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This bicarbonate-based Krebs\u2013Henseleit buffer (KHB) has been frequently modified over many years but typically includes only glucose as a substrate, often to hyperglycaemic levels. However, despite its popularity, hearts perfused under these conditions are close to the limits of substrate and oxygen availability and unable to sustainably respond to increased demand. The aim of the present study was to compare the function, stability, and energetics of hearts perfused with standard glucose-containing KHB with those perfused with a Full Metabolic Buffer (FMB) containing a physiologically appropriate range of substrates, including (in mM) fatty acids (0.4), lactate (1), pyruvate (0.1), glucose (5), glutamate (0.5), \u03b2-hydroxybutyrate (4), and insulin (5\u2005mIU\/L).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Isolated rat hearts were perfused with either KHB or FMB, followed by isoprenaline (1\u2005\u03bcmol\/L for 15 min) to induce stress. Cardiac function was measured via an intraventricular balloon, while energetics and metabolism were assessed with 31P and 1H NMR spectroscopy; action potential\/calcium transients were assessed with cardiac optical mapping. An adapted FMB was also developed for culturing isolated cardiomyocytes, and glycolytic flux in these cells was measured with 2H NMR spectroscopy. In hearts perfused with FMB, basal left ventricular developed pressure was higher (160 \u00b1 7\u2005mmHg vs. 126 \u00b1 6\u2005mmHg in KHB), the phosphocreatine (PCr)\/adenosine triphosphate (ATP) ratio was elevated (1.67 \u00b1 0.1 vs. 1.28 \u00b1 0.05), the Gibbs free energy of ATP hydrolysis was \u22122.9 \u00b1 0.3\u2005kJ\/mol more negative, and mitochondrial membrane potential was more polarized by \u221219 \u00b1 7\u2005mV. Under stress, Langendorff-perfused FMB hearts maintained contractile function with fewer arrhythmias and maintained a higher PCr\/ATP ratio. The metabolic profile was significantly different between hearts perfused with either buffer, with higher levels of key mitochondrial metabolites, such as succinate and fumarate, in FMB hearts. FMB suppressed pacing-induced calcium transient duration alternans compared to KHB-perfused hearts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Compared to KHB, FMB provides substantial advantages for cardiac energetics, metabolism, and function and is therefore a more appropriate buffer to use in cardiovascular metabolism studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag212","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:24:23Z","timestamp":1789755863000},"source":"Crossref","is-referenced-by-count":0,"title":["Beyond glucose: metabolic substrate provision enhances cardiac energetics, function, and stability\n                    <i>ex vivo<\/i>\n                    \u2014\n                    <i>a simple recipe for healthier hearts?<\/i>"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8645-5817","authenticated-orcid":false,"given":"Zoe","family":"Hoare","sequence":"first","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine and Sciences, BHF Centre of Research Excellence, King\u2019s College London , London SE1 7EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7262-7705","authenticated-orcid":false,"given":"Yu Jin","family":"Chung","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine and Sciences, BHF Centre of Research Excellence, King\u2019s College London , London SE1 7EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8001-7181","authenticated-orcid":false,"given":"Edward C T","family":"Waters","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Imaging Sciences, BHF Centre of Research Excellence, King\u2019s College London , London SE1 7EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1765-3176","authenticated-orcid":false,"given":"Abbie","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, College of Medicine and Health, University of Birmingham , Birmingham B15 2TT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Tompkins","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, College of Medicine and Health, University of Birmingham , Birmingham B15 2TT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3030-7364","authenticated-orcid":false,"given":"Christopher","family":"O\u2019Shea","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, 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