Is modulation of sodium-calcium exchange a therapeutic option in heart failure?

Besides the sarcoplasmic reticulum (SR) Ca 2 -ATPase (SERCA), the sarcolemmal Na –Ca exchanger (NCX) is the most important Ca transport protein responsible for maintaining the Ca balance of the myocyte. It catalyzes the transport of Ca across the membrane in exchange for Na in a reversible manner. Its activity is called “forward” when Na is transported inward and Ca outward and “reversed” when ions are transported in the opposite directions. The driving force of NCX depends on Na and Ca concentrations at either side of the plasma membrane and on the membrane potential. NCX is electrogenic and carries inward (depolarizing) current in forward mode and outward (repolarizing) current in reversed mode.1 NCX consists of 9 transmembrane helices and a large cytoplasmic loop. This loop has been shown to contain Ca and Na -binding regulatory sites, which are distinct from the transport sites. Thus, Na and Ca ions are both transport substrates and modulators of activity. At the N-terminal end of the cytoplasmic loop near the membrane–lipid interface, there is a 20-amino acid segment, designated the endogenous XIP region. This region is considered to function as an autoinhibitory domain that plays a central role in NCX regulation. In addition, PIP2, protons, ATP, and PKCdependent effects regulate NCX activity.1–3 More recently, it was shown that the Ca binding protein sorcin exerts stimulatory actions on NCX.4 Altered expression and activity of the sarcolemmal NCX may play a key role for disturbed contractile function and arrhythmogenesis in hypertrophy and heart failure. It has become clear that disturbed excitation–contraction coupling attributable to altered SR Ca accumulation significantly contributes to heart failure pathophysiology.3 Three major factors seem to contribute to disturbed SR Ca accumulation in human heart failure: (1) increased leak of Ca through ryanodine receptors, (2) reduced SERCA activity, and (3) increased transsarcolemmal elimination of Ca by NCX. SR Ca accumulation depends on the activity of SERCA relative to transsarcolemmal Ca elimination by NCX. When protein levels of NCX were measured relative to SERCA, it was observed that this ratio was increased by a factor of 3 in endstage failing myocardium, indicating a relative dominance of NCX over SERCA Ca transport.5 Interestingly, two different phenotypes were identified: (1) endstage failing hearts with a predominant increase in protein levels of NCX, and (2) endstage failing hearts with a predominant decrease in SERCA protein levels. In the former subgroup, diastolic function was preserved because overall cellular capacity to eliminate cytosolic Ca is high. However, systolic function was impaired because Ca is eliminated across the sarcolemmal membrane and therefore SR Ca accumulation is decreased. In the latter group, both SR Ca uptake and global cytosolic Ca elimination are reduced and therefore systolic as well as diastolic function was severely compromised. Enhanced transsarcolemmal relative to SR Ca cycling is most pronounced at high heart rates.5,6 As was indicated in clinical and experimental studies, increased forward mode exchange is arrhythmogenic because of delayed afterdepolarizations after inward current generation.1,3 Furthermore, it was shown that increased expression of NCX increases sensitivity to digitalis and predisposes to free radical induced myocyte dysfunction.3,7 From these considerations, modulation of NCX function in heart failure may be a therapeutic option. Stimulation of forward mode NCX activity would reduce cytosolic Ca , impair systolic, and improve diastolic function. Vice versa, stimulation of reversed mode NCX would increase intracellular Ca and contractility with the risk of diastolic impairment. Inhibition of NCX function should have opposite effects. Apparently, the consequence of nonselective stimulation or inhibition of NCX function is quite complex and unpredictable. Several inhibitors of NCX function have been developed2: KB-R7943 is a well-characterized inhibitor. Intriguingly, KB-R7943 was suggested to exert a preferential effect on reverse-mode NCX activity. First studies also reported high selectivity of the drug; this was yet questioned by other authors. Synthetic peptides are considered as potent and highly selective NCX inhibitors. The NCX inhibiting peptide (XIP) is derived from the primary sequence of cardiac NCX1, binds at the large cytoplasmic loop, and decreases the Vmax of NCX activity. However, it does not appear to permeate through the cell membrane, which limits its use for therapeutic interventions in heart failure. In addition, other peptides, such as the cyclic hexapeptide FRCRCFa and its cell-permeant, N-myristylated derivative Myr-FRCRCFa, which are much smaller than XIP, have been reported to effectively inhibit NCX activity. Recently, new compounds with particularly high selectivity for NCX such as SEA0400 were synthesized.2,8 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Georg-August Universität Göttingen, Herzzentrum, Kardiologie und Pneumologie, Göttingen, Germany. Correspondence to Gerd Hasenfuss, MD, Georg-August-Universität Göttingen, Herzzentrum, Kardiologie und Pneumologie, Robert-KochStr. 40, 37099 Göttingen, Germany. E-mail [email protected] (Circ Res. 2004;95:225-227.) © 2004 American Heart Association, Inc.