# Versatile hiPSC Models and Bioengineering Platforms for Investigation of Atrial Fibrosis and Fibrillation

## TL;DR

This paper proposes using hiPSC-derived cells and 3D bioengineering to create better models of atrial fibrosis, which could improve understanding and treatment of atrial fibrillation.

## Contribution

The paper introduces a novel conceptual roadmap integrating hiPSC-derived cells and 3D techniques to build human-specific models of atrial fibrosis.

## Key findings

- Current AF models fail to replicate complex 3D interactions between human atrial cells and fibrotic extracellular matrix.
- Proposed models will connect fibrotic patterns to arrhythmogenic electrical changes, aiding drug discovery and personalized medicine.

## Abstract

What are the main findings?
This review identifies a critical gap: existing atrial fibrillation (AF) models (animal, 2D) fail to replicate the complex, 3D interplays between human atrial cells and the fibrotic extracellular matrix.We present a conceptual roadmap to address this gap by integrating human-induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes and fibroblasts with 3D bioengineering techniques to build functional, human-specific models of atrial fibrosis.

This review identifies a critical gap: existing atrial fibrillation (AF) models (animal, 2D) fail to replicate the complex, 3D interplays between human atrial cells and the fibrotic extracellular matrix.

We present a conceptual roadmap to address this gap by integrating human-induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes and fibroblasts with 3D bioengineering techniques to build functional, human-specific models of atrial fibrosis.

What are the implications of the main findings?
The bioengineered models developed from this roadmap will allow researchers to mechanistically connect specific fibrotic patterns to the arrhythmogenic electrical conduction changes that drive AF.These high-fidelity in vitro platforms will accelerate the discovery of novel anti-fibrotic drugs and enable patient-specific testing to advance personalized medicine for atrial fibrillation.

The bioengineered models developed from this roadmap will allow researchers to mechanistically connect specific fibrotic patterns to the arrhythmogenic electrical conduction changes that drive AF.

These high-fidelity in vitro platforms will accelerate the discovery of novel anti-fibrotic drugs and enable patient-specific testing to advance personalized medicine for atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder. It is estimated that AF affects over 52 million people worldwide, with its prevalence expected to double in the next four decades. AF significantly increases the risk of stroke and heart failure, contributing to 340,000 excess deaths annually. Beyond these life-threatening complications, AF results in limitations in physical, emotional, and social well-being causing significant reductions in quality of life and resulting in 8.4 million disability-adjusted life-years per year, highlighting the wide-ranging impact of AF on public health. Moreover, AF is increasingly recognized for its association with cognitive decline and dementia. AF is a chronic and progressive disease characterized by rapid and erratic electrical activity in the atria, often in association with structural changes in the heart tissue. AF is often initiated by triggered activity, often from ectopic foci in the pulmonary veins. These triggered impulses may initiate AF via: (1) sustained rapid firing with secondary disorganization into fibrillatory waves, or (2) by triggering micro re-entrant circuits around the pulmonary venous-LA junction and within the atrial body. In each instance, AF perpetuation necessitates the presence of a vulnerable atrial substrate, which perpetuates and stabilizes re-entrant circuits through a combination of slowed and heterogeneous conduction, as well as functional conduction abnormalities (e.g., fibrosis disrupting tissue integrity, and abnormalities in the intercalated disks disrupting effective cell-to-cell coupling). The re-entry wavelength, determined by conduction velocity and refractory period, is shortened by slowed conduction, favoring AF maintenance. One major factor contributing to these changes is the disruption of the extracellular matrix (ECM), which is induced by atrial fibrosis. Fibrosis-driven disruption of the ECM, especially in the heart and blood vessels, is commonly caused by conditions such as aging, hypertension, diabetes, smoking, and chronic inflammatory or autoimmune diseases. These factors lead to excessive collagen and protein deposition by activated fibroblasts (i.e., myofibroblasts), resulting in increased tissue stiffness, maladaptive remodeling, and impaired organ function. Fibrosis typically occurs when cardiac fibroblasts are activated to myofibroblasts, resulting in the deposition of excessive collagen and other proteins. This change in ECM interferes with the normal electrical function of the heart by creating irregular, fibrotic regions. AF and atrial fibrosis have a reciprocal relationship: AF promotes fibrosis through fibroblast activation and extracellular matrix buildup, while atrial fibrosis can sustain and perpetuate AF, contributing to higher rates of AF recurrence after treatments such as catheter ablation or cardioversion.