Article Impact Level: HIGH Data Quality: STRONG Summary of iScience, 27(7), 110395. https://doi.org/10.1016/j.isci.2024.110395 Dr. Xinghang Jiang et al.
Points
- Researchers introduced a nine-amino acid deletion in the titin protein’s A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs), disrupting early cardiac development.
- Zebrafish embryos initially showed impaired cardiac morphology and function but later recovered ventricular function, while adults exhibited persistent atrial fibrillation and atrial myopathy, also seen in hiPSC-aCMs.
- The cardiac abnormalities were linked to an increase in the slow delayed rectifier potassium current (IKs), driven by elevated atrial natriuretic peptide (ANP) levels. This led to shortened action potential duration and AF development.
- The pharmacological blockade of IKs reduced arrhythmic events and improved atrial contractility in zebrafish and hiPSC-aCM models, suggesting a potential therapeutic strategy for AF.
- The study highlights the role of titin in cardiac function and the impact of sarcomeric protein mutations on atrial fibrillation, proposing targeted genetic and molecular profiling for AF treatment.
Summary
In a groundbreaking study investigating the developmental origins of atrial fibrillation (AF), researchers introduced a nine-amino acid deletion within a conserved domain of the giant sarcomeric protein titin’s A-band, both in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). This genetic modification, referred to as ttnaΔ9/Δ9 in zebrafish and TTNΔ9/Δ9 in hiPSC-aCMs, led to early developmental disruptions in cardiac morphology and function in zebrafish embryos. While these zebrafish demonstrated recovery in ventricular function within days, adult specimens exhibited persistent atrial fibrillation and atrial myopathy, which were also observed in the hiPSC-aCM models.
Further analysis revealed that these cardiac abnormalities were associated with an aberrant increase in the slow delayed rectifier potassium current (IKs), driven by elevated atrial natriuretic peptide (ANP) levels. The increase in IKs contributed to a shortened action potential duration, a critical factor in the development of AF. This ion channel remodeling, instigated by the titin deletion, underlines a mechanistic pathway through which structural protein mutations can predispose individuals to atrial fibrillation from an early developmental stage.
Addressing this, the study found that pharmacological blockade of IKs could mitigate arrhythmic events and enhance atrial contractility in zebrafish and hiPSC-aCM models. This intervention points to a potential therapeutic strategy for treating AF, especially in patients with genetic variants in sarcomeric proteins like titin, predisposing them to this condition. The findings underscore the significance of titin’s structural role in cardiac function and highlight the broader implications of sarcomeric protein mutations in the pathology of atrial fibrillation, offering a new avenue for targeted interventions based on genetic and molecular profiling of AF patients.
Link to the article: https://www.cell.com/iscience/fulltext/S2589-0042(24)01620-1
References Jiang, X., Ly, O. T., Chen, H., Zhang, Z., Ibarra, B. A., Pavel, M. A., Brown, G. E., Sridhar, A., Tofovic, D., Swick, A., Marszalek, R., Vanoye, C. G., Navales, F., George, A. L., Khetani, S. R., Rehman, J., Gao, Y., Darbar, D., & Saxena, A. (2024). Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility. iScience, 27(7), 110395. https://doi.org/10.1016/j.isci.2024.110395
