Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.

Abstract

Background: Disease-causative variants in LMNA-encoded lamin A/C cause a genetic cardiomyopathy characterized by atrioventricular block, atrial fibrillation, ventricular arrhythmias, and systolic dysfunction. The influence of LMNA variant type/localization on late gadolinium enhancement (LGE) patterns and clinical outcomes remains unclear.

Methods: Retrospective analysis of 822 genotype-positive patients with arrhythmogenic/dilated cardiomyopathy was used to identify those with disease-causative variants in LMNA. Data on LGE distribution and prevalence of advanced heart failure, thromboembolic and sudden cardiac death/major ventricular arrhythmia events were extracted from the electronic record and analyzed by variant type/localization.

Results: Among the 72/116 (62%) LMNA variant-positive patients with cardiac magnetic resonance imaging data, LGE was observed in 40/72 (56%) cases. Most exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and 6/40 (15%) showed a unique "pseudo-infarct" transmural pattern, predominantly affecting the apical segments. All 6 patients with this distinct LGE pattern harbored C-terminal IgD (immunoglobulin-like domain) variants (p.Arg471His or p.Arg541His). In patients with clinically manifest disease (76/116), those with IgD-localizing variants had a lower prevalence of atrioventricular block (25% versus 72%, P=0.002) and atrial fibrillation (50% versus 81%, P=0.019) but higher rates of thromboembolic events (42% versus 16%, P=0.038). During a median follow-up of 37 months, IgD variant presence independently predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio, 2.391 [95% CI, 1.046-5.464]; P=0.039).

Conclusions: LMNA missense variants localizing to IgD present a distinct apical pseudo-infarct LGE pattern associated with increased risk of ventricular arrhythmias and thromboembolic events but reduced atrioventricular block and atrial fibrillation. Multicenter studies are warranted to develop variant-specific risk-stratification strategies in cardiac laminopathy.