P3487Pre-ischemic succinate dehydrogenase inhibition is protective against ischemia-reperfusion injury in rat and human myocardium with and without diabetes mellitus

• Published in: European heart journal 2019-10, Vol.40 (Supplement_1)
• Main Authors: Jespersen, N R, Hjortbak, M V, Lassen, T R, Stoettrup, N B, Johnsen, J, Tonnesen, P T, Larsen, S, Kimose, H H, Boetker, H E
• Format: Article
• Language: English
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehz745.0355

Abstract Background Ischemia-reperfusion (IR) injury can be attenuated through modulation of mitochondrial metabolism with succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). However, it is unknown whether SDH inhibition yields protection in aged, diabetic individuals and whether protection translate into human cardiac tissue. Purpose We wished to evaluate if SDH inhibition can be protective in aged, diabetic rat hearts and could be translated to the human myocardium. Methods We studied infarct size in aged non-diabetic and diabetic rat hearts subjected to isolated, retrograde perfusion and global ischemia and reperfusion. The hearts were randomized to: Sham hearts, IR injured hearts and IR injured hearts co-perfused with 0.1 mM or 0.6 mM DiMAL. Infarct size and mitochondrial respiratory capacity were evaluated post-ischemic. To translate our findings into human cardiac tissue, we tested the efficacy of DiMAL treatment in human atrial trabeculae from patients with and without diabetes mellitus undergoing cardiac surgery. We randomized atrial trabeculae to: IR injury, IR injury treated with ischemic preconditioning (IPC) and IR injury treated with 5 mM DiMAL. Contractile force recovery and mitochondrial respiratory capacity were evaluated post-ischemic. Results In non-diabetic rat hearts, DiMAL 0.1 mM reduced infarct size/area-at-risk (IS/AAR) compared to IR hearts (53±7% vs. 69±6% of IS/AAR; p