Sex-Specific Cardiac Magnetic Resonance Phenotypes in Danon Disease: A Retrospective Cohort Study.

Abstract

Background: Danon disease (DD), an X-linked disorder due to lysosome-associated membrane protein 2 (LAMP2) mutations, features life-threatening cardiomyopathy. Sex-based cardiac magnetic resonance (cardiac MR) differences are recognized but lack quantitative analysis despite their critical importance in establishing sex-specific diagnostic thresholds and personalized treatment strategies.

Purpose: To investigate sex-based differences in cardiac MR manifestations in DD.

Study type: Retrospective.

Subjects: 24 DD patients (15 males, 9 females; January 2018-February 2025).

Field strength/sequence: 3-T, cine imaging (gradient-echo sequence), late gadolinium enhancement (LGE) imaging (inversion-recovery gradient-echo sequence), T1 mapping (modified look-locker inversion-recovery gradient-echo sequence), T2 mapping (gradient-echo sequence with T2 preparation).

Assessment: Standardized cardiac MR assessed structural indices (LV volumes/mass, wall thickness), functional metrics (EF, strain), and tissue characterization (late gadolinium enhancement [LGE extent, T1/T2 values]).

Statistical tests: Sex comparisons used independent t-tests/Mann-Whitney U for continuous variables; Chi-square/Fisher's exact for categorical variables. p < 0.05 significant.

Results: Males predominantly developed hypertrophic cardiomyopathy (HCM: 73.3%), whereas females universally exhibited dilated cardiomyopathy (DCM: 88.9%) with preserved septal thickness. Ventricular arrhythmias occurred in all females (100% vs. 73.3% in males). Females showed significantly worse left ventricular ejection fraction (LVEF: 37.0% ± 14.0% vs. 49.9% ± 17.9%). Cardiac MR revealed extensive LGE (21.9% ± 11.4%, diffuse free-wall involvement), elevated extracellular volume (ECV) (ECV: 38% ± 12%), and significantly prolonged T1/T2 values (1374 ± 60 ms/46.5 ± 5.4 ms; T1 was higher in females). Global longitudinal strain (GLS: -6.5% ± 4.0%), radial strain (GRS: 16.9% ± 12.2%), and circumferential strain (GCS: -10.6% ± 5.7%) were reduced, with significantly worse systolic impairment in females.

Data conclusion: Sex-specific cardiac MR patterns exist in DD: males predominantly develop HCM, whereas females primarily exhibit DCM, with apical/free wall LGE observed in both sexes, though mid-basal septum sparing is more frequent in males. These findings enable sex-stratified early diagnosis and phenotype-tailored surveillance, guiding clinical management.

Evidence level: 4.

Technical efficacy: Stage 2.