In silico investigation of spontaneous calcium release on premature ventricular contractions in human ventricles

Aim: Sarcoplasmic reticulum (SR) calcium overload increases spontaneous calcium release, causing delayed afterdepolarizations (DADs) that promote premature ventricular contractions (PVCs). In this study, we modified a detailed human ventricular model to investigate quantitatively how SR calcium features at the subcellular scale influence cellular DADs, facilitating the onset of PVCs at the tissue level. Methods: Based on the 4-state Shannon model, calcium-induced-calcium release flow into the dyadic cleft via the SR ryanodine receptor (RyR2) in Ten Tusscher and Panfilov (TP06) model was modified. SR calcium release was varied by changing SR calcium content for simulating beta-adrenergic stimulation. The cellular DAD amplitude required to depolarize the cell to threshold and trigger an action potential (AP) was quantified. A one-dimensional cable model, which contained a central area of contiguous myocytes susceptible to DADs, was constructed to investigate requirements for DADs to overcome the source-sink mismatch and trigger PVCs. Results and Conclusion: Depending on the content of SR calcium, SR calcium release in cardiac cell resulted in DADs. When the amplitude of a DAD is above a certain threshold (20.7 mV, from -86.2 mV to -65.5 mV), a suprathreshold DAD in single cell can trigger an AP, which can cause a PVC in cardiac tissue. However, the subthreshold DADs didn't produce APs but formed a conduction block region. The number of contiguous susceptible myocytes required for a suprathreshold DAD to trigger a propagating AP is 76 in a cardiac cable with 100 cells, corresponding to 11.4 mm. The number was significantly decreased by increased SR calcium load, reduced gap junction and fibrosis. In conclusion, SR calcium overload caused by electrical remodeling in combination with slow conduction induced by structural remodeling decreased the number significantly but still require synchronization mechanisms for DADs to overcome the source-sink mismatch to trigger PVCs.