Analysis of left ventricular mass in untreated men and in men treated with agalsidase-β: data from the Fabry Registry

Abstract

Fabry disease (FD) (OMIM 301500) is a rare disorder in which globotriaosylceramide and other glycosphingolipids accumulate within lysosomes because of insufficient activity of α-galactosidase A. 1,2 Over time, the glycosphingolipid substrate progressively accumulates within blood vessels and various other cell types throughout the body. The initial signs and symptoms of FD frequently include neuropathic pain in the extremities, hypohidrosis, angiokeratomas, and gastrointestinal discomfort. 3 Over a period of decades, the accumulation of glycosphingolipids impairs vital organ function, putting patients at risk of developing renal failure, stroke, and cardiovascular dysfunction. [4][5][6] Because it is an X-linked disorder, hemizygous males typically experience the most severe manifestations of FD, 1 but heterozygous females can also develop serious complications. [4][5][6][7] The cardiovascular manifestations of FD can include leftventricular hypertrophy (LVH), atrial and left-ventricular arrhythmias, heart block, valvular dysfunction, angina, and arterial wall thickening. 4,5,[8][9][10][11][12][13] As the disease progresses, the hypertrophy becomes more severe, including the development of myocardial fibrosis and serious cardiac events including cardiac-related death. 4,5,8,11 Agalsidase-β, a recombinant form of human α-galactosidase A (Fabrazyme, Genzyme a Sanofi Company, Cambridge, MA), is approved for use as enzyme replacement therapy (ERT) for FD. In clinical studies, agalsidase-β at a dose of 1 mg/kg/2 weeks cleared microvascular endothelial glycosphingolipid deposits from the heart, as well as from kidney and skin, within 5 months. 14 It also provided long-term stabilization of renal function in patients with mild renal involvement 15 and delayed time to renal, cardiovascular, and cerebrovascular events in patients with more advanced FD. 16 Because it is a rare disorder, the randomized clinical trials of agalsidase-β included a relatively limited number of subjects with FD. 14,16 Several prospective, observational studies have reported cardiac data from patients treated with agalsidase-β, but these also involved only small numbers of patients. 17,18 Purpose: The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-β (recombinant human α-galactosidase A) on left ventricular hypertrophy. Methods:Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-β (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression.Results: For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was −3.6 g/year (n = 31) compared with +9.5 g/year in untr...

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study

“…The most common cardiac manifestation of Fabry disease is hypertrophic cardiomyopathy 46. LVH is an important risk factor for predicting cardiac events (heart failure and myocardial infarction) in Fabry disease 43 47. Reduction of LV mass has been associated with improved outcomes in Fabry disease; a 3-year study in patients with Fabry disease without myocardial fibrosis found that post-treatment reductions in LV mass were associated with improvement in stress exercise 48.…”

Clinic-Pathologic Features and Renal Outcome of Fabry Disease: Data from a Chinese Cohort

“…Cardiac complications are common and the main cause of death in FD [33]. The most frequent cardiac manifestation is LVH, an important risk factor for cardiac events [34]. Of the patients initially diagnosed with hypertrophic cardiomyopathy, 3.9-12% are eventually found to have FD.…”

Fabry disease: Multi-disciplinary evaluation after 15 years of treatment with agalsidase beta

“…Only one patient showed echocardiographical signs of LVH, whereby the thickness of the IVS and the LVPW after 10 years of ERT was normal. As is repeated in the bibliography, an increase in the thickness of the IVS, LVPW, and LVMI is related to age, justified by the fact that the only patient with signs of LVH was the oldest in our series (Germain et al 2013). Agalsidase Beta has proved to be effective in reducing left ventricular mass in patients who commenced ERT between the ages of 18 and 30 according to a recent survey conducted by the Fabry Registry (Germain et al 2013).…”