Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility
Xinghang Jiang,
Olivia T. Ly,
Hanna Chen,
Ziwei Zhang,
Beatriz A. Ibarra,
Mahmud A. Pavel,
Grace E. Brown,
Arvind Sridhar,
David Tofovic,
Abigail Swick,
Richard Marszalek,
Carlos G. Vanoye,
Fritz Navales,
Alfred L. George, Jr.,
Salman R. Khetani,
Jalees Rehman,
Yu Gao,
Dawood Darbar,
Ankur Saxena
Affiliations
Xinghang Jiang
Department of Cell, Developmental, and Integrative Biology, UAB Heersink School of Medicine, Birmingham, AL 35233, USA; Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA
Olivia T. Ly
Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA
Hanna Chen
Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA
Ziwei Zhang
Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL 60612, USA
Beatriz A. Ibarra
Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA
Mahmud A. Pavel
Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA
Grace E. Brown
Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA
Arvind Sridhar
Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; Department of Physiology, University of Illinois Chicago, Chicago, IL 60612, USA
David Tofovic
Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; Department of Medicine, Jesse Brown Veterans Administration, Chicago, IL 60612, USA
Abigail Swick
Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA
Richard Marszalek
Department of Physiology, University of Illinois Chicago, Chicago, IL 60612, USA
Carlos G. Vanoye
Department of Pharmacology, Northwestern University, Chicago, IL 60611, USA
Fritz Navales
Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA
Alfred L. George, Jr.
Department of Pharmacology, Northwestern University, Chicago, IL 60611, USA
Salman R. Khetani
Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA
Jalees Rehman
Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; Department of Biochemistry and Molecular Genetics, University of Illinois Chicago, Chicago, IL 60607, USA
Yu Gao
Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL 60612, USA
Dawood Darbar
Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; Department of Medicine, Jesse Brown Veterans Administration, Chicago, IL 60612, USA; Corresponding author
Ankur Saxena
Department of Cell, Developmental, and Integrative Biology, UAB Heersink School of Medicine, Birmingham, AL 35233, USA; Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA; O'Neal Comprehensive Cancer Center, Birmingham, AL 35233, USA; Corresponding author
Summary: 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 ttnaΔ9/Δ9 zebrafish embryos’ cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days. Despite normal ventricular function, ttnaΔ9/Δ9 adults exhibit AF and atrial myopathy, which are recapitulated in TTNΔ9/Δ9-hiPSC-aCMs. Additionally, action potential is shortened and slow delayed rectifier potassium current (IKs) is increased due to aberrant atrial natriuretic peptide (ANP) levels. Strikingly, suppression of IKs 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.
