Cardioprotective effect of succinate dehydrogenase inhibition in rat hearts and human myocardium with and without diabetes mellitus

Figures

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  Figure 1. Study design of the isolated rat heart study. An overview of the two experimental series of the isolated rat heart study including subgroups and perfusion protocols. IR: Ischemia reperfusion, DiMAL: Dimethyl Malonate, VF: Ventricular fibrillation.

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  Figure 2. Study design of human study. An overview of the experimental series of the study including subgroups and perfusion protocols. IR: Ischemia reperfusion, IPC: Ischemic preconditioning, DiMAL: Dimethyl Malonate, AFLI: Atrial fibrillation.

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  Figure 3. Isolated rat heart study – Dose-response relationship and infarct size. Dose-response relationship showing the effect of DiMAL on infarct size (IS) as a percentage of area at risk (AAR) in non-diabetic rat hearts (a) and IS/AAR of different intervention groups in non-diabetic and diabetic ZDF rat hearts (b). IR: Ischemia reperfusion, DiMAL: Dimethyl Malonate. Data are the mean ± SD. *P < 0.05 between indicated groups.

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  Figure 4. Human study – Dose-response relationship and contractile force recovery. Dose-response relationship between DiMAL and contractile force recovery in non-diabetic human atrial trabeculae (a) and contractile force recovery of non-diabetic and diabetic human atrial trabeculae given as a ratio of contractile force in the reperfusion compared to the pre-ischemic value (b). IR: Ischemia reperfusion, DiMAL: Dimethyl Malonate, IPC: Ischemic preconditioning. Data are mean ± SD. *P < 0.05 between indicated groups. P-values at the top indicate overall effect of diabetes and interventions by two-way ANOVA, respectively.

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  Figure 5. Isolated rat heart study - Mitochondrial respiratory capacity. Representative graph of mitochondrial respiratory capacity from a Sham heart. Below mitochondrial respiratory capacity. GM, state 2 respiration with glutamate + malate (a); GM3, state 3 respiration with glutamate and malate (b); GMS3, state 3 respiration with glutamate, malate and succinate (c); 4o, state 4 respiration with oligomycin (d); FCCP, non-coupled state by FCCP (e); RCR with complex I-linked substrates (f). Data are mean ± SD. *P < 0.05 between indicated groups. P-values at the top indicate overall effect of diabetes and interventions by two-way ANOVA, respectively.

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  Figure 6. Human study - Mitochondrial respiratory capacity. Representative graph of mitochondrial respiratory capacity from an IR heart trabecula. Below mitochondrial respiratory capacity. GM, state 2 respiration with glutamate + malate (a); GM3, state 3 respiration with glutamate and malate (b); GMS3, state 3 respiration with glutamate, malate and succinate (c); 4o, state 4 respiration with oligomycin (d); FCCP, non-coupled state by FCCP (e); RCR with complex I-linked substrates (f). Data are mean ± SD. *P < 0.05 between indicated groups. P-values at the top indicate overall effect of diabetes and interventions by two-way ANOVA, respectively.

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  Figure 7. Isolated rat heart study - Mitochondrial fatty acid respiratory capacity. Summarized data of mitochondrial fatty acid respiratory capacity in each respiratory state. MOc, state 2 respiration with malate and octanoyl-l-carnitine; MOc3, state 3 respiration with malate and octanoyl-l-carnitine; RCR with fatty acids. Data are the mean ± SD. *P < 0.05 between indicated groups. P-values at the top indicate overall effect of diabetes and interventions by two-way ANOVA, respectively.

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  Figure 8. Isolated rat heart study - Mitochondrial enzyme activity. Enzyme activity of citrate synthase (CS) and β-hydroxyacyl-CoA dehydrogenase (HAD) (a,b). Below protein content of individual electron transport chain complex I-V in non-diabetic (c) and diabetic (d) heart tissue. At the bottom Complex II activity in non-diabetic and diabetic tissue (e) and interstitial succinate concentrations (f). IR: Ischemia reperfusion, DiMAL: Dimethyl malonate. Data are the mean ± SD. *P < 0.05 between indicated groups. P-values at the top indicate overall effect of diabetes and interventions by two-way ANOVA, respectively.