adrenomedullin and Cardiac-Output--Low

Plasma concentrations of the recently discovered hormones adrenomedullin (ADM), from vascular tissue, and brain natriuretic peptide (BNP), secreted by myocardium, are elevated in patients with heart failure. We tested the hypotheses that short-term increments in circulating levels of these hormones, within the pathophysiological range, would have biological effects and that the 2 hormone systems interact. Eight patients with heart failure (left ventricular ejection fractions <35%) received 4-hour infusions of BNP (3.0 pmol. kg(-1). min(-1)) alone, ADM (2.7 pmol. kg(-1). min(-1) and 5.4 pmol. kg(-1). min(-1) for 2 hours each) alone, ADM and BNP combined, and placebo. BNP and ADM infusions raised plasma levels of the respective peptide within the pathophysiological range. Arterial blood pressure fell (P<0.05) with all peptide infusions, but cardiac output was unchanged. Heart rate increased with ADM and combined infusions (P<0.01). Sodium excretion rose (P<0.05), and creatinine clearance was sustained during both BNP and combined infusions. Urine volume increased in response to BNP alone (P=0.02). Despite a >2-fold increase in plasma renin with both ADM and combined infusions (P<0.05), plasma aldosterone remained lower than time-matched placebo levels. Plasma noradrenaline was increased by combined, BNP, and higher dose ADM infusions (P<0.05). ADM suppressed plasma cGMP (P<0.05) and inhibited the plasma cGMP response to BNP (P<0.05). The vascular hormones ADM and BNP, produced by myocardium, at plasma concentrations within the pathophysiological range have hemodynamic, renal, and hormonal effects and measurable interactions in patients with heart failure.

Topics: Adrenomedullin; Aged; Blood Pressure; Cardiac Output, Low; Cross-Over Studies; Diuresis; Drug Combinations; Drug Interactions; Echocardiography; Heart Rate; Hormones; Humans; Male; Middle Aged; Natriuresis; Natriuretic Peptide, Brain; Peptides; Single-Blind Method; Vasodilator Agents

To assess the predictive value of atrial natriuretic peptide, β-type natriuretic peptide, copeptin, mid-regional pro-adrenomedullin (MR-proADM) and cardiac troponin I (cTn-I) as indicators of low cardiac output syndrome in children with congenital heart disease undergoing cardiopulmonary bypass (CPB).. After corrective surgery for congenital heart disease under CPB, 117 children (aged 10 days to 180 months) were enrolled in a prospective observational pilot study during a 2-year period. The patients were classified according to whether they developed low cardiac output syndrome. Biomarker levels were measured at 2, 12, 24, and 48 hours post-CPB. The clinical data and outcome variables were analyzed by a multiple logistic regression model.. Thirty-three (29%) patients developed low cardiac output syndrome (group 1) and the remaining 84 (71%) patients were included in group 2. cTn-I levels >14 ng/mL at 2hours after CPB (OR, 4.05; 95%CI, 1.29-12.64; P=.016) and MR-proADM levels>1.5 nmol/L at 24hours following CPB (OR, 15.54; 95%CI, 4.41-54.71; P<.001) were independent predictors of low cardiac output syndrome.. Our results suggest that cTn-I at 2hours post-CPB is, by itself, an evident independent early predictor of low cardiac output syndrome. This predictive capacity is, moreover, reinforced when cTn-I is combined with MR-proADM levels at 24hours following CPB. These 2 cardiac biomarkers would aid in therapeutic decision-making in clinical practice and would also enable clinicians to modify the type of support to be used in the pediatric intensive care unit.

Topics: Adrenomedullin; Analysis of Variance; Biomarkers; Cardiac Output, Low; Cardiopulmonary Bypass; Child; Child, Preschool; Female; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Male; Operative Time; Peptide Fragments; Pilot Projects; Postoperative Complications; Protein Precursors; Troponin

The role of biomarkers in asymptomatic diastolic dysfunction (DD) has not been investigated so far. The aim of the study was to evaluate the clinical associations and the diagnostic property of different biomarkers in patients with asymptomatic DD.. Within a population based observational study, healthy participants (50-85 years) with an LVEF ≥ 50 % and no cardiovascular risk factor were prospectively identified. Patients were classified as having either DD (grade ≥ 1, n = 103) or no DD (CON: n = 85). All patients underwent physical examination including medical history, six-minute-walk-testing, QoL (SF-36), comprehensive echocardiography and blood sampling to measure routine values and specified biomarkers (NTproBNP, MRproANP, GDF-15, MRproADM, CTproET1, CTproAVP).. In the DD-group plasma concentration of GDF-15 (p = 0,002), MRproADM (p < 0,001), and CTproAVP (p = 0,003) were significantly higher than in the CON-group. In contrast, NTproBNP (p = 0,390), MRproANP (p = 287), and CTproET1 (p = 0,393) did not differ. GDF-15, MRproADM and CTproAVP were significantly associated with the presence of DD. However, the significance of the seen associations was lost after multiple adjustments. NTproBNP, MRproANP, and MRproADM were significantly related to E / e' as a continuous measure of diastolic function. The significance of the seen associations was lost after multiple adjustments. In ROC analyses, none of the investigated biomarkers was able to relevantly improve the diagnosis of DD.. In patients with asymptomatic DD plasma concentrations of GDF-15, MRproADM and CT-proAVP were significantly higher when compared with controls. In contrast, NTproBNP, MRproANP and CTproET1 did not differ. After adjustment for age, sex, BMI and renal function, no significant association between DD or E / e' and different biomarkers could be observed. Furthermore, none of the investigated biomarkers was able to substantially improve the diagnosis of DD.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cardiac Output, Low; Endothelin-1; Female; Glycopeptides; Growth Differentiation Factor 15; Heart Failure, Diastolic; Humans; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Protein Precursors; Reference Values; Risk Factors

Low cardiac output syndrome (LCOS) remains a major perioperative complications in infants subjected to open-heart surgery with cardiopulmonary bypass (CPB). The present study investigated whether perioperative blood assessment of a potent vasoactive peptide namely adrenomedullin (AM) can predict the risk of LCOS.. We measured AM levels in 48 patients (LCOS: n = 9; controls: n = 39) undergone to open-heart surgery with CPB at five predetermined time points before, during and after the surgery. Clinical, laboratory and perioperative data were analyzed by a multiple logistic regression model.. AM significantly decreased (p < 0.01) during and after the surgical procedure exhibiting a dip at the end of the CPB. Multivariable analysis demonstrated significant correlations among LCOS, AM measured at the end of CPB (p < 0.001), and cooling duration (p < 0.05). AM at 27 pg/L cutoff achieved a sensitivity of 100% and a specificity of 64.1%, while cooling at 11-min cutoff combined a sensitivity of 55.6% and a specificity of 92.3% for LCOS prediction.. This study suggests that AM can constitute, alone or combined with standard parameters, a promising predictor of LCOS in infants subjected to open-heart surgery with CPB.

Topics: Adrenomedullin; Age Factors; Cardiac Output, Low; Cardiopulmonary Bypass; Case-Control Studies; Female; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Male; Postoperative Complications; Prognosis; Sensitivity and Specificity

We and other investigators have reported that short- and long-term treatment with adrenomedullin has beneficial effects in heart failure. This study examined the effects of long-term treatment with a vasopeptidase inhibitor plus adrenomedullin in a model of heart failure in rats and assessed potential mechanisms of action.. Dahl salt-sensitive rats aged 11 weeks were randomly divided into three groups: an omapatrilat group, an omapatrilat plus adrenomedullin group, and an untreated group. The effects of these treatments were evaluated after 7 weeks of treatment.. Omapatrilat monotherapy significantly improved left ventricular weight (LVW), blood pressure (BP), and central hemodynamics as compared with the untreated group. Omapatrilat decreased the gene expression levels of adrenomedullin and atrial natriuretic peptide (ANP) in the left ventricle. In addition, omapatrilat decreased mRNA levels of transforming growth factor-beta (TGF-beta), collagen I, collagen III, plasminogen activator inhibitor-1 (PAI-1), and intercellular adhesion molecule-1 (ICAM-1) in the left ventricle, and omapatrilat decreased perifibrosis score and myocyte area histologically. Omapatrilat plus adrenomedullin further improved LVW, central hemodynamics, and mRNA expression of TGF-beta, collagen I, collagen III, PAI-1, and ICAM-1 without changing BP. Omapatrilat plus adrenomedullin further reduced mRNA levels of ANP and adrenomedullin without altering levels of ANP or adrenomedullin in plasma. Interestingly, omapatrilat slightly decreased mRNA levels of subunits of NADPH oxidase, whereas omapatrilat plus adrenomedullin further decreased these variables.. Our results suggest that combined treatment with adrenomedullin and omapatrilat may be a new strategy for the management of heart failure, acting partly by inhibition of the extracellular matrix gene, adhesion molecule, antifibrinolysis, and oxidative stress production.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Collagen; Disease Progression; Drug Therapy, Combination; Gene Expression Regulation; Heart Ventricles; Intercellular Adhesion Molecule-1; Male; NADPH Oxidases; Plasminogen Activator Inhibitor 1; Pyridines; Rats; Rats, Inbred Dahl; RNA, Messenger; Thiazepines; Transforming Growth Factor beta

Adrenomedullin (ADM) release is enhanced in pheochromocytoma, chronic heart failure (HF), hypertension and renal diseases. This study was designed to test the hypothesis that ADM secretion increases also in response to acute stimuli, such as static effort and to compare plasma ADM response to this stimulus in patients with chronic HF and healthy persons. Eight male HF patients (II/III class NYHA) and eight healthy subjects (C) performed two 3-min bouts of static handgrip at 30% of maximal voluntary contraction, alternately with each hand without any break between the bouts. At the end of both exercise bouts and in 5 min of the recovery period, plasma ADM and catecholamines were determined. In addition, heart rate, blood pressure, and stroke volume (SV) were measured. The baseline plasma ADM and noradrenaline levels were higher, whilst plasma adrenaline and SV were lower in HF patients than in C group. The 1st exercise bout caused an increase in plasma ADM from 3.32 +/- 0.57 to 4.98 +/- 0.59 pmol l(-1) (p<0.01) in C and from 6.88 +/- 0.58 to 7.80 +/- 0.43 pmol x l(-1) (p<0.02) in HF patients. The 2nd exercise bout did not produce further elevation in plasma ADM and during recovery the hormone concentration declined to pre-exercise or lower values. There were no differences between groups in exercise-induced increases in plasma ADM. Plasma ADM correlated with SV (r = -0.419) and with noradrenaline concentrations (r = 0.427). It is concluded that static exercise causes the short-lasting increase in plasma ADM concentration which is similar in healthy subjects and in patients with mild heart failure.

Topics: Adrenomedullin; Aged; Blood Pressure; Cardiac Output; Cardiac Output, Low; Epinephrine; Hand Strength; Heart Rate; Humans; Male; Middle Aged; Norepinephrine; Osmolar Concentration; Peptides; Stroke Volume; Vascular Resistance

This study investigated whether cAMP signal transduction regulates coronary microvascular NO production after heart failure (HF), a state in which endothelial NO synthase (eNOS) is downregulated.. Myocardial microvessels were isolated. Nitrite, the hydration product of NO, from these vessels was quantified by using the Griess reaction. Forskolin (10(-4) mol/L), 8-bromo-cAMP (10(-2) mol/L), isoproterenol (10(-4) mol/L), or adrenomedullin (10(-6) mol/L) significantly increased nitrite release by 78+/-8, 84+/-14, 71+/-11, and 73+/-15 pmol/mg, respectively, from isolated microvessels from normal canine hearts (P<0.05 versus control). Bradykinin (10(-5) mol/L) and acetylcholine (10(-5) mol/L) increased nitrite release by 83+/-13 and 72+/-6 pmol/mg, respectively (P<0.05 versus control). However, NO production induced by bradykinin and acetylcholine was markedly reduced after HF (46+/-7 and 39+/-7 pmol/mg, respectively; P<0.05 versus normal), reflecting eNOS downregulation (55% in eNOS protein). Surprisingly, NO production in response to forskolin, 8-bromo-cAMP, isoproterenol, and adrenomedullin not only was preserved but also was substantially enhanced in these microvessels after HF (121+/-14, 124+/-21, 107+/-18, and 122+/-16 pmol/mg, respectively; P<0.05 versus normal group) and was associated with an upregulation of protein kinase B (220% increase in protein kinase B protein). All these responses were in an NO synthase or a protein kinase A inhibitor-blockable manner.. Our data indicate that cAMP signal transduction may be an important potential compensatory pathway to increase myocardial microvascular NO production after HF when eNOS is downregulated.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Acetylcholine; Adrenomedullin; Animals; Bradykinin; Cardiac Output, Low; Cardiotonic Agents; Cholinergic Agents; Colforsin; Coronary Vessels; Cyclic AMP; Dogs; Down-Regulation; Endothelium, Vascular; Isoproterenol; Nitric Oxide; Nitric Oxide Synthase; Peptides; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction

Endothelin-1 (ET-1) and adrenomedullin (ADM) are both produced in the arterial wall, but have opposing biological actions. Evidence from experimental animals suggests a functional interaction between ET-1 and ADM. We have tested this in humans. Small resistance arteries were obtained from gluteal biopsies taken from patients with chronic heart failure (CHF) due to coronary heart disease (CHD), or with CHD and preserved ventricular function. The contractile responses to big ET-1 and to ET-1 in both sets of vessels were studied in the absence (control) and presence of ADM at 20 pmol/l (low ADM) or 200 pmol/l (high ADM), using wire myography. ADM did not affect the conversion of big ET-1 into ET-1 in vessels from patients with either CHD or CHF. Low ADM did not alter the contractile response to ET-1 in vessels from patients with CHF. Low ADM was not tested in vessels from patients with CHD, but high ADM did not affect this response in arteries from these patients. High ADM did, however, significantly reduce the vasoconstrictor effect of ET-1 in vessels from patients with CHF. The maximum response, as a percentage of the response to high potassium, was 199% (S.E.M. 25%) in the control experiments (n=14), 205% (27%) in the low-ADM (n=7) studies and 150% (17%) in the high-ADM (n=6) experiments (P<0.001). Furthermore, the Hill coefficient increased from 0.57+/-0.05 in the absence of ADM to 1.16+/-0.15 in the high-ADM experiments, indicating that ADM at 200 pmol/l specifically antagonized one receptor type in vessels from patients with CHF. We conclude that there is a one-site receptor interaction between ADM and ET-1 that is specific for vessels from patients with CHF. This functional interaction between ADM and ET-1 in resistance arteries may be of pathophysiological importance in CHF.

Topics: Adrenomedullin; Analysis of Variance; Cardiac Output, Low; Case-Control Studies; Coronary Disease; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; Male; Myography; Peptides; Receptors, Endothelin; Vascular Resistance; Vasoconstriction; Vasodilator Agents

To investigate the relation between plasma adrenomedullin and the severity of diastolic dysfunction in patients with heart failure.. Prospective study.. University teaching hospital.. 77 patients (mean (SEM) age 66.3 (1.2) years; 75% male) who were being followed in the outpatient clinic after admission to hospital for acute heart failure.. Same day echocardiography with Doppler studies; determination of venous adrenomedullin concentration by radioimmunoassay.. Plasma adrenomedullin concentration and its correlation with systolic and diastolic function.. 31 patients (40%) had isolated diastolic dysfunction (ejection fraction > 50%), and the remaining 46 had a depressed ejection fraction (< 50%). Of the patients with diastolic dysfunction, 17 had a restrictive filling pattern. In all but one of these there was coexisting systolic failure (chi(2) = 10.7, p = 0.001). Patients with systolic heart failure and a restrictive filling pattern (group 1, n = 16) had a higher plasma adrenomedullin than those with systolic failure and a non-restrictive filling pattern (group 2, n = 30) or with isolated diastolic heart failure and a non-restrictive filling pattern (group 3, n = 30) (mean (SEM): 91.7 (21.1) v 38.4 (8.8) v 34.0 (6.5) pmol/l, both p < 0.05). All heart failure values were higher (p < 0.01) than the control value (6.9 (1.2) pmol/l). Ejection fraction and left ventricular dimensions were similar in groups 1 and 2. Plasma adrenomedullin did not correlate with ejection fraction or New York Heart Association functional class. Stepwise multiple regression analysis showed that the presence of a restrictive filling pattern was the only independent variable associated with a high plasma adrenomedullin.. Plasma adrenomedullin concentrations in patients with heart failure are determined by the presence of diastolic dysfunction, and are especially raised in the presence of a restrictive filling pattern. There appears to be no correlation with systolic dysfunction.

Topics: Acute Disease; Adrenomedullin; Aged; Biomarkers; Cardiac Output, Low; Diastole; Echocardiography; Female; Humans; Male; Peptides; Prospective Studies; Radioimmunoassay; Systole; Ventricular Dysfunction, Left

Adrenomedullin, a potent endogenous vasodilating and natriuretic peptide, may play an important role in the pathophysiology of chronic heart failure. Plasma levels of immunoreactive adrenomedullin were examined for prediction of prognosis in chronic heart failure.. Plasma levels of immunoreactive-ADM (ir-ADM) were measured by radioimmunoassay in 117 chronic heart failure patients with idiopathic or ischaemic cardiomyopathy (mean ejection fraction: 28 +/- 10%, in the NYHA functional class I/II/III/IV:8/73/29/7, and treated with ACE inhibitors and diuretics. Plasma levels of immunoreactive adrenomedullin were significantly increased in chronic heart failure patients by comparison to controls (618 +/- 293 pg x ml(-1) vs 480 +/- 135 pg x ml(-1), P=0.01). During the follow-up period (237 +/- 137 days) 14 cardiovascular deaths and four urgent cardiac transplantations occurred. In the univariate Cox model, immunoreactive adrenomedullin plasma levels were related to prognosis (P=0.004). A multivariate analysis including heart rate, systolic blood pressure, NYHA class, left ventricular ejection fraction, left ventricular echocardiographic end-diastolic diameter, plasma levels of immunoreactive adrenomedullin, endothelin-1, norepinephrine and atrial natriuretic peptide was performed: plasma levels of immunoreactive adrenomedullin (P=0.03), of endothelin-1 (P=0.0001), and systolic blood pressure (P=0.003) were significantly associated with outcome.. Our results suggest that elevated plasma levels of immunoreactive adrenomedullin are an independent predictor of prognosis in predominantly mild to moderate chronic heart failure treated by conventional therapy and provide additional prognostic information.

Topics: Adrenomedullin; Adult; Aged; Cardiac Output, Low; Chronic Disease; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peptides; Prognosis; Radioimmunoassay

Plasma adrenomedullin (AM), a novel hypotensive peptide, has been shown to increase in heart failure (HF). This study sought to examine the cardiovascular and renal effects of intravenous infusion of AM in HF rats and sham-operated rats (control) using two doses of AM that would not induce hypotension. Rat AM-(1-50) was intravenously administered at rates of 0.01 (low) and 0.05 (high) microg. kg body wt-1. min-1. Low-dose AM increased urine flow (+21% in HF, +29% in control) and urinary sodium excretion (+109% in HF, +123% in control) without changes in any hemodynamic variables. In contrast, high-dose AM slightly decreased mean arterial pressure (-3% in HF, -5% in control) and significantly increased cardiac output (+20% in HF, +12% in control). Infusion of high-dose AM resulted in significant decreases in right ventricular systolic pressure (-11%) and right atrial pressure (-28%) only in HF rats. High-dose AM significantly increased glomerular filtration rate (+10% in HF, +16% in control) and effective renal plasma flow (+25% in HF, +46% in control) as well as urine flow and urinary sodium excretion. In summary, intravenous infusion of AM exerted diuresis and natriuresis without inducing hypotension and, in the higher dose, produced beneficial hemodynamic and renal vasodilator effects in rats with compensated HF.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Blood Circulation; Cardiac Output, Low; Cardiovascular System; Glomerular Filtration Rate; Hemodynamics; Injections, Intravenous; Kidney; Male; Neurotransmitter Agents; Peptides; Pulmonary Circulation; Rats; Rats, Wistar; Renal Circulation

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