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. 2024 Nov;10(11):2445-2457.
doi: 10.1016/j.jacep.2024.07.029. Epub 2024 Oct 23.

Clinical Characteristics and Outcomes in Patients With Atrial Fibrillation and Pathogenic TTN Variants

Zain M Virk  1 , Majd A El-Harasis  1 , Zachary T Yoneda  1 , Katherine C Anderson  1 , Lili Sun  2 , Joseph A Quintana  1 , Brittany S Murphy  1 , James L Laws  1 , Giovanni E Davogustto  1 , Matthew J O'Neill  1 , Bibin T Varghese  1 , Diane M Crawford  1 , Hollie L Williams  1 , Mahsima Shabani  1 , Cassady J Pelphrey  1 , Dakota D Grauherr  1 , Kelsey Tomasek  1 , Yan Ru Su  1 , Megan C Lancaster  1 , Quinn S Wells  3 , Jeffrey M Dendy  1 , Pablo Saavedra  1 , Juan C Estrada  1 , Travis D Richardson  1 , Sharon T Shen  1 , Arvindh N Kanagasundram  1 , Jay A Montgomery  1 , Christopher R Ellis  1 , George H Crossley  1 , Harikrishna Tandri  1 , Prince J Kannankeril  4 , Steven A Lubitz  5 , William G Stevenson  1 , Fei Ye  6 , Patrick T Ellinor  7 , Lynne W Stevenson  1 , Dan M Roden  3 , M Benjamin Shoemaker  8
Affiliations
Free article

Clinical Characteristics and Outcomes in Patients With Atrial Fibrillation and Pathogenic TTN Variants

Zain M Virk et al. JACC Clin Electrophysiol. 2024 Nov.
Free article

Abstract

Background: TTN encodes a sarcomeric protein called titin. Pathogenic rare variants in TTN are the most common finding in patients with atrial fibrillation (AF) and positive genetic testing.

Objectives: This study sought to define the characteristics and outcomes in patients with AF and pathogenic TTN variants compared with genotype-negative patients with AF.

Methods: Patients who presented initially with AF were enrolled in an AF registry. Retrospectively they underwent research sequencing for cardiomyopathy and arrhythmia genes. TTN(+) AF cases were defined as participants with pathogenic or likely pathogenic (P/LP) rare variants located in exons with high cardiac expression. They were matched 1:2 with control subjects with no P/LP variants. Phenotyping used retrospective manual chart review.

Results: Among 2794 participants; 57 (2.0%) TTN(+) AF cases were identified and matched with 114 control subjects. Low QRS complex voltage was present more often in TTN(+) AF cases (18% vs 5%; P < 0.01), with no difference in PR, QRS interval, or QTc. More TTN(+) AF cases had persistent AF at enrollment (44% vs 30%; P = 0.028) and had undergone multiple cardioversions (61% vs. 37%; P < 0.01). By end of follow-up (median 8.3 years; Q1, Q3: 4.5, 13.7 years), 11% of TTN(+) AF cases developed sustained ventricular tachycardia/ventricular fibrillation, 44% left ventricular (LV) systolic dysfunction (LV ejection fraction <50%), and 47% met a combined endpoint of sustained ventricular tachycardia/ventricular fibrillation or LV systolic dysfunction.

Conclusions: TTN(+) AF patients undergo more cardioversions and have more persistent forms of AF. Approximately 50% develop LV systolic dysfunction and/or malignant ventricular arrhythmias. These results highlight the need for diagnostic evaluation and management in TTN(+) patients beyond the usual care for AF.

Keywords: TTN, ventricular tachycardia; Titin; ablation; cardiomyopathy; genetic testing; heart failure.

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Conflict of interest statement

Funding Support and Author Disclosures This work was supported by grants from the American Heart Association (AHA20SCG35540034 [to Dr Shoemaker] and AHA18SFRN34110369 [to Dr Roden]) and the National Institutes of Health (R01HL155197 [to Dr Shoemaker]); and was also supported by CTSA award (UL1TR000445) from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the AHA or National Institutes of Health. Dr Kanagasundram has received speaker fees from Biosense Webster and Janssen. Dr Montgomery has received research funding from Medtronic. Dr Ellis has received research funding from Boston Scientific, Medtronic, and Boehringer Ingelheim; and has received consulting fees from Medtronic, Boston Scientific, Abbott Medical, and Atricure. Dr Crossley has received consulting fees or honoraria from Bayer Healthcare, Boston Scientific, Janssen Pharmaceuticals, Medtronic, and Spectranetics. Dr Richardson has received research funding from Medtronic and Abbott; and has served as a consultant for Philips and Biosense Webster. Dr Tandri has received a research grant from Abbott. Dr Stevenson has received honoraria from Abbott, Boston Scientific, Medtronic, Johnson and Johnson, and Biotronik; and has received research funding from Adagio Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.