Plasma proenkephalin A and incident chronic kidney disease and albuminuria in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.

BACKGROUND: Plasma proenkephalin A (PENK-A) is a precursor of active enkephalins. Higher blood concentrations have been associated with estimated glomerular filtration rate (eGFR) decline in European populations. Due to the significant disparity in incident chronic kidney disease (CKD) between White and Black people, we evaluated the association of PENK-A with incident CKD and other kidney outcomes among a biracial cohort in the U.S. METHODS: In a nested cohort of 4,400 participants among the REasons for Geographic And Racial Differences in Stroke, we determined the association between baseline PENK-A concentration and incident CKD using the creatinine-cystatin C CKD-EPI 2021 equation without race coefficient, significant eGFR decline, and incident albuminuria between baseline and a follow-up visit 9.4 years later. We tested for race and sex interactions. We used inverse probability sampling weights to account for the sampling design. RESULTS: At baseline, mean (SD) age was 64 (8) years, 49% were women, and 52% were Black participants. 8.5% developed CKD, 21% experienced ≥ 30% decline in eGFR and 18% developed albuminuria. There was no association between PENK-A and incident CKD and no difference by race or sex. However, higher PENK-A was associated with increased odds of progressive eGFR decline (OR: 1.12; 95% CI 1.00, 1.25). Higher PENK-A concentration was strongly associated with incident albuminuria among patients without diabetes mellitus (OR: 1.29; 95% CI 1.09, 1.53). CONCLUSION: While PENK-A was not associated with incident CKD, its associations with progression of CKD and incident albuminuria, among patients without diabetes, suggest that it might be a useful tool in the evaluation of kidney disease among White and Black patients.

Bioactive adrenomedullin (bio-ADM) is associated with endothelial dysfunction in infants and children with complex congenital heart disease undergoing open-heart surgery on cardiopulmonary bypass.

OBJECTIVES: Children with congenital heart disease (CHD) undergoing cardiac surgery on cardiopulmonary bypass (CPB) are at risk for systemic inflammation leading to endothelial dysfunction associated with increased morbidity. Bioactive adrenomedullin (bio-ADM) is a peptide regulating vascular tone and endothelial permeability. The aim of this study was to evaluate the dynamics of plasma bio-ADM in this patient cohort and its role in capillary leak. METHODS: Plasma samples from 73 pediatric CHD patients were collected for bio-ADM measurement at five different timepoints (TP) in the pre-, intra-, and post-operative period. The primary endpoint was a net increase in bio-ADM levels after surgery on CPB. Secondary endpoints included association of bio-ADM levels with clinical signs for endothelial dysfunction. RESULTS: Bio-ADM levels increased after surgery on CPB from pre-operative median of 12 pg/mL (IQR [interquartile range] 12.0-14.8 pg/mL) to a maximum post-operative median of 48.8 pg/mL (IQR 34.5-69.6 pg/mL, p<0.001). Bio-ADM concentrations correlated positively with post-operative volume balance, (r=0.341; p=0.005), increased demand for vasoactive medication (duration: r=0.415; p<0.001; quantity: TP3: r=0.415, p<0.001; TP4: r=0.414, p<0.001), and hydrocortisone treatment for vasoplegia (bio-ADM median [IQR]:129.1 [55.4-139.2] pg/mL vs. 37.9 [25.2-64.6] pg/mL; p=0.034). Patients who required pleural effusion drainage revealed higher bio-ADM levels compared to those who did not (median [IQR]: 66.4 [55.4-90.9] pg/mL vs. 40.2 [28.2-57.0] pg/mL; p<0.001). CONCLUSIONS: Bio-ADM is elevated in children after cardiac surgery and higher levels correlate with clinical signs of capillary leakage. The peptide should be considered as biomarker for endothelial dysfunction and as potential therapeutic target in this indication.

Assessing GFR With Proenkephalin.

Introduction: In clinical practice, kidney (dys)function is monitored through creatinine-based estimations of glomerular filtration rate (eGFR: Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). Creatinine is recognized as a late and insensitive biomarker of glomerular filtration rate (GFR). The novel biomarker proenkephalin (PENK) may overcome these limitations, but no PENK-based equation for eGFR is currently available. Therefore, we developed and validated a PENK-based equation to assess GFR. Methods: In this international multicenter study in 1354 stable and critically ill patients, GFR was measured (mGFR) through iohexol or iothalamate clearance. A generalized linear model with sigmoidal nonlinear transfer function was used for equation development in the block-randomized development set. Covariates were selected in a data-driven fashion. The novel equation was assessed for bias, precision (mean ± SD), and accuracy (eGFR percentage within ±30% of mGFR, P30) in the validation set and compared with MDRD and CKD-EPI. Results: Median mGFR was 61 [44-81] ml/min per 1.73 m2. In order of importance, PENK, creatinine, and age were included, and sex or race did not improve performance. The PENK-based equation mean ± SD bias of the mGFR was 0.5 ± 15 ml/min per 1.73 m2, significantly less compared with MDRD (8 ± 17, P < 0.001) and 2009 CKD-EPI (5 ± 17, P < 0.001), not reaching statistical significance compared with 2021 CKD-EPI (1.3 ± 16, P = 0.06). The P30 accuracy of the PENK-based equation was 83%, significantly higher compared with MDRD (68%, P < 0.001) and 2009 CKD-EPI (76%, P < 0.001), similar to 2021 CKD-EPI (80%, P = 0.13). Conclusion: Overall, the PENK-based equation to assess eGFR performed better than most creatinine-based equations without using sex or race.

Peptidylglycine α-amidating monooxygenase and adrenomedullin measurement in patients with hepatic cirrhosis.

Background: Peptidylglycine α-amidating monooxygenase (PAM) is an enzyme involved in the maturation of regulatory peptides. Here we examined PAM activity and adrenomedullin (bio-ADM) concentrations in patients with hepatic cirrhosis and determined net changes across the liver, kidneys and leg. Materials & methods: A total of 48 patients with hepatic cirrhosis and 16 control subjects were included. All patients and controls underwent an invasive procedure with blood collected across organs. Results: PAM activity was increased in cirrhotic patients but without a net change across the liver, leg or kidney. In contrast, bio-ADM concentrations were associated with severity of disease and found to be higher in venous blood from the liver. Conclusion: Increased PAM activity in patients with hepatic cirrhosis may reflect other organs involved in cirrhotic disease.

Severe liver disease is a life-threatening condition that affects people all over the world. To improve doctors' ability to diagnose the disease and to follow the disease as it progresses, there is a need for new tools. Biomarkers are often used as such tools for measuring the presence and severity of a disease. In this study, we examined two potential biomarkers in blood from patients with severe liver disease: peptidylglycine α-amidating monooxygenase (PAM) activity and bioactive adrenomedullin (bio-ADM). We examined whether these biomarkers are present in blood and in amounts associated with disease severity. We also tested if the diseased liver releases the biomarkers. We found that bio-ADM is increased in blood from patients with severe liver disease and that the liver itself releases bio-ADM to the bloodstream. For PAM activity, we also detected increased activity in blood associated with disease severity. In contrast, however, this biomarker was not shown to be released by the liver. Taken together, the two biomarkers may help to improve severe liver disease diagnosis and maybe allow for biochemical follow-up as the disease progresses.

Plasma Pro-Enkephalin A and Incident Cognitive Impairment: The Reasons for Geographic and Racial Differences in Stroke Cohort.

Background Cardiovascular disease is a risk factor for cognitive impairment. Evidence links both lower and higher concentration of the circulating opioid pro-enkephalin A (PENK-A) with stroke risk. We studied the association of plasma PENK-A with incident cognitive impairment. Methods and Results REGARDS (Reasons for Geographic and Racial Differences in Stroke) is a prospective cohort study of 30 239 adults enrolled from 2003 to 2007. Baseline PENK-A was measured in a nested case-control study of 462 participants who developed cognitive impairment over 4.7 years, and 556 controls. Logistic regression and spline plots adjusted for confounders estimated odds ratios (ORs) of cognitive impairment by baseline PENK-A. Interaction terms tested for differences in associations by age, sex, and race. Baseline PENK-A was comparable between cases and controls. There were significant differences in the association of PENK-A with cognitive impairment by sex and age (adjusted P=0.003 and 0.06, respectively). In women but not men, spline plots showed that higher and lower PENK-A were associated with decreased odds of cognitive impairment (ORs for 10th and 90th percentiles versus median, 0.65 [95% CI, 0.43-0.96] and 0.64 [95% CI, 0.41-0.99]), with no difference by age. In men ≥65 years of age but not younger men, higher PENK-A was associated with decreased odds for cognitive impairment (OR for fourth versus first quartile 0.47 [95% CI, 0.22-0.99]); this pattern was not confirmed with spline plotting. Conclusions High and low levels of circulating opioid PENK-A were associated with decreased odds of future cognitive impairment in specific subgroups. Additional research is warranted to understand the biology underlying this association and the observed differences by sex.

Proenkephalin A as a marker for glomerular filtration rate in critically ill children: validation against gold standard iohexol GFR measurements.

OBJECTIVES: Accurate determination of glomerular filtration rate (GFR) is important. Several endogenous biomarkers exist for estimating GFR, yet, they have limited accuracy, especially in the paediatric population. Proenkephalin A 119-159 (PENK) is a novel and promising GFR marker, but its relation with age in children remains unknown. Also, the value of PENK has never been validated against measured GFR (mGFR) in children when compared to traditional GFR markers including serum creatinine (SCr), SCr-based estimated GFR (eGFR) and cystatin C (cysC). METHODS: Critically ill children and term-born neonates were included in this single-centre, prospective study. Iohexol-based mGFR, SCr, and cysC were determined in each patient. eGFR was calculated using the bedside Schwartz equation, incorporating SCr and height. Spearman correlation coefficients were calculated to determine the correlation between mGFR and PENK, SCr, cysC and eGFR. RESULTS: For 97 patients (56 children and 41 neonates), mGFR, SCr, cysC and PENK levels were available. PENK levels were higher in young children and decreased to adult PENK reference values around two years of age. PENK levels were highly correlated with mGFR (ρ=-0.88, p<0.001), and similar to mGFR-eGFR correlation (ρ=-0.87, p<0.001). For cysC and SCr the correlation with mGFR was lower (ρ=-0.77 and ρ=-0.46, respectively. Both p<0.001). CONCLUSIONS: The correlation of PENK with mGFR was as good as SCr-based eGFR-mGFR correlation. To determine the added value of PENK in paediatric clinical care and prior to implementation, PENK reference values are needed and the development and validation of a paediatric PENK-based eGFR equation is necessary.

Bioactive adrenomedullin for assessment of venous congestion in heart failure.

AIMS: Bioactive adrenomedullin (bio-ADM) is a vascular-derived peptide hormone that has emerged as a promising biomarker for assessment of congestion in decompensated heart failure (HF). We aimed to evaluate diagnostic and prognostic performance of bio-ADM for HF in comparison to amino-terminal pro-B-type natriuretic peptide (NT-proBNP), with decision thresholds derived from invasive haemodynamic and population-based studies. METHODS AND RESULTS: Normal reference ranges for bio-ADM were derived from a community-based cohort (n = 5060). Correlations with haemodynamic data were explored in a cohort of HF patients undergoing right heart catheterization (n = 346). Mortality and decision cutoffs for bio-ADM was explored in a cohort of patients presenting in the ER with acute dyspnoea (n = 1534), including patients with decompensated HF (n = 570). The normal reference range was 8-39 pg/mL. The area under the receiver operating characteristic curve (AUROC) for discrimination of elevated mean right atrial pressure (mRAP) and pulmonary arterial wedge pressure (PAWP) was 0.74 (95% CI = 0.67-0.79) and 0.70 (95% CI = 0.64-0.75), respectively, with optimal bio-ADM decision cutoff of 39 pg/mL, concordant with cubic spline analyses. NT-proBNP discriminated PAWP slightly better than mRAP (AUROC 0.73 [95% CI = 0.68-0.79] and 0.68 [95% CI = 0.61-0.75]). Bio-ADM correlated with (mRAP, r = 0.55) while NT-proBNP correlated with PAWP. Finally, a bio-ADM decision cutoff of 39 pg/mL associated with 30 and 90 day mortality and conferred a two-fold increased odds of HF diagnosis, independently from NT-proBNP. CONCLUSIONS: Bio-ADM tracks with mRAP and associates with measures of systemic congestion and with mortality in decompensated HF independently from NT-proBNP. Our findings support utility of bio-ADM as a biomarker of systemic venous congestion in HF and nominate a decision threshold.

Bioactive adrenomedullin in sepsis patients in the emergency department is associated with mortality, organ failure and admission to intensive care.

BACKGROUND: Adrenomedullin is a vasoactive hormone with potentially prognostic and therapeutic value, which mainly has been investigated in intensive care unit (ICU) settings. The triaging in the emergency department (ED) of patients to the right level of care is crucial for patient outcome. OBJECTIVES: The primary aim of this study was to investigate the association of bioactive adrenomedullin (bio-ADM) with mortality among sepsis patients in the ED. Secondary aims were to investigate the association of bio-ADM with multiple organ failure (MOF), ICU admission and ED discharge. METHODS: In this prospective observational cohort study, adult sepsis patients in the ED (2013-2015) had blood samples collected for later batch analysis of bio-ADM. Odds ratios (OR) with 95% confidence interval (CI) for bio-ADM were calculated. RESULTS: Bio-ADM in 594 sepsis patients was analyzed of whom 51 died within 28 days (8.6%), 34 developed severe MOF, 27 were ICU admitted and 67 were discharged from the ED. The median (interquartile range) bio-ADM was 36 (26-56) and 63 (42-132) pg/mL among survivors and non-survivors, respectively, 81 (56-156) pg/mL for patients with severe MOF and 77 (42-133) pg/mL for ICU admitted patients. Each log-2 increment of bio-ADM conferred an OR of 2.30 (95% CI 1.74-3.04) for mortality, the adjusted OR was 2.39 (95% CI 1.69-3.39). The area under the receiver operating characteristic curve of a prognostic mortality model based on demographics and biomarkers increased from 0.80 to 0.86 (p = 0.02) when bio-ADM was added. Increasing bio-ADM was associated with severe MOF, ICU admission and ED discharge with adjusted ORs of 3.30 (95% CI 2.13-5.11), 1.75 (95% CI 1.11-2.77) and 0.46 (95% CI 0.32-0.68), respectively. CONCLUSION: Bio-ADM in sepsis patients in the ED is associated with mortality, severe MOF, ICU admission and ED discharge, and may be of clinical importance for triage of sepsis patients in the ED.

Proenkephalin A and bioactive adrenomedullin are useful for risk prognostication in cardiac surgery.

Introduction: Various clinical scores have been developed to predict organ dysfunction and mortality in patients undergoing cardiac surgery, but outcome prediction may be inaccurate for some patient groups. Proenkephalin A (penKid) and bioactive adrenomedullin (bio-ADM) have emerged as promising biomarkers correlating with shock and organ dysfunction. This imposes the question of whether they can be used as prognostic biomarkers for risk stratification in the perioperative setting of cardiac surgery. Methods: Patients undergoing cardiac surgery were prospectively enrolled in this observational study. PenKid and bio-ADM plasma levels, as well as markers evaluating inflammation and organ dysfunction, were measured at five perioperative time points from before the induction of anesthesia to up to 48 h postoperatively. Clinical data regarding organ dysfunction and patient outcomes were recorded during the intensive care unit (ICU)-stay with a special focus on acute kidney injury (AKI). Results: In 136 patients undergoing cardiac surgery, the bio-ADM levels increased and the penKid levels decreased significantly over time. PenKid was associated with chronic kidney disease (CKD), the incidence of AKI, and renal replacement therapy (RRT). Bio-ADM was associated with lactate and the need for vasopressors. PenKid was useful to predict an ICU-length of stay (LOS)>1 day and added prognostic value to the European System for Cardiac Operative Risk Evaluation Score (EuroSCORE) II when measured after the end of cardiopulmonary bypass and 24 h after cardiac surgery. For bio-ADM, the same was true when measured 24 h after surgery. PenKid also added prognostic value to the EuroSCORE II for the combined outcome "ICU length of stay >1 day and in-hospital mortality." Conclusion: The combination of preoperative EuroSCORE II and intraoperative measurement of penKid may be more useful to predict a prolonged ICU LOS and increased mortality than EuroSCORE II alone. Bio-ADM correlates with markers of shock. More research is encouraged for early risk stratification and validation of penKid and bio-ADM as a tool involved in clinical decisions, which may enable the early initiation of organ protective strategies.

Plasma Proneurotensin and Prediction of Cause-Specific Mortality in a Middle-aged Cohort During Long-term Follow-up.

CONTEXT: Neurotensin is associated with cardiometabolic diseases but its role with mortality risk in humans is unknown. OBJECTIVE: This work aims to examine the prediction of proneurotensin (Pro-NT) with respect to total and cause-specific mortality in a middle-aged cohort. METHODS: In the population-based middle-aged cohort (n = 4632; mean age, 57 years) of the Malmö Diet and Cancer Study, Pro-NT was assessed and total as well as cause-specific mortality was studied. Main cause of death was based on the International Classification of Diseases. RESULTS: During a mean follow-up of 20 ±â€…3 years, 950 men and 956 women died. There was significantly increased mortality risk in individuals belonging to the highest quartile (Q) of Pro-NT (Q4, Pro-NT ≥ 149 pmol/L) compared with Qs 1 to 3 (Pro-NT < 149 pmol/L), hazard ratio (HR), 95% CI of 1.29 (1.17-1.42; P < .001). Data were adjusted for sex and age. No significant interaction was observed between Pro-NT and sex on mortality risk. Individuals within Q4 vs Qs 1 to 3 had an HR of 1.41 (95% CI, 1.18-1.68; P < .001) for death due to cardiovascular disease (n = 595/4632); 2.53 (95% CI, 1.37-4.67; P = .003), due to digestive tract disease (n = 42/4632), 1.62 (95% CI, 1.04-2.52; P = .032) due to mental and behavioral disease (n = 90/4632); and 1.91 (95% CI, 1.15-3.19; P = .013) due to unspecific causes (n = 64/4632). There was no significant relationship between Pro-NT and deaths due to cancer, infections, neurological, or other causes. Adjustment for cardiovascular risk factors only marginally changed these results. CONCLUSION: The relationship between Pro-NT and total mortality risk was mainly driven by cardiovascular mortality, but high Pro-NT also predicts death from digestive, mental, and behavioral disease and deaths attributed to unspecific causes.

Plasma Pro-Enkephalin A and Ischemic Stroke Risk: The Reasons for Geographic and Racial Differences in Stroke Cohort.

OBJECTIVES: The opioid neuropeptide pro-enkephalin A (PENK-A) may be a circulating marker of cardiovascular risk, with prior findings relevant to heart failure, kidney disease, and vascular dementia. Despite these findings, the association of PENK-A with ischemic stroke is unknown, so we examined this association in a prospective cohort study and analyzed differences by race and sex. MATERIALS AND METHODS: The REasons for Geographic and Racial Differences in Stroke study (REGARDS) is a prospective cohort study of 30,239 Black and White adults. Plasma PENK-A was measured in 473 participants that developed first-time ischemic stroke over 5.9 years and 899 randomly selected participants. Cox models adjusted for demographics and stroke risk factors were used to calculate hazard ratios (HRs) of stroke by baseline PENK-A. RESULTS: PENK-A was higher with increasing age, female sex, White race, lower body mass index, and antihypertensive medication use. Each SD higher increment of PENK-A was associated with an adjusted HR of 1.20 (95% CI 1.01-1.42) for stroke, with minimal confounding by stroke risk factors. Spline plots suggested a U-shaped relationship, particularly in White men, with an adjusted HR 3.88 (95% CI 1.94-7.77) for the 95th versus 50th percentile of PENK-A in White men. CONCLUSIONS: Higher baseline plasma PENK-A was independently associated with future stroke risk in REGARDS. This association was most apparent among White men. There was little confounding by established stroke risk factors, suggesting a possible causal role in stroke etiology. Further research is needed to understand the role of endogenous opioids in stroke pathogenesis.

Bioactive adrenomedullin a prognostic biomarker in patients with mild to moderate dyspnea at the emergency department: an observational study.

Acute dyspnea with underlying congestion is a leading cause of emergency department (ED) visits with high rates of hospitalization. Adrenomedullin is a vasoactive neuropeptide hormone secreted by the endothelium that mediates vasodilation and maintains vascular integrity. Plasma levels of biologically active adrenomedullin (bio-ADM) predict septic shock and vasopressor need in critically ill patients and are associated with congestion in patients with acute heart failure (HF) but the prognostic value in unselected dyspneic patients at the ED is unknown. The purpose of this study is to test if bio-ADM predicts adverse outcomes when sampled in patients with acute dyspnea at presentation to the ED. In this single-center prospective observational study, we included 1402 patients from the ADYS (Acute DYSpnea at the Emergency Department) cohort in Malmö, Sweden. We fitted logistic regression models adjusted for sex, age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine, and C-reactive protein (CRP) to associate bio-ADM plasma levels to mortality, hospitalization, intravenous (IV) diuretic treatment and HF diagnosis. Using receiver operating characteristic (ROC) curve analysis we evaluated bio-ADM discrimination for these outcomes compared to a reference model (sex, age, NT-proBNP, creatinine, and CRP). Model performance was compared by performing a likelihood ratio test on the deviances of the models. Bio-ADM (per interquartile range from median) predicts both 90-day mortality [odds ratio (OR): 1.5, 95% confidence interval (CI) 1.2-2.0, p < 0.002] and hospitalization (OR: 1.5, 95% CI 1.2-1.8, p < 0.001) independently of sex, age, NT-proBNP, creatinine, and CRP. Bio-ADM statistically significantly improves the reference model in predicting mortality (added χ2 9.8, p = 0.002) and hospitalization (added χ2 14.1, p = 0.0002), and is associated with IV diuretic treatment and HF diagnosis at discharge. Plasma levels of bio-ADM sampled at ED presentation in acutely dyspneic patients are independently associated with 90-day mortality, hospitalization and indicate the need for decongestive therapy.

Pro-neurotensin/Neuromedin N and Hypertension Risk: A Prospective Study.

BACKGROUND: Neurotensin, a neuropeptide with direct cardiac effects, has been associated with prospective risk of hypertension-related conditions through measurement of its precursor, pro-neurotensin/neuromedin N (pro-NT/NMN). Its association with incident hypertension has not been evaluated. METHODS: From 2003 to 2007, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black or White adults age ≥45. Pro-NT/NMN was measured in 1,692 participants without baseline hypertension (self-reported antihypertensive use or blood pressure ≥140/90 mm Hg) who underwent follow-up assessment in 2013-2016. A sensitivity analysis was conducted using a lower threshold (≥130/80 mm Hg) to define hypertension. Three robust Poisson regression models were fitted to risk of incident hypertension, adding demographics, cardiometabolic risk factors, and dietary covariates. RESULTS: Six hundred and fourteen participants developed hypertension over 9.4 years of follow-up. Pro-NT/NMN ranged from 14 to 1,246 pmol/l, with median [interquartile range] 154 [112, 206] pmol/l. Pro-NT/NMN was not associated with hypertension overall (fully adjusted incidence rate ratio per SD increment log pro-NT/NMN 1.03, 95% confidence interval 0.95-1.11). Results of sensitivity analysis did not differ substantially. CONCLUSIONS: Baseline pro-NT/NMN was not associated with incident hypertension. This may be a result of neurotensin's long-term interactions with other molecular regulators of blood pressure, such as the renin-angiotensin-aldosterone system.

Elevated Plasma Bioactive Adrenomedullin and Mortality in Cardiogenic Shock: Results from the OptimaCC Trial.

AIMS: Bioactive adrenomedullin (bio-ADM) was recently shown to be a prognostic marker in patients with acute circulatory failure. We investigate the association of bio-ADM with organ injury, functional impairment, and survival in cardiogenic shock (CS). METHODS: OptimaCC was a multicenter and randomized trial in 57 patients with CS. In this post-hoc analysis, the primary endpoint was to assess the association between bio-ADM and 30-day all-cause mortality. Secondary endpoints included adverse events and parameters of organ injury or functional impairment. RESULTS: Bio-ADM values were higher in 30-day non-survivors than 30-day survivors at inclusion (median (interquartile range) 67.0 (54.6-142.9) pg/mL vs. 38.7 (23.8-63.6) pg/mL, p = 0.010), at 24 h (p = 0.012), and up to 48 h (p = 0.027). Using a bio-ADM cutoff of 53.8 pg/mL, patients with increased bio-ADM had a HR of 3.90 (95% confidence interval 1.43-10.68, p = 0.008) for 30-day all-cause mortality, and similar results were observed even after adjustment for severity scores. Patients with the occurrence of refractory CS had higher bio-ADM value at inclusion (90.7 (59.9-147.7) pg/mL vs. 40.7 (23.0-64.7) pg/mL p = 0.005). Bio-ADM values at inclusion were correlated with pulmonary vascular resistance index, estimated glomerular filtration rate, and N-terminal pro-B-type natriuretic peptide (r = 0.49, r = -0.47, and r = 0.64, respectively; p < 0.001). CONCLUSIONS: In CS patients, the values of bio-ADM are associated with some parameters of organ injury and functional impairment and are prognostic for the occurrence of refractory CS and 30-day mortality.

Proenkephalin and the risk of new-onset heart failure: data from prevention of renal and vascular end-stage disease.

BACKGROUND: Enkephalins of the opioid system exert several cardiorenal effects. Proenkephalin (PENK), a stable surrogate, is associated with heart failure (HF) development after myocardial infarction and worse cardiorenal function and prognosis in patients with HF. The association between plasma PENK concentrations and new-onset HF in the general population remains to be established. HYPOTHESIS: We hypothesized that plasma PENK concentrations are associated with new-onset HF in the general population. METHODS: We included 6677 participants from the prevention of renal and vascular end-stage disease study and investigated determinants of PENK concentrations and their association with new-onset HF (both reduced [HFrEF] and preserved ejection fraction [HFpEF]). RESULTS: Median PENK concentrations were 52.7 (45.1-61.9) pmol/L. Higher PENK concentrations were associated with poorer renal function and higher NT-proBNP concentrations. The main determinants of higher PENK concentrations were lower estimated glomerular filtration rate (eGFR), lower urinary creatinine excretion, and lower body mass index (all p < .001). After a median 8.3 (7.8-8.8) years follow-up, 221 participants developed HF; 127 HFrEF and 94 HFpEF. PENK concentrations were higher in subjects who developed HF compared with those who did not, 56.2 (45.2-67.6) versus 52.7 (45.1-61.6) pmol/L, respectively (p = .003). In competing-risk analyses, higher PENK concentrations were associated with higher risk of new-onset HF (hazard ratio [HR] = 2.09[1.47-2.97], p < .001), including both HFrEF (HR = 2.31[1.48-3.61], p < .001) and HFpEF (HR = 1.74[1.02-2.96], p = .042). These associations were, however, lost after adjustment for eGFR. CONCLUSIONS: In the general population, higher PENK concentrations were associated with lower eGFR and higher NT-proBNP concentrations. Higher PENK concentrations were not independently associated with new-onset HFrEF and HFpEF and mainly confounded by eGFR.

Pro-Neurotensin/Neuromedin N and Risk of Incident Metabolic Syndrome and Diabetes Mellitus in the REGARDS Cohort.

CONTEXT: The peptide neurotensin is implicated in insulin resistance, diabetes mellitus (DM), and cardiovascular disease. OBJECTIVE: We studied the association of neurotensin's stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN) with incident metabolic syndrome (MetS) and DM. METHODS: We included 3772 participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study who completed the baseline exam (2003-2007), the follow-up exam (2013-2016), and had pro-NT/NMN measured by immunoassay. Weighted logistic regression models were fitted to incident DM, incident MetS, and each MetS component, separately, incorporating demographics, metabolic risk factors, homeostasis model of insulin resistance (HOMA-IR), and diet scores. Incident MetS was defined by 3 or more harmonized criteria at follow-up in those with fewer than 3 at baseline. Incident DM was defined by use of hypoglycemic drugs/insulin, fasting glucose 126 mg/dL or greater, or random glucose 200 mg/dL or greater in those without these at baseline. RESULTS: Median (IQR) plasma pro-NT/NMN was 160 pmol/L (118-218 pmol/L). A total of 564 (of 2770 without baseline MetS) participants developed MetS, and 407 (of 3030 without baseline DM) developed DM. Per SD higher log-pro-NT/NMN, the demographic-adjusted odds ratio (OR) and 95% CI of incident MetS was 1.22 (1.11-1.35), 1.16 (1.00-1.35) for incident low high-density lipoprotein (HDL), and 1.25 (1.11-1.40) for incident dysglycemia. The association of pro-NT/NMN with MetS was attenuated in the model adding HOMA-IR (OR per SD log-pro-NT/NMN 1.14; 95% CI, 1.00-1.30). There was no association with incident DM (OR per SD log-pro-NT/NMN 1.06; 95% CI, 0.94-1.19). CONCLUSION: Pro-NT/NMN was associated with MetS and 2 components, dysglycemia and low HDL, likely explained by insulin resistance.

Circulating levels of growth hormone in postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder with poorly understood etiology and underlying pathophysiology. Since cardiovascular morbidity has been linked to growth hormone (GH), we studied GH levels in patients with POTS. We conducted an age-sex-matched case-control study in patients with POTS (age 31 ± 9 years; n = 42) and healthy controls (32 ± 9 years; n = 46). Plasma GH levels were measured using high-sensitivity chemiluminescence sandwich immunoassay. The burden of orthostatic intolerance symptoms was assessed by the Orthostatic Hypotension Questionnaire (OHQ), consisting of a symptom assessment scale (OHSA) and a daily activity scale (OHDAS). POTS patients had significantly higher composite OHQ score than controls, more symptoms and less activity. Supine heart rate and diastolic blood pressure (BP), but not systolic BP, were significantly higher in POTS. Median plasma GH levels were significantly lower in POTS (0.53 ng/mL) than controls (2.33 ng/mL, p = 0.04). GH levels were inversely related to OHDAS in POTS and supine systolic BP in POTS and controls, but not heart rate neither group. POTS is associated with lower GH levels. Impairment of daily life activities is inversely related with GH in POTS. A higher supine diastolic BP is inversely associated with GH levels in POTS and healthy individuals.

Precursor fractions of neurotensin and enkephalin might point to molecular mechanisms of cancer risk modulation during a lifestyle-intervention in germline BRCA1/2 gene mutation carriers.

BACKGROUND: Germline BRCA1/2 mutation 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. METHODS: The 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. RESULTS: At 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. CONCLUSION: Our results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.

Circulating pro-neurotensin levels predict bodyweight gain and metabolic alterations in children.

BACKGROUND AND AIMS: 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. METHODS AND RESULTS: 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 ß-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 ß = 0.24; p = 0.036). CONCLUSIONS: 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.

In-hospital mortality and organ failure after open and endovascular thoraco-abdominal aortic surgery can be predicted by increased levels of circulating dipeptidyl peptidase 3.

OBJECTIVES: Endovascular and open thoraco-abdominal aortic aneurysm (TAAA) repair is associated with specific complications. Circulating dipeptidyl peptidase 3 (cDPP3) is a novel biomarker that shows a strong association with organ failure which has not been assessed in surgical settings. Therefore, the objective of this study was to assess the prognostic capabilities of cDPP3 for predicting patient survival and organ failure following open and endovascular TAAA repair. METHODS: Thirty-three patients undergoing TAAA repair were assessed in this prospective observational single-centre study. cDPP3 levels were serially measured perioperatively until 72 h after admission to the intensive care unit (ICU). In-hospital mortality and any organ failure were the clinical end points. RESULTS: Postoperative organ failure was detected in 17 patients (51.5%), and 6 patients died after surgery (18.2%). At 12 h after admission to the ICU, cDPP3 levels were significantly increased in patients who died or developed organ failure (P < 0.001). cDPP3 levels after surgery demonstrated a remarkable predictive accuracy for in-hospital mortality [12 h area under the receiver operating characteristic curve (AUC): 0.907 (P < 0.001), 24 h AUC: 0.815 (P = 0.016), 48 h AUC: 0.914 (P = 0.003)] and the development of organ failure [12 h AUC: 0.882 (P < 0.001), 24 h AUC: 0.850 (P < 0.001), 48 h AUC: 0.846 (P < 0.001)]. Additionally, a significant correlation between cDPP3, the sequential organ failure assessment score and procalcitonin, C-reactive protein and interleukin-6 levels (P < 0.001, P < 0.001, P = 0.011, P = 0.007, respectively) based on all available measurements and time points was observed. CONCLUSIONS: The present findings highlight the role of cDPP3 as an early, highly specific postoperative biomarker for prediction of in-hospital mortality and organ failure after TAAA repair.