Figure 2 – Inhibition of NCX promotes SCRs but has biphasic effects on DADs and spontaneous APs (SAP).

A) Reducing NCX monotonically decreases the rate threshold of SCRs (i), whereas the rate thresholds of DADs (ii) and SAP, defined as DADs with amplitudes over 70 mV, (iii) display biphasic dependence. B) Effect of altered NCX fraction on voltage (i) and global cytosolic Ca²⁺ concentration (ii) in cells with sparse (left), intermediate (middle), and dense (right) tubules following pacing at 3 Hz to examine the occurrence of DADs, SAPs and SCRs. C) Mechanism underlying NCX inhibition promoting SCRs but having biphasic effects on DADs and SAP. Biomarkers were determined from the first 100 ms of no-stimulation period and normalized to those of cells with a retained NCX fraction of 1.0. Lower NCX expression is associated with reduced NCX contribution to Ca²⁺ extrusion (i) and smaller SCR-induced voltage changes/SCR amplitude ratio (ii). Less NCX extrusion results in elevated cleft Ca²⁺ concentration, augmented RyR P_o and leak leading to increased SCRs. While SCRs lead to DADs and SAP this transition is abated by the reduced SCR-induced changes in V_m, thus explaining the biphasic effects of reduced NCX.