STRUCTURAL AND FUNCTIONAL MECHANISMS OF DIASTOLIC AND SYSTOLIC DYSFUNCTION IN FABRY DISEASE CARDIOMYOPATHY

Fabry disease is a rare and underestimated X-linked disorder caused by the deficiency of lysosomal enzyme alpha-galactosidase A. The enzymatic deficit results in progressive intracellular accumulation of glycosphingolipids. Both hemizygote males and heterozygote female manifest the disease, with a reduction of life-expectancy of approximately 20 and 15 years respectively. Cardiac involvement is the most important cause of death. The mechanisms through which gene alteration causes the myocardial damage are still unclear as well as to which extent myocardial abnormalities are reversible with enzyme replacement therapy (ERT). This study will allow improving the understanding of the pathogenesis of the cardiac damage in Fabry disease, analysing the tissue and cellular determinants of myocardial dysfunction before and after a substantial period of ERT. The possible link between the genetic defect and the alteration in cardiomyocyte function will be investigated analysing the imbalance of intracellular signalling pathways due to glycosphingolipid accumulation. The definition of these mechanisms will clarify to which extent the cardiac dysfunction can be reverted in different stages of the disease, with an optimisation of the timing of starting ERT. Moreover the study will allow defining new variables to assess the real effect of ERT at cardiac level. Such parameters will be useful also for the assessment of new therapeutic strategies under evaluation in clinical trials, such as chaperone therapy. Finally, the identification of intracellular mechanisms responsible of the alteration of cardiac function will open the field for the investigation of additional therapeutic options, aimed to revert these mechanisms, optimising the treatment of Fabry disease.