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Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (&lt;\u200924\u00a0h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28\u00a0days. Male C57BL\/6\u00a0J mice were subjected to 30\u00a0min left anterior coronary artery (LAD) occlusion, before reperfusion for 28\u00a0days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson\u2019s trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~\u200947%), fractional shortening (~\u200923%) and elevated collagen deposition 28\u00a0days post-MI. Malonate, administered as a single infusion (16\u00a0mg\/kg\/min for 10\u00a0min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~\u200960%) and fractional shortening (~\u200930%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16\u00a0mg\/kg\/min 10\u00a0min infusion led to robust long-term cardioprotection with preserved ejection fraction (&gt;\u200960%) and fractional shortening (~\u200930%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.<\/jats:p>","DOI":"10.1007\/s00395-024-01063-z","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T11:01:55Z","timestamp":1718190115000},"page":"691-697","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia\/reperfusion injury"],"prefix":"10.1007","volume":"119","author":[{"given":"Jiro","family":"Abe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Vujic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiran A.","family":"Prag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5192-580X","authenticated-orcid":false,"given":"Thomas","family":"Krieg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,12]]},"reference":[{"key":"1063_CR1","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1161\/CIRCULATIONAHA.120.049952","volume":"143","author":"J Bae","year":"2021","unstructured":"Bae J, Salamon RJ, Brandt EB, Paltzer WG, Zhang Z, Britt EC, Hacker TA, Fan J, Mahmoud AI (2021) Malonate promotes adult cardiomyocyte proliferation and heart regeneration. 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