Structural heterogeneity promotes triggered activity, reflection and arrhythmogenesis in cardiomyocyte monolayers

Area of Science:

• Cardiology
• Electrophysiology
• Biophysics

Background:

• Patients with structural heart disease are prone to arrhythmias through poorly understood mechanisms.
• Tissue expansions may contribute to arrhythmias by creating a source-to-sink mismatch.

Purpose of the Study:

• To investigate if tissue expansions promote early after-depolarizations (EADs) and impulse reflection in neonatal rat ventricular cardiomyocyte monolayers.
• To determine the role of increased sodium current (INa) in EADs and reflection.

Main Methods:

• Optical mapping of electrical propagation in patterned cardiomyocyte monolayers with structural heterogeneities (wide regions connected by a thin isthmus).
• Adenoviral transfer of Nav1.5 to increase INa and application of veratridine (a persistent INa agonist).
• Computer simulations to model electrical propagation and the role of persistent INa.

Main Results:

• Structural heterogeneities facilitated EADs, retrograde propagation (reflection), and reentry.
• Increased Nav1.5 expression and veratridine significantly increased EADs and reflection incidence.
• Reflection led to functional reentry and complex rhythms; it was rare without structural heterogeneities.

Conclusions:

• A combination of structural heterogeneity (substrate) and increased persistent INa (trigger) promotes impulse reflection and arrhythmogenesis.
• The study elucidates mechanisms linking structural heart disease to arrhythmias via EADs and reflection.
• Findings highlight the critical role of INa in cardiac arrhythmogenesis.