3–11.5)
52 31/21 66 (57–76) 24.8 (23.5–26.6) 25/27 18/34 36/16 14/38 18/34 1/51 5/47 5/47 15/37 12/40 7/45 8.2 (4.1–11.2) 11.3 (6.4–14.3) 14 (13–15) 0 (0–1) 9 (6–16) 14/38 8/44 1/51 8/44 172 (160–187) 101 (91–108) 12.8 (11.3–16.0) 13.7 (10.5–15.5) 8.9 (6.5–11.9)
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.001 < 0.001 0.004 NS NS NS 0.024 NS NS NS NS NS
Continuous variables were reported as medians with interquartile ranges. Categorical variables were showed as counts (percentages). Intergroup comparison was made using the χ2 test, Fisher exact test or Mann-Whitney U test where appropriate.
Fig. 1. Graph portraying relationship between serum omentin-1 concentrations and other variables including Glasgow coma scale scores, intracerebral hemorrhage scores, hematoma volumes and intraventricular hemorrhage. GCS indicates Glasgow coma scale; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage. 171
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concentrations were inversely correlated with hemorrhagic severity reflected by ICH scores, GCS scores, hematoma volume and intraventricular hemorrhage; (2) serum omentin-1 concentrations, as a categorical variable, and hematoma volume were independently associated with 90-day poor outcome; (3) serum omentin-1 concentrations showed similar prognostic predictive ability, as compared to hematoma volume, and it also significantly improved the prognostic predictive power of hematoma volume. Overall, it is suggested that serum omentin-1 might serve as a potential prognostic biomarker for ICH. Omentin-1 had been proved to play a beneficial role in preventing atherosclerosis [21,22]. Some evidence showed that low concentrations of omentin-1 were intimately linked to the presence of coronary artery disease and its severity [23,24]. Similarly, in humans with acute ischemic stroke, low concentrations of omentin-1 were related to stroke risk, severity and outcome [16–18]. The mechanisms of omentin-1′s roles on stroke outcome need further demonstration. However, accumulating data indicated that omentin-1 might exert anti-inflammatory, anti-oxidative and anti-apoptotic effects [25–27]. Thus, depletion of omentin-1 after acute stroke might have a deleterious effect on neuronal cells. Subsequently, it is assumed that supplementation of omentin-1 might be beneficial for recovery of neurologic function. Generally, ICH scores and GCS scores are very often utilized to assess hemorrhagic severity [4,6]; hematoma volume is directly correlated with the degree of hemorrhagic brain injury [5]; and extension of hematoma into intraventricular cavity is obviously relevant to the extent of bleedings [28]. Serum omentin-1 concentrations were negatively correlated with National Institutes of Health Stroke Scale score and lesion volume in patients with acute ischemic stroke [16]. Consistently we found that ICH patients with serum omentin-1 concentrations < median value had significantly higher ICH score, lower GCS score and larger hematoma volume, as well as had a substantially higher proportion of intraventricular hemorrhage. Taken together, serum omentin-1 concentrations should be linked to stroke severity
Fig. 2. Graph showing the change of serum omentin-1 concentrations according to modified Rankin scale scores among patients with spontaneous acute intracerebral hemorrhage.
the preceding significant variables were incorporated in the Logistic regression model, it was proved that serum omentin-1 concentrations less than 147.9 ng/ml and hematoma volume independently predicted 90-day poor outcome among ICH patients (Fig. 3). In Fig. 4, serum omentin-1 concentrations significantly predicted post-stroke 90-day poor outcome among this group of ICH patients. Also, its predictive capability was equivalent to that of hematoma volume (AUC, 0.854; 95% CI, 0.771–0.915; P = 0.NS). Moreover, it substantially improved AUC of hematoma volume to 0.921 (95% CI, 0.852–0.965; P = 0.008). 4. Discussion The main findings of this study were that (1) serum omentin-1
Table 2 Baseline characteristics by 90-day functional outcome among intracerebral hemorrhage patients. Parameters
Poor outcome
Good outcome
p-Value
Number Gender (Male/Female) Age (y) Body mass index (kg/m2) Smoking (yes/no) Drinking (yes/no) History of hypertension (yes/no) History of diabetes (yes/no) History of hyperlipidemia (yes/no) History of congestive heart failure (yes/no) History of coronary artery disease (yes/no) History of chronic kidney disease (yes/no) Pre-stroke statin treatment (yes/no) Pre-stroke usage of antiplatelet agents (yes/no) Pre-stroke usage of anticoagulants (yes/no) Time from onset to admission (h) Time from onset to blood-collection (h) Glasgow coma scale score Intracerebral hemorrhage score Hematoma volume (ml) Lobar hemorrhage (yes/no) Infratentorial hemorrhage (yes/no) Subarachnoidal extension of hematoma (yes/no) Intraventricular extension of hematoma (yes/no) Systolic arterial pressure (mmHg) Diastolic arterial pressure (mmHg) Blood glucose level (mmol/l) Serum C-reactive protein level (mg/l) Blood white blood cell count (×109/l) Serum omentin-1 levels < 147.9 ng/ml (yes/no)
58 35/23 74 (63–80) 24.8 (23.8–26.4) 28/30 24/34 44/14 18/40 25/33 5/53 4/54 3/55 14/44 13/45 6/52 9.2 (3.6–14.4) 12.1 (5.2–15.8) 12 (11–14) 2 (1–2) 21 (8–31) 13/45 13/45 4 /54 25/33 173 (159–187) 103 (97–108) 14.8 (11.3–19.4) 14.0 (11.8–17.2) 8.8 (6.3–11.5) 40/18
46 22/24 64 (56–72) 24.7 (22.4–26.7) 25/21 16/30 32/14 13/33 13/33 2/44 6/40 5/41 14/32 10/36 6/40 6.5 (3.3–10.9) 8.5 (5.1–13.7) 14 (14–15) 0 (0–1) 9 (5–12) 12/34 1/45 2/44 1/45 172 (160–189) 100 (90–107) 12.3 (11.2–14.9) 12.8 (10.1–14.5) 9.0 (6.5–11.9) 12/34
NS 0.001 NS NS NS NS NS NS NS NS NS NS NS NS NS NS < 0.001 < 0.001 < 0.001 NS 0.003 NS < 0.001 NS NS 0.023 0.010 NS < 0.001
Continuous variables were reported as medians with interquartile ranges. Categorical variables were showed as counts (percentages). Intergroup comparison was made using the χ2 test, Fisher exact test or Mann-Whitney U test as appropriate. 172
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Fig. 3. Graph depicting odds ratio values for the independent association with 90-day poor outcome after spontaneous acute intracerebral hemorrhage. Modified Rankin scale scores was defined as poor outcome. OR means odds ratio.
5. Conclusions Reduced serum omentin-1 concentrations, in inverse correlation with hemorrhagic severity, are significantly associated with post-stroke 90-day worse prognosis, indicating serum omentin-1 might have the potential to be a useful prognostic biomarker for ICH. CRediT authorship contribution statement Guo-Hai Zhang: Conceptualization, Methodology, Software. ZheHao Ye: Data curation, Writing - original draft. Hao-Jie Guan: Visualization, Investigation. Mi Guo: Supervision. Xin-Xiang Zhou: Software, Validation. Yu-Yu Xu: Writing - review & editing. Acknowledgements
Fig. 4. Graph displaying receiver-operating characteristic curve utilizing serum omentin-1 concentrations for investigating 90-day poor outcome after spontaneous acute intracerebral hemorrhage. Circle indicates the optimal cut-off point of serum omentin-1 concentrations by Youden method. AUC denotes area under curve. 95% CI means 95% CI.
We are deeply appreciative of the participants in this study and thank all staffs for their support and assistance. References
including ICH. Modified Rankin scale is a common clinical grade, which is used to assess functional outcome of stroke [20]. Generally, modified Rankin scale score > 2 is designated as a poor outcome [20]. In human ischemic stroke, serum omentin-1 concentrations were independently associated with 3-month functional outcome [17,18]. Similarly, in the current study, ICH patients with higher modified Rankin scale score showed significantly lower serum omentin-1 concentrations. While modified Rankin scale score was identified as a categorical variable, patients with a poor outcome had a significantly higher percentage of serum omentin-1 concentrations < median value. Using multivariate analysis, it was proved that both serum omentin-1 and hematoma volume retained as the two independent predictors for 90-day poor outcome after the onset of stroke. More intriguingly, serum omentin-1 concentrations not only had similar prognostic ability as compared to hematoma volume, but also significantly improved the prognostic capability of hematoma volume. In summary, serum omentin-1 might represent a promising prognostic biomarker for ICH.
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Impact of serum omentin-1 concentrations on functional outcome among acute intracerebral hemorrhage patients
T
⁎
Guo-Hai Zhanga, , Zhe-Hao Yea, Hao-Jie Guana, Mi Guob, Xin-Xiang Zhouc, Yu-Yu Xud a
Department of Neurosurgery, The Shengzhou Hospital of Traditional Chinese Medicine, 208 Yiyuan Road, Shengzhou 312400, Zhejiang Province, China Department of Neurosurgery, The Shengzhou People’s Hospital, 666 Dangui Road, Shengzhou 312400, Zhejiang Province, China c Department of Neurology, The Shengzhou People’s Hospital, 666 Dangui Road, Shengzhou 312400, Zhejiang Province, China d Department of Neurology, The Shengzhou Hospital of Traditional Chinese Medicine, 208 Yiyuan Road, Shengzhou 312400, Zhejiang Province, China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Intracerebral hemorrhage Omentin-1 Prognosis
Background: Reduced serum omentin-1 concentrations might be related to an increased risk for poor functional outcome after acute ischemic stroke. We intended to explore whether serum omentin-1 could be a promising prognostic biomarker for acute intracerebral hemorrhage. Methods: A total of 104 consecutive patients with hemorrhagic stroke underwent 90-day follow-up. The modified Rankin scale score > 2 was evaluated as worse prognosis. A multivariable logistic model was conFig.d for assessing the relationship between serum omentin-1 concentrations and functional outcome. Results: Serum omentin-1 concentrations, with the median value of 147.9 ng/ml (interquartile range, 114.7–199.8 ng/ml), were substantially declined with rising modified Rankin scale scores (P < 0.001). Serum omentin-1 concentrations < 147.9 ng/ml was independently related to higher risk of 90-day worse prognosis (odds ratio, 3.789; 95% confidence interval, 1.819–8.608; P = 0.018). Under receiver operating characteristic curve, an optimal value of serum omentin-1 concentrations was selected as 179.7 ng/ml, which yielded 0.88 sensitivity value and 0.70 specificity value for discriminating patients at risk of 90-day worse prognosis (area under curve, 0.82; 95% confidence interval, 0.73–0.89). Conclusions: Lower serum omentin-1 concentrations are closely associated with poor functional outcome after hemorrhagic stroke, substantializing serum omentin-1 as a potential prognostic biomarker for acute intracerebral hemorrhage.
1. Introduction Spontaneous intracerebral hemorrhage (ICH) is one of the commonest causes of death and long-term disability worldwide [1–3]. ICH score, Glasgow coma scale (GCS) score and hematoma volume were often recorded to assess the severity and prognosis of ICH [4–6]. In recent decades, researchers have paid more attention to identification of prognostic biomarkers, because early prediction of prognosis can aid in the modification of therapeutic strategies and further improvement of stroke outcomes [7–9]. Omentin has been identified as a new adipokine, which is originally derived from the omental adipose tissue and exerts anti-inflammatory, anti-oxidative and anti-apoptotic effects [10,11]. It has two isoforms as follows: omentin-1 and omentin-2, among which omentin-1 was the predominant form in the human blood [12]. Omentin-1 is associated with obesity, metabolic syndrome, diabetes and hypertension [13–15]. Recently, a decreased concentration of
serum omentin-1 was suggested as a biomarker for stroke risk, severity and functional outcome among ischemic stroke patients [16–18]. 2. Materials and methods 2.1. Patients From December 2015 to December 2018, all first-ever spontaneous ICH patients at our hospital were consecutively enrolled in this prospective and observational study. We required that all patients be admitted within 24 h after symptom onset of stroke. The exclusion criteria were (1) age < 18 y; (2) bleedings due to underlying vascular lesions, venous sinus thrombosis, infarction or tumors; (3) a surgical procedure; and (4) other diseases such as autoimmune diseases, severe infection, pregnancy or known malignancies. This study conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the
Abbreviations: CT, computerized tomography; ICH, intracerebral hemorrhage; GCS, Glasgow coma scale ⁎ Corresponding author. E-mail address: [email protected] (G.-H. Zhang). https://doi.org/10.1016/j.cca.2020.01.026 Received 6 January 2020; Received in revised form 19 January 2020; Accepted 24 January 2020 Available online 25 January 2020 0009-8981/ © 2020 Elsevier B.V. All rights reserved.
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total of 104 spontaneous ICH patients constituted such a group of study cases, who included 57 males and 47 females as well as were aged from 45 to 89 y (median, 66.5 y; interquartile range, 57–76 y), body mass index ranged from 19.2 to 28.4 kg/m2 (median, 24.8 kg/m2; interquartile range, 23.6–26.6 kg/m2). In total, 53 patients were cigarette smoker and 40 patients consumed alcohol. Medical histories included hypertension (76 cases), diabetes mellitus (31 cases), hyperlipidemia (38 cases), congestive heart failure (7 cases), coronary artery disease (10 cases) and chronic kidney disease (8 cases). Some patients underwent pre-stroke specific drug therapies as follows: statin (28 cases), antiplatelet agents (23 cases) and anticoagulants (12 cases). Patients were admitted from 0.8 to 24.0 h (median, 8.5 h; interquartile range, 3.5 to 12.6 h) and their peripheral blood was collected from 1.7 to 26.1 h (median, 11.6 h; interquartile range, 5.2–14.8 h). As regards stroke severity, the median values of GCS scores and ICH scores were 15 (range, 4–15; interquartile range, 12–15) and 1 (range, 0–5; interquartile range, 0–2) respectively. We also recorded some radiological parameters, namely hematoma location (lobar hematoma, 25 cases; infratentorial hemorrhage, 14 cases), the presence of intraventricular bleeding (26 cases), subarachnoidal extension of hematoma (6 cases) and hematoma volume (range, 2–47 ml; median, 12 ml; interquartile range, 6–22 ml). The median values of systolic arterial pressure and diastolic arterial pressure were 172 mmHg (range, 125–216 mmHg; interquartile range, 160–187 mmHg) and 101 mmHg (range, 70–114 mmHg; interquartile range, 92–108 mmHg) respectively.
Institutional Review Board of our hospital. Written informed consent was acquired from their immediate family members. 2.2. Baseline data collection Demographic characteristics (age, gender and body mass index), lifestyle parameters (smoking and alcohol consumption), medical histories (hypertension, diabetes mellitus, hyperlipidemia, congestive heart failure, coronary artery disease and chronic kidney disease) and pre-stroke treatment (statin, antiplatelet agents and anticoagulants) were collected upon admission via in-person interviews with the patients or their family members. Both Glasgow coma scale (GCS) score and ICH score were utilized to evaluate stroke severity at admission [4,6]. Radiological parameters included hematoma location (lobar or infratentorial), the presence of intraventricular bleeding, subarachnoidal extension of hematoma and hematoma volume measured based on ABC/2 method [19]. A poor functional outcome was defined as a combination of major disability and death during the 90-day follow-up period after stroke onset. Major disability was referred to as a score of 3–5 on the modified Rankin scale. A score of 6 on the modified Rankin scale indicated death [20]. 2.3. Immune analysis Blood samples were obtained at hospital admission. After 30 min of clotting, the serum was separated and then stored at −80 °C until assayed. Serum omentin-1 concentrations were gauged using an enzymelinked immunosorbent assay kit (Immuno-Biological Laboratories CO., Ltd., Gunma, Japan) according to the manufacturer’s instructions. A standard curve was plotted, from which the omentin-1 concentrations of unknown samples were estimated. Every 3 months, samples were in duplicate analyzed by the same laboratory technician blinded to the characteristics and functional outcome of the study participants.
3.2. Serum omentin-1 concentrations and stroke severity Among ICH patients, serum omentin-1 concentrations range from 43.8 to 338.9 ng/ml, with the median value of 147.9 ng/ml (interquartile range, 114.8–199.8 ng/ml). Patients were stratified into two groups according to the median value of serum omentin-1 concentrations (namely, < 147.9 ng/ml and > 147.9 ng/ml). Afterwards, the demographic, clinical, and biochemical parameters were compared between the two groups (Table 1). When compared to patients with serum omentin-1 concentrations above 147.9 ng/ml, those with serum omentin-1 concentrations below 147.9 ng/ml exhibited the significantly lower GCS scores, ICH scores and hematoma volumes, as well as had the substantial lower percentage of intraventricular bleedings. There were no significant differences between the 2 groups in term of age, gender, body mass index and other variables listed in Table 1. Also, serum omentin-1 was a continuous variable, and its correlations with the preceding hemorrhagic severity, namely GCS scores, ICH scores, hematoma volumes and intraventricular bleeding, were displayed in Fig. 1.
2.4. Statistical analysis Count (percentage) and median with interquartile range were applied for reporting the results of categorical and continuous variables respectively. Comparisons were done using the Mann-Whitney U test, χ2 test or Kruskal-Wallis H test as appropriate. Patients were dichotomized according to median value of serum omentin-1 concentrations, which was thereby identified as a categorical variable. Using Spearman’s correlation coefficients, we assessed relationship between other variables and serum ometin-1, as a continuous variable. The binary logistic regression model was conFig.d to determine correlation of serum omentin-1 concentrations with functional outcome. Significant variables in univariate analyses were incorporated in the multivariate model and adjusted odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated for describing association. Receiver operating characteristic (ROC) curve was plotted to assess the prognostic predictive accuracy of serum omentin-1 concentrations and the area under the curve (AUC) was estimated. Statistics was completed with the Statistical Package for the Social Sciences ver. 20.0 (IBM). A P < 0.05 was considered statistically significant.
3.3. Serum omentin-1 concentrations and functional outcome At 90 days after the onset of stroke, 5, 15, 26, 17, 15, 8 and 18 patients had modified Rankin scale 0, 1, 2, 3, 4, 5 and 6 respectively. Therefore, the proportion of patients suffering from a poor outcome was 55.8% (58/104). Circulating omentin-1 concentrations were significantly lower in patients with the development of a poor outcome than in other remainders (132.4 (103.4–162.4) vs. 200.7 (141.4–237.7) ng/ml, P < 0.001). Just as displayed in Fig. 2, serum omentin-1 concentrations were remarkably decreased with increasing modified Rankin scale scores (P < 0.001). In Table 2, as compared with the patients without a poor outcome, the patients with a poor outcome tended to be older, and have higher ICH scores, lower GCS scores and larger hematoma volumes; more patients with a poor outcome had infratentorial hemorrhage or intraventricular bleedings; blood glucose concentrations and serum C-reactive protein concentrations were significantly higher in patients who experienced a poor outcome than in those developing a good prognosis; moreover, patients with a poor outcome exhibited the higher proportion of serum omentin-1 concentrations below 147.9 ng/ml than those with a good prognosis. When
3. Results 3.1. Patient characteristics During the study period, a total of 137 first-ever spontaneous ICH patients admitted within 24 h after symptom onset of stroke were firstly assessed. Afterwards, we excluded 2 patients aged < 18 y, 15 patients with intracerebral bleedings due to underlying vascular lesions, venous sinus thrombosis, infarction or tumors, 5 patients undergoing a surgical procedure and 11 patients with other diseases such as autoimmune diseases, severe infection, pregnancy or known malignancies. At last, a 170
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Table 1 Baseline characteristics according to median value of serum omentin-1 levels among intracerebral hemorrhage patients. Parameters
< 147.9 ng/ml
< 147.9 ng/ml
P-Value
Number Gender (male/female) Age (y) Body mass index (kg/m2) Smoking (yes/no) Drinking (yes/no) History of hypertension (yes/no) History of diabetes (yes/no) History of hyperlipidemia (yes/no) History of congestive heart failure (yes/no) History of coronary artery disease (yes/no) History of chronic kidney disease (yes/no) Pre-stroke statin treatment (yes/no) Pre-stroke usage of antiplatelet agents (yes/no) Pre-stroke usage of anticoagulants (yes/no) Time from onset to admission (h) Time from onset to blood-collection (h) Glasgow coma scale score Intracerebral hemorrhage score Hematoma volume (ml) Lobar hemorrhage (yes/no) Infratentorial hemorrhage (yes/no) Subarachnoidal extension of hematoma (yes/no) Intraventricular extension of hematoma (yes/no) Systolic arterial pressure (mmHg) Diastolic arterial pressure (mmHg) Blood glucose level (mmol/l) Serum C-reactive protein level (mg/l) Blood white blood cell count (×109/l)
52 26/26 70 (58–80) 25.0 (23.6–26.4) 28/24 22/30 40/12 17/35 20/32 6/46 5/47 3/49 13/39 11/41 5/47 8.9 (3.3–15.9) 11.6 (4.5–18.4) 12 (11–15) 1 (1–2) 15 (8–30) 11/41 6/46 5/47 18/34 172 (157–188) 102 (96–107) 14.1 (11.3–17.8) 13.4 (11.8–16.2) 8.8 (6.3–11.5)
52 31/21 66 (57–76) 24.8 (23.5–26.6) 25/27 18/34 36/16 14/38 18/34 1/51 5/47 5/47 15/37 12/40 7/45 8.2 (4.1–11.2) 11.3 (6.4–14.3) 14 (13–15) 0 (0–1) 9 (6–16) 14/38 8/44 1/51 8/44 172 (160–187) 101 (91–108) 12.8 (11.3–16.0) 13.7 (10.5–15.5) 8.9 (6.5–11.9)
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.001 < 0.001 0.004 NS NS NS 0.024 NS NS NS NS NS
Continuous variables were reported as medians with interquartile ranges. Categorical variables were showed as counts (percentages). Intergroup comparison was made using the χ2 test, Fisher exact test or Mann-Whitney U test where appropriate.
Fig. 1. Graph portraying relationship between serum omentin-1 concentrations and other variables including Glasgow coma scale scores, intracerebral hemorrhage scores, hematoma volumes and intraventricular hemorrhage. GCS indicates Glasgow coma scale; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage. 171
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concentrations were inversely correlated with hemorrhagic severity reflected by ICH scores, GCS scores, hematoma volume and intraventricular hemorrhage; (2) serum omentin-1 concentrations, as a categorical variable, and hematoma volume were independently associated with 90-day poor outcome; (3) serum omentin-1 concentrations showed similar prognostic predictive ability, as compared to hematoma volume, and it also significantly improved the prognostic predictive power of hematoma volume. Overall, it is suggested that serum omentin-1 might serve as a potential prognostic biomarker for ICH. Omentin-1 had been proved to play a beneficial role in preventing atherosclerosis [21,22]. Some evidence showed that low concentrations of omentin-1 were intimately linked to the presence of coronary artery disease and its severity [23,24]. Similarly, in humans with acute ischemic stroke, low concentrations of omentin-1 were related to stroke risk, severity and outcome [16–18]. The mechanisms of omentin-1′s roles on stroke outcome need further demonstration. However, accumulating data indicated that omentin-1 might exert anti-inflammatory, anti-oxidative and anti-apoptotic effects [25–27]. Thus, depletion of omentin-1 after acute stroke might have a deleterious effect on neuronal cells. Subsequently, it is assumed that supplementation of omentin-1 might be beneficial for recovery of neurologic function. Generally, ICH scores and GCS scores are very often utilized to assess hemorrhagic severity [4,6]; hematoma volume is directly correlated with the degree of hemorrhagic brain injury [5]; and extension of hematoma into intraventricular cavity is obviously relevant to the extent of bleedings [28]. Serum omentin-1 concentrations were negatively correlated with National Institutes of Health Stroke Scale score and lesion volume in patients with acute ischemic stroke [16]. Consistently we found that ICH patients with serum omentin-1 concentrations < median value had significantly higher ICH score, lower GCS score and larger hematoma volume, as well as had a substantially higher proportion of intraventricular hemorrhage. Taken together, serum omentin-1 concentrations should be linked to stroke severity
Fig. 2. Graph showing the change of serum omentin-1 concentrations according to modified Rankin scale scores among patients with spontaneous acute intracerebral hemorrhage.
the preceding significant variables were incorporated in the Logistic regression model, it was proved that serum omentin-1 concentrations less than 147.9 ng/ml and hematoma volume independently predicted 90-day poor outcome among ICH patients (Fig. 3). In Fig. 4, serum omentin-1 concentrations significantly predicted post-stroke 90-day poor outcome among this group of ICH patients. Also, its predictive capability was equivalent to that of hematoma volume (AUC, 0.854; 95% CI, 0.771–0.915; P = 0.NS). Moreover, it substantially improved AUC of hematoma volume to 0.921 (95% CI, 0.852–0.965; P = 0.008). 4. Discussion The main findings of this study were that (1) serum omentin-1
Table 2 Baseline characteristics by 90-day functional outcome among intracerebral hemorrhage patients. Parameters
Poor outcome
Good outcome
p-Value
Number Gender (Male/Female) Age (y) Body mass index (kg/m2) Smoking (yes/no) Drinking (yes/no) History of hypertension (yes/no) History of diabetes (yes/no) History of hyperlipidemia (yes/no) History of congestive heart failure (yes/no) History of coronary artery disease (yes/no) History of chronic kidney disease (yes/no) Pre-stroke statin treatment (yes/no) Pre-stroke usage of antiplatelet agents (yes/no) Pre-stroke usage of anticoagulants (yes/no) Time from onset to admission (h) Time from onset to blood-collection (h) Glasgow coma scale score Intracerebral hemorrhage score Hematoma volume (ml) Lobar hemorrhage (yes/no) Infratentorial hemorrhage (yes/no) Subarachnoidal extension of hematoma (yes/no) Intraventricular extension of hematoma (yes/no) Systolic arterial pressure (mmHg) Diastolic arterial pressure (mmHg) Blood glucose level (mmol/l) Serum C-reactive protein level (mg/l) Blood white blood cell count (×109/l) Serum omentin-1 levels < 147.9 ng/ml (yes/no)
58 35/23 74 (63–80) 24.8 (23.8–26.4) 28/30 24/34 44/14 18/40 25/33 5/53 4/54 3/55 14/44 13/45 6/52 9.2 (3.6–14.4) 12.1 (5.2–15.8) 12 (11–14) 2 (1–2) 21 (8–31) 13/45 13/45 4 /54 25/33 173 (159–187) 103 (97–108) 14.8 (11.3–19.4) 14.0 (11.8–17.2) 8.8 (6.3–11.5) 40/18
46 22/24 64 (56–72) 24.7 (22.4–26.7) 25/21 16/30 32/14 13/33 13/33 2/44 6/40 5/41 14/32 10/36 6/40 6.5 (3.3–10.9) 8.5 (5.1–13.7) 14 (14–15) 0 (0–1) 9 (5–12) 12/34 1/45 2/44 1/45 172 (160–189) 100 (90–107) 12.3 (11.2–14.9) 12.8 (10.1–14.5) 9.0 (6.5–11.9) 12/34
NS 0.001 NS NS NS NS NS NS NS NS NS NS NS NS NS NS < 0.001 < 0.001 < 0.001 NS 0.003 NS < 0.001 NS NS 0.023 0.010 NS < 0.001
Continuous variables were reported as medians with interquartile ranges. Categorical variables were showed as counts (percentages). Intergroup comparison was made using the χ2 test, Fisher exact test or Mann-Whitney U test as appropriate. 172
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Fig. 3. Graph depicting odds ratio values for the independent association with 90-day poor outcome after spontaneous acute intracerebral hemorrhage. Modified Rankin scale scores was defined as poor outcome. OR means odds ratio.
5. Conclusions Reduced serum omentin-1 concentrations, in inverse correlation with hemorrhagic severity, are significantly associated with post-stroke 90-day worse prognosis, indicating serum omentin-1 might have the potential to be a useful prognostic biomarker for ICH. CRediT authorship contribution statement Guo-Hai Zhang: Conceptualization, Methodology, Software. ZheHao Ye: Data curation, Writing - original draft. Hao-Jie Guan: Visualization, Investigation. Mi Guo: Supervision. Xin-Xiang Zhou: Software, Validation. Yu-Yu Xu: Writing - review & editing. Acknowledgements
Fig. 4. Graph displaying receiver-operating characteristic curve utilizing serum omentin-1 concentrations for investigating 90-day poor outcome after spontaneous acute intracerebral hemorrhage. Circle indicates the optimal cut-off point of serum omentin-1 concentrations by Youden method. AUC denotes area under curve. 95% CI means 95% CI.
We are deeply appreciative of the participants in this study and thank all staffs for their support and assistance. References
including ICH. Modified Rankin scale is a common clinical grade, which is used to assess functional outcome of stroke [20]. Generally, modified Rankin scale score > 2 is designated as a poor outcome [20]. In human ischemic stroke, serum omentin-1 concentrations were independently associated with 3-month functional outcome [17,18]. Similarly, in the current study, ICH patients with higher modified Rankin scale score showed significantly lower serum omentin-1 concentrations. While modified Rankin scale score was identified as a categorical variable, patients with a poor outcome had a significantly higher percentage of serum omentin-1 concentrations < median value. Using multivariate analysis, it was proved that both serum omentin-1 and hematoma volume retained as the two independent predictors for 90-day poor outcome after the onset of stroke. More intriguingly, serum omentin-1 concentrations not only had similar prognostic ability as compared to hematoma volume, but also significantly improved the prognostic capability of hematoma volume. In summary, serum omentin-1 might represent a promising prognostic biomarker for ICH.
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