Fabry disease (FD) is an X-linked inborn error caused by mutations of alfa-galactosidase A gene (GLA); the deficiency/absence of alfa-Gal A activity results in the systemic accumulation of globotriaosylceramide and related glycosphingolipids within the lysosomes in microvascular endothelial cells, vascular smooth muscle cells, renal tubular cells, podocytes and cardiomyocytes, fovouring renal failure, cardio-cerebrovascular disease and premature demise. Cardiac involvement causing FD Cardiomyopathy (FDCM) is frequent in FD.
Treatment of FB is actually based on the administration of enzyme replacement therapy (ERT) and/or the use of chaperone therapy. Early ERT administration, particularly in the pre-hypertrophic FDCM, prevents progression of the disease. Mechanisms of resistance to ERT are still unclear although expansion of interstitial space as well as myocardial fibrosis appear to be implicated. Myocardial inflammation has been indicated as potentially contributive to myocardial fibrosis and interstitial expansion. Immune-mediated myocarditis has been histologically recognized in FDCM, suggesting mechanisms inducing the interstitial release of the highly in immunogenic globotrioacylceramide (Gb3) in pts with suitable HLA characteristic an autoimmune response.
These observations forward the need of a sensitive and specific serologic biomarker of myocardial inflammation in order to halt, through administration of low dose of immunosuppression, its deleterious effect on disease progression and ERT resistance.
The aim of the study is the serum assessment of anti-Gb3 antibody as biomarker of coexistent myocardial inflammation in pts with FDCM. Its level will be compared with that of normal controls and patients with various cardiomyopathies including idiopathic dilated and hypertrofic cardiomyophy. Finally anti-Gb3 antibody titre will be correlated with severity of MI (number of CD45Ro+ T lymphocytes/2mm tissue section), in order to establish its sensitivity.
There is growing evidence that myocardial inflammation (MI) can be cause of progression of FDCM as well as unnoticed mechanism of disease resistance to enzyme replacement therapy.
Indeed MI promotes cell dysfunction and death causing expansion of interstitial space through edema, inflammatory cells infiltration and myocardial fibrosis that result in both ventricular diastolic and systolic dysfunction. In addition, microaneurysm formation that is commonly seen in the postero-lateral segment of the left ventricle (1) can well be the result of a chronic unopposed MI.
With regard to the origin of MI associated to FDCM, an overlapping infectious disease and an autoimmune disorder could be both taken under consideration. Indeed, many congenital disorders like mitral valve prolapse, bicuspid aortic valve, right ventricular cardiomyopathy and hypertrophic cardiomyopathy (2) present an increased risk of cardiac infection. However, it has been recently reported (3) that infectious and particularly viral agents are not implicated in the generation of MI as Polymerase Chain Reaction using a large molecular panel failed to show viral genomes in inflamed myocardial tissue with FDCM. On the other hand, the strong positivity of immunohistochemistry and immunofluorescence for anti-heart and antimyosin antibodies suggest MI to have an autoimmune/dysreactive origin.
To this regard, globotriaocylcleramide (Gb3), the major component of FD storage material, is constantly released by engulfed cardiomyocytes along a constitutional secretory pathway or as a result of cell necrosis. Gb3 is recognized as a powerful immunogenic molecule that may promote and perpetuate an inflammatory autoimmune disorder.
Serum assessment of anti-Gb3-antibody and the demonstration that its title increases with the severity of MI would confirm the implication of that pathway.
The identification of a sensitive biomarker of myocardial inflammation in pts with FDCM can allow the introduction of immune-suppressive therapy that may halt the progression of FDCM and improve the efficacy of ERT. The expected time for study accomplisnment is of 24 months. It includescost development of ELISA kit for Gb3, equipment, payment for a dedicate payment for dedicate tachician, publications costs.
1: Chimenti C, Morgante E, Tanzilli G, Mangieri E, Critelli G, Gaudio C, Russo MA, Frustaci A. Angina in fabry disease reflects coronary small vessel disease. Circ Heart Fail. 2008 Sep;1(3):161-9.
2: Frustaci A, Verardo R, Caldarulo M, Acconcia MC, Russo MA, Chimenti C. Myocarditis in hypertrophic cardiomyopathy patients presenting acute clinical deterioration. Eur Heart J. 2007 Mar;28(6):733-40.
3: Frustaci A, Verardo R, Grande C, Galea N, Piselli P, Carbone I, Alfarano M, Russo MA, Chimenti C. Immune-Mediated Myocarditis in Fabry Disease Cardiomyopathy. J Am Heart Assoc. 2018 Sep 4;7(17):e009052.