Background:

Right heart failure (RHF) increases mortality of patients, independently of their underlying diseases. To advance the development of therapies targeting the right ventricle (RV), it is essential to understand which processes drive the transition from adaptive to maladaptive RV remodelling and failure. The animal model of pulmonary artery banding (PAB) allows the investigation of RV pressure overload independently of pulmonary arterial function. However, current data do not sufficiently explain mechanisms that distinguish adaptive from maladaptive remodelling. It is described that deterioration of systolic function upon pressure overload in the left ventricle (LV) strongly depends on mouse strain. C57bl/6J (6J) mice are protected compared to C57bl/6N (6N) mice because of a loss of function mutation in the mitochondrial transhydrogenase Nnt leading to a diminished release of mitochondrial reactive oxygen species. Here, we sought to characterize the PAB model in 6J and 6N animals to advance the understanding of the pathophysiology of RHF.

Methods and Results:

PAB was performed in 6J or 6N mice by constricting the pulmonary artery to a diameter of 300µm. Mice were analysed by echocardiography after 2 and 4 weeks (wks). RV systolic function, reflected by fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE), was significantly impaired after 2 wks and remained unchanged until 4 wks post PAB. In line with observations in the LV, RV function was significantly worse in 6N mice compared to 6J mice after PAB (6J vs 6N, TAPSE, 2wks: 0.81±0.14 vs 0.57±0.13mm; 4wks: 0.90±0.11 vs 0.59±0.12mm, N=13-21; p<0.0001). Accordingly, RV dilation was significantly more pronounced in 6N compared to 6J mice (6J vs 6N, 4wks: 2.53±0.36 vs 3.38±0.66mm, N=13-21; p<0.0001) and diastolic RV wall thickness was lower in 6N compared to 6J mice. This was accompanied with congruent expression of the fetal gene program (ANP, BNP and MYH6/MYH7), with 6N mice showing a significantly higher ANP expression compared to 6J mice after 4 wks (6J vs 6N: 0.45±0.15 vs 1.02±0.64, N=6-9; p<0.05). In contrast, RV hypertrophy, reflected by Fultons-Index, was significantly increased after 2 wks of PAB to the same extent in both strains. Importantly, symptoms of heart failure (ascites, macroscopic signs of liver congestion) only occurred in 6N but not in 6J mice and 2 week-mortality was significantly higher in 6N animals. Interestingly, impaired signalling of vascular endothelial growth factor (VEGF) and, consecutively, capillary rarefaction is discussed as a potential mechanism of RHF development. We found that VEGF expression was significantly lower in 6N compared to 6J mice after 4 wks (6J vs 6N: 1.43±0.33 vs 0.67±0.49, N=6-9; p<0.01). Analysis of RV morphology and function, fetal gene and VEGF expression in 6J mice upon PAB with mild stenosis (450µm) and moderate stenosis (350µm) in comparison to severe stenosis of 300µm, revealed progressively increasing RV remodelling with enhanced afterload but not with time, and confirmed the absence of RHF in the 6J mouse strain.

Conclusion:

Increasing afterload leads to enhanced maladaptive remodelling of the RV with increased hypertrophy and impaired RV function. The occurrence of RHF may depend on the presence of oxidative species and disturbed VEGF signalling. Genetic background of animals is highly important for RV phenotype in this model and can determine the incidence of RHF.