Mid-regional Pro-adrenomedullin Research Articles

A17402 Mid-regional proadrenomedullin predicts reduced blood pressure and glucose elevation over time despite enhanced progression of obesity markers

A17402 Mid-regional proadrenomedullin predicts reduced blood pressure and glucose elevation over time despite enhanced progression of obesity markers

Prognostic value of plasma MR-proADM vs NT-proBNP for heart failure in people with type 2 diabetes: the SURDIAGENE prospective study.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes. Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation. We included 1438 participants (age 65 ± 11years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (adjHR [95%CI] 1.83 [1.51, 2.21] and 2.20 [1.86, 2.61], respectively, per 1 SD log10 increment, both p < 0.001). MR-proADM contributed significant supplementary information to the prognosis of heart failure when we considered the clinical risk factors (integrated discrimination improvement [IDI, mean ± SEM] 0.021 ± 0.007, p = 0.001) (Table 3). Inclusion of NT-proBNP in the multivariable model including MR-proADM contributed significant complementary information on prediction of heart failure (IDI [mean ± SEM] 0.028 ± 0.008, p < 0.001). By contrast, MR-proADM did not contribute supplementary information on prediction of heart failure in a model including NT-proBNP (IDI [mean ± SEM] 0.003 ± 0.003, p = 0.27), with similar results for heart failure with reduced ejection fraction and preserved ejection fraction. MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.

Plasma levels of mid-regional pro-adrenomedullin in sepsis are associated with risk of death.

Identifying Intensive Care Unit (ICU) patients with sepsis and predicting the risk of death are unmet clinical needs. Prospective observational single-center study of 120 consecutive ICU patients with suspected severe sepsis at Jerez Hospital. Epidemiological, clinical, laboratory data and MR-proADM, Procalcitonin (PCT) and C-reactive protein (CRP) levels were recorded at ICU admission and follow-up. At ICU discharge, 104 patients were diagnosed with severe sepsis and 39 died. Plasma MR-proADM was highly indicative of sepsis: 4.05 nmol/L vs. of 0.309 nmol/L (P<0.001), with area under the ROC curve (AUC-ROC) was 0.947. At 48 hours following admission, the median MR-proADM levels in surviving sepsis patients fell to 1.65 nmol/L but remained higher in the non-survivors (2.475 nmol/L) (P=0.04). On day 5 the levels fell to 1.36 nmol/L in surviving sepsis patients vs. 3.42 nmol/L in the non-survivors (P<0.001). On day 5 the survivors showed greater MR-proADM clearance (62.7% vs. 21.2%). The AUC-ROC on day 5 was 0.825, PCT 0.725 and CRP 0.700. The AUC-ROC to MR-proADM clearance on day 5 was 0.734. In a multivariable model, MR-proADM levels at 48 hours and on day 5 and clearance on day 5 following admission were statistically significant predictive factors of mortality. In clinical practice, in ICU patients admitted with SIRS and organ dysfunction, an MR-proADM cut-off point of 1.425 nmol/L helps to identify those with sepsis. An MR-proADM value above 5.626 nmol/L 48 hours after admission was associated with a high risk of death.

Mid-Regional Pro-Adrenomedullin (MR-proADM) as a Biomarker for Sepsis and Septic Shock: Narrative Review.

Early identification and diagnosis of sepsis and septic shock is vitally important; despite appropriate management, mortality and morbidity rates remain high. For this reason, many biomarkers and screening systems have been investigated in accordance with the precision medicine concept. A narrative review was conducted to assess the role of mid-regional pro-adrenomedullin (MR-proADM) as a biomarker for sepsis and septic shock. Relevant studies were collected via an electronic PubMed, Web of Science, and The Cochrane Library search. The review focused on both diagnosis and prognosis in patients with sepsis and septic shock and specifically in subpopulations of patients with sepsis and septic shock with burns or malignant tumors. No exclusion criteria regarding age, sex, intensive care unit admission, follow-up duration, or co morbidities were used so as to maximize sensitivity and due to lack of randomized controlled trials, opinion paper and reviews were also included in this review. A total of 22 studies, one opinion paper, and one review paper were investigated. MR-proADM levels were found to be useful in assessing patients’ initial evolution and become even more useful during follow-up with increased area under curve values in the mortality prognosis by exceeding values of 0.8 in the data shown in several studies. These results also improve along with other biomarkers or severity scores and especially correlate with the organ failure degree. The results of this study indicate that MR-proADM is a good biomarker for the diagnosis and prognosis of sepsis and septic shock patients as well as for organ failure. Although several publications have discussed its role as a biomarker for pneumonia, its value as a biomarker for sepsis and septic shock should now be assessed in randomized controlled trials and more collaborative prospective studies with larger patient samples.

Mid-regional pro-adrenomedullin predicts poor outcome in non-selected patients admitted to an intensive care unit

Background Mortality risk and outcome in critically ill patients can be predicted by scoring systems, such as APACHE and SAPS. The identification of prognostic biomarkers, simple to measure upon admission to an intensive care unit (ICU) is an open issue. The aim of this observational study was to assess the prognostic value of plasma mid-regional pro-adrenomedullin (MR-proADM) at ICU admission in non-selected patients in comparison to Acute Physiology and Chronic Health Evaluation II (APACHEII) and Simplified Acute Physiology Score II (SAPSII) scores. Methods APACHEII and SAPSII scores were calculated after 24 h from ICU admission. Plasma MR-proADM levels were measured by TRACE-Kryptor on admission (T0) and after 24 h (T24). The primary endpoint was intra-hospital mortality; secondary endpoint was length of stay (LOS). Results One hundred and twenty-six consecutive non-selected patients admitted to an ICU were enrolled. Plasma MR-proADM levels were correlated with LOS (r=0.28; p=0.0014 at T0; r=0.26; p=0.005 at T24). Multivariate analysis showed that T0 MR-proADM was a significant predictor of mortality (odds ratio [OR]: 1.27; 95% confidence interval [95%CI]: 1.03-1.55; p=0.022). Receiver operating characteristic curves analysis revealed that MR-proADM on ICU admission identified non-survivors with high accuracy, not inferior to the one of APACHEII and SAPSII scores (area under the curve [AUC]: 0.71; 95%CI: 0.62-0.78; p=0.0002 for MR-proADM; AUC: 0.71; 95%CI: 0.62-0.79; p<0.0001 for APACHEII; AUC: 0.8; 95%CI: 0.71-0.87; p<0.0001 for SAPSII). Conclusions Our findings point out a role of MR-proADM as a prognostic tool in non-selected patients in ICUs being a reliable predictor of mortality and LOS and support its use on admission to an ICU to help the management of critically ill patients.

Mid regional pro-adrenomedullin for the prediction of organ failure in infection. Results from a single centre study.

Biomarkers are widely used to confirm the presence of infection. However, it would be of the greatest importance to predict in advance the occurrence or worsening of organ dysfunction in infected patients allowing timely antibiotic escalation. This study investigates the ability of procalcitonin (PCT) and MR-proADM to predict the transition to sepsis in infected patients. The study was conducted in a neurointensive care unit over a three-month period. We included both patients with and without infection to investigate the specificity of organ dysfunction prediction in infected patients. Daily measurement of PCT and MR-proADM, SOFA, Pitt, and CPIS were performed. To measure the correlation between each biomarker and each severity score, linear mixed-effects models were developed. For each biomarker-score combination we tested the correlation of the score with the biomarker measured one and two days before, the same day, and the day after. Sixty-four critically ill patients, 31 with infection, were enrolled. The statistically significant biomarker-score combinations were PCT-SOFA, MR-proADM-SOFA, MR-proADM-Pitt, and MR-proADM-CPIS. The MR-proADM models predicting Pitt and CPIS variations with 24-hour anticipation showed the best fit. The scores increased by 0.6 ± 0.3 and 0.4 ± 0.2 for each unitary biomarker increase, respectively. The MR-proADM-SOFA combinations were equivalent when the biomarker was measured the day before or the same day (score increases were 1.5 ± 0.4 and 1.9 ± 0.4, respectively). The PCT-SOFA model had the best fit when PCT was measured the same day of the score. There was no difference in the predictive ability of the biomarker in infected and non-infected patients. This was a pivotal study conducted in a single neurointensive centre on a limited number of patients, and as such it does not provide definitive conclusions. PR-proADM predicted occurrence and worsening of organ failure in critically ill patients with and without infection. The combination with infection diagnostic biomarkers such as PCT would allow predicting evolution to sepsis in infected patients.

Procalcitonin and MR-Proadrenomedullin Combination with SOFA and qSOFA Scores for Sepsis Diagnosis and Prognosis: A Diagnostic Algorithm.

The third Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as an organ dysfunction consequent to infection. A Sequential Organ Failure Assessment (SOFA) score at least 2 identifies sepsis. In this study, procalcitonin (PCT) and midregional pro-adrenomedullin (MR-proADM) were evaluated along with SOFA and quick SOFA (qSOFA) scores in patients with sepsis or septic shock. A total of 109 septic patients and 50 patients with noninfectious disease admitted at the Department of Internal Medicine and General Surgery of the University Hospital Campus Bio-Medico of Rome were enrolled. PCT and MR-proADM were measured with immunoluminometric assays (Brahms, Hennigsdorf, Germany). Data were analyzed with receiver-operating characteristic (ROC) curve analysis, likelihood ratios, and Mann-Whitney U test using MedCalc 11.6.1.0 package. At ROC curve analysis, PCT showed the highest area under the curve and positive likelihood ratio values of 27.42 in sepsis and 43.62 in septic shock. MR-proADM and SOFA score showed a comparable performance. In septic shock, lactate showed the most accurate diagnostic ability. In sepsis, the best combination was PCT with MR-proADM with a posttest probability of 0.988. Based upon these results, an algorithm for sepsis and septic shock diagnosis has been developed. MR-proADM, SOFA, and qSOFA scores significantly discriminated survivors from nonsurvivors. PCT and MR-proADM test combination represent a good tool in sepsis diagnosis and prognosis suggesting their inclusion in the diagnostic algorithm besides SOFA and qSOFA scores. Furthermore, MR-proADM as marker of organ dysfunction, with a turn around time of about 30 min, has the advantage to be more objective and rapid than SOFA score.

Evaluation of the vasoactive-inotropic score, mid-regional pro-adrenomedullin and cardiac troponin I as predictors of low cardiac output syndrome in children after congenital heart disease surgery.

To determine the predictive value of the inotropic score (IS) and vasoactive-inotropic score (VIS) in low cardiac output syndrome (LCOS) in children after congenital heart disease surgery involving cardiopulmonary bypass (CPB), and to establish whether mid-regional pro-adrenomedullin (MR-proADM) and cardiac troponin I (cTn-I), associated to the IS and VIS scores, increases the predictive capacity in LCOS. A prospective observational study was carried out. A Paediatric Intensive Care Unit. A total of 117children with congenital heart disease underwent CPB. Patients were divided into two groups: LCOS and non-LCOS. The clinical and analytical data were recorded at 2, 12, 24 and 48h post-CPB. Logistic regression was used to develop a risk prediction model using LCOS as dependent variable. LCOS, IS, VIS, MR-proADM, cTn-I, age, sex, CPB time, PIM-2, Aristotle score. While statistical significance was not recorded for IS in the multivariate analysis, VIS was seen to be independently associated to LCOS. On the other hand, VIS>15.5 at 2h post-CPB, adjusted for age and CPB timepoints, showed high specificity (92.87%; 95%CI: 86.75-98.96) and increased negative predictive value (75.59%, 95%CI: 71.1-88.08) for the diagnosis of LCOS at 48h post-CPB. The predictive power for LCOS did not increase when VIS was combined with cTn-I >14ng/ml at 2h and MR-proADM >1.5nmol/l at 24h post-CPB. The VIS score at 2h post-CPB was identified as an independent early predictor of LCOS. This predictive value was not increased when associated with LCOS cardiac biomarkers. The VIS score was more useful than IS post-CPB in making early therapeutic decisions in clinical practice post-CPB.

Elevated levels of adrenomedullin in eutopic endometrium and plasma from women with endometriosis

To test adrenomedullin (Adm, ADM) as a downstream target of signal transducer and activator of transcription 3 (STAT3) in endometrial cells and to test midregional proadrenomedullin (MR-proADM) as a biomarker of endometriosis. Cross-sectional analysis of Adm expression in eutopic endometrium and of MR-proADM in plasma from women with and without endometriosis; and prospective study of MR-proADM levels in women with endometriosis undergoing surgical resection of ectopic lesions. Academic medical centers. Fifteen patients with endometriosis and 11 healthy control subjects who donated eutopic endometrial biopsies; and 28 patients with endometriosis and 19 healthy control subjects who donated plasma for MR-proADM analysis. None. Adm mRNA levels according to quantitative real-time polymerase chain reaction after activation of STAT3 by interleukin-6 (IL-6) in Ishikawa cells; immunohistochemistry for ADM in eutopic endometrial biopsies from women with endometriosis compared with healthy donors; and MR-proADM levels measured by commercial immunoassay in plasma from healthy women and women with endometriosis who subsequently underwent surgical resection of ectopic lesions. Activation of STAT3 by IL-6 up-regulated Adm mRNA expression in Ishikawa cells. ADM protein levels were elevated in the eutopic endometrium of women with endometriosis. MR-proADM concentrations were higher in women with endometriosis but were not correlated with disease stage, corrected by surgery, or predictive of fertility outcome. MR-proADM may be able to serve as a biomarker of endometriosis, but it is unknown whether elevated MR-proADM levels are secondary to the estrogenic and inflammatory properties of endometriosis or an inciting pathogenic factor.

Biomarker guided triage can reduce hospitalization rate in community acquired febrile urinary tract infection

Febrile urinary tract infections (fUTI) can often be treated safely with oral antimicrobials in an outpatient setting. However, a minority of patients develop complications that may progress into septic shock. An accurate assessment of disease severity upon emergency department (ED) presentation is therefore crucial in order to guide the most appropriate triage and treatment decisions. Consecutive patients were enrolled with presumptive fUTI across 7 EDs in the Netherlands. The biomarkers mid-regional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-reactive protein (CRP), and a clinical score (PRACTICE), were compared in their ability to predict a clinically severe course of fUTI, initial hospital admission and subsequent readmission using area under the receiver operating characteristic (AUROC) curves. Biomarker concentrations were measured in 313 patients, with 259 (83%) hospitalized upon ED presentation, and 54 (17%) treated as outpatients. Of these outpatients, 12 (22%) were later hospitalized. MR-proADM had the highest diagnostic accuracy for predicting a complicated fUTI (AUROC [95% CI]: 0.86 [0.79-0.92]), followed by PCT (AUROC [95% CI]: 0.69 [0.58-0.80]). MR-proADM concentrations were unique in being significantly elevated in patients directly admitted and in outpatients requiring subsequent hospitalization, compared to those completing treatment at home. A virtual triage algorithm with an MR-proADM cut-off of 0.80nmol/L resulted in a hospitalization rate of 66%, with only 2% secondary admissions. MR-proADM could accurately predict a severe course in patients with fUTI, and identify greater patient numbers who could be safely managed as outpatients. An initial assessment on ED presentation may focus resources to patients with highest disease severities.

Current and future circulating biomarkers for cardiac amyloidosis.

Cardiac amyloidosis (CA) comprises a heterogeneous group of medical conditions affecting the myocardium. It presents with proteinaceous infiltration with variable degrees of severity, prevalence and evolution. Despite this heterogeneity, erroneous protein folding is the common pathophysiologic process, yielding the formation of a single misfolded protein (monomer) that progressively evolves and ultimately forms amyloid fibers. Additionally, by seeding out from the organs of origin, intermediates called oligomers metastasize and restart the process. Such self-echoing behavior makes the secondary affected organs as important as the primary ones. Unfortunately, CA can be clinically challenging and only suggestive in a late stage of its natural history, leaving a narrow therapeutic time window available. In light of the evolutionary nature of amyloidosis, here, we propose a new classification of the currently used biomarkers based on time stages with different specificity and applicability across CA subtypes. Early markers (free light chains, serum amyloid A, β2-microglobulin, osteopontin and osteoprotegerin) can be employed for disease detection. Intermediate markers [soluble suppression of tumorigenicity 2 (sST-2), midregional proadrenomedullin (MR-proADM), von Willebrand factor (vWF), hepatocyte growth factor (HGF), matrix metalloproteinases (MMPs) and tissue inhibitor metalloproteinases (TIMPs)] can provide information on the biological mechanisms of myocardial damage. As in heart failure, late-stage biomarkers (troponins and natriuretic peptides) can help clinicians with prognosis and therapeutic response evaluation in CA. Such findings have generated a remarkable foundation for our current knowledge on CA. Nevertheless, we envision a future class of biomarkers targeted at upstream events capable of detecting folding defects, which will ultimately expand the therapeutic window.

The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis - a secondary analysis of a large randomised controlled trial

BackgroundThis study assessed the ability of mid-regional proadrenomedullin (MR-proADM) in comparison to conventional biomarkers (procalcitonin (PCT), lactate, C-reactive protein) and clinical scores to identify disease severity in patients with sepsis.MethodsThis is a secondary analysis of a randomised controlled trial in patients with severe sepsis or septic shock across 33 German intensive care units. The association between biomarkers and clinical scores with mortality was assessed by Cox regression analysis, area under the receiver operating characteristic and Kaplan-Meier curves. Patients were stratified into three severity groups (low, intermediate, high) for all biomarkers and scores based on cutoffs with either a 90% sensitivity or specificity.Results1089 patients with a 28-day mortality rate of 26.9% were analysed. According to the Sepsis-3 definition, 41.2% and 58.8% fulfilled the criteria for sepsis and septic shock, with respective mortality rates of 20.0% and 32.1%. MR-proADM had the strongest association with mortality across all Sepsis-1 and Sepsis-3 subgroups and could facilitate a more accurate classification of low (e.g. MR-proADM vs. SOFA: N = 265 vs. 232; 9.8% vs. 13.8% mortality) and high (e.g. MR-proADM vs. SOFA: N = 161 vs. 155; 55.9% vs. 41.3% mortality) disease severity. Patients with decreasing PCT concentrations of either ≥ 20% (baseline to day 1) or ≥ 50% (baseline to day 4) but continuously high MR-proADM concentrations had a significantly increased mortality risk (HR (95% CI): 19.1 (8.0–45.9) and 43.1 (10.1–184.0)).ConclusionsMR-proADM identifies disease severity and treatment response more accurately than established biomarkers and scores, adding additional information to facilitate rapid clinical decision-making and improve personalised sepsis treatment.

Plasma midregional proadrenomedullin (MR-proADM) concentrations and their biological determinants in a reference population.

Midregional proadrenomedullin (MR-proADM) is emerging as a prognostic biomarker for detecting the failure of multiple organs. Establishment of scientifically robust reference intervals facilitates interpretation of laboratory test results. The objectives of this study were (i) to establish reliable reference intervals for plasma MR-proADM using a commercially available automated fluoroimmunoassay in apparently healthy individuals, and (ii) to identify biological determinants of MR-proADM concentrations. A total of 506 questionnaire-identified apparently healthy adults were enrolled in a single-center, cross-sectional study. A final reference group (n=172) was selected after exclusion of obese individuals, those with increased values of laboratory biomarkers indicating asymptomatic myocardial injury or dysfunction, ongoing inflammation, diabetes, dyslipidemia and renal dysfunction and outliers. The 2.5th and 97.5th percentile intervals for MR-proADM values in the reference group (90% confidence interval) were 0.21 (0.19-0.23) and 0.57 (0.55-0.59) nmol/L, respectively. Although older age, higher values of HbA1c, C-reactive protein, B-type natriuretic peptide and body mass index, together with a history of smoking and a decreased estimated glomerular filtration rate were significantly associated with increasing concentrations of MR-proADM in both univariate and multivariate analyses, magnitudes of these relationships were modest and did not substantially influence MR-proADM reference intervals. Sex-dependent difference in MR-proADM reference intervals was not detected [0.19 (0.16-0.22)-0.56 (0.54-0.60) nmol/L in females vs. 0.22 (0.20-0.25)-0.58 (0.57-0.63) nmol/L in males]. Our study successfully established robust reference intervals for MR-proADM concentrations in plasma. Considering the negligible influence of potential biological determinants on plasma MR-proADM, we recommend the adoption of single reference intervals for adult population as a whole.

Prognostic Impact of Copeptin and Mid-Regional Pro-Adrenomedullin in Chronic Heart Failure with Regard to Comorbidities

The aim of the study is to evaluate the impact of new humoral substances: copeptin and mid- regional proadrenomedullin (MR-proADM) on one-year survival of patients with stable systolic chronic heart failure (CHF) and to compare them with AHEAD score assessing the comorbidities. The FAR NHL (FARmacology and NeuroHumoraL activation) registry is a database of patients with stable CHF (ejection fraction (EF) <50%) treated in specialized HF departments. AHEAD score is a simple bed-side mortality predictive model based on age and comorbidities. Primary endpoint after 1-year follow-up was: death or hospitalization for decompensation of HF or heart transplantation or LVAD implantation. To whole FAR NHL registry, a total amount of 1088 patients were included, in 552 of them the levels of copeptin and MR-proADM were available. Mean age was 65+12 years, mean EF was 31+9%. Patients without primary endpoint were assigned as group A (469 pts), those with the primary endpoint group B (83 pts). There were statistically significant differences between the groups in the levels of copeptin: group A median 15.9 pmol/l (3.4-50.9) vs group B 23.7 pmol/l(5.0-89.44) (p<0.001), MR-proADM: group A median 0.63 nmol/l(0.32-1.34) vs group B 0.74 nmol/l (0.4-1.94) (p<0.001). Relationship of AHEAD score to primary endpoint in the first year of follow-up was not significant, but within 24th month it reached statistical significance: p= 0.017. Patients with higher AHEAD score (more comorbidities) reached more often the primary end-point. The cutt-off value ≥ 23.7 for copeptin had 50.6% sensitivity and 73.3%. The cut –off value for MR-proADM ≥ 0.58 had higher sensitivity 79.5% and lower specificity 42.0%. For both humoral substances there was statistical significant difference for discrimination of patients with primary endpoint in lower AHEAD score groups. However, in the highest AHEAD score the level of these substances lost their predictive value.

Preoperative Midregional Pro-Adrenomedullin and High-Sensitivity Troponin T Predict Perioperative Cardiovascular Events in Noncardiac Surgery

Objective: We evaluated the utility of preoperative midregional (MR) pro-adrenomedullin (proADM) and cardiac troponin T (TnT) for improved detection of patients at high risk for perioperative cardiac events and mortality after major noncardiac surgery. Subjects and Methods: This prospective, single-center, observational study enrolled 79 patients undergoing major noncardiac surgery. After initial clinical assessment (clinical history, physical examination, echocardiogram, blood tests, and chest X-ray), MR-proADM and high-sensitivity TnT (hsTnT) were measured within 48 h prior to surgery by immunoluminometric and electrochemiluminescence immunoassay. Patients were followed by the consulting physician until discharge or up to 14 days in the hospital after surgery. Perioperative cardiac events included myocardial infarction and development or aggravation of congestive heart failure. Data were compared between patients who developed target events and event-free patients. Results: Within 14 days of monitoring, 14 patients (17.72%) developed target events: 9 (11.39%) died and 5 (6.33%) developed cardiovascular events. The average age of the patients was 71.29 ± 6.62 years (range: 55–87). Sex, age, and hsTnT did not significantly differ between groups. MR- proADM concentration was higher in deceased patients (p = 0.01). The upper quartile of MR-proADM was associated with a fatal outcome (66.7 vs. 20.0%, p < 0.01) and with cardiovascular events (64.3 vs. 16.9%, p < 0.01). MR-proADM above the cutoff value (≥0.85) was associated with a fatal outcome (88.9 vs. 20.0%, p < 0.01) and cardiovascular events (71.4 vs. 28.6%, p < 0.01); this association was not observed for hsTnT. Conclusion: Preoperative measurement of MR-proADM provides useful information for perioperative cardiac events in high-risk patients scheduled for noncardiac surgery.

Usefulness of midregional pro-adrenomedullin as a marker of organ damage and predictor of mortality in patients with sepsis

BackgroundMidregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP) and sepsis. In this paper, we examined the ability of MR-proADM to predict organ damage and long-term mortality in sepsis patients, compared to that of procalcitonin, C-reactive protein and lactate. MethodsThis was a prospective observational cohort, enrolling severe sepsis or septic shock patients admitted to internal service department. The association between biomarkers and 90-day mortality was assessed by Cox regression analysis and Kaplan–Meier curves. The accuracy of biomarkers for mortality was determined by area under the receiver operating characteristic curve (AUROC) analysis. ResultsA total of 148 patients with severe sepsis, according to the criteria of the campaign to survive sepsis, were enrolled. Eighty-five (57.4%) had sepsis according to the new criteria of Sepsis-3. MR-proADM showed the best AUROC to predict sepsis as defined by the Sepsis-3 criteria (AUROC of 0.771, 95% CI 0.692–0.850, p <0.001) and was the only marker independently associated with Sepsis-3 criteria (OR = 4.78, 95% CI 2.25–10.14; p < 0.001) in multivariate analysis.MR-proADM was the biomarker with the best AUROC to predict mortality in 90 days (AUROC of 0.731, CI 95% 0.612–0.850, p <0.001) and was the only marker that kept its independence [hazard ratio (HR) of 1.4, 95% CI 1.2-1.64, p <0.001] in multivariate analysis. The cut-off point of MR-proADM of 1.8 nmol/L (HR of 4.65, 95% CI 6.79–10.1, p < 0.001) was the one that had greater discriminative capacity to predict 90 days mortality. All patients with MR-proADM concentrations ≤0.60 nmol/L survived up to 90 days. In patients with SOFA ≤ 6, the addition of MR-proADM to SOFA score increased the ability of SOFA to identify non-survivors, AUROC of 0.65 (CI 95% 0.537–0.764) and AUROC of 0.700 (CI 95% 0.594–0.800), respectively (p < 0.05 for both). ConclusionsMR-proADM is a good biomarker in the early identification of high risk septic patients and may contribute to improve the predictive capacity of SOFA scale, especially when scores are low.

Role of some biomarkers in determining the risk of mortality of hospitalized patients with community- acquired pneumonia

Introduction: Various biomarkers are used to determine the severity and risk of mortality in community-acquired pneumonia (CAP). The aim of this article is to evaluate the prognostic value for in-hospital mortality of leukocyte count (Leuk), C-reactive protein (CRP), procalcitonin (PCT), and mid-regional proadrenomedullin (MR-proADM) in CAP patients. Materials and Methods: This was a prospective study including a total of 92 CAP patients hospitalized in the Clinic of Pneumology and Phthisiatry at St. Marina University Hospital of Varna. Biomarkers were determined at hospitalization, Leuk - by automated methodology, CRP - by latex-enhanced immuno-turbidimetric method, and both MR-proADM and PCT - by standard ELISA. CAP severity was estimated by Pneumonia Severity Index (PSI) and CURB-65. Results: The patients were at a mean age of 59.2±16.8 years, 68.5% were men. In-hospital mortality was 7.6%. The optimal cut-off value of MR-proADM for in-hospital mortality was 0.88 ng/mL (sensitivity 85.7% and specificity 85.8%). The positive predictive value was 33.3% and the negative predictive value was 98.6%. The optimal cut-off value of PCT was 1.84 ng/mL (sensitivity 71.4% and specificity 81.1%). The positive predictive value was 23.8% and the negative predictive value was 97.1%. Cut-off values for CRP and Leuk could not be established. By performing ROC curves, MR-proADM, PSI, PCT and CURB-65 were good predictors for in-hospital mortality (AUC 0.91, 0.90, 0.89, and 0.86, respectively). Conclusion: MR-proADM and PCT are promising markers in predicting CAP prognosis. Their predictive value for mortality is similar to that of PSI and CURB-65. CRP and Leuk cannot serve as predictors.

Effect of liraglutide on atrial natriuretic peptide, adrenomedullin, and copeptin in PCOS.

ContextWomen with polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease (CVD), and biomarkers can be used to detect early subclinical CVD. Midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial natriuretic peptide (MR-proANP) and copeptin are all associated with CVD and part of the delicate system controlling fluid and hemodynamic homeostasis through vascular tonus and diuresis. The GLP-1 receptor agonist liraglutide, developed for treatment of type 2 diabetes (T2D), improves cardiovascular outcomes in patients with T2D including a decrease in particular MR-proANP.ObjectiveTo investigate if treatment with liraglutide in women with PCOS reduces levels of the cardiovascular biomarkers MR-proADM, MR-proANP and copeptin.MethodsSeventy-two overweight women with PCOS were treated with 1.8 mg/day liraglutide or placebo for 26 weeks in a placebo-controlled RCT. Biomarkers, anthropometrics, insulin resistance, body composition (DXA) and visceral fat (MRI) were examined.ResultsBaseline median (IQR) levels were as follows: MR-proADM 0.52 (0.45–0.56) nmol/L, MR-proANP 44.8 (34.6–56.7) pmol/L and copeptin 4.95 (3.50–6.50) pmol/L. Mean percentage differences (95% CI) between liraglutide and placebo group after treatment were as follows: MR-proADM −6% (−11 to 2, P = 0.058), MR-proANP −25% (−37 to −11, P = 0.001) and copeptin +4% (−13 to 25, P = 0.64). Reduction in MR-proANP concentration correlated with both increased heart rate and diastolic blood pressure in the liraglutide group. Multiple regression analyses with adjustment for BMI, free testosterone, insulin resistance, visceral fat, heart rate and eGFR showed reductions in MR-proANP to be independently correlated with an increase in the heart rate.ConclusionIn an RCT, liraglutide treatment in women with PCOS reduced levels of the cardiovascular risk biomarkers MR-proANP with 25% and MR-proADM with 6% (borderline significance) compared with placebo. The decrease in MR-proANP was independently associated with an increase in the heart rate.

Vasoactive mid-regional pro-adrenomedullin is associated with cognitive decline accompa-nying deep white matter lesions in the brain: A longitudinal brain MRI study

Background: Adrenomedullin is a vasoreactive physiological peptide with vasodilative and immunomodulatory actions distributed in the vascular system in the animal brain. However, few previous studies have investigated the significance of mid-regional pro-adrenomedullin (MR-proADM) levels and ischemic cerebral deep white matter lesions (DWMLs) in association with cognitive decline in humans.

Prognostic importance of emerging cardiac, inflammatory, and renal biomarkers in chronic heart failure patients with reduced ejection fraction and anaemia: RED-HF study.

AimsTo test the prognostic value of emerging biomarkers in the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED‐HF) trial.Methods and resultsCirculating cardiac [N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), and high‐sensitivity troponin T (hsTnT)], neurohumoral [mid‐regional pro‐adrenomedullin (MR‐proADM) and copeptin], renal (cystatin C), and inflammatory [high‐sensitivity C‐reactive protein (hsCRP)] biomarkers were measured at randomization in 1853 participants with complete data. The relationship between these biomarkers and the primary composite endpoint of heart failure hospitalization or cardiovascular death over 28 months of follow‐up (n = 834) was evaluated using Cox proportional hazards regression, the c‐statistic and the net reclassification index (NRI). After adjustment, the hazard ratio (HR) for the composite outcome in the top tertile of the distribution compared to the lowest tertile for each biomarker was: NT‐proBNP 3.96 (95% CI 3.16–4.98), hsTnT 3.09 (95% CI 2.47–3.88), MR‐proADM 2.28 (95% CI 1.83–2.84), copeptin 1.66 (95% CI 1.35–2.04), cystatin C 1.92 (95% CI 1.55–2.37), and hsCRP 1.51 (95% CI 1.27–1.80). A basic clinical prediction model was improved on addition of each biomarker individually, most strongly by NT‐proBNP (NRI +62.3%, P < 0.001), but thereafter was only improved marginally by addition of hsTnT (NRI +33.1%, P = 0.004). Further addition of biomarkers did not improve discrimination further. Findings were similar for all‐cause mortality.ConclusionOnce NT‐proBNP is included, only hsTnT moderately further improved risk stratification in this group of chronic heart failure with reduced ejection fraction patients with moderate anaemia. NT‐proBNP and hsTnT far outperform other emerging biomarkers in prediction of adverse outcome.