title: Myofilament degradation and dysfunction of human cardiomyocytes in Fabry disease.
abstract: Early detection of myocardial dysfunction in Fabry disease (FD) cardiomyopathy suggests the contribution of myofilament structural alterations. Six males with untreated FD cardiomyopathy submitted to cardiac studies, including tissue Doppler imaging and left ventricular endomyocardial biopsy. Active and resting tensions before and after treatment with protein kinase A (PKA) were determined in isolated Triton-permeabilized cardiomyocytes. Cardiomyocyte cross-sectional area, glycosphingolipid vacuole area, myofibrillolysis, and extent of fibrosis were also determined. Biopsies of mitral stenosis in patients with normal left ventricles served as controls. Active tension was four times lower in FD cardiomyocytes and correlated with extent of myofibrillolysis. Resting tension was six times higher in FD cardiomyocytes than in controls. PKA treatment decreased resting tension but did not affect active force. Protein analysis revealed troponin I and desmin degradation products. FD cardiomyocytes were significantly larger and filled with glycosphingolipids. Fibrosis was mildly increased compared with controls. Tissue Doppler imaging lengthening and shortening velocities were reduced in FD cardiomyocytes compared with controls, correlating with resting and active tensions, respectively, but not with cardiomyocyte area, percentage of glycosphingolipids, or extent of fibrosis. In conclusion, myofilament degradation and dysfunction contribute to FD cardiomyopathy. Partial reversal of high resting tension after pharmacological PKA treatment of cardiomyocytes suggests potential benefits from enzyme replacement therapy and/or energy-releasing agents.
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele La Pisana, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Chimenti
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Nicky M
authors.initials: NM
authors.lastname: Boontje
authors.forename: Francesco
authors.initials: F
authors.lastname: DeCobelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Esposito
authors.forename: Jean G F
authors.initials: JG
authors.lastname: Bronzwaer
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Matteo A
authors.initials: MA
authors.lastname: Russo
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.forename: Andrea
authors.initials: A
authors.lastname: Frustaci
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
mesh_terms: D008841:Actin Cytoskeleton / Q000473:pathology* / Q000502:physiology; D000328:Adult; D001696:Biomechanical Phenomena; D003094:Collagen / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D003893:Desmin / Q000378:metabolism; D000795:Fabry Disease / Q000473:pathology* / Q000503:physiopathology; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D019210:Troponin I / Q000378:metabolism; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D003893:Desmin; D006028:Glycosphingolipids; D019210:Troponin I; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases; D000519:alpha-Galactosidase