Objective: The aim of the present study was to investigate the functional activity and expression of the sarcolemmal Na + /Ca 2 + -exchanger in the failing human heart. Methods: Left ventricular samples were taken from eleven patients with end-stage heart failure and six organ donors (normal controls). The Na + /Ca 2 + -exchanger activity was assessed by measuring Na + gradient-induced 4 5 Ca 2 + transport into sarcolemmal vesicles of quantitatively collected crude membrane preparations. The abundance of the Na + /Ca 2 + -exchanger protein was determined by Western blot analysis using a specific antiserum and the results were normalized to myocyte specific β-myosin heavy chain protein content. Results: In membrane preparations of failing human hearts, both the Na + gradient-induced 4 5 Ca 2 + transport activity and the level of immunoreactive Na + /Ca 2 + -exchanger protein were increased (P < 0.01) by 87% and 160% compared to controls, respectively. Conclusions: In human end-stage heart failure the increased sarcolemmal Na + /Ca 2 + -exchanger activity appears to be due to an elevated expression of this protein. An increase in the expression and activity of the Na + /Ca 2 + -exchanger in the failing human heart may be of important functional significance: while a resulting increase in Ca 2 + extrusion across the sarcolemma may limit diastolic Ca 2 + overload, a corresponding influx of Na + may be associated with membrane depolarization and enhanced arrhythmogenesis if the Na + /Ca 2 + -exchanger operates primarily in the forward mode.