Endocardial I_to-slow Overexpression and Fibrotic Remodeling Underlying Pause-Dependent Early Repolarization in Humans

Area of Science:

• Cardiology
• Electrophysiology
• Genetics

Background:

• Early repolarization syndrome (ERS) presents diverse clinical and mechanistic origins within the J-wave spectrum.
• Conduction, repolarization, and structural factors influence ERS electrocardiography phenotypes.

Purpose of the Study:

• To investigate the role of endocardial electrical and structural remodeling in malignant ERS phenotypes and arrhythmogenesis.
• To analyze familial cases of drug-refractory ERS.

Main Methods:

• In vivo electrocardiographic imaging and ex vivo ventricular analyses were performed on two siblings with ERS.
• Techniques included optical mapping, microelectrode recordings, cardiac MRI, histology, genetic sequencing, and molecular profiling.
• Multiscale simulations were used to test mechanistic hypotheses.

Main Results:

• Long pacing cycle lengths or pauses induced endocardial biphasic action potential upstrokes and phase 1 notch amplification, linked to slow transient outward potassium current (I_to,slow).
• Pause-dependent conduction slowing was observed in one sibling, suggesting an additional I_to,slow-related conduction mechanism.
• Endocardial K_V1.4 overexpression and diffuse collagen deposition were identified, contributing to proarrhythmic substrate.

Conclusions:

• Endocardial I_to,slow abnormalities drive pause-dependent J waves in ERS, with structural remodeling synergizing to promote arrhythmogenesis.
• Distinct mechanisms observed between siblings highlight the heterogeneity of J-wave syndromes.