Mechanisms Underlying Sinus Node Dysfunction in a Rat Model of Genetic Atrial Cardiomyopathy

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Sinoatrial node (SAN) dysfunction causes atrial dysrhythmia and is linked to inherited atrial cardiomyopathies.
• MYL4 gene variants lead to familial atrial cardiomyopathy, early SAN dysfunction, and pacemaker dependency.
• This study investigates the mechanisms of SAN dysfunction in a rat model with a MYL4 E11K mutation.

Purpose of the Study:

• To elucidate the molecular and cellular mechanisms underlying sinoatrial node dysfunction (SND) in familial atrial cardiomyopathy.
• To characterize the impact of the MYL4 E11K mutation on SAN structure and electrophysiology.
• To provide insights into the progression of SND associated with atrial cardiomyopathies.

Main Methods:

• Echocardiography and in vivo telemetry for cardiac assessment.
• Intracardiac electrophysiology and ex vivo optical mapping for SAN function analysis.
• Patch-clamp electrophysiology, Ca2+ imaging, qPCR, and Masson's trichrome staining for cellular and molecular interrogation.

Main Results:

• Mutant Myl4-p.E11K+/+ rats showed significantly impaired SAN function compared to wild-type.
• Reduced SAN conduction velocity, decreased funny and L-type Ca2+ currents, and dysregulated Ca2+ homeostasis were observed.
• Increased collagen deposition (fibrosis) in the SAN region was evident in mutant rats.

Conclusions:

• The Myl4-p.E11K+/+ mutation progressively impairs SAN function with aging.
• Abnormalities in ion channel properties, Ca2+ handling, and SAN structure contribute to SND.
• This research offers novel insights into the mechanisms of SAN dysfunction in atrial cardiomyopathy.