| Autor: |
Jespersen NR; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. n.riise.jespersen@clin.au.dk., Hjortbak MV; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark., Lassen TR; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark., Støttrup NB; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark., Johnsen J; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark., Tonnesen PT; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark., Larsen S; Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.; Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland., Kimose HH; Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark., Bøtker HE; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. |
| Abstrakt: |
Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). Whether SDH inhibition yields protection in diabetic individuals and translates into human cardiac tissue remain unknown. In isolated perfused hearts from 24 weeks old male Zucker diabetic fatty (ZDF) and age matched non-diabetic control rats and atrial trabeculae from patients with and without diabetes, we compared infarct size, contractile force recovery and mitochondrial function. The cardioprotective effect of a 10 minutes DiMAL administration prior to global ischemia and ischemic preconditioning (IPC) was evaluated. In non-diabetic hearts exposed to IR, DiMAL 0.1 mM reduced infarct size compared to IR (55 ± 7% vs. 69 ± 6%, p < 0.05). Mitochondrial respiration was reduced by DiMAL 0.6 mM compared to sham and DiMAL 0.1 mM (p < 0.05). In diabetic hearts an increased concentration of DiMAL (0.6 mM) was required for protection compared to IR (64 ± 13% vs. 79 ± 8%, p < 0.05). Mitochondrial function remained unchanged. In trabeculae from humans without diabetes, IPC and DiMAL improved contractile force recovery compared to IR (43 ± 12% and 43 ± 13% vs. 23 ± 13%, p < 0.05) but in patients with diabetes only IPC provided protection compared to IR (51 ± 15% vs. 21 ± 8%, p < 0.05). Neither IPC nor DiMAL modulated mitochondrial respiration in patients. Cardioprotection by SDH inhibition is possible in human tissue, but depends on diabetes status. The narrow therapeutic range and discrepancy in respiration between experimental and human studies may limit clinical translation. |
