adrenomedullin and Heart-Defects--Congenital

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

In mammals, seven proprotein convertases (PCs) cleave secretory proteins after basic residues, and four of them are called furin-like PCs: furin, PC5, PACE4, and PC7. In vitro, they share many substrates. However, furin is essential during development since deficient embryos die at embryonic day 11 and exhibit multiple developmental defects, particularly defects related to the function of endothelial cells. To define the role of furin in endothelial cells, an endothelial cell-specific knockout (ecKO) of the Furin gene was generated. Newborns die shortly after birth, indicating that furin is essential in these cells. Magnetic resonance imaging revealed that ecKO embryos exhibit ventricular septal defects (VSD) and/or valve malformations. In addition, primary cultures of wild-type and ecKO lung endothelial cells revealed that ecKO cells are unable to grow. Growth was efficiently rescued by extracellular soluble furin. Analysis of the processing of precursors of endothelin-1 (ET-1), adrenomedullin (Adm), transforming growth factor β1 (TGF-β1), and bone morphogenetic protein 4 (BMP4) confirmed that ET-1, Adm, and TGF-β1 are in vivo substrates of endothelial furin. Mature ET-1 and BMP4 forms were reduced by ~90% in ecKO purified endothelial cells from lungs.

Topics: Adrenomedullin; Animals; Animals, Newborn; Bone Morphogenetic Protein 4; Cell Proliferation; Cells, Cultured; Embryo, Mammalian; Endothelial Cells; Endothelin-1; Female; Furin; Gene Knockout Techniques; Heart Defects, Congenital; Humans; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Transforming Growth Factor beta1

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

Brain injury is a major adverse event after cardiac surgery, especially when extracorporeal circuits are used. We evaluated whether cardiopulmonary bypass (CPB) affects cerebrovascular resistance and plasma concentrations of adrenomedullin (AM), a vasoactive peptide regulating cerebral blood flow.. We evaluated 50 infants (age <1 year) with congenital heart defects, matched according to a 2-year follow-up; 40 infants had no overt neurological injury, and 10 had brain damage. Blood samples were taken before surgery, during surgery before CPB, at the end of CPB, at the end of surgery, and at 12 h after surgery. Neurological outcome was evaluated before surgery, on postoperative day 7, and 2 years after surgery. We measured AM concentrations and used Doppler velocimetry to measure middle cerebral artery (MCA) pulsatility index (PI).. The highest MCA PI values and lowest AM concentrations occurred at the end of CPB and of the surgical procedure. Infants who developed abnormal neurologic sequelae had significantly (P <0.001 for both) higher MCA PI values and lower AM concentrations than patients with normal neurologic outcome at the end of CPB and after surgery. As single markers for predicting neurological abnormalities, AM (cutoff: 17.4 ng/L) achieved a sensitivity of 100% and a specificity of 73.0% and MCA PI (cutoff value: 1.8) a sensitivity of 100% and a specificity of 56.8%.. AM concentrations and MCA PI patterns change during CPB, mainly in infants with brain damage, and may be useful for early identification of infants at risk for brain damage.

Topics: Adrenomedullin; Cardiopulmonary Bypass; Case-Control Studies; Cerebrovascular Circulation; Female; Heart Defects, Congenital; Humans; Hypertension; Infant; Infant, Newborn; Male; Middle Cerebral Artery; Monitoring, Physiologic; Muscle Hypotonia; Predictive Value of Tests; Pulsatile Flow; Seizures; Syndrome

Topics: Adrenomedullin; Child; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension; Hypertension, Pulmonary; Male; Nitric Oxide

This study was designed to investigate the pathophysiological role of adrenomedullin (ADM) in congenital heart disease.. Forty-eight children with congenital heart disease confirmed by cardiac echocardiography and catheterization were studied. The patients were divided into three groups on the basis of hemodynamic indices measured during cardiac catheterization: high pulmonary blood flow with (group 1) or without (group 2) pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg) and a cyanosis group (without high pulmonary blood flow) (group 3). Six children who recovered from Kawasaki disease were used as a Control group. Plasma ADM levels were measured by radioimmunoassay.. The plasma ADM levels from the femoral vein were significantly higher than those from femoral artery in patients with congenital heart disease. The patients from group 1 and group 3 had higher plasma ADM levels (1.9 +/- 1.8 pmol/L and 2.4 +/- 1.3 pmol/L, respectively) than the controls (1.0 +/- 1.4 pmol/L; P < 0.01). Plasma ADM levels were significantly negatively correlated with mean systemic arterial pressure, oxygen saturation in mixed vein and oxygen saturation in systemic artery (r=-0.401, -0.562, -0.600, respectively; P < 0.01) but positively correlated with pulmonary vascular resistance (r=0.406; P < 0.01).. Plasma ADM levels are increased in congenital heart disease with high pulmonary blood flow and hypertension or with cyanosis. Plasma ADM levels are related to pulmonary arterial resistance and hypoxemia. Increased ADM levels may play roles in reducing the pulmonary arterial resistance and alleviating hypoxemia in these patients.

Topics: Adolescent; Adrenomedullin; Blood Pressure; Child; Child, Preschool; Female; Heart Defects, Congenital; Humans; Infant; Male; Peptides; Pulmonary Artery

To evaluate the effect and clinical significance of adrenomedulin (ADM) and urotensin-II (UII) on pulmonary hypertension (PH), by detecting their levels of patients with congenital heart disease and pulmonary hypertension.. 52 patients with congenital heart disease who had left-to-right shunt were selected randomly. 52 patients were divided three groups according to pulmonary artery systolic pressure (PASP): group A was not pulmonary hypertension (PASP < 30 mm Hg, n = 17); group B was mild pulmonary hypertension (PASP30-49 mm Hg, n = 18); group C was moderate and severe pulmonary hypertension (PASP > or = 50 mm Hg, n = 17). The plasma levels of ADM and UII were detected at each period by radioimmunoassay (RIA) method. It was analyzed the changes of their levels within pre-operation, 20 mins and 7 days post-operation and the interrelation between them and PASP.. (1) Following the severity degree of pulmonary hypertension, the plasma levels of ADM increase. There is positive correlation between PAP and plasma level of ADM (pre-operation r = 0.8012, P < 0.01; 20 min post-operation r = 0.6325, P < 0.01; 7 d post-operation r = 0.7126, P < 0.01). (2) Following the severity degree of pulmonary hypertension, the plasma levels of UII don't change obviously. There is no correlation between PAP and plasma level of UII (P > 0.05). (3) The plasma levels of ADM: group A (pre-operation: 33 pg/ml +/- 5 pg/ml, 20 mins post-operation: 29 pg/ml +/- 4 pg/ml, 7 d post-operation: 20 pg/ml +/- 3 pg/ml); group B (pre-operation: 44 pg/ml +/- 8 pg/ml, 20 mins post-operation: 40 pg/ml +/- 6 pg/ml, 7 d post-operation: 34 pg/ml +/- 4 pg/ml); group C (pre-operation: 60 pg/ml +/- 10 pg/ml, 20 mins post-operation: 58 pg/ml +/- 8 pg/ml, 7d post-operation: 38 pg/ml +/- 4 pg/ml). Plasma level of ADM of each group after CPB is lower than that of each group before operation. It is statistical difference only 7 days post-operation (group A q = 5.41, P < 0.01; group B q = 4.76, P < 0.01; group C q = 6.32, P < 0.01). (4) The plasma levels of UII: group A (pre-operation: 2.2 pmol/L +/- 0.5 pmol/L, 20 mins post-operation: 2.2 pmol/L +/- 0.44 pmol/L, 7 d post-operation: 2.2 pmol/L +/- 0.6 pmol/L); group B (pre-operation: 2.7 pmol/L +/- 0.6 pmol/L, 20 mins post-operation: 2.6 pmol/L +/- 0.6 pmol/L, 7 d post-operation: 2.6 pmol/L +/- 0.5 pmol/L); group C (pre-operation: 2.9 pmol/L +/- 0.6 pmol/L, 20 mins post-operation: 2.6 pmol/L +/- 0.7 pmol/L, 7 d post-operation: 2.8 pmol/L +/- 0.4 pmol/L). Compared with that of each group before operation, Plasma level of UII of each group after operation is no obvious difference (P > 0.05).. (1) Following the severity degree of pulmonary hypertension, the plasma levels of ADM increase. ADM plays an important role in the formation of pulmonary hypertension and restructure. (2) Following the severity degree of pulmonary hypertension, the plasma levels of UII don't change obviously. There is no correlation between PAP and plasma level of UII, but UII may be play an important role in the formation of pulmonary hypertension and restructure. (3) Measuring the levels of ADM may be a reliable method to follow the change of pulmonary pressure and worsening of pulmonary hypertension.

Topics: Adolescent; Adrenomedullin; Adult; Child; Child, Preschool; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Urotensins; Young Adult

To elucidate the effect of adrenomedullin (AM) on fluid homeostasis under cardiopulmonary bypass (CPB), we investigated the serial changes in plasma AM and other parameters related to fluid homeostasis in 13 children (average age, 28.2 months) with congenital heart disease during cardiac surgery under CPB. Arterial blood and urine samples were collected just after initiation of anesthesia, just before commencement of CPB, 10 min before the end of CPB, 60 min after CPB, and 24 h after operation. Plasma AM levels increased significantly 10 min before the end of CPB and decreased 24 h after operation. Urine volume increased transiently during CPB, which paralleled changes in AM. Simple regression analysis showed that plasma AM level correlated significantly with urinary vasopressin, urine volume, urinary sodium excretion, and plasma osmolarity. Stepwise regression analysis indicated that urine volume was the most significant determinant of plasma AM levels. Percent rise in AM during CPB relative to control period correlated with that of plasma brain natriuretic peptide (r = 0.57, P < 0.01). Our results suggest that AM plays an important role in fluid homeostasis under CPB in cooperation with other hormones involved in fluid homeostasis.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Cardiopulmonary Bypass; Child; Child, Preschool; Female; Heart Defects, Congenital; Homeostasis; Humans; Infant; Male; Natriuretic Peptide, Brain; Peptides; Vasopressins

Adrenomedullin is a novel hypotensive peptide originally isolated from human pheochromocytoma. Accumulating evidence suggests the possible involvement of adrenomedullin in the physiology of the pulmonary circulation and the pathophysiology of hypoxaemia. The aim of the present study was to investigate the pathophysiological significance of adrenomedullin in hypoxaemia caused by congenital cyanotic heart disease. Subjects were 16 patients with congenital cyanotic heart disease aged 0.8-10 years (Group C) and 12 age-matched control subjects (patients with coronary artery dilatation after Kawasaki disease; Group N). Plasma adrenomedullin concentrations were measured, using radioimmunoassay, in femoral venous, pulmonary arterial and pulmonary venous blood obtained during cardiac catheterization. Plasma adrenomedullin concentrations in Group C were significantly (3-fold) higher than those in Group N at all sampling sites. In Group C, plasma adrenomedullin concentrations in pulmonary venous blood were significantly lower than those in pulmonary arterial blood. Pulmonary uptake of adrenomedullin in Group C was significantly greater than that in Group N. Patients with congenital cyanotic heart disease showed elevated plasma adrenomedullin concentrations and an increased uptake of adrenomedullin in the pulmonary circulation, which may act to dilate pulmonary vessels and increase pulmonary blood flow to alleviate hypoxaemia. Intrinsically increased adrenomedullin levels may function as a compensatory mechanism for hypoxaemia in congenital cyanotic heart disease.

Topics: Adrenomedullin; Cardiac Catheterization; Child; Child, Preschool; Female; Femoral Vein; Heart Defects, Congenital; Hemodynamics; Humans; Hypoxia; Infant; Male; Peptides; Pulmonary Artery; Pulmonary Veins

Adrenomedullin is a newly identified peptide with profound hypotensive effects. We investigated perioperative adrenomedullin levels among patients with congenital heart disease with and without pulmonary hypertension.. Levels of plasma adrenomedullin, endothelin-1, and nitric oxide metabolites were measured in three groups: (1) low pulmonary flow (n=11); (2) high flow/low pulmonary arterial pressure (less than 60% systemic pressure) (n=9); and (3) high flow/high pressure (n=10). Samples were obtained preoperatively, on and off pump, and 3, 6, and 12 hours after bypass.. Adrenomedullin levels were highest in the low pulmonary flow group (189.7+/-15 pg/mL low flow versus 103.1+/-9.5 pg/mL high flow/low pulmonary and 139+/-17.5 pg/mL high flow/high pressure at 12 hours; p < or = 0.05). The arterial pressure/systemic pressure remained significantly lower in the high flow/low pulmonary pressure compared with the high flow/high pressure group (0.37+/-0.08 versus 0.62+/-0.11; p < 0.005). Perioperative endothelin-1 and nitric oxide levels remained low in the low pulmonary flow group but increased progressively in both high flow groups.. Circulating plasma adrenomedullin appears to affect baseline vascular tone in patients with intact endothelial function. It may interact with nitric oxide and endothelin-1 to help regulate blood pressure perioperatively in patients with congenital heart disease.

Topics: Adrenomedullin; Blood Pressure; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Peptides; Pulmonary Circulation; Risk Factors

To elucidate the pathophysiologic significance of adrenomedullin in pulmonary hypertension, we measured plasma adrenomedullin-like immunoreactivity (AM-LI) concentrations in blood samples obtained from various sites during cardiac catheterization by using radioimmunoassay in patients with pulmonary hypertension in comparison with patients without pulmonary hypertension. In patients with pulmonary hypertension, plasma AM-LI concentrations were significantly elevated and there was a significant uptake of AM-LI in pulmonary circulation, indicating the involvement of adrenomedullin in the cardiovascular regulation of pulmonary circulation in pulmonary hypertension.

Topics: Adolescent; Adrenomedullin; Child; Child, Preschool; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Peptides; Radioimmunoassay