Myocardial Storage, Inflammation, and Cardiac Phenotype in Fabry Disease After One Year of Enzyme Replacement Therapy

Abstract

Background: Cardiac response to enzyme replacement therapy (ERT) in Fabry disease is typically assessed by measuring left ventricular mass index using echocardiography or cardiovascular magnetic resonance, but neither quantifies myocardial biology. Low native T1 in Fabry disease represents sphingolipid accumulation; late gadolinium enhancement with high T2 and troponin elevation reflects inflammation. We evaluated the effect of ERT on myocardial storage, inflammation, and hypertrophy.

Methods: Twenty patients starting ERT (60% left ventricular hypertrophy-positive) were compared with 18 patients with early disease and 18 with advanced disease over 1 year at 3 centers. Cardiovascular magnetic resonance (left ventricular mass index, T1, T2, global longitudinal strain, and late gadolinium enhancement) and biomarkers (high-sensitive troponin-T and NT-proBNP [N-terminal Pro-B-type natriuretic peptide]) at baseline (pre-ERT) and 12 months were performed. Early disease controls were stable, treatment-naïve patients (mainly left ventricular hypertrophy-negative); advanced disease controls were stable, established ERT patients (mainly left ventricular hypertrophy-positive).

Results: Over 1 year, early disease controls increased maximum wall thickness and left ventricular mass index (9.8±2.7 versus 10.2±2.6 mm; P=0.010; 65±15 versus 67±16 g/m²; P=0.005) and native T1 fell (981±58 versus 959±61 ms; P=0.002). Advanced disease controls increased T2 in the late gadolinium enhancement area (57±6 versus 60±7 ms; P=0.023) with worsening global longitudinal strain (-13.2±3.4 versus -12.1±4.8; P=0.039). Newly treated patients had a small reduction in maximum wall thickness (14.8±5.9 versus 14.4±5.7 mm; P=0.028), stable left ventricular mass index (93±42 versus 92±40 g/m²; P=0.186) and a reduction in T1 lowering (917±49 versus 931±54 ms; P=0.017).

Conclusions: Fabry myocardial phenotype development is different at different disease stages. After 1 year of ERT initiation, left ventricular hypertrophy-positive patients have a detectable, small reduction in left ventricular mass and storage.

Keywords: Fabry disease; inflammation; myocardium; sphingolipid; troponin.

Figure 1.

Example case. A 60-year-old Fabry Disease male with left ventricular hypertrophy, low T1 (902 ms), and basal inferolateral late gadolinium enhancement (LGE) before initiation of enzyme replacement therapy (ERT). T2 corresponding to the LGE area is high at 66 ms with high troponin level. After 1 y of initiation of ERT, T1 partially normalized to 940 ms, and limited regression of left ventricular mass index (LVMi) was observed (−4 g/m²). T2 at the LGE area remained high at 67 ms with no significant troponin level change.

Figure 2.

Left ventricular mass indexed (LVMi) and native T1 before and after initiation of enzyme replacement therapy (ERT) at 12 months in left ventricular hypertrophy (LVH)–positive and LVH-negative Fabry Disease. *P<0.05= statistically significant.

Figure 3.

Left ventricular mass indexed (LVMi), native T1, T2 at late gadolinium enhancement (LGE) area or basal inferolateral (BIFL) wall if no LGE and troponin levels at baseline and 12 months in all 3 groups. *P<0.05= statistically significant. ERT indicates enzyme replacement therapy.