adrenomedullin and Cardiovascular-Diseases

Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with sepsis; thus, AM is expected to be a useful clinical marker and therapeutic agent for inflammation. However, as the increase in AM levels in cardiovascular diseases (CVDs) is relatively low compared to that in infectious diseases, the value of AM as a marker of CVDs seems to be less important. Limitations pertaining to the administrative route and short half-life of AM in the bloodstream (<30 min) restrict the therapeutic applications of AM for CVDs. In early human studies, various applications of AM for CVDs were attempted, including for heart failure, myocardial infarction, pulmonary hypertension, and peripheral artery disease; however, none achieved success. We have developed AM as a therapeutic agent for inflammatory bowel disease in which the vasodilatory effect of AM is minimized. A clinical trial evaluating this AM formulation for acute cerebral infarction is ongoing. We have also developed AM derivatives that exhibit a longer half-life and less vasodilative activity. These AM derivatives can be administered by subcutaneous injection at long-term intervals. Accordingly, these derivatives will reduce the inconvenience in use compared to that for native AM and expand the possible applications of AM for treating CVDs. In this review, we present the latest translational status of AM and its derivatives.

Topics: Adrenomedullin; Cardiovascular Diseases; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction

The peptide hormone adrenomedullin (ADM) consists of 52 amino acids and plays a pivotal role in the regulation of many physiological processes, particularly those of the cardiovascular and lymphatic system. Like calcitonin (CT), calcitonin gene-related peptide (CGRP), intermedin (IMD) and amylin (AMY), it belongs to the CT/CGRP family of peptide hormones, which despite their low little sequence identity share certain characteristic structural features as well as a complex multicomponent receptor system. ADM, IMD and CGRP exert their biological effects by activation of the calcitonin receptor-like receptor (CLR) as a complex with one of three receptor activity-modifying proteins (RAMP), which alter the ligand affinity. Selectivity within the receptor system is largely mediated by the amidated C-terminus of the peptide hormones, which bind to the extracellular domains of the receptors. This enables their N-terminus consisting of a disulfide-bonded ring structure and a helical segment to bind within the transmembrane region and to induce an active receptor confirmation. ADM is expressed in a variety of tissues in the human body and is fundamentally involved in multitude biological processes. Thus, it is of interest as a diagnostic marker and a promising candidate for therapeutic interventions. In order to fully exploit the potential of ADM, it is necessary to improve its pharmacological profile by increasing the metabolic stability and, ideally, creating receptor subtype-selective analogs. While several successful attempts to prolong the half-life of ADM were recently reported, improving or even retaining receptor selectivity remains challenging.

Topics: Adrenomedullin; Animals; Binding Sites; Calcitonin; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Cardiovascular Diseases; Central Nervous System; Gene Expression Regulation; Humans; Islet Amyloid Polypeptide; Lymphatic System; Models, Molecular; Neoplasms; Peptide Hormones; Protein Binding; Signal Transduction

Several peptides play an important role in physiological and pathological conditions into the cardiovascular system. In addition to well-known vasoactive agents such as angiotensin II, endothelin, serotonin or natriuretic peptides, the vasoconstrictor Urotensin-II (Uro-II) and the vasodilators Urocortins (UCNs) and Adrenomedullin (AM) have been implicated in the control of vascular tone and blood pressure as well as in cardiovascular disease states including congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Therefore these peptides, together with their receptors, become important therapeutic targets in cardiovascular diseases (CVDs). Circulating levels of these agents in the blood are markedly modified in patients with specific CVDs compared with those in healthy patients, becoming also potential biomarkers for these pathologies. This review will provide an overview of current knowledge about the physiological roles of Uro-II, UCN and AM in the cardiovascular system and their implications in cardiovascular diseases. It will further focus on the structural modifications carried out on original peptide sequences in the search of analogues with improved physiochemical properties as well as in the delivery methods. Finally, we have overviewed the possible application of these peptides and/or their precursors as biomarkers of CVDs.

Topics: Adrenomedullin; Animals; Biological Products; Biomarkers; Cardiovascular Diseases; Humans; Urocortins; Urotensins

Many neurohumoral factors play important roles in the regulation of the cardiovascular system and in the pathophysiology of cardiovascular disease. Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in the acid extract of human pheochromocytoma tissue but now known to exert a variety of effects within the cardiovascular system. AM expression is widely distributed throughout the cardiovascular system and has been identified in the heart, lungs, blood vessels and kidneys. In addition, the co-localization of AM and its receptor components suggest AM acts as an autocrine and/or paracrine factor to play a key role in the regulation of cardiovascular function. Evidence also strongly suggests that cardiovascular disease is associated with elevated levels of AM in plasma and tissue. In this review, we describe the pathophysiological changes in plasma and local AM associated with myocardial infarction, heart failure and pulmonary hypertension. We also describe the clinical application of AM in cardiovascular disease from the viewpoints of diagnosis and treatment.

Topics: Adrenomedullin; Animals; Biomarkers; Cardiovascular Diseases; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction

Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the calcitonin gene-related peptide (CGRP) / adrenomedullin (AM) family. The biological actions of this family are attributed to their actions at three receptor subtypes comprising the calcitonin receptor-like receptor (CLR) complexed with one of three receptor activity modifying proteins. In contrast to AM and CGRP, IMD binds non-selectively to all three receptor subtypes: CGRP, AM1, AM2. The peptide displays an overlapping but differential and more restricted distribution across the healthy systemic and pulmonary vasculature, heart and kidney relative to CGRP and AM. This, combined with tissue, regional and cell-type specific receptor expression, underpins differences in regard to magnitude, potency and duration of haemodynamic, cardiac and renal effects of IMD relative to those of AM and CGRP, and receptor-subtype involvement. In common with other family members, IMD protects the mammalian vasculature, myocardium and kidney from acute ischaemia-reperfusion injury, chronic oxidative stress and pressure-loading; IMD inhibits apoptosis, attenuates maladaptive tissue remodelling and preserves cardiac and renal function. Robust upregulation of IMD expression in rodent models of cardiovascular and renal disease argues strongly for the pathophysiological relevance of this particular counter-regulatory peptide. Such findings are likely to translate well to the clinic: early reports indicate that IMD is expressed in and protects cultured human vascular and cardiac non-vascular cells from simulated ischaemia-reperfusion injury, primarily via the AM1 receptor, and may have utility as a plasma biomarker in cardiovascular disease. These observations should provide the rationale for short-term administration of the peptide in acute disease, including myocardial infarction, cerebrovascular insult, cardiac and renal failure.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Cardiovascular System; Humans; Inflammation; Kidney Diseases; Lung Diseases; Organ Specificity; Oxidative Stress; Peptide Hormones; Protective Agents; Receptors, Adrenomedullin; Receptors, Calcitonin Gene-Related Peptide; Reperfusion Injury

Cardiovascular disease (CVD) risk screening is performed by multivariate methods relying on calculators derived from the Framingham study, other epidemiological studies or primary care records. However, it only identifies 70% of individuals at risk for CVD events and there has been interest in adding other risk factors to improve its predictive capacity. The addition of a family history of premature CVD is well established and there is evidence for adding lipoprotein (a) in some populations and possibly C-reactive protein may be suitable for general use in CVD risk assessment. Most new biochemical and imaging markers have been assessed in the context of improving risk classification in intermediate-risk groups rather than in the general population. There is evidence that N-terminal pro-B-type natriuretic peptide and coronary artery calcium score add significantly to risk prediction. The data for carotid intima-media thickness, ankle-brachial index are less strong and high sensitivity troponins look promising, but have had only limited data to date. Large scale meta-analyses ideally of pooled primary patient data will be required to determine the best additional markers to add to conventional risk prediction and in what groups to apply them.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adrenomedullin; Ankle Brachial Index; Arginine; Biomarkers; Blood Flow Velocity; C-Reactive Protein; Cardiovascular Diseases; Carotid Intima-Media Thickness; Early Diagnosis; Humans; Lipoprotein(a); Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Risk Assessment; Troponin; Vascular Calcification; Vasodilation

Topics: Adrenomedullin; Animals; Calcitonin Receptor-Like Protein; Cardiovascular Diseases; Carrier Proteins; Crystallography, X-Ray; Humans; Molecular Targeted Therapy; Receptor Activity-Modifying Protein 2; Receptors, Adrenomedullin; Receptors, G-Protein-Coupled

Biomarkers have been intensively studied in community-acquired pneumonia (CAP) in recent years. In the context of the CAPNETZ study we had the unique opportunity to evaluate old and new biomarkers in a multicentre study with a high number of patients.. In several substudies we found the following results: procalcitonin, CRP and leukocytes show highest values in patients with typical bacterial etiology of CAP, but do not allow individual prediction of etiology. Patients without antibiotic pre-treatment show higher values of biomarkers compared to patients with antibiotic pre-treatment. New cardiovascular biomarkers are good predictors for short- and long-term mortality in CAP, superior to the inflammatory markers procalcitonin, CRP and leukocytes and at least comparable to the clinical CRB-65 score. Pro-Adrenomedullin is among the new biomarkers the one with the best prognostic value.. Biomarkers correlate with the severity of CAP but do not allow individual prediction of etiology. New cardiovascular biomarkers are suitable for the evaluation of short- and long-term prognosis in CAP. The combination of several biomarkers reflecting different pathophysiological pathways has the potential to improve management of CAP in the future.

Topics: Adolescent; Adrenomedullin; Adult; Age Distribution; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Community-Acquired Infections; Comorbidity; Endothelin-1; Female; Germany; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Protein Precursors; Respiratory Rate; Survival Analysis; Vasopressins; Young Adult

Adrenomedullin (AM) is a novel hypotensive peptide that exerts a variety of strongly protective effects against multiorgan damage. AM-specific receptors were first identified as heterodimers composed of calcitonin-receptor-like receptor (CLR), a G protein coupled receptor, and one of two receptor activity-modifying proteins (RAMP2 or RAMP3), which are accessory proteins containing a single transmembrane domain. RAMPs are required for the surface delivery of CLR and the determination of its phenotype. CLR/RAMP2 (AM₁ receptor) is more highly AM-specific than CLR/RAMP3 (AM₂ receptor). Although there have been no reports showing differences in intracellular signaling via the two AM receptors, in vitro studies have shed light on their distinct trafficking and functionality. In addition, the tissue distributions of RAMP2 and RAMP3 differ, and their gene expression is differentially altered under pathophysiological conditions, which is suggestive of the separate roles played by AM₁ and AM₂ receptors in vivo. Both AM and the AM₁ receptor, but not the AM₂ receptor, are crucial for the development of the fetal cardiovascular system and are able to effectively protect against various vascular diseases. However, AM₂ receptors reportedly play an important role in maintaining a normal body weight in old age and may be involved in immune function. In this review article, we focus on the shared and separate functions of the AM receptor subtypes and also discuss the potential for related drug discovery. In addition, we mention their possible function as receptors for AM2 (or intermedin), an AM-related peptide whose biological functions are similar to those of AM.

Topics: Adrenomedullin; Aging; Amino Acid Sequence; Animals; Body Weight; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Cardiovascular Diseases; Cell Line; Gene Expression; Humans; Mice; Mice, Transgenic; Molecular Sequence Data; Protein Transport; Rats; Rats, Transgenic; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptors, Adrenomedullin; Receptors, Calcitonin; Sequence Alignment; Signal Transduction

Adrenomedullin (AM) is an endogenous vasodilatory peptide hormone, which plays a key role in the regulation and preservation of cardiovascular and pulmonary functions. Clinical and experimental studies have demonstrated that AM represents an alternative therapeutic option in the treatment of pulmonary hypertension. In addition, AM proved to be useful in the treatment of cardiovascular dysfunctions, such as arterial hypertension and congestive heart failure following myocardial infarction. Recent research has also shown that AM plays a pivotal role in the development of sepsis-associated hemodynamic and microcirculatory disorders. Experimental studies also suggest that infusion of exogenous AM might be a rational approach to prevent and treat hypodynamic septic shock. The objectives of this review article are to characterize the regulative properties of AM and to discuss clinical and experimental studies which allow to judge the role of AM in the setting of cardiovascular dysfunction and sepsis.

Topics: Adrenomedullin; Amino Acid Sequence; Cardiovascular Diseases; Hemodynamics; Homeostasis; Humans; Molecular Sequence Data; Peptides; Sepsis; Signal Transduction

Adrenomedullin (AM) is a 52 amino acid peptide that plays a critical role in several diseases such as hypertension, cancer, diabetes, cardiovascular and renal disorders, among others. Interestingly, AM behaves as a protective agent against some pathologies, yet is a stimulating factor for other disorders. Thus, AM can be considered as a new and promising target for the design of non-peptidic modulators that could be useful for the treatment of those pathologies, by regulating AM levels or the activity of AM. A full decade on from its discovery, much more is known about AM molecular biology and pharmacology, but this knowledge still needs to be applied to the development of clinically useful drugs.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Drug Delivery Systems; Drug Design; Humans; Neoplasms; Peptides

Adrenomedullin (AM) is a vasodilator peptide that originally isolated from pheochromocytoma tissue. However, the mRNA is expressed in the normal adrenal gland, heart, kidney and blood vessels. The human AM gene is located in the short arm of chromosome 11 and is composed of 4 exons. There are 2 single nucleotide polymorphisms in introns 1 and 3, and the 3'-end of the AM gene is flanked by a microsatellite marker of cytosine-adenine repeats that is associated with an increased risk of developing hypertension and diabetic nephropathy. AM gene expression is promoted by various stimuli, including inflammation, hypoxia, oxidative stress, mechanical stress and activation of the renin-angiotensin and sympathetic nervous systems. The AM gene promoter region possessed binding site for several transcription factors, including nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2). Further, plasma AM levels are increased in patients with various cardiovascular diseases, including hypertension, heart failure and renal failure. These findings suggest that AM plays a role in the development of or response to cardiovascular disease. Indeed, experimental and clinical studies have demonstrated that systemic infusion of AM may have a therapeutic effect on myocardial infarction, heart failure and renal failure. Further, vasopeptidase inhibitors which augment the bioactivity of endogenous AM may benefit patients with hypertension and arteriosclerosis. Finally, the angiogenic and cytoprotective properties of AM may have utility in revascularization and infarcted myocardium and ischemic limbs. Because of the potential clinical benefits of AM, indications for use and optimal dosing strategies should be established.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Carcinogens; Cardiovascular Diseases; Cell Transplantation; Genetic Therapy; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Molecular Sequence Data; Myocardial Infarction; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Renal Insufficiency; Renin-Angiotensin System; Signal Transduction

Topics: Adrenomedullin; Animals; Blood Pressure; Cardiovascular Diseases; Endothelium, Vascular; Gene Expression Regulation; Humans; Neovascularization, Physiologic; Nitric Oxide; Oxidative Stress; Peptides; Receptors, Adrenomedullin; Receptors, Peptide; Transcription, Genetic; Trinucleotide Repeats; Vasodilation

Topics: Adrenomedullin; Angiotensin II; Cardiovascular Diseases; Humans; Hypertension; Insulin Resistance; Metabolic Syndrome; Renin-Angiotensin System; Sodium Chloride

Adrenomedullin (AM) is a 52-amino acid peptide with a pluripotential activity. AM is expressed in many tissues throughout the body, and plays a critical role in several diseases such as cancer, diabetes, cardiovascular and renal disorders, among others. While AM is a protective agent against cardiovascular disorders, it behaves as a stimulating factor in other pathologies such as cancer and diabetes. Therefore, AM is a new and promising target for the development of molecules which, through their ability to regulate AM levels, could be used in the treatment of these pathologies.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus; Drug Design; Humans; Molecular Sequence Data; Neoplasms; Peptides; Sequence Alignment

A novel vasodilator, adrenomedullin (AM), which acts as an autocrine/paracrine factor in cardiovascular system, has antiproliferative and antimigrative effects. AM gene transfer prevents the development of cuff-induced vascular injury. Moreover, AM knockout mice exhibited an increase in angiotensin (Ang) II/salt loading-induced coronary arterial lesion, hypoxia-induced pulmonary vascular damage, and cuff-induced vascular injury associated with enhancement in reactive oxygen species (ROS) generation. In addition, AM expression was stimulated by ROS, and AM directly inhibits oxidative stress so that AM might be a negative feedback substance against ROS-induced organ damages. In addition, AM increases nitric oxide and ameliorates insulin resistance, leading to oxidative stress. Consequently, endogenous AM might compensatively inhibit the development of vascular diseases at least partly through an antioxidative effect.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Humans; Insulin Resistance; Nitric Oxide; Peptides; Reactive Oxygen Species; Receptors, Adrenomedullin; Receptors, Peptide; Vascular Diseases; Vasodilation

Adrenomedullin (AM), inducing a potent and powerful hypotensive activity caused by dilatation of resistance vessels, has elicited interest for its cardiovascular actions. AM is secreted from various cell type, including vascular endothelial and smooth muscle cell. AM plasma levels are increased in various cardiovascular diseases as heart failure and hypertension and may be involved in pathophysiological changes in cardiovascular diseases.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Chronic Disease; Glomerulonephritis; Heart Failure; Homeostasis; Humans; Hypertension; Hypertension, Pulmonary; Myocardial Infarction; Peptides; Rats; Shock, Septic

Topics: Adrenomedullin; Animals; Arteriosclerosis; Biomarkers; Body Fluids; Cardiovascular Diseases; Cardiovascular System; Cell Division; Glomerular Mesangium; Hemodynamics; Humans; Kidney Failure, Chronic; Kidney Tubules, Distal; Myocardial Infarction; Peptides; Renal Circulation; Renal Dialysis; Sodium; Ventricular Remodeling

This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM). CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas. They share vasodilator activity, albeit to varying extents depending on species and tissue. In particular, CGRP has potent activity in the cerebral circulation, which is possibly relevant to the pathology of migraine, whilst vascular sources of AM contribute to dysfunction in cardiovascular disease. Both peptides exhibit potent activity in microvascular beds. All three peptides can act on a family of CGRP receptors that consist of calcitonin receptor-like receptor (CL) linked to one of three receptor activity-modifying proteins (RAMPs) that are essential for functional activity. The association of CL with RAMP1 produces a CGRP receptor, with RAMP2 an AM receptor and with RAMP3 a CGRP/AM receptor. Evidence for the selective activity of the first nonpeptide CGRP antagonist BIBN4096BS for the CGRP receptor is presented. The cardiovascular activity of these peptides in a range of species and in human clinical conditions is detailed, and potential therapeutic applications based on use of antagonists and gene targeting of agonists are discussed.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Blood Vessels; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Humans; Inflammation; Microcirculation; Molecular Sequence Data; Peptides; Receptors, Adrenomedullin; Receptors, Calcitonin Gene-Related Peptide; Receptors, Peptide; Tissue Distribution; Vasodilation

Adrenomedullin (AM) is a peptide that possesses potentially beneficial properties. Since the initial discovery of the peptide by Kitamura et al. in 1993, the literature has been awash with reports describing its novel mechanisms of action and huge potential as a therapeutic target. Strong evidence now exists that AM is able to act as an autocrine, paracrine, or endocrine mediator in a number of biologically significant functions, including the endothelial regulation of blood pressure, protection against organ damage in sepsis or hypoxia, and the control of blood volume through the regulation of thirst. Its early promise as a potential mediator/modulator of disease was not, however, entirely as a result of the discovery of physiological functions but due more to the observation of increasing levels measured in plasma in direct correlation with disease progression. In health, AM circulates at low picomolar concentrations in plasma in 2 forms, a mature 52-amino acid peptide and an immature 53-amino acid peptide. Plasma levels of AM have now been shown to be increased in a number of pathological states, including congestive heart failure, sepsis, essential hypertension, acute myocardial infarction, and renal impairment. These earliest associations have been further supplemented with evidence of a role for AM in other pathologies including, most intriguingly, cancer. In this review, we offer a timely review of our current knowledge on AM and give a detailed account of the putative role of AM in those clinical areas in which the best therapeutic opportunities might exist.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Humans; Inflammation; Kidney Diseases; Neoplasms; Neovascularization, Pathologic; Peptides; Sepsis

Topics: Adrenomedullin; Animals; Biomarkers; Calcitonin Receptor-Like Protein; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Peptides; Receptor Activity-Modifying Proteins; Receptors, Calcitonin

Topics: Adrenomedullin; Animals; Antioxidants; Cardiovascular Diseases; Disease Models, Animal; Homozygote; Humans; Insulin Resistance; Kidney Diseases; Mice; Mice, Knockout; Oxidative Stress; Peptides

Topics: Adrenomedullin; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Humans; Lipoproteins; Mucous Membrane; Neurosecretory Systems; Peptides; Thromboplastin; Tissue Distribution

Topics: Adrenomedullin; Angiotensin II; Animals; Antioxidants; Cardiovascular Diseases; Cyclic N-Oxides; Humans; Insulin Resistance; Life Style; Lipoproteins, LDL; Nitric Oxide; Oxidative Stress; Peptides; Reactive Oxygen Species; Receptors, LDL; Receptors, Oxidized LDL; Scavenger Receptors, Class E; Spin Labels

We discovered adrenomedullin (AM) from human pheochromocytoma tissue by monitoring the elevating activity of intracellular cyclic AMP (cAMP) in rat platelets in 1993. Since the discovery of AM, it has attracted intense interest from cardiovascular researchers because AM elicits multiple biological activities, including a potent and powerful hypotensive activity caused by dilatation of resistance vessels. AM is biosynthesized and secreted from tissues, including cardiovascular organs. In addition to AM, "proadrenomedullin N-terminal 20 peptide (PAMP)," another biologically active peptide, was found to be processed from the AM precursor. Plasma AM levels are increased in various cardiovascular and renal diseases. AM, therefore, seems to function as a novel system that controls circulation and body fluid, and may be involved in pathophysiological changes in cardiovascular diseases. Therefore, in this review we will focus on the structure of AM and its gene, distribution, receptor, and the physiological and pathological roles of AM in cardiovascular disease.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Cardiovascular Diseases; Cardiovascular System; Cells, Cultured; Humans; Molecular Sequence Data; Peptide Fragments; Peptides; Proteins

Although the biological effects of adrenomedullin (AM) and PAMP have been reported extensively in animal studies and from in-vitro experiments, relatively little information is available on responses to the hormone administered to man. This review summarizes data from the few studies carried out in man. In healthy volunteers, i.v. infusion of AM reduces arterial pressure, probably at a lower rate of administration than is required to elicit other responses. AM stimulates heart rate, cardiac output, plasma levels of cAMP, prolactin, norepinephrine and renin whilst inhibiting any concomitant response in plasma aldosterone. Little or no increase in urine volume or sodium excretion has been observed. Patients with essential hypertension differ only in showing a greater fall in arterial pressure and in the development of facial flushing and headache. In patients with heart failure or chronic renal failure, i.v. AM has similar effects to those seen in normal subjects but also induces a diuresis and natriuresis, depending on the dose administered. Infusion of AM into the brachial artery results in a dose-related increase in forearm and skin blood flow, more prominent and more dependent on endogenous nitric oxide in healthy volunteers than in patients with cardiac failure. When infused into a dorsal hand vein, AM partially reversed the venoconstrictor action of norepinephrine. Although much more information is required to clarify the role of AM under physiological and pathophysiological circumstances, it is clear that it has prominent hemodynamic and neurohormonal effects, though generally lesser urinary effects when administered short-term in doses sufficient to raise its levels in plasma to those seen in a number of clinical disorders. The only study of PAMP in man showed that its skeletal muscle vasodilator potency, when infused into the brachial artery of healthy volunteers, was less than one hundredth that of AM, and it was without effect on skin blood flow.

Topics: Adrenomedullin; Cardiovascular Diseases; Clinical Trials as Topic; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Kidney Failure, Chronic; Peptide Fragments; Peptides; Proteins; Veins

Adrenomedullin (ADM), a 52-amino acid ringed-structure peptide with C-terminal amidation, was originally isolated from human pheochromocytoma. ADM mediates vasodilatory and natriuretic properties through the second messenger cyclic adenosine 3',5'-monophosphate (cAMP), nitric oxide and the renal prostaglandin system. ADM immunoreactivity and its gene are widely distributed in cardiovascular, pulmonary, renal, gastrointestinal, cerebral and endocrine tissues. ADM is also synthesized and secreted from vascular endothelial and smooth muscle cells. When injected intravenously, ADM increases flow rates predominantly in organs in which the ADM gene is highly expressed, suggesting that ADM acts as a local autocrine and/or paracrine vasoactive hormone. In addition, ADM is a circulating hormone and its plasma concentration is increased in various cardiorenal diseases such as hypertension, chronic renal failure and congestive heart failure. Current evidence suggests that ADM plays an important role in fluid and electrolyte homeostasis and cardiorenal regulation, however further investigations are required to address the importance of ADM under various physiological and pathophysiological conditions.

Topics: Adrenomedullin; Amino Acid Sequence; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Humans; Molecular Sequence Data; Peptides

Adrenomedullin (ADM) is a recently discovered peptide with potent vasorelaxing and natriuretic properties originally isolated from human pheochromocytoma. Adrenomedullin has been reported to be present in normal adrenal medulla, heart, lung and kidney as well as in plasma and urine. ADM shares some structural homology with calcitonin gene related peptide (CGRP). ADM acts on target cells through its unique receptors and CGRP1 receptors. In both cases cyclic AMP seems to be the main second messenger. ADM may function as a circulating hormone and as an autocrine/paracrine mediator involved in the regulation of cardiovascular system and renal function. Plasma concentration of ADM is elevated in patients with congestive heart failure, arterial hypertension, pulmonary hypertension, renal failure and sepsis suggesting its role in pathophysiology of these disorders. Recently another product od adrenomedullin gene, proadrenomedullin N-terminal 20-peptide (PAMP) has been described. This peptide has also vasodilating activity resulting from its inhibitory action on norepinephrine release from sympathetic endings and adrenal medulla.

Topics: Adrenal Gland Neoplasms; Adrenomedullin; Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cyclic AMP; Humans; Kidney; Membrane Proteins; Peptides; Pheochromocytoma; Receptors, Adrenomedullin; Receptors, Peptide

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Blood Glucose; Bronchodilator Agents; Cardiotonic Agents; Cardiovascular Diseases; Humans; Hyperaldosteronism; Kidney Failure, Chronic; Peptides; Reference Values; Shock, Septic; Tumor Cells, Cultured

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Cardiovascular Diseases; Hemodynamics; Humans; Molecular Sequence Data; Natriuresis; Peptides; Protein Precursors; Proteins; Receptors, Peptide; Vasodilation

We have discovered a novel hypotensive peptide, designated "adrenomedullin", in human pheochromocytoma extracts. It has potent and long-lasting vasodilatory effects in several vascular systems. In addition to adrenomedullin, another hypotensive peptide, termed PAMP, is also produced from the adrenomedullin precursor. Although initially isolated from human pheochromocytoma and porcine adrenal medullary tissue, adrenomedullin mRNA is highly expressed in several peripheral organs including cardiovascular tissues. Taken together with the presence of adrenomedullin-specific receptors on VSMCs and the significant increase in plasma immunoreactive adrenomedullin levels in patients with hypertension, renal failure and congestive heart failure, adrenomedullin may participate in the pathogenesis of these diseases as a factor regulating blood pressure and circulation.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Cardiovascular Diseases; Humans; Molecular Sequence Data; Peptides; Vasodilator Agents

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Antihypertensive Agents; Blotting, Northern; Cardiovascular Diseases; Humans; Hypertension; Hypotension; Molecular Sequence Data; Peptide Fragments; Peptides; Proteins; Radioimmunoassay; Rats

Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the variability in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B-type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection.. Study subjects participated in PRESCRIPT, a randomized controlled trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents during surgery as well as the occurrence of perioperative cardiovascular events.. A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41-0.63) nmol/L and 68.7 (27.9-150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P =0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P =0.013 and OR: 1.54, P =0.017, respectively).. plasma MR-proADM or NT-proBNP should not be considered as biomarkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk.

Topics: Adrenal Gland Neoplasms; Adrenergic Antagonists; Adrenomedullin; Adult; Aged; Biomarkers; Blood Pressure; Cardiovascular Diseases; Cross-Sectional Studies; Female; Follow-Up Studies; Heart Failure; Humans; Intraoperative Complications; Male; Middle Aged; Natriuretic Peptide, Brain; Pheochromocytoma; Prognosis; Risk Assessment; Treatment Outcome

Topics: Adrenomedullin; Aged; Albuminuria; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycopeptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Peptide Fragments; Protein Precursors; Receptors, Urokinase Plasminogen Activator; Risk Factors; Tumor Necrosis Factor-alpha

The mid-regional part of the prohormone of adrenomedullin (MR-proADM) is emerging as a novel risk indicator in patients with cardiac disease. We investigated MR-proADM levels and their changes over 5 years in elderly community-dwellers, together with the underlying cardiovascular and metabolic conditions, and the prognostic implications of these measurements.. MR-proADM was analyzed using a sandwich immunoassay (Thermo Fisher Scientific) in participants from the PIVUS study. Measurements were performed at 70 (n=1002) and 75 years of age (n=795) together with various measurements of other markers of cardiovascular function. In cross-sectional analyses, MR-proADM was independently related to current smoking, renal dysfunction, obesity, lower left-ventricular ejection fraction, and higher levels of N-terminal pro-B-type natriuretic peptide and C-reactive protein. There were no independent associations to other cardiovascular risk factors or vascular pathologies. MR-proADM levels predicted all-cause mortality during 8.0 years of follow-up independent of cardiovascular risk indicators (adjusted HR 5.1 [95% CI 2.8-9.5]; p<0.001) using results obtained at 70 and 75 years as updated covariates. Baseline MR-proADM levels improved prognostic discrimination (IDI=0.018 [p=0.001]). Also the change in MR-proADM levels over time independently predicted all-cause mortality occurring after 75 years (adjusted HR 13.4 [95% CI 3.5-50.5]; p<0.001).. MR-proADM levels in the elderly integrate information on several relevant aspects in cardiovascular disease, namely cardiovascular risk factors including obesity, low-grade inflammation, renal dysfunction and left-ventricular abnormalities. Furthermore, MR-proADM and its changes over time predicted mortality, and might provide utility as an indicator of the overall cardiovascular risk burden.

Topics: Adrenomedullin; Aged; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Male; Metabolic Diseases; Population Surveillance; Predictive Value of Tests; Prospective Studies; Residence Characteristics; Sweden; Vasodilation

Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy.. We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; P(interaction)=0.012).. In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.

Topics: Adrenomedullin; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Coronary Disease; Death; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Indoles; Male; Middle Aged; Peptide Fragments; Prognosis; Protein Precursors; Risk; Stress, Physiological; Stroke Volume

The aim of this study was to determine the prognostic utility of serial measurement of the cardiovascular biomarker midregion proadrenomedullin (MR-proADM) in patients admitted with lower respiratory tract infection. In a previous trial in dyspneic patients (BACH trial) we could show that serial measurement of MR-proADM proves useful for risk assessment and patient monitoring. Models designed to evaluate serial biomarker measurements usually fail to answer two fundamental questions necessary to judge their clinical relevance: whether serial measurements provide additional information on top of the first measurement, and, if yes, at which time point a re-evaluation may be clinically useful.. We apply an adapted time-dependent Cox model to data from the ProHosp trial, a prospective trial, which was observational in regards to application of prognostic biomarkers, where blood draws for biomarker evaluation were collected at day of patient inclusion, days 3, 5 and 7. In this trial, the cardiovascular biomarker MR-proADM was evaluated for its ability to predict survival in comparison to clinical risk scores.. With the adapted time-dependent Cox model, we could demonstrate a significant added value of the follow up measurements on top of that obtained on admission. Despite a high correlation between serial measurements, the gain can be observed as early as 3 days after inclusion. We illustrate the added prognostic value and clinical relevance of re-evaluation via Kaplan-Meier plots.. We could demonstrate that the prognostic biomarker MR-proADM can potentially serve as a outcome monitoring marker in patients admitted with lower respiratory tract infections.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Protein Precursors; Regression Analysis; Respiratory Tract Infections; Survival Rate; Time Factors

Background Premature and early menopause are independently associated with greater risk of cardiovascular disease (CVD). However, mechanisms linking age of menopause with CVD remain poorly characterized. Methods and Results We measured 71 circulating CVD protein biomarkers in 1565 postmenopausal women enrolled in the FHS (Framingham Heart Study). We examined the association of early menopause with biomarkers and tested whether early menopause modified the association of biomarkers with incident cardiovascular outcomes (heart failure, major CVD, and all-cause death) using multivariable-adjusted linear regression and Cox models, respectively. Among 1565 postmenopausal women included (mean age 62 years), 395 (25%) had a history of early menopause. Of 71 biomarkers examined, we identified 7 biomarkers that were significantly associated with early menopause, of which 5 were higher in women with early menopause including adrenomedullin and resistin, and 2 were higher in women without early menopause including insulin growth factor-1 and CNTN1 (contactin-1) (Benjamini-Hochberg adjusted

Topics: Adrenomedullin; Biomarkers; Cardiovascular Diseases; Female; Humans; Menopause; Menopause, Premature; Middle Aged; Risk Factors

Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort.. Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8-9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603-1551).. MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72-3.26) and 2.31 (1.67-3.20)) and cardiovascular mortality (4.28 (2.19-8.39) and 4.44 (2.25-8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality.. We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.

Topics: Adrenomedullin; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Female; Humans; Inflammation; Male; Middle Aged; Obesity; Peptide Fragments; Prospective Studies; Protein Precursors; Risk Factors

Plasma levels of the hypotensive peptides of adrenomedullin and atrial and B-type natriuretic peptides (AM, ANP, BNP) are possible biomarkers for cardiovascular diseases. Increased variability of body mass index (BMI) over a certain period of time has been reported to be associated with cardiovascular morbidity or mortality. The aim of this study is to examine clinical significance of those hypotensive peptides as biomarkers by analyzing the relationship between plasma levels of the peptides and year-by-year variability of BMI in the general population without overt cardiovascular diseases. The subjects were 427 local residents (141 males and 286 females) attending their annual health check-up, who had been examined at least 5 times over the preceding period of 10 years. They were divided into two groups of low or high variability by the median of coefficient of variation (CV) of BMI values for each gender. Plasma AM levels of those with high year-by-year variability of BMI were significantly increased, as compared to the group with low variability, in both genders; meanwhile, such a difference was not noted in plasma levels of the natriuretic peptides. No significant differences were found in the basal parameters, which could affect plasma AM level, such as age, BMI, blood pressure or serum creatinine, between two groups. In conclusion, increase in plasma AM was associated with high year-by-year variability of BMI in the general population without overt heart disease. This relationship between the two suggests that increased plasma AM level is a cardiovascular risk marker.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Body Mass Index; Cardiovascular Diseases; Female; Healthy Volunteers; Humans; Male; Natriuretic Peptide, Brain

Following the SEPSIS-3 consensus, detection of organ failure as assessed by the SOFA (Sequential Organ Failure Assessment) score, is mandatory to detect sepsis. Calculating SOFA outside of the Intensive Care Unit (ICU) is challenging. The alternative in this scenario, the quick SOFA, is very specific but less sensible. Biomarkers could help to detect the presence of organ failure secondary to infection either in ICU and non-ICU settings.. We evaluated the ability of four biomarkers (C-Reactive protein (CRP), lactate, mid-regional proadrenomedullin (MR-proADM) and procalcitonin (PCT)) to detect each kind of organ failure considered in the SOFA in 213 patients with infection, sepsis or septic shock, by using multivariate regression analysis and calculation of the area under the receiver operating curve (AUROC).. In the multivariate analysis, MR-proADM was an independent predictor of five different failures (respiratory, coagulation, cardiovascular, neurological and renal). In turn, lactate predicted three (coagulation, cardiovascular and neurological) and PCT two (cardiovascular and renal). CRP did not predict any of the individual components of SOFA. The highest AUROCs were those of MR-proADM and PCT to detect cardiovascular (AUROC, CI95%): MR-proADM (0.82 [0.76-0.88]), PCT (0.81 [0.75-0.87] (P < .05) and renal failure: MR-proADM (0.87 [0.82-0.92]), PCT (0.81 [0.75-0.86]), (P < .05). None of the biomarkers tested was able to detect hepatic failure.. In patients with infection, MR-proADM was the biomarker detecting the largest number of SOFA score components, with the exception of hepatic failure.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Area Under Curve; Blood Coagulation Disorders; C-Reactive Protein; Cardiovascular Diseases; Female; Heart Failure; Humans; Infections; Intensive Care Units; Lactic Acid; Liver Failure; Male; Middle Aged; Multivariate Analysis; Nervous System Diseases; Organ Dysfunction Scores; Peptide Fragments; Procalcitonin; Protein Precursors; Renal Insufficiency; Respiratory Insufficiency; ROC Curve; Sepsis; Shock, Septic

Volume status is a key parameter for cardiovascular-related mortality in dialysis patients. Although N-terminal pro-B-type natriuretic peptide (NT-proBNP), myeloperoxidase, copeptin, and pro-adrenomedullin have been reported as volume markers, the relationship between body fluid status and volume markers in dialysis patients is uncertain. Therefore, we investigated the utility of volume status biomarkers based on body composition monitor (BCM) analyses.We enrolled pre-dialysis, hemodialysis (HD), and peritoneal dialysis (PD) patients and age- and gender-matched healthy Korean individuals (N = 80). BCM and transthoracic echocardiography were performed and NT-proBNP, myeloperoxidase, copeptin, and pro-adrenomedullin concentrations were measured. Relative hydration status (ΔHS, %) was defined in terms of the hydration status-to-extracellular water ratio with a cutoff of 15%, and hyperhydrated status was defined as ΔHS > 15%.Although there were no significant differences in total body water, extracellular water, or intracellular water among groups, mean amount of volume overload and hyperhydrated status were significantly higher in HD and PD patients compared with control and pre-dialysis patients. Mean amount of volume overload and hyperhydrated status were also significantly associated with higher NT-proBNP and pro-adrenomedullin levels in HD and PD patients, although not with myeloperoxidase or copeptin levels. Furthermore, they were significantly associated with cardiac markers (left ventricular mass index, ejection fraction, and left atrial diameter) in HD and PD patients compared with those in the control and pre-dialysis groups.On the basis of increased plasma NT-proBNP and pro-adrenomedullin concentrations, we might be able to make predictions regarding the volume overload status of dialysis patients, and thereby reduce cardiovascular-related mortality through appropriate early volume control.

Topics: Adrenomedullin; Adult; Biomarkers; Body Composition; Body Fluids; Cardiovascular Diseases; Case-Control Studies; Dialysis; Echocardiography; Female; Glycopeptides; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peritoneal Dialysis; Peroxidase; Protein Precursors; Renal Dialysis; Republic of Korea; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D.. We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6-17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP.. A total of 126 CV events occurred (median follow-up 4.8 [4.1-5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89-202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64-4.00] and 3.32 [1.64-6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32-56] pmol/l) did not have an increased risk (HR 2.18 [0.78-6.14]).. Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.

Topics: Adrenomedullin; Aged; Biomarkers; Cardiovascular Diseases; Denmark; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Incidence; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Assessment; Risk Factors; Stroke Volume; Up-Regulation; Ventricular Function, Left

Topics: Adrenomedullin; Adult; Aged; Ankle Brachial Index; Anticoagulants; Asymptomatic Diseases; Atrial Fibrillation; Atrial Natriuretic Factor; C-Reactive Protein; Cardiovascular Diseases; Carotid Intima-Media Thickness; Female; Fibrinogen; Germany; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phenprocoumon; Protein Precursors; Pulmonary Embolism; Risk Factors; Stroke; Stroke Volume; Vascular Stiffness; Venous Thrombosis; Warfarin

Cardiovascular biomarkers might help to identify fetuses or pregnancies at risk.. To examine the umbilical cord neonatal and maternal levels of cardiovascular biomarkers at the time of delivery, and to correlate maternal and fetal biomarker levels to each other, to gestational age and to delivery mode.. In a prospective, observational, cross-sectional, single-center study biomarkers were measured in paired maternal and umbilical venous cord blood samples.. The sample cohort included 66 sets of fetal and maternal blood samples (11 after multiple gestation, 53 after cesarean section, 17 after exposure to labor).. Midregional pro-adrenomedullin (MRproADM), midregional-pro atrial natriuretic peptide (MRproANP), brain natriuretic peptide (BNP), n-terminal-pro brain natriuretic peptide (NTproBNP), copeptin, and high sensitive troponin I (hsTnI) levels were measured.. Mean ± SEM for biomarker levels in umbilical venous/maternal blood were: MRproADM [nmol/L] 1.02 ± 0.04/1.24 ± 0.08, MRproANP [pmol/L] 215.53 ± 12.96/54.65 ± 3.41, BNP [pg/mL] 32.02 ± 3.37/19.76 ± 3.29, NTproBNP [pg/mL] 1228.94 ± 91.73/71.48 ± 8.65, copeptin [pmol/L] 103.42 ± 22.89/10.41 ± 1.71, and hsTnI [pg/mL] 13.54 ± 5.17/4.91 ± 2.37. Fetal MRproANP, NTproBNP, and BNP were inversely correlated with gestational age. Maternal and fetal MRproANP (r=0.472, p=0.002) and copeptin (r=0.572, p<0.001) levels were correlated, whereas there was no feto-maternal correlation for the other biomarkers. Fetal copeptin was elevated after exposure to labor.. Biomarker levels appear to be regulated independently in mother and fetus. Fetal biomarkers are influenced by gestational age and delivery mode. In this study on term and near term pregnancies without specific fetal pathology, correlation between paired maternal and fetal biomarker levels was weak or not demonstrable.

Topics: Adrenomedullin; Adult; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Female; Fetal Blood; Glycopeptides; Humans; Infant, Newborn; Infant, Premature; Male; Protein Precursors; Troponin I

The elevation of bradykinin (BK) level during attacks of hereditary angioedema due to C1-Inhibitor deficiency (C1-INH-HAE) is well known. We previously demonstrated that endothelin-1 (ET-1) level also increases during C1-INH-HAE attacks. Although BK and ET-1 are both potent vasoactive peptides, the vasoregulatory aspect of the pathomechanism of C1-INH-HAE has not yet been investigated. Hence we studied the levels of vasoactive peptides in controls and in C1-INH-HAE patients, as well as evaluated their changes during C1-INH-HAE attacks. The levels of arginine vasopressin (AVP), adrenomedullin (ADM) and ET-1 were measured in the plasma of 100 C1-INH-HAE patients in inter-attack periods and of 111 control subjects, using BRAHMS Kryptor technologies. In 18 of the 100 C1-INH-HAE patients, the levels of vasoactive peptides were compared in blood samples obtained during attacks, or in inter-attack periods. AVP, ADM and ET-1 levels were similar in inter-attack samples from C1-INH-HAE patients and in the samples of controls, although cardiovascular risk has an effect on the levels of vasoactive peptides in both groups. The levels of all three vasoactive peptides increased during C1-INH-HAE attacks. Moreover, the levels of ET-1 and ADM as well as their changes during attacks were significantly correlated. This study demonstrated that vascular regulation by vasoactive peptides is affected during C1-INH-HAE attacks. Our results suggest that the cooperation of several vasoactive peptides may be necessary to counterbalance the actions of excess BK, and to terminate the attacks. This may reveal a novel pathophysiological aspect of C1-INH-HAE.

Topics: Adrenomedullin; Adult; Angioedemas, Hereditary; Arginine Vasopressin; Cardiovascular Diseases; Case-Control Studies; Complement C1 Inhibitor Protein; Disease Progression; Endothelin-1; Female; Hereditary Angioedema Types I and II; Humans; Male; Middle Aged; Risk Factors; Young Adult

Several biomarkers have individually been shown to be useful for risk stratification in patients with acute myocardial infarction (MI). The optimal multimarker strategy remains undefined.. Biomarkers representing different pathobiological axes were studied, including myocardial stress/structural changes (NT-pro B-type natriuretic peptide [NT-proBNP], midregional proatrial natriuretic peptide [MR-proANP], suppression of tumorigenicity 2 [ST2], galectin-3, midregional proadrenomedullin [MR-proADM], and copeptin), myonecrosis (troponin T), and inflammation (myeloperoxidase [MPO], high sensitivity C-reactive protein [hsCRP], pregnancy-associated plasma protein A [PAPP-A], and growth-differentiation factor-15 [GDF-15]), in up to 1258 patients from Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28), a randomized trial of clopidogrel in ST-elevation MI (STEMI). Patients were followed for 30 days. Biomarker analyses were adjusted for traditional clinical variables. Forward step-wise selection was used to assess a multimarker strategy. After adjustment for clinical variables and using a dichotomous cutpoint, 7 biomarkers were each significantly associated with a higher odds of cardiovascular death or heart failure (HF) through 30 days, including NT-proBNP (adjusted odds ratio [ORadj], 2.54; 95% CI, 1.47-4.37), MR-proANP (2.18; 1.27-3.76), ST2 (2.88; 1.72-4.81), troponin T (4.13; 1.85-9.20), MPO (2.75; 1.20-6.27), hsCRP (1.96, 1.17-3.30), and PAPP-A (3.04; 1.17-7.88). In a multimarker model, 3 biomarkers emerged as significant and complementary predictors of cardiovascular death or HF: ST2 (ORadj, 2.87; 1.61-5.12), troponin T (2.34; 1.09-5.01 and 4.13, 1.85-9.20, respectively for intermediate and high levels), and MPO (2.49; 1.04-5.96). When added to the TIMI STEMI Risk Score alone, the multimarker risk score significantly improved the C-statistic (area under the curve, 0.75 [95% CI, 0.69-0.81] to 0.82 [0.78-0.87]; P=0.001), net reclassification index (0.93; P<0.001), and integrated discrimination index (0.09; P<0.001).. In patients with STEMI, a multimarker strategy that combines biomarkers across pathobiological axes of myocardial stress, myocyte necrosis, and inflammation provides incremental prognostic information for prediction of cardiovascular death or HF.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Proteins; C-Reactive Protein; Cardiovascular Diseases; Female; Galectin 3; Galectins; Glycopeptides; Growth Differentiation Factor 15; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Natriuretic Peptide, Brain; Odds Ratio; Peptide Fragments; Peroxidase; Pregnancy-Associated Plasma Protein-A; Prognosis; Protein Precursors; Risk Assessment; ST Elevation Myocardial Infarction; Troponin T

The inflammatory biomarker pro-adrenomedullin (ProADM) provides additional prognostic information for the risk stratification of general medical emergency department (ED) patients. The aim of this analysis was to develop a triage algorithm for improved prognostication and later use in an interventional trial.. We used data from the multi-national, prospective, observational TRIAGE trial including consecutive medical ED patients from Switzerland, France and the United States. We investigated triage effects when adding ProADM at two established cut-offs to a five-level ED triage score with respect to adverse clinical outcome.. Mortality in the 6586 ED patients showed a step-wise, 25-fold increase from 0.6% to 4.5% and 15.4%, respectively, at the two ProADM cut-offs (≤0.75nmol/L, >0.75-1.5nmol/L, >1.5nmol/L, p ANOVA <0.0001). Risk stratification by combining ProADM within cut-off groups and the triage score resulted in the identification of 1662 patients (25.2% of the population) at a very low risk of mortality (0.3%, n = 5) and 425 patients (6.5% of the population) at very high risk of mortality (19.3%, n = 82). Risk estimation by using ProADM and the triage score from a logistic regression model allowed for a more accurate risk estimation in the whole population with a classification of 3255 patients (49.4% of the population) in the low risk group (0.3% mortality, n = 9) and 1673 (25.4% of the population) in the high-risk group (15.1% mortality, n = 252).. Within this large international multicenter study, a combined triage score based on ProADM and established triage scores allowed a more accurate mortality risk discrimination. The TRIAGE-ProADM score improved identification of both patients at the highest risk of mortality who may benefit from early therapeutic interventions (rule in), and low risk patients where deferred treatment without negatively affecting outcome may be possible (rule out).

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Emergency Service, Hospital; Female; Gastrointestinal Diseases; Humans; Infections; International Agencies; Male; Middle Aged; Nervous System Diseases; Prognosis; Prospective Studies; Risk Assessment; Severity of Illness Index; Triage

It has been postulated that patients with heart failure have a high risk of ventricular arrhythmias and sudden cardiac death resulting from anxiety-induced autonomic arousal. In the prospective and multicenter DIAST-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) study, we therefore, tested the hypothesis that adrenomedullin (ADM), a well-established predictor for cardiovascular outcome, is associated with self-rated anxiety symptoms in patients at risk of suffering from or actually with overt heart failure.. Study participants with risk factors for diastolic dysfunction were requested to complete the Hospital Anxiety and Depression Scale (HADS), and plasma mid-regional pro-adrenomedullin (MR-proADM) concentrations were measured.. In bivariate analysis, we found significantly lower plasma MR-proADM levels in patients with elevated HADS-anxiety scores above the clinically relevant cut-off level of ≥11 (n=118, 536pmol/l, interquartile range [IQR] 449-626) as compared to non-anxious study participants (n=1,292, 573pmol/l, IQR 486-702, p=0.001). A set of multivariate models adjusted for potential confounders confirmed the negative association between self-rated anxiety symptoms and plasma MR-proADM. In similar models, no significant association was detected between HADS-depression scores and MR-proADM.. The inverse relationship between plasma MR-proADM and anxiety observed in patients with cardiovascular risk factors supports a previous experimental study using a mutant mouse line with a brain-specific loss of ADM expression which displayed hyperactive and over-anxious behavior. Further experimental and clinical studies are warranted to test the hypothesis that also in humans ADM acts as a neuromodulator with anxiolytic properties.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Anxiety; Cardiovascular Diseases; Depression; Diagnostic Self Evaluation; Female; Humans; Male; Middle Aged; Prospective Studies; Risk Factors

Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer.. We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint.. During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP.. Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Topics: Adrenomedullin; Aged; Asymptomatic Diseases; Atrial Natriuretic Factor; Austria; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Endothelin-1; Female; Glycopeptides; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Neoplasm Staging; Neoplasms; Peptide Fragments; Prospective Studies; Protein Precursors; Troponin T

The midregional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction and has been associated with a variety of diseases. Our aim was to investigate whether MR-proADM is associated with new-onset albuminuria and cardiovascular (CV) and all-cause mortality in patients with type 2 diabetes treated in primary care.. Patients with type 2 diabetes participating in the observational Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study were included. Cox regression analyses were used to assess the relation of baseline MR-proADM with new-onset albuminuria and CV and all-cause mortality. Risk prediction capabilities of MR-proADM for new-onset albuminuria and CV and all-cause mortality were assessed with Harrell's C and the integrated discrimination improvement.. In 1,243 patients (mean age 67 [±12] years), the median follow-up was 5.6 years (interquartile range 3.1-10.1); 388 (31%) patients died, with 168 (12%) CV deaths. Log2 MR-proADM was associated with CV (hazard ratio 1.96 [95% CI 1.27-3.01]) and all-cause mortality (1.78 [1.34-2.36]) after adjusting for age, sex, BMI, smoking, systolic blood pressure, cholesterol-to-HDL ratio, duration of diabetes, HbA1c, ACE inhibitor/angiotensin receptor blocker, history of CV diseases, log serum creatinine, and log albumin-to-creatinine ratio. MR-proADM slightly improved mortality risk prediction. The age- and sex-adjusted, but not multivariate-adjusted, MR-proADM levels were associated with new-onset albuminuria.. MR-proADM was associated with CV and all-cause mortality in patients with type 2 diabetes after a median follow-up of 5.6 years. There was no independent relationship with new-onset albuminuria. In the availability of an extensive set of risk factors, there was little added effect of MR-proADM in risk prediction of CV and all-cause mortality.

Topics: Adrenomedullin; Aged; Albuminuria; Biomarkers; Blood Pressure; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Netherlands; Peptide Fragments; Prognosis; Protein Precursors; Risk Factors

Midregional pro-adrenomedullin (MR-proADM) and C-terminal pro-vasopressin (copeptin) are novel biomarkers providing prognostic information in various settings. We aimed to (1) assess the kinetics of MR-proADM and copeptin during cardiopulmonary exercise testing (CPET); (2) assess the relationship of MR-proADM and copeptin measured at rest with peak oxygen consumption (peak VO2) and other key CPET parameters; (3) compare this relationship to that of B-type natriuretic peptide (BNP).. In 162 patients undergoing symptom-limited CPET for evaluation of exercise intolerance, MR-proADM, copeptin, and BNP were measured at rest and peak exercise.. There was a significant rise in copeptin and BNP (p < 0.001) but not in MR-proADM (p = 0.60) from rest to peak exercise. MR-proADM (r = -0.57; p < 0.001) and BNP (r = -0.49; p < 0.001) but not copeptin were significantly and inversely related to peak VO2. MR-proADM was inversely correlated to the percentage of predicted heart rate achieved and peak oxygen pulse and directly related to the peak ventilation/carbon dioxide production relationship, the physiological dead space-to-tidal volume ratio, and the alveolo-arterial oxygen gradient (p ≤ 0.01 for all), and these associations were at least as strong as for BNP. In contrast, copeptin was not significantly related to any of these parameters (p > 0.05 for all).. In contrast to BNP and copeptin, MR-proADM is not immediately affected by a maximal exercise test. MR-proADM but not copeptin is at least as good an indicator of low peak VO2 and CPET parameters reflecting an impaired cardiac output reserve, ventilatory efficiency and diffusion capacity as BNP, and thereby a global cardiopulmonary stress marker.

Topics: Adrenomedullin; Aged; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Exercise; Exercise Tolerance; Female; Glycopeptides; Heart Rate; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen Consumption; Respiratory Tract Diseases; Tidal Volume

To investigate the ability of cardiovascular plasma biomarkers to identify imminent preeclampsia (PE) among pregnant women at triage.. C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adrenomedullin (MR-proADM), and mid-regional pro-atrial natriuretic peptide (MR-proANP) were prospectively measured in pregnant women presenting at the obstetrical triage units of the University Hospitals of Basel and Zurich, Switzerland. Logistic regression and receiver operating characteristics (ROC) analysis was used to assess and quantify the predictive ability of cardiovascular biomarkers.. Of the 147 included women, 27 (18.4%) were diagnosed at admission with PE. All biomarker levels were significantly higher in participants with PE as compared to controls. However, only MR-proANP, MR-proADM and CT-proET-1 were significant and independent predictors of PE, after taking into account the effect of various clinical confounders. The area under the ROC curve (AUC) was 0.62 (95% confidence interval 0.50-0.73) for copeptin, 0.64 (0.52-0.76) for MR-proADM, 0.71 (0.61-0.82) for CT-proET-1, and 0.83 (0.73-0.92) for MR-proANP. The combination of MR-proANP and MR-proADM resulted in the highest diagnostic performance (AUC 0.88; 0.79-0.96).. Assessment of the cardiovascular plasma biomarkers MR-proANP and MR-proADM holds promise to support diagnosis of PE at triage.

Topics: Adrenomedullin; Adult; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Endothelin-1; Epidemiologic Studies; Female; Glycopeptides; Humans; Peptide Fragments; Pre-Eclampsia; Pregnancy; Protein Precursors; Triage

To evaluate the significance of plasma adrenomedullin and calcitonin gene-related peptide (CGRP) concentration in patients with Type 2 diabetes mellitus who are treated for hypertension and dyslipidemia.. Plasma adrenomedullin and CGRP concentration, transthoracal echocardiography and ABPM were evaluated in 82 patients with Type 2 diabetes mellitus and 41 control subjects with no previous cardiovascular disease. All the subjects had casual blood pressure ≤140/90 mmHg or received antihypertensive medication, were treated by statin if LDL cholesterol was≥3mmol/L, by fibrates if triacylglyceroles≥2 mmol/L.. The mean age was 61±6 in patients with diabetes mellitus and 61±5 years in control subjects (p=0.9). Plasma CGRP was 3.0±1.8 in patients with diabetes mellitus and 2.3±1.0 ng/ml in control subjects (p=0.09). Plasma adrenomedullin was 2.2±0.9 in patients with diabetes mellitus and 2.8±1.1 ng/ml in control subjects (p=0.01). In patients with diabetes mellitus mass index of the left ventricle was significantly higher and the parameters of diastolic function were more deteriorated. Plasma adrenomedullin and CGRP correlated significantly negatively with serum creatinine and positively with mean 24 hours arterial blood pressure in patients with diabetes mellitus but not in control subjects. Plasma adrenomedullin concentration in patients with diabetes mellitus treated for hypertension was significantly reduced.. Despite concentration plasma adrenomedullin and CGRP modulation by cardioprotective treatment both neuropeptides remained involved in regulation of hemodynamic and metabolic parameters in patients with Type 2 diabetes mellitus. The low plasma of adrenomedullin in patients with Type 2 diabetic may be marker of the efficient intervention on cardiovascular risk factors.

Topics: Adrenomedullin; Aged; Antihypertensive Agents; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Humans; Hypertension; Hypolipidemic Agents; Male; Middle Aged; Prognosis; Risk Factors

Midregional proadrenomedullin (MR-proADM) is a protein, which exerts various effects on the cardiovascular system. Recent studies underscored its prognostic implications in patients with acute dyspnea and cardiovascular diseases. Therefore, we aimed to determine the distribution of MR-proADM in the general population and to reveal potential associations of MR-proADM with cardiovascular risk factors and measures of subclinical cardiovascular disease.. MR-proADM plasma concentrations were determined in individuals of the population-based cohort of the Gutenberg Health Study (N = 5000) using a commercially available fluoroimmunoassay. Individuals were enrolled between April 2007 and October 2008. Subclinical cardiovascular disease was assessed using echocardiographic and functional measures of myocardial and vascular function. The mean age of the study population was 55.5 ± 10.9 years. In the overall population we determined a median MR-proADM plasma concentration of 0.44 nmol/L in men and women. MR-proADM concentrations were elevated in individuals with hypertension, diabetes, dyslipidemia, known cardiovascular disease, heart failure, peripheral artery disease, atrial fibrillation, and history of myocardial infarction and stroke. In men, we observed a positive association of MR-proADM with reduced ejection fraction, intraventricular septal diameter, wall thickness, and echocardiographic measures of diastolic dysfunction.. In this study, we present age-dependent reference values for MR-proADM in a representative population sample. Elevated MR-proADM plasma concentrations were strongly associated with classical cardiovascular risk factors and manifest cardiovascular diseases. Furthermore, we revealed a gender-specific association with echocardiographic measures of hypertension. MR-proADM seems to be a promising prognostic biomarker for subclinical and manifest cardiovascular disease.

Topics: Adrenomedullin; Adult; Age Factors; Aged; Asymptomatic Diseases; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Echocardiography; Female; Fluoroimmunoassay; Germany; Humans; Linear Models; Male; Middle Aged; Peptide Fragments; Phenotype; Predictive Value of Tests; Prevalence; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment; Risk Factors; Sex Factors; Up-Regulation

Elevated plasma adrenomedullin (ADM) levels are associated with cardiovascular diseases. Single nucleotide polymorphisms (SNPs) in the gene encoding ADM (ADM) are associated with plasma ADM levels. The presence of a nuclear factor for interleukin-6 (IL-6) expression binding site in the promoter region of the ADM gene suggests a possible relationship between the expression of the ADM and IL-6. Therefore, we investigated whether plasma ADM levels are related to SNPs in the gene encoding IL-6 (IL6).. Plasma ADM levels were measured in 476 subjects in the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2). The subjects were genotyped for three tagging SNPs in the IL6 gene.. The minor allele frequencies of the IL6 SNPs rs17147230, rs1800796 and rs2069837 were 41·8%, 20·0% and 15·4%, respectively. The tagging SNP, rs17147230, was associated with plasma ADM levels after adjusting for age and sex (β=-0·096, P = 0·034). The association was significant in women (β=-0·115, P = 0·021) but not in men. Among all subjects, plasma ADM levels decreased with an increasing number of minor alleles of rs17147230 in multivariate analysis (P = 0·034). Compared to subjects with the AA genotype, subjects with the TT genotype had plasma ADM levels 12·8% lower (95% CI: 0·6-23·5%, P = 0·041). Haplotype analysis demonstrated a significant association of the haplotype ACA with plasma ADM levels in women (P < 0·05).. Plasma ADM levels are related to the SNP rs17147230 in IL6 gene. The effect of the polymorphism on inflammation and cardiovascular disease remains to be determined.

Topics: Adrenomedullin; Adult; Asian People; Cardiovascular Diseases; Female; Gene Frequency; Genotype; Haplotypes; Hong Kong; Humans; Interleukin-6; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Prevalence; Risk Factors; Sex Factors

Topics: Adrenomedullin; Aged; Biomarkers; Cardiovascular Diseases; Child; Community-Acquired Infections; Forecasting; Hospital Mortality; Humans; Middle Aged; Pneumococcal Vaccines; Pneumonia, Pneumococcal; Protein Precursors; Vaccines, Conjugate

Experimental 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 age, body mass index and kidney function. The aim of this study was to evaluate the prognostic performance of MR-proADM in the general population, controlling for these potential confounders.. 7903 subjects (mean age 49 ± 13 years, 49% male) from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort with a median follow-up of 10.5 years were enrolled in a prospective cohort study.. Mean baseline MR-proADM was 0.39 ± 0.14 nmol/l. In cross-sectional analyses, age, blood pressure, C reactive protein, cystatin-C, N-terminal pro-brain type natriuretic peptide and urinary albumin excretion remained as independent determinants of MR-proADM. In prospective analyses, MR-proADM was associated with the primary endpoint (combined cardiovascular mortality and cardiovascular morbidity), with event rates ranging from 8% in the lowest quintile to 45% in the highest quintile (p for trend <0.001) independent of age, sex, components of the Framingham risk score and other cardiovascular markers. Overall Net Reclassification Improvement against the Framingham risk score was 2.2%, which was non-significant. However, significant modification of the effect of MR-proADM on outcome by age was observed. In subjects aged ≤70 years (N=7475), 8.8% were correctly reclassified in a higher risk category (p=0.017) and 3.4% in a lower risk category (p<0.001). In subjects aged >70 years (N=428) there was no improvement of reclassification (p=0.32).. This study gives a detailed overview of the distribution of ADM in a general population and provides evidence that it is a potent and interesting biomarker in predicting cardiovascular events. These results seem especially applicable to younger subjects.

Topics: Adrenomedullin; Adult; Age Factors; Aged; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Immunoassay; Kaplan-Meier Estimate; Male; Middle Aged; Peptide Fragments; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment; Risk Factors

High levels of the plasma peptides mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-atrial natriuretic peptide (MR-proANP) are associated with clinical outcomes in the general population. Data in patients with chronic kidney disease are sparse. We therefore investigated the association of MR-proANP and MR-proADM levels with all-cause and cardiovascular (CV) mortality, CV events and peripheral arterial disease in 201 incident dialysis patients of the INVOR-Study prospectively followed for a period of up to more than 7 years. The overall mortality rate was 43%, thereof 43% due to CV events. Both baseline MR-proANP and MR-proADM were associated with higher risk of all-cause (HR = 1.44, p = 0.001 and HR = 1.32, p = 0.002, respectively) and CV mortality (HR = 1.75, p<0.001 and HR = 1.41, p = 0.007, respectively) after adjustment for age, sex, previous CV events, diabetes mellitus and time-dependent type of renal replacement therapy. We then stratified patients in high risk (both peptides in the upper tertile), intermediate risk (only one of the two peptides in the upper tertile) and low risk (none in the upper tertile). Although demographic, clinical and laboratory variables were similar among the intermediate and high risk group, to be with both parameters in the upper tertile was associated with a 3-fold higher risk for all-cause (HR = 2.87, p<0.001) and CV mortality (HR = 3.58, p = 0.001). In summary, among incident dialysis patients MR-proANP and MR-proADM were shown to be associated with all-cause and CV mortality, with the highest risk when both parameters were in the upper tertiles.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Cardiovascular Diseases; Cohort Studies; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Renal Dialysis; Risk Factors; Treatment Outcome

Adrenomedullin (ADM) plays an important role in inflammation and is a marker of future cardiovascular events. We studied common single nucleotide polymorphisms (SNPs) in the gene encoding ADM and their relationship with the plasma levels of ADM and other inflammatory markers.. Plasma ADM, interleukin 6 (IL6), fibrinogen, and C-reactive protein (CRP) were measured in 476 subjects from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study-2. Four tag SNPs in ADM were genotyped.. Plasma ADM level increased with decreasing plasma IL6 level (β=-0.116, P=0.014). Plasma ADM level was not related to plasma levels of CRP and fibrinogen, and other clinical characteristics, except age (P=0.049). The four SNPs, rs3814700, rs11042725, rs34354539, and rs4910118, had minor allele frequencies of 31.1, 28.7, 33.8, and 23.4% respectively. Carriers of the minor allele of rs4910118 had a mean plasma ADM level that was 10.5% (95% confidential interval: 2.5-17.8%) lower than the non-carriers (β=-0.115, P=0.011). Haplotype analysis revealed a similar significant association with plasma ADM (P=0.040). In multivariate analysis, the presence of the minor allele of rs4910118, but not plasma IL6, was independently associated with plasma ADM (P=0.010).. Plasma ADM correlates with plasma IL6 level, consistent with its role in inflammation. It is related to an SNP common in Chinese, independent of other covariates. ADM genotype should be included in future studies of cardiovascular risk prediction.

Topics: Adrenomedullin; Adult; Age Factors; Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Female; Fibrinogen; Gene Frequency; Genotype; Haplotypes; Hong Kong; Humans; Interleukin-6; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Risk Factors; Sex Factors

Adrenomedullin (ADM) is a vasodilatory peptide. Its plasma levels or its precursors have not been evaluated in large populations of patients with chronic heart failure (CHF). We sought to explore mid-regional proADM (MR-proADM).. We assessed MR-proADM in 501 CHF patients [age 63 +/- 11 years, New York Heart Association (NYHA) class I/II/III/IV 9/44/39/8%, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 878 pg/mL (interquartile range-IQR 348-2480 pg/mL), median left ventricular ejection fraction (LVEF) 31% (IQR 25-37%)]. Mid-regional pro-adrenomedullin levels (median 0.64 nmol/L, IQR 0.49-0.87 nmol/L) increased with NYHA class (P < 0.0001). During 1-year follow-up, 70 patients (14%) died. Increasing MR-proADM was a predictor of poor survival at 12 months (hazard ratio 1.82, 95% confidence interval 1.24-2.66, P = 0.002) after multivariable adjustment. In receiver-operating characteristic curve analysis of 12-month survival, the area under the curve for MR-proADM and NT-proBNP was similar (P = 0.3). Comparison of Cox proportional hazard models using the likelihood ratio chi(2) statistic showed that both NT-proBNP and MR-proADM added prognostic value to a base model of LVEF, age, creatinine, and NYHA class. Adding MR-proADM to the base model had stronger prognostic power than adding NT-proBNP (both P < 0.01).. Mid-regional pro-adrenomedullin is an independent predictor of mortality in CHF patients, which adds prognostic information to NT-proBNP.

Topics: Adrenomedullin; Cardiovascular Diseases; Confidence Intervals; Europe; Female; Heart Failure; Humans; Immunoassay; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Prospective Studies; ROC Curve; Statistics as Topic; Statistics, Nonparametric; Survival Analysis; Treatment Outcome; Vasodilation

Several new biomarkers are related to mortality in community-acquired pneumonia (CAP).. Aim of this study was to compare new biomarkers for the prediction of short- and long-term all-cause mortality in CAP.. We enrolled 728 patients (59.0 ± 18.2 yr) with CAP. Midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), proarginin-vasopressin (copeptin), proendothelin-1 (CT-proET-1), procalcitonin (PCT), C-reactive protein, white blood cell (WBC) count, and clinical confusion, respiratory rate, blood pressure, and age over 65 years (CRB-65) score were determined on admission. Patients were followed up for 180 days.. In patients who died of any cause within 28 and 180 days (2.5 and 5.1%, respectively), MR-proADM, MR-proANP, copeptin, CT-proET-1 and PCT as well as CRB-65 were significantly higher compared with survivors. MR-proADM had the best performance for 28 days (HR 3.67) and 180 days (HR 2.84) survival. The C index of MR-proADM for 28-day survival (0.85) was superior to MR-proANP (0.81), copeptin (0.78), CT-proET-1 (0.79), and CRB-65 (0.72) for the prediction of mortality. For prediction of mortality at 180 days, the C index of MR-proADM (0.78) was higher than that for MR-proANP (0.74), copeptin (0.73), CT-proET-1 (0.76), PCT, C-reactive protein, and white blood cells. MR-proADM was independent of CRB-65, and added prognostic information for short- and long-term mortality. MR-proADM was an independent and strong predictor of short- and long-term mortality.. All new biomarkers were good predictors of short- and long-term all-cause mortality, superior to inflammatory markers, and at least comparable to CRB-65 score. MR-proADM showed the best performance. A combination of CRB-65 with MR-proADM might be the best predictor for mortality.

Topics: Adolescent; Adrenomedullin; Adult; Age Distribution; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Community-Acquired Infections; Comorbidity; Endothelin-1; Female; Germany; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Protein Precursors; Respiratory Rate; Survival Analysis; Vasopressins; Young Adult

Topics: Adrenomedullin; Cardiovascular Diseases; Humans; Immunoradiometric Assay; Shock, Septic

The increased cardiovascular risk in diabetes has been linked to endothelial and renal dysfunction. The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes.. This was a prospective, observational study design with a composite end point (death or unexpected admission to hospital due to a cardiovascular event) on 781 patients with type 2 diabetes (54 events, median duration of observation 15 months). The four stable precursor peptides midregional adrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), COOH-terminal proendothelin-1 (CT-proET-1), and COOH-terminal provasopressin or copeptin (CT-proAVP) were determined at baseline, and their association to renal function and cardiovascular events was studied using stepwise linear and Cox logistic regression analysis and receiver operating characteristic analysis, respectively.. MR-proADM, CT-proET-1, CT-proAVP, and MR-proANP were all elevated in patients with future cardiovascular events and independently correlated to serum creatinine. MR-proADM and MR-proANP were significant predictors of a future cardiovascular event, with MR-proANP being the stronger (area under the curve 0.802 +/- 0.034, sensitivity 0.833, specificity 0.576, positive predictive value 0.132, and negative predictive value 0.978 with a cutoff value of 75 pmol/l).. The four serum markers of vasoactive and natriuretic peptides are related to both kidney function and cardiovascular events, thus linking two major complications of diabetes, diabetic nephropathy and cardiovascular disease.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Endothelin-1; Female; Glycopeptides; Humans; Kidney; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Protein Precursors

Prior studies have demonstrated conflicting results regarding how much information novel biomarkers add to cardiovascular risk assessment.. To evaluate the utility of contemporary biomarkers for predicting cardiovascular risk when added to conventional risk factors.. Cohort study of 5067 participants (mean age, 58 years; 60% women) without cardiovascular disease from Malmö, Sweden, who attended a baseline examination between 1991 and 1994. Participants underwent measurement of C-reactive protein (CRP), cystatin C, lipoprotein-associated phospholipase 2, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide (N-BNP) and underwent follow-up until 2006 using the Swedish national hospital discharge and cause-of-death registers and the Stroke in Malmö register for first cardiovascular events (myocardial infarction, stroke, coronary death).. Incident cardiovascular and coronary events.. During median follow-up of 12.8 years, there were 418 cardiovascular and 230 coronary events. Models with conventional risk factors had C statistics of 0.758 (95% confidence interval [CI], 0.734 to 0.781) and 0.760 (0.730 to 0.789) for cardiovascular and coronary events, respectively. Biomarkers retained in backward-elimination models were CRP and N-BNP for cardiovascular events and MR-proADM and N-BNP for coronary events, which increased the C statistic by 0.007 (P = .04) and 0.009 (P = .08), respectively. The proportion of participants reclassified was modest (8% for cardiovascular risk, 5% for coronary risk). Net reclassification improvement was nonsignificant for cardiovascular events (0.0%; 95% CI, -4.3% to 4.3%) and coronary events (4.7%; 95% CI, -0.76% to 10.1%). Greater improvements were observed in analyses restricted to intermediate-risk individuals (cardiovascular events: 7.4%; 95% CI, 0.7% to 14.1%; P = .03; coronary events: 14.6%; 95% CI, 5.0% to 24.2%; P = .003). However, correct reclassification was almost entirely confined to down-classification of individuals without events rather than up-classification of those with events.. Selected biomarkers may be used to predict future cardiovascular events, but the gains over conventional risk factors are minimal. Risk classification improved in intermediate-risk individuals, mainly through the identification of those unlikely to develop events.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; Cystatin C; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Proportional Hazards Models; Risk Assessment; Risk Factors

Adrenomedullin (AM) is a peptide involved both in the pathogenesis of cardiovascular diseases and in circulatory homeostasis. The high-affinity AM receptor is composed of receptor activity-modifying protein 2 or 3 (RAMP2 or -3) and the GPCR calcitonin receptor-like receptor. Testing our hypothesis that RAMP2 is a key determinant of the effects of AM on the vasculature, we generated and analyzed mice lacking RAMP2. Similar to AM-/- embryos, RAMP2-/- embryos died in utero at midgestation due to vascular fragility that led to severe edema and hemorrhage. Vascular ECs in RAMP2-/- embryos were severely deformed and detached from the basement membrane. In addition, the abnormally thin arterial walls of these mice had a severe disruption of their typically multilayer structure. Expression of tight junction, adherence junction, and basement membrane molecules by ECs was diminished in RAMP2-/- embryos, leading to paracellular leakage and likely contributing to the severe edema observed. In adult RAMP2+/- mice, reduced RAMP2 expression led to vascular hyperpermeability and impaired neovascularization. Conversely, ECs overexpressing RAMP2 had enhanced capillary formation, firmer tight junctions, and reduced vascular permeability. Our findings in human cells and in mice demonstrate that RAMP2 is a key determinant of the effects of AM on the vasculature and is essential for angiogenesis and vascular integrity.

Topics: Adrenomedullin; Animals; Arteries; Calcitonin Receptor-Like Protein; Capillary Permeability; Cardiovascular Diseases; Cells, Cultured; Edema; Embryo Loss; Embryonic Stem Cells; Endothelium, Vascular; Female; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Knockout; Neovascularization, Physiologic; Pregnancy; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Calcitonin; Receptors, Peptide; Tight Junctions

Growth of blood and lymphatic vessels is essential in the developing embryo and in the pathogenesis of human diseases such as cancer, but the signaling pathways that regulate vessel growth and function are not yet well characterized. In this issue of the JCI, studies by Fritz-Six et al. and Ichikawa-Shindo et al. demonstrate that loss of signaling by the adrenomedullin peptide results in embryonic edema and death (see the related articles beginning on pages 40 and 29, respectively). Remarkably, this phenotype is attributed to defects in lymphatic vessels by one group and to defects in blood vessels by the other. In addition to defining what I believe to be a novel angiogenic signaling pathway, these studies demonstrate the intricate molecular, genetic, and physiologic relationships between blood and lymphatic vessels that must be considered by investigators of vascular biology.

Topics: Adrenomedullin; Animals; Arteries; Calcitonin Receptor-Like Protein; Capillary Permeability; Cardiovascular Diseases; Cells, Cultured; Edema; Embryo Loss; Embryonic Stem Cells; Endothelium, Vascular; Female; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Knockout; Neovascularization, Physiologic; Pregnancy; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Calcitonin; Receptors, Peptide; Tight Junctions

This study investigated the predictive power of plasma adrenomedullin (AM) for future cardiovascular (CV) events. In 121 patients with multiple CV risk factors and/or disease, plasma concentrations of AM, high sensitive C-reactive protein (hs-CRP), and adiponectin were measured. During follow-up periods (mean, 3.5 years) after the baseline assessment, 28 patients newly experienced CV events such as stroke/transient ischemic attack, acute coronary syndrome, and congestive heart failure. The plasma level of AM, but not hs-CRP or adiponectin, was significantly higher in patients who had CV events than in event-free subjects. When the patients were divided into three groups by tertiles of basal levels of AM (<10.1, 10.1-13.1, and > or =13.1 fmol/mL), cumulative event-free rates by the Kaplan-Meier method were decreased according to the increase in basal AM levels (83.2%, 68.6%, and 52.8% in the lowest, middle, and highest tertiles of AM, respectively; log-rank test, P=0.033). By univariate Cox regression analysis, previous coronary artery disease, creatinine clearance, and plasma AM and hs-CRP levels were significantly associated with CV events during follow-up. Among these possible predictors, high plasma AM (P=0.004) and low creatinine clearance (P=0.043) were independent determinants for morbidity in multivariate analysis. These findings indicate that plasma AM is a powerful independent predictor of future CV events in high-risk patients, suggesting its predictive value is superior to that of hs-CRP or adiponectin.

Topics: Adiponectin; Adrenomedullin; Aged; C-Reactive Protein; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Risk Factors

Adrenomedullin (AM) is a potent vasodilator peptide in plasma at picomolar levels. Polymorphisms in the human AM gene have been associated with genetic predisposition to diabetic nephropathy and proteinuria with essential hypertension, and numerous studies have demonstrated that endogenous AM plays a role in protecting the heart and kidneys from fibrosis resulting from cardiovascular disease. Elevated plasma levels of AM are associated with pregnancy and sepsis and with cardiovascular stress and hypertension. However, there are no reports of the effects of genetic differences in the expression of the endogenous AM gene and of gender on blood pressure in these circumstances or on the pathological changes accompanying hypertension. To address these questions, we have generated mice having genetically controlled levels of AM mRNA ranging from approximately 50% to approximately 140% of wild-type levels. These modest changes in AM gene expression have no effect on basal blood pressure. Although pregnancy and sepsis increase plasma AM levels, genetically reducing AM production does not affect the transient hypotension that occurs during normal pregnancy or that is induced by treatment with lipopolysaccharide. Nor does the reduction of AM affect chronic hypertension caused by a renin transgene. However, 50% normal expression of AM enhances cardiac hypertrophy and renal damage in male, but not female, mice with a renin transgene. These observations suggest that the effect of gender on the role of AM in counteracting cardiovascular damage in humans merits careful evaluation.

Topics: Adrenomedullin; Analysis of Variance; Animals; Blood Pressure; Cardiovascular Diseases; Female; Gene Expression; Male; Mice; Mice, Transgenic; Pregnancy; Sex Factors

Increased arterial stiffness and higher plasma natriuretic peptide and homocysteine levels are associated with elevated risk for cardiovascular disease. Little is known about the relations of natriuretic peptides and homocysteine to arterial wall stiffness in the community.. We assessed the relations of plasma N-terminal atrial natriuretic peptide, B-type natriuretic peptide, adrenomedullin, and homocysteine concentrations to arterial stiffness in participants in the Framingham Heart Study. Central pulse pressure, forward pressure wave, reflected pressure wave, carotid-femoral pulse wave velocity, and carotid-radial pulse wave velocity were assessed by tonometry in 1962 participants (mean age, 61 years; 56% women) in the Framingham Heart Study. Central systolic and diastolic blood pressures were 123/75 mm Hg in men and 119/66 mm Hg in women. After adjustment for age and clinical covariates, N-terminal atrial natriuretic peptide and B-type natriuretic peptide were associated with carotid-femoral pulse wave velocity (men: partial correlation, 0.069, P = 0.043 and r = 0.115, P < or = 0.001, respectively; women: r = -0.063, P = 0.037 and r = -0.062, P = 0.040), and carotid-radial pulse wave velocity (men: r = -0.090, P = 0.009 and r = -0.083, P < or = 0.015; women: r = -0.140, P < or = 0.001 and r = -0.104, P = 0.001, respectively). In men, N-terminal atrial natriuretic peptide and B-type natriuretic peptide also were associated with forward and reflected wave and carotid pulse pressure. In men, adrenomedullin was associated with mean arterial pressure (r = 0.089, P = 0.009), and homocysteine was associated with carotid-femoral pulse wave velocity (r = 0.072, P = 0.036), forward pressure (r = 0.079, P = 0.02), and central pulse pressure (r = 0.072, P = 0.035). Interaction tests indicated sex differences in the relations of several biomarkers to measures of arterial stiffness.. Plasma natriuretic peptide, adrenomedullin, and homocysteine levels are associated with alterations in conduit vessel properties that differ in men and women.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Female; Homocysteine; Humans; Male; Manometry; Massachusetts; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Protein Precursors; Risk Factors

This study aimed to determine whether there is an adrenomedullin (AM)-mediated protective effect of postmenopausal estrogen/progestin therapy (HRT) against cardiovascular disorders.. A total of 22 post-menopausal women without hysterectomy undergoing postmenopausal symptoms (aged 43-52) were treated with conjugated equine estrogen (0.625 mg/die) plus medroxyprogesterone acetate (2.5 mg/die) for six months. The flow velocity of the right middle cerebral artery [measured as resistance index (RI) and pulsatility index (PI)], plasma levels of adrenomedullin and endothelin- 1 (ET-1), mean baseline ratio of AM to ET-1, and lipid profiles were assessed before and after HRT.. A statistically significant difference was found for triglycerides, total cholesterol, AM/ET-1 ratio and right middle cerebral artery PI (p<0.05), without any significant differences in HDL, LDL, AM, ET-1, systolic blood pressure, diastolic blood pressure, a right middle cerebral artery RI (p>0.05) between pre- and post- HRT.. Adrenomedullin may be added to other vasoactive peptides as a new potential candidate for HRT-mediated vascular protection. The ratio of AM/ET-1 vs AM or ET-1 alone may be a useful biological marker of this protection.

Topics: Adrenomedullin; Blood Pressure; Cardiovascular Diseases; Cerebrovascular Circulation; Endothelin-1; Estrogen Replacement Therapy; Female; Humans; Lipids; Middle Aged

Epicardial white adipose tissue (eWAT) is in close contact with coronary vessels and therefore could alter coronary homeostasis. Adrenomedullin (AM) is a potent vasodilatator and antioxidative peptide which has been shown to play a cytoprotective role in experimental models of acute myocardial infarction. We studied, using immunohistochemistry and qRT-PCR, the expression of AM and its receptors calcitonin receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP)2 and -3 in paired biopsies of subcutaneous WAT (sWAT) and eWAT obtained from patients with coronary artery disease (CAD) or without CAD (NCAD). In eWAT obtained from NCAD or CAD patients, immunoreactivity for AM, CRLR, and RAMP2 and -3 was detected in blood vessel walls and isolated stromal cells close to adipocytes. Some of the AM positive stromal cells colocalized CD68 immunoreactivity. eWAT from CAD patients showed increased AM immunoreactivity and AM gene expression. CRLR mRNA levels were comparable in sWAT of both groups and decreased by 40-50% in eWAT, irrespectively of the coronary status. RAMP2 mRNA concentrations did not change while RAMP3 mRNA levels increased in sWAT from CAD patients. There was a positive linear relationship between eWAT 11beta-hydroxysteroid dehydrogenase type 1 mRNA (11beta-HSD-1, the enzyme that converts inactive to active glucocorticoids) and AM mRNA. In conclusion, we demonstrate that AM and its receptors are expressed in eWAT. Our data suggest that eWAT AM, which could originate from macrophages, is related to 11beta-HSD-1 expression. AM synthesis, which is increased in eWAT during chronic CAD in humans, can play a cardioprotective role.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Adipose Tissue, White; Adrenomedullin; Adult; Aged; Biopsy; Calcitonin Receptor-Like Protein; Cardiovascular Diseases; Female; Gene Expression Regulation; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Middle Aged; Pericardium; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric

Adrenomedullin (AM) is a potent endothelial-derived vasodilator secreted under the influence of various stimuli such as hypoxia, shear stress and cytokines. As all of these stimuli might be active under the conditions of obstructive sleep apnoea (OSA), we hypothesized that vascular AM production is increased in these patients. The study included 41 consecutive OSA patients and 28 control subjects without sleep-disordered breathing who were recruited from a pool of patients hospitalized for other reasons. Both groups were matched for anthropometric and comorbid factors. In all patients, i.e. OSA and controls, peripheral venous blood samples were taken at 07:00 hours after diagnostic polysomnography. In subsets of OSA patients, this was repeated after two nights of continuous positive airway pressure (CPAP) therapy (n = 28) and after several months of constant CPAP use (n = 11). The controls and the untreated OSA patients did not have serial blood sampling. In all blood samples, plasma AM levels were measured by an enzyme immunoassay kit. At baseline, the OSA patients had markedly elevated AM concentrations when compared to the controls. There were no differences between normo- and hypertensive OSA patients. After two nights of CPAP therapy, AM levels significantly decreased. Patients on long-term CPAP treatment showed complete normalization of plasma AM concentrations. In conclusion, this pilot study suggests that circulating AM is increased in untreated OSA irrespective of coexistent arterial hypertension and declines after CPAP therapy. AM upregulation might be considered as an adaptive mechanism to counteract the emergence of OSA-related cardiovascular disease.

Topics: Adrenomedullin; Anthropometry; Body Mass Index; Cardiovascular Diseases; Continuous Positive Airway Pressure; Female; Humans; Male; Middle Aged; Peptides; Polysomnography; Sleep Apnea, Obstructive

It is well documented that there are gender differences in the incidence and patterns of cardiovascular diseases but the reasons are unclear. Sex steroids may modulate the behaviour of vascular endothelial cells, which in turn act by paracrine processes to alter adjacent vascular smooth muscle activity. We hypothesised that the sex steroids alter the percentage of vascular endothelial cells that secrete the vasodilator peptide, adrenomedullin and modify the adrenomedullin-stimulating action of angiotensin-II. The percentage of adrenomedullin-secreting human aortic endothelial cells was determined using the cell immunoblot method. Cells were incubated with selected concentrations of angiotensin-II, oestradiol and testosterone alone and sex steroids in combination with angiotensin-II. Adrenomedullin mRNA expression in endothelial cells was quantified by real-time PCR. It was observed that at 4 h, angiotensin-II increased the percentage of adrenomedullin-secreting cells in a concentration-dependent manner. Testosterone at physiological concentrations was observed to increase the number of adrenomedullin-secreting cells whilst oestradiol had no effect. Addition of testosterone to angiotensin-II resulted in less than additive increases in the number of cells secreting adrenomedullin. Oestradiol reduced the angiotensin-II-induced increase in adrenomedullin-secreting cells. Adrenomedullin mRNA expression was significantly increased by testosterone and there was also a trend for an increase in adrenomedullin mRNA expression, which occurred when cells were incubated with angiotensin-II. Our results point to a complex interplay between the sex steroids and angiotensin-II in regulating adrenomedullin production by human endothelial cells, which may contribute to gender-related differences in vascular disease in humans.

Topics: Adrenomedullin; Angiotensin II; Aorta; Cardiovascular Diseases; Dose-Response Relationship, Drug; Endothelial Cells; Endothelium, Vascular; Estradiol; Female; Gonadal Steroid Hormones; Humans; Immunoblotting; Male; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stimulation, Chemical; Testosterone

Adrenomedullin (AM) is a hypotensive peptide that functions as an important regulator in the cardiovascular and renal systems. The current study explored the potential therapeutic effects of delivering the human AM cDNA via a novel double-stranded adeno-associated virus vector (dsAAV) on hypertension and related complications in spontaneously hypertensive rats (SHR). A single dose of dsAAV-AM vector administered by tail vein injection into adult SHR resulted in significant reduction of systolic blood pressure at 2 weeks after gene delivery. This effect was observed through the entire duration of the experiment period (up to 16 weeks). Administration of dsAAV-AM also resulted in a decrease in total urine microalbumin content. Left ventricle and cardiomyocyte hypertrophy, fibrosis in the heart, glomerular sclerosis, and tubular injuries in the kidney were significantly reduced. Moreover, deterioration of hemodynamic variables was prevented in treated rats, as compared with the control groups. We conclude that AAV-mediated AM delivery can render a longterm and stable reduction of hypertension and protect against renal injury and cardiac remodeling in the spontaneously hypertensive rat model. Further preclinical studies are warranted for the development of a gene therapy strategy for human hypertension.

Topics: Adenoviridae; Adrenomedullin; Albuminuria; Animals; Blood Pressure; Cardiovascular Diseases; DNA Primers; Enzyme-Linked Immunosorbent Assay; Genetic Therapy; Genetic Vectors; Heart; Hypertension; Kidney; Male; Organ Size; Peptides; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction

Diuresis and natriuresis are well-known responses to acute hypoxic exposure. Even though there have been many studies on the hormonal regulation of the hypoxic diuretic response (HDR), most of the fluid-regulating hormones showed no consistent correlation to HDR. The pathophysiology of high altitude related syndromes was often seen to be linked to an impairment of volume regulating processes. Adrenomedullin (AM) is a recently discovered polypeptide with diuretic, natriuretic and vasodilatory properties whose production is basically mediated by hypoxia. As yet, little is known about the action of AM under hypoxic conditions in vivo. We present evidence that AM may play a role in the physiology and pathophysiology of human adaption to high altitude.

Topics: Acclimatization; Adaptation, Physiological; Adrenomedullin; Altitude; Altitude Sickness; Cardiovascular Diseases; Diuresis; Humans; Hypoxia; Kidney; Natriuresis; Peptides; Risk Factors; Water-Electrolyte Balance

Adrenomedullin (ADM) is a potent vasodilatory peptide, and circulating concentrations have been described for several disease states, including dysfunction of the cardiovascular system and sepsis. Reliable quantification has been hampered by the short half-life, the existence of a binding protein, and physical properties. Here we report the technical evaluation of an assay for midregional pro-ADM (MR-proADM) that does not have these problems.. MR-proADM was measured in a sandwich immunoluminometric assay using 2 polyclonal antibodies to amino acids 45-92 of proADM. The reference interval was defined in EDTA plasma of 264 healthy individuals (117 male, 147 female), and increased MR-proADM concentrations were found in 95 patients with sepsis and 54 patients with cardiovascular disease.. The assay has an analytical detection limit of 0.08 nmol/L, and the interassay CV was <20% for values >0.12 nmol/L. The assay was linear on dilution with undisturbed recovery of the analyte. EDTA-, heparin-, and citrate-plasma samples were stable (<20% loss of analyte) for at least 3 days at room temperature, 14 days at 4 degrees C, and 1 year at -20 degrees C. MR-proADM values followed a gaussian distribution in healthy individuals with a mean (SD) of 0.33 (0.07) nmol/L (range, 0.10-0.64 nmol/L), without significant difference between males or females. The correlation coefficient for MR-proADM vs age was 0.50 (P < 0.001). MR-proADM was significantly (P < 0.001) increased in patients with cardiovascular disease [median (range), 0.56 (0.08-3.9) nmol/L] and patients with sepsis [3.7 (0.72-25.4) nmol/L].. MR-proADM is stable in plasma of healthy individuals and patients. MR-proADM measurements may be useful for evaluating patients with sepsis, systemic inflammation, or heart failure.

Topics: Adolescent; Adrenomedullin; Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Cardiovascular Diseases; Female; Humans; Immunoassay; Luminescent Measurements; Male; Middle Aged; Molecular Sequence Data; Protein Precursors; Proteins; Sensitivity and Specificity; Sepsis; Temperature; Time Factors

Proadrenomedullin N-terminal 20 peptide (PAMP) processed from an adrenomedullin precursor is a potent hypotensive peptide. It was anticipated that a mature form of PAMP (m-PAMP) and an intermediate PAMP-gly existed together in the blood. To measure concentrations of PAMPs in human plasma directly, we have developed a highly sensitive enzyme immunoassay (immune complex transfer enzyme immunoassay, ICT-EIA).. PAMP was reacted simultaneously with 2,4-dinitrophenyl (DNP)-biotinyl-bovine serum albumin (BSA)-anti-PAMP Fab' conjugate and anti-PAMP Fab'-beta-D-galactosidase conjugate. The immune complex that was formed was initially trapped onto a polystyrene bead coated with anti-DNP IgG, and then transferred onto a second polystyrene bead coated with streptavidin. The resulting three-component complex was then assayed fluorometrically.. The detection limits of ICT-EIA for both m-PAMP and PAMP-gly were 0.1 pmol/l with as little as 10 microl of plasma, and were a hundred times higher than with conventional radioimmunoassay (RIA). Using ICT-EIA, we determined that the plasma concentrations of m-PAMP and PAMP-gly in 51 healthy volunteers were 0.51 +/- 0.19 and 1.15 +/- 0.38 pmol/l (mean +/- SD), respectively. Both plasma m-PAMP and PAMP-gly concentrations in patients with a variety of diseases, including hypertension, heart failure, chronic renal failure, and hemodialysis, were significantly higher than those in healthy subjects. In addition, both plasma m-PAMP and PAMP-gly concentrations in patients with New York Heart Association (NYHA) class I-IV heart failure were increased in proportion to clinical severity.. These sensitive and specific ICT-EIAs may be used as a powerful tool for investigating the cardiovascular system in patients with heart failure.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Animals; beta-Galactosidase; Calibration; Cardiovascular Diseases; Cross Reactions; Female; Humans; Immunoenzyme Techniques; Immunoglobulin Fab Fragments; Male; Middle Aged; Peptides; Rats; Reproducibility of Results; Sensitivity and Specificity

Adrenomedullin (AM), a potent vasodilator peptide, is produced by posttranslational splicing of pro-adrenomedullin together with proadrenomedullin N-terminal 20 peptide (PAMP), another hypotensive peptide. Although both AM and PAMP have the potential not only to decrease blood pressure but also to protect organs from damage, there is no direct evidence for their individual physiological roles in vivo.. Using knockout mice with the disruption of AM peptide alone, we investigated the organ-protective effect of AM. Although the AM(-/-) mutation in mice was embryonic lethal without any apparent phenotypic changes, AM(+/-) mice were viable and fertile; plasma and organ AM concentrations were almost half of those in AM(+/+) mice. With the administration of angiotensin II (Ang II) on a high-salt diet for 12 days, marked perivascular fibrosis and intimal hyperplasia were found in coronary arteries of Ang II/salt-treated AM(+/-) mice, without the AM upregulation that was observed in Ang II/salt-treated AM(+/+) mice. In AM(+/-) mice, Ang II/salt loading increased both urinary excretion of 8-hydroxydeoxyguanosine and isoprostane, markers of oxidative stress. Consistently, immunostaining of both p67phox and gp91phox, subunits of NAD(P)H oxidase and 3-nitrotyrosine, the metabolites of reactive oxygen species (ROS), and the generation of ROS measured by electron spin resonance spectroscopy apparently increased in the Ang II/salt-treated heart. These data suggested that the overproduction of oxidative stress might be involved in the cardiovascular changes induced by Ang II/salt loading.. The evidence presented supports the hypothesis that endogenous AM possesses a protective action against cardiovascular damage, possibly through the inhibition of oxidative stress production.

Topics: Adrenal Glands; Adrenomedullin; Angiotensin II; Animals; Blood Pressure; Cardiovascular Diseases; Coronary Vessels; Female; Genotype; Lung; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; NADH, NADPH Oxidoreductases; NADPH Oxidase 2; NADPH Oxidases; Peptide Fragments; Peptides; Phosphoproteins; Proteins; Reactive Oxygen Species; Sodium, Dietary; Time Factors; Tyrosine

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Humans; Mammals; Mice; Peptides; Receptors, Peptide

Topics: Adrenomedullin; Animals; Anti-Infective Agents; Antihypertensive Agents; Antineoplastic Agents; Apoptosis; Cardiovascular Diseases; Humans; Neoplasms; Peptides; Wound Healing