Biology subjects

Offerhaus, J. A.

Publications and source records attributed to Offerhaus, J. A..

2 recordsLinked to original sources

bioRxiv2025

The Brugada syndrome associated gene WT1 impacts on SCN5A expression and cardiac conduction

Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder caused by conduction slowing primarily affecting the right ventricular (RV) outflow tract (RVOT). A recent genome-wide association study (GWAS) implicated a genomic region in chromosome 11, overlapping the transcription factor WT1, in BrS susceptibility. Here, we investigated the role of WT1 on cardiac conduction using a heterozygous knockout mouse model (Wt1+/-). Transcriptomic analysis revealed increased Scn5a predominantly in Wt1+/- cardiomyocytes located subepicardially in the RV and RVOT without any changes in electrical properties. To unmask an effect on cardiac conduction, we performed optical mapping in a severely challenged setting offered by Scn5a haploinsufficiency, ageing, and exposure to the sodium channel blocker ajmaline and found that diminished Wt1 improved the observed slowed conduction. Examination of human single-nuclei cardiac datasets indicated a strong negative correlation between WT1 and SCN5A expression. In line with this observation, cardiac samples from patients carrying mutations in SCN5A showed increased WT1 protein abundance in histological sections, suggesting that increased WT1, and not loss, is associated with BrS pathophysiology. By deleting the mouse orthologue of a BrS-associated noncoding region (RE) harboring a candidate regulatory element, we established that this RE controls expression of Wt1 specifically in the (sub)epicardium of the RV. Lastly, transient overexpression of WT1 in hiPSC-derived cardiomyocytes resulted in notably reduced sodium current density. Our study thereby identifies the transcription factor WT1 as a novel contributor to the pathophysiology of BrS, at least in part, through SCN5A.

genetics↗

bioRxiv2020

The mechanism underlying J-waves and T-waves in the electrocardiogram of mice and zebra finches

Brief cardiac cycles are required to achieve high heart rates as seen in endothermic animals. A main determinant of the cardiac cycle is the repolarization phase of the cardiac action potential, which is visible in the ECG as a T-wave. In mammals with high heart rates - such as rodents - the repolarization phase is short and the ECG is characterized by a positive deflection following the QRS-complex, the J-wave. It is unclear whether birds with high heart rates show similar ECG characteristics. Here we study cardiac repolarization and the ECG in the zebra finch which has high heart rates. In ex vivo hearts of zebra finch (N=5) and mouse (N=5), pseudo-ECGs and optical action potentials were measured. In both species, total ventricular activation was fast with QRS durations shorter than 10ms. Ventricular activation progressed from the left to the right ventricle in zebra finch whereas the activation pattern was apex-to-base in mouse. In both species, phase 1 early repolarization followed the activation front, causing a positive J-wave in the pseudo-ECG. In zebra finch, late repolarization was directed from the right ventricle to the left ventricle, whereas late repolarization was directed opposite in mouse. Accordingly, on the zebra finch ECG, the J-wave and the T-wave have the same direction, whereas in the mouse the J-wave and the T-wave are discordant. Our findings demonstrate early repolarization and the associated J-wave are not restricted to mammals and that they also occur within birds. Early repolarization may have evolved by convergence in association with high heart rates. Summary statementZebra finches are small birds with high heart rates. Similar to small rodents, the zebra finch ECG contains a J-wave, which is caused by early repolarization

physiology↗