Background: The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, adaptation characteristics of the LV response to chronic pressure overload cannot be simply extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF). However, these changes in mitochondrial function, gene expression and morphology have never been compared directly in RV and LV tissue and cardiomyocytes.

Methods: To identify RV-specific mitochondrial signatures, we established rat models, which show two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). We investigated mitochondrial functional (respiration; respiratory chain enzyme activities) or morphological (electron microscopy) changes and compared mitochondrial biogenesis in the RV and LV tissues at both disease stages. RNA sequencing was utilized to identify differentially expressed mitochondrial genes, which were then confirmed by RT-qPCR. Isolated cardiomyocytes were employed to identify the cellular source of altered gene expression by RT-qPCR and Western Blotting.

Results: Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle at decompensation, were observed in both models. Mitochondrial respiration was similarly impaired at the decompensated stage in both failing ventricles, while respiratory chain activity or mitochondrial biogenesis was more severely deteriorated in the failing LV. Bioinformatic analyses of the RNA-seq data sets identified specific pathways involving known or predicted mitochondrial genes. Among the confirmed differentially regulated genes were respiratory chain subunits and genes involved in respiratory chain complex assembly or electron transfer to the respiratory chain, suggesting that these might have contributed to the altered mitochondrial function. Changes in tissue as well as cardiomyocyte mRNA and protein expression were more pronounced in the diseased LV in the AOB model. Only few mitochondrial genes showed opposite changes in gene expression in the failing RV and LV.

Conclusions: Mitochondrial dysfunction contributes to disease progression in right and left heart failure. There are profound stage-specific differences in mitochondrial gene expression and function in both ventricles. However, ventricle-specific differences were mostly related to the extent of the observed changes, suggesting that despite developmental, anatomical and functional differences the mitochondrial adaptation to chronic pressure overload is similar in the LV and RV.