The proximity of nNa_Vs to the excitation–contraction coupling machinery can be proarrhythmic. (A) Inferred locations of proteins important in excitation–contraction coupling are shown under control conditions (left) and after augmentation of flux through Na_Vs (right). Compared with cNa_Vs, nNa_Vs appear to be located closer to the excitation–contraction coupling machinery, including LTCCs and NCX in the T-tubule membrane and RyRs and SERCA in the local SR membrane. An increase in Na⁺ influx through nNa_Vs will lead to increased local [Na⁺] (red dots), reduced Ca²⁺ removal via NCX, and increased SR [Ca²⁺] (blue dots). (B) Hypothetical action potentials (left), intracellular [Ca²⁺] (middle), and SR [Ca²⁺] (right) under control conditions (solid black lines), after augmentation of cNa_Vs (dashed red lines), and after augmentation of nNa_Vs (solid red lines). Increased flux through either cNa_Vs or nNa_Vs will prolong the AP and increase SR [Ca²⁺] load. When this occurs through nNa_Vs, however, the local signaling means that the increase in SR [Ca²⁺] will be greater, increasing the risk of spontaneous, arrhythmogenic Ca²⁺ release.