Adrenomedullin

Longitudinal and cross-sectional associations of myocardial stress markers with kidney function and chronic kidney disease in the BiomarCaRE project.

Jie-Sheng Lin, Tanja Zeller, Wolfgang Koenig +16 more

Given the complex relationship between cardiovascular disease (CVD) and chronic kidney disease (CKD), CVD-related markers may serve as CKD biomarkers. We examined associations of three major CVD-markers [mid-regional pro-adrenomedullin (MR-proADM), MR-pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)] with CKD. Cross-sectional analyses included up to 61,830 participants, and longitudinal analyses (NT-proBNP only) 4205 individuals. Kidney function was assessed by estimated glomerular filtration rate (eGFR) using creatinine, cystatin C, or both (eGFRcr-cys). Markers were categorized into four groups. Cross-sectional analyses found that higher levels of all three markers were consistently associated with lower eGFR and higher CKD prevalence. For example, per 1 standard deviation (SD) increase in log-transformed NT-proBNP, corresponding to a 2.71-fold increase in the original concentration, was associated with -2.35 (-2.49, -2.21) ml/min/1.73m2 lower eGFRcr-cys, and the highest NT-proBNP group had a 5.72-fold higher odds of CKDcr-cys (eGFRcr-cys < 60 ml/min/1.73m2) compared with the lowest. Associations with eGFR were stronger among participants with CVD and diabetes. In longitudinal analyses, participants with higher baseline NT-proBNP had faster declines in eGFR, with a 10-year decline of -1.37 (-1.77, -0.98) ml/min/1.73m2 eGFRcr-cys per 1 SD increase, and higher CKD incidence. These findings suggest MR-proADM, MR-proANP, and NT-proBNP as CKD biomarkers.

Menstrual cycle phase and hormonal contraceptive use influence circulating proforms of atrial natriuretic peptide, adrenomedullin, and the vasopressin proxy copeptin in healthy women.

Anne Sophie Broholt Jensen, Janne Gasseholm Bentzen, Jens P Goetze +6 more

Cardiovascular disease is the main cause of mortality among women. However, the menstrual cycle and hormonal contraception are often overlooked in research. This study investigates whether concentrations of common cardiovascular biomarkers (natriuretic peptides, adrenomedullin, and copeptin) change during a menstrual cycle and with hormonal contraception use.

Bio-Adrenomedullin Predicts Death and Major Adverse Cardiovascular Events in Cardiac Amyloidosis: A Cross-Continental Multicenter Study.

Maximilian L Müller, Fabian Knebel, Katrin Hahn +10 more

Bio-ADM (bioactive adrenomedullin) is a vasoactive peptide hormone that predicts clinical outcomes in heart failure-the main driver of adverse outcomes in cardiac amyloidosis (CA). This prospective observational study sought to assess the prognostic role of bio-ADM in CA.

Cardiovascular Disease and COVID-19: Is There a Place for Mid-Regional Pro-Adrenomedullin? Preliminary Data from a Clinical Cohort.

Paulina Pietraszko, Marcin Żórawski, Emilia Bielecka-Richter +4 more

Mid-regional pro-adrenomedullin (MR-proADM) has emerged as a promising biomarker reflecting endothelial dysfunction and systemic inflammation. Its prognostic role in cardiovascular complications, particularly in the context of COVID-19 infection, remains under investigation. This study aimed to evaluate MR-proADM concentrations in patients with and without cardiovascular disease and COVID-19 and to assess its association with cardiac complications and biomarkers of myocardial injury. A total of 157 patients (mean age: 72.3 years; 66 men) hospitalized in a tertiary referral center were enrolled. The study population consisted of three groups: patients with cardiovascular disease and COVID-19 (n = 64), patients with cardiovascular disease but no COVID-19 (n = 74), and a control group without cardiovascular disease or COVID-19 (n = 17). Plasma MR-proADM levels were measured, and their relationship with cardiovascular complications (chronic heart failure and myocardial infarction) and standard cardiac biomarkers (troponin T, troponin I, and proBNP) was analyzed. The mean MR-proADM concentration in the overall cohort was 91.48 ± 71.96 pmol/L (median: 77.95; range: 5.81-429.20). Distributions of MR-proADM, troponin T (M = 143.12 ± 733.93 ng/L), troponin I (M = 143.37 ± 749.85 ng/L), and proBNP (M = 2080.29 ± 3632.03 pg/mL) deviated significantly from normality (Shapiro-Wilk, all p < 0.001). No significant differences in MR-proADM concentrations were observed between patients with COVID-19 vs. without (93.78 ± 56.94 vs. 92.08 ± 82.82 pmol/L, p = 0.842) and between active infection vs. past COVID-19 (93.78 ± 56.94 vs. 85.98 ± 50.39 pmol/L, p = 0.869). A trend toward higher MR-proADM concentrations was observed in patients with cardiovascular disease compared to those without, with mean levels of 93.56 ± 74.90 vs. 74.33 ± 37.43 pmol/L, respectively. The frequency of chronic heart failure (55.0% vs. 54.5%, p = 1.000) and myocardial infarction (11.3% vs. 20.8%, p = 0.128) did not differ between patients with low vs. high MR-proADM (cut-off: median). Logistic regression confirmed that MR-proADM did not significantly predict either chronic heart failure (Nagelkerke R2 = 0.002, p = 0.660) or myocardial infarction (Nagelkerke R2 = 0.006, p = 0.465). Correlation analysis showed no significant associations between MR-proADM and proBNP (ρ = 0.09, p = 0.323), troponin T (ρ = 0.22, p = 0.065), or troponin I (ρ = 0.16, p = 0.088). MR-proADM levels did not differ significantly between patients stratified by COVID-19 infection or cardiovascular disease and were not predictive of heart failure or myocardial infarction. Moreover, no correlations were found with standard cardiac biomarkers. These results suggest that, in this cohort, MR-proADM did not provide additional prognostic information for cardiovascular complications.

Prognostic utility of mid-regional pro-adrenomedullin and growth differentiation factor 15 in patients undergoing transfemoral transcatheter aortic valve implantation.

Kerstin Piayda, Stanislav Keranov, Luisa Schulz +11 more

Risk prediction in patients with severe, symptomatic aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) remains an unsolved issue. In addition to classical risk scoring systems, novel circulating biomarkers like mid-regional pro-adrenomedullin (MR-proADM) and growth differentiation factor 15 (GDF-15) may be of value in assessing risk.

Early Use of Innovative Biomarkers Such as Mid-Regional Pro-Adrenomedullin and SeptiCyte® RAPID in Post-Cardiac Surgery Patients: Pilot Case Series.

Chiara Risso, Lorenzo Vay, Francesca Sciascia +5 more

Prognostic uncertainty and missed diagnoses of sepsis remain frequent after cardiopulmonary bypass (CPB) surgery, where systemic inflammatory response (SIRS) arises from surgical trauma, blood activation in the extracorporeal circuit, ischemia/reperfusion injury, and endotoxin release. Among innovative biomarkers, pro-adrenomedullin (pro-ADM), particularly its stable fragment mid-regional pro-adrenomedullin (MR-proADM), has shown promise for detecting endothelial dysfunction and predicting organ failure in sepsis. SeptiCyte® RAPID (Seattle, WA, USA) also represents a novel diagnostic tool that assesses the host immune response by quantifying PLA2G7 and PLAC8 gene expression in whole blood, offering potential for early differentiation between sepsis and sterile inflammation. We analyzed traditional and innovative biomarkers within 24 h post-CPB in a pilot group of patients admitted to the cardiac Intensive Care Unit of the "Città della Salute e della Scienza" University Hospital (Turin, Italy) between June and November 2023. Data from the following 14 patients were collected: 7 undergoing surgery for infective endocarditis (IE, Group 1) and 7 having standard elective cardiac surgery (Group 2). Procalcitonin (PCT), lactate, and pro-ADM increased in Group 1 but not in Group 2. SeptiCyte® RAPID showed a moderate, borderline increase in Group 1. The innovative biomarkers had a good performance in patients exhibiting signs of organ dysfunction and in subjects demonstrating at least cardiovascular and/or pulmonary damage and under vasopressor and inotropic support. Although limited by the small sample, our preliminary data suggest no biomarker alterations in patients with standard elective cardiac surgery, unlike in those with IE.

Association between plasma mid-regional pro-adrenomedullin levels and muscle properties.

Hiroshi Akasaka, Yasuharu Tabara, Kazuki Fukuma +10 more

Adrenomedullin exerts a vasodilative effect and is thought to be associated with skeletal muscle properties by regulating microcirculation. This cross-sectional study aimed to clarify the possible association in older adults aged ≥65 years.

Kinetics of adrenomedullin pathway activation in a porcine sepsis model and a human cohort of sepsis and septic shock.

Christoph Thiele, Yulia Ilina, Paul Kaufmann +7 more

Sepsis is a life-threatening condition characterized by endothelial dysfunction. The peptide hormone adrenomedullin (ADM) plays a key role in sepsis owing to its potent vasodilatory effects, ability to maintain vascular integrity, and critical role in modulating immune responses and reducing inflammation. To gain its biological activity, the inactive ADM precursor (ADM-Gly) is converted into its active form (bio-ADM) by peptidylglycine α-amidating monooxygenase (PAM). Here, we present hourly resolved kinetics of ADM activation during early sepsis onset in a porcine model and analyze the AdrenOSS-1 human cohort data to assess biomarker changes in advanced sepsis progression. The porcine model data showed that both bio-ADM and ADM-Gly mean concentrations rose within the first two hours post-induction, preceding measurable sepsis onset, with a greater increase in ADM-Gly (260.8 ± 92.0 pg/mL) compared to bio-ADM (28.0 ± 12.9 pg/mL). PAM activity increased at 6 h (39.3 ± 10.5 Units), accompanied by a rise in the bio-ADM/ADM-Gly ratio. AdrenOSS-1 study revealed that ICU sepsis patients had higher ADM-Gly (121.5 pg/mL [IQR: 44.4-284.1]) and PAM activity (23.5 Units [IQR: 17.7-32.7]) than controls. Elevated ADM-Gly (> 730 pg/mL) and PAM activity (> 35.1 Units) were associated with increased 28-day mortality, with non-survivors exhibiting higher ADM-Gly (603.5 pg/mL [IQR: 131.1-1443]) and PAM activity (28.3 Units [IQR: 19.0-45.1]) than survivors. This study provides novel insights into the dynamics of adrenomedullin (ADM) homeostasis during sepsis progression, highlighting the critical interplay between its glycine-extended precursor (ADM-Gly), fully active form (bio-ADM), and the amidating enzyme PAM. The findings demonstrate that early and significant elevations in ADM-Gly, accompanied by delayed PAM activity, result in incomplete ADM amidation, compromising endothelial barrier function. Elevated ADM-Gly and PAM activity were associated with increased sepsis severity and 28-day mortality, while a higher bio-ADM/ADM-Gly ratio was linked to improved survival. These results underscore the potential of ADM-Gly, bio-ADM, and PAM as biomarkers for sepsis severity and prognosis, and support therapeutic strategies aimed at enhancing PAM activity to restore endothelial integrity and improve patient outcomes in sepsis.

Adrenomedullin production by adult cardiac fibroblasts via NF-κB/STAT6 signaling enhances post-infarction lymphangiogenesis and cardiac repair.

Yuimi Matsuoka, Yuuki Shimizu, Haihang Luo +5 more

Myocardial infarction (MI) remains the leading cause of death worldwide. We previously found that a specific population of human fetal cardiac fibroblasts (fCFs), which express vascular cell adhesion molecule 1 (VCAM1), have cardioprotective effects after MI, inducing reparative cardiac lymphangiogenesis. This study investigated whether adult cardiac fibroblasts (aCFs), which are more feasible for autologous transplantation, differ in surface marker expression and lymphangiogenic potential compared to fCFs. Furthermore, we examined whether aCFs could be exogenously manipulated to acquire fCF-like lymphangiogenic potential and serve as a cell therapy for MI and MI-associated heart failure. In vivo MI models (rat and mouse) and in vitro coculture assays with lymphatic endothelial cells were conducted. We found that TNF-α and IL-4 stimulation induced aCFs to express VCAM1 via NF-κB and STAT6 signaling, yielding a subpopulation termed adult VCAM1+ cardiac fibroblasts (aVCFs). These aVCFs, distinct from myofibroblasts, expressed CD90 and improved cardiac function post-MI. Adrenomedullin (ADM) was identified as a key paracrine effector, and its knockdown attenuated the pro-lymphangiogenic and cardioprotective effects of aVCFs. Our findings demonstrate that aVCFs promote cardiac lymphangiogenesis and protect cardiac function following MI, highlighting their potential as an autologous cell therapy.

Young first-episode psychosis patients exhibit impaired microvascular function in the skin and low systemic nitric oxide availability, independent of classical cardiovascular risk factors.

Joanna Suraj-Prażmowska, Brygida Marczyk, Natalia Śmierciak +7 more

Impaired endothelial function in patients with psychotic disorders may contribute to increased cardiovascular mortality, but the mechanisms involved remain unclear. Here, we comprehensively analyzed endothelial function in 33 young (median age 18: IQR 17-27) patients diagnosed with first-episode psychosis (FEP), examining large vessels (flow-mediated dilation; FMD) and the microcirculation in peripheral vessels (peripheral arterial tonometry following reactive hyperemia; RH-PAT) and in the skin (flow-mediated skin fluorescence; FMSF). We also measured the plasma concentration of nitric oxide (NO) metabolites (nitrite/nitrate) and 18 biomarkers related to endothelial function, including those representative of glycocalyx damage (SDC-1), endothelial inflammation (sVCAM-1), disrupted endothelial permeability (Angpt-1, Angpt-2), and hemostasis (TAFI, THBS-1). In FEP patients, FMD and RH-PAT remained largely unchanged, but skin microcirculation measured by FMSF was impaired, with pronounced alterations in baseline microvascular oscillations and reactive hyperemic response. Plasma nitrite concentration in FEP patients was significantly lowered, but the profile of biomarkers did not display typical pattern of pro-inflammatory and pro-thrombotic changes associated with endothelial dysfunction, but prominent lowering of adrenomedullin and annexin A5 levels. FEP patients had higher white blood cell counts, total cholesterol, and triglycerides levels, but these parameters did not correlate with any of the vascular readouts. In conclusion, young FEP patients displayed a distinct endotype of endothelial dysfunction with impaired systemic NO bioavailability and prominent functional alterations in the microcirculation of the skin. These results indicate that the assessment of functional changes in skin microcirculation by FMSF may provide novel insights into the early negative effects of psychosis on the microvasculature.

New cardiovascular biomarkers in patients with advanced cancer - A prospective study comparing MR-proADM, MR-proANP, copeptin, high-sensitivity troponin T and NT-proBNP.

Markus S Anker, Laura C Lück, Muhammad Shahzeb Khan +16 more

Traditional cardiovascular (CV) biomarkers (high-sensitivity troponinT [hsTnT] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) are important to monitor cancer patients' cardiac function and to assess prognosis. Newer CV biomarkers (mid-regional pro-adrenomedullin [MR-proADM], C-terminal pro-arginine vasopressin [copeptin], and mid-regional pro-atrial natriuretic peptide [MR-proANP]) might outperform traditional biomarkers.

Adjustment of the SMART risk score by bioactive adrenomedullin enables a more accurate prediction of mortality in patients with ASCVD.

Berkan Kurt, Matthias Rau, Oliver Hartmann +18 more

Bioactive adrenomedullin 1-52 (bio-ADM) is a novel biomarker for the assessment of endothelial function and prediction of adverse outcomes in patients with acute heart failure and cardiogenic shock. The SMART (Second Manifestations of Arterial Disease) risk score is a validated tool for risk assessment in patients with established atherosclerotic cardiovascular disease (ASCVD). Here we assessed whether bio-ADM adds incremental prognostic value to the SMART risk score in stable patients with ASCVD.

Adrenomedullin-RAMP2 System Modulates Inflammation and Tissue Repair in Experimental Autoimmune Uveitis Via T-Cell and M2 Macrophage Regulation.

Yorishige Matsuda, Megumu Tanaka, Yunlu Zhao +15 more

Adrenomedullin (AM), a peptide produced by various cells, exerts diverse physiological effects and is regulated by receptor activity-modifying proteins (RAMP2 and 3). Experimental autoimmune uveitis (EAU) is a well-established model for studying human autoimmune uveitis. Hence, we investigated the pathophysiological roles of the AM-RAMP system in uveitis using an optimized EAU mouse model.

Association of ventricular-arterial coupling with biomarkers involved in heart failure pathophysiology - the STANISLAS cohort.

Hannes Holm, Martin Magnusson, Amra Jujić +10 more

Impaired left ventricular-arterial coupling (VAC) has been shown to correlate with worse prognosis in cardiac diseases and heart failure (HF). The extent of the relationship between VAC and circulating biomarkers associated with HF has been scarcely documented. We aimed to explore associations of VAC with proteins involved in HF pathophysiology within a large population-based cohort of middle-aged individuals.

Modifiable risk factors and plasma proteomics in relation to complications of type 2 diabetes.

Ruyi Li, Shufan Tian, Jun Liu +10 more

A comprehensive assessment of combined modifiable risk factors with common complications of type 2 diabetes (T2D) is lacking, and the potential role of proteomics remains unclear. Here, we examine the associations of cardiovascular health (CVH) score and degree of risk factor control with common diabetic complications using data from the UK Biobank (n = 14,102). Furthermore, we explore the mediation effects of plasma proteomics in a subset with proteomic data (n = 1287). Over median follow-ups of 12.4-13.4 years, higher CVH score and higher degree of risk factor control are associated with lower risks of 30 and 22 of 45 adverse outcomes among individuals with T2D, respectively. Mediation analyses reveal that mortality and multiple vascular diseases share common mediators, such as uromodulin and pro-adrenomedullin. These findings highlight the importance of risk factors modification in reducing disease burden among people with T2D and facilitate the understanding of mediation effects of plasma proteins underlying these associations.

Natriuretic Peptides and Soluble ST2 Improve Echocardiographic and Invasive Long-Term Survival Prediction in Patients Evaluated for Diastolic Dysfunction.

Horațiu Suciu, Paul-Adrian Călburean, Adina Huțanu +8 more

This study aimed to investigate the impact of long-term survival on cardiac serum biomarkers such as natriuretic peptides (mid-regional pro-atrial natriuretic peptide [MR-proANP], B-type natriuretic peptide [BNP], N-terminal prohormone BNP [NT-proBNP]), soluble ST2 (sST2), galectin-3 and mid-regional pro-adrenomedullin (MR-proAMD). Consecutive patients hospitalized in a tertiary center, undergoing echocardiographic and invasive left cardiac catheterization for diastolic dysfunction assessment were prospectively included in this study. Cardiac biomarkers were determined from pre-procedural peripheral venous blood samples. A total of 110 patients were included, with a median follow-up of 1.66 (1.23-2.16) years during which 16 (14.5%) patients died. A total of 45.4% (50) of patients had diastolic dysfunction. In the univariate Cox regression, long-term survival was predicted by BNP (p < 0.0001, HR = 0.39 [0.20-0.53]), NT-proBNP (p < 0.0001, HR = 0.40 [0.22-0.55]), MR-proANP (p = 0.001, HR = 0.30 [0.11-0.46]), sST2 (p < 0.0001, HR = 0.47 [0.30-0.60]), but not with MR-proAMD (p = 0.77) or galectin-3 (p = 0.76). In the final stepwise multivariable Cox regression non-invasive and invasive models, NT-proBNP and sST2 remained independent predictors of survival. Natriuretic peptides (BNP and NT-proBNP) and sST2 were predictors of long-term survival, while MR-proANP, MR-proADM and galectin-3 did not have predictive values. NT-proBNP and sST2 improved survival prediction in both a non-invasive scenario (including clinical, serum and echocardiographic parameters) and an invasive clinical scenario (including left heart catheterization parameters). The sST2 pathway could provide a target for therapeutic intervention.

Pro-adrenomedullin as an independent predictive biomarker for heart failure in atrial fibrillation and flutter.

Gaifeng Hu, Xiaodong Peng, Liu He +6 more

This study aimed to investigate potential biomarkers for predicting incident heart failure (HF) in patients with atrial fibrillation and flutter (AF and AFL), utilizing proteomic data from the UK Biobank Pharma Proteomics Project (UKB-PPP).

Adrenomedullin 2/Intermedin Exerts Cardioprotective Effects by Regulating Cardiomyocyte Mitochondrial Function.

Yunlu Zhao, Takayuki Sakurai, Akiko Kamiyoshi +11 more

Adrenomedullin 2 (AM2) plays critical roles in regulating blood pressure and fluid balance. However, the specific involvement of AM2 in cardiac hypertrophy has not been comprehensively elucidated, warranting further investigation into its molecular mechanisms and therapeutic implications.

Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood-brain barrier.

Denian Wang, Zhi Yang, Pengfei Wu +6 more

Anxiety disorder, a prevalent mental health issue, is one of the leading causes of disability worldwide. Damage to the blood-brain barrier (BBB) is implicated in anxiety, but its regulatory mechanisms remain unclear. Herein, we show that adrenomedullin 2 (ADM2), a novel angiogenic growth factor, alleviates autistic and anxiety-like behaviors in mice. Based on transcriptome analysis and biochemical analyses, we found that ADM2 facilitates the expression of insulin-like growth factor 2 (IGF-II), which then triggers the activation of the AKT-GSK3β-mTOR signaling pathway via the IGF-II receptor (IGF-IIR), rather than the IGF-I receptor (IGF-IR). Furthermore, as evidenced by increased Evans blue staining and decreased VE-cadherin levels, the BBB exhibited dysfunction in ADM2 knockout mice with anxiety-like behaviors. In in vitro studies, ADM2 administration promoted the expression of VE-cadherin and decreased IGF-II leakage through the endothelial barrier in a BBB model. Taken together, ADM2 may alleviate anxiety-like behavior and social deficits by enhancing BBB integrity and increasing IGF-II levels in the brain. These findings highlight the potential of ADM2 as a therapeutic target for anxiety and related mental disorders.

Postmortem study of adrenomedullin and cortisol in femoral serum and pericardial fluid related to acute pulmonary edema.

Daniel Martínez-Jiménez, Juan Pedro Hernández Del Rincón, Maria Sabater-Molina +4 more

Currently, various tools aid in determining the cause of death and the circumstances surrounding it. Thanatochemistry is one such method that provides insights into the physiopathological mechanisms of death and the behavior of specific biomarkers in different body fluids postmortem. Certain biomarkers, characterized by their stability and specificity to vital tissues like the lungs, are associated with mechanisms contributing to death, such as acute pulmonary edema (APE). This study aims to analyze the behavior of midregional pro-adrenomedullin (MR-proADM) and cortisol levels, measured in pericardial fluid and femoral serum, in relation to the severity of APE, categorized according to specific criteria. Samples were collected from a total of 92 corpses (77 males, 15 females) with a mean age of 56.7 ± 15.2 years. The severity of APE associated with the deaths was classified into three groups: slight or absent (n = 7; 8.6%), medium or moderate (n = 16; 19.8%), and intense (n = 58;71.6%).The determination of MR-proADM and cortisol levels was conducted using ELISA kits and an Immunoassay Analyzer, respectively. Our results reveal a significant increase in MR-proADM concentration with the severity of APE. Furthermore, a correlation was established between cortisol and MR-proADM concentrations in both pericardial fluid and femoral serum samples. This indicates that the severity of APE influences the production of ADM, regardless of the specific underlying pathophysiological mechanisms. Cortisol values were also found to be higher in the intense APE group compared to the moderate group.This study contributes to our understanding of the relationship between MR-proADM and cortisol, and the severity of APE, shedding light on potential applications in postmortem investigations.

Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes.

Haaglim Cho, Chien-Cheng Lai, Rémy Bonnavion +11 more

Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin's actions go beyond metabolic cells and also involve blood vessels, where insulin increases capillary blood flow and delivery of insulin and nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibited insulin signaling in human endothelial cells through protein-tyrosine phosphatase 1B-mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial nitric oxide-synthase activation and skeletal muscle perfusion were increased. Treating mice with adrenomedullin mimicked the effect of obesity and induced endothelial and systemic insulin resistance. Endothelial loss or blockade of the adrenomedullin receptor improved obesity-induced insulin resistance. These findings identify a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes.

Adrenomedullin in pulmonary hypertension.

Toshio Nishikimi, Hideyuki Kinoshita, Hideaki Inazumi +4 more

Adrenomedullin (AM) exerts strong pulmonary vasodilatory effects. These effects are mediated in part by nitric oxide. Plasma AM levels are increased in patients with pulmonary hypertension and correlate with disease severity and poor outcomes. Acute administration of AM improves the haemodynamics in patients with pulmonary hypertension, while chronic administration prevents the onset of pulmonary hypertension in animal models and delays its progression. Thus, AM is closely related to the pathophysiology of pulmonary hypertension and may be a promising therapeutic target.

Pro-adrenomedullin associates with congestion in acute heart failure patients.

Benedikt N Beer, Saman Keshtkaran, Caroline Kellner +7 more

Congestion is a major determinant of outcomes in acute heart failure. Its assessment is complex, making sufficient decongestive therapy a challenge. Residual congestion is frequent at discharge, increasing the risk of re-hospitalization and death. Mid-regional pro-adrenomedullin mirrors vascular integrity and may therefore be an objective marker to quantify congestion and to guide decongestive therapies in patients with acute heart failure.

Plasma Protein Biomarkers and Long-Term Cardiovascular Mortality Risk in Patients With Chronic Coronary Heart Disease.

Ralph A H Stewart, Kristy P Robledo, Andrew M Tonkin +9 more

Protein biomarkers that reflect different pathophysiological pathways have been associated with the risk of adverse cardiovascular events. However, it is uncertain whether these associations are sustained with increasing years after the biomarkers are measured.

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

Julia Baldwin, Michel Burnier, Belen Ponte +4 more

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.

Differential expression of components of the CGRP-receptor family in human coronary and human middle meningeal arteries: functional implications.

Tessa de Vries, Dennis Schutter, Antoon van den Bogaerdt +4 more

Different responses in human coronary arteries (HCA) and human middle meningeal arteries (HMMA) were observed for some of the novel CGRP receptor antagonists, the gepants, for inhibiting CGRP-induced relaxation. These differences could be explained by the presence of different receptor populations in the two vascular beds. Here, we aim to elucidate which receptors are involved in the relaxation to calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2) in HCA and HMMA.

The Role of Adrenomedullin as a Predictive Marker of the Risk of Death and Adverse Clinical Events: A Review of the Literature.

Matteo Antonio Sacco, Saverio Gualtieri, Fabrizio Cordasco +6 more

Adrenomedullin (ADM) is a vasodilatory peptide that plays a crucial role in maintaining cardiovascular health through its various biological functions. ADM was discovered in the acidic extract of human pheochromocytoma tissue and has been recognized for its significant effects on the vascular system. The main functions of ADM include vasodilation, controlling blood pressure and maintaining vascular integrity, although its role on cardiovascular health is broader. Research has shown that elevated levels of adrenomedullin have been observed in a large number of severe diseases, with high risk of death. In this work, we examined the role of ADM as a predictive molecule of the risk of mortality and adverse clinical outcome through a narrative review of the scientific literature. The results were divided based on the pathologies and anatomical districts examined. This review demonstrates how ADM shows, in many diseases and different systems, a close correlation with the risk of mortality. These results prove the value of ADM as a prognostic marker in various clinical contexts and diseases, with utility in the stratification of the risk of clinical worsening and/or death and in the evaluation of therapeutic efficacy. The results open new perspectives with respect to the concrete possibility that ADM enters clinical practice as an effective diagnostic and prognostic marker of death as well as a molecular target for therapies aimed at patient survival.

Calcitonin gene-related peptide and intermedin induce phosphorylation of p44/42 MAPK in primary human lymphatic endothelial cells in vitro.

Shirin R Hasan, Dimitrios Manolis, Ewan Stephenson +3 more

Calcitonin gene-related peptide (CGRP) and adrenomedullin 2/intermedin (AM2/IMD) play important roles in several pathologies, including cardiovascular disease, migraine and cancer. The efficacy of drugs targeting CGRP signalling axis for the treatment of migraine patients is sometimes offset by side effects (e.g. inflammation and microvascular complications, including aberrant neovascularisation in the skin). Recent studies using animal models implicate CGRP in lymphangiogenesis and lymphatic vessel function. However, whether CGRP or AM2/IMD can act directly on lymphatic endothelial cells is unknown. Here, we found that CGRP and AM2/IMD induced p44/42 MAPK phosphorylation in a time- and dose-dependent manner in primary human dermal lymphatic endothelial cells (HDLEC) in vitro, and thus directly affected these cells. These new findings reveal CGRP and AM2/IMD as novel regulators of LEC biology and warrant further investigation of their roles in the context of pathologies associated with lymphatic function in the skin and other organs, and therapies targeting CGRP signalling axis.

Biologically active adrenomedullin as a marker for residual congestion and early rehospitalization in patients hospitalized for acute heart failure: Data from STRONG-HF.

Geert Voordes, Beth Davison, Jan Biegus +30 more

Biologically active adrenomedullin (bio-ADM) is a promising marker of residual congestion. The STRONG-HF trial showed that high-intensity care (HIC) of guideline-directed medical therapy (GDMT) improved congestion and clinical outcomes in heart failure (HF) patients. The association between bio-ADM, decongestion, outcomes and the effect size of HIC of GDMT remains to be elucidated.

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

Lee Ti Davidson, Jan Engvall, Simona I Chisalita +2 more

There is currently limited understanding of the relationship between copeptin, the midregional portion of proadrenomedullin (MRproADM) and the midregional fragment of the N-terminal of proatrial natriuretic peptide (MRproANP), and arterial disorders. Toe brachial index (TBI) and aortic pulse wave velocity (aPWV) are established parameters for detecting arterial disorders. This study evaluated whether copeptin, MRproADM, and MRproANP were associated with TBI and aPWV in patients with type 2 diabetes with no history of cardiovascular disease (CVD).