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This makes PFKFB2 loss critical to understand in metabolic heart disease, of which impaired insulin signaling is a hallmark. Prolongation of the QT interval, risk of arrhythmia, and sudden cardiac death are also augmented in metabolic heart disease, raising a question as to whether potential crosstalk between glycolytic dysregulation and electrophysiological dysfunction exists.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We therefore assessed the impact of PFKFB2 loss on cardiac electrophysiology using a cardiomyocyte-specific PFKFB2 knockout mouse model (cKO) and litter-matched controls (CON). To do so, we employed electrocardiography in the fed state and following 12 hours of fasting, examining physiology both at baseline and in the presence of an acute stimulant stress. To further investigate the arrhythmia mechanism, we used patch-clamp electrophysiology and IonOptix Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient measurements in ventricular cardiomyocytes isolated from CON and cKO hearts.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The hearts of cKO mice exhibited prolonged repolarization, marked by QT and action potential duration prolongations. This occurred with impaired Ca\n                    <jats:sup>2+<\/jats:sup>\n                    reuptake and increased spontaneous Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release events in ventricular cardiomyocytes. Ultimately, these changes culminated in ventricular tachyarrhythmia in cKO mice, which was enhanced in the fed relative to the fasted state.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These data suggest that in the presence of sufficient glucose availability, cardiac glycolytic dysregulation at the phosphofructokinase nexus is sufficient to promote cardiac electrophysiological instability.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Clinical Perspective<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What is Known:<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Metabolic heart diseases, such as heart failure with preserved ejection fraction and diabetic cardiomyopathy, are associated with heightened risks of arrhythmogenesis and sudden cardiac death.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What the Study Adds:<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Here, we show for the first time that PFKFB2 is decreased in human hearts with heart failure with preserved ejection fraction.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Furthermore, we show that loss of cardiac PFKFB2 is sufficient to promote impaired ventricular repolarization at baseline and ventricular tachyarrhythmia upon stress test.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>This identifies PFKFB2 stabilization and activation as key potential targets in conferring electrophysiological stability in metabolic heart disease.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.19.699308","type":"posted-content","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T23:20:20Z","timestamp":1769124020000},"source":"Crossref","is-referenced-by-count":0,"title":["PFKFB2 Gates a Relationship Between Cardiac Glycolytic Regulation and Electrophysiological Function"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8421-6268","authenticated-orcid":false,"given":"Kylene M.","family":"Harold","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States"},{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, 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