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

BACKGROUND TTN encodes a sarcomeric protein called titin. Pathogenic rare variants in TTN are the most commonfinding 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 TTNvariants compared with genotype-negative patients with AF.METHODS Patients who presented initially with AF were enrolled in an AF registry. Retrospectively they underwentresearch sequencing for cardiomyopathy and arrhythmia genes. TTN(þ) AF cases were defined as participants withpathogenic or likely pathogenic (P/LP) rare variants located in exons with high cardiac expression. They were matched 1:2with control subjects with no P/LP variants. Phenotyping used retrospective manual chart review.RESULTS Among 2794 participants; 57 (2.0%) TTN(þ) AF cases were identified and matched with 114 control subjects.Low QRS complex voltage was present more often in TTN(þ) AF cases (18% vs 5%; P < 0.01), with no difference in PR,QRS interval, or QTc. More TTN(þ) AF cases had persistent AF at enrollment (44% vs 30%; P ¼ 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(þ) 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(þ) AF patients undergo more cardioversions and have more persistent forms of AF.Approximately 50% develop LV systolic dysfunction and/or malignant ventricular arrhythmias. These resultshighlight the need for diagnostic evaluation and management in TTN(þ) patients beyond the usual care for AF.