Anderson-Fabry disease in heart failure

Abstract

Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene that result in deficiency of the enzyme alpha-galactosidase A. The worldwide incidence of Fabry’s disease is reported to be in the range of 1 in 40,000–117,000, although this value may be a significant underestimate given under recognition of symptoms and delayed or missed diagnosis. Deficiency in alpha-galactosidase A causes an accumulation of neutral glycosphingolipids such as globotriaosylceramide (Gb3) in lysosomes within various tissues including the vascular endothelium, kidneys, heart, eyes, skin and nervous system. Gb3 accumulation induces pathology via the release of pro-inflammatory cytokines, growth-promoting factors and by oxidative stress, resulting in myocardial extracellular matrix remodelling, left ventricular hypertrophy (LVH), vascular dysfunction and interstitial fibrosis. Cardiac involvement manifesting as ventricular hypertrophy, systolic and diastolic dysfunction, valvular abnormalities and conduction tissue disease is common in AFD and is associated with considerable cardiovascular morbidity and mortality from heart failure, sudden cardiac death and stroke-related death.

Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology

“…In patients with HCM caused by rare storage disorders (e.g. Anderson–Fabry, Danon and Pompe diseases), HF most commonly takes the HFpEF phenotype due to an extensive, concentric increase in LV wall thickness . The increased wall thickness is caused partly by myocyte hypertrophy (due to lysosomal accumulation of glycosphingolipids), and partly by interstitial fibrosis stimulated by overproduction of profibrotic cytokines .…”

“…Anderson–Fabry, Danon and Pompe diseases), HF most commonly takes the HFpEF phenotype due to an extensive, concentric increase in LV wall thickness . The increased wall thickness is caused partly by myocyte hypertrophy (due to lysosomal accumulation of glycosphingolipids), and partly by interstitial fibrosis stimulated by overproduction of profibrotic cytokines . Asymmetric LV hypertrophy in storage disorders is rare (< 2.5%), while biventricular hypertrophy may occur in up to 25% of patients .…”

Mechanical dispersion in Fabry disease assessed with speckle tracking echocardiography

“…CRT has been proven to be useful for reducing ventricular dyssynchrony, decreasing filling pressures, and reversing remodeling, which result in reduced volumes and improvement in LV systolic function. [39][40][41] Biering-Sørensen et al 42 conducted a study on 3445 patients with HF and preserved EF, and they reported MD in 12% of the patients. However, MD did not predict poor outcomes.…”

Ultrastructural Evidence of Glycosphingolipid Degradation After Enzyme Replacement Therapy in Patients With Fabry Disease

“…Please find supplementary file(s); http://dx.doi.org/10.1253/circj.CJ-19-0127 T he enzyme α-galactosidase A is insufficient in Fabry disease, which causes an accumulation of neutral glycosphingolipids in various tissues. 1 We recently had the opportunity to examine endomyocardial biopsy and/or autopsy specimens from 3 patients with Fabry disease before and after enzyme replacement therapy (ERT). Supplementary Table lists the patient profiles.…”