{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T06:17:45Z","timestamp":1788329865972,"version":"build-2803163510"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Although operative and perioperative care continues to improve for patients with single ventricle (SV) congenital heart disease, long\u2010term morbidities and mortality remain high. Importantly, phosphodiesterase\u20105 inhibitor (PDE5i) therapies are increasingly used, but their direct myocardial effects in SV congenital heart disease remain poorly understood. We previously demonstrated that the failing SV myocardium is characterized by increased PDE5 (phosphodiesterase\u20105) activity and impaired mitochondrial bioenergetics. Here we sought to determine whether systemic circulating factors contribute to pathological metabolic remodeling in SV congenital heart disease, and whether PDE5i therapy mitigates these changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Using an established in\u00a0vitro model whereby primary cardiomyocytes are treated with patient sera \u00b1 PDE5i, we assessed the impact of circulating factors on cardiomyocyte metabolism. Mass spectrometry\u2010based lipidomics and metabolomics assessed phospholipid and metabolite changes. Mitochondrial bioenergetics were evaluated using the Seahorse Bioanalyzer and a stable isotope\u2010based enzyme activity assay. Relative mitochondrial copy number was quantified using reverse transcriptase\u2013quantitative polymerase chain reaction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our data suggest that circulating factors contribute to fundamental changes in cardiomyocyte bioenergetics, including impaired mitochondrial function associated with decreased cardiolipin and other phospholipid species, impaired carnitine palmitoyltransferase activity, increased reactive oxygen species generation, and altered metabolite milieu. PDE5i treatment partially reversed these abnormalities by restoring phosphatidylglycerol levels, reducing reactive oxygen species, increasing carnitine palmitoyltransferase activity, improving energy production, and normalizing several metabolic intermediates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Together, these data suggest circulating factors directly impair cardiomyocyte mitochondrial bioenergetics and may drive systemic metabolic dysfunction in SV congenital heart disease. PDE5i therapy partially attenuates these effects, supporting metabolic modulation as a potential therapeutic strategy for SV failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.042725","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:38:28Z","timestamp":1787225908000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating Factors in Single Ventricle Heart Disease Impair Cardiomyocyte Bioenergetics, With Partial Rescue by PDE5 Inhibition"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2431-2212","authenticated-orcid":false,"given":"Anastacia M.","family":"Garcia","sequence":"first","affiliation":[{"name":"University of Colorado Anschutz Medical Campus, Children's Hospital Colorado","place":["Aurora, 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