Abstract

Introduction: Pathogenic titin ( TTN ) variants are associated with malignant ventricular tachycardia (VT) that often arises from fibrosis in the basal LV and may occur before severe LV systolic dysfunction. Late gadolinium enhancement (LGE) can identify the substrate for VT, but measurement of LGE in the basal LV is technically challenging. As genetic testing identifies more patients with earlier stages of TTN cardiomyopathy, methods are needed to stratify their risk for malignant VT. Hypothesis: LGE burden in the basal LV is greater in patients with pathogenic TTN variants compared to controls, and is associated with a higher risk of malignant VT. Methods: Patients with early-onset AF and/or ventricular arrhythmias (VAs) unrelated to ischemic heart disease underwent genetic sequencing. Cases had pathogenic or likely-pathogenic (P/LP) rare TTN variants. Controls had no P/LP variants in cardiomyopathy or arrhythmia genes and were matched by age, sex, and whether they had predominately AF or VAs. Cardiac MRIs were reanalyzed by two readers blinded to case/control status. Basal LV LGE was quantified using the 5-SD signal intensity method of 3 short axis segmented inversion recovery images 8mm apart beginning at the first segment below the LVOT. Risk of malignant VT was defined as: Low Risk (≤100 PVCs per day, no NSVT, no VT), Moderate Risk (NSVT or >100 PVCs per day), or High Risk (prior sustained VT). Results: There were 16 TTN cases and 17 controls. Age ( TTN 53 years [Q1-Q3: 49-59]; controls 51 years [42-59]) and LVEF ( TTN 56% [49-62]; controls 60% [55-63]) were similar. Reanalysis identified basal LGE (defined as ≥5% burden) in 14 patients (42%) compared to only 7 (21%) in the original clinical reports. LVEF was >50% in 10 of 14 patients with LGE. TTN cases had significantly higher basal LGE burden compared to controls ( TTN 9.0% [4.8-13.5] vs. controls 1.4% [0.0-2.3], p<0.01). High and Moderate Risk groups for malignant VT had significantly more basal LV LGE compared to the Low Risk group (High Risk: N=2, median 16.1% [15.3-16.9]; Moderate Risk: N=9, 10.0% [5.9-13.4]; Low Risk: N=22, 2.1% [0.0-3.7] p=0.01). Conclusion: Among patients with relatively preserved LV systolic function, pathogenic TTN variants were associated with greater burden of LGE in the basal LV compared to controls, and basal LGE was associated with severity of ventricular arrhythmias. Measurement of LGE in the basal LV may be useful to assess arrhythmia risk in patients with pathogenic TTN variants.