Transcriptomic profiles of ischemic and non-ischemic right ventricular heart failure

Abstract Background/Introduction Left ventricular heart failure (LVHF) results in passive increased pressure transmission to pulmonary vessels, leading to augmented right ventricular (RV) afterload. This initially leads to compensatory RV hypertrophy (RVH) which can transit to RV heart failure (RVHF), worsening hemodynamics, symptoms and prognosis. RVHF can also be consecutive to pulmonary arterial hypertension (PAH), characterized by pulmonary arterioles stenosis leading to increased RV afterload, resulting initially in compensatory RVH, but which can also trigger RVHF. RVHF is poorly preventable, partly due to a limited mechanistic knowledge. Purpose Characterize the transcriptomic profiles of right heart from two rat models of RVHF: pulmonary artery banding (PAB, similar to PAH in human, non-ischemic), and post-myocardial infarction (MI, consecutive to LVHF, ischemic). Methods PAB was performed in 6-week-old male Wistar rats and MI was induced in 8-week-old male rats by left coronary artery ligation. Echocardiography and pressure-volume loops were used to assess LV and RV function and classify rats into compensatory (RVH) or decompensated (RVHF) groups. Bulk RNA-seq data were generated from the right ventricles of 6-8 rats per group. Differentially expressed (DE) genes were identified using edgeR (false discovery rate 0.05 and log2 fold-change 0.5 or -0.5). Results Differences in hemodynamic responses and RV disease progression emerged between PAB and MI. In PAB, RV systolic pressure and contractility are increased in RVH rats. However, as the disease progresses to RVHF, these parameters decline, indicating end-stage RV failure. TAPSE measurements indicate a distinct separation between RVH and RVHF. In the MI model, no clear separation is observed. The right ventricle appear to fail earlier than in PAB, even when exposed to lower afterloads. Overload is likely not the primary determinant of RV disease progression in MI. This is consistent with PAB as a pure pressure overload model, while MI model has a more complex pathology where overload is not the decisive factor. RV transcriptomic profiles were more similar in the different groups of rats (Ctrl, RVH, RVHF) in the PAB model than in the MI model (Figure). In the MI model, 245 genes were DE in RVH compared to controls, and 4997 genes were DE between RVHF and controls. Pathways such as hypoxia and angiogenesis were regulated. In the PAB model, 314 genes were DE in RVH compared to controls, and 5393 genes were DE between RVHF and controls. Associations with muscle structure and energy derivation were observed. Non-coding RNAs were more regulated in the MI model compared to the PAB model (41% vs. 29%, p = 2.2e-16). Conclusions We provide the first transcriptomic landscape of right ventricle from ischemic and non-ischemic models of RVHF and confirm the suitability of these models to study the molecular mechanisms beyond the transition from RVH to RVHF.