Angiopoietin-2 predicts morbidity in adults with Fontan physiology

Shirali, Aditya S.; Lluri, Gentian; Guihard, Pierre; Conrad, Miles; Kim, Helen; Pawlikowska, Ludmila; Boström, Kristina I.; Iruela‐Arispe, M. Luisa; Aboulhosn, Jamil

doi:10.1038/s41598-019-54776-w

Cited by 13 publications

(13 citation statements)

References 31 publications

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“…We found no within-subject differences in plasma concentrations of BMP9 GFD, BMP10 proprotein, or BMP9/10 GFD across different sampling sites, in agreement with a recent report regarding BMP9 GFD (11) and failing to support the idea that ALK1 ligands are the “hepatic factor” required to prevent PAVMs. However, it remains possible that liver-derived BMP9 or BMP9/10 proproteins (not assayed) may exhibit site-dependent concentration differences, or that enzymes required to cleave proproteins are unavailable in the Glenn circulation.…”

Section: Discussionsupporting

confidence: 88%

“…Diagnoses in 38 controls [mean age 5.8 years (4 months - 12.6 years); 21 males, 17 females] included: small shunt lesions (21), repaired forms of congenital heart disease with two-ventricle physiology (11), vascular stenosis (5), valvar obstructive lesions (2), and hypertrophic cardiomyopathy (1). Primary cardiac diagnoses in 9 Glenn cases [mean age 2.9 years (range 22 months to 5.1 years); 7 males, 2 females] included: variants of hypoplastic left heart syndrome (5); pulmonary atresia with intact ventricular septum (2); double outlet right ventricle with pulmonary atresia (1); and heterotaxy with right atrial isomerism (1).…”

Section: Resultsmentioning

confidence: 99%

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In search of “hepatic factor:” Lack of evidence for ALK1 ligands BMP9 and BMP10

Capasso

Trucco

Hindes

et al. 2020

Preprint

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In children with single ventricle physiology, the Glenn procedure is performed to redirect venous return from the superior vena cava directly to the pulmonary arteries and route venous return from the inferior vena cava exclusively to the systemic circulation. Although this surgery successfully palliates the hemodynamic stress experienced by the single ventricle, patients frequently develop pulmonary arteriovenous malformations (PAVMs). Interestingly, PAVMs may regress upon rerouting of hepatic venous effluent to the pulmonary vasculature, suggesting the presence of a circulating "hepatic factor" that is required to prevent PAVMs. Here, we test the hypothesis that hepatic factor is bone morphogenetic protein 9 (BMP9) and/or BMP10. These circulating ligands are produced by the liver and activate endothelial endoglin (ENG)/ALK1 signaling, and mutations in ENG and ALK1 cause hereditary hemorrhagic telangiectasia, a genetic disease associated with AVM development. However, we found no within-subject variation in BMP9, BMP10, or BMP9/10 plasma concentrations when sampled from five cardiovascular sites, failing to support the idea that the Glenn would limit access of these ligands to the lung vasculature. Unexpectedly, however, we found a significant decrease in all three ligand concentrations in Glenn cases versus controls. Our findings suggest that BMP9/BMP10/ENG/ALK1 signaling may be decreased in the Glenn vasculature but fail to implicate these ligands as hepatic factor.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

In search of “hepatic factor:” Lack of evidence for ALK1 ligands BMP9 and BMP10

Capasso

Trucco

Hindes

et al. 2020

Preprint

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“…Altogether, these data further support that sVEGFR1 may have a role in PAVM pathophysiology given that sVEGFR1 sequesters VEGF-A to decrease VEGF-A bioavailability and signaling. Two recent studies have also reported that Angiopoietin-2 is elevated in patients with palliated univentricular CHD compared to patients with biventricular CHD (6,29). Angiopoietin-2 is associated with vascular remodeling, but these studies found no difference in ANG-2 levels in HV blood compared to paired SVC blood.…”

Section: Discussionmentioning

confidence: 93%

“…Angiopoietin-2 is associated with vascular remodeling, but these studies found no difference in ANG-2 levels in HV blood compared to paired SVC blood. Shirali et al (6) 1C, Supplementary Table 1), although these data are from a small sample (n = 7). Finally, an important note is that sVEGFR1 was not quantified in either of these recent studies.…”

Section: Discussionmentioning

confidence: 97%

sVEGFR1 Is Enriched in Hepatic Vein Blood—Evidence for a Provisional Hepatic Factor Candidate?

et al. 2021

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Background: Pulmonary arteriovenous malformations (PAVMs) are common sequelae of palliated univentricular congenital heart disease, yet their pathogenesis remain poorly defined. In this preliminary study, we used paired patient blood samples to identify potential hepatic factor candidates enriched in hepatic vein blood.Methods: Paired venous blood samples were collected from the hepatic vein (HV) and superior vena cava (SVC) from children 0 to 10 years with univentricular and biventricular congenital heart disease (n = 40). We used three independent protein analyses to identify proteomic differences between HV and SVC blood. Subsequently, we investigated the relevance of our quantified protein differences with human lung microvascular endothelial assays.Results: Two independent protein arrays (semi-quantitative immunoblot and quantitative array) identified that soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is significantly elevated in HV serum compared to SVC serum. Using ELISA, we confirmed the previous findings that sVEGFR1 is enriched in HV serum (n = 24, p < 0.0001). Finally, we studied the quantified HV and SVC serum levels of sVEGFR1 in vitro. HV levels of sVEGFR1 decreased tip cell selection (p = 0.0482) and tube formation (fewer tubes [p = 0.0246], shorter tube length [p = 0.0300]) in vitro compared to SVC levels of sVEGFR1.Conclusions: Based on a small heterogenous cohort, sVEGFR1 is elevated in HV serum compared to paired SVC samples, and the mean sVEGFR1 concentrations in these two systemic veins cause pulmonary endothelial phenotypic differences in vitro. Further research is needed to determine whether sVEGFR1 has a direct role in pulmonary microvascular remodeling and PAVMs in patients with palliated univentricular congenital heart disease.

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“…22 Angiopoietin-2 levels were shown to be associated with the burden of atrial arrhythmias. 23 Faecal calprotectin levels may be able to detect the development of protein losing enteropathy in Fontan patients; however, one should strive for earlier identification of Fontan failure as the disease process is difficult to reverse at this stage. 24 Overall, the Fontan circulation is characterised by complex interactions between multiple organ systems with continuous interplay among the heart, lungs, liver, kidneys, and vasculature.…”

Section: Discussionmentioning

confidence: 99%

Utility of biomarkers in adult Fontan patients with decompensated heart failure

Nguyen¹,

Song

Dolgner

et al. 2020

Cardiol Young

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AbstractBackground:The incidence of heart failure is increasing within the Fontan population. The use of serological markers, including B-type natriuretic peptide, has been limited in this patient population.Methods:This was a single-centre retrospective study of Fontan patients in acute decompensated heart failure. Fontan patients underwent a 1:2 match with non-Fontan patients for each heart failure hospitalisation for comparative analysis. A univariate logistic regression model was used to assess associations between laboratory and echocardiographic markers and a prolonged length of stay of 7 days or greater.Results:B-type natriuretic peptide levels were significantly lower in Fontan patients admitted for heart failure than that in non-Fontan patients [390.9 (±378.7) pg/ml versus 1245.6 (±1160.7) pg/ml, respectively, p < 0.0001] and were higher in Fontan patients with systemic ventricular systolic or diastolic dysfunction than that in Fontan patients with normal systemic ventricular function [833.6 (±1547.2) pg/ml versus 138.6 (±134.0) pg/ml, p = 0.017]. The change from the last known outpatient value was smaller in Fontan patients in comparison with non-Fontan patients [65.7 (±185.7) pg/ml versus 1638.0 (±1444.7) pg/ml, respectively, p < 0.0001]. Low haemoglobin and high blood urea nitrogen levels were associated with a prolonged length of stay.Conclusion:B-type natriuretic peptide levels do not accurately reflect decompensated heart failure in Fontan patients when compared to non-Fontan heart failure patients and should, therefore, be used with caution in this patient population.

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Angiopoietin-2 predicts morbidity in adults with Fontan physiology

Cited by 13 publications

References 31 publications

In search of “hepatic factor:” Lack of evidence for ALK1 ligands BMP9 and BMP10

In search of “hepatic factor:” Lack of evidence for ALK1 ligands BMP9 and BMP10

sVEGFR1 Is Enriched in Hepatic Vein Blood—Evidence for a Provisional Hepatic Factor Candidate?

Utility of biomarkers in adult Fontan patients with decompensated heart failure

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