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Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy
Matteo Castrichini1, Ramin Garmany2,3, Konstantinos C Siontis1
1Department of Cardiovascular Medicine Mayo Clinic Rochester MN USA.
Insights
LMNA variants causing genetic cardiomyopathy show distinct patterns on cardiac MRI. Variants in the IgD domain are linked to a "pseudo-infarct" pattern, increasing risks for arrhythmias and clots but decreasing risks for AV block and AFib.
Area of Science:
- Cardiology
- Genetics
- Medical Imaging
Background:
- Lamin A/C (LMNA) variants cause genetic cardiomyopathy with arrhythmias and dysfunction.
- The impact of LMNA variant type and location on cardiac magnetic resonance imaging (MRI) findings and clinical outcomes is not well understood.
Purpose of the Study:
- To investigate the relationship between LMNA variant type/localization, late gadolinium enhancement (LGE) patterns on cardiac MRI, and clinical outcomes in patients with arrhythmogenic/dilated cardiomyopathy.
Main Methods:
- Retrospective analysis of 822 patients with LMNA variants.
- Cardiac MRI data, including LGE distribution, were analyzed.
- Clinical outcomes such as heart failure, thromboembolic events, and sudden cardiac death were assessed based on variant type and localization.
Main Results:
- Among 72 patients with cardiac MRI, 56% showed LGE, predominantly nonischemic midmyocardial/subepicardial patterns.
- A unique "pseudo-infarct" transmural LGE pattern was observed in 15% of cases, exclusively in patients with C-terminal IgD (immunoglobulin-like domain) variants.
- IgD variants were associated with lower rates of atrioventricular block and atrial fibrillation but higher rates of thromboembolic events and predicted sudden cardiac death/major ventricular arrhythmias.
Conclusions:
- LMNA missense variants in the IgD domain are associated with a distinct apical "pseudo-infarct" LGE pattern.
- This pattern correlates with an increased risk of ventricular arrhythmias and thromboembolic events, alongside a reduced risk of atrioventricular block and atrial fibrillation.
- Variant-specific risk stratification strategies are needed for improved management of cardiac laminopathy.
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.
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