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Identifying individuals at elevated risk for mortality, especially from cardiovascular disease, may help guide testing and treatment. Risk factors for mortality differ by sex and race. We investigated the association of growth hormone (GH) with all-cause and cardiovascular mortality in a racially diverse cohort in the United States.Among an age, sex and race stratified subgroup of 1046 Black and White participants from the REasons for Geographic And Racial Disparities in Stroke (REGARDS) study, 881 had GH available; values were logThe mean age was 67.4 years, 51.1% were women, and 50.2% were Black participants. The median GH was 280 (interquartile range 79-838) ng/L. There were 237 deaths and 74 cardiovascular deaths over a mean of 8.0 years. In multivariable Cox analysis, GH was associated with higher risk of all-cause mortality per doubling (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.09-1.25) and cardiovascular mortality (HR 1.21, 95% CI 1.06-1.37). The association did not differ by sex or race (interaction p 0.05). The addition of GH to a model of clinical variables significantly improved the C-index compared to clinical model alone for all-cause and cardiovascular death.Higher fasting GH was associated with higher risk of all-cause and cardiovascular mortality and improved risk prediction, regardless of sex or race.

Background Cardiovascular disease (CVD) is an important cause of morbidity and mortality in breast cancer survivors. Effective screening modalities to identify CVD risk are lacking in this population. Adrenomedullin (ADM) has been suggested as a biomarker for subclinical cardiac dysfunction in the general population. Levels of ADM have been proven to be responsive to lifestyle changes that lead to improved cardiovascular health. As BRCA1/2 mutation carriers are deemed to be at an increased risk for CVD, the aim of this study was to examine plasma ADM levels in a cohort of BRCA mutation carriers and to assess their association with cardiovascular risk factors.Methods Plasma ADM concentrations were measured in 292 female BRCA1/2 mutation carriers with and without a history of breast cancer. Subjects were classified into high versus low ADM levels based on the median ADM level in the entire cohort (13.8 pg/mL). Logistic regression models were used to estimate the odds ratios (OR) of having elevated ADM levels by several cardiovascular risk factors.Results Of all women (median age: 43 years), 57.5% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was three years (range: 0 – 32 years). Women presenting with metabolic syndrome had 22-fold increased odds of having elevated ADM levels (p Conclusions This is the first study in BRCA mutation carriers that has linked circulating ADM levels to traditional cardiovascular risk factors. The long-term clinical implications of these findings are yet to be determined.

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Background: Tumor development requires angiogenesis, and antiangiogenesis has been introduced in the treatment of cancer patients; however, how the cardiovascular phenotype correlates with cancer risk remains ill-defined. Here, we hypothesized that vasoactive peptides previously implicated in angiogenesis regulation predict long-term cancer risk.Methods: We measured midregional proatrial natriuretic peptide (MR-proANP), proadrenomedullin (MR-proADM), and C-terminal preprovasopressin (copeptin) in fasting plasma from participants of the Malmö Diet and Cancer Study that were free from cancer prior to the baseline exam in 1991 to 1994 (1,768 males and 2,293 females). We used Cox proportional hazards models to determine the time to first cancer event in relation to baseline levels of vasoactive peptides during a median follow-up of 15 years.Results: First cancer events occurred in 366 males and in 368 females. In males, one SD increase of MR-proANP, copeptin, and MR-proADM was independently related to incident cancer [HR (95% CI)] by 0.85 (0.74–0.96), P = 0.012; 1.17 (1.04–1.32), P = 0.009; and 1.12 (0.99–1.26), P = 0.065, respectively, and a summed biomarker score identified an almost 2-fold difference in cancer risk between the top and bottom quartile (P < 0.001). In younger males, the biomarker score identified a more than 3-fold increase in risk between the top and bottom quartile (P < 0.001). Among females, we found no relationship between biomarkers and cancer incidence.Conclusions: Our data suggest that vasoactive peptide biomarkers predict cancer risk in males, particularly in younger males.Impact: Our findings may have implications for cancer risk prediction and present novel, potentially drug modifiable, mechanisms underlying cancer development. Cancer Epidemiol Biomarkers Prev; 21(3); 513–22. ©2012 AACR.

BackgroundGermlineBRCA1/2mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)—involved in tumorigenesis and obesity-related diseases—are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC.MethodsThe stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors.ResultsAt SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L,p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = − 0.435; CI − 0.653 to − 0.151;p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061–0.544;p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: − 37.9,p = 0.097/0.080) in multivariate analysis.ConclusionOur results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.

Critical care 25(1), 61 (2021). doi:10.1186/s13054-021-03471-2, Published by BioMed Centra, London

BACKGROUND Kidney failure occurs frequently and is associated with high mortality during sepsis. Proenkephalin (PENK) is an emerging biomarker of kidney function. We explored whether PENK levels could predict severity, organ failure, and mortality in septic patients. METHODS We measured the PENK level in the plasma of 215 septic patients using the sphingotest penKid assay (Sphingotec GmbH, Hennigsdorf, Germany). This was analyzed in terms of sepsis severity, vasopressor use, 30-day mortality, sequential organ failure assessment (SOFA) renal subscore, the Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (CKD-EPI eGFR) categories, and renal replacement therapy (RRT) requirement. RESULTS The PENK levels were significantly higher in patients with septic shock, vasopressor use, and non-survivors than in patients with solitary sepsis, no vasopressor use, and survivors, respectively (P=0.02, P=0.007, P

The tridecapeptide neurotensin has been implicated in the pathogenesis of cardiometabolic disease. Its stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN), has been associated with composite cardiovascular outcomes including coronary heart disease (CHD) and stroke. The exclusive association of pro-NT/NMN with ischemic stroke has not been evaluated. We conducted a prospective case-cohort study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. From 2003 to 2007, REGARDS enrolled 30,239 white or black adults aged ⩾ 45 years. Baseline fasting pro-NT/NMN was measured by immunoassay in the analytic sample including 448 incident ischemic stroke cases and 818 random cohort sample participants. A total of 464 ischemic strokes occurred. Risk of stroke was assessed with a Cox proportional-hazards model incorporating demographic covariates and a second adding stroke risk factors. Increased pro-NT/NMN was associated with ischemic stroke in the demographic model overall (hazard ratio (HR) per standard deviation (SD) pro-NT/NMN 1.16, 95% confidence interval (CI) 1.01–1.33) and in men (HR per SD pro-NT/NMN 1.25, 95% CI 1.04–1.50); HRs were attenuated in the risk factor model. Pre-existing diabetes mellitus and CHD were the largest confounders of ischemic stroke risk, each accounting for an estimated 19% of the association of pro-NT/NMN with ischemic stroke observed in the demographic model. There were no significant interactions of race or sex with pro-NT/NMN. Further research on associations of pro-NT/NMN with stroke risk factors such as diabetes mellitus is indicated.

Background The neuropeptide neurotensin (NT) has been linked to cardiometabolic disease. Cardiovascular risk factors are being recognized as risk factors for cognitive impairment. Objective To examine the association of the stable precursor of NT, pro-neurotensin/neuromedin N (pro-NT/NMN), with incident cognitive impairment (ICI). Methods We conducted a prospective nested case-control study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. In 2003-2007, REGARDS enrolled 30,239 Black and White adults aged ≥45 years. ICI was identified using a 3-test cognitive battery administered biannually. Baseline pro-NT/NMN was measured by immunoassay in 393 cases of ICI and 490 controls after 3.4 years follow up. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race, age, and sex differences were studied with stratified models and interaction testing. Results Pro-NT/NMN was higher in Black participants and those with hypertension and diabetes. Women with a 4th versus 1st-quartile pro-NT/NMN had 2.28-fold increased odds of ICI (95% CI 1.08-4.78) after adjusting for risk factors and incident stroke. There was no association of higher pro-NT/NMN quartiles with ICI in the overall group or men. There were no race or age differences in associations. Conclusion In this biracial population-based study, elevated systemic pro-NT/NMN was associated with more than doubled risk of ICI in women but not men. Others reported sex-specific associations in women for cardiovascular mortality and diabetes with higher pro-NT/NMN, supporting a role for future research on sex differences in the neurotensinergic system.

The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi.Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up.Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7-37.5] vs. 50.8 [IQR: 36.5-78.1] vs. 54.6 [IQR: 42.0-97.1] vs. 57.4 [IQR: 48.5-161.6]; MR-proADM [nmol/L]: 0.87 [IQR: 0.64-1.12] vs. 1.25 [IQR: 0.93-1.79] vs. 1.42 [IQR: 0.95-1.90] vs. 1.60 [IQR: 1.12-2.46], P.0001 for all). The ratios bio-ADM/MR-proADM and BNP/NT-proBNP increased during ARNi-therapy proving improved availability of bioactive peptides. The proportional increase of bio-ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin-angiotensin system blocker therapy, i.e. ACEi or ARB (P.05 for all), indicating that activation of the ADM-axis arises particularly from NEPinhibition.The significant increase of MR-proADM and bio-ADM together with an elevated bioADM/MR-proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM-axis represents a so far unrecognized effect of ARNi.

BACKGROUND: Risk factors for cardiovascular disease (CVD) and breast cancer overlap substantially. Identification of the underlying mechanisms associated with this co-occurrence is of great public health importance. Adrenomedullin (AM) is an almost ubiquitously expressed peptide with vasodilator and natriuretic properties. Previous studies have observed a link between high AM levels and worse prognosis in patients with myocardial infarction and heart failure, indicating a crucial role in the pathophysiology of CVD. Moreover, AM is expressed in 80% of sporadic breast cancers, and the degree of expression is associated with tumour growth, local tumour progression and bone metastases. High plasma AM levels are linked to arterial hypertension, diabetes, obesity and smoking. Preliminary evidence suggests that AM influences the osteoclast differentiation mediated by Receptor Activator of NF-κB Ligand (RANKL), an important signalling pathway in BRCA1-associated breast tumorigenesis. OBJECTIVE: Besides an elevated risk of breast cancer, recent studies revealed that BRCA mutation carriers are potentially at higher cardiovascular risk. The value of AM in BRCA mutation carriers is unknown. The aim of this study was to examine circulating plasma AM levels in BRCA mutation carriers and assess their association with modifiable risk factors. METHODS: AM concentrations were measured in 290 BRCA1/2 mutation carriers without overt CVD, participating in the randomized controlled LIBRE study (NCT numbers: NCT02087592, NCT02516540), by an immunoassay (sphingotest® bio-ADM®). Subjects were classified into high versus low AM levels based on the median plasma AM level in the entire cohort (13.9 pg/mL). Univariate logistic regression models were used to estimate the odds ratio (OR) of having high circulating AM levels by metabolic syndrome (MetS), cardiorespiratory fitness (CRF), body mass index (BMI), circulating insulin, smoking, current age, BRCA mutation status (BRCA1 or BRCA2) and previous diagnosis of breast cancer. MetS was defined in accordance with the criteria of the Third Adult Treatment Panel (ATP III). CRF was measured by peak oxygen uptake (VO2peak) assessed on a cycle ergometer via standardized cardiopulmonary exercise testing. RESULTS: Of all women (median age: 43 years), 57.9% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was 3 years (range: 0-32 years). Women fulfilling the criteria of metabolic syndrome had over 17 times higher odds of having increased AM levels compared to those who did not meet the criteria (OR = 17.49, p < 0.001). Moreover, high AM levels were associated with lower VO2peak (OR = 0.91, p < 0.001), higher BMI (OR = 1.24, p < 0.001) and higher circulating insulin levels (OR = 1.1, p < 0.001). AM levels were higher in women who have ever smoked (OR = 1.73, p = 0.022), and AM levels increased with the number of pack-years smoked (OR = 1.03, p = 0.06). AM levels were not associated with age (p = 0.143), BRCA mutation status (p = 0.51) or previous diagnosis of breast cancer (p = 0.48). After adjustment for confounding variables, we observed that MetS (OR = 10.78, p = 0.002) and VO2peak (OR = 0.92, p = 0.001) were independent determinants of circulating AM. CONCLUSIONS: This is the first study in BRCA mutation carriers that has linked circulating AM levels to MetS and CRF. The long-term clinical implications of these findings are yet to be determined. Conflict of interest: The study is funded by the German Cancer Aid (Deutsche Krebshilfe) within the Priority Program “Primary Prevention of Cancer” (Grant no. 110013). JS and OH are employed by Sphingotec GmbH, a company having patent rights in and commercializing the bio-ADM assay. SG and MK received grants from Sphingotec GmbH. JL, MYD, MB and MH have nothing to disclose. Citation Format: Jacqueline Lammert, Sabine Grill, Maryam Yahiaoui-Doktor, Maryam Basrai, Joachim Struck, Oliver Hartmann, Martin Halle, Marion Kiechle. High circulating levels of adrenomedullin are associated with metabolic syndrome and low cardiorespiratory fitness in BRCA1 and BRCA2 mutation carriers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-16.

Objectives Acute kidney injury (AKI) is common in critically ill children, but current biomarkers are suboptimal. Proenkephalin A 119–159 (PENK) is a promising new biomarker for AKI in adults, but pediatric data is lacking. We determined PENK reference intervals for healthy children, crucial for clinical implementation, and explored concentrations in critically ill infants aged under 1 year. Methods Observational cohort study in healthy infants and critically ill children aged 0–1 years. Reference values were determined using generalized additive models. Plasma PENK concentrations between healthy children and critically ill children with and without AKI, were compared using linear mixed modelling. The performance of PENK as AKI biomarker was compared to cystatin C (CysC) and β-trace protein (BTP) using receiver-operating-characteristic (ROC) analysis. Results PENK concentrations in 100 healthy infants were stable during the first year of life (median 517.3 pmol/L). Median PENK concentrations in 91 critically ill children, were significantly higher in those with AKI (n=40) (KDIGO Stage 1 507.9 pmol/L, Stage 2 704.0 pmol/L, Stage 3 930.5 pmol/L) than non-AKI patients (n=51, 432.2 pmol/L) (p Conclusions PENK reference values are much higher in young infants than adults, but clearly discriminate between children with and without AKI, with comparable or better performance than CysC and BTP. Our results illustrate the importance of establishing age-normalized reference values and indicate PENK as a promising pediatric AKI biomarker.

Aims: Proneurotensin is a strong predictor of cardiometabolic disease, however, the effect of lifestyle change on proneurotensin has not been investigated. Middle Eastern (ME) immigrants represent the largest and fastest growing minority population in Europe and are a high-risk population for obesity and type 2 diabetes. In this randomised controlled lifestyle intervention (RCT) addressing ME immigrants to Sweden where weight-loss was previously studied as the main outcome, as a secondary analysis we aimed to study change in proneurotensin during follow-up and if baseline proneurotensin predicted weight loss.Methods: Immigrants from the Middle East at high risk for type 2 diabetes were invited to participate in this RCT adapted lifestyle intervention of four months’ duration. The intervention group (N=48) received a culturally adapted lifestyle intervention comprising seven group sessions and a cooking class addressing healthier diet and increased physical activity. The control group (N=44) received treatment as usual with information to improve lifestyle habits on their own. Data assessed using mixed effects regression.Outcomes: Primary outcome; change in proneurotensin. Secondary outcome; change in BMI in relation to baseline plasma concentration of proneurotensin.Results: During the four months follow up, weight was significantly reduced in the intervention (-2.5 kg) compared to the control group (0.8 kg) (β -0.12, 95% CI -0.24 to -0.01, P=0.028). Proneurotensin increased to a significantly greater extent in the intervention compared to the control group during follow up (28.2 vs 3.5 pmol/L) (β 11.4; 4.8 to 18.02, PP=0.041).Conclusion: In consistence with data from surgical weight loss, this RCT paradoxically shows increased levels of proneurotensin during a multifactorial lifestyle intervention resulting in weight loss. Long term studies of proneurotensin following weight loss are needed.Trial registration: This study is a secondary analysis of the RCT trial registered at www.clinicaltrials.gov NCT01420198 (date of registration Aug 19th 2011).The performance and results of this trial conform to the CONSORT 2010 guidelines.

Background Proenkephalin (PENK), a stable endogenous opioid biomarker related to renal function, has prognostic utility in acute and chronic heart failure. We investigated the prognostic utility of PENK in heart failure with preserved ejection fraction (HFpEF), and its relationship to renal function, Body Mass Index (BMI), and imaging measures of diastolic dysfunction. Methods In this multicentre study, PENK was measured in 522 HFpEF patients (ejection fraction > 50%, 253 male, mean age 76.13 ± 10.73 years) and compared to 47 age and sex-matched controls. The primary endpoint was 2-years composite of all-cause mortality and/or heart failure rehospitalisation (HF). A subset (n = 163) received detailed imaging studies. Results PENK levels were raised in HFpEF (median [interquartile range] 88.9 [62.1–132.0]) compared to normal controls (56.3 [47.9–70.5]). PENK was correlated to urea, eGFR, Body Mass Index and E/e′ (rs 0.635, − 0.741, − 0.275, 0.476, respectively, p

Contains fulltext : 206328.pdf (Publisher’s version ) (Open Access) Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin-angiotensin-aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio-ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio-ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non-neutralizing ADM-binding antibody with a half-life of 15 days. Adrecizumab binds at the N-terminal epitope of ADM, leaving the C-terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM-binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.

Background Quantifying the activity of the adrenomedullin system might help to monitor and guide treatment in acute heart failure (AHF) patients. The aims were to (1) identify AHF patients with marked benefit or harm from specific treatments at hospital discharge and (2) predict mortality by quantifying the adrenomedullin system activity. Methods This was a prospective multicentre study. AHF diagnosis and phenotype were centrally adjudicated by two independent cardiologists among patients presenting to the emergency department with acute dyspnoea. Adrenomedullin system activity was quantified using the biologically active component, bioactive adrenomedullin (bio-ADM), and a prohormone fragment, midregional proadrenomedullin (MR-proADM). Bio-ADM and MR-proADM concentrations were measured in a blinded fashion at presentation and at discharge. Interaction with specific treatments at discharge and the utility of these biomarkers on predicting outcomes during 365-day follow-up were assessed. Results Among 1886 patients with adjudicated AHF, 514 patients (27.3%) died during 365-day follow-up. After adjusting for age, creatinine, and treatment at discharge, patients with bio-ADM plasma concentrations above the median (> 44.6 pg/mL) derived disproportional benefit if treated with diuretics (interaction p values n = 764) (interaction p values p p Conclusions Quantifying the adrenomedullin’s system activity may help to personalise post-discharge diuretic treatment and enable accurate risk-prediction in AHF.

Proenkephalin A 119-159 (penKid) has been proposed as a sensitive biomarker of renal function. This study evaluated the association of concentrations of plasma penKid with death and risk of acute kidney injury (AKI) in severely ill burn patients.A prospective observational study in two centers with severely ill adult burn patients was conducted. The inclusion criteria were total body surface area (TBSA) burns15%, with burn injury occurring72 h before intensive care unit (ICU) admission and plasma sample taken at admission. The primary endpoint was 90-day mortality. The secondary endpoints were AKI and a combined endpoint of 90-day mortality and/or AKI. Mortality was also evaluated in the sub-group of patients with sub-clinical AKI, defined as a patient without AKI but with elevated penKid.A total of 113 consecutive patients were enrolled. The median age was 48 years (Interquartile range [IQR] 33-64), the median burn TBSA was 35% (IQR 25-53), and 90-day mortality was 31.9%. Thirty-one percent of the patients had AKI, and 41.6% of patients had the combined endpoint. There was a stepwise decrease in survival from patients without AKI, sub-AKI, and with AKI (survival rate 90.0% [95% CI 82.7-97.9], 66.7% [95% CI 48.1-92.4], and 31.4% [95% CI 19.3-51.3], respectively, p0.001). Plasma penKid concentration was significantly higher in non-survivors compared to survivors (86.9 pmol/L [IQR 53.3-166.1] versus 52.9 pmol/L [IQR 37.1-70.7]; p = 0.0001) and in patients with AKI compared to patients without AKI (86.4 pmol/L [IQR 56.5-153.4] versus 52.5 pmol/L [IQR 35.5-71.2]; p0.001). Penkid provided added value on top of serum creatinine (Screat) and Sepsis Related Organ Failure Assessment (SOFA) scores to predict 90-day mortality (combined c-index of 0.738 versus 0.707; p = 0.024 and 0.787 versus 0.752; p0.001).Plasma penKid concentration at admission was associated with an increased risk of death in burn patients. PenKid has additional prognostic value on top of Screat and SOFA to predict 90-day mortality.

Neurotensin (NT) is an intestinal peptide released after fat ingestion, which regulates appetite and facilitates lipid absorption. Elevated plasma levels of its stable precursor pro-neurotensin (pro-NT) are associated with type 2 diabetes, obesity and cardiovascular mortality in adult populations; no data on pro-NT and metabolic disease are available in children. Aim of the study was to evaluate plasma pro-NT in relation to the presence of obesity in children, and to test if high pro-NT associates with the development of metabolic impairment later in life.For this longitudinal retrospective study, we studied 151 overweight/obese children undergoing metabolic evaluations at University of Cagliari, Italy. Pro-NT was also assessed in 46 normal-weight, age-, sex-comparable normal-weight children, selected as a reference group. At the baseline, pro-NT was comparable between overweight/obese and normal-weight children and correlated positively with age (p 0.001), triglycerides (p 0.001) and inversely with HDL levels (p = 0.008). Plasma pro-NT associated with high triglycerides with OR = 5.9 (95%CI: 1.24-28.1; p = 0.026) after adjustment for multiple confounders. At the 6.5-year follow-up, high basal pro-NT associated with impaired β-cell function to compensate for insulin-resistance (disposition index: r = -0.19, p = 0.035) and predicted bodyweight increase, as indicated by percentage change of standard deviation score BMI (median(95%CI) = +20.8(+4.9-+27.5)% in the highest tertile), independently from age, sex, triglycerides and insulin-resistance (standardized β = 0.24; p = 0.036).Elevated pro-NT levels in children are significantly associated with weight gain later in life and may represent a marker of susceptibility to metabolic impairment in presence of obesity.

Background: In rodents, neurotensin contributes to high fat diet induced obesity by facilitation of intestinal fat absorption. The effect of oral lipid load on plasma proneurotensin and relationship with plasma triglycerides in humans is unknown.Aim: To investigate the acute effects of an oral lipid load on proneurotensin and plasma triglycerides and their interrelationships in healthy individuals.Setting/ Methods: Twenty-two healthy subjects were given 150 mL of full milk cream (54g fat) and 59 mL of pure olive oil (54 g fat) in the fasted state at two different occasions separated by at least 1 week in random order. Venous blood was drawn at fasted before 0 hours (h) and at 1 h, 2 h and 4 h after ingestion. Post-ingested values of proneurotensin and plasma triglycerides were compared with fasting levels and post ingestion Area Under the Curve (AUC) of proneurotensin was correlated with that of plasma triglycerides.Results: An immediate rise of plasma proneurotensin and plasma triglycerides were observed after ingestion of cream with maximum increase at 2 h for proneurotensin [mean (95% confidence interval)] of 22 (12-31) pmol/L (P and at 3 h for triglycerides of 0.60 (0.43-0.78) mmol/L (P Similarly, plasma proneurotensin and plasma triglycerides increased after ingestion of olive oil with maximum increase of proneurotensin at 3 h of 62 (46-78) pmol/L (P and plasma triglycerides at 3 h of 0.32 (0.18-0.45) mmol/L (P The post lipid load AUC for proneurotensin correlated significantly with the AUC for plasma triglycerides both after cream (r=0.49, P=0.021) and olive oil (r=0.55, P=0.008), respectively.Conclusion: Proneurotensin increases after an oral lipid load of both cream and olive oil and the rise of post-ingestion plasma triglycerides is significantly related to the rise of post-ingestion proneurotensin.

Adrenomedullin is a vasoactive peptide that improves endothelial barrier function in sepsis, but may also cause hypotension and organ failure. Treatment with a non-neutralizing monoclonal anti-adrenomedullin antibody showed improvement in murine sepsis models. We tested the effects of the humanized monoclonal anti-adrenomedullin antibody Adrecizumab in a porcine two-hit model of hemorrhagic and septic shock.In this randomized, blinded study 12 German Landrace pigs were bled to half of baseline mean arterial pressure for 45 min. Sepsis was induced using an Escherichia coli clot placed into the abdominal cavity 6 h after hemorrhagic shock. Animals received either 2 mg/kg BW anti-adrenomedullin antibody or vehicle solution immediately after sepsis induction. After 4 h, resuscitation was initiated using balanced crystalloids and noradrenalin to maintain a central venous pressure of 8 to 12 mm Hg, a mean arterial pressure ≥ 65 mm Hg, and a ScvO2 ≥70% for another 8 h. Hemodynamic parameters, laboratory parameters, and kidney histology were assessed.The amount of volume resuscitation was significantly lower and significantly less animals developed a septic shock in the antibody-treated group, compared with the vehicle group. Kidney histology showed significantly lower granulocytes in both cortex and medulla in antibody-treated animals, while the remaining four kidney measures (serum creatinine and urine output and cortical and medullary injury in histopathology) did not reach the significance levels. After induction of sepsis, plasma adrenomedullin increased immediately in both the groups, but increased quicker and more pronounced in the antibody group.In this two-hit shock model, treatment with an anti-adrenomedullin antibody significantly increased plasma adrenomedullin levels, while significantly less animals developed septic shock and renal granulocyte extravasation was significantly reduced. Thus, therapy with Adrecizumab may provide benefit in sepsis, and clinical investigation of this drug candidate is warranted.

International audience; Rationale: Subclinical acute kidney injury (sub-AKI) refers to patients with low serum creatinine but elevated alternative biomarkers of AKI. Its incidence and outcome in critically ill patients remain, however, largely unknown. Plasma proenkephalin A 119–159 (penKid) has been proposed as a sensitive biomarker of glomerular function.Objectives: In this ancillary study of two cohorts, we explored the incidence and outcome of sub-AKI based on penKid.Methods: A prospective observational study in ICUs was conducted. FROG-ICU (French and European Outcome Registry in ICUs) enrolled 2,087 critically ill patients, and AdrenOSS-1 (Adrenomedullin and Outcome in Severe Sepsis and Septic Shock-1) enrolled 583 septic patients. The primary endpoint was 28-day mortality after ICU admission. Sub-AKI was defined by an admission penKid concentration above the normal range (i.e., >80 pmol/L) in patients not meeting the definition of AKI. A sensitivity analysis was performed among patients with estimated glomerular filtration rate above 60 ml/min/1.73 m2 at ICU admission.Measurements and Main Results: In total, 6.1% (122/2,004) and 6.7% (39/583) of patients from the FROG-ICU and AdrenOSS-1 cohorts met the definition of sub-AKI (11.6% and 17.5% of patients without AKI). In patients without AKI or with high estimated glomerular filtration rate, penKid was associated with higher mortality (adjusted standardized hazard ratio [HR], 1.4 [95% confidence interval, 1.1–1.8]; P = 0.010; and HR, 1.6 [95% confidence interval, 1.3–1.8]; P

Aims:\ud Recently, bio‐adrenomedullin (bio‐ADM) was proposed as a congestion marker in heart failure (HF). In the present study, we aimed to study whether bio‐ADM levels at discharge from a hospital admission for worsening HF could provide additional information on (residual) congestion status, diuretic dose titration and clinical outcomes.\ud \ud Methods and results:\ud Plasma bio‐ADM was measured in 1236 acute HF patients in the PROTECT trial at day 7 or discharge. Median discharge bio‐ADM was 33.7 [21.5–61.5] pg/mL. Patients with higher discharge bio‐ADM levels were hospitalised longer, had higher brain natriuretic peptide levels, and poorer diuretic response (all P 3) (odds ratio 4.35, 95% confidence interval 3.37–5.62; P

Introduction: Neurotensin (NT) is a neuropeptide implicated in cardiovascular and metabolic disease. As such, it is a candidate risk factor for cognitive impairment. We are not aware of studies reporting the relationship of NT and incident cognitive impairment (ICI). NT can be estimated in plasma by measuring its stable equimolar precursor, pro-neurotensin/neuromedin N (pro-NT/NMN). Hypothesis: Higher fasting plasma pro-NT/NMN is associated with risk of ICI. Methods: Prospective nested case-control study in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. REGARDS enrolled 30,239 Black and White adults aged ≥45 from 2003-2007. Baseline pro-NT/NMN was measured by immunoassay in 497 controls and 399 cases of ICI over 3.5 years follow up. ICI was identified using a 3-test cognitive battery biannually. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race and sex differences were studied with stratified models and interaction testing (with p Results: There was no association of 4 th vs. 1 st -quartile proNT/NMN with ICI in the overall group (see table), nor significant associations of the 2 nd and 3 rd quartiles with ICI in any group The OR differed significantly by sex; women had a 90% increased odds in the demographic-adjusted model, only slightly attenuated by risk factor adjustment. There was no race difference in associations. Conclusions: Higher circulating pro-NT/NMN was associated with ICI in women but not men. This could be due to cerebral vasoconstrictive effects of NT and estrogen-mediated differences in transcription. Confirmatory study is required.

Cardiovascular disease is a leading cause of death. Proneurotensin is a biomarker associated with the development of cardiovascular disease, cardiovascular mortality, and all-cause mortality. We assessed the association of fasting proneurotensin with mortal events by gender and race (black–white) in a US population. Using a case-cohort subpopulation of the Reasons for Geographic and Racial Differences in Stroke study, fasting proneurotensin was measured on a 1,046-person subcohort and in 651 participants with incident coronary heart disease. Higher proneurotensin was associated with all-cause mortality (hazard ratio [HR] 1.6 per interquartile range, 95% confidence interval [CI] 1.3 to 1.9) and cardiovascular mortality (HR 1.8, 95% CI 1.2 to 2.6). For all-cause and cardiovascular mortality, association was stronger in women (HR 1.9, 95% CI 1.4 to 2.6 and HR 2.5, 95% CI 1.4 to 4.7, respectively) than men (HR 1.4, 95% CI 1.0 to 1.8 and HR 1.4, 95% CI 0.9 to 2.3, respectively), although this difference was not significant. Proneurotensin predicted all-cause mortality in both races and was not predictive of cardiovascular mortality in whites but was in blacks. Proneurotensin was not associated with incident coronary heart disease events. Elevated proneurotensin levels predicted all-cause and cardiovascular mortality in both genders, with a trend toward stronger association in women. Associations were similar in blacks and whites. In conclusion, proneurotensin may be a useful biomarker for all-cause and cardiovascular mortality regardless of race, and it is potentially specific in women.

Neurotensin is a peptide with effects on appetite and intestinal lipid absorption. Experimental data suggest a role in glucose homeostasis, while human data is missing. Here, 20 morbidly obese subjects either underwent biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB) in a randomized fashion. Before and 1 year after surgery, anthropometric data, body composition, clinical biochemistry, insulin sensitivity by means of euglycemic hyperinsulinemic clamps (HEC) and fasting plasma proneurotensin 1-117 were analyzed. Plasma proneurotensin increased significantly more 1 year after BDP than RYGB (P = 0.028), while weight loss was comparable. After metabolic surgery, proneurotensin correlated positively with insulin sensitivity (M-value) (r = 0.55, P < 0.001), while an inverse relationship with fasting glucose, HOMA-IR and HbA1c was observed (P < 0.05 for all components). After adjustment for age and gender, proneurotensin and BMI remained independently related with delta of M-value (beta = 0.46 and beta = 0.51, P < 0.05, resp.). From these data we conclude that proneurotensin positively correlates with insulin sensitivity uniquely after weight loss induced by metabolic surgery in humans. BDP leads to a stronger increase in the anorexigenic peptide compared to RYGB.

Context The gut hormone neurotensin promotes fat absorption, diet-induced weight gain, and liver steatosis. Its stable precursor-hormone fragment “proneurotensin” predicts cardiometabolic disease in middle-aged populations, especially in women. Objective To test if proneurotensin predicts cardiovascular disease (CVD) and diabetes development in an elderly population and whether there are gender differences in this respect. Design, Setting, and Participants Fasting proneurotensin was measured in plasma from 4804 participants (mean age 69 ± 6 years) of the Malmö Preventive Project and subjects were followed up for development of CVD and diabetes during 5.4 years. Main Outcome Measures Multivariate adjusted Cox proportional hazard models CVD were used to relate the proneurotensin to the risk of incident CVD and diabetes in all subjects and in gender-stratified analyses. Results In total, there were 456 first CVD events and 222 incident cases of diabetes. The hazard ratio [HR (95% confidence interval)] for CVD per 1 standard deviation (SD) increment of proneurotensin was 1.10 (1.01 to 1.21); P = 0.037, and the above vs below median HR was 1.27 (1.06 to 1.54); P = 0.011, with similar effect sizes in both genders. There was no significant association between proneurotensin and incident diabetes in the entire population (P = 0.52) or among men (P = 0.52). However, in women proneurotensin predicted diabetes incidence with a per 1 SD increment HR of 1.28 (1.30 to 1.59); P = 0.025 and an above vs below median HR of 1.41 (1.10 to 1.80); P = 0.007. Conclusions In the elderly population, proneurotensin independently predicts development of CVD in both genders, whereas it only predicts diabetes in women.

BACKGROUND: Proenkephalin (pro-ENK) was recently found to be associated with low estimated glomerular filtration rate (eGFR). The association of pro-ENK with urinary albumin excretion (UAE), another marker for chronic kidney disease (CKD), has not been investigated. We examined the association of pro-ENK with eGFR and UAE as markers of CKD.METHODS: We included 4375 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. CKDeGFR was defined as development of eGFR 30 mg/24 h.RESULTS: Baseline median pro-ENK was 52.2 (IQR: 44.9-60.5) pmol/L. After a median follow-up of 8.4 (IQR: 7.9-8.9) years, 183 subjects developed CKDeGFR and 371 developed CKDUAE. The association of pro-ENK with CKDeGFR was modified by sex (Pinteraction CONCLUSIONS: High pro-ENK is associated with increased risk of CKDeGFR in men, but not in women. No association of pro-ENK with CKDUAE was observed. These results should be interpreted with caution, since residual confounding and potential overfitting of models could have influenced the results.

IntroductionSepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)-a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay-for kidney events in sepsis and septic shock.MethodsThe Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality.ResultsMedian age was 66 years (interquartile range 55-75), and 28-day mortality was 22% (95% confidence interval [CI] 19%-25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median= 65 [IQR= 45-106] vs. 179 [114-242]; 53 [39-70] vs. 133 [79-196] pmol/l; and 70 [47-121] vs. 174 [93-242] pmol/l, all P< 0.0001), also after adjustment for confounding factors (adjusted odds ratio= 3.3 [95% CI = 1.8-6.0], 3.9 [95% CI = 2.1-7.2], and 3.4 [95% CI = 1.9-6.2], all P&nbsp

Selenium is a nutrient with antioxidant effects and thus is protective against cardiovascular disease [(1)][1], as demonstrated by a meta-analysis revealing a significant inverse correlation between selenium levels and the incidence of atherosclerotic coronary heart disease (CHD) [(2)][2]. However

Background Adrenomedullin (ADM) is a circulating peptide known to regulate vasodilation and vascular integrity. Increased plasma ADM concentrations have been described for several life-threatening conditions, including cardiovascular diseases and septic shock. Reliable methods for the simple quantification of bioactive ADM (bio-ADM) are lacking. Methods Monoclonal antibodies against the amidated C-terminus and middle portion of bio-ADM were generated and used for the development of a 1-step immunometric assay for the specific quantification of bio-ADM in plasma. The assay was developed in a microtiter plate/chemiluminescence label format with a significantly reduced incubation time. Precision, linearity, specimen stability, and distribution of results in healthy subjects were evaluated. Results The use of monoclonal antibodies against predetermined epitopes of bio-ADM enabled the development of an assay for the determination of bio-ADM directly in EDTA plasma. Plasma samples were stable for up to 24 h at ambient temperature and over multiple freeze–thaw cycles without loss of immunoreactivity. The assay had a limit of detection of 3 pg/mL and a limit of quantification of 11 pg/mL. The assay exhibited acceptable linearity characteristics and was not influenced by complement factor H, a putative ADM-binding protein. In healthy subjects, bio-ADM concentrations were all above the limit of detection, and approximately half of them were above the limit of quantification. Conclusions By using monoclonal antibodies with defined epitope specificities, we have developed a simple, rapid, accurate, and sensitive sandwich immunoassay for bio-ADM. The assay is a potentially novel tool to support patient management, particularly in acute care in the field of sepsis and other indications, which are currently being investigated, such as acute heart failure.

Background Growth hormone (GH) has been linked to cardiovascular disease but the exact mechanism of this association is still unclear. We here test if the fasting levels of GH are cross-sectionally associated with carotid intima media thickness (IMT) and whether treatment with fluvastatin affects the fasting level of GH. Methods We examined the association between GH and IMT in 4425 individuals (aged 46–68 years) included in the baseline examination (1991–1994) of the Malmö Diet and Cancer cardiovascular cohort (MDC-CC). From that cohort we then studied 472 individuals (aged 50-70 years) who also participated (1994–1999) in the β-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS), a randomized, double blind, placebo-controlled, single-center clinical trial. Using multivariate linear regression models we related the change in GH-levels at 12 months compared with baseline to treatment with 40 mg fluvastatin once daily. Results In MDC-CC fasting values of GH exhibited a positive cross-sectional relation to the IMT at the carotid bulb independent of traditional cardiovascular risk factors (p = 0.002). In a gender-stratified analysis the correlation were significant for males (p = 0.005), but not for females (p = 0.09). Treatment with fluvastatin was associated with a minor reduction in the fasting levels of hs-GH in males (p = 0.05) and a minor rise in the same levels among females (p = 0.05). Conclusions We here demonstrate that higher fasting levels of GH are associated with thicker IMT in the carotid bulb in males. Treatment with fluvastatin for 12 months only had a minor, and probably not clinically relevant, effect on the fasting levels of hs-GH. Electronic supplementary material The online version of this article (doi:10.1186/s12872-017-0563-9) contains supplementary material, which is available to authorized users.

Background: \ud \ud Proenkephalin (pro-ENK) has emerged as a novel biomarker associated with both renal function and cardiac function. However, its clinical and prognostic value have not been well evaluated in symptomatic patients with heart failure.\ud \ud Methods and Results: \ud \ud The association between pro-ENK and markers of renal function was evaluated in 95 patients with chronic heart failure who underwent renal hemodynamic measurements including renal blood flow (RBF) and glomerular filtration rate (GFR) using131I-Hippuran and 125I-Iothalamate clearances, respectively. The association between pro-ENK and clinical outcome in acute heart failure was assessed in another 1589 patients. Pro-ENK was strongly correlated with both RBF (P*lt;0.001) and GFR (P