Basic/Translational Science -> Intact Heart Electrophysiology (includes Pharmacology and Optical Mapping) D-AB19 - Basic Science: What Lies Beneath (ID 20) Abstract

D-AB19-02 - Concomitant Endocardial Upregulation Of The Slow Transient Outward Potassium Channel And Regional Micro-structural Alterations As A Novel Mechanism Of Human J-wave Syndromes (ID 1505)


Background: Electrocardiographic J-Waves are associated with an increased risk of ventricular fibrillation (VF), but their putative mechanisms, mainly based on animal experiments focusing on either repolarization or conduction abnormalities, remain debated.
Objective: To elucidate the electrophysiological and structural substrates underlying J-Wave Syndromes (JWS) from ex vivo human hearts.
Methods: Two human hearts from siblings (female, 11 and 15yrs) with JWS who died following VF storm were obtained through our organ donor program. Epi- and endocardial optical mapping of the right ventricle (RV) and anterolateral LV was performed. Microelectrode recordings were obtained from the LV endocardium. Action potential (AP) characteristics were quantified at different pacing frequencies (0.5 to 2Hz) and using S1-S2 protocols with coupling intervals up to 2.5s. Histology, Western Blot and whole exome sequencing were also performed. All results were compared to 3 control hearts without J-Waves.
Results: ECG prior to death showed pause dependent augmentation of the J-Waves in both siblings. In the ex vivo heart investigations, long pacing pauses or bradycardia (0.5Hz) induced a heterogeneous increase of the AP notch (phase 1 repolarization) and delayed AP plateau, which were observed in the lateral RV endocardium and LV endocardium, but not in the RV or LV epicardium. No conduction abnormalities on epi- or endocardium were found. In both hearts, 4-aminopyridine (1mM) reduced the AP notch amplitude (44 vs 8mV, p<0.05). Histology revealed increased collagen content and fatty tissue infiltrations in the regions with altered AP morphologies. Kv1.4 (Ito,s) was found to be significantly upregulated in the endocardium, whereas Kv4.2 and Kv4.3 (Ito,f) expression levels were unaltered, irrespective of the investigated region. Desmoglein-2 was significantly downregulated in both ventricles. Of 63 genes responsible for cardiomyopathies and primary electrical disorders, only one, likely benign, splicing variant in ACTC1 was found at the heterozygous state.
Conclusion: These unique human heart data demonstrate a novel endocardial-specific mechanism underlying JWS through a combination of Ito,s overexpression and regional micro-structural alterations.