Fig. (3).

Altered NCX activity as a therapeutic target in heart failure. A: Experimental Ca²⁺ transients from SERCA2 knockout mice are dramatically reduced (left panel). Modeling data predict that simultaneous NCX ablation increases Ca²⁺ transient magnitude (right). This indicates that NCX competes with SERCA2a for the same pool of Ca²⁺ and reduces SR Ca²⁺ content and release. Data are adapted from [227], with permission. B: NCX activity could be therapeutically modulated by direct targeting or altering electrochemical gradients. NCX inhibitors attenuate cellular Ca²⁺ extrusion and thereby increase cellular Ca²⁺ load and ultimately contractility. Inhibition of NKA similarly inhibits NCX-mediated Ca²⁺ extrusion by increasing cellular Na⁺ levels. However, prevention of Ca²⁺ overload is desirable in patients at risk for arrhythmia, and this may be attained by inhibition of Na+ influx pathways, which augments Ca²⁺ extrusion.