Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility

Developmental causes of the most common arrhythmia, atrial fibrillation (AF), are poorly defined, with compensation potentially masking arrhythmic risk. Here, we delete 9 amino acids (Δ9) within a conserved domain of the giant protein titin's A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that ttna^Δ9/Δ9 zebrafish embryos’ cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days. Despite normal ventricular function, ttna^Δ9/Δ9 adults exhibit AF and atrial myopathy, which are recapitulated in TTN^Δ9/Δ9-hiPSC-aCMs. Additionally, action potential is shortened and slow delayed rectifier potassium current (I_Ks) is increased due to aberrant atrial natriuretic peptide (ANP) levels. Strikingly, suppression of I_Ks in both models prevents AF and improves atrial contractility. Thus, a small internal deletion in titin causes developmental abnormalities that increase the risk of AF via ion channel remodeling, with implications for patients who harbor disease-causing variants in sarcomeric proteins.