Local Control Model of a Human Ventricular Myocyte: An Exploration of Frequency-Dependent Changes and Calcium Sparks.

Calcium (Ca 2+ ) sparks are the elementary events of excitation-contraction coupling, yet they are not explicitly represented in human ventricular myocyte models. A stochastic ventricular cardiomyocyte human model that adapts to intracellular Ca 2+ ([Ca 2+ ] i ) dynamics, spark regulation, and frequency-dependent changes in the form of locally controlled Ca 2+ release was developed. The 20,000 CRUs in this model are composed of 9 individual LCCs and 49 RyRs that function as couplons. The simulated action potential duration at 1 Hz steady-state pacing is ~0.280 s similar to human ventricular cell recordings. Rate-dependence experiments reveal that APD shortening mechanisms are largely contributed by the L-type calcium channel inactivation, RyR open fraction, and [Ca 2+ ] myo concentrations. The dynamic slow-rapid-slow pacing protocol shows that RyR open probability during high pacing frequency (2.5 Hz) switches to an adapted "nonconducting" form of Ca 2+ -dependent transition state. The predicted force was also observed to be increased in high pacing, but the SR Ca 2+ fractional release was lower due to the smaller difference between diastolic and systolic [Ca 2+ ] SR . Restitution analysis through the S1S2 protocol and increased LCC Ca 2+ -dependent activation rate show that the duration of LCC opening helps modulate its effects on the APD restitution at different diastolic intervals. Ultimately, a longer duration of calcium sparks was observed in relation to the SR Ca 2+ loading at high pacing rates. Overall, this study demonstrates the spontaneous Ca 2+ release events and ion channel responses throughout various stimuli.