%0 Journal Article
%T Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility.
%A Jiang X
%A Ly OT
%A Chen H
%A Zhang Z
%A Ibarra BA
%A Pavel MA
%A Brown GE
%A Sridhar A
%A Tofovic D
%A Swick A
%A Marszalek R
%A Vanoye CG
%A Navales F
%A George AL
%A Khetani SR
%A Rehman J
%A Gao Y
%A Darbar D
%A Saxena A
%J iScience
%V 27
%N 7
%D 2024 Jul 19
%M 39100923
%F 6.107
%R 10.1016/j.isci.2024.110395
%X 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.