Millions of adults have atrial fibrillation, which is an irregular heartbeat in the upper heart chambers. This increases the risk of heart failure, stroke, and death. Many genetic mutations in developing fetuses can cause adult atrial fibrillation, including ones that shorten the large protein titin in heart muscle cells.
In a study with zebrafish and human heart cells, researchers found that a tiny deletion in the A-band of titin (losing just nine amino acids out of 27,000 to 35,000) causes a defect in the embryonic heart, leading to adult arrhythmia.
Scientists at the University of Alabama at Birmingham and the University of Illinois Chicago discovered that this small deletion in titin caused unexpected changes in heart muscle cells, creating an increased potassium ion current called /ks.
Researchers found that blocking the altered /ks current improved heart function in zebrafish embryos with a nine amino acid deletion and also prevented atrial fibrillation in human cells with the same deletion.
“This could help both children and adults,” said Dr. Ankur Saxena from UAB. “By targeting ion channel remodeling, new drug treatments might restore normal heart rhythm and improve heart function.”
In studying zebrafish and human heart cells with a nine-amino acid deletion, researchers from UAB and the University of Illinois Chicago found that zebrafish embryos had temporary heart issues, like smaller size and slower blood circulation, but recovered in a few days.
However, both embryonic and adult zebrafish with the mutation had lasting heart enlargement and atrial fibrillation. In adult zebrafish and human heart cells, the mutation caused heart disorganization and weaker contractions.
The researchers explored why these defects led to adult atrial fibrillation. They found that the hormone ANP was overexpressed due to ventricular dysfunction, increasing the /ks potassium current. This change affected potassium channel proteins in both zebrafish and human cells. Reducing ANP improved heart contractions, and tests showed a higher peak /ks current.
Researchers wrote, “Understanding how developmental defects cause a higher risk of atrial fibrillation in adults has been difficult, with few examples. In this study, we deleted nine amino acids in titin’s A-band to explore this link. We found that this small change affects ion channels and weakens heart contractions. Early heart problems and recovery led to abnormal ANP expression and ion channel changes. This suggests that small structural mutations might cause hidden issues that lead to atrial fibrillation in adults.”
Journal reference :
- Xinghang Jiang, Olivia T. Ly et al., Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility. iScience. DOI: 10.1016/j.isci.2024.110395.
