The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h 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 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) 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 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), 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.

线粒体代谢物琥珀酸是缺血/再灌注损伤 (IRI) 的关键驱动因素。使用丙二酸再灌注时抑制琥珀酸脱氢酶 (SDH) 来靶向琥珀酸代谢是在小鼠和猪体内心肌梗死 (MI) 模型中实现短期（<24 小时再灌注）心脏保护的有效治疗策略。我们的目的是评估再灌注时给予丙二酸抑制 IRI 是否可以预防 28 天后评估的 MI 后心力衰竭 (HF)。对雄性 C57BL/6 J 小鼠进行 30 分钟的左冠状动脉前部 (LAD) 闭塞，然后再灌注 28 天。再灌注时以单剂量输注丙二酸或不含丙二酸的对照。通过超声心动图评估心脏功能，通过马森三色染色评估纤维化。心肌梗死后 28 天，不含丙二酸的再灌注显着降低了射血分数 (~ 47%)、缩短分数 (~ 23%) 和增加的胶原沉积。再灌注时单次输注丙二酸（16 mg/kg/min，持续 10 分钟）可产生显着的心脏保护作用，保留射血分数 (~ 60%) 和缩短分数 (~ 30%)，并减少胶原沉积。使用酸化丙二酸制剂，通过单羧酸转运蛋白 1 增强其对心肌细胞的摄取，10 分钟输注 1.6 和 16 mg/kg/min 均能产生强大的长期心脏保护作用，并保留射血分数 (> 60%) 和缩短分数 ( ~ 30%），并且胶原蛋白沉积比对照心脏显着减少。再灌注时给予丙二酸可预防心肌梗死后心力衰竭。丙二酸的酸化使较低剂量的丙二酸也能实现心肌梗死后的长期心脏保护作用。 因此，再灌注时给予酸化丙二酸是预防 IRI 和 MI 后心力衰竭的一种有前景的治疗策略。