{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T07:11:03Z","timestamp":1764832263031,"version":"3.46.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004411","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002651","name":"Barth Syndrome Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002651","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontierspartnerships.org"],"crossmark-restriction":true},"short-container-title":["J. Pharm. Pharm. Sci."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Mutations in the\n                      <jats:italic>tafazzin<\/jats:italic>\n                      gene lead to impaired remodeling of cardiolipin, thereby impairing mitochondrial function and causing Barth syndrome (BTHS), a rare X-linked genetic disorder characterized by cardiomyopathy. Previous studies in a mouse model of BTHS, secondary to knockdown of\n                      <jats:italic>Tafazzin<\/jats:italic>\n                      (TazKD mice), also observed perturbations in mitochondrial substrate metabolism and a hypertrophic cardiomyopathy. BTHS may be characterized by increased cardiac ketone metabolism, as myocardial protein expression of the ketolytic enzyme, \u03b2-hydroxybutyrate dehydrogenase 1 (BDH1), was markedly increased in TazKD mice. We therefore determined whether increasing ketone supply in TazKD mice may have therapeutic utility against their cardiac abnormalities.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We treated TazKD mice and their wild-type littermates with either the sodium-glucose cotransporter-2 inhibitor, empagliflozin (10\u00a0mg\/kg), or a ketone ester (KE; 1719\u00a0mg\/kg) once daily for 7-week, and performed ultrasound echocardiography to assess cardiac structure and function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Treatment of TazKD mice with either empagliflozin or a KE increased circulating ketone levels. However, neither approach proved capable of alleviating the cardiac hypertrophy present in TazKD mice, as their increased left ventricular wall thickness and decreased left ventricular diameter remained comparable to that observed in vehicle control treated animals. We also observed that empagliflozin and KE treatment did not impact key markers of cardiac hypertrophy in TazKD mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Increasing circulating ketone levels did not alleviate the cardiac hypertrophy in TazKD mice, suggesting that such an approach would not improve outcomes in BTHS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/jpps.2025.15688","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:10:30Z","timestamp":1764828630000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological increases in circulating ketones fail to alleviate the hypertrophic cardiomyopathy present in the Tafazzin knockdown mouse model of Barth syndrome"],"prefix":"10.3389","volume":"28","author":[{"given":"Tanin","family":"Shafaati","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda A.","family":"Greenwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina T.","family":"Saed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seyed Amirhossein","family":"Tabatabaei Dakhili","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan S. 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