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

This project aims to enhance understanding of sinoatrial node function and its dysfunction in heart rhythm disorders using innovative in vitro models derived from human pluripotent stem cells.

Subsidie
€ 1.797.105
2024

Projectdetails

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. This extraordinary biological feat is a result of intrinsic features such as SAN tissue architecture.

Modulation of SAN Function

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

  1. Abnormal heart rate (brady or tachycardias)
  2. SAN exit block (lack of atrial activation)
  3. 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

The specific objectives of this research are:

  1. 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. Gain insights into the relationship between SAN dysfunction and atrial fibrillation: By assessing MYH6 variants associated with both these diseases.

  3. 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.

Financiële details & Tijdlijn

Financiële details

Subsidiebedrag€ 1.797.105
Totale projectbegroting€ 1.797.105

Tijdlijn

Startdatum1-5-2024
Einddatum30-4-2029
Subsidiejaar2024

Partners & Locaties

Projectpartners

  • STICHTING AMSTERDAM UMCpenvoerder

Land(en)

Netherlands

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