A titin missense variant drives atrial electrical remodeling and is associated with atrial fibrillation

Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, affects more than 60 million people worldwide and is associated with increased risk for stroke, heart failure, and dementia, justifying it as a major public healthcare burden (Brundel et al., 2022; Elliott et al., 2023). AF is characterized by irregular and often abnormally fast heart rates (Schotten et al., 2011; Markides and Schilling, 2003). Over the last decade, tremendous progress has been made in understanding the genetic architecture of AF (Lee et al., 2023; Feghaly et al., 2018; Sagris et al., 2022). Genome-wide association studies have identified over 140 common loci associated with AF, while family-based studies have implicated rare variants primarily encoding ion channels (Roselli et al., 2020; Roselli et al., 2018). Although AF has been traditionally classified as a ‘channelopathy’, variants in myocardial sarcomeric proteins such as titin have been increasingly associated with familial or early-onset AF (Choi et al., 2018; Chalazan et al., 2021).

The TTN gene encodes for a massive myofilament (~4200 kDa), titin, which stretches along the Z-disk (N-terminus) to the M-band (C-terminus) region of the sarcomere (Labeit and Kolmerer, 1995; Granzier and Labeit, 2004). Titin serves as a molecular scaffold for other muscle proteins, participates in downstream signaling, and provides passive tension in cardiac muscle (LeWinter et al., 2007; Linke and Hamdani, 2014). Due to its large size, the rate of genetic variation in TTN is high, including both truncating (TTNtvs) and missense variants (TTNmvs) (Schafer et al., 2017; Begay et al., 2015). The prevalence of rare TTNtvs and TTNmvs in the general population is 2% and 5.7%, respectively (Vissing et al., 2021; Akinrinade et al., 2019; Weston et al., 2024). While TTNtvs are the most common genetic cause (10–20%) of dilated cardiomyopathy (DCM), TTNmvs are often disregarded in clinical practice and are considered benign in DCM-specific variant interpretation frameworks based on the American College of Medical Genetics (ACMG) recommendations (Martínez-Barrios et al., 2022; Richards et al., 2015). Yet, TTNmvs may have the potential to confer disease, as a recent study in two families revealed that TTNmvs in a conserved cysteine of TTN can cause DCM (Domínguez et al., 2023). Another study demonstrated segregation of a novel TTNmv in five individuals with atrioventricular block in a Chinese family, suggesting that TTNmvs may also be implicated in arrhythmia syndromes (Liu et al., 2020). To date, a relationship between rare TTNmvs and AF has not been explored at either clinical or mechanistic levels. This has potentially heightened importance across racial and ethnic groups, in whom the likelihood of detecting variants of uncertain significance (which are predominantly TTNmvs) is higher than in individuals of European descent (Chen et al., 2023).

Despite the clinical importance, the pharmacological therapy of AF is limited in part because of the incomplete understanding of the myocardial substrate for AF, as human atrial tissue is rarely available, and the limitations of existing in vitro and in vivo models (Ly et al., 2021). However, human-induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-CMs) not only possess the complex array of cardiac ion channels that make up the atrial action potential (AP) but also hold great promise for modeling AF (Ly et al., 2022; Nicholson et al., 2022). Modeling patient-specific mutations associated with familial AF using mature human iPSC-CMs offers a powerful, naturally integrated system with distinct advantages over animal models and heterologous expression systems (Hong et al., 2021). Recent reports using human iPSC-CM models have elucidated the pathophysiological mechanisms of DCM (Poetsch and Guan, 2020), hypertrophic cardiomyopathy (Li et al., 2018), Brugada syndrome (Nijak et al., 2021), long QT syndrome (Moretti et al., 2010), and AF (Ly et al., 2022; Hong et al., 2021; Benzoni et al., 2020). Human iPSC-CMs also have the potential to uncover the molecular mechanisms of AF, as they can be easily modified to contain the precise genetic background of the individual patient (Simons et al., 2023; Brown et al., 2024; Jiang et al., 2024).

To examine the potential role of TTNmvs in AF, we examined the prevalence of rare TTNmvs in a single-center cohort of African American and Hispanic/Latinx individuals with AF who underwent whole exome sequencing, compared clinical characteristics between TTNmv carriers and non-carriers, and evaluated whether TTNmvs were associated with increased risk of AF or heart failure (HF)-related hospitalizations. To explore whether the TTNmvs may be mechanistically linked to the development of AF, we introduced a rare TTNmv (TTN-T32756I) into human iPSC-aCMs using clustered regularly interspaced short palindromic repeats-associated 9 (CRISPR-Cas9). We performed electrophysiological (EP), pharmacological, and mechanistic analyses to elucidate the mechanisms underlying TTNmv-induced AF. Our study demonstrated that TTN-T32756I iPSC-aCMs exhibited a striking AF-like EP phenotype in vitro. Transcriptomic analyses revealed that this TTNmv enhances the activity of the Four-and-a-half LIM domain protein 2 (FHL2), which, in turn, modulates the slow delayed rectifier potassium current (I_Ks), thereby promoting AF susceptibility.

We identified an association between TTNmvs and adverse clinical outcomes in a multiethnic cohort of patients with AF and elucidated a causal mechanism by which a TTNmv can drive atrial remodeling and promote AF development. Although TTNtvs are a well-recognized cause of DCM and have been associated with early-onset AF (Choi et al., 2018; Goodyer et al., 2019), the role of TTNmvs in the pathogenesis of either arrhythmia or cardiomyopathy is unknown. Here, we demonstrate that rare, deleterious TTNmvs are associated with an elevated risk of hospitalization in a multiethnic cohort of patients with AF and show that a TTNmv can promote AF by impairing contractility and remodeling ion channels in atrial cardiomyocytes. Furthermore, we demonstrate that augmented I_Ks activity mediated by FHL2 can create a substrate for AF. Together, these findings establish a mechanistic role for TTNmvs in AF pathogenesis and highlight I_Ks and FHL2 as potential therapeutic targets for TTN-related arrhythmias.

The genetic architecture of AF is complex, with both monogenic and polygenic contributions that intersect with age and comorbidities to define an individual’s risk. Despite AF being traditionally considered an ion channelopathy, the sarcomeric gene, TTN, is the most common in which rare loss-of-function variants have been associated with AF (Choi et al., 2018; Yoneda et al., 2021), and the penetrance of such variants was found to be even greater for AF than for HF in the UK Biobank (Choi et al., 2020). As rare TTN variants comprise the strongest monogenic contribution to AF risk, we sought to explore whether TTNmvs may similarly affect AF development or outcomes. A study of 147 probands with DCM identified 44 severe TTNmvs in 37 probands, which clustered in the A-band region (Begay et al., 2015). There were no differences in heart transplant-free survival between carriers and noncarriers. In a more recent study of 530 subjects with DCM using more stringent allele-frequency criteria, 31 predicted deleterious variants were identified, also predominantly located in the A-band (Akinrinade et al., 2019). However, these TTNmvs were found at similar frequencies to reference populations. Finally, a study of two families with DCM demonstrated segregation of TTNmvs affecting the same highly conserved cysteine residue in the I-band, which showed impaired contraction and folding at physiological temperatures in a homozygous iPSC model, demonstrating that a TTNmv can cause DCM (Domínguez et al., 2023).

We identified TTNmvs in 58% of subjects in our cohort, and 33% carried a potentially deleterious variant, as predicted by REVEL in silico. This frequency was higher than the 37/147 (25.2%) of TTNmv carriers in a DCM cohort (Begay et al., 2015), understanding that differing methods of bioinformatic filtering may limit the ability for direct comparison. Consistent with prior studies, most deleterious variants in our study were found in the A-band (Roberts et al., 2015; Akinrinade et al., 2016), where TTNtvs have been most strongly linked to disease. The presence of predicted deleterious TTNmvs was associated with a higher LV end-diastolic diameter, but without a statistically significant difference in LVEF, potentially suggesting overlap between subclinical left ventricular cardiomyopathy and AF in these subjects. Notably, rates of baseline heart failure diagnosis (encompassing both reduced and preserved ejection fraction) were similar based on TTNmv carrier status. We also noted higher ventricular rate and QTc interval on index ECGs in these subjects. Rare deleterious variants in TTN have previously been associated with changes in the QT interval (Kapoor et al., 2016), but the mechanism for this remains unclear. Finally, evidence on the relationship between TTNmvs and clinical outcomes is sparse, with only a few studies examining event-free survival in DCM patients. We observed a significant association between TTNmv presence and increased cumulative incidence of AF or HF-related hospitalizations, which remained unchanged in multivariable adjustment and in sensitivity analyses. This importantly suggests that TTNmvs may correlate with disease severity. Our cohort is derived from a single-center multi-ethnic registry of individuals with AF. It lacks a matched cohort of non-AF controls to compare the incidence of TTNmvs. Further study exploring these associations in multi-ethnic, larger validation cohorts that include both AF and non-AF individuals, and examining AF-specific measures such as arrhythmia burden or treatment response, will be necessary to fully understand the clinical importance of TTNmvs in AF.

Prediction of missense variant impact using in silico tools and algorithms can be limited by low specificity, contributing to challenges in clinical interpretation (Richards et al., 2015). Functional studies are often helpful in these cases to confirm or support variant pathogenicity. As existing in vitro or in vivo models do not adequately replicate the complexity of AF, human iPSC-aCMs possess the complex array of cardiac ion channels that make up the atrial AP and provide an adequate model to establish causal relationships in AF (Ly et al., 2021). We identified the missense variant TTN-T32756I in three unrelated subjects in our multiethnic AF registry. Hypertension is a common comorbidity in patients with AF and could contribute to disease progression. However, all three individuals carrying TTN-T32756I exhibited early-onset AF (onset before 66 years), with one case occurring as early as 36 years. This suggests a two-hit mechanism, in which genetic predisposition and comorbidities influence disease risk. Importantly, our iPSC model isolates the genetic effects of TTN-T32756I from other factors, supporting a direct pathogenic role. Remarkably, a single amino acid change in the giant protein titin results in aberrant contractility and EP remodeling without affecting sarcomeric integrity. Although we did not observe any defects in the sarcomere, in a separate study, including T32756I in the same area, caused significant perturbation in sarcomere assembly (Jiang et al., 2024). T32756 corresponds to a conserved threonine of the Ig139 domain (UniProt# Q8WZ42, predicted Ig155 by TITINdb2), and the replacement of a conserved hydrophilic residue (Thr) in WT with a hydrophobic residue (Ile) may cause thermal instability and destabilize the domain. It is now well recognized that point mutations may drastically disrupt the Ig domains and could unfold under pathological conditions (Li et al., 2000). Such mutations have been proposed to modify titin-based passive stiffness and may lead to cardiomyopathy. Missense mutations such as T2850I, R57C, and S22P in the I-band titin have been reported to significantly destabilize Ig domains and display a higher tendency to unfold (Zuo et al., 2021; Anderson et al., 2013). Likewise, T32756I may unfold under the physiological settings and increase susceptibility to protein loss (haploinsufficiency) or degradation (poison peptide effect), leading to impaired sarcomere function. Furthermore, as titin acts as a crucial signaling hub that transduces mechanical forces to downstream signaling pathways within cardiomyocytes and interacts with various sarcomeric proteins and signaling molecules (Granzier and Labeit, 2004; Krüger and Linke, 2011), subtle destabilization of the Ig139 domain by the T32756I could alter the biochemical signals that regulate various downstream signaling pathways involved in cardiac function and adaptation. Hence, the contractile and ion channel dysfunction caused solely by homozygosity for T32756I in iPSC-aCMs suggests that the TTN-T32756I missense variant can drive atrial remodeling. While our CRISPR-edited isogenic TTN-T32756I iPSC-aCMs provide genetically controlled for minimizing the genetic background variability and dissecting variant-specific effects, future studies using multiple iPSC backgrounds and patient-derived lines will be critical for confirming the robustness and generalizability of the observed phenotypes.

Although several studies have identified possible pathways associated with TTNtvs and AF, the pathogenic mechanisms of TTNmv-associated AF remain unclear. We show for the first time that the T32756I creates an EP substrate for AF by ion channel remodeling with an enhanced I_Ks, which is mediated by a titin-interacting protein FHL2. FHL2 is enriched in cardiac muscle and is a multifunctional protein that regulates cardiac myocyte signaling and function (Tran et al., 2016). FHL2 interacts with KCNE1, which binds to the outer face of the KCNQ1 channel pore domain and may modify the interactions between the voltage sensor, S4-S5 linker, and the pore domain to augment the channel current (Kupershmidt et al., 2002). It has been suggested that FHL2 interacts with the titin N2B segment, titin kinase domain, and forms a complex with other proteins, such as MURF1 and MURF2, calmodulin, and Nbr1, playing a role in hypertrophy signaling and the atrophy response (Sun et al., 2024; Liang et al., 2018). It also binds to the edge of titin (M-line), which is in close proximity to T32756I and interacts with myospryn and obscurin (Henderson et al., 2017). It is tempting to postulate that T32756I may interfere with FHL2’s interaction with titin, thereby disrupting subsequent mechano-biochemical signaling and increasing FHL2’s availability for binding to the KCNQ1-KCNE1 complex. While our study provides mechanistic insights into the role of the TTN-32756I missense variant in AF, TTNmvs may modulate ion channels and regulate atrial rhythmicity through multiple interrelated signaling pathways. Further studies are needed to fully uncover the molecular basis of this regulation and its implications for AF pathophysiology and potential therapeutic interventions.

In summary, this study demonstrates an association between TTNmvs and AF, suggesting that TTNmvs may contribute to adverse clinical outcomes in patients with AF and establishing a mechanism by which a particular TTNmv may influence AF development. We identify a critical role for FHL2 in modulating the atrial action potential by interacting with the Kv7.1–KCNE1 complex, thereby enhancing I_Ks in TTN-T32756I iPSC-aCMs. Importantly, suppression of FHL2 rescued the augmented I_Ks, indicating that targeting FHL2 or I_Ks may help restore sinus rhythm and improve atrial contractility. These findings provide mechanistic insight into how TTNmvs can promote arrhythmogenesis and highlight KCNQ1 and FHL2 as potential therapeutic targets for TTN-related AF. Further studies are warranted to validate this mechanism and to determine whether TTNmvs in other titin domains induce AF through similar pathways. Although the effects of TTN-T32756I in iPSC-derived ventricular cardiomyocytes remain to be explored, future work may clarify whether this variant produces comparable or distinct EP alterations. Collectively, our findings broaden the understanding of TTN-related atrial pathophysiology, underscore the importance of incorporating TTNmvs into genomic analyses of AF, and emphasize the value of functional validation in advancing precision medicine for patients carrying rare sarcomeric variants.

Availability of deidentified individual-level clinical and whole exome sequencing is subject to restrictions from the UIC Institutional Review Board and cannot be publicly released due to privacy and ethical concerns. Clinical data that support the findings of this study are available from the corresponding author upon reasonable request and completion of a data use agreement. However, aggregate data that preserve individual privacy are incorporated inside the manuscript and supplemental materials. The ClinVar accession number for the variant studied is VCV000178164.47. The RNA-Seq data reported in this article were deposited into the NCBI's Gene Expression Omnibus (GEO) database with the accession number GSE312917. Electrophysiology, microscopy, and other raw and analyzed data can be accessed at Mendeley Data (DOI:10.17632/3s8w9kr5hz.1, https://data.mendeley.com/datasets/3s8w9kr5hz/1). Code Availability: R version 4.2.1 and packages (arsenal [Heinzen et al., 2021a]; ggplot2 [Heinzen et al., 2021b]; ggsurvfit [Sjoberg et al., 2025a]; gtsummary [Sjoberg et al., 2025b]; reda [Wang et al., 2025]; survival [Therneau et al., 2026]; tidycmprsk [Sjoberg and Fei, 2025c]) are available at https://cran.r-project.org/. Variants are annotated with Ensembl Variant Effect Predictor (https://www.ensembl.org/info/docs/tools/vep/index.html) and CardioDB (https://cardiodb.org/titin) for TTN region and percent spliced in (PSI).

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   A titin missense variant drives atrial electrical remodeling and is associated with atrial fibrillation.

   https://doi.org/10.17632/3s8w9kr5hz.1
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Author details

1. Mahmud Arif Pavel

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Contributed equally with

   Hanna Chen and Michael Hill

   For correspondence

   gmmahmud@uic.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0005-2813-315X

2. Hanna Chen

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Contributed equally with

   Mahmud Arif Pavel and Michael Hill

   Competing interests

   No competing interests declared

3. Michael Hill

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Data curation, Software, Formal analysis, Validation, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Mahmud Arif Pavel and Hanna Chen

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5973-0804

4. Arvind Sridhar

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

5. Miles Barney

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Data curation, Formal analysis, Investigation, Visualization

   Competing interests

   No competing interests declared

6. Jaime DeSantiago

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Data curation, Formal analysis, Investigation, Visualization, Methodology

   Competing interests

   No competing interests declared

7. Abhinaya Baskaran

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

8. Asia Owais

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

9. Shashank Sandu

   Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

10. Faisal A Darbar

    Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

    Contribution

    Data curation, Formal analysis

    Competing interests

    No competing interests declared

11. Aylin Ornelas Loredo

    Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

    Contribution

    Data curation, Formal analysis, Investigation

    Competing interests

    No competing interests declared

12. Bahaa Al-Azzam

    Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States

    Contribution

    Formal analysis, Investigation

    Competing interests

    No competing interests declared

13. Brandon Chalazan

    1. Division of Genetics, Genomics, and Metabolism, Department of Pediatrics, Lurie Children’s Hospital of Chicago, Chicago, United States
    2. Department of Pharmacology, Northwestern University, Chicago, United States

    Contribution

    Resources, Data curation, Formal analysis

    Competing interests

    No competing interests declared

14. Jalees Rehman

    1. Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States
    2. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, United States

    Contribution

    Conceptualization, Resources, Supervision, Project administration

    Competing interests

    Reviewing editor, eLife

    "This ORCID iD identifies the author of this article:" 0000-0002-2787-9292

15. Dawood Darbar

    1. Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, United States
    2. Department of Pharmacology,University of Illinois at Chicago, Chicago, United States
    3. Jesse Brown Veterans Administration Medical Center, Chicago, United States

    Contribution

    Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

    For correspondence

    darbar@uic.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4103-5977

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