Predictive potential of various plasma inflammation-, angiogenesis-, and extracellular matrix remodeling-associated mediators for intra-amniotic inflammation and/or microbial invasion of the amniotic cavity in preterm labor.

PURPOSE: To determine whether various inflammatory-, angiogenic/anti-angiogenic-, and extracellular matrix remodeling-associated proteins in plasma, alone or in combination with conventional blood-based markers, can predict intra-amniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) in women with spontaneous preterm labor (PTL). METHODS: A total of 193 singleton pregnant women with PTL (23-33 weeks) were included in this retrospective cohort study. Plasma samples were obtained at the time of amniocentesis. Amniotic fluid (AF) was cultured for microorganism detection and consequent MIAC diagnosis. IL-6 levels were determined in AF and used to identify IAI (AF IL-6 ≥ 2.6 ng/mL). Endostatin, haptoglobin, IGFBP-2/3, LBP, M-CSF, MMP-2/8, pentraxin 3, PlGF, S100A8/A9, and VEGFR-1 levels were assayed in plasma samples by ELISA. CRP levels and neutrophil-to-lymphocyte ratio (NLR) were measured. RESULTS: Plasma LBP, MMP-8, and S100A8/A9 levels, CRP levels, and NLR were significantly higher, and plasma IGFBP-2 and MMP-2 levels were significantly lower in women with IAI/MIAC than in those without this condition, whereas no baseline variables differed significantly between the two groups. Using a stepwise regression analysis, a noninvasive prediction model for IAI/MIAC was developed, which included plasma LBP, MMP-2, and MMP-8 levels (area under the curve [AUC], 0.785). The AUC for this prediction model was significantly or borderline greater than that of any single factor included in the model. CONCLUSIONS: IGFBP-2, LBP, MMP-2, MMP-8, and S100A8/A9 may represent valuable plasma biomarkers for predicting IAI/MIAC in women with PTL. Combination of LBP, MMP-2, and MMP-8 expression data can significantly improve the predictive potential for IAI/MIAC.

Biomarkers of Pulmonary Hypertension Are Altered in Children with Down Syndrome and Pulmonary Hypertension.

OBJECTIVE: To evaluate the performance of pulmonary hypertension (PH) biomarkers in children with Down syndrome, an independent risk factor for PH, in whom biomarker performance may differ compared with other populations. STUDY DESIGN: Serum endostatin, interleukin (IL)-1 receptor 1 (ST2), galectin-3, N-terminal pro hormone B-natriuretic peptide (NT-proBNP), IL-6, and hepatoma-derived growth factor (HDGF) were measured in subjects with Down syndrome and PH (n = 29), subjects with Down syndrome and resolved PH (n = 13), subjects with Down syndrome without PH (n = 49), and subjects without Down syndrome with World Symposium on Pulmonary Hypertension group I pulmonary arterial hypertension (no Down syndrome PH group; n = 173). Each biomarker was assessed to discriminate PH in Down syndrome. A classification tree was created to distinguish PH from resolved PH and no PH in children with Down syndrome. RESULTS: Endostatin, galectin-3, HDGF, and ST2 were elevated in subjects with Down syndrome regardless of PH status. Not all markers differed between subjects with Down syndrome and PH and subjects with Down syndrome and resolved PH. NT-proBNP and IL-6 levels were similar in the Down syndrome with PH group and the no Down syndrome PH group. A classification tree identified NT-proBNP and galectin-3 as the best markers for sequentially distinguishing PH, resolved PH, and no PH in subjects with Down syndrome. CONCLUSIONS: Proteomic markers are used to improve the diagnosis and prognosis of PH but, as demonstrated here, can be altered in genetically unique populations such as individuals with Down syndrome. This further suggests that clinical biomarkers should be evaluated in unique groups with the development of population-specific nomograms.

Mature Adult Mice With Exercise-Preconditioning Show Better Recovery After Intracerebral Hemorrhage.

Background and Purpose: Physical exercise offers therapeutic potentials for several central nervous system disorders, including stroke and cardiovascular diseases. However, it is still mostly unknown whether and how exercise preconditioning affects the prognosis of intracerebral hemorrhage (ICH). In this study, we examined the effects of preconditioning on ICH pathology in mature adult mice using treadmill exercise. Methods: Male C57BL/6J (25-week old) mice were subjected to 6 weeks of treadmill exercise followed by ICH induction. Outcome measurements included various neurological function tests at multiple time points and the assessment of lesion volume at 8 days after ICH induction. In addition, plasma soluble factors and phagocytotic microglial numbers in the peri-lesion area were also measured to determine the mechanisms underlying the effects of exercise preconditioning. Results: The 6-week treadmill exercise preconditioning promoted recovery from ICH-induced neurological deficits in mice. In addition, mice with exercise preconditioning showed smaller lesion volumes and increased numbers of phagocytotic microglia. Furthermore, the levels of several soluble factors, including endostatin, IGFBP (insulin-like growth factor-binding protein)-2 and -3, MMP (matrix metallopeptidase)-9, osteopontin, and pentraxin-3, were increased in the plasma samples from ICH mice with exercise preconditioning compared with ICH mice without exercise. Conclusions: These results suggest that mice with exercise preconditioning may suffer less severe injury from hemorrhagic stroke, and therefore, a habit of physical exercise may improve brain health even in middle adulthood.

Elevated Endostatin Expression Is Regulated by the pIgA Immune Complex and Associated with Disease Severity of IgA Nephropathy.

BACKGROUND/AIMS: Renal vascular injury accounts for the poor outcomes of patients with IgA nephropathy (IgAN). In this study, we investigated whether endostatin, a potent inhibitor of angiogenesis, is associated with IgAN. METHODS: Serum endostatin levels were detected in patients with IgAN, disease controls, and healthy controls, and the correlation among endostatin and clinicopathologic manifestations, as well as prognosis in patients with IgAN, was analyzed. In addition, serum endostatin levels were compared in patients "before" and "after" treatment. Data on endostatin expression in the renal interstitium of patients with IgAN were downloaded and analyzed from the GSE35489 array in the GEO database. The poly-IgA1 (pIgA) immune complex is widely recognized as the "trigger" of IgAN initiation. pIgA in the plasma of patients was extracted and used to stimulate human glomerular endothelial cells (GECs). Endostatin, IL-6, and CXCL1 in the cell supernatant were detected by ELISA kits. RESULTS: We found that serum endostatin levels were significantly increased in patients with IgAN, as was endostatin expression in the renal interstitium. Patients with IgAN were divided into 2 groups according to the median value. The high endostatin expression group had significantly higher levels of serum creatinine and BUN and more severe tubular/interstitial damage. Moreover, patients with arteriolar injury and endothelial cell proliferation had higher serum endostatin levels. Patients with high serum endostatin levels had poor prognosis. According to the in vitro experiment, the GEC apoptosis rate and the supernatant levels of endostatin, IL-6, and CXCL1 were significantly increased following pIgA stimulation. CONCLUSION: Our study found that elevated endostatin expression was associated with disease severity and poor prognosis in patients with IgAN and can be upregulated by pIgA, but how it participates in the pathogenesis of IgAN deserves further exploration.

Assessment of selected angiogenesis markers in the serum of middle-aged male patients with plaque psoriasis.

Local angiogenesis accompanies inflammation in psoriasis-affected skin. To determine the serum concentrations of selected pro- and anti-angiogenic factors and their interrelationships in patients with plaque psoriasis. The study included 41 men diagnosed with psoriasis, aged 43.5 ± 11.7 years. The Psoriasis Area and Severity Index score was 23.4 ± 5.2 points. The control group consisted of 38 healthy, age-matched men. The levels of pro-angiogenic cytokines and angiogenesis inhibitors, including fibroblast growth factor 1 (FGF-1), vascular endothelial growth factor A (VEGF-A), endostatin, and angiostatin, were determined from the serum of patients and controls using enzyme-linked immunosorbent assays. Compared with controls, patients with psoriasis had a significantly lower concentration of FGF-1 (P = .01) but higher concentrations of endostatin (P = .04) and angiostatin (P = .02). The concentration of VEGF-A was also higher in patients with psoriasis but not significantly (P = .25). The concentration of C-reactive protein (CRP) was significantly higher among patients with psoriasis than controls (P < .0001). Among controls, CRP concentrations did not correlate significantly with the concentrations of FGF-1, VEGF-A, endostatin, or angiostatin. Among patients with psoriasis, CRP concentrations correlated moderately with the concentrations of VEGF-A (r = .35; P = .02) and angiostatin (r = .31; P = .04). The concentration of VEGF-A correlated positively with PASI (r = .05; P = .0009) and BSA values (r = .39; P = .01). Psoriasis is associated with an altered systemic balance between pro-angiogenic and anti-angiogenic factors. The increase in serum angiogenesis inhibitors may be associated with unfavorable changes in the development of coronary collateral circulation. However, the clinical significance of this has not yet been established.

Effect of Age and Acute Exercise on Circulating Angioregulatory Factors.

The balance of angiogenic factors, including vascular endothelial growth factor (VEGF), and angiostatic factors, like thrombospondin-1 (TSP-1) and endostatin, controls striated muscle angiogenic responses to exercise training. The effect of age on circulating levels of these factors following a bout of exercise is unclear. The authors hypothesized that older adults would have lower circulating VEGF but higher TSP-1 and endostatin after exercise compared with young adults. Ten young and nine older participants cycled for 45 min at 60% estimated HRmax. Serum [VEGF], [TSP-1], and [endostatin] obtained before (PREX), immediately after (POSTX0), and 3 hr after (POSTX3) exercise were analyzed. [VEGF] increased in older adults only from PREX to POSTX0 (p < .05). [TSP-1] increased in both age groups (p < .05). There was no effect of age or exercise on [endostatin]. In conclusion, immediately after exercise, both groups had a similar increase in [TSP-1], but [VEGF] increased in older adults only.

Endostatin Is an Independent Risk Factor of Graft Loss after Kidney Transplant.

BACKGROUND: Endostatin is a 20-kDa C-terminal fragment of collagen XVIII, known for its ability to inhibit the proliferation of capillary endothelial cells. Previous studies suggested that circulating endostatin independently predicts incident chronic kidney disease. However, the impact of endostatin on graft loss level in kidney transplant recipients (KTRs) remains unknown. METHODS: We conducted a prospective observational cohort study in 574 maintenance KTRs. Patients were followed for kidney graft loss and all-cause mortality during a median follow-up of 48 months. Serum-, and urine-samples and clinical data were collected at baseline. Serum Endostatin concentration was analyzed by an ELISA. RESULTS: Among 574 patients, 37 patients had graft loss and 62 patients died. For graft loss, the optimal cut-off value based on receiver operating characteristics analysis (area under the curve 0.79, 95% CI 0.71-0.86, p < 0.001) of endostatin was 147.3 pmol/L. Kaplan-Meier curves revealed that higher serum endostatin concentrations positively correlated with graft loss (p < 0.001). Multivariable Cox regression analyses showed that baseline endostatin concentrations were significantly associated with graft loss after adjusting for graft loss risk factors (adjusted hazard ratio [HR] 8.34; 95% CI 2.19-31.72; p = 0.002). The adjusted HRs for classical graft loss risk factors such as baseline estimated glomerular filtration rate and urinary protein excretion were lower (1.91 and 5.44, respectively). In contrast to graft loss, baseline endostatin concentrations were not associated with all-cause mortality. CONCLUSION: Increased serum endostatin at baseline is independently associated with the risk of graft loss in KTRs.

Blood biomarkers predictive of epilepsy after an acute stroke event.

OBJECTIVE: Blood biomarkers have not been widely investigated in poststroke epilepsy. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and analyze their association with the development of epilepsy at long term. METHODS: A panel of 14 blood biomarkers was evaluated in patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z-scores. Stroke and epilepsy-related variables were also assessed: stroke severity, determined by National Institutes of Health Stroke Scale (NIHSS) score, stroke type and cause, time from stroke to onset of late seizures, and type of seizure. Multiple Cox regression models were used to identify clinical variables and biomarkers independently associated with epilepsy. RESULTS: From a cohort of 1115 patients, 895 patients were included. Mean ± standard deviation (SD) age was 72.0 ± 13.1 years, and 57.8% of patients were men. Fifty-one patients (5.7%) developed late seizures, with a median time to onset of 232 days (interquartile range [IQR] 86-491). NIHSS score ≥8 (P < .001, hazard ratio [HR] 4.013, 95% confidence interval [CI] 2.123-7.586) and a history of early onset seizures (P < .001, HR 4.038, 95% CI 1.802-9.045) were factors independently associated with a risk of developing epilepsy. Independent blood biomarkers predictive of epilepsy were high endostatin levels >1.203 (P = .046, HR 4.300, 95% CI 1.028-17.996) and low levels of heat shock 70 kDa protein-8 (Hsc70) <2.496 (P = .006, HR 3.795, 95% CI 1.476-9.760) and S100B <1.364 (P = .001, HR 2.955, 95% CI 1.534-5.491). The risk of epilepsy when these biomarkers were combined increased to 17%. The area under the receiver-operating characteristic (ROC) curve of the predictive model was stronger when clinical variables were combined with blood biomarkers (74.3%, 95% CI 65.2%-83.3%) than when they were used alone (68.9%, 95% CI 60.3%-77.6%). SIGNIFICANCE: Downregulated S100B and Hsc70 and upregulated endostatin may assist in prediction of poststroke epilepsy and may provide additional information to clinical risk factors. In addition, these data are hypothesis-generating for the epileptogenic process.

Plasma endostatin predicts kidney outcomes in patients with type 2 diabetes.

Novel biomarkers are needed to predict kidney function decline in patients with type 2 diabetes, especially those with preserved glomerular filtration rate (GFR). There are limited data on the association of markers of endothelial dysfunction with longitudinal GFR decline. We used banked specimens from a nested case-control study in the Action to Control Cardiovascular Disease (ACCORD) trial (n=187 cases: 187 controls) and from a diverse contemporary cohort of type 2 diabetic patients from the Mount Sinai BioMe Biobank (n=871) to assess the association of plasma endostatin and kidney outcomes. We measured plasma endostatin at enrollment and examined its association with a composite kidney outcome of sustained 40% decline in estimated GFR or end-stage renal disease. Baseline plasma endostatin levels were higher in participants with the composite outcome. Each log2 increment in plasma endostatin was associated with approximately 2.5-fold higher risk of the kidney outcome (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI] 1.5-4.3 in ACCORD and adjusted hazard ratio [HR] 2.6; 95% CI 1.8-3.8 in BioMe). Participants in the highest vs. lowest quartile of plasma endostatin had approximately four-fold higher risk for the kidney outcome (adjusted OR 3.6; 95% CI 1.8-7.3 in ACCORD and adjusted HR 4.4; 95% CI 2.3-8.5 in BioMe). The AUC for the kidney outcome improved from 0.74 to 0.77 in BioMe with the addition of endostatin to a base clinical model. Plasma endostatin was strongly associated with kidney outcomes in type 2 diabetics with preserved eGFR and improved risk discrimination over traditional predictors.

Antiangiogenesis and medical therapy failure in intracranial atherosclerosis.

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and the one with the worst prognosis. In this study, we assessed the hypothesis that the balance of circulating pro- and antiangiogenic factors plays a role in the evolution of the disease and can be used as a potential marker for the disease course and a target for treatment. Seventy-four patients with severe ICAD were enrolled in this prospective observational study, medically optimized, and followed for 6 months. Thirteen pro- and eight antiangiogenic factors were measured in the participants' serum using a sandwich multiplex ELISA. Angiogenic profiles were calculated using principal component analysis. We tested the association between angiogenic profiles and recurring cerebrovascular events despite intensive medical therapy, disability at 6 months after enrollment, and angiographic neovascularization in patients who failed medical treatment and underwent indirect revascularization surgery. There is a strong association between a functionally antiangiogenic profile and recurrent stroke or TIA in patients with ICAD (OR = 7.2, CI 2.4-34.4). Multivariable regression analysis showed that this antiangiogenic profile was also associated with poor functional status after 6 months (p = 0.002), independent from other clinical features such as history of previous stroke, diabetes, and age. In patients who failed medical management and underwent indirect revascularization surgery, high endostatin and angiostatin levels were also associated with low angiographic neovascularization (p = 0.02). The results of this study point to the striking importance of antiangiogenesis as a determinant of ICAD patient prognosis and suggest a possible new target for therapy.

In systemic sclerosis, microvascular and hands digital arteries damage correlates with serum levels of endostatin.

OBJECTIVE: In SSc, vascular injury leads to endothelial dysfunction with reduced capillary blood flow and tissue hypoxia. In SSc, the angiogenesis is impaired and implicated in the microvascular damage. In severe vascular damage, VEGF is reduced and endostatin is increased. The aim of this study was to evaluate the correlation between endostatin serum levels and microvascular and digital arteries damage. METHODS: Seventeen patients with SSc were enrolled in this study. Serum endostatin levels were determined. All patients underwent a NVC, CDUS, and LDPI. RESULTS: The serum level of endostatin significantly (P < .05) increased with NVC progression damage. The mean perfusion significantly (P < .05) decreased with NVC progression damage. Multiple regression analysis showed a significant correlation between endostatin serum level and RI (r = .34, P < .05), PI (r = .60, P < .01), S/D ratio (r = .76, P < .0001), and mean perfusion (r = -.68, P < .001). Endostatin serum levels significantly (P < .05) increased with progression of CDUS damage. CONCLUSIONS: Increased serum endostatin levels are associated with digital vascular damage. In patients with SSc, endostatin is a marker of skin perfusion and digital arteries damage of hands.

Circulating Vascular Basement Membrane Fragments are Associated with the Diameter of the Abdominal Aorta and Their Expression Pattern is Altered in AAA Tissue.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterised by enhanced proteolytic activity, and extracellular matrix (ECM) remodelling in the vascular wall. Type IV and XVIII collagen/endostatin are structural proteins in vascular basement membrane (VBM), a specialised ECM structure. Here the association between plasma levels of these collagens with the aortic diameter and expansion rate is studied, and their expression in aortic tissue characterised. METHODS: This was a retrospective population based cohort study. Type IV and XVIII collagen/endostatin were analysed in plasma by ELISA assay in 615 men, divided into three groups based on the aortic diameter: 1) normal aorta ≤ 25 mm, 2) sub-aneurysmal aorta (SAA) 26-29 mm, and 3) AAA ≥ 30 mm. Follow up data were available for 159 men. The association between collagen levels and aortic diameter at baseline, and with the expansion rate at follow up were analysed in ordinal logistic regression and linear regression models, controlling for common confounding factors. Tissue expression of the collagens was analysed in normal aorta (n = 6) and AAA (n = 6) by immunofluorescence. RESULTS: Plasma levels of type XVIII collagen/endostatin (136 ng/mL [SD 29] in individuals with a normal aorta diameter, 154 ng/ml [SD 45] in SAA, and 162 ng/ml [SD 46] in AAA; p = .001) and type IV collagen (105 ng/mL [SD 42] normal aorta, 124 ng/ml [SD 46] SAA, and 127 ng/ml [SD 47] AAA; p = .037) were associated with a larger aortic diameter. A significant association was found between the baseline levels of type XVIII/endostatin and the aortic expansion rate (p = .035), but in the multivariable model, only the initial aortic diameter remained significantly associated with expansion (p = .005). Altered expression patterns of both collagens were observed in AAA tissue. CONCLUSION: Plasma levels of circulating type IV and XVIII collagen/endostatin increase with AAA diameter. The expression pattern of VBM proteins is altered in the aneurysm wall.

Prediction of organ involvement in systemic sclerosis by serum biomarkers and peripheral endothelial function.

OBJECTIVES: To identify prognostic factors among serum biomarkers and endothelial vasodilator function findings in patients with systemic sclerosis (SSc). METHODS: This is a clinical observational study. We assessed 60 consecutive SSc patients (44 limited cutaneous-type, 16 diffuse cutaneous-type). Circulating growth differentiation factor-15 (GDF-15), placenta growth factor (PlGF), endostatin, vascular endothelial growth factor (VEGF), and pentraxin 3 (PTX3) were measured by ELISA. Peripheral endothelial function was measured by forearm blood dilatation response to brachial artery occlusion using noninvasive plethysmography (EndoPAT2000), which is associated with nitric-oxide-dependent vasodilatation and yields a reactive hyperemia index (RHI). We evaluated whether abnormalities in these values were associated with type of SSc - namely, diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc) - or organ involvement including interstitial lung disease (ILD), digital ulcer (DU) and estimated right ventricular systolic pressure (RVSP) by echocardiography >30 mmHg. RESULTS: SSc patients showed significantly elevated serum GDF-15, PlGF, endostatin and VEGF but not PTX3 compared with controls. GDF-15 and PlGF were high in dcSSc patients. EndoPAT-RHI was low, and incidence of RVSP >30 mmHg was high in dcSSc. Multivariate analysis revealed that elevated GDF-15 was highly predictive of dcSSc, ILD or RVSP >30 mmHg. PlGF for DU was also found. Conversely, a low EndoPAT-RHI value was predictive of the presence of dcSSc, ILD or DU. CONCLUSIONS: This is the first study to inclusively investigate the relationships among biomarkers, EndoPAT-RHI and organ involvement in patients with SSc. Our data suggest a complex pathological progression of SSc through fibrotic impairment and microvascular damage.

Derivation and validation of plasma endostatin for predicting renal recovery from acute kidney injury: a prospective validation study.

BACKGROUND: Acute kidney injury (AKI) is associated with high morbidity and mortality in surgical patients. Nonrecovery from AKI may increase mortality and early risk stratification seems key to improving clinical outcomes. The aim of the current study was to explore and validate the value of endostatin for predicting failure to recover from AKI. METHODS: We conducted a prospective cohort study of 198 patients without known chronic kidney disease who underwent noncardiac major surgery and developed new-onset AKI in the first 48 h after admission to the ICU. The biomarkers of plasma endostatin, neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C were detected immediately after AKI diagnosis. The primary endpoint was nonrecovery from AKI (within 7 days). Cutoff values of the biomarkers for predicting nonrecovery were determined in a derivation cohort (105 AKI patients). Predictive accuracy was then analyzed in a validation cohort (93 AKI patients). RESULTS: Seventy-six of 198 (38.4%) patients failed to recover from AKI onset, with 41 in the derivation cohort and 35 in the validation cohort. Compared with NGAL and cystatin C, endostatin showed a better prediction for nonrecovery, with an area under the receiver operating characteristic curve (AUC) of 0.776 (95% confidence interval (CI) 0.654-0.892, p < 0.001) and an optimal cutoff value of 63.7 ng/ml. The predictive ability for nonrecovery was greatly improved by the prediction model combining endostatin with clinical risk factors of Sequential Organ Failure Assessment (SOFA) score and AKI classification, with an AUC of 0.887 (95% CI 0.766-0.958, p < 0.001). The value of the endostatin-clinical risk prediction model was superior to the NGAL-clinical risk and cystatin C-clinical risk prediction models in predicting failure to recover from AKI, which was supported by net reclassification improvement and integrated discrimination improvement. Further, the endostatin-clinical risk prediction model achieved sensitivity and specificity of 94.6% (76.8-99.1) and 72.7% (57.2-85.0), respectively, when validated in the validation cohort. CONCLUSION: Plasma endostatin shows a useful value for predicting failure to recover from AKI. The predictive ability can be greatly improved when endostatin is combined with the SOFA score and AKI classification.

The association between circulating endostatin levels and incident myocardial infarction.

OBJECTIVE: Increased levels of circulating endostatin have been observed in patients with prevalent ischemic heart disease. However, the association between circulating endostatin, and incident myocardial infarction (MI) is less studied. Our main aim was to study the association between circulating endostatin and incident MI in the community adjusted for established cardiovascular risk factors in men and women. DESIGN: Circulating endostatin was measured in a nested case control study based on three large community-based Swedish cohorts, including 533 MI cases, and 1003 age-, sex- and cohort-matched controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with adjustments for established cardiovascular risk factors. RESULTS: Higher endostatin was associated with a higher incidence of MI independently of established cardiovascular risk factors (OR 1.19, 95% CI 1.03-1.37, p = .02), but this association was abolished after additional adjustment for C-reactive protein. Sex-stratified analyses suggest that the association was substantially stronger in women as compared to men. CONCLUSIONS: In our community based sample, higher endostatin predicted incident myocardial infarction predominantly in women but not independently of CRP. Thus, our findings do not support a broad utility of endostatin measurements for the prediction of incident myocardial infarction in clinical practice.

Circulating endostatin and the incidence of heart failure.

OBJECTIVE: Circulating levels of endostatin are elevated in many underlying conditions leading to heart failure such as hypertension, diabetes, chronic kidney disease and ischemic heart disease. Yet, the association between endostatin and the incidence of heart failure has not been reported previously in the community. DESIGN: We investigated the longitudinal association between serum endostatin levels and incident heart failure in two community-based cohorts of elderly: Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 966; mean age 70 years, 51% women, 81 events, mean follow-up 10 years) and Uppsala Longitudinal Study of Adult Men (ULSAM, n = 747 men; mean age 78 years, 98 heart failure events, mean follow-up 8 years). We also investigated the cross-sectional association between endostatin and echocardiographic left ventricular systolic function and diastolic function (ejection fraction and E/A-ratio, respectively). RESULTS: Higher serum endostatin was associated with an increased risk for heart failure in both cohorts after adjustment for established heart failure risk factors, glomerular filtration rate and N-terminal pro-brain natriuretic peptide (NT-proBNP) (PIVUS: multivariable hazard ratio (HR) per 1-standard deviation (SD) increase, HR 1.46 (95%CI, 1.17-1.82, p < .001); ULSAM: HR 1.29 (95%CI, 1.00-1.68, p < .05). In cross-sectional analyses at baseline, higher endostatin was significantly associated with both worsened left ventricular systolic and diastolic function in both cohorts. Conclusion Higher serum endostatin was associated with left ventricular dysfunction and an increased heart failure risk in two community-based cohorts of elderly. Our findings encourage further experimental studies that investigate the role of endostatin in the development of heart failure.

The association between circulating endostatin and a disturbed circadian blood pressure pattern in patients with type 2 diabetes.

BACKGROUND: Endostatin, cleaved from collagen XVIII in the extracellular matrix, is a promising circulating biomarker for cardiovascular damage. It possesses anti-angiogenic and anti-fibrotic functions and has even been suggested to be involved in blood pressure regulation. Less is known if endostatin levels relate to circadian blood pressure patterns. In the present paper we studied the association between circulating levels of endostatin and nocturnal dipping in blood pressure. METHODS: We used the CARDIPP-study, a cohort of middle aged, type 2 diabetics (n = 593, 32% women), with data on both 24-hour and office blood pressure, serum-endostatin, cardiovascular risk factors, and incident major cardiovascular events. Nocturnal dipping was defined as a >10% difference between day- and night-time blood pressures. RESULTS: Two-hundred four participants (34%) were classified as non-dippers. The mean endostatin levels were significantly higher in non-dippers compared to dippers (mean ± standard deviation: 62.6 ± 1.8 µg/l vs. 58.7 ± 1.6 µg/l, respectively, p = .007). Higher serum levels of endostatin were associated with a diminished decline in nocturnal blood pressure adjusted for age, sex, HbA1c, mean systolic day blood pressure, hypertension treatment, glomerular filtration rate, and prevalent cardiovascular disease (regression coefficient per SD increase of endostatin -0.01, 95% CI, -0.02-(-0.001), p = .03). Structural equation modelling analyses suggest that endostatin mediates 7% of the association between non-dipping and major cardiovascular events. CONCLUSION: We found an independent association between higher circulating levels of endostatin and a reduced difference between day- and night-time systolic blood pressure in patients with type 2 diabetes. Yet endostatin mediated only a small portion of the association between non-dipping and cardiovascular events arguing against a clinical utility of our findings.

Serum level of endostatin and digital ulcers in systemic sclerosis patients.

Patients with systemic sclerosis (SSc) are at a high risk of the development of ischaemic digital ulcers (DUs) that can be complicated with infections, gangrene, and osteomyelitis. The aim of this study is to evaluate the role of endostatin in scleroderma DUs.In total, 90 SSc patients were enrolled in this study. Serum endostatin levels and DU assessment were determined in all SSc patients. The serum levels of endostatin significantly increased with progression of capillaroscopic damage (P < .01). The serum levels of endostatin are significantly (P < .05) higher in SSc patients with new DUs than in SSc patients without new DUs (127 ± 31.1 ng/mL vs 116.3 ± 39.7 ng/mL). The Receiver Operating Characteristic (ROC) curves demonstrated good accuracy of new DU prediction for the serum level of endostatin (0.70, P < .01 [95% confidence interval (CI) 0.59-0.81]). Using a cut-off value of 116 ng/mL, the odds ratio was 2.609 (CI 1.075-6.330, P < .05). The serum levels of endostatin are significantly (P < .01) higher in SSc patients with infected DUs than in SSc patients without infected DUs (139.2 [114.6-340.91] ng/mL vs 117.5 [64.3-163.9] ng/mL). Serum levels of endostatin are higher in patients with DUs, especially in those with infected DUs.

EFFECT OF OBESITY PRESENCE ON INSULIN-LIKE GROWTH FACTOR-1 AND ENDOSTATIN IN PATIENTS WITH MYOCARDIAL INFARCTION.

Aim of the study - to study the markers of angiogenesis‒IGF-1 and endostatin ‒ in patients with acute myocardial infarction according to the presence or absence of obesity. The study involved 105 patients with acute myocardial infarction (MI) with concomitant obesity who were treated in the infarctional department (mean age 64.6±7.4 years), 55 of them ‒ with acute MI with comorbidant obesity and 60 patients ‒ with acute MI without obesity. The groups were comparable by sex and age. The control group consisted of 20 healthy persons of corresponding age and sex. In obese and non-obese patients with MI the levels of IGF-1 were statistically significantly higher than those of persons in the control group (p<0.05). The levels of IGF-1 in acute MI with obesity were statistically significantly higher than in the serum of patients with MI without obesity (180.64±12.2 ng/ml and 128.76±8.1 ng/ml, accordingly, p<0.05). Patients with acute MI showed increased IGF-1 and endostatin in comparison with the controls. The presence of obesity in MI was accompanied by an increased IGF-1 and decreased endostatin as compared to patients with MI. In patients with MI and obesity, high activity of IGF-1 was accompanied by high levels of proaterogenic lipids with reduced volumes and thickening of the interventricular wall of the left ventricle. Unlike IGF-1 hyperendostatinemia was associated with left ventricle dilation.

Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study.

BACKGROUND AND PURPOSE: Stroke diagnosis could be challenging in the acute phase. We aimed to develop a blood-based diagnostic tool to differentiate between real strokes and stroke mimics and between ischemic and hemorrhagic strokes in the hyperacute phase. METHODS: The Stroke-Chip was a prospective, observational, multicenter study, conducted at 6 Stroke Centers in Catalonia. Consecutive patients with suspected stroke were enrolled within the first 6 hours after symptom onset, and blood samples were drawn immediately after admission. A 21-biomarker panel selected among previous results and from the literature was measured by immunoassays. Outcomes were differentiation between real strokes and stroke mimics and between ischemic and hemorrhagic strokes. Predictive models were developed by combining biomarkers and clinical variables in logistic regression models. Accuracy was evaluated with receiver operating characteristic curves. RESULTS: From August 2012 to December 2013, 1308 patients were included (71.9% ischemic, 14.8% stroke mimics, and 13.3% hemorrhagic). For stroke versus stroke mimics comparison, no biomarker resulted included in the logistic regression model, but it was only integrated by clinical variables, with a predictive accuracy of 80.8%. For ischemic versus hemorrhagic strokes comparison, NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) >4.9 (odds ratio, 2.40; 95% confidence interval, 1.55-3.71; P<0.0001) and endostatin >4.7 (odds ratio, 2.02; 95% confidence interval, 1.19-3.45; P=0.010), together with age, sex, blood pressure, stroke severity, atrial fibrillation, and hypertension, were included in the model. Predictive accuracy was 80.6%. CONCLUSIONS: The studied biomarkers were not sufficient for an accurate differential diagnosis of stroke in the hyperacute setting. Additional discovery of new biomarkers and improvement on laboratory techniques seem necessary for achieving a molecular diagnosis of stroke.