Pullamsetti, Soni SavaiKhassafi, FatemehFatemehKhassafi2025-04-222025-04-222024PMC11358157https://jlupub.ub.uni-giessen.de/handle/jlupub/20479https://doi.org/10.22029/jlupub-19830The functionality of the right ventricle (RV) has a significant impact on prognosis and functional outcome in patients with pulmonary hypertension (PH). However, our knowledge of RV remodeling and its molecular properties under different disease conditions such as PH is limited. Therefore, the aim of this study is to describe the molecular profile of adaptive and maladaptive right ventricular remodeling and dysfunction in PH. To achieve this goal, we adopted an integrative analysis approach using transcriptomics and proteomics in humans as well as different animal models of PH with RV dysfunction. First, we performed a comparative analysis of two animal models (MCT and PAB). Using an unsupervised clustering approach, we identified different subgroups within the decompensated RV states and described the "early" to "late" maladaptive RV transition, a classification that was largely confirmed by the hemodynamic measurements. In addition, we generated RNA-seq data from RV tissue of 40 patients clinically categorized as adaptive and maladaptive RV hypertrophy and identified distinct subgroups of compensated and decompensated RV by their distinct molecular phenotype through a similar analytical approach. Our integrative analysis revealed that extracellular matrix remodeling, together with a strong downregulation of fatty acid β-oxidation, characterizes the early decompensation phase of RV, while several estrogen-related signaling pathways are associated with the sex-specific differences in RV adaptation. Next, we integrated the RV transcriptome with an independent plasma proteome cohort to assess the circulating levels of our targets. We then validated our final candidates in a second independent cohort of pulmonary arterial hypertension (PAH) patients and introduced a panel of five ECM-related proteins that could significantly classify patients with compensated or decompensated RV. In particular, NID1 and C1QTNF1 were found to be particularly significant in predicting early and late decompensated RV state, while correlating with functional parameters and clinical outcomes, demonstrating their potential as prognostic biomarkers for PAH-associated RV dysfunction. Altogether, our study uncovered novel subgroups of human RV remodeling beyond clinical measurements, while the combination with proteomic analysis revealed five potential RV-specific biomarkers for PAH. Furthermore, highlighting the molecular phenotype of the early and late subgroups of maladaptive RV provides new potential therapeutic targets for RV dysfunction to intervene in the transition from compensation to decompensation, thereby enhancing survival and quality of life in PAH.enCC0 1.0 Universalddc:570ddc:610