Circulating mid-regional proadrenomedullin is a predictor of mortality in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Although there is increasing understanding of the changes in the laboratory parameters of Coronavirus disease 2019 (COVID-19), the correlation between circulating Mid-regional Proadrenomedullin (MR-proADM) and mortality of patients with COVID-19 is not fully understood. In this study, we conducted a systematic review and meta-analysis to evaluate the prognostic value of MR-proADM in patients with COVID-19. METHODS: The PubMed, Embase, Web of Science, Cochrane Library, Wanfang, SinoMed and Chinese National Knowledge Infrastructure (CNKI) databases were searched from 1 January 2020 to 20 March 2022 for relevant literature. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess quality bias, STATA was employed to pool the effect size by a random effects model, and potential publication bias and sensitivity analyses were performed. RESULTS: 14 studies comprising 1822 patients with COVID-19 met the inclusion criteria, there were 1145 (62.8%) males and 677 (31.2%) females, and the mean age was 63.8 ± 16.1 years. The concentration of MR-proADM was compared between the survivors and non-survivors in 9 studies and the difference was significant (P < 0.01), I2 = 46%. The combined sensitivity was 0.86 [0.73-0.92], and the combined specificity was 0.78 [0.68-0.86]. We drew the summary receiver operating characteristic (SROC) curve and calculated the area under curve (AUC) = 0.90 [0.87-0.92]. An increase of 1 nmol/L of MR-proADM was independently associated with a more than threefold increase in mortality (odds ratio (OR) 3.03, 95% confidence interval (CI) 2.26-4.06, I2 = 0.0%, P = 0.633). The predictive value of MR-proADM for mortality was better than many other biomarkers. CONCLUSION: MR-proADM had a very good predictive value for the poor prognosis of COVID-19 patients. Increased levels of MR-proADM were independently associated with mortality in COVID-19 patients and may allow a better risk stratification.

Plasma mid-regional proadrenomedullin level in children with pulmonary hypertension associated with CHD.

Adrenomedullin has been shown to inhibit proliferation in pulmonary artery smooth muscle cells and to alleviate pulmonary artery collagen accumulation in pulmonary hypertension. We aimed to assess mid-regional proadrenomedullin level in children with pulmonary hypertension due to CHDs. The current study was conducted in the Pediatric Cardiology Unit, Tanta University Hospital, on 50 children with CHDs: twenty-five patients had a complication of pulmonary hypertension and the other 25 patients without pulmonary hypertension. Another 25 children without CHDs were concluded as a control group. We performed complete history taking, full clinical assessment, chest X-ray, electrocardiogram, and echocardiographic assessment. Plasma level of mid-regional proadrenomedullin was assessed using a sandwich enzyme-linked immunosorbent assay test. Our results showed that the mean plasma level of mid-regional proadrenomedullin was significantly increased in patients with pulmonary hypertension. Significant positive correlation was found between mid-regional proadrenomedullin and mean pulmonary artery pressure. The best cut-off point of mid-regional proadrenomedullin as a diagnostic biomarker to discriminate patients with CHDs complicated with pulmonary hypertension was 199.22 nmol/l. Mid-regional proadrenomedullin significantly increased in patients with pulmonary hypertension who died as compared to patients who survived, with the best cut-off point was 428,8 nmol/l. We concluded that plasma levels of mid-regional proadrenomedullin were significantly elevated in children with pulmonary hypertension complicated by the CHDs. It could be used as a cardiac biomarker in these patients, with good diagnostic and prognostic value.

Mid-Regional Proadrenomedullin in COVID-19-May It Act as a Predictor of Prolonged Cardiovascular Complications?

The rising prevalence of cardiovascular disease (CVD) and the impact of the SARS-CoV-2 pandemic have both led to increased mortality rates, affecting public health and the global economy. Therefore, it is essential to find accessible, non-invasive prognostic markers capable of identifying patients at high risk. One encouraging avenue of exploration is the potential of mid-regional proadrenomedullin (MR-proADM) as a biomarker in various health conditions, especially in the context of CVD and COVID-19. MR-proADM presents the ability to predict mortality, heart failure, and adverse outcomes in CVD, offering promise for improved risk assessment and treatment strategies. On the other hand, an elevated MR-proADM level is associated with disease severity and cytokine storms in patients with COVID-19, making it a predictive indicator for intensive care unit admissions and mortality rates. Moreover, MR-proADM may have relevance in long COVID, aiding in the risk assessment, triage, and monitoring of individuals at increased risk of developing prolonged cardiac issues. Our review explores the potential of MR-proADM as a predictor of enduring cardiovascular complications following COVID-19 infection.

Mid-Regional Pro-Adrenomedullin Can Predict Organ Failure and Prognosis in Sepsis?

Sepsis causes immune dysregulation and endotheliitis, with an increase in mid-regional pro-adrenomedullin (MR-proADM). The aim of the study is to determine an MR-proADM value that, in addition to clinical diagnosis, can identify patients with localized infection or those with sepsis/septic shock, with specific organ damage or with the need for intensive care unit (ICU) transfer and prognosis. The secondary aim is to correlate the MR-proADM value with the length of stay (LOS). In total, 301 subjects with sepsis (124/301 with septic shock) and 126 with localized infection were retrospectively included. In sepsis, MR-proADM ≥ 3.39 ng/mL identified acute kidney injury (AKI); ≥2.99 ng/mL acute respiratory distress syndrome (ARDS); ≥2.28 ng/mL acute heart failure (AHF); ≥2.55 ng/mL Glascow Coma Scale (GCS) < 15; ≥3.38 multi-organ involvement; ≥3.33 need for ICU transfer; ≥2.0 Sequential Organ Failure Assessment (SOFA) score ≥ 2; and ≥3.15 ng/mL non-survivors. The multivariate analysis showed that MR-proADM ≥ 2 ng/mL correlates with AKI, anemia and SOFA score ≥ 2, and MR-proADM ≥ 3 ng/mL correlates with AKI, GCS < 15 and SOFA score ≥ 2. A correlation between mortality and AKI, GCS < 15, ICU transfer and cathecolamine administration was found. In localized infection, MR-proADM at admission ≥ 1.44 ng/mL identified patients with AKI; ≥1.0 ng/mL with AHF; and ≥1.44 ng/mL with anemia and SOFA score ≥ 2. In the multivariate analysis, MR-proADM ≥ 1.44 ng/mL correlated with AKI, anemia, SOFA score ≥ 2 and AHF. MR-proADM is a marker of oxidative stress due to an infection, reflecting severity proportionally to organ damage.

Prognostic value of copeptin and mid-regional proadrenomedullin in COVID-19-hospitalized patients.

BACKGROUND: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality. METHODS: Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC). RESULTS: Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001). CONCLUSIONS: Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.

Effect of adrenaline on serum mid-regional pro-atrial natriuretic peptide and central blood volume.

NEW FINDINGS: What is the central question in this study? Atrial natriuretic peptide (ANP) is secreted in response to atrial wall distension and thus allows for evaluation, albeit indirect, of the central blood volume. Adrenaline has chronotropic and inotropic effects. We evaluated whether the chronotropic and inotropic effects of adrenaline were reflected in mid-regional proANP. What is the main finding and its importance? Central blood volume remained stable with infusion of adrenaline and yet mid-regional proANP increased. Thus, the chronotropic and inotropic state of the heart or adrenaline directly induces release of ANP variants from the myocytes. ABSTRACT: Atrial natriuretic peptide (ANP) has vasodilatory, natriuretic and diuretic properties. It is secreted in response to atrial wall distension and thereby provides an indirect evaluation of central blood volume (CBV). Adrenaline has chronotropic and inotropic effects that increase cardiac output. In the present study, we evaluated whether these effects were influenced by an increase in CBV and reflected in mid-regional proANP (MR-proANP) concentrations in the circulation, a stable proxy marker of bioactive ANP. Changes in CBV were evaluated by thoracic electrical admittance and haemodynamic variables monitored by pulse-contour analysis during two intervals with graded infusion of adrenaline. Adrenaline infusion increased heart rate (by 33 ± 18%) and stroke volume (by 6 ± 13%), hence cardiac output (by 42 ± 23%; all P < 0.05). The increase in cardiac output did not result from an increase in CBV, because thoracic electrical admittance remained stable (-3 ± 17%; P = 0.230). Serum MR-proANP concentrations were increased (by 26 ± 25%; P < 0.001) by adrenaline infusion and remained elevated 60 min postinfusion. We conclude that MR-proANP in the circulation is affected not only by CBV, but also by increased chronotropy/inotropy of the heart, or that adrenaline directly induces release of ANP variants from the myocytes.

Circulating Biomarkers Predict Symptomatic but Not Asymptomatic Carotid Artery Stenosis.

BACKGROUND: Subjects exposed to risk factors such as age, gender, hypertension, diabetes mellitus, and smoking are prone to atherosclerotic events. AIMS: The main aim of this longitudinal cohort study was to determine whether the role of novel plasma biomarkers for atherosclerotic carotid artery disease is different in subjects developing symptomatic carotid artery stenosis (CAS), as opposed to those with incident asymptomatic CAS. METHODS: The following biomarkers were measured in 5,550 middle-aged subjects in a population-based cohort study: C-reactive protein (CRP), lipoprotein-associated phospholipase A2 mass and activity, proneurotensin, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), N-terminal pro-B-type natriuretic peptide (NT pro-BNP), copeptin, and cystatin C. After exclusion of those with prevalent CAS, subjects were thereafter followed in national patient registers for 23.4 (interquartile range 19.5-24.3) years regarding incident symptomatic and asymptomatic CAS. RESULTS: Among 110 patients with confirmed incident CAS, 56 were symptomatic and 54 were asymptomatic. When including conventional risk markers in a Cox regression analysis, NT pro-BNP (hazard ratio [HR] 1.59; 95% confidence interval [CI]: 1.20-2.11), MR-proADM (HR 1.40; CI: 1.13-1.73), cystatin C (HR 1.21; CI: 1.02-1.43), and CRP (HR 1.53; CI: 1.13-1.73) were independently associated with incident symptomatic CAS, whereas no plasma biomarker was associated with incident asymptomatic CAS. CONCLUSION: Plasma biomarkers NT pro-BNP, MR-proADM, cystatin C, and CRP were independently associated with incident symptomatic CAS, whereas no such association could be demonstrated with incident asymptomatic CAS. As these biomarkers indicate future development of clinically relevant atherosclerotic CAS, their potential utility in relation to intensified preventive measures and selection of potential candidates for carotid surgery should be further evaluated.

Mid-regional plasma pro-atrial natriuretic peptide and stroke volume responsiveness for detecting deviations in central blood volume following major abdominal surgery.

BACKGROUND: A reduced central blood volume is reflected by a decrease in mid-regional plasma pro-atrial natriuretic peptide (MR-proANP), a stable precursor of ANP, and a volume deficit may also be assessed by the stroke volume (SV) response to head-down tilt (HDT). We determined plasma MR-proANP during major abdominal procedures and evaluated whether the patients were volume responsive by the end of the surgery, taking the fluid balance and the crystalloid/colloid ratio into account. METHODS: Patients undergoing pancreatic (n = 25), liver (n = 25), or gastroesophageal (n = 38) surgery were included prospectively. Plasma MR-proANP was determined before and after surgery, and the fluid response was assessed by the SV response to 10° HDT after the procedure. The fluid strategy was based mainly on lactated Ringer's solution for gastroesophageal procedures, while for pancreas and liver surgery, more human albumin 5% was administered. RESULTS: Plasma MR-proANP decreased for patients undergoing gastroesophageal surgery (-9% [95% CI -3.2 to -15.3], p = .004) and 10 patients were fluid responsive by the end of surgery (∆SV > 10% during HDT) with an administered crystalloid/colloid ratio of 3.3 (fluid balance +1389 ± 452 ml). Furthermore, plasma MR-proANP and fluid balance were correlated (r = .352 [95% CI 0.031-0.674], p < .001). In contrast, plasma MR-proANP did not change significantly during pancreatic and liver surgery during which the crystalloid/colloid ratio was 1.0 (fluid balance +385 ± 478 ml) and 1.9 (fluid balance +513 ± 381 ml), respectively. For these patients, there was no correlation between plasma MR-proANP and fluid balance, and no patient was fluid responsive. CONCLUSION: Plasma MR-proANP was reduced in fluid responsive patients by the end of surgery for the patients for whom the fluid strategy was based on more lactated Ringer's solution than human albumin 5%.

Relation between Mid-Regional Pro-Adrenomedullin in Patients with Chronic Heart Failure and the Dose of Diuretics in 2-Year Follow-Up-Data from FAR NHL Registry.

Background and Objectives: The aim of this paper is to evaluate the impact of humoral substance mid-regional pro-adrenomedullin (MR-proADM) on the two-year survival of patients with chronic heart failure and relate it to the dosage of furosemide. Materials and Methods: The data is taken from the stable systolic heart failure (EF < 50%) FAR NHL registry (FARmacology and NeuroHumoraL activation). The primary endpoint at two-year follow-up was death, heart transplantation, or LVAD implantation. Results: A total of 1088 patients were enrolled in the FAR NHL registry; MR-proADM levels were available for 569 of them. The mean age was 65 years, and 81% were male. The aetiology of HF was ischemic heart disease in 53% and dilated cardiomyopathy in 41% of patients. The mean EF was 31 ± 9%. Statistically significant differences (p < 0.001) were obtained in several parameters: patients with higher MR-proADM levels were older, rated higher in NYHA class, suffered more often from lower limb oedema, and had more comorbidities such as hypertension, atrial fibrillation, diabetes, and renal impairment. MR-proADM level was related to furosemide dose. Patients taking higher doses of diuretics had higher MR-proADM levels. The mean MR-proADM level without furosemide (n = 122) was 0.62 (±0.55) nmol/L, with low dose (n = 113) 1−39 mg/day was 0.67 (±0.30) nmol/L, with mid dose (n = 202) 40−79 mg/day was 0.72 (±0.34) nmol/L, with high dose (n = 58) 80−119 mg/day was 0.85 (±0.40) nmol/L, and with maximum dose (n = 74) ≥120 mg/day was 1.07 (±0.76) nmol/L, p < 0.001. Patients with higher MR-proADM levels were more likely to achieve the primary endpoint at a two-year follow-up (p < 0.001) according to multivariant analysis. Conclusions: Elevated plasma MR-proADM levels in patients with chronic heart failure are associated with an increased risk of death and hospitalization. Higher MR-proADM levels in combination with increased use of loop diuretics reflect residual congestion and are associated with a higher risk of severe disease progression.

Modulatory effect of resveratrol and melatonin on natural killer cell activity and adrenomedullin in diabetic rats.

BACKGROUND: Epidemiological evidence suggests that diabetes poses a high risk for many chronic diseases, especially cardiovascular diseases, and cancer by stimulating many inflammatory and immunological pathogenic mediators and affecting natural killer (NK)-cell activity. In this study, the effects of melatonin and resveratrol on IL-6, TNF-alpha, oxidant/antioxidant capacity, NK-cell activity, and mid-regional proadrenomedullin (MR-proADM) levels of diabetic rats were investigated. METHODS: In the study, 28 Sprague Dawley rats were randomly divided into the control group (group I) and 3 streptozotocininduced diabetes mellitus (DM) groups (group II, III, and IV), each group consisting of 7 rats. Five mg/kg/day melatonin to group III and 5 mg/kg/day resveratrol (intraperitoneal) to group IV was given. At the end of 3 weeks, NK-cell activity, total antioxidant/oxidant capacity, MR-proADM, IL-6, and TNF-alpha levels were measured in intracardiac blood taken under anesthesia. RESULTS: NK-cell activity of group II was found lower than group I, group III, and group IV (7.4 ± 2.0 vs. 22.5 ± 11.9, 30.6 ± 22.5 and 20.4 ± 9.1 pg/mL; p = 0.0018, respectively). The difference was more prominent in diabetic rats receiving melatonin (p < 0.01). TNF-alpha levels of group II were higher than the group I (p < 0.05). The MR-proADM levels of group II were found to be lower than the group I and group III (6.4 ± 3.6 vs. 14.4 ± 3.2 and 14.0 ± 4.2 ng/L; p < 0.05, respectively). In addition, NK-cell activity was moderately correlated with MR-proADM (r = 0.5618, p = 0.0019).

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.

Mid-regional pro-atrial natriuretic peptide independently predicts short-term mortality in COVID-19.

BACKGROUND: Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a strong prognostic marker in several inflammatory, respiratory and cardiovascular conditions, but has not been studied in COVID-19 yet. METHODS: This prospective, observational study of patients with COVID-19 infection was conducted from 6 June to 26 November 2020 in different wards of a tertiary hospital. MR-proANP, N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitive cardiac troponin I levels on admission were collected and tested for their association with disease severity and 28-day mortality. RESULTS: A total of 213 eligible patients with COVID-19 were included in the final analyses of whom 13.2% (n = 28) died within 28 days. Median levels of MR-proANP at admission were significantly higher in nonsurvivors (307 pmol/L IQR, [161 - 532] vs 75 pmol/L [IQR, 43 - 153], P < .001) compared to survivors and increased with disease severity and level of hypoxaemia. The area under the ROC curve for MR-proANP predicting 28-day mortality was 0.832 (95% CI 0.753 - 0.912, P < .001). An optimal cut-off point of 160 pmol/L yielded a sensitivity of 82.1% and a specificity of 76.2%. MR-proANP was a significant predictor of 28-day mortality independent of clinical confounders, comorbidities and established prognostic markers of COVID-19 (HR 2.77, 95% CI 1.21 - 6.37; P = .016), while NT-proBNP failed to independently predict 28-day mortality and had a numerically lower AUC compared to MR-proANP. CONCLUSION: Higher levels of MR-proANP at admission are associated with disease severity of COVID-19 and act as a powerful and independent prognostic marker of 28-day mortality.

Biomarkers in patients with Takotsubo cardiomyopathy compared to patients with acute anterior ST-elevation myocardial infarction.

Background: Takotsubo cardiomyopathy (TTC) is a syndrome of acute non-coronary heart failure with similar symptoms and electrocardiograms to acute anterior ST-elevation myocardial infarction (STEMI). Little is known about the pathophysiology of TTC. We assessed admission plasma concentrations of biomarkers reflecting neuroendocrine response (copeptin, mid-regional-pro-adrenomedullin, pro-atrial-natriuretic-peptide, soluble thrombomodulin (sTM), syndecan-1) and inflammation (suppression-of-tumorigenicity 2 (ST2), high-sensitive C-reactive-protein) in TTC patients and compared to patients with acute anterior STEMI.Materials and methods: Twenty TTC patients were matched with 40 STEMI patients by age, gender and left ventricular ejection fraction. Blood was sampled upon hospital admission immediately before acute coronary angiography.Results: The groups had similar comorbidities. TTC patients had higher plasma concentrations of sTM: 7.94 (5.89;9.61) vs. 6.42 (5.50;7.82)ng/ml, p = 0.04 and ST2 (53 (32;157) vs. 45 (31;55)ng/ml, p = 0.008) and higher heart rate: 101 ([Formula: see text]33) vs. 76([Formula: see text]14)bpm, p = 0.0001, but lower concentrations of copeptin (10.4 (7.6;39) vs. 92.3 (13;197)pmol/l, p < 0.05) and troponin T (348 (98;759) vs. 1190 (261;4105)ng/l, p = 0.04).Conclusion: TTC patients had higher plasma concentrations of sTM and ST2, higher heart rate and lower copeptin and troponin T concentrations compared to acute anterior STEMI patients. This study contributes to the hypothesis that TTC patients have endothelial cell damage and are hemodynamically more stable than patients with acute anterior STEMI on admission.

Elevated MR-proANP plasma concentrations are associated with sepsis and predict mortality in critically ill patients.

BACKGROUND AND AIMS: Mid-regional pro atrial natriuretic peptide (MR-proANP) is an established biomarker for heart failure, based on its key role in regulating homeostasis of water balance and blood pressure. The aim of the study was to determine the value of MR-proANP as a clinical biomarker in critical illness and/or sepsis. Upon admission to the medical intensive care unit (ICU), we investigated MR-proANP plasma concentrations in 217 critically ill patients (144 with sepsis, 73 without sepsis). Results were compared with 65 healthy controls. RESULTS: MR-proANP plasma levels were significantly elevated in critically ill patients, when compared to healthy controls. Notably, MR-proANP levels were significantly higher in ICU patients with sepsis. MR-proANP levels were not associated with metabolic comorbidities like diabetes or obesity. In critically ill patients, MR-proANP plasma concentrations correlated with inflammatory cytokines, markers of organ dysfunction and several adipocytokines, such as resistin, retinol-binding protein 4 (RBP4) and adiponectin. Importantly, high MR-proANP plasma levels were associated with mortality, as MR-proANP levels above 227.0 pmol/l indicated a particularly increased mortality risk in ICU patients. The association between MR-proANP and mortality was independent of single organ failure and inflammation markers. CONCLUSION: Our study emphasizes the role of circulating MR-proANP as a biomarker in critically ill patients, in which high MR-proANP indicates organ dysfunction, sepsis and mortality risk. The association between high MR-proANP and inflammatory as well as adipose tissue-derived endocrine mediators warrants further pathophysiological investigations.

New approaches for the detection of invasive fungal diseases in patients following liver transplantation-results of an observational clinical pilot study.

PURPOSE: Despite antifungal prophylaxis following liver transplantation (LTX), patients are at risk for the development of subsequent opportunistic infections, such as an invasive fungal disease (IFD). However, culture-based diagnostic procedures are associated with relevant weaknesses. METHODS: Culture and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of ß-D-glucan (BDG), galactomannan (GM), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A and mid-regional proadrenomedullin (MR-proADM) were evaluated in 93 patients at 6 consecutive time points within 28 days following LTX. RESULTS: A NGS-based diagnostic approach was shown to be suitable for the early identification of fungal pathogens in patients following LTX. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with an IFD. CONCLUSION: Plasma measurements of MR-proADM and IL-17A as well as a NGS-based diagnostic approach were shown to be attractive methodologies to attenuate the weaknesses of routinely used culture-based diagnostic procedures for the determination of an IFD in patients following LTX. However, an additional confirmation within a larger multicenter trial needs to be recommended. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00005480 .

[The relevance of biomarkers in acute heart failure]. / Bedeutung von Biomarkern bei akuter Herzinsuffizienz.

Biomarkers may help to rapidly differentiate heart failure from noncardiac causes of acute dyspnea. Natriuretic peptides are especially useful for this purpose and should be measured in all patients presenting with acute onset dyspnea. Due to their excellent negative predictive value, a normal serum concentration of natriuretic peptides makes acute heart failure unlikely. Assays exist for B­type natriuretic peptide (BNP), N­terminal pro-B-type natriuretic peptide (NT-proBNP) and midregional pro-atrial natriuretic peptide (MR-proANP) with established cut-offs in the acute setting. Importantly, in patients treated with an angiotensin receptor-neprilysin inhibitor (ARNI), NT-proBNP (or MR-proANP) should be used instead of BNP, since the latter is increased by ARNI treatment. Besides their established diagnostic value in heart failure patients, the measurement of natriuretic peptides provides prognostic information and may help in guiding therapy. Additionally, multiple other biomarkers reflect several pathophysiological processes involved in heart failure patients. Their diagnostic and prognostic impact in heart failure needs to be established.

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.

Adrenomedullin as a Biomarker of Heart Failure.

Adrenomedullin (AM) is a vasodilatory peptide originally discovered in human pheochromocytoma tissue. Although AM is highly expressed in the adrenal glands, heart, lungs, and kidneys, vascular endothelium and smooth muscle are thought to be the main source of plasma AM. The AM precursor is processed to AM-glycine, which is then converted to AM-mature through C-terminal amidation. In this process, mid-regional pro-adrenomedullin (MR-proAM) is also produced. Plasma AM, AM-mature, AM-glycine, and MR-proAM levels are all higher in patients with heart failure than healthy subjects in proportional to the disease severity. All molecular forms of AM are prognostic markers for heart failure.

Natriuretic Peptides in Heart Failure: Atrial and B-type Natriuretic Peptides.

The natriuretic peptides play a vital role in normal physiology and as counter-regulatory hormones in heart failure (HF). Clinical assessment of their levels (for B-type natriuretic peptide [BNP], N-terminal proBNP, and the midregion of N-terminal pro-atrial natriuretic peptide) have become valuable tools in diagnosing patients with HF as well as risk stratifying and guiding therapy. Their roles have further expanded beyond HF to other cardiovascular conditions and for risk stratification in asymptomatic individuals. Understanding the clinical use of these hormones is vital to achieving their full potential.

Prognostic value of PCT, copeptin, MR-proADM, MR-proANP and CT-proET-1 for severe acute dyspnea in the emergency department: the BIODINER study.

CONTEXT: Acute dyspnea is a frequent complaint in patients attending the emergency department (ED). OBJECTIVE: To evaluate the accuracy of PCT, MR-proANP, MR-proADM, copeptin and CT-proET1 for the risk-stratification of severe acute dyspnea patients presenting to the ED. METHODS: Multicenter prospective study in adult patients with a chief complaint of acute dyspnea. Pro-hormone type biomarkers concentrations were measured on arrival. Combined primary endpoint was a poor outcome. RESULTS: Three hundred and ninety-four patients were included, 137 (35%) met the primary endpoint. MR-proADM was the only biomarker associated with the primary endpoint (odds ratio 1.43 [95%CI: 1.13-1.82], p = 0.003) as were the presence of paradoxical abdominal breathing (odds ratio 2.48 [95%CI: 1.31-4.68]) or cyanosis (odds ratio 3.18 [1.46-6.89]) Conclusions: In patients with severe acute dyspnea in the ED, pro-hormone type biomarkers measurements have a low added value to clinical signs for the prediction of poor outcome.