Metabolic Pathways of Cardiac Dysfunction After Preeclampsia in Transgenic Rat Model

Objective: Preeclampsia (PE), the most common pregnancy disease, is the main cause for maternal and fetal mortality and morbidity worldwide. It is characterized by a sudden increase in blood pressure in combination with signs of end organ damage, e.g. proteinuria. The mechanisms how pathological pregnancy leads to future cardiovascular morbidity are poorly understood. There are number of risk factors shared between PE and cardiovascular disease such as endothelial dysfunction, obesity, hypertension, thus, leading to a hypothesis that metabolic disturbance may be a possible underlying common mechanism. More nuanced changes in biological processes postpartum in heart after PE are often overlooked and require comprehensive animal models to detect dysregulated metabolic pathways. Design and method: We used well-established transgenic rat model for PE and RNA-sequencing to create expression profiles at different time points (non-pregnant, end of pregnancy and postpartum) of preeclamptic rats and healthy controls. We performed bioinformatical analysis to identify differentially expressed genes for different groups of comparisons (physiological and pathological changes) in 4 heart regions. We used gene set enrichment analysis to identify affected biological processes with comparison to existing heart failure models. To support gene expression data and identify the most affected heart regions we also used speckle tracking echocardiography and immunostaining. Results: We found that all heart regions of PE animals are still affected post-partum (PEpp), while healthy controls recover after pregnancy (WTpp). Data from echocardiography and histological staining support the hypothesis of persistent cardiovascular changes after PE. Using RNAseq data, 39 genes were found to be differentially expressed in all heart regions of the heart of preeclamptic rats compared to the controls (adjusted p-value < 0.05, |logFC| > 2). Among the most disrupted pathways are fatty acid metabolism, oxidative phosphorilation and interferon-alpha/gamma responses. Conclusions: Our expression data supports the hypothesis that preterm metabolic aging of the heart could be the reason for increased cardiovascular risk after a preeclamptic pregnancy.