Document Type
Article
Publication Date
4-2025
Identifier
DOI: 10.1161/JAHA.124.038061
Abstract
BACKGROUND: There is significant interest in NO pathway modulators, specifically type 5 phosphodiesterase inhibitors (PDE5is), to treat patients with a Fontan circulation. Trials, however, have had mixed results. The relationship between the NO pathway and clinical status in patients with Fontan circulation is a significant knowledge gap.
METHODS AND RESULTS: We performed targeted metabolomic analysis using liquid chromatography coupled to mass spectrometry to quantify plasma NO pathway metabolite concentrations from 2 well-characterized populations of patients with Fontan circulation: the Boston Adult Congenital Heart Disease Biobank and Fontan Udenafil Exercise Longitudinal studies. We investigated associations between NO metabolite concentrations and clinical outcomes, exercise capacity, and response to PDE5is. Increased plasma concentration of asymmetric dimethyl arginine (ADMA), an inhibitor of NO production, was associated with risk for hospitalization or death. Increased ADMA and symmetric dimethyl arginine (another inhibitor of NO production) concentrations were associated with decreased baseline exercise capacity among patients with Fontan circulation with
CONCLUSIONS: Plasma concentrations of metabolites that inhibit NO flux are associated with negative clinical outcomes and worse exercise capacity. Moreover, metabolite shifts over time associated with increased NO flux are associated with improved exercise capacity. In patients with a Fontan circulation, the NO pathway modulators ADMA and symmetric dimethyl arginine may be useful as biomarkers of clinical status and predictive of response to PDE5is.
Journal Title
J Am Heart Assoc
Volume
14
Issue
7
First Page
038061
Last Page
038061
MeSH Keywords
Humans; Phosphodiesterase 5 Inhibitors; Arginine; Biomarkers; Male; Female; Fontan Procedure; Heart Defects, Congenital; Adult; Metabolomics; Young Adult; Treatment Outcome; Exercise Tolerance; Sulfonamides; Pyrimidines; Adolescent; Nitric Oxide; Longitudinal Studies; Chromatography, Liquid; Benzenesulfonamides
PubMed ID
40135558
Keywords
Fontan; metabolomics; nitric oxide; type 5 phosophodiesterase inhibitor
Recommended Citation
Cedars A, Manlhiot C, Chinni BK, et al. Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation. J Am Heart Assoc. 2025;14(7):e038061. doi:10.1161/JAHA.124.038061
Comments
This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.
Publisher's Link: https://doi.org/10.1161/jaha.124.038061