Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension

Right ventricular (RV) function is critical to prognosis in all forms of pulmonary hypertension. Here we perform molecular phenotyping of RV remodeling by transcriptome analysis of RV tissue obtained from 40 individuals, and two animal models of RV dysfunction of both sexes. Our unsupervised clustering analysis identified 'early' and 'late' subgroups within compensated and decompensated states, characterized by the expression of distinct signaling pathways, while fatty acid metabolism and estrogen response appeared to underlie sex-specific differences in RV adaptation. The circulating levels of several extracellular matrix proteins deregulated in decompensated RV subgroups were assessed in two independent cohorts of individuals with pulmonary arterial hypertension, revealing that NID1, C1QTNF1 and CRTAC1 predicted the development of a maladaptive RV state, as defined by magnetic resonance imaging parameters, and were associated with worse clinical outcomes. Our study provides a resource for subphenotyping RV states, identifying state-specific biomarkers, and potential therapeutic targets for RV dysfunction. Khassafi et al. identify molecular subgroups of right ventricular (RV) dysfunction using transcriptomic analysis of RV samples from individuals with compensated RV hypertrophy or decompensated RV failure and two rat models of RV dysfunction. Several extracellular matrix genes found to be deregulated in decompensated RV subgroups were validated at the protein level in two independent cohorts of individuals with pulmonary arterial hypertension, revealing their predictive biomarker potential in maladaptive RV development.