# Biomaterial Platforms to Model the Role of Mechanical Overload in MYBPC3-Linked Hypertrophic Cardiomyopathy

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $388,000

## Abstract

Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart disease and
the most common cause of sudden death in young people. While genetic studies have
identified specific sarcomere genes associated with HCM, they fail to predict which
patients will develop HCM. This proposal is motivated by mounting clinical and animal
model evidence for mechanical epigenetic factors possibly explaining this variance.
These data suggest that mechanical overload on the heart, caused by hypertension,
can act together with sarcomere mutations to cause maladaptive hypertrophic
remodeling in HCM. We are also motivated by the need to identify the factors underlying
the failure of drug treatments to reverse HCM: although medicines that reduce blood
pressure can reverse idiopathic (non-genetic) hypertrophy, they fail to reverse the
course of symptomatic HCM. Based upon these prior data, we hypothesize that HCM
mutations alter the magnitude of cardiac overload required to induce hypertrophic
remodeling and shorten the timeframe over which remodeling is reversible.
We aim to dissect the molecular mechanisms through which mechanical loading
integrates with sarcomere mutations to cause structural and functional pathology in
HCM linked to mutations in Myosin Binding Protein C (MYBPC3). This is possible for
the first time because we have developed a medium-throughput, human induced
pluripotent stem cell (iPSC) derived micro-heart muscle model system that allows us to
apply a controlled magnitude of mechanical overload to iPSC-derived cardiomyocytes.
This system will enable us to characterize the effects of overload on micro-heart muscle
derived from both iPSC without disease mutations, and from iPSC engineered to harbor
HCM patient specific MYPBC3 mutations (Aim 1). We will extend our magnetic hydrogel
technologies to dynamically control the magnitude of mechanical overload on micro-
heart muscles in situ, enabling us to determine mechanisms through which HCM
mutations render cardiomyocytes resistant to blood pressure reducing therapeutics (Aim
2). Finally, we will determine molecular mechanisms linking mechanical overload and
MYBPC3 mutations with hypertrophic remodeling (Aim 3).

## Key facts

- **NIH application ID:** 10279401
- **Project number:** 1R01HL159094-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Nathaniel Huebsch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,000
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10279401

## Citation

> US National Institutes of Health, RePORTER application 10279401, Biomaterial Platforms to Model the Role of Mechanical Overload in MYBPC3-Linked Hypertrophic Cardiomyopathy (1R01HL159094-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10279401. Licensed CC0.

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