# Novel bioengineering models to dissect cardiac cell-cell defects in arrhythmogenic cardiomyopathy

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $253,500

## Abstract

PROJECT SUMMARY
Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive fibrofatty replacement of the
myocardium, arrhythmias, and sudden death. Fibrofatty substitution in arrhythmogenic cardiomyopathy
contributes to worsening arrhythmogenesis by creating a non-conductive substrate, and causes ventricular
dysfunction leading to heart failure. The mechanisms underlying this disease are still unclear; a better
understanding of the pathogenesis is needed to find better options for clinical management. To address this
challenge, reliable species-specific models are needed; here we propose to develop a novel human model,
that will serve as a system to study the pathogenesis of cardiac fibrofatty infiltration. This study integrates
engineering and biomedical sciences, applying tissue engineering, cardiac physiology, bioinformatics and stem
cell technologies. Our long-term goal is to provide a model of fibrofatty myocardial infiltration to investigate
underlying disease mechanisms, which will lead to the development of greatly needed therapies for patients
who suffer from cardiac diseases related to the presence of fibrofatty infiltration. The central objective of this
proposal is to demonstrate that fibrofatty infiltration of the myocardium can be replicated in a 3D engineered
cardiac tissue, resembling deficient contractility and altered electrophysiological properties that mimic what is
observed in patients that suffer from ACM. The molecular signatures of fibrofatty infiltration in the context of our
engineered cardiac tissue model will also be analyzed. We will approach this in two aims. In Aim 1 we will
develop a 3D engineered cardiac tissue model of fibrofatty infiltration of the myocardium using hiPSCs from
patients with ACM. We will combine hiPSC-cardiomyocytes and hiPSC-epicardial cells treated to undergo
epithelial-mesenchymal transition; aiming to resemble the ACM functional phenotype. In Aim 2, exploiting the
role of the epicardium as source of fibrofatty infiltration; we will develop a 3D engineered cardiac tissue model
of myocardial fibrofatty infiltration using hiPSCs from healthy donors. In this study, we propose a strategy
based on evidence that fibrofatty infiltration is induced from epicardial activation; hiPSC-derived epicardial cells
will be treated to induce their further differentiation into fibroblasts and adipocytes. We will examine functional
and structural properties, along with single-cell transcriptomics of the engineered cardiac tissue models. We
expect that results from this study will advance our understanding of the contribution of specific cues from
ACM-related cells in the pathogenesis of fibrofatty remodeling; our physiologically relevant model will serve to
unravel the cell-cell cross-talk and mechanisms responsible for initiation and progression of fibrofatty infiltration
of the myocardium. This project will improve the health of patients with ACM by leading the development of a
human model of the disea...

## Key facts

- **NIH application ID:** 10827986
- **Project number:** 5R21HL165298-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Irene Cal y Mayor-Turnbull
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $253,500
- **Award type:** 5
- **Project period:** 2023-04-12 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827986

## Citation

> US National Institutes of Health, RePORTER application 10827986, Novel bioengineering models to dissect cardiac cell-cell defects in arrhythmogenic cardiomyopathy (5R21HL165298-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10827986. Licensed CC0.

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