Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation
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 circ...
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2025-04-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.038061 |
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| author | Ari Cedars Cedric Manlhiot Bhargava Kumar Chinni Alexander R. Opotowsky Kristian Becker Anne Le Pratik Khare Jong Love Ko Allen Everett Shelby Kutty Mark W. Russell R. Mark Payne Andrew M. Atz Brian W. McCrindle Rahul H. Rathod Matthew Lewis David Goldberg Kevin Hill Michelle Ploutz Jon Detterich Kurt Schumacher Robert Whitehill Daniel J. Penny Mark Cartoski Rachel Sullivan Matthew Files Ruchira Garg Jonathan Wagner Roni Jacobsen Todd Nowlen Scott Fletcher Jennifer Conway Gi Boem Kim Fred Wu Victor Zak |
| author_facet | Ari Cedars Cedric Manlhiot Bhargava Kumar Chinni Alexander R. Opotowsky Kristian Becker Anne Le Pratik Khare Jong Love Ko Allen Everett Shelby Kutty Mark W. Russell R. Mark Payne Andrew M. Atz Brian W. McCrindle Rahul H. Rathod Matthew Lewis David Goldberg Kevin Hill Michelle Ploutz Jon Detterich Kurt Schumacher Robert Whitehill Daniel J. Penny Mark Cartoski Rachel Sullivan Matthew Files Ruchira Garg Jonathan Wagner Roni Jacobsen Todd Nowlen Scott Fletcher Jennifer Conway Gi Boem Kim Fred Wu Victor Zak |
| author_sort | Ari Cedars |
| collection | DOAJ |
| description | 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 <90% predicted peak oxygen uptake, and change in ADMA and symmetric dimethyl arginine concentrations were predictive of change in exercise capacity over time. Treatment with the PDE5i udenafil uncoupled this association. Finally, baseline ADMA and symmetric dimethyl arginine concentrations predicted response to PDE5is among patients with subnormal peak oxygen uptake. 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. |
| format | Article |
| id | doaj-art-3825a71b44e04a83bb8a8d1205cddc06 |
| institution | Kabale University |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-3825a71b44e04a83bb8a8d1205cddc062025-08-20T03:24:32ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-04-0114710.1161/JAHA.124.038061Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan CirculationAri Cedars0Cedric Manlhiot1Bhargava Kumar Chinni2Alexander R. Opotowsky3Kristian Becker4Anne Le5Pratik Khare6Jong Love Ko7Allen Everett8Shelby Kutty9Mark W. Russell10R. Mark Payne11Andrew M. Atz12Brian W. McCrindle13Rahul H. Rathod14Matthew Lewis15David Goldberg16Kevin Hill17Michelle Ploutz18Jon Detterich19Kurt Schumacher20Robert Whitehill21Daniel J. Penny22Mark Cartoski23Rachel Sullivan24Matthew Files25Ruchira Garg26Jonathan Wagner27Roni Jacobsen28Todd Nowlen29Scott Fletcher30Jennifer Conway31Gi Boem Kim32Fred Wu33Victor Zak34Johns Hopkins University Baltimore MD USAJohns Hopkins University Baltimore MD USAJohns Hopkins University Baltimore MD USACincinnati Children’s Hospital University of Cincinnati College of Medicine Cincinnati OH USACincinnati Children’s Hospital University of Cincinnati College of Medicine Cincinnati OH USAGigantest Inc. Baltimore MD USAJohns Hopkins University Baltimore MD USAJohns Hopkins University Baltimore MD USAJohns Hopkins University Baltimore MD USAJohns Hopkins University Baltimore MD USAC.S. Mott Children’s Hospital University of Michigan Ann Arbor MI USARiley Hospital for Children Indianapolis IN USADepartment of Pediatrics Medical University of South Carolina Charlotte SC USALabatt Family Heart Centre The Hospital for Sick Children, University of Toronto ON CanadaBoston Children’s Hospital Boston MA USAColumbia University New York NY USAChildren’s Hospital of Philadelphia Philadelphia PA USADuke University Medical Center Durham NC USAUniversity of Utah Salt Lake City UT USAChildren’s Hospital Los Angeles Los Angeles CA USAC.S. Mott Children’s Hospital University of Michigan Ann Arbor MI USAChildren’s Healthcare of Atlanta Atlanta GA USATexas Children’s Hospital Houston TX USANemours Childrens Health Wilmington DE USAMonroe Carrell Jr. Children’s Hospital at Vanderbilt University Nashville TN USASeattle Children’s Hospital Seattle WA USACedars‐Sinai Medical Center Los Angeles CA USAChildren’s Mercy Kansas City Kansas City MO USAChildren’s Hospital of Colorado Denver CO USAPhoenix Children’s Hospital Phoenix AZ USAChildren’s Nebraska Omaha NE USAStollery Children’s Hospital Edmonton AB CanadaSeoul National University Hospital Seoul South KoreaBoston Children’s Hospital Boston MA USACarelon Research Newton MA USABackground 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 <90% predicted peak oxygen uptake, and change in ADMA and symmetric dimethyl arginine concentrations were predictive of change in exercise capacity over time. Treatment with the PDE5i udenafil uncoupled this association. Finally, baseline ADMA and symmetric dimethyl arginine concentrations predicted response to PDE5is among patients with subnormal peak oxygen uptake. 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.https://www.ahajournals.org/doi/10.1161/JAHA.124.038061Fontanmetabolomicsnitric oxidetype 5 phosophodiesterase inhibitor |
| spellingShingle | Ari Cedars Cedric Manlhiot Bhargava Kumar Chinni Alexander R. Opotowsky Kristian Becker Anne Le Pratik Khare Jong Love Ko Allen Everett Shelby Kutty Mark W. Russell R. Mark Payne Andrew M. Atz Brian W. McCrindle Rahul H. Rathod Matthew Lewis David Goldberg Kevin Hill Michelle Ploutz Jon Detterich Kurt Schumacher Robert Whitehill Daniel J. Penny Mark Cartoski Rachel Sullivan Matthew Files Ruchira Garg Jonathan Wagner Roni Jacobsen Todd Nowlen Scott Fletcher Jennifer Conway Gi Boem Kim Fred Wu Victor Zak Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease Fontan metabolomics nitric oxide type 5 phosophodiesterase inhibitor |
| title | Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation |
| title_full | Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation |
| title_fullStr | Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation |
| title_full_unstemmed | Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation |
| title_short | Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation |
| title_sort | methylated arginine metabolites as biomarkers for clinical status and response to type 5 phosphodiesterase inhibition in patients with fontan circulation |
| topic | Fontan metabolomics nitric oxide type 5 phosophodiesterase inhibitor |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.038061 |
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