Unraveling pacemaker (dys)function using novel stem cell-derived human heart models

Introduction

The pacemaker cells of the sinoatrial node (SAN) trigger three billion heartbeats in an average human lifespan. At the start of each beat, the SAN must generate enough current to drive the surrounding atrial tissue, which contains 10,000 times as many cells as the SAN itself.

Biological Mechanisms

This extraordinary biological feat is a result of intrinsic features such as SAN tissue architecture. In addition, SAN function is modulated by extrinsic inputs from the autonomic nervous system, which adjusts the pace from beat-to-beat, for example during exercise.

SAN Dysfunction

Any disturbances to these core activities result in SAN dysfunction, which includes:

• Abnormal heart rate (brady or tachycardias)
• SAN exit block (lack of atrial activation)
• Chronotropic incompetence (inability to increase heart rate)

SAN dysfunction is also a major trigger for atrial fibrillation, the most common form of arrhythmia.

Research Goals

The goal of this ERC-StG proposal is to make significant leaps in our understanding of the intrinsic and extrinsic factors that regulate SAN function in health and disease using innovative multi-cell type as well as multi-organ in vitro models created from human pluripotent stem cells.

Objectives

1. Role of SAN Subpopulations: Determine the role of SAN subpopulations, particularly transitional cells, in facilitating impulse propagation at the pacemaker-atrial interface by evaluating an SCN5A loss-of-function mutation.

2. Insights into SAN Dysfunction and Atrial Fibrillation: Gain insights into the relationship between SAN dysfunction and atrial fibrillation by assessing MYH6 variants associated with both these diseases.

3. Impact of Neurodegenerative Diseases: Unravel how damage to autonomic function in the higher orders of the brain, for example, in neurodegenerative diseases such as Huntington’s, disrupts the electrical activity of pacemaker cells.

Conclusion

This research will provide exquisite knowledge of the fundamental principles that regulate pacemaker function, which is essential to effectively address SAN dysfunction and atrial arrhythmias.