Abstract 3156: Myofilament Dysfunction in Human Cardiomyocytes with Fabry Disease
Background: Abnormal Tissue Doppler imaging (TDI) velocities are detectable even in the pre-hypertrophic phase of Fabry disease (FD) cardiomyopathy.
Hypothesis: Impairment of cardiomyocyte relaxation and contractility is a main determinant of cardiac dysfunction in FD.
Methods: Active and passive tension before and after protein kinase A (PKA) and myofilament protein composition were determined in isolated cardiomyocytes from ventricular biopsies of 8 males (41±11 yrs) with untreated FD. Myofilament structure was analysed by electron microscopy. Cardiomyocyte cross sectional area, percent area occupied by glycosphyngolipids vacuoles and extent of fibrosis were morphometrically evaluated. Controls were ventricular biopsies from donor hearts and from patients with mitral stenosis.
Results: Resting tension was higher in FD cardiomyocytes than in cells from controls (9.2±2.4 vs 3.5±1.7 kN/m2, p< 0.001). Active force was lower (2.4±0.9 vs 20.3±3.0 kN/m2, p<0.001) and correlated with myofibrillar density. PKA decreased passive tension in FD cardiomyocytes (5.3±2.4 vs 9.2±2.4 kN/m2, p<0.001), but did not affect active force. Protein analysis revealed degradation of troponin I and desmin. Cardiomyocyte cross-sectional area in FD was larger compared to controls (767±241 vs 215±90μm2) and glycosphyngolipids occupied more than 50% of the cell area. TDI relaxation velocities were reduced in FD vs controls and correlated with resting tension (Spearman rho=0.98 p<0.001 for septal E/EA and 0.94 p<0.001 for lateral E/EA), glicosphyngolipids vacuoles (Spearman rho=0.78 p<0.05 for septal E/EA and 0.73 p<0.05 for lateral E/EA) and cardiomyocyte area (Spearman rho=0.78 p<0.05 for septal E/EA and 0.72 p<0.05 for lateral E/EA) but not with fibrosis, that was only slightly increased vs controls (7.4±4.4 vs 4.1±2.5). TDI contraction velocities were also reduced and correlated with decreased active force (Spearman rho=0.98 p<0.001 for septal Sa and 0.84 p<0.001 for lateral Sa).
Conclusion: Myofilament dysfunction and protein degradation promoted by glycosphyngolipids accumulation are major determinants of cardiac functional abnormalities in FD. Thus, enzyme enhancement/replacement therapy may have a role even in the advanced phases of the disease.