BACKGROUND: Sarcolemmal Na/Ca exchange (NCX) regulates cardiac Ca
and contractility. NCX function during the cardiac cycle is determined
by intracellular Ca and Na (Cai, and Nai) and membrane potential
(Em), which all change in human heart failure (HF). Therefore, changes
in NCX function may contribute to abnormal Ca regulation in human
HF. METHODS AND RESULTS: We assessed the cellular bases of differences
in NCX function in ventricular myocytes from failing (F) and nonfailing
(NF) human hearts. Allosteric activation of NCX by Cai was comparable
in F and NF myocytes (K1/2=150+/-31 nmol/L, n=7). The steady-state
relation between Cai and NCX current (INCX) was used to infer the
local submembrane Cai (Casm) that is sensed by NCX dynamically
during the action potential (AP) and Ca transient (37 degrees C).
This involved "tail" INCX measurement during abrupt repolarization
of APs and Ca transients, where peak inward INCX indicates Casm.
This allows inference of the direction of Ca transport by the NCX
during the AP. In NF myocytes, NCX extrudes Ca for most of the AP.
Three factors shift the direction of NCX-mediated Ca transport (to
favor more Ca influx) in F versus NF myocytes, as follows: (1) reduced
Casm, (2) prolonged AP duration, and (3) elevated Nai. CONCLUSIONS:
These results show that Ca entry through NCX may limit systolic dysfunction
due to reduced sarcoplasmic reticulum Ca stores in HF but could contribute
to slow decay of the Cai transient and to diastolic dysfunction.