# Assessing myofilament phenotype and contractile response to pharmacotherapies in a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model of hypoplastic left heart syndrome (HLHS)

> **NIH NIH R03** · UNIVERSITY OF COLORADO DENVER · 2022 · $77,750

## Abstract

Project Summary
 Despite tremendous advances in surgical technique and post-operative care, children with hypoplastic
left heart syndrome (HLHS) remain at lifelong risk for systolic failure of the systemic right ventricle (RV). In
HLHS patients, traditional adult heart failure medications have been overall ineffective in preventing pathologic
cardiac remodeling or preserving contractile function. Thus, once children with HLHS develop heart failure
symptomatology secondary to decreased cardiac function, heart transplantation is often the only long-term
therapeutic option.
 The central hypothesis of this proposal is that HLHS cardiomyocytes have inherent alterations at the
level of the myofilament that may confer a heart failure predisposition and alter the contractile response to
medical heart failure therapies. Preliminary data demonstrates abnormalities in calcium sensitivity and
decreased cardiac troponin I phosphorylation in cardiomyocytes from HLHS subjects with end-stage heart
failure. Nevertheless, there is a need to expand upon these studies utilizing a HLHS model system to further
evaluate the impact of these myofilament changes. Therefore, the goal of this proposal is to develop a human
induced pluripotent stem cell cardiomyocytes (hiPSC-CM) model derived from HLHS subjects to define the
myofilament contribution to the contractile abnormalities present in HLHS and assess the impact of
myofilament differences on the contractile response to HF therapies. Patient-specific HLHS hiPSC-CM will be
generated from 3 HLHS subjects with end-stage heart failure, and the myofilament contractile phenotype will
be defined through mechanical studies of skinned hiPSC-CM, quantification of myofilament protein isoforms,
and assessment of myofilament post-translational modifications. These findings will be paired with the
myofilament phenotype demonstrated in the explanted, HLHS heart tissue from the same subject. Additionally,
myofilament assessments will be performed following treatment of HLHS hiPSC-CM with current and emerging
HF pharmacotherapies in order to directly measure the consequences of drug therapy on the HLHS
myofilament.
 Ultimately, augmenting mechanistic understanding of the contractile dysfunction present in HLHS
cardiomyocytes has the potential to improve outcomes for HLHS patients by informing an accurate HF risk-
stratification paradigm. Furthermore, prioritizing an HLHS-specific appraisal of the contractile response to
pharmacotherapies may result in personalized pharmacologic strategies to preserve systemic RV function.

## Key facts

- **NIH application ID:** 10460367
- **Project number:** 5R03HL158725-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Stephanie Jialing Nakano
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $77,750
- **Award type:** 5
- **Project period:** 2021-08-03 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460367

## Citation

> US National Institutes of Health, RePORTER application 10460367, Assessing myofilament phenotype and contractile response to pharmacotherapies in a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model of hypoplastic left heart syndrome (HLHS) (5R03HL158725-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10460367. Licensed CC0.

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