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The physiologic process of postnatal ductus arteriosus (DA) closure consists of vasoconstriction followed by vascular remodeling. We have recently reported that B-type natriuretic peptide (BNP), a potent vasodilator, also has anti-remodeling effects in pulmonary vasculature. However, its effects on DA have not been elucidated. We investigated whether BNP can prevent DA closure, and if so, the underlying mechanisms. Using in vivo studies, we examined effects of BNP (10 mg/kg, ip at birth) on DA closure in neonatal rats within 4 h after birth. We found that in control rats, the DA spontaneously closed at 4 h with a decreased DA diameter, enhanced intimal thickening, and luminal occlusion. BNP prevented DA closure at 4 h with a preserved DA diameter, attenuated intimal thickening, and preserved luminal patency. Ex vivo , BNP attenuated oxygen-induced vasoconstriction of isolated DA rings of newborn rats. These vasodilating effects were blunted by Rp-8-Br-PET-cGMPS, a cGMP inhibitor. In vitro , BNP inhibited angiotensin II (Ang II)-induced proliferation and migration of DA smooth muscle cells (DASMCs). BNP inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production and calcium overload in DASMCs. Finally, BNP inhibited Ang II-induced ERK1/2 activation. These in vitro effects were antagonized by Rp-8-Br-PET-cGMPS. In conclusion, BNP prevents postnatal DA closure by both vasodilation and anti-remodeling through the cGMP pathway. The mechanisms underlying anti-remodeling effects include anti-poliferation and anti-migration, with attenuation of mitochondrial ROS production and intracellular calcium and ERK1/2 signaling. Therefore, the BNP/cGMP pathway can be a promising therapeutic target for clinical management of DA patency., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Pulmonary vascular remodeling, characterized by disordered proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a pathognomonic feature of pulmonary arterial hypertension. Thus, pharmacologic strategy targeting on anti-proliferation and anti-migration of PASMCs may have therapeutic implications for PAH. Here we investigated the effects and underlying mechanisms of B-type natriuretic peptide (BNP) on angiotensin II (Ang II)-induced proliferation and migration of PASMCs. Proliferation and migration of PASMCs cultured from Wistar rats were induced by Ang II, with or without BNP treatment. In addition, potential underlying mechanisms including cell cycle progression, Ca(2+) overload, reactive oxygen species (ROS) production, signal transduction of MAPK and Akt, and the cGMP/PKG pathway were examined. We found that BNP inhibited Ang II-induced PASMCs proliferation and migration dose dependently. BNP could also arrest the cell cycle progression in the G0/G1-phase. In addition, BNP attenuated intracellular calcium overload caused by Ang II. Moreover, Ang II-induced ROS production was mitigated by BNP, with associated down-regulation of NAD(P)H oxidase 1 (Nox1) and reduced mitochondrial ROS production. Finally, Ang II-activated MAPKs and Akt were also counteracted by BNP. Of note, all these effects of BNP were abolished by a PKG inhibitor (Rp-8-Br-PET-cGMPS). In conclusion, BNP inhibits Ang II-induced PASMCs proliferation and migration. These effects are potentially mediated by decreased calcium influx, reduced ROS production by Nox1 and mitochondria, and down-regulation of MAPK and Akt signal transduction, through the cGMP/PKG pathway. Therefore, this study implicates that BNP may have a therapeutic role in pulmonary vascular remodeling., (© 2013 Wiley Periodicals, Inc.)

Objective: The study objective was to determine the association between preoperative B-type natriuretic peptide levels and outcome after total cavopulmonary connection. Surgical palliation of univentricular cardiac defects requires a series of staged operations, ending in a total cavopulmonary connection. Although outcomes have improved, there remains an unpredictable risk of early total cavopulmonary connection takedown. The prediction of adverse postoperative outcomes is imprecise, despite an extensive preoperative evaluation., Methods: We prospectively enrolled 50 patients undergoing total cavopulmonary connection. We collected preoperative clinical data, preoperative plasma B-type natriuretic peptide levels, and postoperative outcomes, including the incidence of an adverse outcome within 1 year of surgery (defined as death, total cavopulmonary connection takedown, or the need for cardiac transplantation)., Results: The mean age of patients was 4.7 years (standard deviation, 2.1 years). The median (interquartile range) preoperative B-type natriuretic peptide levels were higher in patients who required total cavopulmonary connection takedown and early postoperative mechanical cardiac support (n = 3; median, 55; interquartile range, 42-121) compared with those with a good outcome (n = 47; median, 11; interquartile range, 5-17) (P < .05). A preoperative B-type natriuretic peptide level of 40 pg/mL or greater was highly associated with the need for total cavopulmonary connection takedown (sensitivity, 100%; specificity, 93%; P < .05), yielding a positive predictive value of 50% and a negative predictive value of 100%. Higher preoperative B-type natriuretic peptide levels also were associated with longer intensive care unit length of stay, longer hospital length of stay, and increased incidence of low cardiac output syndrome (P < .05)., Conclusions: Preoperative B-type natriuretic peptide blood levels are uniquely associated with the need for mechanical support early after total cavopulmonary connection and total cavopulmonary connection takedown, and thus may provide important information in addition to the standard preoperative assessment., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: B-type natriuretic peptide is used in the diagnosis, risk stratification, and management of adult patients with cardiac disease. However, its use in infants with congenital heart disease has been limited, particularly in the perioperative period. Our objective was to determine the alterations in perioperative B-type natriuretic peptide levels and their predictive value on postoperative outcomes, in infants undergoing congenital heart surgery., Methods: We prospectively enrolled 115 patients: 24 with univentricular heart disease undergoing a modified Norwood procedure, 11 with d-transposition of the great arteries, 55 with hemodynamically important left-to-right shunt, and 25 with tetralogy of Fallot undergoing primary repair. Clinical data and B-type natriuretic peptide samples were collected before and 2, 12, and 24 hours after cardiopulmonary bypass. Univariate analysis and multivariate linear regression analysis were performed., Results: The perioperative B-type natriuretic peptide levels were lesion specific. Patients with d-transposition of the great arteries and univentricular heart disease had high preoperative B-type natriuretic peptide levels that decreased postoperatively, and those with hemodynamically important left-to-right shunts and tetralogy of Fallot had lower preoperative levels that increased during the first 12 hours postoperatively. The patients with univentricular heart disease with an adverse outcome had a significantly greater 24-hour B-type natriuretic peptide level than those without (P < .05). Those with hemodynamically important left to right shunts and an adverse outcome had a greater 12-hour B-type natriuretic peptide level than those without (P < .05). A 12-hour postoperative/preoperative ratio greater than 45 was 100% sensitive and 82% specific for an adverse outcome in the patients with tetralogy of Fallot., Conclusions: The perioperative changes in B-type natriuretic peptide levels and their ability to predict outcomes are lesion-specific. Characterization of these changes might be useful in caring for infants after congenital heart surgery., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: To determine whether B-type natriuretic peptide (BNP) predicts indomethacin responsiveness in premature neonates with patent ductus arteriosus (PDA)., Study Design: Premature neonates receiving indomethacin for an echocardiograhically large (diameter>1.5 mm) and clinically significant PDA were prospectively studied. All neonates underwent paired echocardiography and BNP measurements at baseline and 24 hours after each dose of indomethacin. After treatment, neonates who responded (with closed or insignificant PDA) and neonates who did not respond (with persistent significant PDA requiring surgical ligation) were compared., Results: Thirty-one premature neonates (mean gestational age, 30 weeks) underwent 119 paired echocardiography and BNP determinations. Mean BNP levels (1286+/-986 pg/mL) associated with significant PDA (n=96) were higher than those associated with closed or insignificant PDA (n=23; 118+/-124 pg/mL; P<.001). Twenty-three neonates responded and 8 neonates did not respond to indomethacin. Mean baseline BNP levels were higher in neonates who were non-responders (2234+/-991 pg/mL) than neonates who were responders (983+/-814 pg/mL; P=.001). A baseline BNP level>1805 pg/mL had a sensitivity rate of 88% and a specificity rate of 87% for predicting indomethacin non-responsiveness (P=.003)., Conclusions: High baseline BNP levels predict poor responses to indomethacin and the need for surgery in premature neonates with PDA., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Objectives: To determine B-type natriuretic peptide (BNP) levels in infants and children with acute lung injury (ALI), and to investigate associations between BNP levels and clinical outcome., Design: Prospective observational study., Subjects: After informed consent, plasma was collected from 48 pediatric patients on day 1 of ALI., Methodology: Plasma BNP levels were measured by immunoassay on day 1 of ALI in 48 pediatric patients. Associations between BNP levels and outcome were determined., Results: The mean PaO(2)/FiO(2) at the onset of ALI was 155 (+/-74) and BNP values ranged from 5 to 2,060 pg/ml with a mean of 109 (+/-311). BNP levels were inversely correlated with ventilator-free days (Spearman rho -0.30, P = 0.04), and positively correlated with exhaled tidal volume (Spearman rho 0.44, P = 0.02). BNP levels were higher in patients receiving inotropic support (n = 12) than patients not receiving inotropic support (n = 33, P = 0.02). BNP levels were correlated with PRISM III scores (Spearman rho 0.55, P < 0.001) and PELOD scores (Spearman rho 0.4, P = 0.006). Mortality for the cohort was 15%. BNP levels were higher in non-survivors (n = 7) than survivors (n = 41, P = 0.055)., Conclusions: BNP levels are elevated in children with ALI/ARDS early in the disease course, and increased levels are associated with worse clinical outcome.

Objective: The objective of the study was to determine perioperative B-type natriuretic peptide levels in infants and children undergoing bidirectional cavopulmonary anastomosis or total cavopulmonary connection, and the predictive value of B-type natriuretic peptide levels for outcome., Methods: Plasma B-type natriuretic peptide levels were measured before and 2, 12, and 24 hours after surgery in 36 consecutive patients undergoing bidirectional cavopulmonary anastomosis (n = 25) or total cavopulmonary connection (n = 11). B-type natriuretic peptide levels were evaluated as predictors of outcome., Results: B-type natriuretic peptide levels increased after surgery, peaking at 12 hours in most patients. In the bidirectional cavopulmonary anastomosis group, patients with 12-hour B-type natriuretic peptide > or = 500 pg/mL had a longer duration of mechanical ventilation (165 +/- 149 hours vs 20 +/- 9 hours, P = .004), longer intensive care unit stay (11 +/- 7 days vs 4 +/- 2 days, P = .001), and longer hospital stay (20 days +/- 12 vs 9 days +/- 5, P = .003). A 12-hour B-type natriuretic peptide > or = 500 pg/mL had a sensitivity of 80% and a specificity of 80% for predicting an unplanned surgical or transcatheter cardiac intervention, including transplantation (P = .03). In the total cavopulmonary connection group, preoperative B-type natriuretic peptide levels were highest in patients with total cavopulmonary connection failure compared with patients with a good outcome (88 +/- 46 pg/mL vs 15 +/- 6 pg/mL, P = .03)., Conclusion: Postoperative B-type natriuretic peptide levels predict outcome after bidirectional cavopulmonary anastomosis, and preoperative levels are greater in patients with both early and late total cavopulmonary connection failure compared with patients with a good outcome.

Objective: Extracorporeal life support is used in 3% to 8% of infants and children after cardiac surgery. B-type natriuretic peptide may have utility as a biomarker in these patients. The objective of this study was to investigate potential associations between changes in B-type natriuretic peptide during trials off extracorporeal life support and clinical outcome., Methods: Ten infants and children requiring extracorporeal life support after cardiac surgery were studied prospectively. Before separation from extracorporeal life support, a shunt was placed in the circuit, allowing for temporary trials off life support. Serum lactate, arterial-venous oxyhemoglobin saturation difference, and B-type natriuretic peptide levels were determined before each trial off life support and at the end of each trial off life support, and the ability to predict postoperative outcome from these data was evaluated., Results: During trials off extracorporeal life support, lactate, the arterial-venous oxyhemoglobin saturation difference, and B-type natriuretic peptide levels increased above pre-trial values (P < .05). Only the arterial-venous oxyhemoglobin saturation difference predicted successful separation from extracorporeal life support after a trial (P < .05). There were no associations between long-term outcome and alterations in lactate and the arterial-venous oxyhemoglobin saturation difference during the final trials off life support. However, an increase in B-type natruiretic peptide levels during the final trial off life support (trial/pre-trial ratio of >1) had a sensitivity of 80% and a specificity of 100% for predicting the need for an unplanned operation or death within 3 months (P < .05)., Conclusion: B-type natriuretic peptide determinations may be a useful tool for clinicians caring for infants and children requiring extracorporeal life support after cardiac surgery.