Clin Res Cardiol (2021)
DOI DOI https://doi.org/10.1007/s00392-021-01843-w
Stress and metabolic pathways associated with inflammation and oxidative stress in RV and LV HFrEF
M. Herwig1, A. Kovacs1, M. Sieme1, S. Delatat1, S. Pabel2, D. Kolijn1, E. Robinson3, S. Van Linthout4, S. Heymans3, C. Tschöpe5, L. Van Heerebeek6, A. Mügge7, S. T. Sossalla2, N. Hamdani1
1Molekulare und Experimentelle Kardiologie, Ruhr-Universität Bochum, Bochum; 2Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg; 3Cardiovascular Research Institute Maastricht (CARIM), Maastricht, NL; 4Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin; 5CC11: Med. Klinik m.S. Kardiologie, Charité - Universitätsmedizin Berlin, Berlin; 6Amsterdam University Medical Center, Amsterdam, NL; 7Med. Klinik II, Kardiologie, Kath. Klinikum Bochum gGmbH, Bochum;

Background: Since anatomic and hemodynamic factors in the right ventricle (RV) are different from those in the left ventricle (LV), we hypothesized that mechano-sensing is differentially regulated in the RV vs. LV during the pathogenesis of heart failure (HF). Accordingly, we examined chronic changes in RV and LV structure and function in patients with HF associated with oxidative stress and inflammation and explored distinct regional differences between the ventricles and their differential molecular mechanistic via clearing up distinct pathophysiological regulation of key signalling pathways and cardiomyocyte function in RV vs. LV.  

Methods: We used cardiac LV and RV biopsies from HF patients with reduced ejection fraction (<40%, HFrEF) and compared them to non-failing human hearts from donor groups (controls). Protein kinase activities, levels of inflammatory and oxidative parameters, gene expressions, protein expressions and phosphorylation of several sarcomeric proteins including titin, cMyBPC, and cTnI were measured. The cellular mechanical performance was assessed in single skinned cardiomyocytes.        


Results: In HFrEF vs. control, we observed an increase of inflammatory and oxidative parameters in both LV and RV, but more pronounced in the LV. In human HFrEF, Ca2+-sensitivity was higher in both ventricles compared to controls, and higher in the LV vs. RV HFrEF. cTnI phosphorylation was decreased in the HFrEF LV and RV, but cMyBP-C phosphorylation was decreased only in the HF LV. Titin phosphorylation was unaltered at S4010/S4062/S12022, decreased at S4099, and increased at S11878 in the HF LV. In contrast, titin phosphorylation was decreased at S4010, increased at S4062/S11878/S12022, and unaltered at S4099 in the RV. The cardiomyocyte passive tension (Fpassive) was in increased in both HFrEF RV and HF LV. Distinct kinases activities were found in the LV vs. RV. CaMKII treatment could restore this increase in the RV but not in the LV maybe due to the fact that CaMKII activity was decreased in the RV, but elevated in the LV. PKG treatment also restored Fpassive in both ventricles with a more pronounced effect in the LV compared to RV. CaMKII oxidation was increased in HFrEF in both ventricles, but more elevated in the LV, CaMKII expression was increased in both LV and RV, and CaMKII auto-phosphorylation was unchanged in RV but significantly increased in LV. Gene expression analyses revealed an increased expression of the CaMKII targets HDAC4, NFAT and MAPK1 in both LV and RV in HF vs. controls, as wells as the PKG targets PDE2a and PDE9a, while PDE1 and PDE5 were upregulated only in the LV, but unchanged in the RV. Further, we found increased gene expression of sGC, GC-A, and GC-B in the LV, but no changes in the RV.               


Conclusions: Our data suggest that distinct pathophysiological modulation of signalling pathways mediated by oxidative stress in the LV and RV of the failing heart may open up a new avenue to novel therapeutic options of targeting the LV independent of the RV and vice versa.

 
https://dgk.org/kongress_programme/jt2021/aP998.html