A titin missense variant drives atrial electrical remodeling and is associated with atrial fibrillation

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Cardiac Electrophysiology

Background:

• Genetic variants, both common and rare, are known risk factors for atrial fibrillation (AF).
• While titin (TTN) truncating variants are linked to arrhythmias, the role of TTN missense variants (TTNmvs) in AF pathogenesis is poorly understood.
• Existing research suggests TTN variants may contribute to AF through atrial myopathy, but the precise mechanisms require elucidation.

Purpose of the Study:

• To investigate the association of rare TTNmvs with adverse clinical outcomes in AF patients.
• To identify the underlying molecular mechanisms by which a specific TTN missense variant (T32756I) contributes to AF.
• To explore the potential role of titin-binding proteins in TTN-mv-associated cardiac dysfunction.

Main Methods:

• Utilized human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) to model the TTN-T32756I variant.
• Assessed cellular contractility, ion channel activity (specifically KCNQ1/Kv7.1), and calcium homeostasis in mutant iPSC-aCMs.
• Investigated the interaction between titin, the protein Four-and-a-Half Lim domains 2 (FHL2), and potassium channel subunits (KCNQ1/KCNE1).

Main Results:

• The TTN-T32756I variant in iPSC-aCMs resulted in aberrant contractility and dysregulated calcium homeostasis.
• Mutant cells exhibited increased activity of the cardiac potassium channel KCNQ1 (Kv7.1) due to enhanced binding of FHL2 to KCNQ1 and KCNE1, increasing the slow delayed rectifier potassium current (Iks).
• Suppression of FHL2 normalized the Iks in mutant iPSC-aCMs, confirming FHL2's role as an Iks modulator.

Conclusions:

• A single amino acid change in titin can alter cardiac function, leading to ion channel remodeling and AF.
• The findings reveal a novel mechanism linking titin variants, FHL2, potassium channels, and AF pathogenesis.
• Highlight the need for high-throughput screening of TTNmvs and suggest titin-potassium channel interactions as a potential therapeutic target for AF.