APD restitution controls arrhythmia emergence in cardiac tissue with RyR2 dysfunction.

The connection between molecular defects in the cardiac ryanodine receptor (RyR2) and arrhythmias remains poorly understood. To investigate this link, we developed a multiscale computational model that integrates RyR2 gating and electrical propagation in cardiac tissue. We find that increased RyR2 open probability enhances calcium (Ca) release during the action potential (AP), triggering two distinct arrhythmogenic mechanisms that depend on subcellular structure. In cells with a well-developed t-tubule system, Ca influx through L-type calcium channels activates Ca sparks near the cell membrane. Leaky RyR2s amplify this recruitment, increasing Ca release and inward sodium-calcium exchange current and delaying repolarization. In cells lacking transverse tubules, the same Ca influx initiates regenerative Ca waves that propagate into the cell, again activating the sodium-calcium exchanger and prolonging repolarization. Although the underlying pathways differ (spark recruitment amplification vs. wave propagation), both lead to prolonged APs and early afterdepolarizations. We show further that, although these events are random at the cellular level, their synchronization in tissue depends critically on the slope of the action potential duration (APD) restitution curve. When this slope exceeds one, localized Ca disturbances synchronize across tissue, leading to alternation in APD on every other beat. This transition creates steep spatial voltage gradients, resulting in conduction block. However, when the restitution slope is below one, Ca disturbances remain unsynchronized and have no effect on electrical activity in tissue. These findings suggest that the slope of the APD restitution curve is a key mechanism linking RyR2 dysfunction to arrhythmias at the organ scale. KEY POINTS: Defects in the cardiac calcium release channel RyR2 are linked to cardiac arrhythmias, but how molecular changes produce tissue-scale disturbances is not well understood. Using a multiscale computational model, we connect RyR2 gating defects to calcium cycling within cells and to the propagation of electrical activity in tissue. Depending on subcellular structure, leaky RyR2 channels can either promote regenerative calcium waves in cells with sparse t-tubules or enhance calcium spark recruitment in cells with dense t-tubules; both mechanisms prolong the action potential and trigger early afterdepolarizations. At the tissue level, whether these events synchronize depends on the slope of the action potential duration restitution curve: shallow slopes suppress synchrony, whereas steep slopes drive alternans, conduction block and arrhythmia.