Chamber-specific transcriptional responses in atrial fibrillation

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Atrial fibrillation (AF) is a common arrhythmia, but its underlying molecular mechanisms remain unclear.
• Understanding the molecular basis of atrial substrate vulnerability is crucial for developing targeted therapies.

Purpose of the Study:

• To identify chamber-specific transcriptional differences in atrial cardiomyocytes (CMs) in patients with AF and heart failure (HF).
• To investigate the role of the Notch pathway in AF pathogenesis and its impact on atrial CMs.

Main Methods:

• Transcriptional profiling of human atrial CMs from patients with AF+HF and HF alone.
• Utilizing a murine genetic model to study the effects of transient Notch signaling activation in CMs.
• Assessing cellular electrophysiologic changes in response to Notch activation.

Main Results:

• Distinct gene expression signatures were identified in left versus right atrial CMs, particularly in AF+HF patients.
• Notch pathway activation in human and murine atrial CMs led to increased ploidy and an AF-like transcriptomic profile.
• Notch activation caused chamber-specific electrophysiologic alterations, including prolonged action potential duration in the left atrium and reduced upstroke velocity in the right atrium.

Conclusions:

• The Notch pathway plays a significant role in AF pathogenesis by altering atrial CMs' molecular and electrophysiologic properties.
• Increased Notch pathway activity represents a shared mechanism predisposing to AF in both humans and mice.
• These findings provide a foundation for novel therapeutic strategies targeting the Notch pathway in AF.