Effect of Migalastat on Cardiac Involvement in Fabry Disease
Effect of Migalastat on Cardiac Involvement in Fabry Disease
Anderson-Fabry Disease (AFD) is one of the rare lysosomal storage disorders for which a cause
 - specific therapy is available. Recently, a new specific drug has been marketed, namely
 Migalastat, a small-molecule pharmacological chaperone. The effect of Migalastat on cardiac
 involvement has been assessed so far by 2D echocardiography, demonstrating a significant
 reduction in left ventricular (LV) mass after 18 months of therapy. Calculation of LV mass by
 2D echocardiography is limited by geometrical assumptions and quality of echocardiographic
 window, with a strong impact on accuracy. Cardiac Magnetic Resonance (CMR) overcomes these
 limitations, thus representing the gold standard technique for ventricular mass, volumes and
 function estimation. Moreover, CMR offers the unique possibility to perform a non-invasive
 tissue characterization, including the detection of both myocardial fibrosis by Late
 Gadolinium Enhancement and sphingolipid storage by T1 mapping. Beyond an accurate
 morphological description and a detailed tissue characterization, a complete cardiological
 assessment should also integrate functional data and bio-humoral profile.

 This study is designed to provide a comprehensive evaluation of the therapeutic effect of
 Migalastat (123 mg every other day) on cardiac involvement after 18 months of therapy,
 integrating a morphological, functional and bio-humoral assessment.
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.

 MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the
 post-transcriptional level. MiRNAs have emerged as key regulators of several physiological
 and pathophysiological processes. Besides their intracellular function, recent studies
 demonstrated that miRNAs can be exported or released by cells and circulate in blood in a
 remarkably stable form. The discovery of circulating miRNAs opens the possibilities to use
 circulating miRNA patterns as biomarkers for several pathologies also for cardiovascular
 diseases. In a recent study, a common microRNA signature in AFD patients regardless of gender
 and age has been identified.15 miRNAs differentially expressed between 10 AFD subjects and 10
 normal controls (NC) have been found. The levels of these 15 miRNAs in plasma sample of 10
 subjects with LVH and no mutation in the Galactosidase Alpha (GLA) gene have also been
 studied. Among these 15 miRNAs, 3 discriminated AFD patients from subjects with LVH. In
 particular, 2 microRNAs (mir-199a-5p and mir126a-3p) were up-regulated and 1 miRNA
 (mir-423-5p) was down-expressed in AFD patients. Interestingly, in a recent study increased
 plasmatic levels of miR-126 and miR-199a were significantly associated with a lower major
 adverse Cardiovascular (CV) event rate in patients with coronary artery disease. Instead,
 elevated plasmatic levels of mir-423-5p is strongly related to the clinical diagnosis of
 Heart Failure. Several evidences indicate that the aberrantly expressed plasmatic miRNAs in
 AFD are linked to microvascular or macrovascular damage involved in the typical AFD
 vasculopathy and could be attractive as diagnostic markers as well as for the monitoring of
 the pharmacological treatment.

 Integration of all these aspects allows a complete morpho-functional evaluation of cardiac
 involvement in AFD and a detailed monitoring of the effects of specific drugs.

 This study is designed to provide a comprehensive evaluation of the therapeutic effect of
 Migalastat on cardiac involvement, integrating a morphological, functional and bio-humoral
 assessment of heart involvement. 15 patients with amenable mutation, clinical indication to
 Migalastat and signs of early or overt cardiac involvement with will undergo a complete
 cardiological evaluation before and 18 months after therapy with Migalastat. The
 cardiological assessment will include ECG, 2D echocardiography, CMR, cardio-pulmonary test,
 dosage of peripheral biomarkers (TnT High Sensitive; NT-proBNP, mir-199a-5p and mir126a-3p,
 mir-423-5p).
Inclusion Criteria:

 -  Genetic diagnosis of Fabry Disease and amenable mutation

 -  Clinical indication to Migalastat

 -  Signs of clinical or preclinical cardiac involvement (low T1 values with or without
 left ventricular hypertrophy)

 -  Age >16

 -  Ability to give a complete informed consent (for minor patients informed consent will
 be given by parents)

 Exclusion Criteria:

 -  Contraindication to Migalastat (pregnancy, age <16, Glomerular Filtration Rate <30
 ml/min, hypersensitivity to the active ingredient)

 -  Contraindication to CMR study (metallic fragment or foreign body, known
 claustrophobia, PaceMaker/Implantable Cardioverter Defibrillator not CMR conditional,
 electronic implant or device, eg, insulin pump or other infusion pump)