# Mechanisms of Right Ventricular Dysfunction in Scleroderma-associated PAH

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $658,783

## Abstract

Project Summary
Systemic sclerosis (SSc), is a heterogeneous disorder characterized by dysfunction of the
endothelium, and dysregulation of fibroblasts and the immune system. SSc-associated
pulmonary arterial hypertension (SSc-PAH), a common and often underdiagnosed complication
of SSc, is a devastating syndrome leading uniformly to death through right ventricular (RV)
failure. In the previous funding period, we demonstrated depressed intrinsic RV myocardial
function in SSc-PAH compared to idiopathic PAH using gold standard RV pressure-volume (PV)
analysis, and further revealed that in vivo dysfunction significantly correlates with profound
sarcomeric dysfunction in SSc-PAH skinned cardiomyocytes (obtained from RV biopsies) as
reflected by a marked decline in peak calcium-activated tension and enhanced calcium
sensitivity. These novel findings, combined with preliminary analyses showing decreased
troponin-I (TnI) phosphorylation and myosin binding protein-C (MyBP-C) degradation in RV
myocardium, support the hypothesis that sarcomere dysfunction is a primary mechanism for RV
failure, and likely early demise, in SSc-PAH. We also applied non-invasive RV imaging,
including speckle-tracking echocardiography to assess RV regional function, and cardiac
magnetic resonance (CMR) to assess RV remodeling, fibrosis, and myocardial perfusion to
show that some of these parameters may predict survival. Our overall hypothesis is that
impaired regional microperfusion and fibrosis, resulting in altered contractile function, are 1)
pathobiologic processes at the core of RV maladaptation and decreased SSc-PAH survival; 2)
can be detected non-invasively; and 3) can only respond to RV-targeted therapy. In Aim 1 we
will assess treatment responsiveness of the RV rest function, physiologic reserve, and RV-
Pulmonary arterial interaction in SSc-PAH patients by means of PV analysis and right heart
catheterization. In Aim 2 we will derive optimal non-invasive measures of RV performance that
respond to therapy and predict time to clinical worsening and survival. And in Aim 3 we will test
whether best practice combination PAH therapy, or RV sarcomere sensitizers, improve pre-
treatment sarcomere dysfunction in RV myofilaments isolated from SSc-PAH patients.

## Key facts

- **NIH application ID:** 10165783
- **Project number:** 5R01HL114910-08
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Paul M. Hassoun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $658,783
- **Award type:** 5
- **Project period:** 2012-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165783

## Citation

> US National Institutes of Health, RePORTER application 10165783, Mechanisms of Right Ventricular Dysfunction in Scleroderma-associated PAH (5R01HL114910-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10165783. Licensed CC0.

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