Novel Biomarkers of Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

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Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a complex disorder of the pulmonary vasculature resulting in progressive adaptive and maladaptive morphological and functional changes in the right ventricle (RV), ultimately leading to RV failure, the single most crucial negative determinant of survival in PAH. RV evaluation has been well established using hemodynamic and noninvasive imaging techniques, including right heart catheterization and pressure-volume loops (PV-loops) technology, and cardiac magnetic resonance (CMR), respectively. There is a clinical need to identify reliable, noninvasive, and cost-effective biomarkers with mechanistic significance, that can assess RV function, remodeling, and guide therapeutic interventions. In preclinical studies, our group has demonstrated that an imbalance between angiostatic and angiogenic factors is critical for disease progression and subsequent RV dysfunction. We have shown that the angiostatic peptide endostatin (ES), a cleaved product from Collagen 18a1 (Col18a1), is elevated in PAH and associated with increased mortality. Furthermore, ES induces thrombospondin 1 (TSP1) release with deleterious downstream hemodynamic and morphologic RV outcomes. In this context, this proposal's global objective is to identify the angiostatic molecules within the Col18a1/ES/TSP1 pathway as reliable biomarkers of the association between PAH and RV function and remodeling. To test our hypothesis, we will use data from two sets of well-defined cohorts. This project has three novel aims. First, to define associations between ES and TSP1 plasma levels in PAH and RV dysfunction and pathologic RV remodeling, we will measure ES and TSP1 levels in the plasma of patients with and without PAH from a completed NIH/NHLBI study led by my sponsor. RV function will be derived from multi-beat-PV loops with measurement of the ratio of end-systolic elastance (Ees) and effective arterial elastance (Ea), as a surrogate of RV-PA coupling. RV remodeling will be assessed using RV mass and VMI (Ventricular Mass Index: ratio between RV and LV mass) by CMR. Second, to define RV Col18a1 and TSP1 expression in PAH and the association with RV dysfunction and remodeling, we will asses the spatial RV localization of Col18a1 and TSP1 expression, by immunohistochemistry, in human hearts obtained from autopsies of PAH patients; and the correlation of Col18a1 and TSP1 mRNA expression, from RV endomyocardial biopsy samples collected by my sponsor, with RV function and remodeling as decribed above. Third, to define response to therapy in ES and TSP1 plasma levels in PAH and their correlation with improvement in RV dysfunction and remodeling, we will assay ES and TSP1 levels from plasma of participants who are being enrolled in a second prospective NIH/NHLB parent study led by my sponsor. Using a matched paired analysis, we will identify changes in ES and TSP1 levels pre and post-therapy and their correlation with RV function and remodeling. Successful completion of these aims will support the use of ES and TSP1 as novel, noninvasive, and reliable biomarkers that can track RV function and remodeling in PAH.