Cardiomyopathy phenotyping and risk-stratification in danon disease

Abstract

Abstract Background Danon Disease (DD) is a rare, X-linked vacuolar myopathy due to mutations in Lysosomal Associated Membrane Protein 2 (LAMP-2). Though it is strongly associated with severe cardiomyopathy, heart failure and sudden death, there is no data on typical cardiac magnetic resonance (CMR) imaging characteristics in DD and their association with clinical severity and outcome. Purpose To phenotype and risk-stratify DD patients. Methods CMR scans of confirmed DD patients recruited in a global registry were prospectively analyzed for biventricular volumes, ejection fraction (EF), left ventricular (LV) strain, mass (LVM) and late gadolinium enhancement (LGE) in a core-lab blinded fashion. A major adverse cardiac event (MACE) was a composite of death, heart transplant and implantable cardioverter defibrillator (ICD) for secondary prevention. Results 12 DD patients (5 males [42%], median age 13 yrs [interquartile range (IQR) 5]) were included. LV hypertrophy (LVH) was present in 10/12 (83%), associated with LV dilation in 2 females. LVH was typically asymmetric in females (5/7) and concentric in males (3/5); right ventricular (RV) hypertrophy frequent in females (4/7). LV strain was reduced (global circumferential strain [GCS] −12±4%) and LGE common (73%), often extensive and always sparing the basal-mid septum. LGE was strongly associated with heart failure (BNP r=0.9, p=0.0021). Patients with MACE (6 [50%], median follow-up 2.9 yrs) had elevated LVM (241±63 g, p=0.032), impaired LV strain (GCS: −9.8±3.9, p=0.02) and higher LGE mass (median 56 g [IQR 35], p=0.021) compared to those without events during follow-up (LVM 155±56 g, GCS −14.9±1.6, LGE mass 0 g [IQR 8]). CMR characteristics were predictors of MACE (LV strain: hazard ratio [HR] 1.4, p=0.021; LGE mass: HR 1.1, p=0.03). Conclusions LGE sparing the basal-mid septum was pathognomonic in DD. LVH with reduced LV strain was the most common DD phenotype but the spectrum included LV dilation and RV hypertrophy in females. CMR characteristics (LV strain and LGE) were associated with heart failure and predicted worse outcome (heart transplant and fatal arrhythmias). CMR phenotyping and risk-stratification of this severe and underrecognized cardiomyopathy may aid diagnosis and clinical management in DD patients who need selection for early heart transplant, ICD implantation and targeted gene therapy. Danon Disease Phenotypes and Outcome Funding Acknowledgement Type of funding source: Other. Main funding source(s): National Institute of Health and Rocket Pharmaceuticals