# Mechanisms and treatment of right ventricular sarcomere dysfunction in scleroderma-associated pulmonary arterial hypertension

> **NIH NIH K23** · JOHNS HOPKINS UNIVERSITY · 2022 · $177,120

## Abstract

Steven Hsu, M.D. is an Assistant Professor in the Division of Cardiology at Johns Hopkins University. Dr. Hsu
seeks an NIH Mentored Patient-Oriented Research Career Development Award in order to obtain the expertise
and skills necessary to launch a translational research career focused on human right ventricular (RV) failure.
Dr. Hsu has elected to work with primary mentor Dr. David Kass, a pioneer in cardiac physiology and
molecular pathobiology, and co-mentor Dr. Paul Hassoun, a thought leader in pulmonary hypertension. Both
occupy complementary areas of research expertise, work together seamlessly, and boast long track records of
successful funding and training of physician-scientists. A complementary group of collaborators will assist in
the research and form an advisory committee as well. Dr. Hsu will leverage their combined mentorship to study
the molecular underpinnings of RV sarcomere dysfunction in human scleroderma-associated pulmonary
arterial hypertension (PAH). The specific aims of his research proposal are to: (1) identify the alterations in
sarcomere proteins troponin I and myosin-binding protein C that underlie the in vivo RV dysfunction of human
scleroderma-associated PAH; and (2) determine which RV-directed pharmacotherapies would best restore
function in failing RV sarcomeres isolated from these same subjects. Dr. Hsu's career development training
objectives during this award period are to develop proficiency in clinical studies, master invasive RV pressure-
volume hemodynamics, broaden his translational basic science skillset, and prepare for independent
investigator funding. These will enable Dr. Hsu's long-term goal of developing a career dedicated to the
translational investigation of human RV heart failure. PAH is a deadly disease resulting from a pathologic
increase in pulmonary vascular load. Although pulmonary vasodilator therapies have helped many, the
scleroderma-associated PAH subgroup lags far behind its PAH counterparts in terms of functional capacity and
survival. Dr. Hsu has first authored two high impact publications showing that failure of RV adaptation in
scleroderma-associated PAH is the likely culprit. Scleroderma-associated PAH patients suffer disproportionate
RV contractile dysfunction when compared to idiopathic PAH and normal controls, both at the in vivo RV
chamber level and the ex vivo RV sarcomere level. Understanding and treating this RV dysfunction would meet
a major unmet need in the care of patients with PAH. Preliminary work thus far points towards explanatory
molecular alterations in the key sarcomere proteins troponin I and myosin-binding protein C. The proposed
research will test the centrality of these two sarcomere proteins to the chamber and cellular RV dysfunction of
human scleroderma-associated PAH, while also determining the efficacy of therapeutics directed against the
failing RV sarcomere. In doing so, this work seeks to clarify the molecular mechanisms of RV failure in
scleroderma-ass...

## Key facts

- **NIH application ID:** 10376761
- **Project number:** 5K23HL146889-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Steven Hsu
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $177,120
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376761

## Citation

> US National Institutes of Health, RePORTER application 10376761, Mechanisms and treatment of right ventricular sarcomere dysfunction in scleroderma-associated pulmonary arterial hypertension (5K23HL146889-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10376761. Licensed CC0.

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