Endocardial KV1.4 overexpression and Ito,slow-driven abnormalities underlie pause-dependent J waves in 2 siblings with early repolarization syndrome, synergizing with structural remodeling.
Case Report (n=2)
Endocardial Ito,slow-driven abnormalities and structural remodeling synergistically promote arrhythmogenesis in early repolarization syndrome.
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 Long pacing cycle lengths or pauses induced endocardial biphasic optical action potential upstrokes and amplification of the phase 1 notch in ERS. Their rate dependence, suppression by 4-aminopyridine, and insensitivity to flecainide implicated slow transient outward potassium current (Ito,slow)-mediated repolarization mechanism. Pause-dependent conduction slowing appeared in the second ERS sibling, pointing to an additional Ito,slow-related conduction mechanism in this case. Molecular profiling revealed endocardial KV1.4 overexpression, supporting Ito,slow involvement. Diffuse collagen deposition found in both right ventricles may provide a synergistic proarrhythmic substrate. In silico, Ito,slow 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 In these ERS cases, endocardial Ito,slow-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.
Walton et al. (Sun,) conducted a case report in Early repolarization syndrome (n=2). In vivo electrocardiographic imaging and ex vivo analyses vs. ERS-absent control hearts was evaluated on Mechanisms of pause-dependent early repolarization. Endocardial KV1.4 overexpression and Ito,slow-driven abnormalities underlie pause-dependent J waves in 2 siblings with early repolarization syndrome, synergizing with structural remodeling.