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Mitochondrial metabolic remodeling in myocardium of patients with early contractile dysfunction

Chronic heart failure (CHF) is associated with remodeling of cardiac energy metabolism; however, human studies have been largely limited to its final phases - the end-stage CHF (1-4). In the current study, we examined mitochondrial function in myocardium of patients undergoing coronary artery bypass graft surgery and being at various levels of cardiac contractile spectrum. Our aim was to investigate if alterations in mitochondrial ability to oxidize substrate are present even before the end-stage contractile failure ensues. Samples of left ventricular myocardium from forty patients undergoing coronary artery bypass grafting were obtained by subepicardial needle biopsy. All patients had left ventricular ejection fraction (LVEF) higher than >40%. Mitochondrial oxidation of carbohydrate and fatty acid metabolites (pyruvate and palmitoyl- carnitine, respectively), as well as maximal oxidative capacity were assessed by respirometry in saponin- permeabilized myocardial fibers. Expression of key factors influencing mitochondrial oxidative function (respiratory complexes, beta oxidation enzymes, mitofusin-2 and PGC-1α) was assessed by immunoblotting. Accumulation of ceramide was evaluated by immunofluorescence. Univariable and multivariable linear regression analysis was used for testing the association between ejection fraction and mitochondrial respiration under different conditions. Pearson correlation analysis was used to assess potential relations between EF and other parameters. LVEF was positively associated with mitochondrial oxidative capacity, but not with oxidation of individual substrates (Figure 1A-C) and this relationship persisted after adjusting for age, sex, body mass index and diabetes status. Citrate synthase activity (indicator of mitochondrial content) did not associate with LVEF (Figure 1D). LVEF was positively correlated with mitochondrial biogenesis and remodeling factors (PGC-1 and mitofusin-2), as well as with expression of key - oxidation enzymes (VLCAD and HADHA ; Figure 1E-H). Moreover, LVEF was negatively associated myocardial accumulation of ceramide (Figre 1I). Our study shows that relationship between cardiac contractility and mitochondrial functional capacity exists even in patients with normal- to- moderately decreased cardiac systolic function. Also, it suggests that reduced capacity for fatty acid oxidation and increased accumulation of toxic ceramide is present even in the early phases of cardiac systolic decline. References 1. Sabbah HN, Gupta RC, Singh-Gupta V, Zhang K, Lanfear DE. Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide. Cardiovasc Drugs Ther. 2018 Aug ; 32(4):319–28. 2. Lemieux H, Semsroth S, Antretter H, Höfer D, Gnaiger E. Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart. The International Journal of Biochemistry & Cell Biology. 2011 Dec ; 43(12):1729–38. 3. Scheiber D, Jelenik T, Zweck E, Horn P, Schultheiss H-P, Lassner D, et al. High-resolution respirometry in human endomyocardial biopsies shows reduced ventricular oxidative capacity related to heart failure. Exp Mol Med. 2019 Feb ; 51(2):1–10. 4. Stride N, Larsen S, Hey-Mogensen M, Sander K, Lund JT, Gustafsson F, et al. Decreased mitochondrial oxidative phosphorylation capacity in the human heart with left ventricular systolic dysfunction. European Journal of Heart Failure. 2013 Feb ; 15(2):150–7.

mitochondria; human heart; metabolic remodeling; contractile dysfunction

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