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 the disease. We have found recently, that mitochondrial oxidative stress is causally related to RHF upon pressure overload in mice. Here, we sought to enlarge our understanding of RHF development and of the potential of anti-oxidative therapy.

Methods and Results:

To induce pressure overload, the model of pulmonary artery banding (PAB) was performed in C57BL/6N mice by constricting the pulmonary artery (PA) to a diameter of 300 µm. After 2 and 4 weeks, echocardiography, invasive pressure-volume loop analysis and graded maximal exercise test using a treadmill was performed. After 2 weeks, RV systolic function, reflected by tricuspid annular plane systolic excursion (TAPSE), was significantly impaired compared to control mice (p<0.001) and RV and right atrial (RA) dilation was significantly increased (RVID d p<0.0001; RA area p<0.001). Accordingly, exercise capacity was significantly impaired after 2 weeks of PAB (running distance p<0.01). Hemodynamic investigation revealed, that stroke volume was profoundly decreased and end-systolic pressure volume relation and arterial elastance were markedly increased after 2 weeks of PAB compared to control mice. Interestingly, these hemodynamic parameters, as well as RV TAPSE and RV and RA dilation, did not further deteriorate significantly from 2 to 4 weeks. In contrast, RV-PA coupling (Ees/Ea), as assessed from pressure-volume loop analyses, was significantly impaired after 4 compared to 2 weeks of PAB (p<0.01), indicating that Ees/Ea is a sensitive parameter reflecting RHF progression.

To test whether pharmacological mitigation of the levels of mitochondrial reactive oxygen species can prevent the progression of RHF, mice were treated with mitoTEMPO (0.7 mg/kg/day) for up to 6 weeks via osmotic minipumps. Whereas after 2 weeks of PAB and concomitant treatment, RA dilation was already significantly reduced compared to vehicle-treated mice (p<0.05), after long-term treatment for 6 weeks during PAB, mitoTEMPO application significantly improved systolic RV function (p<0.05), hepatic venous congestion (p<0.01) and the clinical heart failure score (p<0.01). Hemodynamic parameters in these animals are currently under investigation.

Conclusion:

Right ventricular-pulmonary arterial coupling is appropriate to detect RHF progression. Treatment of mice exposed to RV pressure overload improves RV systolic function and reduces RHF symptoms. 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.