adrenomedullin and Ventricular-Dysfunction--Left

Increase in adrenomedullin (ADM) plasma levels in congestive heart failure (HF) patients is due to many cardiac and systemic factors, particularly to greater fluid retention and to activation of sympathetic nervous system. Aim of this study was to assess the role of plasma ADM levels in HF patients treated by cardiac resynchronization therapy (CRT).. 50 patients, mean age 70 years, 34 male, New York Heart Association (NYHA) Class III-IV HF, left ventricular ejection fraction (LVEF) < 35%, underwent CRT. All patients were in sinus rhythm and with complete left bundle branch block (QRS duration 138 +/- 6 msec). A complete echoDoppler exam, blood samples for brain natriuretic peptide (BNP), and ADM were obtained from 2 to 7 days before implantation.. At 16 +/- 6 months follow-up, >or=1 NYHA Class improvement was observed in 38 patients. However, a >10% reduction in end-systolic dimensions (ESD) was reported in 21 patients (Group I): -16.6 +/- 1.8%; in the remaining 29 patients ESD change was almost negligible: -2.0 +/- 1.03% (Group II), P < 0.0001. The two groups were comparable for age, sex, cause of LV dysfunction, therapy, QRS duration at baseline, preimplantation ESD, LVEF%, and BNP. Significantly higher pre implantation ADM levels were present in Group I than in Group II (27.2 +/- 1.8 pmol/l vs 17.9 +/- 1.4, P = 0.0003).. Significantly higher ADM levels indicate a subgroup of patients in whom reverse remodeling can be observed after CRT. Patients with lower ADM basal values before CRT could represent a group in whom the dysfunction is so advanced that no improvement can be expected.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cardiac Pacing, Artificial; Female; Heart Failure; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

We sought to assess plasma concentrations of the amino (N)-terminal portion of pro-brain natriuretic peptide (N-BNP) and adrenomedullin for prediction of adverse outcomes and responses to treatment in 297 patients with ischemic left ventricular (LV) dysfunction who were randomly assigned to receive carvedilol or placebo.. Although neurohormonal status has known prognostic significance in heart failure, the predictive power of either N-BNP or adrenomedullin in chronic ischemic LV dysfunction has not been previously reported.. Plasma N-BNP and adrenomedullin were measured in 297 patients with chronic ischemic (LV) dysfunction before randomization to carvedilol or placebo, added to established treatment with a converting enzyme inhibitor and loop diuretic (with or without digoxin). The patients' clinical outcomes, induding mortality and heart failure events, were recorded for 18 months.. Above-median N-BNP and adrenomedullin levels conferred increased risks (all p < 0.001) of mortality (risk ratios [95% confidence intervals]: 4.67 [2-10.9] and 3.92 [1.76-8.7], respectively) and hospital admission with heart failure (4.7 [2.2-10.3] and 2.4 [1.3-4.5], respectively). Both of these predicted death or heart failure independent of age, New York Heart Association functional class, LV ejection fraction, previous myocardial infarction or previous admission with heart failure. Carvedilol reduced the risk of death or heart failure in patients with above-median levels of N-BNP or adrenomedullin, or both, to rates not significantly different from those observed in patients with levels below the median value.. In patients with established ischemic LV dysfunction, plasma N-BNP and adrenomedullin are independent predictors of mortality and heart failure. Carvedilol reduced mortality and heart failure in patients with higher pre-treatment plasma N-BNP and adrenomedullin.

Topics: Adrenergic beta-Antagonists; Adrenomedullin; Biomarkers; Carbazoles; Carvedilol; Chronic Disease; Heart Failure; Humans; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Peptides; Prognosis; Propanolamines; Risk Factors; Ventricular Dysfunction, Left

The main impact of myocardial infarction (MI) is shifting from acute mortality to adverse remodeling, chronic left ventricular (LV) dysfunction, and heart failure.. The aim of this study was to assess relationships between levels of circulating biomarkers and the function of LV after MI.. This was a prospective study of 80 patients with MI treated with percutaneous coronary intervention. Novel biomarkers including mid‑regional pro‑adrenomedullin (MR‑proADM), Notch‑1, syndecan‑4, myeloperoxidase, S‑100 protein, soluble ST‑2, as well as markers of inflammatory response and tissue injury: galectin‑3, C‑reactive protein (CRP), lactate dehydrogenase (LDH), and interleukin‑6 (IL‑6) were assessed in the acute phase of MI. Echocardiography was performed at baseline and 6 month Results: Adverse remodeling, defined as more than 20% increase in LV end‑diastolic volume, occurred in 26% of patients. Reverse remodeling (>10% reduction in LV end‑systolic volume) was observed in 52% of patients. In the univariable analysis, higher levels of MR‑proADM and LDH were predictors of adverse remodeling and higher levels of MR ‑proADM, LDH, CRP, and IL ‑6 were negative predictors of reverse remodeling. In the multivariable model, LDH remained an independent predictor of adverse remodeling (odds ratio [OR], 3.13; 95% CI, 1.42-8.18; P = 0.003) and a negative predictor of reverse remodeling (OR, 0.37; 95% CI, 0.17-0.8; P = 0.005).. LDH and MR ‑proADM seem to be promising biomarkers of adverse remodeling. On the other hand, higher levels of these biomarkers were associated with reduced chance of occurrence of favorable reverse remodeling in MI patients. However, further studies on larger groups of patients are necessary to confirm these data.

Topics: Adrenomedullin; Biomarkers; C-Reactive Protein; Humans; L-Lactate Dehydrogenase; Myocardial Infarction; Percutaneous Coronary Intervention; Prospective Studies; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

A potentially new marker of cardiovascular diseases - proadrenomedullin is the precursor of adrenomedullin, which is a multifunctional peptide hormone, produced in most of the tissues in response to cellular stress, ischemia, and hypoxia.. Ninety-three people, aged 51-79 years, were included in the study. Exclusion criteria were severe or corrected valvular disease, acute coronary syndrome, age ≥ 80 years, glomerular filtration rate < 45 ml/min, active infectious diseases, and cancer. The subjects were observed for adverse events, including reduced left ventricular ejection fraction (LVEF) by ≥ 10%, first incidence of atrial fibrillation (AF), and the necessity of using dopamine during hospitalization.. Use of pressure amines, occurrence of the first AF episode, and left ventricular dysfunction defined by a decrease in LVEF by at least 10% compared to the value before surgery were reported in the perioperative period. No death, sudden cardiac arrest with effective resuscitation, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, or heart failure were observed. Significantly higher proadrenomedullin concentration was observed in the group with reduced postoperative LVEF (1.68 vs. 0.77 nmol/l, P=0.005). The relative risk of a decrease in ejection fraction in the group of patients with proadrenomedullin concentration ≥ 0.77 nmol/l was more than twelve-fold higher (95% confidence interval 1.69-888.33; P=0.013) than in the group of patients with a concentration of proadrenomedullin < 0.77 nmol/l.. The higher baseline concentration of proadrenomedullin has a predominantly predictive value of postoperative left ventricular systolic dysfunction.

Topics: Adrenomedullin; Coronary Artery Bypass; Humans; Protein Precursors; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

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

Intermedin (IMD) is a cardiac peptide synthesized in a prepro form, which undergoes a series of proteolytic cleavages and amidations to yield the active forms of 47 (IMD(1-47)) and 40 amino acids (IMD(8-47)). There are several lines of evidence of increased IMD expression in rat models of cardiac pathologies, including congestive heart failure and ischaemia; however, its myocardial effects upon cardiac disease remain unexplored. With this in mind, we investigated the direct effects of increasing concentrations of IMD(1-47) (10(-10) to10(-6) m) on contraction and relaxation of left ventricular (LV) papillary muscles from two rat models of chronic pressure overload, one induced by transverse aortic constriction (TAC), the other by nitric oxide (NO) deficiency due to chronic NO synthase inhibition (NG-nitro-l-arginine, l-NAME), and respective controls (Sham and Ctrl). In TAC and l-NAME rats, exogenous administration of IMD(1-47) elicited concentration-dependent positive inotropic and lusitropic effects. By contrast, in Sham and Ctrl rats, IMD(1-47) induced a negative inotropic response without a significant effect on relaxation. Both TAC and l-NAME rats presented LV hypertrophy, elevated LV systolic pressures, preserved systolic function and elevated peroxynitrite levels. In the normal myocardium (Ctrl and Sham), IMD(1-47) induced a 3-fold increase of endothelial nitric oxide synthase (eNOS) phosphorylation at Ser(1177), indicating enhanced eNOS activity. In TAC and l-NAME rats, eNOS phosphorylation was increased at baseline, and its response to IMD(1-47) was blunted. In addition, the distinct myocardial response to IMD(1-47) was accompanied by distinct subcellular mechanisms. While in Sham rats the addition of IMD(1-47) induced the phosphorylation of cardiac troponin I due to NO/cGMP activation, in TAC rats IMD(1-47) induced phospholamban phosphorylation possibly associated with cAMP/protein kinase A activation. Therefore, we demonstrated for the first time a reversed myocardial response to IMD(1-47) neurohumoral stimulation due to impairment of eNOS activation in TAC and l-NAME rats. These results not only reveal the distinct myocardial effects and subcellular mechanisms for IMD(1-47) in normal and hypertrophic hearts, but also highlight the potential pathophysiological relevance of cardiac endothelial dysfunction in neurohumoral myocardial action.

Topics: Adrenomedullin; Animals; Blood Pressure; Enzyme Inhibitors; Hemodynamics; Male; Muscle Relaxation; Myocardial Contraction; Neuropeptides; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Papillary Muscles; Rats; Ventricular Dysfunction, Left; Ventricular Function

To evaluate whether plasma adrenomedullin is involved in the previously reported significant inverse correlation between left ventricular (LV) end-diastolic pressure (peak velocity of early transmitral flow/peak velocity of early diastolic mitral annular motion ratio [E/E' ]) and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus, mild-to-moderate renal function impairment and LV relaxation impairment (E'≤7.1 cm/s).. Plasma adrenomedullin concentration, E/E' and eGFR were assessed in 82 patients with type 2 diabetes.. Plasma adrenomedullin concentration was positively correlated with eGFR in patients with or without LV relaxation impairment, and inversely correlated with E/E' in patients with LV relaxation impairment. Multivariate linear regression analysis supported a role for plasma adrenomedullin in the association between E/E' and eGFR.. These results support the hypothesis that adrenomedullin modulates the interaction between the heart and kidneys in early subclinical cardiorenal syndrome in patients with type 2 diabetes mellitus.

Topics: Adrenomedullin; Aged; Cardio-Renal Syndrome; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Ventricular Dysfunction, Left

Quality of life (QoL) is impaired in diastolic heart failure. Little is known about QoL in diastolic dysfunction (DD) without heart failure.. In the DIAST-CHF observational study, outpatients with risk factors for or a history of heart failure were included. In a cross-sectional analysis, we classified patients with preserved systolic function as having normal diastolic function (N, n = 264) or DD without (DD-, n = 957) or with (DD+, n = 321) elevated filling pressures according to echocardiography. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire.. Short Form 36 physical function (SF-36-PF) was worse in DD+ (mean ± SD 67.2 ± 25.6) than in DD- (76.2 ± 22.7, P < .05) than in N (mean ± SD 81.1 ± 23.5, P < .01). Other physical dimensions and the physical component score were also lower in DD, whereas the mental component score did not differ. The SF-36-PF correlated weakly with echocardiographic indicators of diastolic function. In multivariate linear regression controlling for age, sex, body mass index, depressiveness as assessed by Patient Health Questionnaire 9, N-terminal probrain-type natriuretic peptide, and midregional proadrenomedullin (MR-proADM), individual echocardiographic parameters or grade of DD was not independently associated with SF-36-PF, whereas the presence of DD+ was. Both N-terminal probrain-type natriuretic peptide and MR-proADM were independently associated with SF-36-PF, with MR-proADM showing the stronger association.. Physical dimensions of QoL are reduced in DD. Impaired SF-36-PF is only weakly associated with DD per se but rather seems to be contingent on the presence of elevated filling pressures. Biomarkers are more strongly and independently associated with SF-36-PF and may be more adequate surrogate markers of QoL in DD than echocardiographic measurements.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cross-Sectional Studies; Echocardiography; Female; Heart Failure, Diastolic; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Protein Precursors; Quality of Life; Risk Factors; Ventricular Dysfunction, Left

Our previous study showed elevation of plasma adrenomedullin (ADM) during static handgrip in patients with heart failure (HF). It is hypothesized that ADM increases with left ventricle dysfunction during handgrip and thus plays a compensatory role. In the present study pre-ejection period (PEP) and left ventricular ejection time (LVET) were used to assess cardiac performance in 24 male HF patients (II/III class NYHA) during two 3-min bouts of handgrip at 30% of maximal voluntary contraction (MVC) performed alternately with each hand without any break between the bouts. Plasma ADM, noradrenaline (NA), adrenaline (A), heart rate (HR), blood pressure (BP) and stroke volume (SV) were determined. During handgrip plasma ADM, NA, A, HR, BP, PEP/LVET increased, PEP was prolonged and LVET shortened. The increases in plasma ADM correlated with changes in: PEP (r = -0.881), LVET (r = 0.713), PEP/LVET (r = -0.769), SV (r = 0.836), diastolic BP (r = 0.700), total peripheral resistance (TPR) (r = 0.718) and noradrenaline (r = 0.756). The study demonstrated that in HF patients changes in plasma ADM during handgrip are related to cardiac performance.

Topics: Adrenomedullin; Blood Pressure; Epinephrine; Exercise Test; Hand Strength; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Norepinephrine; Radioimmunoassay; Severity of Illness Index; Stroke Volume; Systole; Time Factors; Ventricular Dysfunction, Left

Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers.. A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminometric assay.. Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p

Topics: Adrenomedullin; Aged; Biomarkers; Chronic Disease; Cross-Sectional Studies; Endothelin-1; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Ventricular Dysfunction, Left

In ambulatory patients with coronary artery disease (CAD) we aimed to evaluate the diagnostic performance of mid-regional pro-adrenomedullin (MR-proADM) for the detection or exclusion of impaired left ventricular ejection fraction (LVEF).. MR-proADM levels were measured in blood samples taken from 102 outpatients with CAD classified according to the New York Heart Association (NYHA) and Canadian Cardiovascular society (CCS) I-II. Increased levels of MR-proADM correlated with impaired LVEF (r=-0.21, p=0.046). The optimal threshold of MR-proADM for identification of impaired LVEF <50% was 0.54 nmol/L with an area under the ROC curve (AUC) of 0.64 (p=0.06). In univariate and multivariate calculation, MR-proADM >0.54 nmol/L remained associated with left ventricular dysfunction even after adjusting for age and gender. The negative predictive value (NPV) for MR-proADM

Topics: Adrenomedullin; Area Under Curve; Biomarkers; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Protein Precursors; Risk Factors; ROC Curve; Sensitivity and Specificity; Ventricular Dysfunction, Left

The aim of this study was to evaluate the plasma levels of the adrenomedullin (ADM) and atrial natriuretic peptide (ANP) in adult and pediatric patients with congestive heart failure (CHF) of various etiologies and to investigate their relations with haemodynamic variables e.g. echocardiographic left ventricular ejection fraction (LVEF) and fractional shortening (FS).. The study was made in 38 adult and 21 pediatric patients with CHF of various etiologies and compared with 15 adult and 10 pediatric normal healthy controls. Patients with CHF were classified according to the New York Heart Association (NYHA) functional classification into grades II to IV in adult patients and into grade IV in all pediatric patients. ADM and ANP plasma levels were determined prior to the treatment with enzyme immunoassay.. A statistically significant difference in the plasma levels of ADM and ANP were found between pediatrics and adult patients and corresponding healthy controls. Their levels were progressively increased with severity of NYHA class in adult patients. We found a significant positive correlation between plasma levels of each of ADM and ANP and pulse rate, systolic and diastolic blood pressure; and a significant negative correlation between their plasma levels and echocardiographic LVEF and FS. A significant positive correlation between plasma levels of ADM and ANP in both pediatrics and adult patients were also found.. Plasma levels of ADM and ANP increased in adult and pediatric patients with CHF irrespective of the cause. They were positively correlated with each other and negatively correlated with LVEF and FS. These findings might have important clinical implications in that a noninvasive blood test may be used to identify high-risk subjects for HF for more invasive procedures.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Child; Child, Preschool; Female; Heart Failure; Humans; Infant; Male; Middle Aged; Pulse; Ventricular Dysfunction, Left; Ventricular Function, Left

It is expected that mesenchymal stem cells (MSCs) will be a cell source for cardiac reconstruction because of their differentiation potential and ability to supply growth factors. However, poor viability at the transplanted site often hinders the therapeutic potential of MSCs. Here, in a trial designed to address this problem, a non-viral carrier of cationized polysaccharide is introduced for genetic engineering of MSCs. Spermine-introduced dextran of cationized polysaccharide (spermine-dextran) was internalized into MSCs by way of a sugar-recognizable receptor to enhance the expression level of plasmid deoxyribonucleic acid (DNA). When genetically engineered by the spermine-dextran complex with plasmid DNA of adrenomedullin (AM), MSCs secreted a large amount of AM, an anti-apoptotic and angiogenic peptide. Transplantation of AM gene-engineered MSCs improved cardiac function after myocardial infarction significantly more than MSCs alone. Thus, this genetic engineering technology using the non-viral spermine-dextran is a promising strategy to improve MSC therapy for ischemic heart disease.

Topics: Adrenomedullin; Animals; Cations; Dextrans; DNA; Drug Carriers; Genetic Enhancement; Genetic Vectors; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myocardial Infarction; Rats; Rats, Inbred Lew; Recovery of Function; Transfection; Treatment Outcome; Ventricular Dysfunction, Left; Viruses

Adrenomedullin (ADM) is an endogenous peptide with favorable hemodynamic effects in vivo. In this study, we characterized the direct functional effects of ADM in isolated preparations from human atria and ventricles. In electrically stimulated human nonfailing right atrial trabeculae, ADM (0.0001-1 micromol/l) increased force of contraction in a concentration-dependent manner, with a maximal increase by 35 +/- 8% (at 1 micromol/l; P < 0.05). The positive inotropic effect was accompanied by a disproportionate increase in calcium transients assessed by aequorin light emission [by 76 +/- 20%; force/light ratio (DeltaF/DeltaL) 0.58 +/- 0.15]. In contrast, elevation of extracellular calcium (from 2.5 to 3.2 mmol/l) proportionally increased force and aequorin light emission (DeltaF/DeltaL 1.0 +/- 0.1; P < 0.05 vs. ADM). Consistent with a cAMP-dependent mechanism, ADM (1 micromol/l) increased atrial cAMP levels by 90 +/- 12%, and its inotropic effects could be blocked by the protein kinase A (PKA) inhibitor H-89. ADM also exerted positive inotropic effects in failing atrial myocardium and in nonfailing and failing ventricular myocardium. The inotropic response was significantly weaker in ventricular vs. atrial myocardium and in failing vs. nonfailing myocardium. In conclusion, ADM exerts Ca(2+)-dependent positive inotropic effects in human atrial and less-pronounced effects in ventricular myocardium. The inotropic effects are related to increased cAMP levels and stimulation of PKA. In heart failure, the responsiveness to ADM is reduced in atria and ventricles.

Topics: Adrenomedullin; Cardiotonic Agents; Dose-Response Relationship, Drug; Heart Atria; Humans; Myocardial Contraction; Ventricular Dysfunction, Left

Increased circulating adrenomedullin (AM) concentration has been reported in congestive heart failure (HF) and considered as a possible marker of cardiac dysfunction.. The study was undertaken to assess the relationship between circulating AM concentration and left ventricular (LV) functional state, estimated by echo-Doppler techniques in patients with mild to moderate HF and different degrees of LV dysfunction.. Plasma AM, B-type natriuretic peptide (BNP), and N-terminal (NT) proBNP levels were measured in 55 patients with HF (New York Heart Association [NYHA] I n = 8, II n = 26, III n = 21) and in 20 controls; dP/dt was calculated by the Doppler tracing of the mitral regurgitation jet.. The study was completed in 51 patients. Adrenomedullin levels were higher than in controls (19.2 +/- 1.4 vs. 13.3 +/- 0.7, p < 0.005) and elevated in proportion to NYHA functional class. B-type natriuretic peptide and NT-proBNP were 344 +/- 67 vs. 12 +/- 2 pg/ml and 2196 +/- 623 vs. 52 +/- 4 pg/ml, respectively (p < 0.0001); dP/dt was better related to AM (r = 0.582, p < 0.001) than to the other peptides. Adrenomedullin was significantly (p < 0.001) different between patients grouped according to the dP/dt cut-off predictive of event-free survival.. The combination of depressed contractility and increased AM may provide a clue for further characterization of the severity of LV dysfunction in HF, independent of baseline LV ejection fraction.

Topics: Adrenomedullin; Aged; Biomarkers; Case-Control Studies; Echocardiography, Doppler; Echocardiography, Transesophageal; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peptides; Predictive Value of Tests; Probability; Prognosis; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Survival Analysis; Ventricular Dysfunction, Left

Levels of adrenomedullin (AM), a potent vasodilatory peptide, have been shown to increase in the early stage of acute myocardial infarction (AMI). The purpose of this study was to determine whether coronary sinus-aortic step-up of mature forms of AM is accelerated in patients with AMI after reperfusion.. The subjects were 29 consecutive patients with a first episode of anterior AMI and 10 normal controls. All patients with AMI underwent balloon reperfusion therapy within 24 h after symptom onset. Plasma levels of two molecular forms of AM (an active, mature form [AM-m] and an intermediate, inactive glycine-extended form [AM-Gly]) in the aorta and coronary sinus (CS) were measured by specific immunoradiometric assay after reperfusion.. Plasma levels of AM-m and AM-Gly in the aorta and CS were higher in AMI patients than in controls. CS-aortic step-up of AM-m, which is an index of myocardial production of AM-m, was significantly greater in AMI patients than in controls (1.7 +/- 1.4 vs. 0.4 +/- 0.3 pmol/L, P < 0.01). However, there was no significant difference in CS-aortic step-up of AM-Gly (P = 0.30). AMI patients with left ventricular dysfunction (n = 10) had a significantly higher CS-aortic AM-m step-up than AMI patients without left ventricular dysfunction (n = 19). AM-m in the aorta and CS negatively correlated with the left ventricular ejection fraction (r = -0.50, r = -0.48, P < 0.01).. Myocardial synthesis of AM-m is accelerated in patients with reperfused AMI, especially in patients with critical left ventricular dysfunction. Increased myocardial synthesis of active AM may protect against cardiac dysfunction, myocardial remodeling, or both after the onset of AMI.

Topics: Adrenomedullin; Aged; Coronary Circulation; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Peptides; Up-Regulation; Ventricular Dysfunction, Left

Plasma adrenomedullin (AM) reflects cardiac dysfunction and predicts survival after myocardial infarction. The present study was designed to investigate whether the mature AM (mAM) reflects status of cardiac function, systemic blood volume, or inflammation in hemodialysis patients with cardiovascular disease, and whether mortality and additional cardiovascular morbidity can be predicted by mAM.. Plasma levels of mAM, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), norepinephrine (NE), and C-reactive protein (CRP) before hemodialysis were measured in 67 chronic hemodialysis patients with cardiovascular disease, along with 2-dimensional and Doppler echocardiographic variables.. By univariate regression analysis, mAM correlated negatively with pulmonary venous flow velocity ratio and left ventricular (LV) ejection fraction and positively with LV inflow velocity ratio, LV end-diastolic, end-systolic volume indexes, plasma CRP level, and removal fluid volume by ultrafiltration. Multivariate stepwise regression analysis revealed that mAM reflected all variables better than log [ANP], log [BNP], and log [NE]. During a 1-year follow-up period, 7 patients died and 8 had additional cardiovascular events. Event-free Kaplan-Meier curves based on the median mAM (4.55 pmol/L) showed that patients with high plasma mAM levels had higher mortality and morbidity than those with low plasma mAM levels (P = 0.0056). By Cox multivariate proportional hazard analysis, mAM was related to mortality and morbidity [hazard ratio (HR) 4.55, 95% CI 1.2-16.8, P= 0.023).. Plasma mAM reflects cardiac dysfunction, excessive blood volume, and inflammation better than ANP, BNP, and NE, resulting in a predictor of mortality and cardiovascular morbidity in hemodialysis patients with cardiovascular disease.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Volume; C-Reactive Protein; Female; Humans; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Peptides; Predictive Value of Tests; Renal Dialysis; Ventricular Dysfunction, Left

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

We examined the effects of TCV-116, an angiotensin II type 1 receptor antagonist, on endothelial-cell nitric oxide synthase (eNOS), inducible NOS (iNOS), and adrenomedullin (ADM) expression in the left ventricle (LV) and evaluated these relation to myocardial remodeling in failing heart of Dahl salt-sensitive hypertensive rats (DS) fed a high-salt diet. TCV-116 (DSHF-T, 5 mg/kg/day, subdepressor dose) or vehicle (DSHF-V) were given from left ventricular hypertrophy to heart failure stage for 7 weeks. Markedly increased left ventricular end-diastolic diameter and reduced fractional shortening in DSHF-V was significantly ameliorated in DSHF-T. The eNOS mRNA and protein in the LV was significantly suppressed in DSHF-V compared with control rats (DR-C), and significantly increased in DSHF-T compared with DSHF-V. The iNOS mRNA and protein, ADM mRNA and immunoreactive ADM contents, and type I collagen mRNA in the LV were significantly increased in DSHF-V compared with DR-C, and significantly decreased in DSHF-T compared with DSHF-V. DSHF-V showed a significant increase of the wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by TCV-116. In conclusion, myocardial remodeling and heart failure in DS rats fed a high-salt diet were significantly ameliorated by a subdepressor dose of TCV-116, which may be due to a increased in eNOS and a decreased in iNOS mRNA and protein expression in the LV. Moreover, the ADM mRNA and immunoreactive ADM contents are upregulated in failing heart of DS rats fed a high-salt diet, and increased ADM expression may have a role in the defense mechanism against further cardiac dysfunction and impaired myocardial remodeling.

Topics: Adrenomedullin; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Disease Models, Animal; Endothelium, Vascular; Heart Failure; Hypertrophy, Left Ventricular; Immunohistochemistry; Male; Myocardial Reperfusion; Myocardium; Nitric Oxide; Organ Size; Peptides; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetrazoles; Ventricular Dysfunction, Left; Ventricular Remodeling

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 is a recently discovered endogenous peptide with hypotensive and natriuretic actions in normal animals. Circulating and ventricular adrenomedullin are elevated in congestive heart failure, suggesting a possible role in the pathophysiology of this disease. No studies have previously examined the effects of adrenomedullin in heart failure.. Eight sheep with pacing-induced heart failure received human adrenomedullin(1-52) at 10 and 100 ng x kg(-1) x min(-1) I.V. for 90 minutes each. Compared with vehicle control data, adrenomedullin increased plasma cAMP (high dose, P<.05) in association with dose-dependent falls in calculated peripheral resistance (13 mm Hg x L(-1) x min(-1), P<.001), mean arterial pressure (9 mm Hg, P<.001), and left atrial pressure (5 mm Hg, P<.001) and increases in cardiac output (0.5 L/min, P<.001). Adrenomedullin increased urine sodium (threefold, P<.05), creatinine (P<.05) and cAMP excretion (P<.01), creatinine clearance (P<.05), and renal production of cAMP (P<.05), whereas urine output was maintained during infusion and raised after infusion (P<.05). Adrenomedullin reduced plasma aldosterone levels (P<.05), whereas plasma atrial and brain natriuretic peptide concentrations were unchanged during infusion and rose after infusion (P<.01 and P<.05, respectively). Plasma catecholamine, cortisol, renin, calcium, and glucose concentrations were not significantly altered.. Adrenomedullin reduced ventricular preload and afterload and improved cardiac output in sheep with congestive heart failure. Despite the clear fall in arterial pressure, adrenomedullin increased creatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomedullin in the regulation of pressure and volume in heart failure and raise the possibility of a new therapeutic approach to this disease.

Topics: Adrenomedullin; Animals; Blood Glucose; Blood Pressure; Calcium; Cardiac Output; Creatinine; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Epinephrine; Female; Heart Failure; Hemodynamics; Hydrocortisone; Norepinephrine; Pacemaker, Artificial; Peptides; Potassium; Renal Circulation; Sheep; Vasodilator Agents; Ventricular Dysfunction, Left

Plasma adrenomedullin (AM) levels are reportedly increased in heart failure, but whether the cardiac production and secretion of AM is increased in heart failure remains unknown. To investigate the sites of production and secretion of AM in heart failure, we measured plasma AM levels and peptide and mRNA levels of AM in various tissues in rats with heart failure. We also examined whether the heart actually secretes AM into the circulation in patients with heart failure. We measured plasma and tissue AM levels by specific radioimmunoassay and AM mRNA by Northern blot analysis in rats with heart failure produced by aortocaval fistula. We also measured plasma AM levels in the coronary sinus and aorta in patients with left ventricular dysfunction before and after rapid right ventricular pacing. The increase in plasma AM levels in heart failure rats correlated with ventricular weight. Tissue AM levels were increased in the heart and lungs but not in the kidneys or adrenals of rats with heart failure. Similarly, tissue AM mRNA levels were also increased in the heart and lungs of heart failure rats. Plasma AM levels were higher in the coronary sinus than in the aorta in patients with left ventricular dysfunction. Rapid right ventricular pacing increased plasma atrial natriuretic peptide but not AM. These results suggest that plasma AM levels are increased in heart failure in proportion to the severity of heart failure and that cardiac production and secretion of AM is increased in heart failure rats. The lung may be another site for increased production of AM in heart failure rats. Human failing heart actually secretes AM into the circulation, and the regulation of AM secretion appears to differ from that of atrial natriuretic peptide.

Topics: Adrenal Glands; Adrenomedullin; Animals; Female; Heart; Heart Failure; Humans; Kidney; Lung; Male; Middle Aged; Myocardium; Organ Size; Peptides; Rats; Rats, Wistar; Reference Values; Regression Analysis; Ventricular Dysfunction, Left; Ventricular Function, Right