ST2, IL‐33 and BNP in predicting major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Blood samples were collected from the included AMI patients (n = 180) who underwent PCI. All patients were divided into the MACEs and MACEs‐free groups. Enzyme‐linked immunosorbent assay was performed to measure serum levels of ST2, IL‐33 and BNP. Severity of coronary artery lesion was evaluated by Gensini score. Pearson correlation analysis was used. A receiver operating characteristics curve was drawn to evaluate the potential roles of ST2, IL‐33 and BNP in predicting MACEs, and Kaplan–Meier curve to analyse the 1‐year overall survival rate. Logistic regression analysis was conducted to analyse the independent risk factors for MACEs. Compared with the MACEs‐free group, the serum levels of ST2, IL‐33 and BNP were significantly higher in the MACEs group. Serum levels of ST2, IL‐33 and BNP were positively correlated with each other and positively correlated with Gensini score. The area under curves of ST2, IL‐33 and BNP, respectively, were 0.872, 0.675 and 0.902. The relative sensitivity and specificity were, respectively, 76.27% and 85.92%, 69.49% and 58.68%, as well as, 96.61% and 77.69%. Serum levels of ST2, IL‐33 and BNP were independent risk factors for MACEs. The 1‐year overall survival rate was higher in AMI patients with lower serum levels of ST2, IL‐33 and BNP. In conclusion, serum levels of ST2, IL‐33 and BNP have potential value in predicting MACEs in AMI patients undergoing PCI.This study investigated roles of serum  AMI is the most common and dangerous cardiac emergency with high mortality worldwide, which is commonly known as a heart attack occurring when blood stops flowing to a portion of the heart, causing damage to the heart muscle due to not receiving enough oxygen Serum ST2, the most prominent orphan member of interleukin‐1 (IL‐1) receptor, has been recognized to negatively regulate Toll‐like receptor/IL‐1 receptor signalling and function as a critical effector molecule of T helper type 2 (TH2) responses i) chest pain lasting more than 30 min.; (ii) the dynamic electrocardiogram change; (iii) levels of serum markers of myocardial injury were changed; (iv) the coronary angiography showed that patients could receive PCI for anatomy in infarct‐related artery. Exclusion criteria: (i) patients with survival time less than 24 hrs after onset; (ii) patients with other heart disease, combined acute and chronic infection; (iii) patients with abnormal pulmonary artery and/or aorta; (iv) patients with liver and kidney dysfunctions or malignant tumours; (v) patients who underwent cardiology‐related surgery before; (vi) patients with serum creatinine more than 3.0 mg/dl; and (vii) patients whose recent treatment may affect serum levels of ST2, IL‐33 and BNP. All patients were divided into the MACEs group (AMI patients with MACEs) and the MACEs‐free group (AMI patients without MACEs). MACEs include nonfatal myocardial infarction, angina, malignant arrhythmia and death From January 2014 to June 2015, 180 patients  diagnosed as a first episode of AMI in the Department of Cardiology in Shanghai Jiao Tong University Affiliated Sixth People's Hospital were enrolled in this study. The patients underwent PCI successfully. Clinical data of all patients were recorded. All patients were in accordance with the diagnostic criteria for AMI by American College of Cardiology (ACC) or American Heart Association (AHA) All AMI patients received PCI surgery as soon as possible after admission to open the infarct‐related artery. The patients were given 300 mg of aspirin and Plavix orally. Routine coronary angiography was conducted to determine the infarction and stenosis. The conventional PCI surgery was performed, and the vascular patency rate of all patients was 100%. Blood flow reached thrombolysis in myocardial infarction (TIMI) grade III. The colour Doppler echocardiography was conducted 1 week after surgery. After discharge, all patients were treated in accordance with the standard treatment of myocardial infarction Patients received coronary angiography immediately after admission, which was performed in the cath laboratory, with a digital subtraction machine . After conventional disinfection and local anaesthesia, the patients were supine; the catheter was from the puncture artery to the left and right coronary artery. Coronary angiography was conducted from multiple angles, including more than three positions above the right coronary artery, and more than six positions above left coronary artery. Other positions were selected if necessary. The coronary angiography was performed by cardiologists in Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Meanwhile, two interventional cardiologists judged the stenosis of coronary artery by double‐blind method, which was calculated by the percentage of 1 .Different weight coefficients were given according to the location of the diseased vessels. Weight coefficient for left main vessel is 5; with 2.5 for proximal lesion of the left circumflex and the anterior descending branch of circumflex, 1.5 for middle segments of anterior descending lesions, 1 for the right coronary artery, anterior descending artery, diagonal branch, posterior branch of left ventricle and obtuse marginal branch, and 0.5 for other vessels. According to the degree of vascular stenosis, 1 point indicates <25%, 2 points for 26–50%, 4 points for 51–75%, 8 points for 76–90%, 16 points for 91–99% and 32 points for 100%. The total score of each branch blood vessel = scores of the stenosis degree × weight coefficient r/min for 10 min. at 4°C. The serum was separated and then stored at −80°C for the detection of ST2, IL‐33 and BNP levels.The age, gender, other baseline characteristics, heart rate, history of hypertension, diabetes mellitus and smoking of all AMI patients were recorded. Two tubes of venous blood (each 4 ml) of all AMI patients in the fasting state were collected, one of which was used for routine blood examination, to measure blood urea nitrogen (BUN), creatinine (Cr), uric acid (UA), high‐sensitive C‐reactive protein (hs‐CRP), total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), triglyceride (TG), high‐density lipoprotein cholesterol (HDL‐C) and other parameters. The other tube of blood was centrifuged under the condition of 3000 The serum levels of ST2 and IL‐33 were detected using ELISA Kit . The serum level of BNP was detected using human brain natriuretic peptide ELISA Kit  in strict accordance with the kit instructions. The ELISA Kit was placed at room temperature for 30 min. The standard product was diluted according to the instructions, prepared for use. The serum was thawed at room temperature for 30 min., followed by adding samples, mixing liquid, washing, coloration and the termination. The microplate reader  was finally used to determine optical density (OD) value under 450 nm. Linear regression equation for the standard curve was calculated according to the standard OD values. Next, the actual concentrations were calculated.All the patients were followed up for 1 year by outpatient or telephone, with the follow‐up rate 100%. The occurrence of MACEs and the survival of all patients were recorded.t‐test. Enumeration data were presented as percentage or rate, which was analysed by chi‐square test. Pearson correlation analysis was performed to analyse the correlations among serum ST2, IL‐33 and BNP levels and the correlations of serum ST2, IL‐33 and BNP levels with Gensini scores. Receiver operating characteristics (ROC) curve was drawn to evaluate the potential roles of ST2, IL‐33 and BNP in predicting MACEs. Logistic regression analysis was conducted to analyse the independent risk factors for MACEs in AMI patients. Kaplan–Meier curve was adopted to analyse the 1‐year overall survival rate of AMI patients. P < 0.05 was considered statistically significant.SPSS 20.0 statistical software  was used for statistical analysis. Measurement data were expressed as mean ± standard deviation (mean ± S.D.). Comparison between two groups was made using independent sample P > 0.05), while it had correlations with the Gensini score at admission and hs‐CRP , hypertension history, diabetes mellitus history, smoking history, heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, TG, LDC‐C, HDL‐C, troponin I (cTn I) and creatine kinase‐MB (CK‐MB) . The cut‐off value was 733.82 pg/ml, the sensitivity was 76.27%, and specificity was 85.92%. The area under the ROC curve of IL‐33 at admission in predicting MACEs was 0.675 . The cut‐off value of IL‐33 was 387.75 pg/ml, the sensitivity was 69.49%, and specificity was 58.68%. The area under the ROC curve of BNP at admission in predicting MACEs was 0.902 . The cut‐off value of BNP was 285.73 pg/ml, the sensitivity was 96.61%, and specificity was 77.69% , but Gensini score and hs‐CRP were not independent risk factors for MACEs , while seven patients died in the MACEs‐free group, with the mortality rate 5.79% (7/121). The 1‐year overall survival rate was lower in the MACEs group than the MACEs‐free group (P < 0.05).Taken the average serum levels of ST2, IL‐33, BNP of all the AMI patients as the dividing line, all patients were divided into low ST2 group (ST2 ≤ 733.82 pg/ml) and high ST2 group (ST2 > 733.82 pg/ml), low IL‐33 group (IL‐33 ≤ 387.75 pg/ml) and high IL‐33 group (IL‐33 > 387.75 pg/ml), and low BNP group (BNP ≤ 285.73 pg/ml) and high BNP group (BNP > 285.73 pg/ml). The 1‐year mortality rate was 5.08% 6/118) in the low ST2 group, 16.13% (10/62) in the high ST2 group, 4.49% (4/89) in the low IL‐33 group, 13.19% (12/91) in the high IL‐33 group, 4.17% (4/96) in the low BNP group and 14.29% (12/84) in the high BNP group. As Figure /118 in tAs AMI is becoming a global acute disease which extremely threatens human health, initial biomarkers of AMI may be very important to improve the outcome. MACEs refer to complications occurring in AMI patients after operation, among which cardiogenic shock is related with a high mortality rate; therefore, a great deal of early treatments is under investigation to avoid or minimize MACEs First of all, the findings in our study indicate that serum levels of ST2, IL‐33 and BNP are significantly higher in AMI patients with MACEs than those without MACEs, and that AMI patients with high serum levels of ST2, IL‐33 and BNP have a lower 1‐year survival rate. ST2 is a member of IL‐1 receptor family, and IL‐33 is a cytokine belonging to IL‐1 family; IL‐33 is identified as the specific functional ligand of ST2 and the binding of IL‐33 to cells which express ST2 might result in nuclear factor kappa B (NF‐kB) and MAP kinases activation, leading to the induction of TH2 cytokines and balancing ongoing inflammatory TH1 responses et al. has pointed out that serum BNP level is a potent predictor for severity of CAD in the analysis of the predicting ability of NT‐proBNP based on Gensini scoring In addition, the results reveal that serum levels of ST2, IL‐33 and BNP are positively correlated with Gensini score. Gensini score, a quantitative digital method which shows the severity of CAD applied in combination with image analyses. It is reported that patients with impaired glucose tolerance showed higher Gensini score than those with normal glucose tolerance In conclusion, serum levels of ST2, IL‐33 and BNP are high in AMI patients with MACEs, and AMI patients with high serum levels of ST2, IL‐33 and BNP have a low 1‐year survival rate. Besides, positive correlations are found in serum levels of ST2, IL‐33 and BNP and Gensini score. Therefore, we may conclude that serum levels of ST2, IL‐33 and BNP may have great predictive value in MACE after PCI in patients with AMI. However, due to the limitation of study time, only a 1‐year follow‐up in AMI patients was conducted in our study, further studies with more long‐term observations are still needed to determine the predictive value of serum levels of ST2, IL‐33 and BNP in AMI patients.The authors have declared that no competing interests exist.


Most children and adolescents with chronic health conditions have impaired health-related quality of life and are at high risk of internalizing and externalizing problems. However, few patients present clinically significant symptoms. Using a decision-tree approach, this study aimed to identify risk profiles for psychological problems based on measures that can be easily scored and interpreted by healthcare professionals in pediatric settings. The participants were 736 children and adolescents between 8–18 years of age with asthma, epilepsy, cerebral palsy, type-1diabetes or obesity. The children and adolescents completed self-report measures of health-related quality of life (DISABKIDS-10) and psychological problems (Strengths and Difficulties Questionnaire). Sociodemographic and clinical data were collected from their parents/ physicians. Children and adolescents were classified into the normal (78.5%) or borderline/clinical range (21.5%) according to the Strengths and Difficulties Questionnaire cut-off values for psychological problems. The overall accuracy of the decision-tree model was 78.1% , with 4 profiles predicting 71.5% of borderline/clinical cases. The strongest predictor of psychological problems was a health-related quality of life standardized score below the threshold of 57.5 for patients with cerebral palsy, epilepsy or obesity and below 70.0 for patients with asthma or diabetes. Other significant predictors were low socio-economic status, single-parent household, medication intake and younger age. The model showed adequate validity  and accuracy . The identification of pediatric patients at high risk for psychological problems may contribute to a more efficient allocation of health resources, particularly with regard to their referral to specialized psychological assessment and intervention. Over the past few decades, scientific and technological advances in medicine have resulted in epidemiological changes marked by an increased prevalence of pediatric chronic health conditions  and by The most widely accepted models of child adjustment to pediatric chronic health conditions conceptualize adaptation as a multi-dimensional construct, including physical health, mental health  and social functioning . InternaIn primary care practice, physicians tend to underestimate psychosocial and functional impairments, and even severe psychological problems are often undetected and untreated, mostly because of lack of time and expertise in psychological assessment –22. Two In this context of routine monitoring and screening, short-form questionnaires that summarize scores into a single value (or index) have been found to be reliable and valid measures for global HrQoL assessment, while reducing response burden and saving administration costs ,29. The th percentile for same age and same sex peers according to the Centers for Disease Control and Prevention growth curves ) and moderate/severe .Clinical data were provided by the parents and/or physicians and included the use of medication and specific information for each clinical group. Specifically, the physicians classified asthma severity into 4 levels 2 = 16.84, p = .16 for the SDQ Emotional Symptoms scale; χ(12)2 = 12.29, p = .42 for the SDQ Conduct Problems scale; χ(8)2 = 9.28, p = .32 for the SDQ Hyperactivity/Inattention scale; χ(12)2 = 5.14, p = .95 for the SDQ Peer Relationship Problems scale; and χ(54)2 = 39.68, p = .93 for the DISABKIDS-10 Index) and less than 5% of the values were replaced with the individual mean score for each variable. Descriptive statistics were obtained for sociodemographic and clinical variables and the sample characteristics were compared between diagnostic groups by using one-way analyses of variance (ANOVA) followed by post-hoc pairwise comparisons with Bonferroni correction for continuous variables and by χ2-tests for categorical variables.The statistical analyses were conducted with the Statistical Package for the Social Sciences . Except for sociodemographic and clinical variables, missing data that were random (Little’s Missing Completely at Random [MCAR] Tests: χ2) that compare the squared deviations between observed and expected frequencies, with Bonferroni adjusted p-values for multiple comparisons with an overall error rate of .05  and obesity groups  and that children and adolescents with diabetes or obesity belonged to a single-parent household less often than did patients with asthma , epilepsy  or cerebral palsy . No significant differences between diagnostic groups were found for family SES or the primary caregiver’s psychiatric history.The diagnostic groups differed significantly in terms of the patients’ age, gender and family structure. Bonferroni post-hoc analyses showed that patients with obesity were significantly older than patients with epilepsy, with a mean difference (2(1) = 18.20, p < .01] or diabetes were , whereas children and adolescents with cerebral palsy or obesity used medication less often than did patients with asthma , epilepsy  or diabetes . In addition, pediatric asthma patients had better HrQoL than patients with cerebral palsy  or obesity  and fewer borderline/clinically significant psychological symptoms compared to children/adolescents with epilepsy  or obesity , whereas patients with diabetes had fewer psychological symptoms than the epilepsy group . In terms of the specific clinical characteristics of the sample, more than half of pediatric asthma patients had intermittent asthma ; the mean severity score for patients with epilepsy was 2.63, SD = 1.31; the great majority of children and adolescents with cerebral palsy had a mild form of the condition, including spastic subtypes  with no limitations in walking  and a mean IQ of 93.11, SD = 18.30 (range from 70 to 147); the mean glycated hemoglobin level of children with diabetes was 7.91, SD = 2.30%; and the standardized body mass index (zBMI) of children and adolescents with overweight/obesity was M = 1.90, SD = 0.41.Regarding the clinical characteristics of the sample, patients with epilepsy were medicated less often than those with asthma [χThe preliminary analyses revealed weak to moderate correlations between the risk factors, with correlation coefficients ranging from .00 (between age group and disease severity) to -.55 (between diagnosis and medication). In addition the Variance Inflation Factor (VIF) values ranged from 1.03 to 1.78 (mean VIF = 1.08) and the Tolerance values were higher than .56, indicating that the model was not limited by multicollinearity problems.SE = .02), with 11 terminal nodes derived from six predictors . Children’s and adolescents’ gender, disease severity and caregiver’s psychiatric history were also included in the model as risk factors, but as they were non-significant predictors of psychological problems, they were automatically excluded from the model.The decision-tree model predicting borderline/clinical psychological symptoms is shown in Beyond diagnosis, which was forced into the model as the first split variable, HrQoL was the most important predictor of psychological problems among pediatric patients, generating two high-risk profiles that predicted more than 50.0% of borderline/clinical cases: 71.7% of children and adolescents with cerebral palsy, epilepsy or obesity and HrQoL standardized scores below the threshold of 57.5 points and 57.4% of patients with asthma or diabetes and HrQoL scores below 70 points had borderline/clinically significant psychological symptoms. In addition, two medium-risk profiles were derived from the interaction between HrQoL scores and use of medication in pediatric patients with cerebral palsy, epilepsy or obesity: 36.4% of children/adolescents with HrQoL scores between 57.5–80 points and 45.5% of patients with HrQoL scores between 80–87.5 and using medication presented borderline/clinical psychological symptoms. Within the group with asthma or diabetes and HrQoL scores between 70–87.5, children and adolescents with low SES presented a greater likelihood of psychological problems (22.0%) compared to those with medium/high SES (8.2%); for patients with medium/high SES, the last significant predictor was age group, with younger children (14.8%) being at higher risk for psychological problems than adolescents (0.0%). For pediatric asthma or diabetes patients with HrQoL scores above 87.5, the last predictor was family structure, with children and adolescents living in a single-parent household being more likely to present psychological problems (10.3%) than their peers living in a two-parent family (1.9%). For patients with cerebral palsy, epilepsy and obesity and HrQoL scores above 87.5, no additional significant dependence relationships were found between the set of predictors and the outcome variable.The ROC curve for the decision-tree model is presented in The decision-tree emerging from this study can be considered an innovative generic risk assessment tool to identify pediatric patients at greater risk of developing borderline/clinically significant psychological symptoms based on the DISABKIDS-10 Index as a screening HrQoL measure and a brief questionnaire assessing patients’ and families’ sociodemographic and clinical characteristics. The decision-tree model presented adequate validity and accuracy and allowed the identification of two high-risk  and two medium-risk profiles  that predicted 71.5% of borderline/clinical cases. Thus, these four groups of patients must be given priority regarding referral to specialized psychological assessment and interventions in healthcare settings.In the total sample, 21.5% of children and adolescents presented borderline/clinically significant psychological problems according to the SDQ cut-off values. This prevalence of patient-reported psychological problems is comparable to population norms from several European countries –50. HoweThe CHAID algorithm clustered the group of children and adolescents with neurological disorders and obesity into the same node, in which 27.2% of patients had borderline/clinically significant psychological problems, in contrast with a prevalence of 16.3% in the asthma/diabetes node. The results indicated that even after controlling for diagnosis, the best predictor of borderline/clinical psychological problems was the child-reported HrQoL. However, the classification-tree model defined different cut-off points for the DISABKIDS-10 scores depending on the diagnostic group: children and adolescents with asthma or diabetes are at a greater risk of borderline/clinical psychological problems if they had HrQoL scores below 70.0, whereas patients with epilepsy, cerebral palsy or obesity were at high risk if they presented HrQoL scores below 57.5 and medium risk if they had HrQoL scores between 57.5–80.0. Patients with epilepsy, cerebral palsy or obesity and HrQoL scores between 80.0–87.5 were also at medium risk if they were taking medication. These cut-off points reflect the well-documented differences in HrQoL mean scores across chronic health conditions  because Consistent with previous studies ,18,19, SOur findings should be interpreted with caution due to some limitations in the study’s design and procedures. First, the study’s cross-sectional design precluded the establishment of causal links among variables. Thus, we cannot claim that lower HrQoL levels predict an increased likelihood of developing borderline/clinically significant psychological problems. Instead, we suggest that HrQoL and psychological problems should be considered two indicators of the broader construct of psychosocial adaptation that covary . ProspecDespite these limitations, this is the first study to examine the interplay among clinical, sociodemographic and HrQoL data to predict the risk of developing borderline/clinically significant psychological problems, facilitating the development of a screening tool for healthcare providers. There is a growing need to identify at-risk populations in healthcare services, but the limitations of commonly used statistical methods  and finaIn clinical practice, this decision-tree approach would consist of a series of questions that would follow various iterations as necessary, similar to many common diagnostic tools. According to our decision-tree model, the specific diagnostic would determine the influence of all other variables and must be considered first, followed by HrQoL assessment. Another major practical implication of this study is the establishment of condition-specific, clinically meaningful, cut-off points to interpret HrQoL data as assessed by the chronic-generic DISABKIDS-10 Index, which is an essential measurement property when using HrQoL instruments in clinical decision-making . This coS1 File(XLSX)Click here for additional data file.


Spontaneous intracerebral hemorrhage (SICH), defined broadly as intracerebral hemorrhage not related to trauma, results in long-term disability or death in a large proportion of afflicted patients. Current management of this disease is predominantly supportive, including airway protection, optimization of hemodynamic parameters, and management of intracranial pressure. No active treatments that demonstrate beneficial effects on clinical outcome are currently available. Animal models of SICH have allowed for the elucidation of multiple pathways that may be attractive therapeutic targets. A minority of these, such as aggressive blood pressure management and recombinant activated factor VII administration, have led to large-scale clinical trials. There remains a critical need for further translational research in the realm of SICH. Spontaneous intracerebral hemorrhage (SICH), while comprising only 10–20% of all strokes . Long-teDespite the disappointing results of interventional studies to date, there is reason to be hopeful going forward. Advancements in the understanding of secondary injury after SICH have highlighted opportunities for therapeutic intervention . One sucThis review will discuss the classifications and current animal models of SICH, as well as what is known about the pathophysiology of secondary hematoma expansion. The interaction between bench research and clinical trials will be examined, with a focus on blood pressure control and the hemostatic mechanism – two areas where findings in animal models of SICH have lead to large-scale, randomized controlled trials in humans.Broadly, SICH is defined as any intracerebral hemorrhage that is non-traumatic in nature; SICH can be further divided into primary and secondary hemorrhage . PrimarySecondary SICH can be caused by a variety of underlying lesions and pathologies. Vascular malformations that can lead to SICH include arteriovenous malformations , cerebraCurrently, there are two widely used paradigms for modeling of SICH in animals. The first is the intracerebral injection of autologous blood. Initially developed in the 1960s , this moAlthough the precise mechanism for secondary hematoma expansion has yet to be fully elucidated, two predominant models currently exist. The first is the “persistent bleeding” model, which proposes that the vessel or vessels that initially rupture continue to bleed and lead to an enlarging hematoma . The secRegardless of the underlying histopathological cause, experimental evidence suggests that two important contributors to secondary hematoma expansion may be derangement of the coagulation cascade , 42 Fig and hypeNon-pharmacologic disruption of hemostatic mechanisms may be equally important. In an autologous blood injection rat model of intracerebral hemorrhage, Liu et al.  found a The relationship of hypertension to secondary hematoma expansion is more controversial. Although some experimental evidence does exist that higher blood pressures may lead to hematoma expansion and larger overall hematoma volumes , other iAnimal models have suggested that elevations in blood pressure may lead to increased secondary hematoma expansion in SICH. Several observational analyses in patients also suggested that hypertension was associated with worsened clinical outcomes following SICH and that aggressive blood pressure management could offer benefits , 60. Thip = 0.27]  on ordinal analysis of modified Rankin scores at 90 days.The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) was initiated in 2005, with patients randomized to intensive  or standard  groups ( = 0.27] . INTERACp > 0.05), although a trend was noted. The follow-up study, ATACH-2, demonstrated no significant advantage of aggressive blood pressure control  over standard (140–179 mmHg) and was discontinued after 1280 patients were enrolled (p = 0.08). Patients in the intensive treatment group also suffered a significantly higher rate of short-term renal complications, with a rate of 1.6 versus 1.2% in the standard treatment group (p = 0.002).Similarly, early results of the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) study , where penrolled . For thep = 0.19). This led the investigators to conclude that aggressive blood pressure lowering in SICH patients did not lead to lowered cerebral blood flow or risk of perihemorrhagic ischemia. In light of the results of these studies, the most recent American Heart Association/American Stroke Association guidelines recommend an acute systolic blood pressure goal of <140 mmHg and a long-term goal of <130 mmHg to prevent recurrent SICH , although volumes of hematoma expansion remained lower in both rFVIIa groups compared with placebo  , with rat models showing significantly reduced hematoma expansion in animals treated with rFVIIa compared with controls . The resplacebo) .Some concern remained after these studies that patient selection – specifically the enrollment of individuals who were unlikely to suffer hematoma expansion in the first place – may have resulted in the negative results of FAST. Thus, two trials  are ongoing to attempt to resolve this question. Both these studies utilize the so-called “spot sign” for selection of patients who are at higher risk of hematoma expansion. The spot sign is the presence of contrast enhancement within the hematoma mass on CT angiography and has been shown to be strongly associated with both hematoma expansion and poor outcome , 79. HowBecause of the high mortality and incidence of long-term disability associated with SICH, it remains a significant health care burden globally. Current therapeutic options remain limited, but continued investigations into the underlying mechanisms of secondary injury, such as hemorrhage expansion, have yielded promising targets for intervention that continue to warrant further investigation. Further refinement of animal models of SICH, the discovery of therapeutic pathways in the laboratory setting, and the transition of this knowledge into treatments in humans remain critically needed.JG and GH conceived of the topic, drafted the manuscript, and did critical review and revision of manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JP and handling editor declared their shared affiliation, and the handling editor states that the process nevertheless met the standards of a fair and objective review.


It was also correlated with JVR  and baseline hematoma volume  at 12 ± 3 days after onset. In a similar manner, relative PHE volume was significantly associated with JVR  within 72 h of onset and at 12 ± 3 days after onset . JVR is associated with both absolute and relative PHE volumes after ICH.The purpose of this study was to determine whether jugular venous reflux (JVR) is associated with perihematomal edema (PHE) in individuals with intracerebral hemorrhage (ICH). Patients with spontaneous supratentorial ICH within 72 h of symptom onset were enrolled. Baseline brain computed tomography (CT) scan was performed, with a follow-up CT examination at 12 ± 3 days after onset. Jugular venous color Doppler ultrasound was performed at 12 ± 3 days after onset to examine the JVR status. A total of 65 patients with ICH were enrolled. In logistic regression analysis, absolute PHE volume was significantly associated with JVR (OR, 5.46; 95% CI, 1.04–28.63;  Intracerebral hemorrhage (ICH) is a neurological disease with mortality rates within 30 days reaching 30–52% –3. BesidJugular venous reflux (JVR) is widely found in healthy individuals, with a prevalence of about 20–40%, which increases with age . JVR is To test this hypothesis, this cohort study was carried out with the aim to assess the association of JVR and PHE volume.This was a cohort study assessing patients with spontaneous supratentorial intracerebral hemorrhage admitted to the Department of Neurology, Beijing Tiantan Hospital, China. The inclusion criteria were (1) age ≥ 18; (2) admission diagnosis of supratentorial ICH confirmed by brain computed tomography (CT); and (3) baseline CT scan completion within 72 h of onset. The exclusion criteria were (1) infratentorial hemorrhage; (2) primary intraventricular hemorrhage; (3) subsequent surgery; or (4) any suspected cause of secondary ICH. Data were prospectively collected and retrospectively analyzed. This study was approved by the Ethics Committee of Beijing Tiantan Hospital affiliated to the Capital Medical University of China, in compliance with the Declaration of Helsinki. All patients or their legal representatives provided signed informed consent.Eligible patients were assessed for demographics data, clinical data, and hematoma and PHE volumes. Blood samples were collected from each patient on the day of hospital admission for the measurement of blood glucose (GLU), low-density lipoprotein (LDL) levels, and international normalized ratio (INR). Clinical and neurological evaluations were performed to collect data, including first blood pressure measurement after onset, as well as history of smoking, hemorrhagic and ischemic stroke, diabetes mellitus, hypertension, coronary heart disease, and blood diseases (including coagulopathy and leukemia). History of smoking was defined as currently smoking or past smoking . Arterial hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, or self-reported current treatment for arterial hypertension with antihypertensive medications. On the admission day, the patients were assessed for stroke severity, consciousness state, and the level of handicap according to the National Institute of Health Stroke Scale (NIHSS), Glasgow Coma Scale (GCS), and modified Rankin Scale (mRS), respectively.Color Doppler ultrasound was carried out on GE Logiq9 , with the patient lying flat in the supine position and the head straight, using a 4–7 MHz linear transducer after a 10 min of quiet rest. All examinations were performed by an experienced neurosonographer blinded to the patient's clinical data. Sufficient ultrasound gel was applied and appropriate care was given to avoid compression on the neck veins during examination. Bilateral internal jugular veins (IJVs) were examined initially through longitudinal and cross-sectional views from the proximal part of the neck base rostrally to the distal part at the submandibular level to detect spontaneous JVR. The color box was adjusted to include the entire IJV lumen. When retrograde color appeared in the lumen center, the retrograde flow was confirmed by Doppler spectrum. JVR was defined as the retrograde flow >0 seconds detected at the distal part of the IJV (above the inferior jugular bulb)  11, 13,,13, 14. Baseline noncontrast computed tomography (NCCT) was performed within 72 h of onset and repeated at 12 ± 3 days, on a CT scanner , with 512 × 512 matrix, FOV of 15 cm, and slice thickness of 9 or 10 mm  and 4.5 or 5 mm . A roundish or ellipsoid hematoma with smooth margin was classified as regular: one with a pleomorphic contour and several adjacent but separated hematomas, and multicentric hematomas were classified as irregular. Intracranial hematoma (excluding ventricular hemorrhage) and PHE volumes were independently measured by two trained neurologists blinded to clinical data. Images were processed off-line with the Picture Archiving and Communications Systems (PACS). The examiner manually drew regions of interest (ROIs) by tracing the hyperdense area (hematoma) and hypodense region surrounding the hematoma (PHE) throughout the lesion . Thresho t-test or Wilcoxon rank-sum test for continuous variables. The chi-square test or Fisher's exact test was used to compare categorical variables. Multivariate analysis was performed using a logistic regression model to screen risk factors for large PHE. Variables with p < 0.20 were entered in the multivariate analysis, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Two-sided p < 0.05 was considered statistically significant.SPSS for Windows, version 16.0 , was used for all statistical analyses. Demographic and clinical data of patients (with or without JVR) were assessed by Student'sA total of 65 patients were enrolled in this study. Among them, 11 (16.9%) and 7 (10.8%) subjects had right- and left-sided JVR, respectively; 11 patients (16.9%) had bilateral JVR, while 36 subjects (55.4%) showed no JVR. Among 29 JVR-positive patients, there were 10 subjects who had retrograde flow in their IJVs with a duration <0.5 s (0.11–0.49 s). The patients with right-sided, left-sided, and bilateral JVR were assigned to the JVR-positive group; those with no JVR were classified into the JVR-negative group.No extraluminal structural abnormality was found in any subject. In the JVR-negative group, one patient had a dysfunctional valve in the left IJV and one patient had single leaflet valve in the right IJV. Among patients with left-sided JVR, two had single leaflet valve in the left IJV and one had single leaflet valve in the right IJV. Among patients with bilateral JVR, one had single leaflet valve in the left IJV and one had dysfunctional valve in the right IJV. No web, flap, septa, or membrane was observed. The baseline characteristics of the patients are shown in To characterize the relationship between JVR and PHE in ICH patients, PHE volumes were compared between the two groups within 72 h of onset and at 12 ± 3 days after onset. Interestingly, both absolute and relative PHE volumes in the JVR-positive group were significantly higher than those of the JVR-negative group .To further explore the relationship between PHE and JVR, the subjects were further grouped based on average absolute and relative PHE volumes, into the large-volume (exceeding average PHE volume) and small-volume (less than average PHE volume) groups . Interes p < 0.20. Absolute PHE volume within 72 h of onset was significantly associated with JVR (p < 0.05), sex (p = 0.173), smoking history (p = 0.135), hematoma shape (p = 0.095), NIHSS on admission (p < 0.001), mRS on admission (p < 0.05), GCS on admission (p < 0.05), baseline hematoma volume (p < 0.001), first systolic blood pressure (p = 0.189), and first diastolic blood pressure (p < 0.05). Meanwhile, relative PHE volume within 72 h of onset was significantly associated with JVR (p < 0.001), hematoma shape (p < 0.05), NIHSS on admission (p = 0.171), GLU (p = 0.128), baseline hematoma volume (p < 0.001), first systolic blood pressure (p = 0.189), and first diastolic blood pressure (p < 0.05). Furthermore, absolute PHE volume at 12 ± 3 days after onset was significantly associated with JVR (p = 0.001), sex (p = 0.005), hematoma shape (p < 0.05), NIHSS on admission (p = 0.008), mRS on admission (p = 0.071), GCS on admission (p = 0.041), baseline hematoma volume (p < 0.001), and LDL (p = 0.051). Moreover, relative PHE at 12 ± 3 days after onset was significantly associated with JVR (p = 0.001).Logistic regression analysis was carried out for each of the four conditions shown in In multivariate logistic regression analysis, PHE volume remained significantly associated with JVR in all four conditions. JVR and baseline hematoma volume showed significant associations with absolute and relative PHE volumes, within 3 and 12 ± 3 days of onset, respectively, as shown in  p = 0.035) for 72 h absolute PHE; OR = 7.15  for 72 h relative PHE; OR = 17.46  for absolute PHE at 12 ± 3 days; and OR = 6.89  for relative PHE at 12 ± 3 days. These results are similar to those obtained when using JVR > 0 s as the threshold for JVR.The patients were regrouped according to the duration of JVR. Patients with JVR below 0.5 s were considered JVR-negative because JVR below 0.5 s was considered normal in some previous studies , 18–24. This study demonstrated that PHE volumes were significantly higher in ICH patients with JVR compared with the JVR-negative group. In addition, JVR was associated with both absolute and relative PHE volumes in these patients after adjusting for age, sex, first blood pressure measurement after symptom detection, baseline hematoma volume, hematoma shape, GLU, LDL, NIHSS, GCS, and mRS on admission.It is admitted that hematoma volume is the main factor that determines the volume of PHE , 25. In Venous flow from the superficial and deep venous system drains into the transverse sinus, then into the sigmoid sinus, and finally into IJV; indeed, IJVs collect most of the cerebral venous blood, especially in the supine position , 26, 27.Previous studies have shown that JVR in the jugular venous system can cause retrograde hypertension, which can be transmitted to the cerebral venous system , 28, 29.In this study, JVR was detected before ICH. It remains unclear why patients with JVR seemed to be normal before ICH. The intracranial venous system contains about 70% of blood in the cerebral circulation, and ICP can be regulated effectively by the fluctuation of venous blood volume under normal conditions , 33–39. Most previous studies defined JVR as JVR > 0.5 s , 18–24, p = 0.268). Other possible cause of JVR should be further explored in future studies.JVR is a form of functional abnormality of IJV and is usually observed in conjunction with chronic cerebrospinal venous insufficiency (CCSVI) and internal jugular valve insufficiency (IJVI) , 40, 41.There are two forms of JVR:VM-induced and spontaneous types . In prevInevitably, this study had some limitations. (1) We focused solely on JVR, a hemodynamic change in the internal jugular vein, without considering other intracranial venous abnormalities. It is unknown whether such venous abnormalities participated in the formation of perihematomal edema in this study. Thus, future research involving a comprehensive evaluation of intracranial and extracranial venous system is strongly needed. (2) The relatively small sample size of this study should be mentioned. (3) For patient safety, only subjects from the general wards in our institution were enrolled, whose baseline hematoma volumes are usually relatively small. Patients in neural intensive care unit with larger hematoma volumes should be also enrolled in future studies under closer monitoring.The current findings demonstrated that JVR is strongly associated with PHE volume after ICH. Although the exact mechanism remains unclear, it is plausible that JVR retrogradely transmits venous hypertension into the brain.


We assessed arterial stiffness in subjects with Sri Lankan CKDu, in matched controls without CKD and in those with defined CKD. Aortic blood pressure (BP), pulse wave velocity (PWV) and augmentation index (AIx) were assessed in 130 subjects  using the validated TensioMed™ Arteriograph monitor. Brachial and aortic BP was lower in controls than in CKDu and CKD subjects but no different between CKDu and CKD. Controls had a lower PWV compared to subjects with CKDu and CKD. Despite equivalent BP and renal dysfunction, CKDu subjects had a lower PWV than those with CKD . Excluding diabetes accentuated the differences in PWV seen between groups . Sri Lankan CKDu is associated with less arterial stiffening than defined causes of CKD. Whether this translates to lower cardiovascular morbidity and mortality long term is unclear and should be the focus of future studies.Chronic kidney disease (CKD) is common and independently associated with cardiovascular disease (CVD). Arterial stiffness contributes to CVD risk in CKD. In many developing countries a considerable proportion of CKD remains unexplained, termed CKD CKDu is a diagnosis of exclusion, made when a patient fulfills the Kidney Disease Improving Global Outcomes (KDIGO) CKD criteria but without evidence of a recognized cause such as diabetes, hypertension, or glomerulonephritisu has become a leading cause of death in Sri LankaChronic kidney disease (CKD) is a significant cause of morbidity and mortality worldwideu. Furthermore, it remains unclear whether the CVD risk associated with CKDu is the same as that of CKD of known cause. We hypothesised that CKDu patients would have increased arterial stiffness compared to matched controls but that these measures would be no different compared to matched subjects with defined aetiologies for their CKD.CKD is an independent risk factor for cardiovascular disease (CVD)56This was a prospective, cross-sectional case controlled study performed in Anuradhapura, North Central Province and Colombo, Sri Lanka with approval of the Ethics Review Committee, Faculty of Medicine & Allied Sciences, Rajarata University of Sri Lanka and the written informed consent of each subject. The investigations conformed to the principles outlined in the Declaration of Helsinki.u) was defined as evidence of renal dysfunction (proteinuria or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR <60 ml/min/1.73 m2) with no clear aetiological factor . The diagnosis of CKD was based on the same criteria but with an established cause for the renal impairment. A group of age- and sex-matched controls were also recruited from the same geographical area.Subjects were aged between 18 and 85 years. Chronic kidney disease of unknown origin . Measurements were taken as the average of two readings. The Arteriograph utilises brachial pulse oscillations to calculate aortic pulse wave velocity (PWV), augmentation index (AIx), systolic BP and pulse pressure. It also records brachial systolic BP and diastolic BP. The Arteriograph has been validated against an invasive measure of aortic PWV9Blood was sampled routinely for serum creatinine. Creatinine clearance, as an estimate of GFR, was calculated according to the CKD-EPI equationu with which we could perform a power calculation. Thus, based on data from previous studies in western populations12There are no previous studies of pre-dialysis CKDu. As expected, brachial and aortic blood pressure (BP) was lower in controls than in CKDu and CKD subjects. Importantly, CKDu and CKD subjects did not differ in terms of brachial or aortic BP components . A few studiesu), investigated arterial stiffness using the same technique as here, and found that PWV was lower than in those with other causes for their dialysis-requiring renal failureu in Sri LankaMost noteworthy was our finding that, despite similar eGFR and BP, those with CKDu we found no difference in AIx. Whilst PWV and AIx are both used as surrogate measures of arterial stiffness they are not interchangeable. PWV is an assessment of large artery stiffness. AIx is derived from analysis of the pulse contour and is the proportion of central pulse pressure that results from arterial wave reflection. Although the timing of the arrival of the reflected wave at the proximal aorta is largely determined by large artery PWV, AIx is not simply a surrogate measure of PWV. It is influenced by vasoactive drugs independently of PWVu as could under-powering of the study with respect to this parameter.Although PWV varied significantly between CKD and CKDAlthough this is the first study of its kind we recognise a number of limitations. Our study size increases the chances of our results being subject to a type II error. Larger similar studies are needed to confirm our findings. Furthermore, some of the medications taken by our patients, such as ACE inhibitors, angiotensin receptor blockers, and ß blockers may have affected arterial stiffness. However, all patients were stabilised on their therapies and the CKD groups were on similar treatments in this respect. We also saw a high prevalence of diabetes in our cohort and so our findings may not be generalizable to population outside Sri Lanka. Finally, we were unable to assess the influence of proteinuria or other more novel CVD risk factors such as circulating C-reactive protein, asymmetric dimethylarginine or endothelin-1, all of which may contribute to arterial stiffeningu. More importantly, a few clinical trials have demonstrated that differential lowering of PWV with medical treatment results in different cardiovascular or renal outcomes24614et al. have previously shown that treatment of patients with type 2 diabetes and proteinuria with 6 months of valsartan/hydrochlorthiazide reduced PWV by ~14% (12.5 to 10.7 m/s)Measures of arterial stiffness are not currently used in the clinic. However, there have been a number of clinical studies that have examined differences in PWV between health and disease. We have previously shown that patients with CKD stage IV – the mean eGFR in the current study fits into this–had a PWV of 7.0 ± 1.4 m/s compared to 6.2 ± 0.9 m/s in matched controls. This ~13% is difference similar to the magnitude of the difference observed here between CKD and CKDu is associated with less arterial stiffening than other defined causes of CKD. There remain a number of unanswered questions that should be the focus of future work: what is the natural history of arterial stiffness in CKDu; is this modifiable; and, if so, does this translate to lower cardiovascular morbidity and mortality long term compared to other forms of CKD.This is the first study suggesting that Sri Lankan CKDHow to cite this article: Gifford, F. et al. Arterial stiffness & Sri Lankan chronic kidney disease of unknown origin. Sci. Rep.6, 32599; doi: 10.1038/srep32599 (2016).


Our findings propose a need for careful pre-operative evaluation of cardiovascular and pulmonary functions and post-operative fluid management among patients with not only lower but also very high eGFR.Despite a large body of evidence showing the pandemic of chronic kidney disease, the impact of pre-operative kidney function on the risk of post-operative pulmonary complications (PPCs) is not well known. We used multivariable logistic regression analyses with 3-level hierarchical adjustments to identify the association of pre-operative estimated glomerular filtration rate (eGFR) with PPCs in laparoscopic surgeries. Among 452,213 patients between 2005 and 2013 in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Database, a total of 3,727 patients (0.9%) experienced PPCs. We found a gradient association between lower eGFR and higher likelihood of PPCs in the unadjusted model. In the case-mix adjusted model, a reverse-J-shaped association was observed; a small albeit significant association with the highest eGFR category emerged. Further adjustment slightly attenuated these associations, but the PPCs risk in the eGFR groups of <30, 30–60, and ≥120 mL/min/1.73 m The overall incidence of PPCs has been estimated to range from 2.0 to 10.0%4. The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), which is a large national cohort, found that PPCs were by far most costly among post-operative complications5. Therefore, it may improve patient outcome and reduce medical cost if an efficient strategy is developed to identify and manage patients at risk for PPCs.Post-operative pulmonary complications (PPCs) such as pneumonia, failure to wean off the ventilator, and post-extubation respiratory failure are the most frequent morbidity and causes of death after surgery6. Additionally, patients with decreased kidney function have higher prevalence of comorbid conditions  and higher mortality than individuals with normal kidney function, and may be more susceptible to PPCs due to diminished ability to maintain fluid balance. Nevertheless, there are scarce data on the relationship between pre-operative kidney function and PPCs.Chronic kidney disease (CKD), characterized by decreased kidney function, is a major national and international public health issue with an estimated prevalence of 13.6% in the United States7. However, the use of laparoscopy can impair respiratory function through the formation of atelectasis and the ventilation-perfusion mismatch caused by the combined effects of supine position and muscle paralysis9. Pneumoperitoneum with carbon dioxide during laparoscopic surgeries causes cephalad displacement of the diaphragm and accelerates atelectasis formation10, which decreases respiratory compliance and arterial oxygenation12. These unfavorable conditions may be aggravated in the presence of CKD.Laparoscopy has been employed in many surgical procedures to reduce post-operative complications and promote patient recoveryBased on the above, we examined our hypothesis that patients with pre-operative kidney function would have higher incidence of PPCs after laparoscopic surgery by using the ACS-NSQIP database. We also evaluated the association with non-pulmonary infectious complications in order to contrast the relative contribution of kidney function to different subtypes of post-operative complications.2. The prevalence of estimated glomerular filtration rate (eGFR) < 30, 30 to <60, 60 to <90, 90 to <120, and ≥120 mL/min/1.73 m2 were 1.3% , 9.1% , 38.2% , 43.1% , and 8.3% , respectively. Significant trends were observed in all observed variables (Ptrend < 0.001) due to the large sample size. Patients with lower eGFR were older and tended to have a higher prevalence of diabetes, hypertension, chronic obstructive pulmonary disease, dyspnea at moderate exertion, and chronic heart failure, lower concentrations of serum albumin and hematocrit, and a lower prevalence of smoking history.Out of 740,263 patients undergoing laparoscopic surgery identified in the ACS-NSQIP database from 2005 to 2013, 425,213 patients met our eligibility criteria  experienced PPCs  within 30 days after surgery. There was an increasing trend in the rate of PPCs across lower eGFR categories; the incidence of PPCs was 0.4%, 0.6%, 0.9%, 2.2%, and 3.6% in patients with eGFR ≥ 120, 90 to <120, 60 to <90, 30 to <60, and <30 mL/min/1.73 m2 in eGFR showed odds ratios (ORs)  of 6.42 (5.50 to 7.51), 3.90 (3.56 to 4.28), 1.60 (1.48 to 1.73), and 0.74 (0.63 to 0.88), respectively,  were attenuated while the PPCs risk associated with the highest eGFR category  reversed and turned significantly high . The fully adjusted model showed slightly attenuated associations, but the PPCs risk in the eGFR groups of <30, 30 to 60, and >120 mL/min/1.73 m2 retained statistical significance; <30, 30 to <60, and ≥120 mL/min/1.73 m2 in eGFR showed ORs (95% CIs) of 1.82 (1.54 to 2.16), 1.38 (1.24 to 1.54), and 1.28 (1.07 to 1.53), respectively . However, it lost statistical significance with further adjustment  and the eGFR-PPCs association was consistent between obese vs. non-obese patients   and PPCs was robust and strong in subgroup analyses based on sex , race (white vs. non-white), diabetes (with vs. without), BMI (≥30 vs. <30 kg/m2), and surgery type  and the PPCs risk associated with low eGFR was especially pronounced in younger patients   and PPCs was small and inconsistent for sex; high eGFR was associated with higher risk of PPCs among male patients but not among female patients (Pinteraction < 0.001)  Fig. . The adj04) Fig. .The adju01) Fig. .Figure 32, respectively  experienced post-operative non-pulmonary infectious complications  within 30 days after surgery. There was an increasing trend in the rate of post-operative non-pulmonary infectious complications across lower eGFR categories; the incidence of PPCs was 2.9%, 3.6%, 4.0%, 5.2%, and 7.0% in patients with eGFR ≥ 120, 90 to <120, 60 to <90, 30 to <60, and <30 mL/min/1.73 m.9% experPtrend < 0.001, Fig. Ptrend < 0.001 in all adjustment models), the risk associated with eGFR categories was much smaller compared to PPCs; <30, 30 to <60, 60 to <90, and ≥120 mL/min/1.73 m2 in eGFR categories showed fully-adjusted ORs (95% CIs) of 1.11 (0.99 to 1.24), 0.89 (0.84 to 0.95), 0.91 (0.87 to 0.94), and 1.04 (0.96 to 1.11), respectively, (reference: 90 to <120 mL/min/1.73 m2) . In contrast, there was no apparent association between eGFR and non-pulmonary infectious complications, supporting a close link between kidney function and pulmonary complications.This is the largest study, to our knowledge, which has examined the risk of post-operative complications after abdominal surgeries associated with preoperative eGFR, an index of kidney function, using a large contemporary national database of surgical outcomes with prospectively recorded assessments. Our study is also the first to demonstrate that the adjusted risk of PPCs were higher in the range of not only lower but also higher eGFR levels  and generally considered low in morbidity risk. Meanwhile, our study did not find an increased risk of non-pulmonary infectious complications among patients with reduced kidney function, which may reflect the lower baseline risk underlying laparoscopic surgeries vs. cardiac surgeries.There are several studies showing the association of kidney dysfunction with post-operative complications, but most of them examined a composite of heterogeneous outcomes20. Second, elevated fibroblast growth factor 23 (FGF23) levels and vitamin D deficiency may contribute to the development of PPCs. FGF23 increases in the very early course of CKD23, and vitamin D deficiency is also commonly observed in CKD especially among those with proteinuria and diabetes27. Several study have reported that both elevated FGF23 and vitamin D deficiency may cause left ventricular hypertrophy via activation of the calcineurin pathway30 and the renin-angiotensin-aldosterone system33, respectively. Indeed, patients with CKD are at high risk of cardiovascular events and death even in early stages of CKD36. Third, patients with CKD may have impaired respiratory muscle strength due to protein-energy wasting40. Fourth, hypoalbuminemia, which is often observed among patients with CKD, may induce pulmonary congestion. Hypoalbuminemia decrease plasma oncotic pressure and thus promotes movement of fluid out of the pulmonary capilaries42. Indeed, the risk of PPCs associated with eGFR was attenuated in the fully-adjusted model including serum albumin, suggesting the link between hypoalbuminemia and protein-energy wasting.The exact underlying mechanisms of the association between PPCs and lower eGFR remain unclear, but patients with decreased kidney function are less capable to maintain fluid balance by urine in the setting of post-operative fluid infusion, which may lead to hypervolemia and cardiogenic pulmonary edema2 was pronounced among younger vs. older patients . The exact reason for this finding is unclear, but there may be selection bias where older patients underwent invasive therapeutic procedures  only if they do not have apparent health-related problems.We observed a significant effect modification by age against the association between low GFR and PPCs; the PPCs risk associated with eGFR < 60 mL/min/1.73 m2 was not significant probably because female patients, compared to male patients, are likely to have less muscle mass, which might have attenuated the association between PPCs and high eGFR induced by low serum creatinine concentrations. Meanwhile, glomerular hyperfiltration, often defined as GFR ≥ 120 mL/min/1.73 m243, is caused by various clinical conditions such as diabetes, obesity, and sleep apnea44, and may be a marker of early renal damage in pre-diabetes and pre-hypertension45. Second, endothelial dysfunction observed in CKD may increase capillary leak leading to non-cardiogenic pulmonary edema46. Of note, endothelial dysfunction is observed even in pre-diabetes and pre-hypertension, which can cause glomerular hypertension resulting in proteinuria and hyperfiltration at the very beginning period of CKD48. These findings may explain the positive correlation between high eGFR and pulmonary complication risk even after adjustment for diabetes, hypertension and BMI.The association between the highest eGFR group and higher likelihood of PPCs may be explained by frailty and hyperfiltration. Estimated GFR is well known to overestimate actual kidney function in subjects with low muscle mass, and thus frail patients with normal kidney function may have falsely high eGFR and high susceptibility to fluid overload due to weak respiratory muscle. Among female patients, the PPCs risk associated with eGFR ≥ 120 mL/min/1.73 m49. Additionally, the ACS-NSQIP did not record some relevant information such as echocardiography, pulmonary function test, serum levels of FGF23 and 25-hydroxyvitamin D, pleural effusion, obstructive sleep apnea, and asthma. Second, the study population was comprised of patients admitted to hospitals participating in the ACS-NSQIP system and therefore may not reflect all patients across the United States. Third, 97,473 patients (16.6%) were missing serum creatinine values among patients included in this study, and available serum creatinine measures may not be representative of the entire source population. Potential selection bias may exist, such that physicians at participant institutions may be unlikely to re-measure serum creatinine levels in stable patients with serum creatinine data measured by primary care physicians. Fourth, preoperative eGFR may not represent patient kidney function in a stable condition because low eGFR in this study may indicate acute kidney injury in the preoperative period. Exclusion of the emergency cases is our best effort to avoid the influence of acute kidney injury on the association between eGFR and PPCs.Our study has several limitations. First, as the retrospective nature of the observational study, we are not able to estimate the cause-effect relationships, and there may be residual confounding and/or unmeasured cofounders that might have biased the estimated association. For example, the wide variation in hospital setting, hospital quality, surgical strategy, and surgeons’ expertise may confound our study because the ACS-NSQIP database was collected from about 500 hospitals across the United States. Coding errors could potentially have occurred when data was collected by untrained clinical reviewersIn conclusion, both low and extremely high eGFR levels are associated with higher risk of post-operative pulmonary complications, but not non-pulmonary infectious complications, after laparoscopic surgery. Careful preoperative evaluation of cardiovascular and pulmonary functions and post-operative management may be necessary among patients with abnormal eGFR.52. Trained clinical reviewers prospectively collect the ACS-NSQIP data and validated data from medical records on preoperative risk factors, preoperative laboratory values, intraoperative variables, 30-day postoperative mortality, and 30-day morbidity on all patients undergoing major surgeries at participant institutions52. In 2013, the ACS-NSQIP database contained patient data for more than 2.9 million cases from 435 participant hospitals.The ACS-NSQIP is a risk adjusted, surgical outcomes-based program designed to measure and improve the quality of surgical careWe used the ACS-NSQIP database (2005 to 2013) to extract all patients who underwent laparoscopic surgeries with the following current procedural terminology (CPT) codes: cholecystectomy (47562–47564), gastroesophageal reflux , paraesophageal hernia (43280–43282), bariatric surgery , colectomy (44204–44208 and 44210–44212), inguinal hernia (49650 and 49651), incisional hernia (49652–49657), adrenalectomy (60650), appendectomy (44970 and 44979), splenectomy (38120), colostomy , exteriorization of intestine (44227), ileostomy (44186 and 44187), proctectomy , nephrectomy , prostatectomy (55866), hysterectomy , and myomectomy (58545 and 58546)  while patients with end-stage renal disease requiring dialysis were considered to have eGFR <30 mL/min/1.73 m2 irrespective of their eGFR values. BMI was also calculated for each patient using height and body weight. The association of these eGFR categories with each patient characteristic was evaluated by non-parametric trend test54. The primary outcome was PPCs defined as pneumonia, unplanned intubation, or on ventilator for over 48 hours within 30 days after surgery. Comorbid factors were obtained in preoperative period.The primary exposure of interest was kidney function expressed as eGFR. Preoperative serum creatinine concentrations, age, sex, and race were used to calculate eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula56.Patient characteristics are expressed as means ± SD, or percentages, as appropriate. Differences between included and excluded patients were compared by standardized differences due to the large sample size of this study57.Missing covariate data of serum concentrations of albumin was imputed using multiple imputation (MI) on the basis of the variables of age, sex, race, smoking, hematocrit, eGFR, and four comorbid conditions including chronic obstructive pulmonary disease, hypertension, diabetes, and chronic heart failure. We created five MI datasets using the multivariable normal model. In the MI analyses, the analysis of each dataset was carried out separately, and then five sets of estimates (odds ratios) are combined to generate a single set of estimates2 , and their relationship with the outcome was examined using restricted cubic spline functions with a reference at 90 mL/min/1.73 m2 and four knots at the 5th, 35th, 65th, 95th percentile of eGFR. Three levels of hierarchical adjustments were used as follows: (1) unadjusted models; (2) case-mix adjusted models that included age, sex, race and BMI; (3) fully adjusted models that included the above plus smoking, hematocrit, serum concentrations of albumin, and four comorbid conditions described above. Effect modifications against the association of eGFR with PPCs by age (≥60 or <60 years old), sex, race (white or non-white), diabetes, BMI (≥30 or <30 kg/m2), and surgery type  were examined by including each interaction term into the fully adjusted model.Multivariable logistic regression analyses were conducted to examine the association of kidney function with PPCs or non-pulmonary infectious complications using eGFR categories. Estimated GFR was also modeled as continuous variables, where patients with end-stage renal disease requiring dialysis were considered to have eGFR of 7.5 mL/min/1.73 mP values less than 0.05 were considered statistical significance.All analyses were carried out with STATA MP version 13.1 , and Supplemental Materials


This study aimed to compare clinical features and health-related quality of life (HRQoL) in the Chinese chronic kidney disease (CKD) 3 population and determined the necessity of the subdivision of CKD3 in Chinese patients with CKD.Participants with stage 3 CKD (18–74 years of age) were recruited at 39 clinical centers located at 28 cities in 22 provinces of China. The sociodemographic status, medical history, anthropometric measurements, and lifestyle behaviors were documented at entry, and blood and urine samples were collected. The estimated glomerular filtration rate was calculated using the CKD-EPI creatinine equation. The HRQoL was evaluated using the kidney disease quality-of-life instrument. A linear regression model was used to estimate the association between HRQoL and CKD stages (G3b vs G3a).P< 0.01). The HRQoL scores in “physical functioning (PCS)”, “symptoms and problems”, “effects of the kidney disease” and “burden of the kidney disease” were statistically significantly lower in the CKD G3b group compared with the CKD G3a group . Further, CKD G3b was associated with a lower score of physical functioning compared with G3a .The levels of intact parathyroid hormone, systolic blood pressure, uric acid, and high-density lipoprotein cholesterol were statistically significantly higher, whereas the levels of serum bicarbonate and hemoglobin were statistically significantly lower in the G3b group compared with the G3a group. Compared with CKD G3a group, the proportions of subjects with hyperuricemia and anemia were significantly higher in CKD G3b group  contains supplementary material, which is available to authorized users. Chronic kidney disease (CKD) is a dangerous, life-threatening illness defined by declining renal function that gradually progresses to end-stage renal disease (ESRD) . Globall2). Hence, subjects with CKD G3a were considered low-risk compared with patients with CKD G3b. This new classification was based on a meta-analysis performed in 45 cohorts involving over 1.5 million participants mainly from developed countries [In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) recommended reclassifying CKD , which iountries . Howeverountries , 9. Due Patients with CKD experience limited health-related quality of life (HRQoL). While the relationship between HRQoL and increased mortality in patients with ESRD is well-established, little is known about the association between early stage of CKD and HRQoL in China. The present study aims to compare clinical features and CKD-related quality of life in the Chinese CKD3 population and determine the necessity of the subdivision of CKD3 in Chinese patients with CKD.The design and methods of the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) study were published in detail previously , 11. TheThe baseline data included: detailed demographics; financial, sociological and health care related information; medical and family history including previously taken medications; and questionnaires related to quality of life, health behaviors, and physical activity. Height, weight, waist and hip width, resting blood pressure, and heart rate were collected. Laboratory parameters including complete blood count, serum uric acid, serum creatinine, serum cholesterol, serum calcium and phosphate, fasting blood glucose, high-sensitivity C-reactive protein (Hs-CRP), intact parathyroid hormone (iPTH), urine dipstick, albumin-to-creatinine ratio (ACR), 24-h urine protein, electrolytes, 12-lead surface electrocardiography, echocardiogram and lateral abdominal radiograph were collected for each participant.2) and G3b, eGFR: 30–44 mL/(min ⋅ 1.73 m2). The albumin-urine stage was categorized according to an analysis of a spot urine sample: A1 , ACR <30 mg/g creatinine; A2 , 30 ≤ ACR < 300 mg/g creatinine; or A3 , ACR ≥300 mg/g creatinine. The A1 stage was sectioned into groups by ACR as follows: A1a, ACR <10 mg/g creatinine and A1b, 10 ≤ ACR < 30 mg/g creatinine.The eGFR was determined with the chronic kidney disease epidemiology collaboration equation (CKD-EPI) for Chinese patients with CKD. CKD stage was determined using eGFR and ACR levels. The eGFR stage was graded as follows: G3a, eGFR: 45–59 mL/(min ⋅ 1.73 m−) concentration < 22 mmol/L. CKD-MBD was defined as a triad of interrelated abnormalities of serum biochemistry , bone, and vasculature  associated with CKD. Cardiovascular disease (CVD) was defined as the past occurrence of a myocardial infarction, admittance into a hospital for congestive heart failure, or severe cardiac arrhythmia incidents . Echocardiography showed left ventricular end-systolic diameter (LVESD) >50 mm and/or ejection fraction (EF) <50%.CKD-related complications that were assessed included hypertension, diabetes, hyperlipidemia, hyperuricemia, anemia, metabolic acidosis, CKD-mineral and bone disorders (CKD-MBD), and cardiovascular disease (CVD). Baseline hypertension was described as a systolic blood pressure > 140 mmHg; a diastolic blood pressure > 90 mmHg (at least three high readings taken within a week of each other); use of antihypertensive medications; or any self-reported history of hypertension. Patients were considered to have diabetes mellitus if they had a fasting glucose ≥7.0 mmol/L; an HbA1c ≥ 6.5%; took insulin or other anti-diabetic medications; or reported a history of diabetes. Hyperlipidemia was defined as a serum concentration with a total cholesterol level ≥ 5.7 mmol/L and an LDL-cholesterol level ≥ 3.6 mmol/L. Hyperuricemia was defined as a serum concentration of uric acid ≥420 μmol/L for men and ≥360 μmol/L for women. Anemia was determined in patients with a hemoglobin level < 120 g/L for men and <110 g/L for women. Metabolic acidosis was identified as a plasma bicarbonate (HCO3http://www.rand.org/content/dam/rand/pubs/papers/2006/P7994.pdf).The Mandarin Chinese version of kidney disease quality of life (KDQoL)-36 instrument, an globally accepted tool, was used for evaluating HRQoL of patients with CKD . The Mant test (continuous variables), Wilcoxon signed-rank test (variables with high skewness), and chi-square test . The trend analysis in the proportions among ordinal multiple categorical variables was examined using the Mantel–Haenszel test.Continuous variables were presented as means with standard deviations (SDs) except for serum total cholesterol, duration of CKD, ACR, and Hs-CRP. There were displayed as median (interquartile range) due to high skewness. Categorical variables were presented as counts and proportions. The statistical significance of differences in clinical characteristics was examined using Student The associations between CKD-related quality of life and CKD stages (G3b vs G3a) were analyzed using a linear regression model. The variables included in the regression model were gender , age , high school education (yes vs. no), current smoking (yes vs. no), CVD (yes vs. no), diabetes mellitus (yes vs. no), hyperuricemia (yes vs. no), high blood pressure (yes vs. no), albuminuria (A2 vs. A1 and A3 vs. A1), anemia (yes vs. no), CKD-MBD (yes vs. no), hyperlipidemia (yes vs. no), and metabolic acidosis (yes vs. no). Multiple imputations were performed to handle missing data to reduce the loss of information and account for the uncertainty of missing data in the regression analysis. The regression method was used to impute missing values in a normally distributed continuous variable, predictive mean matching method was used in a skewed distributed continuous variable, and logistic regression was used in a categorical variable with binary or ordinal responses. Twenty-five imputed data sets were generated with the number of iterations of 20. Each imputed dataset was analyzed separately, and then pooled results were obtained. The total percentage of individuals imputed was 32% (407/1277).P values were two sided. A P value <0.05 was deemed to be statistically significant. All analyses were performed using the software program the Statistical Analysis System (SAS) .All 2)): CKD G3a, with eGFR range 45–59 , and CKD G3b, with eGFR range 30–44 . As shown in Table P < 0.01). The levels of iPTH, systolic blood pressure, uric acid, and high-density lipoprotein (HDL) cholesterol were statistically significantly higher in the G3b group compared with the G3a group (P < 0.05). The levels of serum bicarbonate and hemoglobin were statistically significantly lower in the G3b group compared with the G3a group (P < 0.05). The proportions of subjects with hyperuricemia and anemia were statistically significantly higher in the CKD G3b group compared with the CKD G3a group . The age- and gender-adjusted prevalence of CKD-related complications in CKD G3b based on the age and gender distribution of CKD G3a was similar to the unadjusted result , but the difference was modest.A population of 1277 patients with CKD3 was recruited for the study. The mean age of patients with CKD3 was 51.68 ± 12.81 years, and 60.9% (813) were male. Demographic and laboratory parameters are presented in Table P for trend <0.01).Patients with CKD G3a and G3b were classified according to the levels of ACR, and the proportions of CKD-related complications, including hypertension, hyperlipidemia, hyperuricemia, anemia, metabolic acidosis, CKD-MBD, and CVD, were compared. A general trend of higher prevalence of hyperuricemia or anemia through increased ACR levels was observed when the G3b group compared with the G3a group . As shown in Table b vs G3a.The present study investigated clinical features and CKD-related quality of life in patients with CKD G3a and CKD G3b from the C-STRIDE Study in China. The findings could be summarized as follows: Significant differences were observed in many important clinical features, including the levels of iPTH, systolic blood pressure, uric acid, HDL cholesterol, serum bicarbonate, and hemoglobin, and the prevalence of hyperuricemia and anemia between the CKD G3b and CKD G3b groups. The HRQoL scores were statistically significantly higher in patients with CKD G3b group compared with scores of patients with CKD G3a. CKD G3b was associated with a lower score of SF12 physical functioning.2) was observed, which was consistent with the proposal to divide stage 3 into two stages [Stage 3 CKD is the first stage that can be identified from the serum creatinine test alone and accounts for the vast majority of people now being detected and labeled with CKD on general practice disease registers . In a nao stages .The results of this study confirmed different clinical features and HRQoL between patients with CKD G3a and G3b in China. Consistently with our findings, Ito et al., in a cross-sectional study of 2088 Japanese patients with type 2 diabetes mellitus, observed that the percentage of patients with diabetic retinopathy, neuropathy and other complications was statistically higher in patients with CKD G3b than in patients with CKD G3a . A groupPrevious results have shown that albuminuria correlates with the risk of adverse outcomes independently of eGFR . Thus, tFunctioning in everyday activities and well-being are essential when considering chronic disease heath care. Previous studies found that patients with CKD undergo a barrage of symptoms and significant impairments in the HRQoL . All HRQ2) are the threshold for the decrease in the HRQoL, especially in PCS [These findings suggested that Chinese patients with CKD3 experience an overall burden of symptoms, impaired physical well-being, and low HRQoL. Patients with CKD G3b had lower scores on all HRQoL dimensions compared with patients with CKD G3a although the differences were small (1 or 2 points) between the two groups. Similar to the findings of the present study, other studies have shown that the differences in scores were quite small but still significant in patients with the early stage of CKD, indicating that KDQoL subscales were sensitive to differences in the CKD stage , 25. Mory in PCS .The present study included the following limitations. Only relationship between variables, and not causal relationships, could be surmised due to the cross-sectional study design. Thus, longitudinal studies that consider qualitative evaluations ought to be conducted to seek a deeper understanding of the clinical difference in the prognosis of patients with CKD3 in China. When interpreting the results, it should be considered that the SF-12 used in the present study did not cover all measures in the HRQoL for patients with CKD, such as sleep, sexual and cognitive functioning.In the present study, modest differences existed in many important clinical features and KDQoL between patients with G3a and G3b CKD in a Chinese population. Also, a significant association between CKD3 subdivision of the disease and PCS was detected. Although further work is needed, we can speculate based on these results the CKD3 subdivision may be clinically meaningful for Chinese patients with CKD.


We aimed to investigate the relationship between myocardial performance index (MPI) and severity of coronary artery disease, as assessed by the Gensini score (GS), in patients with non-ST-segment elevation myocardial infarction (NSTEMI).Ninety patients with an initial diagnosis of NSTEMI were enrolled in our study. They were divided into tertiles according to the GS: low GS <19; mid GS > 19 and ≤ 96; and high GS > 96.The low-, mid- and high-GS groups included 24, 38 and 28 patients, respectively. Clinical features such as gender distribution; body mass index (BMI); prevalence of diabetes mellitus, hypertension and hyperlipidaemia; and smoking status were similar in the three groups. MPI and isovolumic relaxation time were significantly higher in the high-GS group than in the low- and mid-GS groups . Furthermore, the high-GS group had a significantly lower ejection fraction and ejection time . MPI was positively correlated with the GS , and multivariate regression analysis showed that MPI was an independent predictor of the GS .Patients with NSTEMI who fall within the high-risk group may be identified by means of a simple MPI measurement. Non-ST-segment elevation myocardial infarction (NSTEMI) is one of the leading causes of morbidity and mortality, and accounts for high healthcare costs worldwide. The Gensini scoring system, based on angiographic findings, is a valuable method for estimating the severity of coronary artery disease.3Doppler-derived myocardial performance index (MPI), also known as the Tei index, is a new diagnostic method and an alternative to ejection fraction (EF) measurements. This index reflects combined systolic and diastolic function and can be defined as the sum of the isovolumic contraction time and isovolumic relaxation time, divided by the ejection time, with a reported normal mean ± standard deviation (SD) value for the left ventricle of 0.39 ± 0.05.5MPI has been identified as a powerful independent predictor of death from all causes in patients with a recent acute myocardial infarction (AMI). In this study, we aimed to determine the association between the severity of coronary atherosclerosis as assessed by the GS and MPI in patients with NSTEMI.The study was a prospective, single-centre analysis of 90 consecutive patients with an initial diagnosis of NSTEMI. Patients who had valvular heart disease, cardiomyopathy, congestive heart failure, previous cardiac surgery, history of percutaneous coronary intervention, chronic kidney disease, hepatic dysfunction, acute respiratory illness, acute infection, chronic inflammatory disease, or complex congenital heart disease were excluded from the study. Patients who were diagnosed with peripheral arterial disease or a coronary artery disease (CAD) equivalent were also excluded.Data on demographics, established cardiovascular risk factors and medical history were obtained for each patient. Written informed consent was obtained from all subjects, and the investigation conformed to the principles outlined in the Decleration of Helsinki. The local ethics committee approved the study protocol.All patients underwent echocardiographic evaluation using a standard protocol on commercially available systems . Comprehensive two-dimensional (2D) and Doppler echocardiographic evaluation were performed with the patient in the left lateral decubitus position before coronary angiography.Transthoracic echocardiography was performed within the first 24 hours of initial diagnosis. While performing transthoracic echocardiography all patients were monitored by ECG, and echocardiographic parameters were measured with synchronisation by ECG.In the apical four-chamber view, mitral inflow velocities were measured with the Doppler sample placed at the tip of the valve leaflets, at the left ventricular outflow tract, and below the aortic valve plane. All measurements were averaged over three consecutive cardiac cycles.Isovolumic relaxation time (IVRT) was measured from closure of the aortic valve to opening of the mitral valve. Isovolumic contraction time (IVCT) was measured from closure of the mitral valve to opening of the aortic valve. Ejection time (ET) was measured from the opening to the closure of the aortic valve on the left ventricular outflow velocity profile. MPI was calculated as the sum of the IVRT and IVCT divided by the ET. Peak velocities of early (E) and late (A) filling were determined according to the mitral inflow velocity curve.All patients underwent selective coronary angiography via the Judkins technique . All angiograms were evaluated by two experienced interventional cardiologists blinded to the clinical baseline characteristics of the patients. In cases of discrepancy, the opinion of a third interventional cardiologist was obtained, and the final decision was made by consensus.The severity of coronary artery lesions was scored using a modified Gensini scoring system.1 In brief, coronary circulation was divided into eight proximal segments; the percentage by which each lesion in the proximal coronary circulation narrowed the artery was assessed according to the maximal narrowing of the diameter of the artery in all projections.The extent and severity of proximal coronary disease was assessed by assigning points to each lesion as follows: less than 50% stenosis of the luminal diameter, one point; 50 to 74% stenosis, two points; 75 to 99% stenosis, three points; and total obstruction, four points. The points for each lesion in the proximal coronary circulation were added, and a score for the severity of coronary atherosclerosis was obtained.According to the modified Gensini scoring system, the degree of coronary stenosis was classified as follows: mild lesions, one to six points; moderate lesions, seven to 13 points; and severe lesions, > 13 points. Patients were divided into tertiles according to the GS: low GS < 19; mid GS > 19 and ≤ 96; and high GS > 96 points.Statistical analysis was performed using SPSS  for Windows version 12 . Continuous variables are expressed as mean ± SD, and categorical variables are expressed as numbers and percentages. Continuous variables were compared between groups using one-way analysis of variance for normally distributed data, and the chi-squared test was used for nominal variables. Correlations between variables were calculated using the Pearson correlation coefficient. Multiple linear regression analysis was performed to identify the factors related to the GS. A p-value of < 0.05 was considered significant.Of the 90 patients included in this study, 24 were assigned to the low-GS group (26.7%), 38 to the mid-GS group (42.2%) and 28 to the high-GS group (31.1%). The demographic and clinical characteristics of the 90 patients with NSTEMI according to the GS are presented in The mean patient age was significantly higher in the high-GS group than in the low- and mid-GS groups (p = 0.035). However, the groups did not differ significantly with regard to gender; BMI; prevalence of diabetes mellitus, hypertension and hyperlipidaemia; and smoking status.The echocardiographic parameters of the groups are presented in Correlation analysis was performed to investigate the relationship between the MPI, age and GS. MPI was positively correlated with GS ∕ET.6MPI is rapidly increased in the early phase of MI and the degree of increment is associated with both mortality and morbidity.Sahin et al.11To the best of our knowledge, our study is the first to demonstrate the relationship between MPI and GS in patients with NSTEMI. In this study, the prevalence of risk factors did not differ among groups of patients classified according to the GS, and MPI was an independent predictor of GS.There are two treatment strategies for patients with NSTEMI: invasive and conservative. Determination of the number of diseased coronary arteries is important in the decision-making process when selecting the course of treatment. The severity of coronary artery disease is associated with mortality in patients with acute coronary syndromes.Our study has some limitations. First, assessment of coronary angiographic findings was limited to visual interpretation, with inter- and intra-observer variability. Second, the sample size was small and no calculations were made to ensure that the study was adequately powered.MPI was an independent predictor of GS in patients with NSTEMI. Patients with NSTEMI who are at high risk may be identified by a simple MPI measurement, which can be useful in the decision-making process for treatment selection and risk stratification.


Background. Inflammation plays a crucial role in the progression of chronic heart failure (CHF). Ivabradine is known to reduce the morbidity and mortality of patients with CHF under certain conditions. Beyond the reduction of heart rate, only limited knowledge exists about potential anti-inflammatory effects of ivabradine that might contribute to its benefit in CHF. Thus, the present study aimed to investigate the effect of ivabradine on systemic inflammation. Methods. In the present study, 33 patients with CHF due to dilated, ischemic, and hypertensive cardiomyopathy were treated with ivabradine according to the guidelines of the European Society of Cardiology (ESC). A number of circulating dendritic cells as well as inflammatory mediators were investigated using FACS analysis and ELISA, respectively, before and during ivabradine therapy. Results. Treatment with ivabradine resulted in a significant improvement of CHF symptoms as well as an increase in left ventricular ejection fraction. Moreover, ivabradine treatment led to a significant reduction of TNF-alpha (TNF-α) serum levels and a reconstitution of circulating dendritic cells which are known to be reduced in patients with CHF. Conclusion. We show that treatment with ivabradine in patients with CHF resulted in an improvement of HF symptoms and ejection fraction as well as a normalization of inflammatory mediators.  Chronic heart failure (CHF) has a high prevalence and results in increased morbidity and mortality in the western countries . Due to α, and C-reactive protein are increased in CHF [CHF is characterized by the interaction of diverse inflammatory mediators which are considered to contribute to disease progression . For exad in CHF , 4. Thesd in CHF . Furtherd in CHF , 4.According to current guidelines , the basIvabradine is a selective inhibitor of the hyperpolarisation activated cyclic-nucleotide-gated funny current I(f) present in cardiac pacemaker cells of the sinoatrial node . This inResearch investigating the mechanisms leading to the beneficial effects of ivabradine treatment showed that amongst the other effects, it prevents the alteration of endothelial cells. Luong et al. were able to demonstrate in a mouse model that ivabradine treatment suppresses the expression of proinflammatory vascular cell adhesion protein-1 (VCAM-1) and enhances the induction of anti-inflammatory endothelial nitric oxide synthase (eNOS) in the aorta. Luong et al. concluded from their experiments that ivabradine protects arteries by influencing wall shear stress and thus changing local mechanical conditions to trigger an anti-inflammatory response . Li et aIn humans, very limited knowledge exists about the effects of ivabradine on inflammatory mediators so far and the present study aimed to further elucidate this topic. Additionally, to the best of our knowledge, no study has investigated the effect of ivabradine on professional antigen-presenting cells such as dendritic cells yet. Dendritic cells are crucial in adaptive, T cell-derived immune responses. Recent studies have given evidence that the number of circulating myeloid dendritic cells is reduced in patients with stable CHF due to ischemic and nonischemic genesis , but alsThe patients were recruited in the present study in the outpatient clinic for heart failure of the Department of Cardiology of the University Hospital Jena, Germany. Consecutively, 50 patients were recruited into our study if they had stable CHF for more than one year and were under best medical treatment.Age > 18 yearsSinus rhythmHR > 75 bpmLV systolic dysfunction (LV-EF < 50%)Ischemic, dilated, or hypertensive stable CHF > 12 monthsStandard heart failure therapy with beta blockers, ACE-inhibitors, and aldosterone-receptor antagonists (NYHA III-IV) in an adequate dosageExclusion criteria were those which might interfere with the analysis in our study:Recent cardiac decompensation (<3 months)Recent acute coronary syndrome (<3 months)Acute or chronic infectionsMalignanciesAutoimmune diseases, for example, lupus erythematosus and rheumatoid arthritisHyperthyroidismMedication with immunosuppressive agentsAt baseline study visit, the patients were subdivided into three groups according to the etiology of CHF. The decision about the subdivision was made by the same physician who recruited the patients into the study. Patients which could not be subdivided into a subgroup since the etiology of chronic heart failure could not be clearly determined were not included in our study. Ischemic cardiomyopathy Dilated cardiomyopathy Hypertensive cardiomyopathy .Consecutively, 12 patients were subdivided in the ICM group, 11 in the DCM group, and 10 in the HCM group.The recruitment was performed by a physician of the outpatient clinic for heart failure who is specialist in internal medicine as well as cardiology and whose subspecialisation is the treatment of heart failure patients. The inclusion criteria were (except for HR and LV-EF) in concordance with those of the SHIFT study :Age > 18The study protocol was approved by the local ethics committee and conforms to the principles outlined in the “Declaration of Helsinki” (1964). All patients gave informed consent.Evaluation of heart failure symptoms and physical examinationhttp://www.familienmedizin-bremen.de/news/SF36_LQ_Fragebogen_01.pdf.)SF-36 questionnaire Echocardiography with analysis of ejection fraction (Simpson) and LVEDd (M-mode)Serological analysis of inflammatory parameters: TNF-alpha, hsCRP, and IL-6 using ELISACirculating myeloid and plasmacytoid DCs using flow cytometryDuring each study visit , the following analyses were performed:P < 0.05 was considered statistically significant. Parameters which were normally distributed were compared with the paired Student's t-test, otherwise by signed rank test.The statistical analysis used in this study was performed with SigmaPlot Software Version 12.0 (Systat Software Inc.). Data were tested for normal distribution using the Shapiro-Wilk test. All values are presented as mean ± standard error of the mean. During the present study, the effects of ivabradine were investigated in two steps: (1) effects of ivabradine in all patients irrespective of the etiology of heart failure; (2) effects of ivabradine on CHF with respect to its etiology in subgroup analyses.The SF-36 questionnaire provided us information about general health and daily activities reflecting the quality of life during ivabradine therapy compared to baseline visit. The questionnaire showed us significant improvements in general health and daily activities after 6 months of ivabradine treatment. In As expected, ivabradine led to a significant reduction of the heart rate from initially appr. 80 to 64 bpm after 3 months. There was however only a slight difference between the 3 and 6 months . It shouVia FACS analysis, a significant increase of circulating myeloid DCs was observed after ivabradine treatment  . Levels of hsCRP and IL-6 showed only a marginal but no significant reduction during ivabradine treatment  dropped out of the study due to rather unspecific side effects. We assume that this might be associated with negative expectations of the patients about possible side effects of a medication evaluated in a clinical trial. (4) The comparison of the different dosages of ivabradine is limited, since the dosage could be elevated only in two-thirds of the study patients after 3 months. (5) The study was not double-blinded; therefore a suggestive effect, particularly regarding the improvement of CHF symptoms, cannot be excluded.Despite all the improvements observed via ivabradine therapy, certain limitations of our present study have to be mentioned. (1) The number of patients recruited into our study and in particular in the subgroups were relatively small which reduces statistical power and might be responsible for the fact that we often got borderline statistical significant results. (2) The duration of the ivabradine therapy evaluated in this study was only 6 months, which is a relatively short time; hence long-term changes such as remodeling could not be evaluated. This might also explain the fact that, in echocardiography, we only observed significant changes in EF, but not, for instance, changes in LVEDd. (3) An uncommonly large proportion of patients  effect of ivabradine. However, the fact that the heart rate reduction was very similar in DCM, ICM, and HCM, whereas significant immunological changes were only observed in DCM and ICM, might be the first hint to a heart rate independent effect of ivabradine. Further studies are needed to evaluate this issue.