# Multiscale Modeling of Right Ventricular Fibrotic Remodeling in Pulmonary Arterial Hypertension

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $381,665

## Abstract

PROJECT SUMMARY
Pulmonary arterial hypertension (PAH) is a disease of the pulmonary arterial vasculature and its
remodeling, in which patient mortality is significantly associated with impaired RV function. The
prognosis of patients with PAH is very poor with five-year survival <50%, and there are no
available therapies to prevent right heart failure in PAH. Recent studies by the applicant’s group
in animal models of PAH and clinical studies have shown that altered RV diastolic stiffness to be
an important feature of PAH pathogenesis. Here we propose to investigate the structural
mechanisms by which remodeling of RV extracellular matrix (ECM) alters their mechanical
properties and the cellular mechanisms by which changes in RV mechanical loading and material
properties in turn regulate the phenotype and pro-fibrotic signaling of cardiac fibroblasts. Using a
comprehensive time-course in a well-established animal model of PAH progression, we will
conduct detailed in-vivo physiological studies and biaxial tissue biomechanical testing of intact
and decellularized RV samples together with microstructural mathematical modeling to determine
how ECM remodeling alters RV myocardial mechanic and diastolic function. We will then
recapitulate these alterations in RV ECM structure and mechanics in a novel in-vitro model to
investigate how altered ECM structure and loading conditions in PAH regulate RV cardiac
fibroblasts (CFB) differentiation, activation, and pro-fibrotic ECM expression. Finally, we will use
these new in-vitro measurements to extend and validate a mathematical model of mechano-
regulated CBF cell signaling. The specific aims of this proposal will determine the time course
of changes in RV geometry, contractility and diastolic material properties that compensate for
altered hemodynamic loads during PAH and determine how these mechanisms become
maladaptive (Aim 1); the changes in RV myocardial structure and mechanics during adaptive and
maladaptive RV ECM remodeling, and identify the biomechanical stimuli driving these changes
in PAH (Aim 2); and the mechanobiological mechanisms regulating adaptive and maladaptive RV
ECM remodeling during PAH (Aim 3). The overall outcome of the proposed research will be the
discovery of quantitative biological principles of the RV extracellular matrix (ECM) remodeling that
contribute to the changes in diastolic function that occur during the progression of PAH and the
transition to decompensated RV dysfunction.

## Key facts

- **NIH application ID:** 10337231
- **Project number:** 5R01HL155945-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Daniela Valdez-Jasso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $381,665
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337231

## Citation

> US National Institutes of Health, RePORTER application 10337231, Multiscale Modeling of Right Ventricular Fibrotic Remodeling in Pulmonary Arterial Hypertension (5R01HL155945-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10337231. Licensed CC0.

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