Mid-regional pro-ADM Research Articles

Unlocking the potential of biomarkers: The promise of adrenomedullin and its precursors in diagnosing and assessing heart failure

BackgroundSeveral studies have examined the potential of adrenomedullin (ADM), pro-adrenomedullin (Pro-ADM), and mid-regional-pro-ADM (MR-Pro-ADM) as biomarkers for diagnosing and assessing the severity of heart failure (HF), with conflicting results. We aimed to investigate their diagnostic utility and their correlation with HF severity based on the New York Heart Association (NYHA) classification. MethodsWe searched PubMed, EMBASE, and Scopus using a predefined search string. The quality assessment of included studies was conducted using the Newcastle Ottawa Scale (NOS), and the primary outcome was the mean difference (MD) in serum levels of ADM, Pro-ADM, and MR-Pro-ADM, in addition to the area under the curve (AUC). ResultsA total of 28 articles fulfilled our inclusion criteria and were included in our qualitative and quantitative synthesis, with a total of 15,405 subjects. Significant MD in ADM levels in HF patients vs. controls (6.024 [95 % CI 1.691, 10.356]), NYHA I vs. controls (−1.202 [95 % CI -2.111, −0.292]), NYHA IV vs. controls (−7.536 [95 % CI -12.680, −2.393]), NYHA III vs. NYHA IV (−4.438 [95 % CI -7.612, −1.263]), and NYHA I-II vs NYHA III-IV (−2.351 [95 % CI -4.361, −0.341]) were observed. Moreover, a significant MD was observed in pro-ADM levels in NYHA I-II patients vs. controls (−0.960 [95 % CI -1.479, −0.440]), NYHA III-IV vs. controls (−1.979 [95 % CI -2.958, −1.000]), and NYHA I-II vs. NYHA III-IV (−0.966 [95 % CI -1.407, −0.526]). Furthermore, MR-Pro-ADM levels were significantly different in NYHA I-II vs. NYHA III-IV (−0.428 [95 % CI -0.492, −0.365]). MR-Pro-ADM predicted HF with an AUC of 0.781 (95 % CI 0.755, 0.806). ConclusionsAmong HF patients, there was a significant increase in ADM levels compared to control subjects, and these levels increased with the progression of NYHA classes. Similarly, both Pro-ADM and MR-Pro-ADM displayed higher concentrations in NYHA class III-IV HF patients compared to those in NYHA class I-II. However, MR-Pro-ADM exhibited lower accuracy in predicting HF compared to established biomarkers.

B-015 Analytical Verification of MR-proADM Biomarker in Human EDTA Plasma on Immunoassay Analyzer LIAISON® XL of Diasorin

Abstract Background Adrenomedullin (ADM) is a potent vasodilator peptide of 52-aminoacid belonging to the calcitonin family of peptides. Midregional pro-ADM (MR-ProADM) is a precursor for ADM that circulates is in a 1:1 ratio with it, and proportionally represents its levels and activity. Increased ADM circulating concentrations have been described for several disease states, including dysfunction of the cardiovascular system and sepsis. However, reliable ADM quantification has been hampered by the short half-life, the existence of a binding protein, and its physical properties. Hence, quantificacion of MR-proADM represents a more suitable option. The biomarker MR-proADM has been shown to be an accurate prognostic marker for outcome prediction in patients with lower respiratory infections, sepsis, urinary tract infections, and kidney disease. The objective of this study was the verification of the metrological characteristics and the verification of the linearity of quantitative measurement range, as declared by the manufacturer, of the LIAISON® Brahms MR-proADMTM on Liaison® XL (DiaSorin). Methods The verification was performed with two levels of quality controls (QC) from the manufacturer (x̄L=1,19 nmol/L and x̄H=5,48 nmol/L), and residual EDTA plasma samples from patients with an active sepsis code. The evaluation included the assessment of: • Detection capability (including limit of quantification (LoQ) and limit of detection (LoD), measuring three samples at the manufacturer's stated concentration (0.21 nmol/L and 0.09 nmol/L, respectively) in duplicate within 4 runs). • Precision (CV, %) and accuracy (bias, %) within, measuring 10 replicates of each QC level; and between run, measuring 5 replicates for each QC level within 5 runs. • Linearity of the quantitative range of measurement (six intermediate samples prepared by mixing a high concentration sample- XH=9.64 nmol/L- and a low concentration sample, XL=0.59 nmol/L; measured in triplicate). All studies were performed in accordance with the recommendations of the Clinical Laboratory Standards Institute guidelines. Statistical analysis was performed using Microsoft Excel®, 2016. Results All results with diluted samples presented a signal (RLU) higher than that detected in samples without analyte, so the LoD was verified. The precision at the LoQ concentration was 26.7% (acceptance criteria was set as <20%). CV for within-run precision were 4.3% and 2.0% and for between-run precision 6.8% and 7.9% for low (L1) and high (L2) control level, respectively. The average bias was 3.60% for L1 and 4.23% for L2, meeting acceptance criteria (<8%). Linearity was confirmed between 0.59 and 9.64 nmol/L (R2 = 0.995). The biases between the expected and the obtained value were ≤7% through the quantitative range of measurement, except for the lowest concentration sample (close to the quantitation limit). Conclusions Our study showed good compliance with the metrological characteristics declared by the manufacturer for LoD, precision, bias and linearity range. Although the LoQ was not verified, it is outside the clinical decision value in septic patients (< 2.25 nmol/L) and it is not deemed a limitation for clinical practice. Additionally, the Liaison XL® platform permits us to configure an emergency protocol circuit (24/7) with a TAT of 35 min.

Association of mid-regional pro-adrenomedullin with office and 24-h ambulatory blood pressure in a Swiss general population sample.

Adrenomedullin (ADM) is a potent vasodilator. The association between plasma ADM levels and blood pressure (BP) remains unclear. We assessed the association between mid-regional-pro-ADM (MR-proADM) and BP in a multicenter population- and family-based cohort. We used data from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH). We included participants present at both baseline and 3-year follow-up (N = 843). We examined the association of baseline MR-proADM with baseline office and 24 h ambulatory BP as well as the 3-year change in office BP. In secondary analyses, we studied the association between baseline MR-proADM and 3-year changes in pulse wave velocity (PWV), renal resistive index (RRI) and augmentation index (AI). Mixed-effects linear regression models were used. In cross-sectional analyses, MR-proADM was negatively associated with office, 24-h and daytime diastolic BP (DBP). MR-proADM was positively associated with nighttime systolic BP (SBP). In longitudinal analyses, baseline MR-proADM was associated with an increase in office SBP and pulse pressure (PP) over 3 years [β (95% CI): 8.2 (0.4, 15.9) and β (95% CI): 6.4 (0.3, 12.4), respectively] but not with changes in PWV, RRI and AI. The cross-sectional negative association of MR-proADM with DBP is in line with known vasodilatory properties of ADM. The positive association between MR-proADM and nighttime SBP at baseline may reflect endothelial dysfunction believed to be part of the pathogenesis of nocturnal hypertension. The association of higher baseline MR-proADM levels with increased SBP and PP at 3-year follow-up suggests that ADM levels could be a marker of cardiovascular risk.

Mid-regional pro-adrenomedullin and lactate levels for risk stratification in patients with out-of-hospital cardiac arrest.

Adrenomedullin is a free circulating peptide that regulates endothelial barrier function and vascular tone. Here, we sought to study the relationship of adrenomedullin in combination with lactate and the risk of death in patients with out-of-hospital cardiac arrest (OHCA). Mid-regional pro-ADM (MR-proADM) and lactate concentrations were measured in OHCA patients who survived at least 24 h after return of spontaneous circulation. The outcome of interest was all-cause death. Patients were characterized by quartiles (Q) of MR-proADM and lactate concentrations. Cox models were adjusted for age, sex, shockable rhythm, bystander resuscitation, SAPS II score, and eGFR. A total of 232 patients were included in the present study (28% women, 67 years, SAPS II score 80). The median MR-proADM and lactate levels at 24 hours were 1.4 nmol/L (IQR 0.8-2.8 nmol/L) and 1.8 mmol/L (IQR 1.3 to 3.4 mmol/L), respectively. MR-proADM concentrations correlated weakly with lactate levels (r = 0.36, P < 0.001). High (Q4) versus low (Q1-Q3) MR-proADM concentrations were significantly associated with an increased rate of death at 28 days (75.9% vs 45.4%; P < 0.001). After multivariable adjustment (including lactate levels at 24 hours), higher MR-proADM levels were significantly associated with an increased risk of death (Q4 vs. Q1-Q3: adj-HR 1.67, 95%-CI 1.12-2.50; adj-HR for 1 unit increase in standardized biomarker 1.44, 95-CI 1.19-1.73). This relationship remained significant even after further adjustment for baseline NT-proBNP and hsTnT levels. The combination of high MR-proADM and high lactate (Q4) concentration identified patients at particularly elevated risk (adj-HR 3.50; 95% CI 1.92 to 6.39). Higher MR-proADM concentrations are associated with an increased risk of death in patients with OHCA, and the combination of high MR-proADM and lactate levels identifies patients at distinctly elevated risk.

Abstract 14870: Adrenomedullin in Patients With Out-of-Hospital Cardiac Arrest

Introduction: Adrenomedullin (ADM) is a free circulating peptide that regulates endothelial barrier function and vascular tone. Here, we sought to study the relationship of adrenomedullin in combination with lactate and the risk of death in patients with out-of-hospital cardiac arrest (OHCA) of non-traumatic origin. Methods: Mid-regional pro-ADM (MR-proADM) concentrations were measured in OHCA patients after successful ROSC on admission. The outcome of interest was all-cause death. Patients were characterized by quartiles (Q) of MR-proADM and lactate concentrations. Cox models were adjusted for age, sex, shockable rhythm, bystander resuscitation, and baseline eGFR. Results: A total of 232 patients were included in the present study (28% women, 67 years, SAPS II score 80). In total, 132 patients (56.9%) died, and 24 patients had an unfavorable neurologic outcome (i.e., a CPC score of 3-4). The median MR-proADM and lactate levels were 1.4 nmol/L (IQR 0.8 to 2.8 nmol/L) and 4.8 mmol/L (IQR 2.8 to 7.4 mmol/L), respectively. MR-proADM concentrations correlated weakly with lactate levels (r=0.23, P&lt;0.001). High (Q4) versus low (Q1-Q3) MR-proADM concentration was associated with an increased rate of death at 28 days (45.4% vs. 75.9%; P&lt;0.001; Fig A ). After multivariable adjustment (including baseline lactate levels), higher MR-proADM levels were significantly associated with an increased risk of death (Q4 vs. Q1-Q3: adjusted HR 1.84, 95% CI 1.21 to 2.77; adjusted HR for 1 unit increase in standardized biomarker 1.55, 95% CI 1.28 to 1.86). The combination of high MR-proADM and high lactate (Q4) concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; Fig B ). Conclusions: Higher MR-proADM concentration are associated with an increased risk of death in patients with OHCA of non-traumatic origin. The combination of high MR-proADM and high lactate levels identifies patients at distinctly elevated risk.

Comparative performances of soluble urokinase plasminogen activator receptor and Mid-regional proADM to predict composite death and new heart failure rehospitalisation in acutely breathless patients

Abstract Background Soluble urokinase plasminogen activator receptor (suPAR) is a pleotropic receptor, capable of orchestrating plaque vulnerability and vascular immune dysfunction. Mid-regional pro-adrenomedullin (MR-proADM) is the stable peptide precursor of adrenomedullin, with concentrations reflective of vasodilation and cardiac remodelling. We compared the prognostic performances of suPAR and MR-proADM for the composite clinical endpoint of death and new heart failure (HF) in patients with undifferentiated breathlessness. Methods Patients presenting to hospital with the primary complaint of acute dyspnoea were recruited in New Zealand (n=612) and in Singapore (n=483)]. Baseline plasma measurements were undertaken for suPAR (ViroGates) and MR-proADM (Thermo Scientific). Cardiac biomarker levels of NT-proBNP (Roche) was available on all patients. Statistical assessment was made using SPSS v28 (IBM), with all biomarkers treated as continuous variables and presented as median [interquartile range (IQR)]. Prognostic performance of suPAR, MR-proADM and NT-proBNP to predict the composite clinical endpoint of death/new HF at 90-days and 1-yr were assessed using receiver operator curve (ROC) area under the curve (AUC) analysis (Z-scores) and Cox hazard regression analysis (per doubling of biomarker concentrations) after adjustment for traditional risk factors. P-value &amp;lt;0.05 was considered statistically significant. Results In the entire acutely breathless cohort [median age: 65 years (IQR: 52.9–76.0), 63.1% males], 343/1095 of patients had the final adjudication of ADHF. suPAR and MR-proADM concentrations were higher with increasing age (Spearmans rho, r&amp;gt;0.46, P&amp;lt;0.0001), lower eGFR (r&amp;gt;0.58, P&amp;lt;0.0001) and in those with ADHF (r&amp;gt;0.40, P&amp;lt;0.0001). During the follow-up period, 122 patients were categorised with death/new HF by 90-days, rising to 281 at 1-year. suPAR and MR-proADM were able to predict death/new HF at 90-days (both ROC-AUC &amp;gt;0.77) and at 1-year (both ROC-AUC ≥0.78) (Table 1). All markers were however less accurate in predicting this endpoint in the presence of ADHF (ROC-AUC &amp;lt;0.71). After adjustment in Cox-regression modelling, suPAR obtained HR &amp;gt;1.35 per doubling of suPAR concentrations (P=0.001) for outcomes at 90-days and at 1-year (Table 2), achieving the highest prognostic performance for this clinical endpoint, followed by NT-proBNP (HR &amp;gt;1.29) (Table 2), whilst MR-proADM was not an independent predictor of death/HF in this cohort. suPAR was also an independent predictor of death/HF for patients with ADHF, obtaining HR &amp;gt;1.35 per doubling of concentrations. Above a cut-off concentration of 3.6 ng/mL, suPAR was associated with a HR of 2.1 (95% CI: 1.55–2.91) for death/HF at 1-year for acutely dyspnoeic patients. Conclusion suPAR concentrations is superior than MR-proADM in predicting the clinical end-point of death/HF at 1-year in this cohort. It may aid in risk-stratification strategies for the management of acutely breathless patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Heart Foundation of New ZealandHealth Research Council of New Zealand

Plasma mid-regional pro-adrenomedullin: A biomarker of the ischemic penumbra in hyperacute stroke.

Reperfusion therapy has improved the outcomes of ischemic stroke but also emphasized the importance of ischemic penumbra. However, blood biomarkers are currently unavailable for this region. Adrenomedullin (ADM) is a neuroprotective peptide, secreted in a compensatory response to brain ischemia. We thus investigated whether an increase in mid-regional pro-ADM (MR-proADM), a stable peptide fragment of the ADM precursor, could act as a biomarker by predicting the ischemic penumbra in hyperacute ischemic stroke (HAIS). We prospectively enrolled consecutive HAIS patients (n=119; median age, 77 years; male, 59.7%) admitted to our institutes from July 2017 to March 2019 and evaluated plasma MR-proADM levels within 4.5h of onset. MR-proADM levels in HAIS were compared to healthy controls (n=1298; median age, 58 years; male, 33.2%) in the Japan Multi-Institutional Collaborative Cohort Study from 2013 to 2017. Furthermore, we evaluated whether MR-proADM levels were associated with the penumbra estimated by clinical-diffusion mismatch (CDM) (National Institute of Health Stroke Scale [NIHSS] ≥8, diffusion ischemic core volume ≤25 ml), or magnetic resonance angiography-diffusion-weighted imaging mismatch (MDM) (NIHSS ≥5, a proximal vessel occlusion with core volume ≤25 ml, or a proximal vessel stenosis/distal vessel occlusion with core volume ≤15 ml). In a case-control study, multivariate logistic analysis showed a significant association between HAIS and MR-proADM ≥0.54 nmol/L (adjusted odds ratio, 7.92 [95% CI, 4.17-15.02], p < 0.001). Though MR-proADM levels in HAIS did not correlate with the ischemic core volume (rs =0.09, p=0.348), they were higher in HAIS with CDM (n=34; 0.81 vs. 0.61 nmol/L, p < 0.001) or MDM (n=26; 0.83 vs. 0.62 nmol/L, p=0.002). These differences remained significant after adjusting baseline factors (adjusted odds ratio, 4.06 [95% CI, 1.31-12.55], p = 0.015 and 4.65 [1.35-16.11], p = 0.015, respectively). Plasma MR-proADM is elevated in HAIS, especially in those with a substantial penumbra, suggesting potential as a blood biomarker in this region.

Associations of the vasoactive peptides CT-proET-1 and MR-proADM with incident type 2 diabetes: results from the BiomarCaRE Consortium

BackgroundEndothelin-1 (ET-1) and adrenomedullin (ADM) are commonly known as vasoactive peptides that regulate vascular homeostasis. Less recognised is the fact that both peptides could affect glucose metabolism. Here, we investigated whether ET-1 and ADM, measured as C-terminal-proET-1 (CT-proET-1) and mid-regional-proADM (MR-proADM), respectively, were associated with incident type 2 diabetes.MethodsBased on the population-based Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium data, we performed a prospective cohort study to examine associations of CT-proET-1 and MR-proADM with incident type 2 diabetes in 12,006 participants. During a median follow-up time of 13.8 years, 862 participants developed type 2 diabetes. The associations were examined in Cox proportional hazard models. Additionally, we performed two-sample Mendelian randomisation analyses using published data.ResultsCT-proET-1 and MR-proADM were positively associated with incident type 2 diabetes. The multivariable hazard ratios (HRs) [95% confidence intervals (CI)] were 1.10 [1.03; 1.18], P = 0.008 per 1-SD increase of CT-proET-1 and 1.11 [1.02; 1.21], P = 0.016 per 1-SD increase of log MR-proADM, respectively. We observed a stronger association of MR-proADM with incident type 2 diabetes in obese than in non-obese individuals (P-interaction with BMI < 0.001). The HRs [95%CIs] were 1.19 [1.05; 1.34], P = 0.005 and 1.02 [0.90; 1.15], P = 0.741 in obese and non-obese individuals, respectively. Our Mendelian randomisation analyses yielded a significant association of CT-proET-1, but not of MR-proADM with type 2 diabetes risk.ConclusionsHigher concentrations of CT-proET-1 and MR-proADM are associated with incident type 2 diabetes, but our Mendelian randomisation analysis suggests a probable causal link for CT-proET-1 only. The association of MR-proADM seems to be modified by body composition.

Prognostic Value of Mid-Regional Proadrenomedullin Sampled at Presentation and after 72 Hours in Septic Patients Presenting to the Emergency Department: An Observational Two-Center Study.

The prognostic value of mid-regional proADM (MR-proADM) in septic patients presenting to the emergency department (ED) is not well established. In this prospective observational study enrolling septic patients evaluated in two EDs, MR-proADM was measured at arrival (t0) and after 72 h (t72). MR-proADM%change was calculated as follows: (MR-proADMt72h − MR-proADMt0)/MR-proADMt0. In total, 147 patients were included in the study, including 109 with a final diagnosis of sepsis and 38 with septic shock, according to the Sepsis-3 criteria. The overall 28-day mortality (outcome) rate was 12.9%. The AUC for outcome prognostication was 0.66 (95% CI 0.51–0.80) for MR-proADMt0, 0.77 (95% CI 0.63–0.92) for MR-proADMt72 and 0.74 (95% CI 0.64–0.84) for MR-proADM%change. MR-proADMt0 ≥ 2.78 nmol/L, MR-proADMt72 ≥ 2.7 nmol/L and MR-proADM%change ≥ −15.2% showed statistically significant log-rank test results and sensitivity/specificity of 81/65%, 69/80% and 75/70% respectively. In regression analysis, MR-proADM%change was a significant outcome predictor both in univariate and multivariate analysis, after adjustment for age, SOFA and APACHEII scores, providing up to 80% of added prognostic value. In conclusion, time trends of MR-proADM may provide additional insights for patient risk stratification over single sampling. MR-proADM levels sampled both at presentation and after 72 h predicted 28-day survival in septic patients presenting to the ED.

Association between MR-proADM concentration and treatment intensity of antihypertensive agents in chronic kidney disease patients with insufficient blood pressure control

Response to antihypertensive drugs in patients with chronic kidney disease (CKD) has great interindividual variability. Adrenomedullin (ADM) is produced abundantly in hypertension, but clearance is very rapid. Mid-regional proADM (MR-proADM) produced from an ADM precursor is considered a surrogate biomarker for quantification of ADM. We investigated the association of MR-proADM with antihypertensive resistance in CKD patients with poor blood pressure (BP) control. This cross-sectional study analyzed 33 CKD patients with poor BP control defined as failure to achieve target BP despite at least two classes of antihypertensive drugs. Treatment intensity score was calculated to facilitate comparability of antihypertensive regimens across subjects taking different drugs. Plasma MR-proADM concentration was measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Plasma MR-proADM concentration correlated with estimated glomerular filtration rate (eGFR) (r = − 0.777, p < 0.001). Treatment intensity score correlated positively with plasma MR-proADM concentration (r = 0.355, p = 0.043), and the correlation was further enhanced after correction by weight (r = 0.538, p = 0.001). Single and multiple regression analysis identified MR-proADM concentration (p = 0.005) as independently associated with weight-corrected treatment intensity score. MR-proADM may be useful as a biomarker to determine the therapeutic intensity of antihypertensive drugs in CKD patients with poor BP control.

Adrenomedullin: new inhibitory regulator for cortisol synthesis and secretion.

Preterm birth is associated with immaturity of several crucial physiological functions notably those prevailing in the lung and kidney. Recently, a steroid secretion deficiency was identified in very preterm neonates, associated with a partial yet transient deficiency in 11β-hydroxylase activity, sustaining cortisol synthesis. However, the P450c11β enzyme is expressed in preterm adrenal glands, we hypothesized an inhibition of cortisol production by adrenomedullin (ADM), a peptide highly produced in neonates and whose effect on steroidogenesis remains poorly known. We studied the effects of ADM on three models: 104 cord-blood samples of the PREMALDO neonate cohort, genetically targeted mice overexpressing ADM, and two human adrenocortical cell lines (H295R and HAC15 cells). Mid-regional-proADM (MR-proADM) quantification in cord-blood samples showed strong negative correlation with gestational age (P = 0.0004), cortisol production (P < 0.0001), and 11β-hydroxylase activity index (P < 0.0001). Mean MR-proADM was higher in very preterm than in term neonates (1.12 vs 0.60 nmol/L, P < 0.0001). ADM-overexpression mice revealed a lower 11β-hydroxylase activity index (P < 0.05). Otherwise, aldosterone levels measured by LC-MS/MS were higher in ADM-overexpression mice (0.83 vs 0.46 ng/mL, P < 0.05). More importantly, the negative relationship between adrenal ADM expression and aldosterone production found in control was lacking in the ADM-overexpression mice. Finally, LC-MS/MS and gene expression studies on H295R and HAC15 cells revealed an ADM-induced inhibition of both cortisol secretion in cell supernatants and CYP11B1 expression. Collectively, our results converge toward an inhibitory effect of ADM on glucocorticoid synthesis in humans and should be considered to explain the steroid secretion deficiency observed at birth in premature newborns.

MR-proADM as prognostic factor of outcome in COVID-19 patients

Mid Regional pro-ADM (MR-proADM) is a promising novel biomarker in the evaluation of deteriorating patients and an emergent prognosis factor in patients with sepsis, septic shock and organ failure. It can be induced by bacteria, fungi or viruses. We hypothesized that the assessment of MR-proADM, with or without other inflammatory cytokines, as part of a clinical assessment of COVID-19 patients at hospital admission, may assist in identifying those likely to develop severe disease. A pragmatic retrospective analysis was performed on a complete data set from 111 patients admitted to Udine University Hospital, in northern Italy, from 25th March to 15th May 2020, affected by SARS-CoV-2 pneumonia. Clinical scoring systems (SOFA score, WHO disease severity class, SIMEU clinical phenotype), cytokines (IL-6, IL-1b, IL-8, TNF-α), and MR-proADM were measured. Demographic, clinical and outcome data were collected for analysis. At multivariate analysis, high MR-proADM levels were significantly associated with negative outcome (death or orotracheal intubation, IOT), with an odds ratio of 4.284 [1.893–11.413], together with increased neutrophil count (OR = 1.029 [1.011–1.049]) and WHO disease severity class (OR = 7.632 [5.871–19.496]). AUROC analysis showed a good discriminative performance of MR-proADM (AUROC: 0.849 [95% Cl 0.771–0.730]; p < 0.0001). The optimal value of MR-proADM to discriminate combined event of death or IOT is 0.895 nmol/l, with a sensitivity of 0.857 [95% Cl 0.728–0.987] and a specificity of 0.687 [95% Cl 0.587–0.787]. This study shows an association between MR-proADM levels and the severity of COVID-19. The assessment of MR-proADM combined with clinical scoring systems could be of great value in triaging, evaluating possible escalation of therapies, and admission avoidance or inclusion into trials. Larger prospective and controlled studies are needed to confirm these findings.

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin-receptor/neprilysin-inhibitor treatment in chronic systolic heart failure.

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

Midregional proadrenomedullin predicts reduced blood pressure and glucose elevation over time despite enhanced progression of obesity markers.

Elevated plasma levels of the vasodilating hormone adrenomedullin (ADM) predict cardiovascular disease and have been associated with hypertension and obesity. We aimed to examine the independent relationship between ADM and the progression of major cardiometabolic risk factors during long-term follow-up. We studied midregional pro-ADM (MR-proADM) in fasting plasma in 3298 participants from the population-based Malmö Diet and Cancer Study - Cardiovascular Cohort, re-examined after 17 years of follow-up and related baseline MR-proADM to cardiometabolic risk factors cross-sectionally and longitudinally. At baseline, after full adjustment, each SD increment of MR-proADM was independently related to (beta ± standard error, P value) higher SBP (0.956 ± 0.319 mmHg, P = 0.003), BMI (0.912 ± 0.061 kg/m, P = 1.42 × 10), waist (2.28 ± 0.158 cm, P = 8.46 × 10) and fasting blood glucose (0.046 ± 0.018 mmol/l, P = 0.01). After full adjustment, including the baseline level of the risk factor whose degree of progression was studied, each SD increment of MR-proADM predicted significantly reduced progression of SBP (-1.170 ± 0.337 mmHg, P = 0.001) and fasting blood glucose (-0.055 ± 0.023 mmol/l, P = 0.015), but greater increase of BMI (0.101 ± 0.051 kg/m, P = 0.047) and waist (0.600 ± 0.144 cm, P = 3.1 × 10). Despite cross-sectional associations with higher levels of blood pressure and glucose, high levels of MR-proADM predict a slower progression of blood pressure and glycemia during long-term follow-up. Conversely, the cross-sectional associations with higher levels of MR-proADM and obesity were paralleled by a faster progression of obesity markers over time. These results may be important for assessment of long-term effects of therapies modulating levels of ADM.

Association between Mid-Regional Proadrenomedullin Levels and Progression of Deep White Matter Lesions in the Brain Accompanying Cognitive Decline.

Adrenomedullin (ADM) is a vasoreactive physiological peptide with anti-inflammatory effects and vasodilative and immunomodulatory actions that is widely distributed throughout the vascular system of the brain. To investigate mid-regional proADM (MR-proADM), a stable fragment of the ADM precursor, and cerebral deep white matter lesions (DWMLs) in association with cognitive decline. The study participants were 288 patients (194 men, 94 women) who gave consent to participate in a 5-year longitudinal survey on arteriosclerosis from 2008 to 2013. The Fazekas classification system (Grade [G] 0 [normal] to G3 [severe]) was used for the evaluation of DWMLs on brain magnetic resonance imaging (MRI). In addition, all participants were asked to undergo cognitive function tests regarding word/letter fluency, the results of which were assessed for correlations with MR-proADM levels. MR-proADM levels significantly increased with DWML grade progression. The odds ratio for high MR-proADM levels was 3.08 (95% confidence interval: 1.49-5.17) in the groups graded G3 on brain MRI, suggesting that a high level of MR-proADM is an independent risk factor for DWMLs. A significant inverse correlation was observed between MR-proADM levels and cognitive test scores. MR-proADM levels were significantly increased in the G3 group in 2013 compared with 2008. MR-proADM levels were significantly different between the DWML groups and inversely correlated with cognitive function test scores, suggesting that high MR-proADM levels and DWMLs are associated with cognitive decline. Therefore, the MR-proADM level may be an effective candidate as a potential diagnostic surrogate marker of cognitive decline.

Prognostic value of human mature adrenomedullin in patients with acute myocardial infarction.

Adrenomedullin (ADM) correlates with adverse cardiovascular outcomes in patients with acute myocardial infarction (AMI) and in patients with heart failure. Measurement of human mature ADM (mADM) has been difficult, and recent studies have used its surrogate - the mid-regional pro-ADM (MRproADM). Our objective was to determine whether mADM measured by a novel sandwich immunoassay, using the anti-C-terminal and an anti-mid-regional monoclonal antibody, was prognostic of 30-day, 90-day, 1-year, and 2-year major adverse cardiovascular events (MACEs) in 1111 consecutive patients who have suffered an AMI. We also compared it with the effect of MRproADM in the same patient population. A total of 311 (27.0%) patients experienced the primary endpoint at 2 years follow-up. The median (inter-quartile range) of mADM was significantly higher in patients who experienced a 2-year MACE [60.90 (44.00-86.97)] pg/ml, compared to event-free survivors [49.59 (36.20-68.15)] pg/ml (P < 0.001). mADM, taken as 1 SD of the continuous variable, was predictive of MACEs in multivariate analysis, with hazard ratios [95% confidence intervals (CIs)] at 90 days [1.28 (1.01-1.62)], 1 year [1.31 (1.08-1.59)], and 2 years [1.42 (1.07-1.64)]. It was also independently predictive of death at 1-year [1.52 (1.12-2.05)] and 2-year [1.42 (1.07-1.89)] follow-up. mADM was a better predictor of these outcomes than MRproADM, apart from death at 90 days, and combined death and heart failure hospitalization at 1 and 2 years, respectively. Human mADM can be reliably measured and predicts MACE events at medium-term follow-up, and confirms the paradigm of risk stratification using MRproADM - a surrogate for the active hormone. The relationship between mADM and MACE appears to be a continuum.

Is pro-adrenomedullin a more useful marker in hospitalized infants with sepsis?

Dear Editor, We read with great interest the recent article by Benito et al. [1] whose objective was to assess the usefulness of two biomarkers, midregional pro-adrenomedullin (pro-ADM) and C-proendothelin-1 (CT-pro-ET-1), in predicting bacterial infection and, especially, invasive bacterial infection (IBI) in wellappearing infants with fever without source. They found that plasma levels of both endothelium-derived precursor peptides were higher in well-appearing febrile infants with focal and IBI than in patients with viral or self-limited infection. CT-pro-ET-1 showed a significant difference between patients with no bacterial infection and those with focal bacterial infection (p<0.05), but not between patients with focal bacterial infection and IBI. Levels of midregional pro-ADM showed no statistically significant differences among the three groups. These markers had a lower diagnostic accuracy for assessing the severity of bacterial infection than other biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT). In the initial univariate analysis, they found that PCT of ≥0.5 ng/mL, midregional pro-ADM of ≥0.7 nmol/L, andCRPof≥40mg/Lwere significantly associated with IBI. The only independent risk factor identified in the final multivariate model was a higher PCT level (≥0.5 ng/mL). In a recent similar study, we sought to compare sequential measurements of white blood cell count, CRP, interleukin-6 (IL-6), and pro-ADM in proven sepsis and clinical sepsis and the control group in newborns. A total of 76 patients with neonatal sepsis (31 with proven sepsis and 45 with clinical sepsis) and 52 healthy controls were enrolled. Mean baseline serum levels of CRP, IL-6, and pro-ADM were significantly higher in both proven and clinical sepsis groups compared to those in healthy controls (p <0.001 for both). Although mean baseline CRP and IL-6 levels were similar between groups, mean baseline pro-ADM level was higher in the proven sepsis group than that in clinical sepsis group (p <0.001). The calculated cutoff values for CRP, IL-6, and pro-ADM in distinguishing patients with sepsis group were 4.87 mg/L, 26 pg/mL, and 3.9 nmol/L, respectively. Area under the curve analysis for comparing patients with proven sepsis and healthy controls once again revealed the set cutoff values for CRP, IL-6, and pro-ADM to have specificities and positive predictive values of 100 %, with respective sensitivities of 96.7, 93.5, and 93.5 %. Negative predictive values for the three markers were 98.1, 96.2, and 96.2 %, respectively. Our study demonstrated that pro-ADM is a novel marker that may be used especially for the early diagnosis of neonatal sepsis. The fact that pro-ADM levels showed more rapid decreases compared to CRP in our study, we suggested that rather than being used alone, the use of pro-ADM in combination with conventional acute phase reactants may be more useful in the diagnosis and follow-up of patients with neonatal sepsis [2]. In conclusion, in relation to our study, we think that the result by Benito et al. [1] which showed pro-ADM as a weak marker in diagnosis of IBI might be both due to short half-life of the marker and the time of the obtaining the blood (whether early or late in emergency room). In contrast, we found proADM to be useful in the early detection of neonatal sepsis. Results of both studies suggest that pro-ADMmay be a useful marker in closely followed up hospitalized patients rather than outpatient infants and children. M. Y. Oncel (*) :N. Uras :U. Dilmen Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara 06230, Turkey e-mail: dryekta@gmail.com

Significant decrease in plasma midregional proadrenomedullin level in patients with end-stage renal disease after living kidney transplantation

Impaired renal function has been suggested to significantly impact plasma midregional proADM (MR-proADM) level. The aim of this study was to assess whether improvement of renal function after living kidney transplantation has an impact on plasma MR-proADM-like immunoreactive substance (IS) level. Eleven patients with end-stage renal disease (ESRD) who were scheduled to undergo the first living kidney allograft transplantation were enrolled. Plasma MR-proADM-IS levels were measured before and 3, 7, 10, 14, 21, 30, 60 and 90 days after kidney transplantation. Plasma MR-proADM-IS level decreased significantly from day 3 after kidney transplantation compared to before kidney transplantation. A significant negative correlation was observed between creatinine clearance and plasma MR-proADM-IS level from before to 90 days after kidney transplantation (rs=−0.70, p<0.0001). These results suggest that recovery of kidney function after kidney transplantation may lead to decrease in plasma MR-proADM level in patients with ESRD, and that plasma MR-proADM level may depend largely on renal function.

Development and clinical application of an enzyme immunoassay for the determination of midregional proadrenomedullin

Adrenomedullin (ADM) is a 52-amino acid peptide with a variety of physiologic functions such as immunomodulating activity, direct bactericidal activity, maintenance of renal homeostasis, and vasodilatory activity. Midregional proADM (MR-proADM) is derived from a larger 185-amino acid precursor peptide, prepro-adrenomedulin (preproADM), by posttranslational processing. It is suggested to be co-synthesized with ADM in equimolar amounts and has the advantages over ADM in having a longer half-life, no bioactivity, and no binding to protein. Therefore, MR-proADM serves as a surrogate for ADM secretion. In this study, we attempted to develop an enzyme immunoassay (EIA) for quantifying MR-proADM-like immunoreactive substance (IS), which is applicable for monitoring plasma MR-proADM levels. By using β-d-galactosidase-labeled preproADM(83-94) as a marker antigen, anti-rabbit IgG-coated immunoplate as a bound/free separator, and 4-methylumbelliferyl-β-d-galactopyranoside as a fluorogenic substrate, a sensitive and specific EIA was developed for the quantification of MR-proADM-IS in human plasma. The lower limit of quantification was 0.032 pmol/well, and the steep competitive inhibition EIA calibration curve obtained was linear between 0.16 and 10 nmol/L. By using human plasma samples containing 0.2 and 2.0 nmol/L of MR-proADM, the interassay coefficients of variation (reproducibility) were 10.78% and 8.83%, respectively, and intraassay coefficients were 3.91% and 7.81%. Plasma MR-proADM-IS level was significantly higher in patients with chronic renal failure (1.39 ± 0.50 nmol/L) compared with healthy subjects (0.19 ± 0.07 nmol/L). These results suggest that our EIA may be useful to evaluate plasma MR-proADM levels as a biomarker in various clinical settings.

Influence of age on the prognostic value of mid-regional pro-adrenomedullin in the general population

ObjectiveExperimental studies have shown that adrenomedullin (ADM) has an important role in circulatory homeostasis. Mid-regional pro-ADM (MR-proADM) is a stable form of ADM. Observational studies found an important association with...