Published online before print May 8, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070576

Accepted for publication February 21, 2008.

Article

Myofilament Degradation and Dysfunction of Human Cardiomyocytes in Fabry Disease

Cristina Chimenti^*, Nazha Hamdani, Nicky M. Boontje, Francesco DeCobelli, Antonio Esposito, Jean G.F. Bronzwaer, Ger J.M. Stienen, Matteo A. Russo^¶, Walter J. Paulus, Andrea Frustaci^*||@, and Jolanda van der Velden

From the Heart and Great Vessels "Attilio Reale" Department* and Experimental Medicine and Pathology Department,^¶ La Sapienza University, Rome, Italy; Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele La Pisana, Rome, Italy; Radiology Department, San Raffaele Hospital, Milan, Italy; the Molecular and Cellular Cardiology Laboratory,^|| National Institute for Infectious Diseases, "Lazzaro Spallanzani," Rome, Italy; and the Laboratory of Physiology, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands

^@ To whom correspondence should be addressed. E-mail: biocard{at}inmi.it.

	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.