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.

Keywords: Anderson-Fabry disease; GLA gene; Globotriaosylceramide; Heart failure.

Fig. 1

(Histological features of Anderson-Fabry disease). a Masson trichrome stain demonstrating vacuolization within myocytes with extension into the right bundle branch of the conduction pathway. b Section through the left circumflex coronary artery showing diffuse wall thickening without significant luminal occlusion. c Section through the mitral valve apparatus demonstrating mild mitral valve leaflet thickening and ballooning of the anterior and posterior valve leaflets. d H&E staining demonstrating hyaline pink material within the spongiosa and fibrosa. e H&E staining of the ventricular myocardium with evidence of myocyte hypertrophy and marked vacuolization of the cytoplasm of myocytes. f Transverse section of the heart. There is concentric left ventricular hypertrophy associated with thinning of the posterolateral wall (blue arrow). Mild right ventricular hypertrophy is also present and prominent in the posterobasal area of the RV. Fig. 1a–f: Reprinted from Cardiovasc Pathol.; 19(5), Sheppard MN, Cane P, Florio R, Kavantzas N, Close L, Shah J, Lee P, Elliott P; “A detailed pathologic examination of heart tissue from three older patients with Anderson-Fabry disease on enzyme replacement therapy.”; pages 293–301; 2010, reproduced with permission from Elsevier (Sheppard et al. 2010)

Fig. 2

(Echocardiogram features of Anderson-Fabry disease). a Transthoracic echocardiogram (TTE) parasternal long-axis view (PLAX) demonstrating concentric LVH with an interventricular septum (IVS) and left ventricular posterior wall (LVPW) diameter of 16 mm. b Apical 4 chamber view on TTE demonstrating the presence of concentric LVH. c Moderately dilated left atrium (31 cm²) on apical 4-chamber TTE view. d TTE parasternal short-axis view (PSAX) at mid-ventricular level demonstrating concentric LVH and hypertrophied papillary muscles. e TTE subcostal view demonstrating concentric LVH. f Pulsed wave Doppler across mitral valve inflow demonstrating impaired relaxation (grade 1 diastolic dysfunction) with E:A ratio of 0.87

Fig. 3

(Complications of Anderson-Fabry disease). a Mid-LV short-axis view on cardiac MRI (CMRI) showing concentric LVH with dense subepicardial and mid-wall LGE in the inferolateral wall. b Apical left ventricular aneurysm (blue arrow) demonstrated on a 4-chamber view on CMRI. c TTE apical 4-chamber view demonstrating severe eccentric (posteriorly) directed jet of MR due to mitral valve thickening and dysfunction. d 12-Lead electrocardiogram of a patient with conduction disease—borderline RBBB (QRS duration 120 ms) and right axis deviation. There is also presence of large voltage QRS complexes (prominent R waves V4-6) and repolarisation abnormalities with T wave inversion inferolaterally (leads II, III, aVF and V4-6) meeting ECG criteria for LVH. e Chest X-ray demonstrating a dual chamber secondary prevention implantable cardioverter-defibrillator (ICD) in an AFD patient presenting with an out-of-hospital cardiac arrest. f CT coronary angiogram of an AFD patient symptomatic with chest pain, demonstrating a non-calcified proximal LAD plaque lesion (blue arrow) associated with severe stenosis (70–99% diameter reduction)