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Klotho is a well\u2010known anti\u2010ageing factor with relevant cardioprotective actions, at least when renal dysfunction is present, but its actions are much less known when renal function is preserved. This study investigated Klotho as a biomarker and potential novel treatment of IHD\u2010associated complications after myocardial infarction (MI) under preserved renal function. Association between circulating Klotho levels and cardiac injury was investigated in patients after ST\u2010elevation MI (STEMI). Biochemical,\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    cardiac function and histological and molecular studies were performed to determine the effect of recombinant Klotho in the failing hearts of mice after MI. We demonstrated that STEMI patients showed lower systemic Klotho levels, with the lowest Klotho tertile in those patients with higher N\u2010terminal pro B\u2010type natriuretic peptide (NT\u2010proBNP) levels. Mice also showed a decrease in systemic Klotho levels after MI induction. Furthermore, recombinant Klotho administration in mice reduced infarct area and attenuated cardiac hypertrophy and fibrosis. We also demonstrated that Klotho treatment prevented reduction in ejection fraction and MI\u2010related ECG changes, including prolonged QRS, JT, QTc, and T\n                    <jats:sub>peak<\/jats:sub>\n                    T\n                    <jats:sub>end<\/jats:sub>\n                    intervals and premature ventricular contractions. In adult mouse cardiomyocytes, Klotho treatment restricted systolic calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) release and cell shortening disturbances after MI. Klotho prevented increased diastolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak and pro\u2010arrhythmogenic events in PMI mice by blocking activation of the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \/calmodulin\u2010dependent kinase type II (CaMKII) pathway, preventing ryanodine receptor type 2 (RyR\n                    <jats:sub>2<\/jats:sub>\n                    ) hyperphosphorylation. In conclusion, Klotho supplementation protected against functional and structural cardiac remodelling and ameliorated ventricular arrhythmic events by preventing intracardiomyocyte Ca\n                    <jats:sup>2+<\/jats:sup>\n                    mishandling in mice following MI. These data uncover a new cardioprotective role of Klotho, emerging as a biomarker of ventricular injury and potential treatment for patients after MI. \u00a9 2025 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6388","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:15:58Z","timestamp":1736986558000},"page":"342-356","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Recombinant Klotho administration after myocardial infarction reduces ischaemic injury and arrhythmias by blocking intracellular calcium mishandling and\n                    <scp>CaMKII<\/scp>\n                    activation"],"prefix":"10.1002","volume":"265","author":[{"given":"Sara","family":"V\u00e1zquez\u2010S\u00e1nchez","sequence":"first","affiliation":[{"name":"Cardiorenal Translational Laboratory Imas12 Research Institute, Hospital Universitario 12 de Octubre  Madrid Spain"},{"name":"RICORS2040\u2010Renal  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Blasco","sequence":"additional","affiliation":[{"name":"Acute Cardiac Care Units Cardiology Service. Hospital Universitario Puerta de Hierro\u2010Majadahonda  Madrid Spain"},{"name":"Research Ethics Committee Instituto de Investigaci\u00f3n Puerta de Hierro\u2010Segovia de Arana  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Fern\u00e1ndez\u2010Corredoira","sequence":"additional","affiliation":[{"name":"Cardiology Service Hospital Universitario Miguel Servet  Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Cantolla","sequence":"additional","affiliation":[{"name":"Clinical and Invasive Cardiology Group, Instituto de Investigaci\u00f3n Sanitaria del Hospital La Paz (IdiPAZ) Hospital Universitario La Paz  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Mercado\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Cardiorenal Translational Laboratory Imas12 Research Institute, Hospital Universitario 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Rodr\u00edguez\u2010S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Cardiorenal Translational Laboratory Imas12 Research Institute, Hospital Universitario 12 de Octubre  Madrid Spain"},{"name":"RICORS2040\u2010Renal  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Gonz\u00e1lez\u2010Lafuente","sequence":"additional","affiliation":[{"name":"Cardiorenal Translational Laboratory Imas12 Research Institute, Hospital Universitario 12 de Octubre  Madrid Spain"},{"name":"RICORS2040\u2010Renal  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonay","family":"Poveda","sequence":"additional","affiliation":[{"name":"Cardiorenal Translational Laboratory Imas12 Research Institute, Hospital Universitario 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gonz\u00e1lez\u2010Moreno","sequence":"additional","affiliation":[{"name":"Cardiorenal Translational Laboratory Imas12 Research Institute, Hospital Universitario 12 de Octubre  Madrid Spain"},{"name":"RICORS2040\u2010Renal  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3202-9345","authenticated-orcid":false,"given":"Andrea","family":"Matutano","sequence":"additional","affiliation":[{"name":"Acute Cardiac Care Units Cardiology Service. Hospital Universitario Puerta de Hierro\u2010Majadahonda  Madrid Spain"},{"name":"Research Ethics Committee Instituto de Investigaci\u00f3n Puerta de Hierro\u2010Segovia de Arana  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Periba\u00f1ez","sequence":"additional","affiliation":[{"name":"Cardiology Service Hospital Universitario Miguel Servet  Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Garc\u00eda\u2010Consuegra","sequence":"additional","affiliation":[{"name":"Proteomics Unit Institute of Research Imas12, Hospital Universitario 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Volpe","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine Sapienza University of Rome  Rome Italy"},{"name":"IRCCS San Raffaele  Rome 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