Figure 18.

Scheme exploring relationship between perturbations in Ca²⁺ homeostasis, triggering, arrhythmic substrate, and generation of arrhythmia. A: acquired or genetic perturbations resulting in increased release of sarcoplasmic reticular (SR) Ca²⁺ or decreased Ca²⁺ reuptake from cytosol to store both perturb cytosolic Ca²⁺ (B). This in turn alters (C) Na⁺-Ca²⁺ exchange (NCX) electrogenic activity leading to diastolic triggering phenomena. It can also (D) reduce Nav1.5 synthesis or membrane trafficking and therefore its membrane expression, or directly alter Nav1.5 biophysical properties. Both effects potentially slow conduction, resulting in arrhythmic substrate even under conditions of normal action potential recovery as reflected in action potential duration/effective refractory period (APD/ERP) ratios. Combination of C and D culminates in E, potentially fatal ventricular arrhythmia. Possible direct actions of intermediates arising from metabolic change on I_Na are not shown for simplicity.