Cardiac calcium handling in Fabry disease

CARLOS VALVERDE; LUIS GONANO; MUCCI J; GUSTAVO RINALDI; PAULA ROZENFELD; MARTÍN VILA PETROFF; ALICIA MATTIAZZI

Santiago

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

Fabry (Fb) disease is a genetic X-linked lysosomal storage disorder caused by a deficiency in alpha-galactosidase A that affects, inter alia, to cardiac tissue. Clinical evidence indicates that cardiac arrhythmias are common in older patients with Fabry disease, having a significant impact on patient survival. We assessed whether there is a potential arrhythmogenic substrate at the cellular level responsible for triggering the cardiac arrhythmias. A murine model of Fb disease (KO mice) and WT mice were used. Homogenates from freshly isolated hearts from both strains were used for Western blotting for calcium handling proteins. Isolatedmyocytes were employed for evaluating contractility, intracellular Ca transients and SR calciumcontent. Ca sparks and waves were assessed by confocal microscopy. Hearts fromFbmice exhibited a similar protein expression level of CaMKII, NCX, PCaMKII, SERCA2a and RyR2. However, there was a significantly increased phosphorylation of RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. impact on patient survival. We assessed whether there is a potential arrhythmogenic substrate at the cellular level responsible for triggering the cardiac arrhythmias. A murine model of Fb disease (KO mice) and WT mice were used. Homogenates from freshly isolated hearts from both strains were used for Western blotting for calcium handling proteins. Isolatedmyocytes were employed for evaluating contractility, intracellular Ca transients and SR calciumcontent. Ca sparks and waves were assessed by confocal microscopy. Hearts fromFbmice exhibited a similar protein expression level of CaMKII, NCX, PCaMKII, SERCA2a and RyR2. However, there was a significantly increased phosphorylation of RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. cardiac tissue. Clinical evidence indicates that cardiac arrhythmias are common in older patients with Fabry disease, having a significant impact on patient survival. We assessed whether there is a potential arrhythmogenic substrate at the cellular level responsible for triggering the cardiac arrhythmias. A murine model of Fb disease (KO mice) and WT mice were used. Homogenates from freshly isolated hearts from both strains were used for Western blotting for calcium handling proteins. Isolatedmyocytes were employed for evaluating contractility, intracellular Ca transients and SR calciumcontent. Ca sparks and waves were assessed by confocal microscopy. Hearts fromFbmice exhibited a similar protein expression level of CaMKII, NCX, PCaMKII, SERCA2a and RyR2. However, there was a significantly increased phosphorylation of RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. impact on patient survival. We assessed whether there is a potential arrhythmogenic substrate at the cellular level responsible for triggering the cardiac arrhythmias. A murine model of Fb disease (KO mice) and WT mice were used. Homogenates from freshly isolated hearts from both strains were used for Western blotting for calcium handling proteins. Isolatedmyocytes were employed for evaluating contractility, intracellular Ca transients and SR calciumcontent. Ca sparks and waves were assessed by confocal microscopy. Hearts fromFbmice exhibited a similar protein expression level of CaMKII, NCX, PCaMKII, SERCA2a and RyR2. However, there was a significantly increased phosphorylation of RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. ficiency in alpha-galactosidase A that affects, inter alia, to cardiac tissue. Clinical evidence indicates that cardiac arrhythmias are common in older patients with Fabry disease, having a significant impact on patient survival. We assessed whether there is a potential arrhythmogenic substrate at the cellular level responsible for triggering the cardiac arrhythmias. A murine model of Fb disease (KO mice) and WT mice were used. Homogenates from freshly isolated hearts from both strains were used for Western blotting for calcium handling proteins. Isolatedmyocytes were employed for evaluating contractility, intracellular Ca transients and SR calciumcontent. Ca sparks and waves were assessed by confocal microscopy. Hearts fromFbmice exhibited a similar protein expression level of CaMKII, NCX, PCaMKII, SERCA2a and RyR2. However, there was a significantly increased phosphorylation of RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. impact on patient survival. We assessed whether there is a potential arrhythmogenic substrate at the cellular level responsible for triggering the cardiac arrhythmias. A murine model of Fb disease (KO mice) and WT mice were used. Homogenates from freshly isolated hearts from both strains were used for Western blotting for calcium handling proteins. Isolatedmyocytes were employed for evaluating contractility, intracellular Ca transients and SR calciumcontent. Ca sparks and waves were assessed by confocal microscopy. Hearts fromFbmice exhibited a similar protein expression level of CaMKII, NCX, PCaMKII, SERCA2a and RyR2. However, there was a significantly increased phosphorylation of RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. ficant impact on patient survival. We assessed whether there is a potential arrhythmogenic substrate at the cellular level responsible for triggering the cardiac arrhythmias. A murine model of Fb disease (KO mice) and WT mice were used. Homogenates from freshly isolated hearts from both strains were used for Western blotting for calcium handling proteins. Isolatedmyocytes were employed for evaluating contractility, intracellular Ca transients and SR calciumcontent. Ca sparks and waves were assessed by confocal microscopy. Hearts fromFbmice exhibited a similar protein expression level of CaMKII, NCX, PCaMKII, SERCA2a and RyR2. However, there was a significantly increased phosphorylation of RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. ficantly increased phosphorylation of RyR2 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). This increase was not accompanied by a significant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. ficant alteration in SR calcium content but was associated with a significant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease. ficant increase in calcium sparks and waves (in absence and presence of Iso), with respect to WT mice. The increase in RyR2 phosphorylation in Fb mice hearts could be the basis for the higher number of sparks and waves observed in this disease. This provides an arrhythmogenic substrate either trigger or maintain arrhythmias in Fabry disease.