Nuclear factor kappa-B (NFkB) has been postulated to induce cardiac fibrosis and dysfunction in heart failure and triggers inflammatory pathways. NFkB can be induced by damaged mitochondria. Its association with myocardial mitochondrial respiratory function in non-ischemic diabetes-related heart failure in humans is yet unclear. We hypothesized that human ventricular myocardial NFkB expression (i) is increased by type 2 diabetes mellitus (T2DM), and (ii) relates to reduced myocardial mitochondrial respiration. Heart transplant recipients with or without T2DM (as determined by oral glucose tolerance test), about to undergo post-transplant surveillance endomyocardial biopsies, were included, if they had received hearts from donors without T2DM. Thus, time since transplantation equaled diabetes-exposure of the transplanted hearts (2.9±2.4 years). We assessed normalized NFkB p105 subunit (NFkB1) mRNA expression using real-time PCR and myocardial mitochondrial respiration using high-resolution respirometry. Study participants (T2DM: n=17, Non-DM: n=32) had no histological signs of allograft rejection, heart failure (left ventricular ejection fraction 66.2±6.5%) or coronary artery disease. Age and sex distribution were similar between Non-DM and T2DM (p=0.50; p=0.40, respectively). Myocardial NFkB1 expression was 60% higher in T2DM than in Non-DM (0.28 [0.21-0.44] vs. 0.45 [0.29-0.71] arbitrary units, p<0.05). Fasting blood glucose, but not fasting free fatty acids (p=0.55), related to myocardial NFkB1 mRNA expression (r=0.31; p<0.05). NFkB1 expression related inversely to state 3 respiration of fatty acids and glutamate (r=-0.33; p<0.05), suggesting impaired complex I-related respiration. Our findings support the concept of a key role of NFkB in diabetes-related heart failure via altered myocardial respiratory function in humans. NFkB1 might therefore serve as a future target for treating diabetes-related heart disease.


E. Zweck: None. D. Scheiber: None. T. Jelenik: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. P. Horn: None. D. Pesta: None. D. Lassner: None. H. Schultheiss: None. U. Boeken: None. P. AKhyari: None. A. Lichtenberg: None. M. Kelm: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. R. Westenfeld: None. J. Szendroedi: None.


German Research Council (SFB1116); Heinrich-Heine University

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