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

doi:10.1016/j.isci.2024.110395

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

iScience. 2024 Jun 27;27(7):110395. doi: 10.1016/j.isci.2024.110395. eCollection 2024 Jul 19.

Authors

Xinghang Jiang^{1

2

3}, Olivia T Ly^{4

5}, Hanna Chen⁴, Ziwei Zhang⁶, Beatriz A Ibarra^{2

3}, Mahmud A Pavel⁴, Grace E Brown⁵, Arvind Sridhar^{4

7}, David Tofovic^{4

8}, Abigail Swick^{2

3}, Richard Marszalek⁷, Carlos G Vanoye⁹, Fritz Navales^{2

3}, Alfred L George Jr⁹, Salman R Khetani⁵, Jalees Rehman^{4

10}, Yu Gao⁶, Dawood Darbar^{4

8}, Ankur Saxena^{1

2

3

11}

Affiliations

¹ Department of Cell, Developmental, and Integrative Biology, UAB Heersink School of Medicine, Birmingham, AL 35233, USA.
² Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA.
³ University of Illinois Cancer Center, Chicago, IL 60612, USA.
⁴ Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
⁵ Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA.
⁶ Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL 60612, USA.
⁷ Department of Physiology, University of Illinois Chicago, Chicago, IL 60612, USA.
⁸ Department of Medicine, Jesse Brown Veterans Administration, Chicago, IL 60612, USA.
⁹ Department of Pharmacology, Northwestern University, Chicago, IL 60611, USA.
¹⁰ Department of Biochemistry and Molecular Genetics, University of Illinois Chicago, Chicago, IL 60607, USA.
¹¹ O'Neal Comprehensive Cancer Center, Birmingham, AL 35233, USA.

Abstract

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.

Keywords: Biological sciences; Cell biology; Developmental biology; Protein.

Abstract

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