Relationship between Na+-Ca2+-exchanger protein levels and diastolic function of failing human myocardium

Background-In the failing human heart, sarcoplasmic reticulum (SR) calcium handling is impaired, and therefore, calcium elimination and diastolic func tion may depend on the expression of sarcolemmal Na+-Ca2+ exchanger. Methods and Results-Force-frequency relations were studied in ventricular m uscle strip preparations from failing human hearts (n=29). Protein levels o f Na+-Ca2+ exchanger and SR Ca2+-ATPase were measured in the same hearts. H earts were divided into 3 groups by discriminant analysis according to the behavior of diastolic function when stimulation rate of muscle strips was i ncreased from 30 to 180 min(-1). At 180 compared with 30 min(-1), diastolic force was increased by 160%, maximum rate of force decline was decreased b y 46%, and relaxation time was unchanged in group III. In contrast, in grou p I, diastolic force and maximum rate of force decline did not change, and relaxation time decreased by 20%. Na+-Ca2+ exchanger was 66% higher in grou p I than in group III. Na+-Ca2+ exchanger was inversely correlated with the frequency-dependent rise of diastolic force when stimulation rate was incr eased (r=-0.74; P<0.001). Compared with nonfailing human hearts (n=6), SR C a2+-ATPase was decreased and Na+-Ca2+ exchanger unchanged in group III, whe reas Na+-Ca2+ exchanger was increased and SR Ca2+-ATPase unchanged in group I. Results with group II hearts were between those of group I and group LU hearts. Conclusions-By discriminating failing human hearts according to their diast olic function, we identified different phenotypes. Disturbed diastolic func tion occurs in hearts with decreased SR Ca2+-ATPase and unchanged Na+-Ca2exchanger, whereas increased expression of the Na+-Ca2+ exchanger is associ ated with preserved diastolic function.