Tachycardiomyopathy entails a dysfunctional pattern of interrelated mitochondrial functions
2022 | journal article. A publication with affiliation to the University of Göttingen.
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Tachycardiomyopathy entails a dysfunctional pattern of interrelated mitochondrial functions
Paulus, M. G.; Renner, K.; Nickel, A. G.; Brochhausen, C.; Limm, K.; Zügner, E. & Baier, M. J. et al. (2022)
Basic Research in Cardiology, 117(1). DOI: https://doi.org/10.1007/s00395-022-00949-0
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Details
- Authors
- Paulus, Michael G.; Renner, Kathrin; Nickel, Alexander G.; Brochhausen, Christoph; Limm, Katharina; Zügner, Elmar; Baier, Maria J.; Pabel, Steffen ; Wallner, Stefan; Birner, Christoph; Dietl, Alexander
- Abstract
- Abstract Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days ( n = 11, early left ventricular dysfunction) or with up to 380 bpm over 30 days ( n = 24, tachycardiomyopathy, TCM). In n = 26, pacemakers remained inactive (SHAM). Left ventricular tissue was subjected to respirometry, metabolomics and acetylomics. Results were assessed for translational relevance using a human-based model: induced pluripotent stem cell derived cardiomyocytes underwent field stimulation for 7 days (TACH–iPSC–CM). TCM animals showed systolic dysfunction compared to SHAM (fractional shortening 37.8 ± 1.0% vs. 21.9 ± 1.2%, SHAM vs. TCM, p < 0.0001). Histology revealed cardiomyocyte hypertrophy (cross-sectional area 393.2 ± 14.5 µm 2 vs. 538.9 ± 23.8 µm 2 , p < 0.001) without fibrosis. Mitochondria were shifted to the intercalated discs and enlarged. Mitochondrial membrane potential remained stable in TCM. The metabolite profiles of ELVD and TCM were characterised by profound depletion of tricarboxylic acid cycle intermediates. Redox balance was shifted towards a more oxidised state (ratio of reduced to oxidised nicotinamide adenine dinucleotide 10.5 ± 2.1 vs. 4.0 ± 0.8, p < 0.01). The mitochondrial acetylome remained largely unchanged. Neither TCM nor TACH–iPSC–CM showed relevantly increased levels of reactive oxygen species. Oxidative phosphorylation capacity of TCM decreased modestly in skinned fibres (168.9 ± 11.2 vs. 124.6 ± 11.45 pmol·O 2 ·s −1 ·mg −1 tissue, p < 0.05), but it did not in isolated mitochondria. The pattern of mitochondrial dysfunctions detected in two models of tachycardiomyopathy diverges from previously published characteristic signs of other heart failure aetiologies.
- Issue Date
- 2022
- Journal
- Basic Research in Cardiology
- Organization
- Klinik für Kardiologie und Pneumologie ; Deutsches Zentrum für Herz-Kreislauf-Forschung e.V. ; Universitätsmedizin Göttingen
- ISSN
- 0300-8428
- eISSN
- 1435-1803
- Language
- English
- Sponsor
- university hospital regensburg 501100005296
marga und walter boll-stiftung http://dx.doi.org/10.13039/501100011566
deutsche gesellschaft für kardiologie-herz und kreislaufforschung. http://dx.doi.org/10.13039/501100010578
deutsche gesellschaft für innere medizin
fritz thyssen stiftung http://dx.doi.org/10.13039/501100003390
deutsche forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659
Deutsche Stiftung für Herzforschung http://dx.doi.org/10.13039/501100005970
Universitätsklinikum Regensburg 501100005296