1Universitätsklinikum Gießen und Marburg GmbH Klinik für Herz-, Kinderherz- und Gefäßchirurgie Gießen, Deutschland; 2Justus-Liebig Universität Giessen Rudolf Buchheim Institut für Pharmakologie Gießen, Deutschland; 3Justus-Liebig-Universität Giessen Physiologisches Institut Gießen, Deutschland; 4Kerckhoff Klinik GmbH Abteilung für Kardiologie Bad Nauheim, Deutschland; 5Justus-Liebig-Universität Giessen Medizinische Klinik I, Kardiologie und Angiologie Gießen, Deutschland
Background
Until recently, only little attention has been paid to the right ventricle (RV) and it has commonly been thought that the mechanical and molecular characteristics of the RV are similar to those of the left ventricle (LV). However, the RV differs developmentally, anatomically and functionally from the LV, suggesting that the substantial knowledge on molecular events underlying LV failure cannot directly be translated to RV failure. Furthermore, therapies used to treat LV failure fail to improve ventricular function in RV failure.
Methods
We established two rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Animals were characterized by high-resolution echocardiography, micro-CT and pressure-volume loops.
RNA sequencing and proteomic analyses were used to identify differentially expressed genes. Rat data sets were intersected with transcriptome data sets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) in order to identify a common gene signature of the RV failure in rat and human hearts.
Results
Detailed bioinformatics analyses of 181 RNAseq datasets from cardiomyocytes or whole heart samples from these models, led to the identification of gene signatures, protein, and transcription factor (TF) networks specific to ventricles, compensated or decompensated disease states and type of heart failure. RNA-FISH approaches confirmed PAB-mediated regulation of key genes and revealed striking, spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with 95 transcriptome data sets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels strongly correlated with the severity of right heart disease
Conclusion
Our data define a conserved, differentially regulated genetic network that coordinates progressive right heart failure in rats and humans.