Abstract 15564: Transcriptional Profiling Unveils New Molecular Subgroups of Adaptive and Maladaptive Right Ventricular Remodeling in Pulmonary Hypertension

The right ventricle (RV) function plays a crucial role in the prognosis and functional outcome of PAH (Pulmonary Arterial Hypertension) patients. However, RV remodeling and its underlying mechanisms in PAH, and the molecular phenotype of RV in different disease conditions are poorly understood. Therefore, we designed this study to deeply investigate molecular changes underlying right ventricular remodeling and dysfunction in PAH. To this aim, we generated RNA-seq data from 40 patients' RV tissues, clinically classified in adaptive versus maladaptive RV hypertrophy. Using an unsupervised clustering-based analysis, we identified “early” and “late” subgroups in both diseased RV states, associated with patients’ hemodynamic profiles. We then demonstrated that the compensated RV is characterized by an upregulation of cell cycle-associated genes and mitochondrial respiration, whereas excessive levels of extracellular matrix components were central in the decompensation phase. However, dysregulation of fatty acid β-oxidation characterized the early decompensation phase. Furthermore, a comparative analysis from 30 RV samples of monocrotaline (MCT)-induced rat model largely confirmed the stage-specific molecular phenotypes, along with subgroups identification. Finally, we assessed the circulating levels of several dysregulated proteins in two independent cohorts of PAH patients and introduced a panel of five ECM-related proteins that had a significant alteration in patients with compensated vs. decompensated RV in both cohorts. Among those, NID1, C1QTNF1, and CRTAC1 demonstrated higher importance in predicting the development of maladaptive RV hypertrophy in both cohorts, while the correlation of their expression with cardiac functions confirmed their potential biomarker capacity in the prognosis of PAH-associated RV hypertrophy and failure. In conclusion, this comprehensive transcriptome study revealed new subgroups of human RV hypertrophy beyond the clinical measurements, while combination with proteome analysis proposed a panel of potential PAH biomarkers related to patients' RV function. Furthermore, our comparative analysis of two species supports the relevance of current animal models to explore new targets.