Substrate Characterization and Outcomes of Ventricular Tachycardia Ablation in TTN (Titin) Cardiomyopathy

Abstract

Background - Truncating variants of the titin gene (TTNtv) are a leading cause of dilated cardiomyopathy (DCM) and have been associated with an increased risk of ventricular arrhythmias. This study evaluated the substrate distribution and the acute and long-term outcomes of patients with TTN-related cardiomyopathy undergoing ventricular tachycardia (VT) ablation. Methods - This multicenter registry included 15 patients with DCM (age 59±11 years, 93% male, ejection fraction 30±12%) and genotypically confirmed TTNtvs who underwent VT ablation between July 2014 and July 2020. Results - All patients presented with sustained monomorphic VT, including electrical storm in 4 of them. A median of 2 VTs per patient were induced during the procedure (cycle-length 318±68 ms) and the predominant morphologies were left bundle branch block with inferior axis (39%) and right bundle branch block with inferior axis (29%). A complete map of the left ventricle (LV) was created in 12 patients and showed voltage abnormalities mainly at the periaortic (92%) and basal septal region (58%). A preprocedural cardiac magnetic resonance imaging was available in 13 patients and in 11 there was evidence of LV delayed gadolinium enhancement, with predominantly midmyocardial distribution. Sequential ablation from both sides of the septum was required in 47% of patients to target septal intramural substrate and epicardial ablation was performed in 20%. At the end of the procedure, the clinical VT was noninducible in all patients, while in 3 cases a non-clinical VT was still inducible. After a follow-up of 26.5±23.0 months, 53% of patients experienced VT recurrence, 20% received transplant or mechanical circulatory support and 7% died. Conclusion - The arrhythmogenic substrate in TTN-related cardiomyopathy involves the basal septal and perivalvular regions. Long-term outcomes of catheter ablation are modest, with high recurrence rate, likely related to an intramural location of VT circuits.

Value of genotyping and scar‐phenotyping for VT ablation procedures in patients with nonischemic left ventricular cardiomyopathies

“…All but one of the patients with LMNA or TTN variants had VT recurrence after the initial ablation procedure. A deeper location of scarring most likely was the reason for the high prevalence of VT recurrence, which is consistent with prior reports of patients with LMNA or TTN mutations 8,9 . We could demonstrate in another series of patients with NICM that the SDI is a reliable indicator of VT recurrence 6 .…”

“…In this patient series, we assessed scar characteristics in patients with PVs affecting LMNA, TTN, and other genes and compared them with other patients without PVs. Similar to our report, an intramural location of a septal substrate has been described in prior publications focusing on LMNA and TTN variants 8,9 . Scar topography, scar extent and its relation to VT ablation procedures have not been systematically described in these patients.…”

“…Based on the high recurrence rate Kumar et al 9 suggested that ablation procedures in patients with LMNA variants should be considered as a palliative procedure. Similar disappointing ablation results with frequent VT recurrences have been reported in patients with TTN variants 8 . DE‐CMR is beneficial in identifying patients in whom VT recurrence is high, 6 and in whom early considerations for advanced heart failure therapies may be appropriate.…”

“…A deeper location of scarring most likely was the reason for the high prevalence of VT recurrence, which is consistent with prior reports of patients with LMNA or TTN mutations. 8,9 We could demonstrate in another series of patients with NICM that the SDI is a reliable indicator of VT recurrence. 6 A cut-off value of >17% of the projected scar surface being located at a depth of >5 mm was associated with VT recurrence.…”

Localized intramural reentry confined within the ventricular septum in lamin cardiomyopathy

“…Catheter ablation for drug-refractory VT in patients with dilated cardiomyopathies, particularly in those with genetic mutations such as LMNA and TTN , are associated with VT recurrence rates that are among the highest in structural heart disease. 3 , 4 , 5 The advent of improved genetic testing has led to improved identification of likely pathologic variants associated with dilated cardiomyopathy and VT, allowing for better understanding of the substrate and outcomes based on the specific etiology of dilated cardiomyopathy. Patients with pathologic genetic variants, when compared to those without pathologic variants, were shown to have significantly lower 2-year VT-free survival and increased cardiac and all-cause mortality.…”