adrenomedullin and Heart-Diseases

Polymorbid patients, diverse diagnostic and therapeutic options, more complex hospital structures, financial incentives, benchmarking, as well as perceptional and societal changes put pressure on medical doctors, specifically if medical errors surface. This is particularly true for the emergency department setting, where patients face delayed or erroneous initial diagnostic or therapeutic measures and costly hospital stays due to sub-optimal triage. A "biomarker" is any laboratory tool with the potential better to detect and characterise diseases, to simplify complex clinical algorithms and to improve clinical problem solving in routine care. They must be embedded in clinical algorithms to complement and not replace basic medical skills. Unselected ordering of laboratory tests and shortcomings in test performance and interpretation contribute to diagnostic errors. Test results may be ambiguous with false positive or false negative results and generate unnecessary harm and costs. Laboratory tests should only be ordered, if results have clinical consequences. In studies, we must move beyond the observational reporting and meta-analysing of diagnostic accuracies for biomarkers. Instead, specific cut-off ranges should be proposed and intervention studies conducted to prove outcome relevant impacts on patient care. The focus of this review is to exemplify the appropriate use of selected laboratory tests in the emergency setting for which randomised-controlled intervention studies have proven clinical benefit. Herein, we focus on initial patient triage and allocation of treatment opportunities in patients with cardiorespiratory diseases in the emergency department. The following five biomarkers will be discussed: proadrenomedullin for prognostic triage assessment and site-of-care decisions, cardiac troponin for acute myocardial infarction, natriuretic peptides for acute heart failure, D-dimers for venous thromboembolism, C-reactive protein as a marker of inflammation, and procalcitonin for antibiotic stewardship in infections of the respiratory tract and sepsis. For these markers we provide an overview on physiopathology, historical evolution of evidence, strengths and limitations for a rational implementation into clinical algorithms. We critically discuss results from key intervention trials that led to their use in clinical routine and potential future indications. The rational for the use of all these biomarkers, first, tackle diagnostic ambiguity and conse

Topics: Adrenomedullin; Algorithms; Atrial Natriuretic Factor; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Emergency Medicine; Fibrin Fibrinogen Degradation Products; Heart Diseases; Humans; Precision Medicine; Protein Precursors; Respiratory Tract Diseases; Switzerland; Triage; Troponin

Heart failure (HF) results from the impaired ability of heart to fill or pump out blood. HF is a common health problem with a multitude of causes and affects ~30 million people worldwide. Since ageing is a major risk factor for HF and as several treatment options are currently available to prolong the patients' survival, the number of affected patients is expected to grow. Even though traditional methods of assessment have been in use for managing HF, these are limited by time consuming and costly subjective interpretation and also by their invasive nature. Comparatively, biomarkers offer an objective and biologically relevant information that in conjunction with the patients' clinical findings provides optimal picture regarding the status of the HF patient and thus helps in diagnosis and prognosis. The current gold standard biomarkers for the diagnosis and prognosis of HF are B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP). Additional novel biomarkers (e.g., mid-regional pro atrial natriuretic peptide (MR-proANP), mid-regional pro adrenomedullin (MR-proADM), troponins, soluble ST2 (sST2), growth differentiation factor (GDF)-15 and galectin-3) can potentially identify different pathophysiological processes such as myocardial insult, inflammation and remodeling as the causes for the development and progression of HF. Different biomarkers of HF not only reflect the underlying mechanisms/pathways of HF and also its progression and also point specific therapy options. A multi-biomarker approach for personalized medical care is not too far fetched and such approach can greatly enhance diagnosis, prognostication, and therapy guidance for HF. In this review we describe the current status of HF biomarkers in clinical use and in laboratory research and the efforts aimed at the identification of novel biomarkers for HF.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Biomarkers; Disease Progression; Galectin 3; Heart Diseases; Humans; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Risk Factors

Adrenomedullin (AM) is a potent, long-lasting vasoactive peptide originally isolated from human pheochromocytoma. Since its discovery, serum and tissue AM expression have been shown to be increased in experimental models and in patients with cardiac hypertrophy, myocardial infarction and end-stage heart failure with several beneficial effects. Considerable evidence exists for a wide range of autocrine, paracrine and endocrine mechanisms for AM which include vasodilatory, anti-apoptotic, angiogenic, anti-fibrotic, natriuretic, diuretic and positive inotropic. Thus, through regulation of body fluid or direct cardiac mechanisms, AM has additive and beneficial effects in the context of heart disease. Notable molecular mechanisms of AM include cyclic adenosine monophosphate, guanosine-3',5'-monophosphate, PI3K/Akt and MAPK-ERK-mediated cascades. Given the endogenous and multifunctional nature of AM, we consider this molecule to have great potential in the treatment of cardiovascular diseases. In agreement, early experimental and preliminary clinical studies suggest that AM is a new and promising therapy for cardiovascular diseases.

Topics: Adrenomedullin; Animals; Cardiotonic Agents; Cell Communication; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Heart Diseases; Humans; Nucleotides; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

The main disadvantage of doxorubicin (DOX) is that it has cardiotoxic side effects. Our aim is to evaluate the cardioprotective effects of adrenomedullin (ADM) and to compare these effects with melatonin (MEL), it's cardioprotective effects are well known. Rats were divided into four groups: Control group (0.9% NaCl solution, intravenously), Doxorubicin group (45 mg/kg DOX, intravenously), Doxorubicin + Melatonin group (DOX + MEL, 10 mg/kg melatonin, intraperitoneally), Doxorubicin + Adrenomedullin group (DOX + ADM, 12 µg/kg adrenomedullin, intraperitoneally). A single dose of DOX was injected to the experimental groups on day 5, and a single dose of 0.9% NaCl solution was injected to the control group through the tail vein. The animals were anesthetized and ECG recordings were obtained on day 8. For the purpose of biochemical and histological analysis, cardiac tissue biopsy was obtained after ECG recordings. Compared to the control group, the DOX group had significantly increased duration of QRS complex, PR interval, QT interval and QTc interval. QRS complex, QT interval and QTc interval were prolonged with the administration of DOX and shortened with the administration of ADM. MEL weakened the toxic effects of DOX on the cardiac tissue and it is shown histologically. DOX increased interleukins (IL-1α, IL-6, IL-18), tumor necrosis factor-α (TNF-α), hypoxia-inducible factor 1-alpha (HIF-1α), malondialdehyde (MDA), nitric oxide (NO), creatine kinase myocardial band (CK-MB), and total oxidant status (TOS) levels in cardiac tissue, while reducing total antioxidant status (TAS), superoxide dismutase (SOD) and catalase (CAT) levels. MEL administration decreased the levels of CK-MB, MDA, IL-1α, IL-6, IL-18, NO, and TNF-α, whereas ADM only decreased IL-1α, IL-18, MDA and TNF-α levels. In summary, these results show that DOX has toxic effects on rat cardiac tissue which is documented histologically, electrocardiographically and biochemically. MEL alleviated histological damage and showed improvement on the several biochemical parameters of cardiac tissue. ADM brought several electrocardiographic and biochemical parameters closer to normal values.

Topics: Action Potentials; Adrenomedullin; Animals; Anti-Inflammatory Agents; Antioxidants; Cardiotoxicity; Cytokines; Disease Models, Animal; Doxorubicin; Heart Diseases; Heart Rate; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation Mediators; Male; Melatonin; Myocytes, Cardiac; Nitric Oxide; Oxidative Stress; Rats, Wistar

High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism.. We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates.. During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors.. High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Female; Germany; Glycopeptides; Heart Diseases; Humans; Incidence; Insulin Resistance; Male; Middle Aged; Peptide Fragments; Prediabetic State; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment; Risk Factors; Time Factors

Pulmonary hypertension (PH) causes mortality in systemic sclerosis (SSc). Pulmonary arterial hypertension (PAH) and left heart disease (LHD) are frequent causes of PH. Therefore, we studied PAH and LHD in early PH.. A total of 432 French Canadian SSc patients were studied retrospectively. All underwent screening for PH. We analysed clinical, serological, and radiographic data from 26 patients with early PH diagnosed by right heart catheterization (RHC). SSc patients with (n = 21) and without PH (n = 19) were prospectively re-evaluated by cardiac magnetic resonance imaging (MRI) and serial measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the haemodynamic biomarkers mid-regional pro-atrial natriuritic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM).. The most frequent cause of early PH was LHD (58%). PAH was seen in 34% of patients. No association was found between the type of PH and autoantibodies. Early LHD-PH, but not early PAH, was associated with lower NT-proBNP (p = 0.024), but MR-proANP and MR-proADM levels were higher in early LHD-PH than in patients without PH (p = 0.014 and p = 0.012, respectively). Only one patient had abnormal cardiac MRI explaining LHD-PH.. Early PH in SSc, like late PH, is heterogeneous and RHC is essential for determining its underlying cause. The most frequent cause of early PH was LHD. Levels of MR-proANP and MR-proADM, but not NT-proBNP, were increased in early LHD-PH, and may be more reliable than NT-proBNP as a biomarker of early PH in this subgroup of patients. Cardiac MRI did not explain LHD-PH. This study is the first to identify a high frequency of LHD in early PH correlating with normal NT-proBNP levels but increased MR-proANP and MR-proADM levels in SSc patients.

Topics: Adrenomedullin; Adult; Aged; Biomarkers; Canada; Female; Fibrosis; Heart Diseases; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Retrospective Studies; Scleroderma, Systemic

Although adrenomedullin is an indicator of cardiac dysfunction in haemodialysis patients, the clinical significance of midregional proadrenomedullin has not been elucidated. Objectives. We evaluated whether midregional proadrenomedullin reflects cardiac dysfunction, systemic inflammation or blood volume in haemodialysis patients.. Plasma midregional proadrenomedullin, C-reactive protein and delta body weight (indicating excessive blood volume), and two-dimensional as well as Doppler echocardiographic variables were measured just before haemodialysis in 70 patients with cardiovascular disease.. The median value of midregional proadrenomedullin was 1.93 nmol/l before haemodialysis, and these levels were significantly reduced following haemodialysis. Log [midregional proadrenomedullin] was positively correlated with left ventricular end-systolic volume index, diameter of inferior vena cava, C-reactive protein and delta body weight (r = 0.328, r = 0.421, r = 0.356, r = 0.364), and negatively with blood pressure, deceleration time of an early diastolic filling wave, pulmonary venous flow velocity ratio and left ventricular ejection fraction (r = -0.330, r = -0.324, r = -0.479, r = -0.373). Multivariate regression analysis revealed that pulmonary venous flow velocity ratio, diameter of inferior vena cava and C-reactive protein were independently related factors for midregional proadrenomedullin concentration.. Plasma midregional proadrenomedullin levels increase in association with cardiac dysfunction, systemic inflammatory status and systemic blood volume in haemodialysis patients with concomitant cardiovascular disease.

Topics: Adrenomedullin; Aged; Blood Volume; Body Weight; C-Reactive Protein; Echocardiography; Female; Heart Diseases; Humans; Inflammation; Kidney Diseases; Male; Middle Aged; Prospective Studies; Protein Precursors; Proteins; Renal Dialysis

There is evidence that adrenomedullin has autocrine or paracrine activities that oppose cardiac remodelling. However, it remains unclear whether it exerts those local functions in heart failure patients.. To investigate the relation between plasma and pericardial fluid concentrations of adrenomedullin and left ventricular haemodynamic variables.. Samples of plasma and pericardial fluid were obtained from 50 patients undergoing cardiac surgery. They were classified into two groups: group N (n = 27) with a left ventricular end diastolic volume index (LVEDVI) < or = 90 ml/m(2); and group R (n = 23) with LVEDVI > 90 ml/m(2). Plasma and pericardial fluid concentrations of total adrenomedullin (tAM) and mature adrenomedullin (mAM) were measured and related to the preoperative haemodynamic variables.. Pericardial fluid concentrations of mAM were much higher than the plasma concentration in both group N and group R (mean (SEM), 10.6 (1.7) v 3.3 (0.2) fmol/ml, p = 0.0001; and 21.2 (2.8) v 3.9 (0.3) fmol/ml, p < 0.0001, respectively). The ratio mAM/tAM in pericardial fluid was significantly higher than in plasma (0.56 (0.02) v 0.28 (0.02), p < 0.0001). Pericardial fluid concentrations of mAM, but not plasma concentrations, were significantly correlated with LVEDVI, left ventricular end systolic volume index, left ventricular ejection fraction, and left ventricular mass index (r = 0.60, 0.63, -0.54, and 0.47, respectively).. Raised pericardial fluid concentrations of mAM may reflect the actions of adrenomedullin as a local mediator against cardiac remodelling in patients with left ventricular dysfunction.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Aorta, Thoracic; Aortic Diseases; Biomarkers; Body Fluids; Female; Heart Diseases; Humans; Male; Middle Aged; Peptides; Pericardium; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Autocrine Communication; Cardiotonic Agents; Heart; Heart Diseases; Humans; Kidney; Kidney Diseases; Mice; Mice, Knockout; Mice, Transgenic; Paracrine Communication; Peptides

Calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion.

Topics: Adrenomedullin; Animals; Arteriovenous Shunt, Surgical; Blotting, Northern; Body Weight; Heart Diseases; Hemodynamics; Immunohistochemistry; Kidney; Kidney Cortex; Kidney Medulla; Male; Peptides; Radioimmunoassay; Rats; Rats, Wistar; Receptors, Adrenomedullin; Receptors, Peptide; RNA, Messenger

Adrenomedullin (AM) is a potent vasodilator peptide. Plasma AM levels are increased in heart diseases and in sepsis. Heart surgery under cardiopulmonary bypass (CPB) induces a systemic inflammatory response.. We measured plasma AM, cAMP (the second messenger of AM), C-reactive protein (CRP) and haemodynamic parameters in 29 patients undergoing elective open heart surgery, before, during and after anaesthesia and CPB as well as on the first morning after surgery.. Basal AM levels were higher than normal and correlated with systolic pulmonary pressure and pulmonary capillary pressure, but not with other haemodynamic parameters. AM increased during CPB and remained elevated 24 h after the start of surgery. Plasma cAMP increased only at the end of CPB. CRP was increased only in the last sample. At the end of CPB and at the end of surgery AM levels were higher in patients with basal ejection fraction<40% compared with those with ejection fraction >60% [456+/-386 vs 252+/-343 (P<0.03) and 832+/-781 vs 391+/-356 pg/ml (P<0.05), respectively].. We conclude that AM, as inflammation-related cytokines, increases during and after CPB, that cAMP response is unrelated to AM and that AM response is higher in those patients with worse basal ejection fraction.

Topics: Adrenomedullin; Anesthesia, General; Blood Pressure; C-Reactive Protein; Calcitonin Gene-Related Peptide; Cardiac Output; Cardiac Output, Low; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Central Venous Pressure; Cyclic AMP; Elective Surgical Procedures; Female; Heart Diseases; Heart Rate; Humans; Male; Middle Aged; Peptides; Pulmonary Artery; Pulmonary Wedge Pressure; Second Messenger Systems; Stroke Volume; Systemic Inflammatory Response Syndrome; Vascular Resistance; Vasodilator Agents

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Endothelium, Vascular; Heart Diseases; Humans; Hypertension; Kidney Diseases; Peptides; Vasodilator Agents

Adrenomedullin is a novel hypotensive peptide recently discovered in human pheochromocytoma. In the present study, we measured the plasma immunoreactive adrenomedullin of healthy subjects and patients with various diseases. Immunoreactive adrenomedullin was found to circulate in blood of the healthy subjects at a considerable concentration (3.3 +/- 0.3 fmol/ml). Plasma adrenomedullin was significantly increased in the patients with congestive heart failure (5.4 +/- 0.3 fmol/ml), essential hypertension (5.3 +/- 0.4 fmol/ml) and renal disease (4.9 +/- 0.4 fmol/ml). In healthy volunteers physical exercise significantly increased the plasma adrenomedullin concentration. The increase of adrenomedullin was inversely related to systolic blood pressure. These findings indicate that adrenomedullin participates in the circulation control in both physiological and diseased conditions. Although the exact origin of circulating adrenomedullin is still unknown, it is thought to be released rapidly by acute exercise, thereby regulating the cardiovascular system by its vasodilating activity.

Topics: Adrenomedullin; Antihypertensive Agents; Exercise; Heart Diseases; Humans; Hypertension; Kidney Diseases; Male; Peptides; Radioimmunoassay; Reference Values