https://doi.org/10.1007/s00392-025-02625-4
1Herz- und Diabeteszentrum NRW Agnes Wittenborg Institut für translationale Herz-Kreislaufforschung Bad Oeynhausen, Deutschland; 2Ruhr-Universität Bochum Medical Imaging Center - Electron Microscopy Medical Analysis - Core Facility Bochum, Deutschland; 3Herz- und Diabeteszentrum NRW Allgemeine und Interventionelle Kardiologie/Angiologie Bad Oeynhausen, Deutschland
Background:
Right heart failure (RHF) is a late consequence of many cardiovascular disease processes and increases mortality. To advance the development of therapies for right ventricular (RV) failure, it is essential to understand pathomechanisms of the disease. We have recently identified that mitochondrial reactive oxygen species (ROS) in cardiomyocytes contribute to the development of RHF. Therefore, we sought to test the therapeutic potential of mitochondria-targeted antioxidant therapies in a mouse model of RV pressure overload.
Methods and Results:
RV pressure overload was induced in C57BL/6N male mice by constricting the pulmonary artery to a diameter of 300 µm for a period of 6 weeks. Already after 1 week of pulmonary artery banding (PAB), RV systolic function reflected by tricuspid annular plane systolic excursion (TAPSE) was significantly impaired and RV hypertrophy was increased. Ultrastructural analysis of RV myocardium using transmission electron microscopy revealed disorganized mitochondrial arrangement and architecture with dismantled, swollen mitochondria in PAB mice after 1 week compared to control animals. To test for oxidative stress, hyperoxidized peroxiredoxin was quantified, which was significantly increased in RV of PAB mice after 1 week compared to controls. In a preventive approach, PAB mice were treated with SS-31, which improves mitochondrial electron transport chain integrity and reduces ROS release, via osmotic mini pumps for 1 week (3 mg/kg/day). RV myocardium of SS-31-treated PAB mice showed significantly decreased ROS levels and a seemingly intact mitochondrial architecture compared to untreated PAB mice. Interestingly, systolic RV function and RV hypertrophy were not improved by SS-31 treatment in PAB mice. However, RV diastolic function as reflected by e’/a’ (untreated 0.74 ± 0.23 mm vs. SS-31 1.33 ± 0.38 mm; mean ± SD; p<0.01) and RV longitudinal strain (untreated -5.74 ± 1.16 peak% vs. SS-31 -9.43 ± 2.11 peak%; mean ± SD; p<0.01), were significantly improved after SS-31 treatment in PAB mice. The causal relation between oxidative stress, mitochondrial morphology and diastolic function will be elucidated further. Effects after long-term antioxidant treatment were tested in PAB mice by administration of mitoTEMPO (0.7 mg/kg/day) via osmotic pumps for up to 6 weeks. MitoTEMPO application significantly improved systolic RV function (TAPSE: untreated 0.5 mm ± 0.1 mm vs. mitoTEMPO 0.7 mm ± 0.1 mm; mean ± SD; p<0.05). However, RV hypertrophy and right atrial and RV dilation as well as exercise capacity were not improved. In contrast to these mild effects on RV function, the presence and severity of RHF reflected by the extent of hepatic venous congestion, ascites, restricted mobility and increased breathing were profoundly ameliorated by mitoTEMPO treatment after 6 weeks in PAB mice (p<0.0001).
Conclusion:
Short term anti-oxidant treatment of mice exposed to RV pressure overload with SS-31 preserved mitochondrial structure and improved RV diastolic function. In addition, long-term anti-oxidant treatment with mitoTEMPO attenuated RV systolic dysfunction and protected against right heart failure. These data may help to better characterise the potential of mitochondria-targeted antioxidants for the treatment of RHF.