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Sarcoplasmic reticulum (SR) calcium overload in post acidosis can cause triggered activity because spontaneous calcium release (SCR) activates sufficient calcium-sensitive inward currents responsible for delayed afterdepolarizations (DADs). However, little is known about the mechanisms relating SCR and triggered activity on the tissue level in post acidosis.
To better understand the effect of acidosis on SR calcium load, acidosis produced by CO2 increase from 5% to 30%, resulting in intracellular PH change from 7.15 to 6.7, was incorporated into a human myocyte model. The model was modified to include calcium/calmodulin-dependent protein kinase II (CaMKII) activation to investigate its role in post acidosis triggered activity. A homogeneous two-dimensional (2D) tissue model was constructed with cells to compute the spatiotemporal properties of SCR in human heart. Computer simulations were used to predict how these properties of SCR determine DAD magnitude. The minimal area of SCR required to overcome the source-sink mismatch and produce triggered activity in human heart was quantified. Effects of pacing frequency, the acidotic period and fraction of CaMKII activation on induction of triggered activity were examined.
Depending on the SR calcium content, SCR mediated the magnitude of DADs which can trigger an action potential (suprathreshold DAD) if the amplitude is above a certain threshold (18.15 mV, from -84.15 mV to -66 mV). Synchronized cells with suprathreshold DAD can produce triggered activity in human heart. The inducibility of triggered activity depended on the SCR area, which was determined by the amplitude of DAD mediated by acidotic period, pacing frequency and fraction of CaMKII activation. Long acidosis duration and fast pacing rates increased intracellular calcium accumulation and SR calcium load, resulting in a high DAD amplitude, increasing the ‘source' and consequently decreasing the SCR area required to match the ‘sink'. In addition, CaMKII played a key role in genesis of triggered activity by increasing SR calcium content via the phosphorylation of phospholamban due to an increase fraction of CaMKII activation. Our results showed that an increase in SCR led to a higher DAD amplitude and is dictated by the SR content.
These data demonstrate that spatiotemporal synchronization of SCR in a population of cells in tissue can overcome the source-sink mismatch and produce triggered activity which is determined by the SR calcium content in post acidosis.