# Understanding the Mechanisms of Ventricular Dysfunction in Hypoplastic Left Heart Syndrome

> **NIH NIH F30** · STANFORD UNIVERSITY · 2020 · $38,296

## Abstract

PROJECT SUMMARY/ABSTRACT
 Hypoplastic Left Heart Syndrome (HLHS) is the leading cause of neonatal cardiac death in the United
States accounting for 2-3% of all congenital heart disease. While “HLHS” is used to describe a spectrum of
anomalies afflicting the left ventricle, it is defined as the severe underdevelopment of the left heart and ascending
aorta along with atresia or stenosis of the mitral and aortic valves. Currently, the long-standing theory for the
etiology of HLHS proposes that aortic or mitral valve obstructions impair blood flow through the left ventricle
leading to hypoplasia of the left sided structures of the heart. While clinical trials have attempted to relieve blood
flow obstructions in utero, these studies have had limited success in rescuing LV growth and blood flow in human
HLHS fetuses. Here, I present preliminary findings that reveal that cardiomyocytes derived from HLHS patient-
derived human induced pluripotent stem cells (hiPSC) demonstrate significantly reduced contractile force
generation suggesting that intrinsic myocardial dysfunction may contribute to the disruption ventricular blood
flow. These findings raise the exciting possibility of developing therapeutic strategies to potentially improve
myocardial function to prevent LV hypoplasia in utero.
 The overall objective of this proposal is to identify molecular and transcriptional mechanisms giving rise
to impaired contractile function in HLHS ventricular cardiomyocytes. The hypothesis is that HLHS ventricular
cardiomyocytes display dysregulated expression of core transcriptional regulators necessary for the
maintenance of the contractile machinery used for healthy myocardial function. Using the hiPSC model system,
I will use healthy and HLHS patient derived hiPSCs to test the central hypothesis and attain the objective of this
application. Specific Aim 1: Identify the molecular mechanisms giving rise to impaired contractile function in
HLHS hiPSC-derived ventricular cardiomyocytes. Specific Aim 2: Determine the role of cardiomyocyte
transcriptional regulators in cell function and survival in HLHS-hiPSC derived cardiomyocytes. Using
CRISPR/Cas9 genome editing, I will introduce a genetic reporter system that will allow for the isolation of
ventricular and left ventricular cardiomyocytes from hiPSC differentiation in vitro. This will allow for the study of
specific sarcomeric and electrophysiologic mechanisms driving impaired contractile function and to assess
whether these defects are specific to the LV. Using state of the art single cell RNA-sequencing technology, I will
conduct extensive transcriptomic profiling of HLHS hiPSC-cardiomyocytes to identify dysregulated expression
of key transcriptional regulators involved in regulating genes necessary for myocyte function and survival.
 Successful execution of the work proposed will lead to three significant contributions: 1) Will identify
specific molecular drivers of myocardial contractile dysfunction in HLHS, 2) ...

## Key facts

- **NIH application ID:** 10017702
- **Project number:** 5F30HL149152-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Francisco Xavier Galdos
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,296
- **Award type:** 5
- **Project period:** 2019-09-16 → 2022-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017702

## Citation

> US National Institutes of Health, RePORTER application 10017702, Understanding the Mechanisms of Ventricular Dysfunction in Hypoplastic Left Heart Syndrome (5F30HL149152-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10017702. Licensed CC0.

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