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Titin-dependent transient ventricular defects result in adult atrial arrhythmia and impaired contractility

ABSTRACT: Atrial fibrillation (AF), the most common arrhythmia, is occasionally associated with cardiac developmental defects, but causal relationships are poorly defined. Importantly, functional compensation for developmental defects may mask increased risk of arrhythmia in adults. Here, we deleted 9 amino acids (Δ9) within a highly conserved A-band region of titin, a giant protein that serves as a molecular spring in cardiomyocytes, in both zebrafish and human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that the cardiac morphology of ttnaΔ9/Δ9 homozygous zebrafish embryos is perturbed and accompanied by reduced functional output, but ventricular function recovers within a few days of embryonic development, with most embryos reaching adulthood. Despite normal ventricular function, ttnaΔ9/Δ9 adults exhibit AF and atrial cardiomyopathy, with a striking absence of fibrosis, and these findings are recapitulated in TTNΔ9/Δ9-hiPSC-aCMs. Electrophysiological and proteomics analyses reveal atrial action potential shortening and increased expression and function of the cardiac potassium channel Kv7.1 and the slow delayed rectifier potassium current (IKs). Pharmacological suppression of IKs in both models prevents AF and improves atrial contractility. Collectively, these findings reveal how a small internal deletion in a large structural protein causes developmental abnormalities that functionally recover but increase the risk of adult cardiac disease via ion channel remodeling. The observed rescue with targeted antiarrhythmic therapy may have broader implications for the treatment of patients who harbor disease-causing rare variants in sarcomeric proteins.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Danio Rerio (zebrafish) (brachydanio Rerio)

TISSUE(S): Heart

SUBMITTER: Ziwei Zhang

LAB HEAD: Yu Gao

PROVIDER: PXD038300 | Pride | 2024-08-09

REPOSITORIES: Pride

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

Jiang Xinghang X Ly Olivia T OT Chen Hanna H Zhang Ziwei Z Ibarra Beatriz A BA Pavel Mahmud A MA Brown Grace E GE Sridhar Arvind A Tofovic David D Swick Abigail A Marszalek Richard R Vanoye Carlos G CG Navales Fritz F George Alfred L AL Khetani Salman R SR Rehman Jalees J Gao Yu Y Darbar Dawood D Saxena Ankur A

iScience 20240627 7

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 <i>ttna</i> <sup>Δ9/Δ9</sup> zebrafish embryos' cardiac morphology is perturbed and accompanied by reduced functional output, but ventricula ...[more]

PMID: 39100923

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Project description:Atrial fibrillation (AF) has an estimated prevalence of 1.5–2%, making it the most common cardiac arrhythmia. The mechanisms that cause and sustain AF are still not completely understood. An association between AF and systemic as well as local inflammatory processes has been reported, however, the exact mechanisms underlying this association have not been established. While it is understood that tissue resident macrophages can influence cardiac electrophysiology, the effects of activated pro-inflammatory macrophages have not been described yet. This study investigated the pro-arrhythmic effects of activated macrophages (M1) on human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes (aCM), to propose a mechanistic link between inflammation and AF. Two hiPSC lines from healthy individuals were differentiated to aCMs and M1 macrophages. Electrophysiology characteristics of M1 and aCM cocultures were analysed for beat rate irregularity, electrogram amplitude and conduction velocity. M1 cocultures resulted in a significant increase in beat rate irregularity and decrease in electrogram amplitude compared to other conditions tested, including aCMs treated with activated M1 supernatant, which did not produce an increase in irregularity. Conduction analysis further showed significantly lower conduction homogeneity in M1 cocultures. Immunosuppression through glucocorticoids significantly decreased beat irregularity in aCM+M1 cocultures compared to vehicle. RNA sequencing performed in aCMs, revealed downregulation of various ion channels (SCNA5, KCNA5, ATP1A1), as a result of the M1 coculture. Electrophysiology related transcription changes were reversed by glucocorticoid treatment. This study establishes a causal relationship between M1 activation and the development of subsequent atrial arrhythmia, documented as irregularity in spontaneous electrical activation in aCM cocultured with activated macrophages. Further, beat rate irregularity could be alleviated using anti-inflammatory steroidal glucocorticoids. These results strongly support the relevance of the proposed hiPSC-derived coculture model and point at macrophage mediated inflammation as a potential AF mechanism.

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