# Cause and effect of transient changes in stress, gene expression, and RV fiber orientation during RV remodeling, and its impact on RV function and inter-ventricular coupling in pulmonary hypertension

> **NIH NIH R56** · UNIVERSITY OF COLORADO DENVER · 2021 · $404,365

## Abstract

PROJECT SUMMARY
Pulmonary hypertension (PH) is a cardiopulmonary disease that ultimately leads to right
ventricular (RV) failure. Currently there are no approved therapies targeting the RV and most
research is focused on reducing fibrosis, although it is unclear if this will ultimately improve RV
pumping function. However, the orientation of collagen and cardiomyocyte fibers likely have a
major influence on RV function and are largely overlooked in ongoing research and clinical
practice. Furthermore, the role of the LV in RV function is almost completely discounted, but
previous research from the 90’s has suggested that the left ventricle (LV) is more important for
RV function than the contracting RV free wall.
 Our previous data has shown that the mechanics of LV contraction is drastically different
in children with PH and in mice after pulmonary arterial banding (PAB). Furthermore,
mathematical simulations of the heart in our lab have shown that the mechanical burden of the
remodeling and pressure-overloaded RV can result in the mechanistic problems we see in both
ventricles in children with PH. However, two critical questions remain unanswered: how do
changes in RV structure impact RV and LV contractile mechanics, and how do these changes in
LV contractile mechanics impact RV function?
 In this study, we will combine the PAB mouse model with in silico simulations to
investigate how changes in RV fiber orientation and stiffening, in the RV free wall, impact RV
pumping function. Then, we will combine PAB with aortic constriction to study how RV
remodeling interferes with LV torsion and if this interrupts LV-to-RV mechanical assistance
during systole. Finally, by collecting a time course dataset of imaging and gene expression, we
will identify genes that are directly impacted by changes in mechanical stress and how they
trigger their downstream remodeling pathways.
 By bridging the gap between gene expression, structure, function, and inter-ventricular
contractile mechanics, this project could lead to a better understanding of adaptive vs.
maladaptive remodeling pathways. Furthermore, our research is focused on identifying those
remodeling characteristics with the biggest influence on function and could expose gene
expression pathways that will serve as drug targets in future studies.

## Key facts

- **NIH application ID:** 10209842
- **Project number:** 1R56HL152250-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Vitaly Kheyfets
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,365
- **Award type:** 1
- **Project period:** 2021-09-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209842

## Citation

> US National Institutes of Health, RePORTER application 10209842, Cause and effect of transient changes in stress, gene expression, and RV fiber orientation during RV remodeling, and its impact on RV function and inter-ventricular coupling in pulmonary hypertension (1R56HL152250-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10209842. Licensed CC0.

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