Effect of Migalastat on Cardiac Involvement in Fabry Disease

Anderson-Fabry disease is a rare X-linked lysosomal disorder, mainly affecting cardiovascular, renal and nervous systems. Cardiac injury is the leading cause of death in these patients. Heart involvement is characterized by left ventricular hypertrophy (LVH), myocardial scarring and/or inflammation, Bradyarrhythmias or tachyarrhythmias, heart failure and represents the main cause of death in these patients. Since 2001, specific therapies (enzyme replacement therapy (ERT) first and pharmacological chaperone migalastat more recently) are available to treat these patients.

Migalastat is a small-molecule pharmacological chaperone stabilizing specific mutant forms of the enzyme (α-Gal ) and promoting its catabolic function. These mutant forms of α-Gal are defined as amenable to Migalastat. In patients with amenable mutations, orally administered Migalastat is a potential alternative treatment to intravenous ERT. Because of its chemical nature (small molecule) and route of administration (orally), Migalastat would avoid ERT-associated immunogenicity and infusion-associated reactions. Additionally, the higher volume of distribution of migalastat relative to ERT suggests enhanced penetration of organs and tissues. Theoretically, the chaperoning of α-Gal by Migalastat to lysosomes may better mimic natural enzyme trafficking and result in more constant α-Gal activity than biweekly ERT infusions.

Two main clinical studies have been published so far about safety and efficacy of Migalastat in AFD, demonstrating good safety, tolerability and comparable efficacy to ERT. These studies reported a significant decrease in LV mass index assessed by 2D echocardiography (-6,6 g/m2 in 33 patients after 18 months of therapy), mostly in patients with overt cardiac involvement and greater than the changes observed with ERT (-2 g/m2 in 16 patients after 18 months of therapy).

Calculation of LV mass by 2D echocardiography is based on the "Devereux formula", assuming that the LV is a prolate ellipsoid with a 2:1 long/short axis ratio and symmetric distribution of hypertrophy. This is not always the case in AFD Cardiomyopathy, showing a wide variety of hypertrophy patterns. Moreover, since linear measurements of LV wall thickness and diameters are cubed in this formula, even small measurement errors in dimensions or thickness have a strong impact on accuracy.

Cardiac magnetic resonance (CMR) represents the gold standard technique for ventricular mass, volumes and function estimation because of the possibility to directly measure these parameters without geometrical assumption. Therefore, CMR has an excellent inter-study reproducibility both in normal and in pathologic hearts, overcoming 2D echocardiography. Beyond its high reproducibility in LV mass measurement, CMR offers the unique possibility of non-invasive tissue characterization. This concept includes both detection and quantification of myocardial fibrosis by Late Gadolinium Enhancement images and application of new techniques, namely T1 mapping, detecting myocardial sphingolipid storage even before LVH occurs. Also, CMR allows a detailed characterization of myocardial deformation by feature tracking. Feature tracking CMR (FT-CMR) approximately applies the same principles of speckle tracking echocardiography (even though with differences methods of image acquisition and reconstruction) in order to measure global and segmental myocardial deformation. The strength of FT-CMR consists of its relatively unrestricted access to large fields of view, its high spatial resolution and its relatively high signal to noise and contrast to noise ratios.