# Elucidating the Role of Biomechanical Strain in Atrial Physiology and Arrhythmias

> **NIH NIH F30** · YALE UNIVERSITY · 2024 · $33,859

## Abstract

PROJECT SUMMARY/ABSTRACT
MOTIVATION: The burden of atrial fibrillation (AF) and its clinical consequences, which include stroke, heart
failure, and decreased quality of life, are expected to increase dramatically over the next several decades.
Despite this, few disease-modifying therapies exist, and symptomatic treatments are limited by side effects.
Leveraging fundamental discoveries in cardiac tissue biomechanics, this proposal takes a novel approach to
arrhythmia pathogenesis, uncovering biophysical mechanisms that underlie healthy atrial function and
pathological, pro-arrhythmic remodeling. Motivated by a desire to accurately model atrial physiology and
pathology, we use human induced pluripotent stem cell (hiPSC)-derived engineered heart tissue (EHT) and an
electro-mechanical bioreactor to delineate “healthy” vs “diseased” mechanical loading. AIMS: In Aim 1,
physiologically-inspired biomechanical strain is applied to atrial EHTs to improve their functional maturity at the
gene expression, contractile, and electrophysiological level. Successful completion of this aim will broadly
increase the applicability of engineered heart tissue for atrial disease modeling. In Aim 2, a substrate for atrial
arrhythmias will be induced by imposing pathological mechanical strain on atrial EHTs. These abnormal
mechanical strains are directly inspired by clinical imaging findings. Notably, abnormal mechanical loading of
tissue causes contractile dysfunction, along with upregulation of pathological remodeling genes, such as α-
SMA and calmodulin kinase. This suggests that a common, mechanosensitive pathway may be an attractive
upstream target for novel AF therapies. TRAINING: To enable these investigations, the applicant will pursue
new learning in stem cell biology, engineered heart tissue development, in vitro electrophysiology, and electron
microscopy. The training plan, overseen by two co-sponsors in complementary fields (biomedical
engineering/muscle physiology and electrophysiology), will emphasize acquisition of new scientific knowledge
and expertise; rigor, reproducibility, and generalizability of in vitro disease models; clinical correlations; and
professional development. The proposal will leverage cutting-edge technology and expertise at Yale University
and Yale School of Medicine, and fully support the applicant’s future career goal. RELEVANCE: AF affects
millions of Americans, and 10% of those over 80. The

## Key facts

- **NIH application ID:** 10996087
- **Project number:** 5F30HL170584-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ilhan Gokhan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $33,859
- **Award type:** 5
- **Project period:** 2023-09-16 → 2027-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996087

## Citation

> US National Institutes of Health, RePORTER application 10996087, Elucidating the Role of Biomechanical Strain in Atrial Physiology and Arrhythmias (5F30HL170584-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10996087. Licensed CC0.

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