How Gene Mutations Cause Hereditary Heart Rhythm Disorder

Short QT syndrome is a genetic disease that leads to sudden cardiac death at a young age. Mutations in the SLC4A3 gene, which regulates bicarbonate-chloride exchange, were recently described as a potential cause. An international research team including a group from Ruhr University Bochum, Germany, investigated this possibility. The researchers discovered how different variants of the gene affect heart muscle cells: Specifically, the pH level increased and the flow of ion channels was altered. This insight could aid in providing better personal care for persons affected by the disease. The study was published in European Heart Journal on March 5, 2026.

Irregular heartbeat

In order to maintain blood flow, the muscle cells of the heart have to contract and relax in a coordinated manner. This process of contraction and relaxation is electrically controlled by the regulated flow of ions into and out of cells via channels in the cell membrane. This is disrupted in cases of Short QT syndrome, or SQTS. One of the consequences of this is a shortening of the time between contraction and relaxation of the heart muscle cells –known as the QT interval or repolarization time, thereby interrupting the cardiac rhythm.

“The mechanism underlying a shortening of the action potential duration, the shortening of the QT interval, and cardiac rhythm disorders among carriers of SLC4A3 gene mutations was previously unclear,” says Dr. Ibrahim El-Battrawy from Cardiology, rhythmology and research group leader for the Department of Cellular and Translational Physiology at Ruhr University Bochum. The research team examined two variants of the SCL4A3 gene that are causative for familial SQTS in order to gain more insight.

The research focused on two previously undescribed variants in the SLC4A3 gene: p.Arg370Cys and p.Lys531Thr. The team generated human heart muscle cells from induced pluripotent stem cells from the families carrying the gene, and the mutations were corrected with CRISPR/Cas 9 to produce genetically identical cell lines. In addition, the described mutations were inserted in human embryonic kidney cells, or HEK cells. A range of test procedures was conducted to determine how the mutations modify the cells. Patch clamp, Ca2+ transient imaging, single-cell contraction, intracellular pH measurement, protein structural analysis, immunostaining, and optical mapping analyses were used in the organoid model.

It all starts with a change in pH

Cells with the mutated gene exhibited a significantly shortened action potential duration and a high rate of arrhythmic events. The influx and efflux of ion channels was altered: Cells showed a reduction in the L-type calcium current (ICa-L) and a significant increase in the sodium-calcium exchanger current (INCX). The intracellular pH was raised considerably. The research team used ammonium chloride (NH4Cl) to induce such an increase in the pH level compared to wild-type heart cells. In wild-type cells, this treatment also resulted in a reduced action potential duration, an increased INCX, and a reduced ICA-L. “We believe that this all starts with an increase in the intracellular pH,” says El-Battrawy.

Quinidine and sotalol, two antiarrhythmic drugs, prolonged the action potential duration and reduced the frequency of arrhythmias in the mutated cells. “This information is crucial for personalized treatment of SQTS patients with SLC4A3 mutations,” says El-Battrawy.

Reference: Meng Z, Kovacs B, Yan C, et al. SLC4A3-related short QT syndrome assessed in human induced pluripotent stem cell-derived cardiomyocytes: mechanisms of ventricular arrhythmia and sudden cardiac death. Eur Heart J.  2026. doi: 10.1093/eurheartj/ehag068

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.