Biomarkers Improve Diagnostics of Sepsis in Adult Patients With Suspected Organ Dysfunction Based on the Quick Sepsis-Related Organ Failure Assessment (qSOFA) Score in the Emergency Department.

OBJECTIVES: Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool. DESIGN: In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission. SETTING: Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin). PATIENTS: One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79-0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively. CONCLUSIONS: Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission.

Plasma copeptin and markers of arterial disorder in patients with type 2 diabetes, a cross-sectional study.

OBJECTIVES: There is currently limited understanding of the relationship between copeptin, the midregional portion of proadrenomedullin (MRproADM) and the midregional fragment of the N-terminal of proatrial natriuretic peptide (MRproANP), and arterial disorders. Toe brachial index (TBI) and aortic pulse wave velocity (aPWV) are established parameters for detecting arterial disorders. This study evaluated whether copeptin, MRproADM, and MRproANP were associated with TBI and aPWV in patients with type 2 diabetes with no history of cardiovascular disease (CVD). METHODS: In the CARDIPP study, a cross-sectional analysis of 519 patients with type 2 diabetes aged 55-65 years with no history of CVD at baseline, had complete data on copeptin, MRproADM, MRproANP, TBI, and aPWV was performed. Linear regression analysis was used to investigate the associations between conventional CVD risk factors, copeptin, MRproADM, MRproANP, TBI, and aPWV. RESULTS: Copeptin was associated with TBI (ß-0.0020, CI-0.0035- (-0.0005), p = 0.010) and aPWV (ß 0.023, CI 0.002-0.044, p = 0.035). These associations were independent of age, sex, diabetes duration, mean 24-hour ambulatory systolic blood pressure, glycated hemoglobin A1c, total cholesterol, estimated glomerular filtration rate, body mass index, and active smoking. CONCLUSIONS: Plasma copeptin may be a helpful surrogate for identifying individuals at higher risk for arterial disorders. TRIAL REGISTRATION:  ClinicalTrials.gov identifier NCT010497377.

Mid-regional proadrenomedullin, C-terminal proendothelin-1 values, and disease course are not different in critically ill SARS-CoV-2 pneumonia patients with obesity.

BACKGROUND/OBJECTIVES: Patients affected by obesity and Coronavirus disease 2019, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appear to have a higher risk for intensive care (ICU) admission. A state of low-grade chronic inflammation in obesity has been suggested as one of the underlying mechanisms. We investigated whether obesity is associated with differences in new inflammatory biomarkers mid-regional proadrenomedullin (MR-proADM), C-terminal proendothelin-1 (CT-proET-1), and clinical outcomes in critically ill patients with SARS-CoV-2 pneumonia. SUBJECTS/METHODS: A total of 105 critically ill patients with SARS-CoV-2 pneumonia were divided in patients with obesity (body mass index (BMI) ≥ 30 kg/m2, n = 42) and patients without obesity (BMI < 30 kg/m2, n = 63) and studied in a retrospective observational cohort study. MR-proADM, CT-proET-1 concentrations, and conventional markers of white blood count (WBC), C-reactive protein (CRP), and procalcitonin (PCT) were collected during the first 7 days. RESULTS: BMI was 33.5 (32-36.1) and 26.2 (24.7-27.8) kg/m2 in the group with and without obesity. There were no significant differences in concentrations MR-proADM, CT-proET-1, WBC, CRP, and PCT at baseline and the next 6 days between patients with and without obesity. Only MR-proADM changed significantly over time (p = 0.039). Also, BMI did not correlate with inflammatory biomarkers (MR-proADM rho = 0.150, p = 0.125, CT-proET-1 rho = 0.179, p = 0.067, WBC rho = -0.044, p = 0.654, CRP rho = 0.057, p = 0.564, PCT rho = 0.022, p = 0.842). Finally, no significant differences in time on a ventilator, ICU length of stay, and 28-day mortality between patients with or without obesity were observed. CONCLUSIONS: In critically ill patients with confirmed SARS-CoV-2 pneumonia, obesity was not associated with differences in MR-proADM, and CT-proET-1, or impaired outcome. TRIAL REGISTRATION: Netherlands Trial Register, NL8460.

Utility of Measuring Circulating Bio-Adrenomedullin and Proenkephalin for 30-Day Mortality Risk Prediction in Patients with COVID-19 and Non-COVID-19 Interstitial Pneumonia in the Emergency Department.

Background and Objectives: In order to accelerate the risk stratification of patients referred to the Emergency Department (ED) with interstitial pneumonia, it could be useful to provide new and effective laboratory tests for use. The aim of our study was to evaluate the prognostic role of two biomarkers, bio-adrenomedullin (Bio-ADM) and proenkephalin (penKid), in patients with interstitial pneumonia (IP) at ED admission. Materials and Methods: In 153 consecutive patients with IP, both from COVID-19 or non-COVID-19 etiology, we measured, in a prospective observational manner, penKid and Bio-ADM at ED admission and after 24 h. In order to evaluate patient outcomes, 30-day follow-ups were also performed. The endpoints were 24 h, 10-day, and 30-day mortality. Results: Both biomarkers were shown to be good predictors of adverse events at 30 days, with Bio-ADM outperforming penKid. Bio-ADM was linked with 24 h and 10-day patient mortality. Moreover, PenKid was related to parameters defining worsening kidney function. Conclusions: Both in patients with COVID-19 or non-COVID-19 interstitial pneumonia at ED admission, Bio-ADM and penKid were good predictors of patient mortality. To evaluate these two biomarkers could be considered to be useful during the first evaluation in the ED when integrated with clinical scores.

Adrenomedullin Is a Diagnostic and Prognostic Biomarker for Acute Intracerebral Hemorrhage.

Hemorrhagic stroke remains an important health challenge. Adrenomedullin (AM) is a vasoactive peptide with an important role in cardiovascular diseases, including stroke. Serum AM and nitrate-nitrite and S-nitroso compounds (NOx) levels were measured and compared between healthy volunteers (n = 50) and acute hemorrhagic stroke patients (n = 64). Blood samples were taken at admission (d0), 24 h later (d1), and after 7 days or at the time of hospital discharge (d7). Neurological severity (NIHSS) and functional prognosis (mRankin) were measured as clinical outcomes. AM levels were higher in stroke patients at all times when compared with healthy controls (p < 0.0001). A receiving operating characteristic curve analysis identified that AM levels at admission > 69.0 pg/mL had a great value as a diagnostic biomarker (area under the curve = 0.89, sensitivity = 80.0%, specificity = 100%). Furthermore, patients with a favorable outcome (NIHSS ≤ 3; mRankin ≤ 2) experienced an increase in AM levels from d0 to d1, and a decrease from d1 to d7, whereas patients with unfavorable outcome had no significant changes over time. NOx levels were lower in patients at d0 (p = 0.04) and d1 (p < 0.001) than in healthy controls. In conclusion, AM levels may constitute a new diagnostic and prognostic biomarker for this disease, and identify AM as a positive mediator for hemorrhagic stroke resolution.

MR-proADM as marker of endotheliitis predicts COVID-19 severity.

BACKGROUND: Early identification of patients at high risk of progression to severe COVID-19 constituted an unsolved challenge. Although growing evidence demonstrates a direct association between endotheliitis and severe COVID-19, the role of endothelial damage biomarkers has been scarcely studied. We investigated the relationship between circulating mid-regional proadrenomedullin (MR-proADM) levels, a biomarker of endothelial dysfunction, and prognosis of SARS-CoV-2-infected patients. METHODS: Prospective observational study enrolling adult patients with confirmed COVID-19. On admission to emergency department, a blood sample was drawn for laboratory test analysis. Primary and secondary endpoints were 28-day all-cause mortality and severe COVID-19 progression. Area under the curve (AUC) and multivariate regression analysis were employed to assess the association of the biomarker with the established endpoints. RESULTS: A total of 99 patients were enrolled. During hospitalization, 25 (25.3%) cases progressed to severe disease and the 28-day mortality rate was of 14.1%. MR-proADM showed the highest AUC to predict 28-day mortality (0.905; [CI] 95%: 0.829-0.955; P < .001) and progression to severe disease (0.829; [CI] 95%: 0.740-0.897; P < .001), respectively. MR-proADM plasma levels above optimal cut-off (1.01 nmol/L) showed the strongest independent association with 28-day mortality risk (hazard ratio [HR]: 10.470, 95% CI: 2.066-53.049; P < .005) and with progression to severe disease (HR: 6.803, 95% CI: 1.458-31.750; P = .015). CONCLUSION: Mid-regional proadrenomedullin was the biomarker with highest performance for prognosis of death and progression to severe disease in COVID-19 patients and represents a promising predictor for both outcomes, which might constitute a potential tool in the assessment of prognosis in early stages of this disease.

Copeptin, pro-atrial natriuretic peptide and pro-adrenomedullin as markers of hypoxic stress in patients with obstructive sleep apnea-a prospective intervention study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) might lead to oxidative stress, inflammation and elevated circulating copeptin, proANP and proADM levels. We aimed to evaluate whether the levels of these prohormones are higher in patients with OSA and whether they might change under continuous positive airway pressure (CPAP) therapy, serving as potential proxies for the diagnosis and therapy-response in OSA. METHODS: A total of 310 patients with suspicion of OSA were recruited. Screening for OSA was performed using overnight pulse oximetry followed by polygraphy and a venous puncture in the morning. All patients diagnosed with OSA underwent CPAP adaptation. A venous puncture was conducted in the night before CPAP and in the following morning. At 1 and 6 months of treatment, polygraphy was performed, followed by a venous puncture in the morning. In the acquired blood, copeptin, proANP and proADM levels were measured. RESULTS: We analyzed 232 patients with OSA and 30 patients without OSA. Our results indicated that only copeptin levels differed significantly among patients with and without OSA at baseline. In OSA patients, the levels of proADM significantly changed after 1 and 6 months on CPAP therapy, when compared to baseline (p < 0.001 and p = 0.020). Additionally, proANP levels significantly decreased after 12 h on CPAP therapy, as compared to baseline levels (p < 0.001). CONCLUSIONS: Copeptin is significantly associated with the presence of OSA. ProANP levels might serve as a potential proxy for the acute response to non-invasive ventilation (12 h), while proADM reflects the long-term response (1 and 6 months).

Prognostic value of pro-adrenomedullin and copeptin in acute infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is a life-threatening disease whose prognosis is often difficult to predict based on clinical data. Biomarkers have been shown to favorably affect disease management in a number of cardiac disorders. Aims of this retrospective study were to assess the prognostic role of procalcitonin (PCT), pro-adrenomedullin (pro-ADM) and copeptin in IE and their relation with disease characteristics and the traditional biomarker C-reactive protein (CRP). METHODS: We studied 196 patients with definite IE. Clinical, laboratory and echocardiography parameters were analyzed, with a focus on co-morbidities. PCT, pro-ADM and copeptin were measured on stored plasma samples obtained on admission during the acute phase of the disease. RESULTS: Pro-ADM and copeptin were significantly higher in older patients and associated with prior chronic kidney disease. Pro-ADM was an independent predictor of hospital mortality (OR 3.29 [95%C.I. 1.04-11.5]; p = 0.042) whilst copeptin independently predicted 1-year mortality (OR 2.55 [95%C.I. 1.18-5.54]; p = 0.017). A high PCT value was strictly tied with S. aureus etiology (p = 0.001). CRP was the only biomarker associated with embolic events (p = 0.003). CONCLUSIONS: Different biomarkers correlate with distinct IE outcomes. Pro-ADM and copeptin may signal a worse prognosis of IE on admission to the hospital and could be used to identify patients who need more aggressive treatment. CRP remains a low-cost marker of embolic risk. A high PCT value should suggest S. aureus etiology.

The vasoactive peptide MR-pro-adrenomedullin in COVID-19 patients: an observational study.

OBJECTIVES: Midregional pro-adrenomedullin (MR-proADM) is a vasoactive peptide with key roles in reducing vascular hyperpermeability and thereby improving endothelial stability during infection. While MR-proADM is useful for risk stratification in patients with sepsis, clinical data about prediction accuracy in patients with severe acute respiratory syndrome coronavirus 2 disease (COVID-19) is currently missing. METHODS: We included consecutively adult patients hospitalized for confirmed COVID-19 at a tertiary care center in Switzerland between February and April 2020. We investigated the association of MR-proADM levels with in-hospital mortality in logistic regression and discrimination analyses. RESULTS: Of 89 included COVID-19 patients, 19% (n=17) died while in the hospital. Median admission MR-proADM levels (nmol/L) were increased almost 1.5-fold increased in non-survivors compared to survivors (1.3 [interquartile range IQR 1.1-2.3]) vs. 0.8 [IQR 0.7-1.1]) and showed good discrimination (area under the curve 0.78). An increase of 1 nmol/L of admission MR-proADM was independently associated with a more than fivefold increase in in-hospital mortality (adjusted odds ratio of 5.5, 95% confidence interval 1.4-21.4, p=0.015). An admission MR-proADM threshold of 0.93 nmol/L showed the best prognostic accuracy for in-hospital mortality with a sensitivity of 93%, a specificity of 60% and a negative predictive value of 97%. Kinetics of follow-up MR-proADM provided further prognostic information for in-hospital treatment. CONCLUSIONS: Increased levels of MR-proADM on admission and during hospital stay were independently associated with in-hospital mortality and may allow a better risk stratification, and particularly rule-out of fatal outcome, in COVID-19 patients.

The effect of swimming training on adrenomedullin levels, oxidative stress variables, and gastrocnemius muscle contractile properties in hypertensive rats.

Introduction/Aim: Regular exercise may have beneficial effects on high blood-pressure, as shown in different types of experimental hypertension models in rats. The present study aims to investigate the effects of 6-week swimming training on blood pressure, oxidative stress variables of selected tissues, serum adrenomedullin (ADM) levels, and in situ muscle contraction in rats with hypertension induced by Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of endothelial nitric oxide synthases (eNOs). Materials and Methods: Twenty-six male Sprague Dawley, 8 weeks of age, rats were randomly divided into four groups: (I) normotensive (C), (II) normotensive + exercise (E), (III) hypertensive (L), and (IV) hypertensive + exercise (LE). Hypertension was induced by the oral administration of L-NAME (60 mg/kg) for 6 weeks. Exercise was performed 5 times (1-h each) per week for 6 weeks. At the end of the experiment, blood and tissue samples (the gastrocnemius muscle, heart, kidney, and thoracic aorta) were collected following contractile properties of the gastrocnemius muscle in situ weredetermined. In the collected tissues, oxidative stress (e.g., lipid oxidation and antioxidant enzyme activity) and serum ADM levels were measured. 6-week L-NAME administration per se (Group L) led to a significant increase in systolic and diastolic blood pressure compared to other groups.  Results: Importantly, 6-week exercise caused a protective effect of high blood pressure in the rats received L-NAME (Group LE). The level of ADM was lower in the rats received L-NAME than that of the control group. L-NAME increased lipid peroxidation in the thoracic aorta and decreased superoxide dismutase in the heart, kidney and muscle, and decreased catalase and glutathione in the heart. However, the exercise intervention did not have protective effect on the L-NAME-mediated oxidative damage in the collected tissues.  Conclusion: In conclusion, 6-week exercise intervention rescued rats from high blood pressure, but did not have ameliorative effect on the decreased ADM levels.

Pro B-type Natriuretic Peptide and Midregional Proadrenomedullin are Associated with Incident Carotid Stenosis During Long Term Follow-up.

BACKGROUND: Plasma biomarkers may be useful to detect healthy individuals at increased risk for atherosclerotic manifestations, such as carotid artery stenosis. The aim of this longitudinal cohort study was to evaluate new biomarkers in relation to C-reactive protein and conventional risk factors for carotid artery stenosis during long term follow-up METHODS: The following markers were measured in 5550 middle-aged subjects: C-reactive protein, lipoprotein-associated phospholipase A2, proneurotensin, midregional pro-adrenomedullin, midregional pro-atrial natriuretic peptide, N-terminal pro B-type natriuretic peptide, copeptin, and cystatin C. Subjects with prevalent carotid artery stenosis were excluded. Subjects were followed in national patient registers for 23.4 (interquartile range 19.5-24.3) years regarding incident carotid artery stenosis, both operated and non-operated. RESULTS: When including conventional risk markers in Cox regression, N-terminal pro B-type natriuretic peptide (Hazard ratio 1.36; 95% confidence interval 1.12-1.65; p = 0.002) was independently associated with incident carotid artery stenosis, whereas there were trends for C-reactive protein (HR 1.20; 95% confidence interval 0.98-1.48; p = 0.071), and midregional pro-adrenomedullin (Hazard ratio 1.21; 95% confidence interval 0.99-1.47; p = 0.061). Midregional pro-adrenomedullin (Hazard ratio 1.30; 95% confidence interval 1.03-1.65; p = 0.029) was independently associated with incident surgery for carotid artery stenosis, whereas there was a trend for N-terminal pro B-type natriuretic peptide (Hazard ratio 1.31; 95% confidence interval 1.00-1.72; p = 0.052). CONCLUSIONS: N-terminal pro B-type natriuretic peptide and midregional pro-adrenomedullin can be used as predictors for clinically detected carotid artery stenosis during long-term follow-up of healthy subjects.

Use of proteomics to identify biomarkers associated with chronic kidney disease and long-term outcomes in patients with myocardial infarction.

BACKGROUND: Patients with chronic kidney disease (CKD) have poor outcomes following myocardial infarction (MI). We performed an untargeted examination of 175 biomarkers to identify those with the strongest association with CKD and to examine the association of those biomarkers with long-term outcomes. METHODS: A total of 175 different biomarkers from MI patients enrolled in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry were analysed either by a multiple reaction monitoring mass spectrometry assay or by a multiplex assay (proximity extension assay). Random forests statistical models were used to assess the predictor importance of biomarkers, CKD and outcomes. RESULTS: A total of 1098 MI patients with a median estimated glomerular filtration rate of 85 mL min-1 /1.73 m2 were followed for a median of 3.2 years. The random forests analyses, without and with adjustment for differences in demography, comorbidities and severity of disease, identified six biomarkers (adrenomedullin, TNF receptor-1, adipocyte fatty acid-binding protein-4, TNF-related apoptosis-inducing ligand receptor 2, growth differentiation factor-15 and TNF receptor-2) to be strongly associated with CKD. All six biomarkers were also amongst the 15 strongest predictors for death, and four of them were amongst the strongest predictors of subsequent MI and heart failure hospitalization. CONCLUSION: In patients with MI, a proteomic approach could identify six biomarkers that best predicted CKD. These biomarkers were also amongst the most important predictors of long-term outcomes. Thus, these biomarkers indicate underlying mechanisms that may contribute to the poor prognosis seen in patients with MI and CKD.

Bioactive Adrenomedullin, Organ Support Therapies, and Survival in the Critically Ill: Results from the French and European Outcome Registry in ICU Study.

OBJECTIVES: Adrenomedullin has vascular properties and elevated plasma adrenomedullin levels were detected in sepsis. We assessed, in septic and nonseptic ICU patients, the relation between circulating adrenomedullin, the need for organ support and mortality, using an assay of bioactive adrenomedullin. DESIGN: Prospective multicenter observational cohort study. SETTING: Data from the French and euRopean Outcome reGistry in ICUs study. PATIENTS: Consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 hours following ICU admission and discharged from ICU were included. INTERVENTIONS: Clinical and biological parameters were collected at baseline, including bioactive-adrenomedullin. Status of ICU survivors was assess until 1 year after discharge. The main outcome was the need for organ support, including renal replacement therapy and/or for inotrope(s) and/or vasopressor(s). Secondary endpoints were the ICU length of stay and the 28-day all-cause mortality. MEASUREMENTS AND MAIN RESULTS: Median plasma bioactive adrenomedullin (n = 2,003) was 66.6 pg/mL (34.6-136.4 pg/mL) and the median Simplified Acute Physiology Score II score 49 (36-63). Renal replacement therapy was needed in 23% and inotropes(s) and/or vasopressor(s) in 77% of studied patients. ICU length of stay was 13 days (7-21 d) and mortality at 28 days was 22 %. Elevated bioactive adrenomedullin independently predicted 1) the need for organ support (odds ratio, 4.02; 95% CI, 3.08-5.25) in ICU patients whether admitted for septic or nonseptic causes and 2) the need for renal replacement therapy (odds ratio, 4.89; 3.83-6.28), and for inotrope(s) and/or vasopressor(s) (odds ratio, 3.64; 2.84-4.69), even in patients who were not on those supports at baseline. Elevated bioactive adrenomedullin was also associated with a prolonged length of stay (odds ratio, 1.85; 1.49-2.29) and, after adjustment for Simplified Acute Physiology Score II, with mortality (odds ratio, 2.31; 1.83-2.92). CONCLUSIONS: Early measurement of bioactive adrenomedullin is a strong predictor of the need of organ support and of short-term mortality in critically ill patients.

Associations of cardiac stress biomarkers with incident type 2 diabetes and changes in glucose metabolism: KORA F4/FF4 study.

BACKGROUND: High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism. METHODS: We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates. RESULTS: During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors. CONCLUSIONS: High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.

MR-proANP and incident cardiovascular disease in patients with type 2 diabetes with and without heart failure with preserved ejection fraction.

BACKGROUND: Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D. METHODS: We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6-17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP. RESULTS: A total of 126 CV events occurred (median follow-up 4.8 [4.1-5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89-202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64-4.00] and 3.32 [1.64-6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32-56] pmol/l) did not have an increased risk (HR 2.18 [0.78-6.14]). CONCLUSIONS: Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.

Impact of adrenomedullin levels on clinical risk stratification and outcome in subarachnoid haemorrhage.

PURPOSE: To use classification tree analysis to identify risk factors for nonsurvival in a neurological patients with subarachnoid haemorrhage (SAH) and to propose a clinical model for predicting of mortality. METHODS: Prospective study of SAH admitted to a Critical Care Department and Stroke Unit over a 2-year period. Middle region of pro-ADM plasma levels (MR-proADM) was measured in EDTA plasma within the first 24 hours of hospital admission using the automatic immunofluorescence test. A regression tree was made to identify prognostic models for the development of mortality at 90 days. RESULTS: Ninety patients were included. The mean MR-proADM plasma value in the samples analysed was 0.78 ± 0.41 nmol/L. MR-proADM plasma levels were significantly associated with mortality at 90 days (1.05 ± 0.51 nmol/L vs 0.64 ± 0.25 nmol/L; P < .001). Regression tree analysis provided an algorithm based on the combined use of clinical variables and one biomarker allowing accurate mortality discrimination of three distinct subgroups with high risk of 90-day mortality ranged from 75% to 100% (AUC 0.9; 95% CI 0.83-0.98). CONCLUSIONS: The study established a model (APACHE II, MR-proADM and Hunt&Hess) to predict fatal outcomes in patients with SAH. The proposed decision-making algorithm may help identify patients with a high risk of mortality.

MR- proADM to detect specific types of organ failure in infection.

BACKGROUND: Following the SEPSIS-3 consensus, detection of organ failure as assessed by the SOFA (Sequential Organ Failure Assessment) score, is mandatory to detect sepsis. Calculating SOFA outside of the Intensive Care Unit (ICU) is challenging. The alternative in this scenario, the quick SOFA, is very specific but less sensible. Biomarkers could help to detect the presence of organ failure secondary to infection either in ICU and non-ICU settings. MATERIALS AND METHODS: We evaluated the ability of four biomarkers (C-Reactive protein (CRP), lactate, mid-regional proadrenomedullin (MR-proADM) and procalcitonin (PCT)) to detect each kind of organ failure considered in the SOFA in 213 patients with infection, sepsis or septic shock, by using multivariate regression analysis and calculation of the area under the receiver operating curve (AUROC). RESULTS: In the multivariate analysis, MR-proADM was an independent predictor of five different failures (respiratory, coagulation, cardiovascular, neurological and renal). In turn, lactate predicted three (coagulation, cardiovascular and neurological) and PCT two (cardiovascular and renal). CRP did not predict any of the individual components of SOFA. The highest AUROCs were those of MR-proADM and PCT to detect cardiovascular (AUROC, CI95%): MR-proADM (0.82 [0.76-0.88]), PCT (0.81 [0.75-0.87] (P < .05) and renal failure: MR-proADM (0.87 [0.82-0.92]), PCT (0.81 [0.75-0.86]), (P < .05). None of the biomarkers tested was able to detect hepatic failure. CONCLUSIONS: In patients with infection, MR-proADM was the biomarker detecting the largest number of SOFA score components, with the exception of hepatic failure.

Biomarker dynamics in cardiac surgery: a prospective observational study on MR-proADM, MR-proANP, hs-CRP and sP-selectin plasma levels in the perioperative period.

Background: For many biomarkers in cardiac surgery, there is a lack of knowledge regarding the normal dynamics of plasma levels during the perioperative course. The aim of this study was to investigate the perioperative dynamics of MR-proADM, MR-proANP, hs-CRP and sP-selectin in cardiac surgery.Method: A prospective observational pilot study with 20 patients scheduled for open cardiac surgery procedures with cardiopulmonary bypass (CPB). Plasma samples were taken for each patient and biomarker during the pre-, per- and postoperative period until Day 6 postoperatively.Results: MR-proADM increased significantly from 0.62 [IQR; 0.54-0.93] nmol/L preoperatively to 1.20 [1.04-1.80] nmol/L postoperative Day 1. MR-proANP increased significantly from 125 [77-152] pmol/L preoperatively to 198 [168-307] pmol/L on weaning from CPB. hs-CRP increased significantly from 2.5 mg/L [0.4-12] preoperatively to peak at 208 mg/L [186-239] postoperative Day 3. The preoperative level of sP-selectin at 23.0 [21.3-26.3] ng/mL initially fell at weaning from CPB, followed by a significant peak of 25.5 [22.7-27.7] ng/mL 8 h postoperatively.Conclusions: The findings in this study may help to understand the physiology of the biomarkers analysed and their response to cardiac surgical trauma including CPB. Furthermore, these findings will guide us in further research on the clinical usefulness of these biomarkers.

Mortality in cardiogenic shock is stronger associated to clinical factors than contemporary biomarkers reflecting neurohormonal stress and inflammatory activation.

PURPOSE: To validate the IABP-SHOCK II risk score in a Danish cohort and assess the association between the IABP-SHOCK II risk score and admission concentration of biomarkers reflecting neurohormonal - (Copeptin, Pro-atrial natriuretic peptide (proANP), Mid-regional pro-adrenomedullin (MRproADM)) and inflammatory (ST2) activation in patients with CS complicating ST segment elevation myocardial infarction (STEMI). METHODS: A total of 137 consecutive patients admitted with STEMI and CS at two tertiary heart centres were stratified according to the IABP-SHOCK II risk score (0-2; 3/4; 5-9), and had blood sampled upon admission. RESULTS: Plasma concentrations of Copeptin (median (pmol/L) score 0-2: 313; score 3/4: 682; score 5-9: 632 p < 0.0001), proANP (pmol/L) (1459; 2225; 2876 p = 0.0009) and MRproADM (nmol/L) (0.86; 1.2; 1.4 p = 0.04) were significantly associated with the risk score, whereas ST2 (ng/mL) was not (44; 60; 45 p = 0.23). The IABP-SHOCK II risk score predicted 30-day mortality (score 0-2: 22%; score 4/3: 51%; score 5-9: 72%, area under the curve (AUC): 0.73, plogrank < 0.0001), while the tested biomarkers did not (AUC: 0.51

Pro-adrenomedullin in acute decompensation of liver cirrhosis: relationship with acute-on-chronic liver failure and short-term survival.

Background and aim: Acute-on-chronic liver failure (ACLF) is characterized by the presence of acute decompensation (AD) of cirrhosis, organ failures, and high short-term mortality rates. In present study, we explored whether Pro-adrenomedullin (Pro-ADM), a biomarker of sepsis, is a potential marker of outcome in patients admitted for AD or ACLF and whether it might be of additional value to conventional prognostic scoring systems in these patients.Methods: 332 consecutive patients with AD of cirrhosis were prospectively enrolled. Pro-ADM was measured for all patients at baseline. Cox regression analysis was used to evaluate the impact of pro-ADM on short-term survival and developing ACLF during hospital stay.Results: Serum pro-ADM levels were significantly high in non-survivors (p < .001) and showed significant correlation with ALT (r = 0.181, p = .001), INR (r = 0.144, p = .009), TB (r = 0.368, p < .001), Creatinine (r = 0.145, p = .004), MELD score (r = 0.334, p = <.001) and CLI-C OF score (r = 0.375, p= <.001). Serum pro-ADM at admission was shown to be a predictor of 28-day mortality independently of MELD and CLIF-C OF scores. Prognostic models incorporating pro-ADM achieved high C index for predicting 28-day mortality in AD patients of cirrhosis. Moreover, baseline pro-ADM was found to be predictive of ACLF development during hospital stay.Conclusions: Serum pro-ADM levels correlate with multiorgan failure and are independently associated with short-term survival and ACLF development in patients admitted for AD or ACLF.