# Mechanisms linking the frail sarcomere to noncompaction cardiomyopathy

> **NIH NIH K99** · NORTHWESTERN UNIVERSITY · 2024 · $108,935

## Abstract

Project Summary/Abstract
The predominant myosin heavy chain expressed in human heart, beta-MyHC, is encoded by the MYH7 gene.
MYH7 variants are well described in hypertrophic cardiomyopathy and less frequently seen in dilated
cardiomyopathy. A recent series of publications link variants in the 5’ end of the MYH7 gene as implicated in left
ventricular noncompaction cardiomyopathy, often in the setting of a dilated ventricle with impaired function.
Importantly, premature truncations as well as missense variation within the MYH7 gene has been linked to LVNC
in both population studies and in individuals and families. We now generated a heterozygous premature
truncation in MYH7 in human induced pluripotent stem cells (hiPSCs). When differentiated into engineered
human heart tissues, we observe the heterozygous premature truncation in MYH7 produces a phenotype
consistent with excess proliferation and reduced function, which are key features thought to underlie the
development of LVNC in vivo. We hypothesize that truncations and missense variants identified in LVNC are
associated with reduced contractility, rather than hyperdynamic MYH7 variants seen in hypertrophic
cardiomyopathy. Additionally, many missense variants in MYH7 are considered variants of uncertain
significance and methods such as those being used here may help adjudicate variants of risk. Through this
training program under the K99 phase, Dr. Monroe will evaluate missense MYH7 variants associated with LVNC
and evaluate their performance in engineered heart tissues. In his second aim, he will expand the search for
LVNC-associated MYH7 variation to the population scale using linked cardiac imaging and genotype data in the
in population datasets. As Dr. Monroe transitions to his independent phase, he will build from work performed
earlier in his train implicating the Hippo pathway in proliferation and specification. In Aim 3, he will detail new
disease relevance for the Yes-associated protein (YAP) in MYH7-associated LVNC using the models already in
hand and further developed under his K99 training. Finally, in Aim 4, Dr. Monroe uses unbiased approaches to
characterize human cardiomyocyte heterogeneity in healthy and LVNC engineered heart tissues in order to
better delineate the range of differentiation and identify additional downstream pathways that will fuel future
investigations. To promote his career development, Dr. Monroe will draw on the strengths of his mentoring
committee and primary mentor which will focus on expanding his management and his own mentoring skills. His
development plan includes formal and informal courses and workshops aimed at promoting diversity, equity, and
research productivity directed towards improving cardiovascular health.

## Key facts

- **NIH application ID:** 10896446
- **Project number:** 5K99HL168239-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Tanner O Monroe
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $108,935
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-05-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896446

## Citation

> US National Institutes of Health, RePORTER application 10896446, Mechanisms linking the frail sarcomere to noncompaction cardiomyopathy (5K99HL168239-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896446. Licensed CC0.

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