Hypertension exaggerates left ventricular hypertrophy in fabry patients

Objective: Left ventricular hypertrophy (LVH) and dysfunction are the main causes of death in patients with Fabry Disease (FD). Identification of clinical predictors of FD evolution is crucially important for the correct timing of therapeutic intervention. On this ground, we aim to evaluate the impact of hypertension (H) as a predictor of (LVH) progression in FD. Design and method: We compared the FD database (319 patients) with patients from the URRAH study [>15000 patients] for H, indexed ventricular mass (LVMi) and calculated the odds ratio (OR) for LVH development. In a murine model of FD (tg-R301Q/KO mice) we chronically infused phenylephrine (PE,100 mg/Kg, 14-Days) by subcutaneous implantation of miniosmotic pump to increase blood pressure. Results: H in FD compared to URRAH exploded the LVH-OR by 6.3 times. In H patients, LVMi is significantly higher in FD than URRAH patients (FD, no H:98.8±47; FD, H:148.8±67.5 g/m2 p<0.01; URRAH, no H:103.6±29.6; U, H:112.4±31.3 g/m2, p<0.01). The multivariate analysis for sex and age indicated that FD and hypertension interact as independent risk factors for LVH. PE-exposure induced a comparable increase in systolic and diastolic blood pressure in FD and control mice. However, in FD mice PE induced a larger increase of LVMi, alongside with higher Heart-body weight ratio, and higher ANP and MEF2 cardiac levels. In FD heart, PE caused energetic stress signaling activation suggesting the potential involvement of AMPK-FOX03-axis in the hypertrophic response of FD-heart under hemodynamic stress. Conclusions: Our data suggest that H is associated with a higher risk of LVH, representing a clinical predictor of a worsened evolution of FD cardiac phenotype. Data from the murine model confirm the exaggerated hypertrophic response to H of FD heart, probably due to energetic stress induced by the increased cardiac workload.