# Mechanisms of Congenital Heart Valve Disease

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $483,910

## Abstract

Mechanisms of Congenital Heart Valve Disease
Project Summary
Congenital heart valve abnormalities due to morphological or extracellular matrix (ECM) defects can
progress over time to myxomatous valve disease (MVD), necessitating surgical valve replacement. MVD
affects up to 2% of the US population and more than 10% of individuals over 75 have mitral valve
regurgitation. Currently, there is no medical therapy, and, if left untreated, MVD can lead to impaired left
ventricular function, heart failure, and ultimately death. The current standard of care is valve repair or
replacement, which is highly invasive, not always successful, of limited durability, and contraindicated by
age and many common comorbidities. Congenital valve abnormalities, including those associated with
Marfan Syndrome (MF) can develop into progressive MVD characterized by collagen fiber fragmentation
and replacement by mucopolysaccharides and proteoglycans, leading to leaflet thickening and insufficiency.
However, the mechanisms that promote progressive valve leaflet degeneration are not known, and there
are currently no therapies available to prevent or reverse MVD progression. Our recent studies in mouse
models of MVD, including the Fbn1C1039G model of Marfan syndrome, implicate Wnt signaling and myeloid
cell infiltration in progressive MVD. Pigs with gene-edited mutations in Fbn1 also demonstrate
characteristics of MFS, including thickening of mitral valve leaflets. We hypothesize that congenital ECM
abnormalities lead to increased Wnt signaling in valve interstitial cells (VIC)s, resulting in increased cytokine
expression and macrophage infiltration, that contribute to pathologic collagen remodeling and valve
dysfunction characteristic of MVD progression. The Aims are: 1) Identify VIC sublineages, macrophage
populations, and gene expression changes of MVD in mouse, pig and human MFS valves. 2) Determine if
Wnt signaling in Fbn1C1039G valves is required for ECM dysregulation and progression of myxomatous
disease. 3) Determine if infiltrating macrophages contribute to the pathogenic progression of ECM
remodeling and myxomatous valve disease in MFS. The long-term goals of these studies are definition of
regulatory pathways in MVD progression, including MVD resulting from congenital valve defects, and
identification of new nonsurgical therapeutic approaches for MVD.

## Key facts

- **NIH application ID:** 9905548
- **Project number:** 5R01HL143881-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Katherine E Yutzey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,910
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905548

## Citation

> US National Institutes of Health, RePORTER application 9905548, Mechanisms of Congenital Heart Valve Disease (5R01HL143881-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9905548. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*