Reduced Myocardial Mitochondrial ROS Production in Mechanically Unloaded Hearts

Scheiber, Daniel; Zweck, Elric; Horn, Patrick; Albermann, Sophie; Masyuk, Maryna; Boeken, Udo; Saeed, Diyar; Kelm, Malte; Roden, Michael; Szendroedi, Julia; Westenfeld, Ralf

doi:10.1007/s12265-018-9803-3

Cited by 13 publications

(17 citation statements)

References 40 publications

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“…Mitochondrial respiration (oxygen flux) was quantified using an Oxygraph-2 k (Oroboros Instruments, Innsbruck, Austria) using substrate uncoupler inhibitor (SUIT) protocols and was normalized to tissue weight. Mitochondrial function was measured at 37 °C according to established protocols [ 46 ]. Oxygen flux was measured at saturating oxygen levels between 250 and 480 µM.…”

Section: Methodsmentioning

confidence: 99%

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis

et al. 2022

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Aortic valve stenosis (AS) is the most frequent valve disease with relevant prognostic impact. Experimental model systems for AS are scarce and comprehensive imaging techniques to simultaneously quantify function and morphology in disease progression are lacking. Therefore, we refined an acute murine AS model to closely mimic human disease characteristics and developed a high-resolution magnetic resonance imaging (MRI) approach for simultaneous in-depth analysis of valvular, myocardial as well as aortic morphology/pathophysiology to identify early changes in tissue texture and critical transition points in the adaptive process to AS. AS was induced by wire injury of the aortic valve. Four weeks after surgery, cine loops, velocity, and relaxometry maps were acquired at 9.4 T to monitor structural/functional alterations in valve, aorta, and left ventricle (LV). In vivo MRI data were subsequently validated by histology and compared to echocardiography. AS mice exhibited impaired valve opening accompanied by significant valve thickening due to fibrotic remodelling. While control mice showed bell-shaped flow profiles, AS resulted not only in higher peak flow velocities, but also in fragmented turbulent flow patterns associated with enhanced circumferential strain and an increase in wall thickness of the aortic root. AS mice presented with a mild hypertrophy but unaffected global LV function. Cardiac MR relaxometry revealed reduced values for both T1 and T2 in AS reflecting subtle myocardial tissue remodelling with early alterations in mitochondrial function in response to the enhanced afterload. Concomitantly, incipient impairments of coronary flow reserve and myocardial tissue integrity get apparent accompanied by early troponin release. With this, we identified a premature transition point with still compensated cardiac function but beginning textural changes. This will allow interventional studies to explore early disease pathophysiology and novel therapeutic targets.

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Section: Methodsmentioning

confidence: 99%

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis

et al. 2022

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“…We performed HRR in saponine‐permeabilized right ventricular EMB immediately after tissue harvesting using the Oxygraph‐2k (OROBOROS Instruments, Innsbruck, Austria) as previously reported. 22 Investigators were unaware of the histologic rejection diagnosis at the time of respiration analysis. Briefly, substrates were applied in the following order (in mM): 2 malate, 1 octanoyl‐carnitine, 2.5 ADP for the electron transferring flavoprotein complex (CETF), 10 glutamate for electron transport chain (ETC) complex I respiration, 10 succinate for ETC complex II respiration, 0.01 cytochrome C, 0.005 oligomycin, stepwise titration of 0.2 μM carbonyl cyanide‐trifluoromethoxyphenylhydrazone (FCCP) for uncoupled respiration and 5 μM antimycin A. Oxidative capacity was quantified as tissue weight‐normalized oxygen consumption at saturating levels of oxygen, ADP and substrates (State 3 respiration).…”

Section: Methodsmentioning

confidence: 99%

“…Respiratory control ratio and leak control ratio were calculated as state 3 divided by respiration after addition of oligomycin (state 4o) and state 4o divided by uncoupled respiration (state u), respectively. 22 …”

Section: Methodsmentioning

confidence: 99%

“…Briefly, substrates were applied in the following order (in mM): 2 malate, 1 octanoyl‐carnitine, 2.5 ADP for the electron transferring flavoprotein complex (CETF), 10 glutamate for electron transport chain (ETC) complex I respiration, 10 succinate for ETC complex II respiration, 0.01 cytochrome C, 0.005 oligomycin, stepwise titration of 0.2 μM carbonyl cyanide‐trifluoromethoxyphenylhydrazone (FCCP) for uncoupled respiration and 5 μM antimycin A. Oxidative capacity was quantified as tissue weight‐normalized oxygen consumption at saturating levels of oxygen, ADP and substrates (State 3 respiration). Respiratory control ratio and leak control ratio were calculated as state 3 divided by respiration after addition of oligomycin (state 4o) and state 4o divided by uncoupled respiration (state u), respectively 22 …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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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 resultsWe 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/mm 2 (100% sensitivity, 82% specificity; P < 0.0001). Myocardial CD3 + infiltration (r = À0.41, P < 0.05), systemic oxidative stress (thiobarbituric acid reactive substances; r = À0.42, P < 0.01) and myocardial oedema depicted by global CMR derived T2 time (r = À0.62, P < 0.01) correlated with lower oxidative capacity and overt cardiac dysfunction (global longitudinal strain; r = À0.63, 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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Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non‐ischaemic heart failure

et al. 2023

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Aims A causal link between non-ischaemic heart failure (HF) and humoral autoimmunity against G-protein-coupled receptors (GPCR) remains unclear except for Chagas' cardiomyopathy. Uncertainty arises from ambiguous reports on incidences of GPCR autoantibodies, spurious correlations of autoantibody levels with disease activity, and lack of standardization and validation of measuring procedures for putatively cardio-pathogenic GPCR autoantibodies. Here, we use validated and certified immune assays presenting native receptors as binding targets. We compared candidate GPCR autoantibody species between HF patients and healthy controls and tested associations of serum autoantibody levels with serological, haemodynamic, metabolic, and functional parameters in HF. Methods Ninety-five non-ischaemic HF patients undergoing transcatheter endomyocardial biopsy and 60 healthy controls were included. GPCR autoantibodies were determined in serum by IgG binding to native receptors or a cyclic peptide (for β1AR autoantibodies). In patients, cardiac function, volumes, and myocardial structural properties were assessed by cardiac magnetic resonance imaging; right heart catheterization served for determination of cardiac haemodynamics; endomyocardial biopsies were used for histological assessment of cardiomyopathy and determination of cardiac mitochondrial oxidative function by high-resolution respirometry. Results Autoantibodies against β 1 adrenergic (β 1 AR ) , M5-muscarinic (M5AR), and angiotensin II type 2 receptors (AT2R) were increased in HF (all P < 0.001). Autoantibodies against α 1 -adrenergic (α 1 AR) and angiotensin II type 1 receptors (AT1R) were decreased in HF (all P < 0.001). Correlation of alterations of GPCR autoantibodies with markers of cardiac or systemic inflammation or cardiac damage, haemodynamics, myocardial histology, or left ventricular inflammation (judged by T2 mapping) were weak, even when corrected for total IgG. β 1 AR autoantibodies were related inversely to markers of left ventricular fibrosis indicated by T1 mapping (r = À0.362, P < 0.05) and global longitudinal strain (r = À0.323, P < 0.05). AT2R autoantibodies were associated with improved myocardial mitochondrial coupling as measured by high-resolution respirometry in myocardial biopsies (r = À0.352, P < 0.05). In insulin-resistant HF patients, AT2R autoantibodies were decreased (r = À.240, P < 0.05), and AT1R autoantibodies were increased (r = 0.212, P < 0.05). Conclusions GPCR autoantibodies are markedly altered in HF. However, they are correlated poorly or even inversely to haemodynamic, metabolic, and functional markers of disease severity, myocardial histology, and myocardial mitochondrial efficiency. These observations do not hint towards a specific cardio-pathogenic role of GPCR autoantibodies and suggest that further investigations are required before specific therapies directed at GPCR autoantibodies can be clinically tested in non-ischaemic HF.

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Reduced Myocardial Mitochondrial ROS Production in Mechanically Unloaded Hearts

Cited by 13 publications

References 40 publications

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis

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

Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non‐ischaemic heart failure

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