Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting millions and increasing the risk of heart failure, stroke, and death. Genetic studies have identified various loci and rare variants associated with AF, particularly in cardiac ion channels and myocardial structural proteins like myosin heavy chain 6, myosin light chain 4, and titin.

Titin is a critical sarcomeric protein involved in cardiac development and function. Several titin loss-of-function variants are associated with AF; however, the mechanisms remain unclear, especially regarding the understudied, highly conserved A-band Ig-like domains of titin.

A recent study investigates the connection between transient developmental cardiac defects and the onset of AF in adulthood, focusing on a specific small deletion within the titin A-band. This deletion could lead to developmental abnormalities that later predispose individuals to AF through ion channel remodeling and altered cardiac function.

The researchers created a 9-amino acid deletion (D9) within a conserved domain of the titin A-band in both zebrafish (ttnaD9/D9) and human-induced pluripotent stem cell-derived atrial cardiomyocytes (TTND9/D9-hiPSC-aCMs). They found that the ttnaD9/D9 zebrafish embryos exhibited a transient reduction in ventricular function during development, which fully recovered within days.

In contrast to ventricular recovery, ttnaD9/D9 zebrafish exhibited persistent atrial enlargement, reduced atrial contractility, and sarcomeric disorganization, which were also observed in TTND9/D9-hiPSC-aCMs. Both models demonstrated shortened action potentials, and TTND9/D9-hiPSC-aCMs also showed increased slow delayed rectifier potassium current (IKs), as revealed by high-throughput automated patch clamp experiments with the SyncroPatch 384.

Blocking IKs with pharmacological agents rescued the arrhythmia and improved contractility in both zebrafish and hiPSC-aCM models.

Overall, this study suggests that small deletions in titin can cause lasting electrophysiological changes and atrial dysfunction, providing insight into the genetic underpinnings of AF. Targeting IKs could offer a therapeutic strategy for improving cardiac function and preventing AF in patients with similar genetic mutations.

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Find the full article here: https://www.cell.com/iscience/fulltext/S2589-0042(24)01620-1

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