Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

The development of right heart failure under pressure overload is linked to oxidative stress but dissociated from fibrotic remodeling

M. Müller1, C. Bischof1, T. Kapries1, C. Liechty1, S. Wollnitza1, M. Gercek2, D. Dumitrescu2, T. Schubert1, U. Schlomann1, S. Geißen3, A. Sydykov4, R. T. Schermuly4, H. Milting5, V. Rudolph2, A. Klinke1

1Agnes Wittenborg Institut für translationale Herz-Kreislaufforschung, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; 2Allgemeine und Interventionelle Kardiologie/Angiologie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; 3Herzzentrum - Kardiologie, Universitätsklinikum Köln, Köln; 4Medizinische Klinik II - Pneumologie, Universitätsklinikum Gießen und Marburg GmbH, Gießen; 5E.& H. Klessmann-Institut f. kardiovask. Forschung, Herz- und Diabeteszentrum NRW, Bad Oeynhausen;

Background: Right heart failure (RHF) is a late sequela of many cardiovascular disease processes and a driver of mortality. To advance the development of therapies targeting the right ventricle (RV), it is essential to understand pathomechanisms of RHF development. We sought to investigate RHF under pressure overload using the model of pulmonary artery banding (PAB) and to identify underlying pathomechanisms. Given their differential expression of mitochondrial nicotinamide nucleotid transhydrogenase (NNT), C57BL/6J (6J) and C57BL/6N (6N) mice were used to investigate the role of oxidative stress upon RV pressure overload. In addition, RV tissue of explanted hearts of patients with dilated cardiomyopathy (DCM) was analysed. Methods and Results: PAB was performed in 6J or 6N mice (N=8-12 mice) by constricting the pulmonary artery (PA) to a diameter of 300 µm. Mice were analysed by echocardiography after 1, 2 and 4 weeks (wks). RV systolic function, reflected by tricuspid annular plane systolic excursion (TAPSE), was significantly impaired after 1 wk and further declined until 2 and 4 wks post PAB. In 6N mice, it was significantly worse compared to 6J mice (p<0.0001). Accordingly, RV and right atrial (RA) dilation was significantly more pronounced in 6N compared to 6J mice (RVID d p<0.0001; RA area p<0.001). In contrast, the extent of interstitial fibrosis increased over time, but was not different between 6N and 6J mice. Likewise, RV hypertrophy, reflected by Fultons-Index, and cardiomyocyte hypertrophy, reflected by cross-sectional area, were increased to the same extent in both strains. Importantly, the extent of venous liver congestion assessed histologically, indicating the occurrence of heart failure, was significantly higher in 6N compared to 6J mice (p<0.05), and strongly correlated with RA area and negatively with TAPSE. In contrast, venous congestion did not correlate with the extent of RV fibrosis, indicating that structural remodelling was dissociated from the development of RHF. Mechanistically, markers of oxidative stress (DNA-oxidation: 8-hydroxydeoxy-guanosine 8OHdG; peroxiredoxin hyperoxidation: PRX-SO2/3) were significantly more pronounced in RV tissue of 6N compared to 6J mice (8OHdG p<0.01; PRX-SO2/3 p<0.05), which is in accordance with previous findings for the left ventricle. Treatment of mice with the mitochondrial antioxidant mitoTEMPO during PAB improved TAPSE of 6N, but hardly of 6J mice. In line with these observations, analysis of RV tissue from explanted hearts of patients with DCM revealed, that in patients with severely impaired RV function (iRV, N=10), 8OHdG was significantly more abundant compared to patients with normal RV function (nRV, N=11) (p<0.01). Collagen accumulation and cardiomyocyte hypertrophy was not different between the two groups, although iRV patients had significantly higher mean PA pressure and pulmonary capillary wedge (PCW) pressure than nRV patients (PA p<0.01; PCW p<0.01). Conclusion: Oxidative stress is involved in the development of RHF under pressure overload, whereas RV hypertrophy and fibrotic remodeling do not correlate with RV function. Further investigations will follow to give mechanistic insights to the processes of ROS regulation in the pressure-overloaded RV and to the ROS-dependent impairment of RV function, which can help to identify new therapeutic targets for RHF.

https://dgk.org/kongress_programme/jt2022/aP811.html