Developing cardiac organoids with deliberate heterogeneity for modeling sinus node dysfunction

About This Grant

ABSTRACT Sinus node dysfunction (SND) is a significant heart rhythm disorder that affects both young patients with congenital heart conditions and adults due to aging or secondary complications from other heart diseases. For symptomatic patients, pacemaker implantation is often required, particularly in children, where it frequently indicates worsening heart function and poor clinical outcomes. Despite its high prevalence, the underlying causes and progression of SND remain poorly understood. A major challenge in advancing treatments is the lack of a reliable human model that effectively replicates the sinoatrial node and its dysfunction. This project aims to address this gap by utilizing human cardiac pacemaker organoids derived from iPSCs to model SND. We hypothesize that integrating nonmyocytes into these organoids plays a crucial role in accurately mimicking the sinoatrial node and the progression of SND. By applying constant or cyclic mechanical strain, we will simulate the disease environment to better understand its mechanisms. These organoids will mirror the cellular diversity of the native sinoatrial node, offering a rigorous platform to explore the etiology of SND. The ultimate goal is to identify key molecular targets that could lead to novel therapies, reducing the need for permanent pacemaker implants and improving patient outcomes.