Atrial Fibrillation Related Titin Truncation Is Associated with Atrial Myopathy in Patient-Derived Induced Pluripotent Stem Cell Disease Models

BACKGROUND: Protein-truncating mutations in the titin gene are associated with increased risk of atrial fibrillation. However, little is known about the underlying pathophysiology. METHODS: We identified a heterozygous titin truncating variant (TTNtv) in a patient with unexplained early onset atrial fibrillation and normal ventricular function. We generated patient-specific atrial- and ventricular-like induced pluripotent stem cell-derived cardiomyocytes and engineered heart tissue to evaluate the impact of the TTNtv on electrophysiology, sarcomere structure, contractility, and gene expression. RESULTS: We demonstrate that the TTNtv increases susceptibility to pacing-induced arrhythmia, promotes sarcomere disorganization, and reduces contractile force in atrial induced pluripotent stem cell-derived cardiomyocytes compared with their CRISPR/Cas9-corrected isogenic controls. In ventricular induced pluripotent stem cell-derived cardiomyocytes, this variant was associated with abnormal electrophysiology and sarcomere organization without a reduction in contractile force compared with their isogenic controls. RNA-sequencing revealed an upregulation of cell adhesion and extracellular matrix genes in the presence of the TTNtv for both atrial and ventricular engineered heart tissues. CONCLUSIONS: In a patient with unexplained atrial fibrillation, induced pluripotent stem cell-derived cardiomyocytes with a TTNtv showed structural and electrophysiological abnormalities in both atrial and ventricular models, while only atrial engineered heart tissues demonstrated reduced contractility. The observed chamber-specific effect suggests that structural disorganization and reduced contractile function may be associated with atrial myopathy in the presence of truncated titin.