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; 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

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, Salman R. Khetani, Jalees Rehman, Yu Gao, Dawood Darbar^*, Ankur Saxena^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English (US)
Article number	110395
Journal	iScience
Volume	27
Issue number	7
DOIs	https://doi.org/10.1016/j.isci.2024.110395
State	Published - Jul 19 2024

Funding

We thank Dr. Ana Beiriger for creating the model figure. Research funding was provided by R01HL138737, R01HL150586, R01HL148444, 5R35GM133416, 5T32HL139439, and UAB Heersink School of Medicine Start-Up Funds . This work made use of the instruments and services provided by the Electron Microscopy Core, Research Histology Core, Genome Research Core, and Cardiovascular Research Core all in the University of Illinois Chicago\u2019s Research Resources Center, established with the support of the Vice Chancellor of Research. We thank Dr. Ana Beiriger for creating the model figure. Research funding was provided by National Institutes of Health R01HL138737, R01HL150586, R01HL148444, 5R35GM133416, and 5T32HL139439 and by UAB Heersink School of Medicine Start-Up Funds. This work made use of the instruments and services provided by the Electron Microscopy Core, Research Histology Core, Genomics Research Core, and Cardiovascular Research Core all in the University of Illinois Chicago's Research Resources Center, established with the support of the Vice Chancellor of Research. Conceptualization, X.J. O.T.L. D.D. and A.Saxena; methodology, X.J. O.T.L. D.T. Y.G. D.D. and A.Saxena; formal analysis, X.J. O.T.L. Z.Z. B.A.I. M.A.P. A.Sridhar, D.T. A.Swick, C.G.V. and J.R.; investigation, X.J. O.T.L. H.C. Z.Z. B.A.I. M.A.P. G.E.B. A.Sridhar, D.T. A.Swick, R.M. C.G.V. and F.N.; resources, S.R.K. Y.G. D.D. and A.Saxena; writing \u2013 original draft, X.J. O.T.L. D.D. and A.Saxena; writing \u2013 review and editing, X.J. O.T.L. D.T. C.G.V. A.L.G. S.R.K. J.R. D.D. and A.Saxena; visualization, X.J. O.T.L. Z.Z. and A.Saxena; supervision, A.L.G. S.R.K. Y.G. D.D. and A.Saxena; funding acquisition, S.R.K. Y.G. D.D. and A.Saxena, The authors declare no competing interests.

Keywords

Biological sciences
Cell biology
Developmental biology
Protein

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2024.110395

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Jiang, X., Ly, O. T., Chen, H., Zhang, Z., Ibarra, B. A., Pavel, M. A., Brown, G. E., Sridhar, A., Tofovic, D., Swick, A., Marszalek, R., Vanoye, C. G., Navales, F., George, A. L., Khetani, S. R., Rehman, J., Gao, Y., Darbar, D., & Saxena, A. (2024). Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility. iScience, 27(7), Article 110395. https://doi.org/10.1016/j.isci.2024.110395

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

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 ttnaΔ9/Δ9 zebrafish embryos{\textquoteright} 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.",

keywords = "Biological sciences, Cell biology, Developmental biology, Protein",

author = "Xinghang Jiang and Ly, {Olivia T.} and Hanna Chen and Ziwei Zhang and Ibarra, {Beatriz A.} and Pavel, {Mahmud A.} and Brown, {Grace E.} and Arvind Sridhar and David Tofovic and Abigail Swick and Richard Marszalek and Vanoye, {Carlos G.} and Fritz Navales and George, {Alfred L.} and Khetani, {Salman R.} and Jalees Rehman and Yu Gao and Dawood Darbar and Ankur Saxena",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = jul,

day = "19",

doi = "10.1016/j.isci.2024.110395",

language = "English (US)",

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Jiang, X, Ly, OT, Chen, H, Zhang, Z, Ibarra, BA, Pavel, MA, Brown, GE, Sridhar, A, Tofovic, D, Swick, A, Marszalek, R, Vanoye, CG, Navales, F, George, AL, Khetani, SR, Rehman, J, Gao, Y, Darbar, D & Saxena, A 2024, 'Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility', iScience, vol. 27, no. 7, 110395. https://doi.org/10.1016/j.isci.2024.110395

TY - JOUR

T1 - Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility

AU - Jiang, Xinghang

AU - Ly, Olivia T.

AU - Chen, Hanna

AU - Zhang, Ziwei

AU - Ibarra, Beatriz A.

AU - Pavel, Mahmud A.

AU - Brown, Grace E.

AU - Sridhar, Arvind

AU - Tofovic, David

AU - Swick, Abigail

AU - Marszalek, Richard

AU - Vanoye, Carlos G.

AU - Navales, Fritz

AU - George, Alfred L.

AU - Khetani, Salman R.

AU - Rehman, Jalees

AU - Gao, Yu

AU - Darbar, Dawood

AU - Saxena, Ankur

PY - 2024/7/19

Y1 - 2024/7/19

N2 - 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.

AB - 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.

KW - Biological sciences

KW - Cell biology

KW - Developmental biology

KW - Protein

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UR - http://www.scopus.com/inward/citedby.url?scp=85198130395&partnerID=8YFLogxK

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DO - 10.1016/j.isci.2024.110395

M3 - Article

C2 - 39100923

AN - SCOPUS:85198130395

SN - 2589-0042

VL - 27

JO - iScience

JF - iScience

IS - 7

M1 - 110395

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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