Fabry disease (FD) is an inherited X-linked inborn lysosomal storage disorder characterized by intracellular glycosphingolipid depositions resulting from deficient a-galactosidase A activity. Cardiac involvement, consisting of progressive left ventricular (LV) hypertrophy is common (>50%), leading to prominent diastolic LV dysfunction and reduced tissue Doppler systolic shortening velocity. Solitary cardiac involvement (~cardiac variant of FD) accounts for ~9% of both male and female patients diagnosed as hypertrophic cardiomyopathy. To reveal if alterations in myofilament function and protein composition contribute to LV myocardial dysfunction in FD patients, active and passive tension and myofilament protein composition were determined in LV endomyocardial biopsies of 6 patients with the cardiac variant of Fd. Cardiomyocytes were mechanically isolated from LV endomyocardial biopsies, treated with Triton X-100 to remove all membranes, attached between a force transducer and a piezoelectric motor, stretched to a sarcomere length of 2.2 ìm and active and passive tension were determined before and after exogenous treatment with protein kinase A (PKA). Resting tension was higher in FD cardiomyocytes than in cells from a control group (respectively, 9.8±0.95 and 3.5±1.7 kN/m2; P<0.0001), while active force was remarkably lower (respectively, 3.9±1.4 and 20.3±3.0 kN/m2 in FD and control; P<0.0001). PKA treatment of the FD cardiomyocytes decreased resting tension (6.6±1.1 kN/m2; P<0.0001), though active force