Dynamic Regulation of Sodium/Calcium Exchange Function in Human Heart Failure

Abstract

Background— Sarcolemmal Na/Ca exchange (NCX) regulates cardiac Ca and contractility. NCX function during the cardiac cycle is determined by intracellular [Ca] and [Na] ([Ca]_i, and [Na]_i) and membrane potential (E_m), 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 [Ca]_i was comparable in F and NF myocytes (K_1/2=150±31 nmol/L, n=7). The steady-state relation between [Ca]_i and NCX current (I_NCX) was used to infer the local submembrane [Ca]_i ([Ca]_sm) that is sensed by NCX dynamically during the action potential (AP) and Ca transient (37°C). This involved “tail” I_NCX measurement during abrupt repolarization of APs and Ca transients, where peak inward I_NCX indicates [Ca]_sm. 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 [Ca]_sm, (2) prolonged AP duration, and (3) elevated [Na]_i. 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 [Ca]_i transient and to diastolic dysfunction.