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Scheiber, D.* ; Zweck, E.* ; Albermann, S.* ; Jelenik, T.* ; Spieker, M.* ; Bönner, F.* ; Horn, P.* ; Schultheiss, H.P.* ; Aleshcheva, G.* ; Escher, F.* ; Boeken, U.* ; Akhyari, P.* ; Roden, M.* ; Kelm, M.* ; Westenfeld, R.

Human myocardial mitochondrial oxidative capacity is impaired in mild acute heart transplant rejection.

ESC Heart Fail., DOI: 10.1002/ehf2.13607 (2021)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
AIMS: Acute cellular rejection (ACR) following heart transplantation (HTX) is associated with long-term graft loss and increased mortality. Disturbed mitochondrial bioenergetics have been identified as pathophysiological drivers in heart failure, but their role in ACR remains unclear. We aimed to prove functional disturbances of myocardial bioenergetics in human heart transplant recipients with mild ACR by assessing myocardial mitochondrial respiration using high-resolution respirometry, digital image analysis of myocardial inflammatory cell infiltration, and clinical assessment of HTX patients. We hypothesized that (i) mild ACR is associated with impaired myocardial mitochondrial respiration and (ii) myocardial inflammation, systemic oxidative stress, and myocardial oedema relate to impaired mitochondrial respiration and myocardial dysfunction. METHODS AND RESULTS: We classified 35 HTX recipients undergoing endomyocardial biopsy according International Society for Heart and Lung Transplantation criteria to have no (0R) or mild (1R) ACR. Additionally, we quantified immune cell infiltration by immunohistochemistry and digital image analysis. We analysed mitochondrial substrate utilization in myocardial fibres by high-resolution respirometry and performed cardiovascular magnetic resonance (CMR). ACR (1R) was diagnosed in 12 patients (34%), while the remaining 23 patients revealed no signs of ACR (0R). Underlying cardiomyopathies (dilated cardiomyopathy 50% vs. 65%; P = 0.77), comorbidities (type 2 diabetes mellitus: 50% vs. 35%, P = 0.57; chronic kidney disease stage 5: 8% vs. 9%, P > 0.99; arterial hypertension: 59% vs. 30%, P = 0.35), medications (tacrolimus: 100% vs. 91%, P = 0.54; mycophenolate mofetil: 92% vs. 91%, P > 0.99; prednisolone: 92% vs. 96%, P > 0.99) and time post-transplantation (21.5 ± 26.0 months vs. 29.4 ± 26.4 months, P = 0.40) were similar between groups. Mitochondrial respiration was reduced by 40% in ACR (1R) compared with ACR (0R) (77.8 ± 23.0 vs. 128.0 ± 33.0; P < 0.0001). Quantitative assessment of myocardial CD3+ -lymphocyte infiltration identified ACR (1R) with a cut-off of >14 CD3+ -lymphocytes/mm2 (100% sensitivity, 82% specificity; P < 0.0001). Myocardial CD3+ infiltration (r = -0.41, P < 0.05), systemic oxidative stress (thiobarbituric acid reactive substances; r = -0.42, P < 0.01) and myocardial oedema depicted by global CMR derived T2 time (r = -0.62, P < 0.01) correlated with lower oxidative capacity and overt cardiac dysfunction (global longitudinal strain; r = -0.63, P < 0.01). CONCLUSIONS: Mild ACR with inflammatory cell infiltration associates with impaired mitochondrial bioenergetics in cardiomyocytes. Our findings may help to identify novel checkpoints in cardiac immune metabolism as potential therapeutic targets in post-transplant care.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Cellular Heart Transplant Rejection ; Heart Failure ; Mitochondrial Respiration ; Myocardial Inflammation; International Society; Lung Transplantation; Reactive Oxygen; Diagnosis; Activation; Cells; Guidelines; Perforin; Revision; Biopsies
ISSN (print) / ISBN 2055-5822
e-ISSN 2055-5822
Publisher Wiley
Publishing Place One Montgomery St, Suite 1200, San Francisco, Ca 94104 Usa
Reviewing status Peer reviewed
Grants Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
German Research Council