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

BACKGROUND: Early repolarization syndrome (ERS) exhibits diverse clinical and mechanistic origins within the J-wave spectrum. Conduction, repolarization, and structural factors may shape its electrocardiography phenotype. OBJECTIVES: This study sought to determine the contribution of endocardial electrical and structural remodeling to malignant ERS phenotypes and arrhythmogenesis in a familial case. METHODS: Two siblings with malignant and drug-refractory ERS underwent in vivo electrocardiographic imaging and ex vivo analyses of the right and/or left explanted ventricles. Optical mapping, microelectrode recordings, high-field cardiac magnetic resonance, histology, guide DNA/complementary DNA sequencing, reverse-transcription quantitative polymerase chain reaction, and Western blot analyses were compared with ERS-absent control hearts. Findings were integrated with multiscale simulations to test mechanistic hypotheses. RESULTS: enhancement alone reproduced the pause-dependent repolarization phenotype and associated conduction abnormalities, whereas its combination with diffuse structural alterations was required to generate premature beats. CONCLUSIONS: -driven abnormalities underlie pause-dependent J waves, while structural remodeling synergizes to promote arrhythmogenesis. Distinct mechanisms between siblings highlight the mechanistic heterogeneity of J-wave syndromes and refine rather than refute previous hypotheses.