# Novel Biomarkers of Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

> **NIH NIH F32** · JOHNS HOPKINS UNIVERSITY · 2022 · $57,184

## Abstract

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 rem...

## Key facts

- **NIH application ID:** 10533867
- **Project number:** 1F32HL159917-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mario Naranjo Tovar
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $57,184
- **Award type:** 1
- **Project period:** 2022-09-20 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533867

## Citation

> US National Institutes of Health, RePORTER application 10533867, Novel Biomarkers of Right Ventricular Dysfunction in Pulmonary Arterial Hypertension (1F32HL159917-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10533867. Licensed CC0.

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