Search Results (11)

Adrenomedullin (AM) is a bioactive peptide that is strongly induced during severe inflammation, including pneumonia and sepsis, and serves as an organ-protective factor. The plasma concentration of AM is markedly increased in the novel coronavirus disease COVID-19 and is closely related to the severity of the disease and prognosis of patients. We performed two investigator-initiated trials to evaluate the efficacy and safety of AM in patients with moderate-to-severe COVID-19. This multicenter, double-blind, placebo-controlled phase-2a trial evaluated COVID-19 patients with severe (n = 33) and moderate (n = 31) pneumonia in Japan. Patients were randomly assigned to receive either 15 ng/kg/min AM or placebo. The primary endpoint was the duration of mechanical ventilation (MV) for severe pneumonia and oxygen support for moderate pneumonia. The main secondary endpoint was clinical status up to 30 days after the intervention. No differences in primary or secondary endpoints were observed between the AM and placebo groups in patients with severe or moderate pneumonia. In the severe pneumonia group, three patients in the placebo group died due to respiratory failure, and one patient in the AM group died due to respiratory failure. The respiratory function test at 30 days in the moderate pneumonia group tended to be better than that in the AM group and approached significance (p = 0.073). Although mild adverse events caused by the vasodilatory effects of AM were noted, the safety of AM for treating pneumonia was confirmed. In these trials, we did not observe a definitive efficacy of AM in moderate to severe pneumonia. Alternative strategies for the treatment of AM in pneumonia require further research. Full article

Background/Objectives: In the context of acute heart failure, proenkephalin A (penKid) has emerged as a prognostic marker for acute kidney injury (AKI), whereas bioactive adrenomedullin (bio-ADM) has been identified as a significant biomarker linked to shock and organ dysfunction. This raises the question of whether they can serve as predictors of postoperative complications in patients receiving left ventricular assist devices (LVADs). Methods: This observational study prospectively enrolled patients who had received LVAD implantation. Routine laboratory values as well as plasma levels of penKid and bio-ADM were assessed at four time intervals, spanning from preinduction of anesthesia to 48 h post surgery. Clinical data, the HeartMate 3-risk-score (HM3RS), HeartMateII-risk-score (HMRS), Michigan-right-heart-failure risk score (MRHFS), Euromacs-RHFS (EURORHFS), and kidney failure risk score (KFR) were calculated. Multivariate logistic regression and receiver operating characteristic (ROC) analysis were performed. We entered the biomarkers with the established risk scores into the models. Results: In 20 patients who had undergone LVAD implantation, preoperative penKid level was a predictor of postoperative AKI (OR: 1.05, 95%-CI: 1.0–1.09; p = 0.049) and 30-day mortality (OR: 1.01, 95%-CI: 1.0–1.02; p = 0.033). Bio-ADM was the only predictor of postoperative right heart failure (RHF) (OR: 1.11, 95%-CI: 1.01–1.23; p = 0.034) and rehospitalization (OR: 1.06, 95%-CI: 1.0–1.13; p = 0.047). In the ROC analysis, bio-ADM, as a predictor of post-LVAD RHF, had an area under the curve (AUC) of 0.88. When bio-ADM was added to the accepted clinical scores for post-LVAD RHF prediction (CRITT-score, MRHFS, and EURORHFS), the AUC reached 0.98. The AUC for preoperative penKid, as a predictor of postoperative AKI, was 0.95, and after adding its predictive value to the KFR score, the AUC reached 0.97. Conclusions: In the present study, the biomarkers penKid and bio-ADM predicted clinically significant patient outcomes after LVAD implantation such as AKI, RHF, and 30-day mortality. Adding biomarkers to well-established risk scores improved the AUC for prediction of postoperative complications. Full article

Congestion represents a defining hallmark of heart failure (HF) leading to increased morbidity and mortality in HF patients. While it was traditionally viewed as a simple and uniform state of volume overload, contemporary understanding has emphasized its complexity, distinguishing between intravascular, interstitial, and tissue congestion. Congestion contributes to overt clinical manifestation of HF. However, subclinical congestion often goes undetected, increasing the risk of adverse outcomes. Residual congestion, in particular, remains a frequent and challenging issue, with its persistence at discharge being strongly linked to rehospitalization and poor prognosis. Clinical evaluation often fails to reliably identify the resolution of congestion, highlighting the need for supplementary diagnostic methods. Improvement in imaging modalities, including lung ultrasound, venous Doppler, and echocardiography, have significantly enhanced the detection of congestion. Moreover, biomarkers such as natriuretic peptides, bioactive adrenomedullin, soluble CD146, and carbohydrate antigen 125 offer valuable, complementary insights into fluid distribution and the severity of HF congestion. Therefore, a comprehensive, multimodal strategy that integrates clinical evaluation with imaging and biomarker data is crucial for optimizing the management of congestion in HF. Future approaches should prioritize personalized decongestive therapy, addressing both intravascular and tissue congestion, while aiming to preserve renal function and limit neurohormonal activation. Refinement of these strategies holds promise for improving long-term outcomes, reducing rehospitalizations, and enhancing overall patient prognosis. Full article

Peptidylglycine alpha-amidating monooxygenase (PAM) is the only enzyme known to catalyze C-terminal amidation, a final post-translational modification step essential for the biological activity of over 70 bioactive peptides, including adrenomedullin (ADM), calcitonin gene-related peptide (CGRP), amylin, neuropeptide Y (NPY), and others. Bioactive (amidated) peptide hormones play crucial roles in various physiological processes and have been extensively explored as therapeutic compounds in clinical and preclinical research. However, their therapeutic viability is limited due to their short half-life and, in most cases, the need for prolonged infusion to maintain effective concentrations. PAM itself has also been considered as a therapeutic compound aiming to increase the level of amidated peptide hormones; however, similarly to peptide hormones, PAM’s rapid degradation limits its utility. Here, we present a strategy to enhance PAM stability and bioavailability through PEGylation, significantly extending the enzyme’s half-life in circulation assessed in healthy rats. Furthermore, single subcutaneous (s.c.), intramuscular (i.m.), or intraperitoneal (i.p.) administration of PEGylated PAM resulted in a sustained increase in circulating amidating activity, with peak activity observed at 12–24 h post-bolus administration. Notably, amidating activity remained significantly elevated above baseline levels for up to seven days post-administration, with no observable adverse effects. These findings highlight PEGylated PAM’s potential as a viable therapeutic compound. Full article

Sepsis and septic shock are leading causes of morbidity and mortality in both humans and dogs, and early diagnosis is crucial for improving outcomes. This study aimed to evaluate bioactive adrenomedullin (bio-ADM) concentrations in dogs with septic shock (n = 25), dogs with sepsis without evidence of shock (n = 25), and healthy control dogs (n = 25). Plasma bio-ADM concentrations were measured using a human sandwich enzyme-linked immunosorbent assay and reported as median (interquartile range). Plasma bio-ADM concentrations were significantly higher in both septic groups compared to the healthy controls (all <22.4 pg/mL), but not significantly different between the septic shock (75.0 [28.7–115.0] pg/mL) and sepsis (30.7 [22.4–79.7] pg/mL) groups. Dogs with higher illness severity scores had significantly higher bio-ADM concentrations (93.1 [32.2–122.0] pg/mL) than those with lower scores (29.8 [22.4–71.2] pg/mL). However, bio-ADM concentrations did not differ between survivors (33.0 [22.7–76.7] pg/mL) and non-survivors (74.7 [26.1–123.2] pg/mL). Measurement of bio-ADM is a potential marker for canine sepsis, but not for the identification of septic shock, and may provide information on disease severity. Further studies, including those on non-infectious inflammatory conditions, are necessary to better understand the diagnostic utility of bio-ADM measurement and its potential role as a marker of treatment response in dogs with sepsis. Full article

The adrenomedullin level increases in pulmonary arterial hypertension (PAH, and correlates with a high mortality rate. Its active form, bioactive adrenomedullin (bio-ADM), has been recently developed and has significant prognostic applications in acute clinical settings. Aside from idiopathic/hereditary PAH (I/H-PAH), atrial septal defects-associated pulmonary artery hypertension (ASD-PAH) is still prevalent in developing countries and associated with increased mortality. This study aimed to investigate the mortality-wise prognostic value of the plasma bio-ADM level by comparing subjects with ASD-PAH and I/H-PAH with ASD patients without pulmonary hypertension (PH) as a control group. This was a retrospective, observational cohort study. The subjects were Indonesian adult patients who were recruited from the Congenital Heart Disease and Pulmonary Hypertension (COHARD-PH) registry and divided into three groups: (1) ASD without PH (control group), (2) ASD-PAH and (3) I/H-PAH. During right-heart catheterization at the time of diagnosis, a plasma sample was taken and assayed for bio-ADM using a chemiluminescence immunoassay. Follow-up was performed as a part of the COHARD-PH registry protocol in order to evaluate the mortality rate. Among the 120 subjects enrolled: 20 turned out to have ASD without PH, 85 had ASD-PAH and 15 had I/H-PAH. Compared to the control group (5.15 (3.0–7.95 pg/mL)) and ASD-PAH group (7.30 (4.10–13.50 pg/mL)), bio-ADM levels were significantly higher in the I/H-PAH group (median (interquartile range (IQR)): 15.50 (7.50–24.10 pg/mL)). Moreover, plasma bio-ADM levels were significantly higher in subjects who died (n = 21, 17.5%) compared to those who survived (median (IQR): 11.70 (7.20–16.40 pg/mL) vs. 6.90 (4.10–10.20 pg/mL), p = 0.031). There was a tendency toward higher bio-ADM levels in those who died among the PAH subjects, in both ASD-PAH and I/H-PAH groups. In conclusion, the plasma bio-ADM level is elevated in subjects with PAH from both ASD-PAH and I/H-PAH origins, reaching the highest levels in subjects with the I/H-PAH form. A high bio-ADM level tended to be associated with a high mortality rate in all subjects with PAH, indicating a relevant prognostic value for this biomarker. In patients with I/H-PAH, monitoring bio-ADM could represent a valid tool for predicting outcomes, allowing more appropriate therapeutical choices. Full article

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two bioactive peptides derived from the same precursor with several biological functions including vasodilation, angiogenesis, or anti-inflammation, among others. AM and PAMP are widely expressed throughout the gastrointestinal (GI) tract where they behave as GI hormones, regulating numerous physiological processes such as gastric emptying, gastric acid release, insulin secretion, bowel movements, or intestinal barrier function. Furthermore, it has been recently demonstrated that AM/PAMP have an impact on gut microbiome composition, inhibiting the growth of bacteria related with disease and increasing the number of beneficial bacteria such as Lactobacillus or Bifidobacterium. Due to their wide functions in the GI tract, AM and PAMP are involved in several digestive pathologies such as peptic ulcer, diabetes, colon cancer, or inflammatory bowel disease (IBD). AM is a key protective factor in IBD onset and development, as it regulates cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function and mucosal epithelial repair, and promotes a beneficial gut microbiome composition. AM and PAMP are relevant GI hormones that can be targeted to develop novel therapeutic agents for IBD, other GI disorders, or microbiome-related pathologies. Full article

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

Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn’s disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment. Full article

The coronavirus disease 2019 (COVID-19) pandemic has placed a significant burden on hospitals worldwide. Objective biomarkers for early risk stratification and clinical management are still lacking. The aim of this work was to determine whether bioactive adrenomedullin can assist in the risk stratification and clinical management of critically ill COVID-19 patients. Fifty-three patients with confirmed COVID-19 were included in this prospective observational cohort study between March and April 2020. Bioactive adrenomedullin (bio-ADM) plasma concentration was measured daily for seven days after admission. The prognostic value and clinical significance of bio-ADM plasma levels were evaluated for the severity of respiratory failure, the need for extracorporeal organ support and outcome (28-day mortality). Bio-ADM levels increased with the severity of acute respiratory distress syndrome (ARDS; p < 0.001) and were significantly elevated in invasively ventilated patients (p = 0.006) and patients in need of extracorporeal membrane oxygenation (p = 0.040) or renal replacement therapy (RRT; p < 0.001) compared to patients without these conditions. Non-survivors showed significantly higher bio-ADM levels than survivors (p = 0.010). Bio-ADM levels predicted 28-day mortality (C-index 0.72, 95% confidence interval 0.56–0.87, p < 0.001). Bio-ADM plasma levels correlate with disease severity, the need for extracorporeal organ assistance, and outcome, and highlight the promising value of bio-ADM in the early risk stratification and management of patients with COVID-19. Full article

Increased reactive oxygen species (ROS) induced by angiotensin II (Ang II) in the paraventricular nucleus (PVN) play a critical role in sympathetic overdrive in hypertension (OH). Intermedin (IMD), a bioactive peptide, has extensive clinically prospects in preventing and treating cardiovascular diseases. The study was designed to test the hypothesis that IMD in the PVN can inhibit the generation of ROS caused by Ang II for attenuating sympathetic nerve activity (SNA) and blood pressure (BP) in rats with obesity-related hypertension (OH). Male Sprague-Dawley rats (160–180 g) were used to induce OH by feeding of a high-fat diet (42% kcal as fat) for 12 weeks. The dynamic changes of sympathetic outflow were evaluated as the alterations of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to certain chemicals. The results showed that the protein expressions of Ang II type 1 receptor (AT1R), calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2) and RAMP3 were markedly increased, but IMD was much lower in OH rats when compared to control rats. IMD itself microinjection into PVN not only lowered SNA, NADPH oxidase activity and ROS level, but also decreased Ang II-caused sympathetic overdrive, and increased NADPH oxidase activity, ROS levels and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activation in OH rats. However, those effects were mostly blocked by the adrenomedullin (AM) receptor antagonist AM22-52 pretreatment. The enhancement of SNA caused by Ang II can be significantly attenuated by the pretreatment of AT1R antagonist lorsatan, superoxide scavenger Tempol and NADPH oxidase inhibitor apocynin (Apo) in OH rats. ERK activation inhibitor U0126 in the PVN reversed Ang II-induced enhancement of SNA, and Apo and IMD pretreatment in the PVN decreased Ang II-induced ERK activation. Chronic IMD administration in the PVN resulted in significant reductions in basal SNA and BP in OH rats. Moreover, IMD lowered NADPH oxidase activity and ROS level in the PVN; reduced the protein expressions of AT1R and NADPH oxidase subunits NOX2 and NOX4, and ERK activation in the PVN; and decreased Ang II levels-inducing sympathetic overactivation. These results indicated that IMD via AM receptors in the PVN attenuates SNA and hypertension, and decreases Ang II-induced enhancement of SNA through the inhibition of NADPH oxidase activity and ERK activation. Full article