Cardiac calcium handling in Fabry disease

VALVERDE CA; GONANO L; MUCCI J; RINALDI G; ROZENFELD P; VILA-PETROFF M; MATTIAZZI A

Santiago

Congreso; XX Annual Meeting of the International Society for Heart Research Latin American Section; 2012

International Society for Heart Research

Fabry (Fb) disease is a genetic X-linked lysosomal storage disordercaused by a deficiency in alpha-galactosidase A that affects, inter alia, tocardiac tissue. Clinical evidence indicates that cardiac arrhythmias arecommon in older patients with Fabry disease, having a significantimpact on patient survival. We assessed whether there is a potentialarrhythmogenic substrate at the cellular level responsible for triggeringthe cardiac arrhythmias. A murine model of Fb disease (KO mice) andWT mice were used. Homogenates from freshly isolated hearts fromboth strains were used for Western blotting for calcium handlingproteins. Isolatedmyocytes were employed for evaluating contractility,intracellular Ca transients and SR calciumcontent. Ca sparks and waveswere assessed by confocal microscopy. Hearts fromFbmice exhibited asimilar protein expression level of CaMKII, NCX, PCaMKII, SERCA2a andRyR2. However, there was a significantly increased phosphorylation ofRyR2 in the PKA and CaMKII sites in Fb respect toWT (193.3±22.8% vs.100.0±12.4%, 232.5±55.8% vs. 100.0±14.8%, respectively). Thisincrease was not accompanied by a significant alteration in SRcalcium content but was associated with a significant increase incalcium sparks and waves (in absence and presence of Iso), withrespect to WT mice. The increase in RyR2 phosphorylation in Fb micehearts could be the basis for the higher number of sparks and wavesobserved in this disease. This provides an arrhythmogenic substrateeither trigger or maintain arrhythmias in Fabry disease.