The Role of Ca²⁺ Sparks in Force Frequency Relationships in Guinea Pig Ventricular Myocytes

Calcium sparks are the elementary Ca²⁺ release events in excitation-contraction coupling that underlie the Ca²⁺ transient. The frequency-dependent contractile force generated by cardiac myocytes depends upon the characteristics of the Ca²⁺ transients. A stochastic computational local control model of a guinea pig ventricular cardiomyocyte was developed, to gain insight into mechanisms of force-frequency relationship (FFR). This required the creation of a new three-state RyR2 model that reproduced the adaptive behavior of RyR2, in which the RyR2 channels transition into a different state when exposed to prolonged elevated subspace [Ca²⁺]. The model simulations agree with previous experimental and modeling studies on interval-force relations. Unlike previous common pool models, this local control model displayed stable action potential trains at 7 Hz. The duration and the amplitude of the [Ca²⁺]_myo transients increase in pacing rates consistent with the experiments. The [Ca²⁺]_myo transient reaches its peak value at 4 Hz and decreases afterward, consistent with experimental force-frequency curves. The model predicts, in agreement with previous modeling studies of Jafri and co-workers, diastolic sarcoplasmic reticulum, [Ca²⁺]_sr, and RyR2 adaptation increase with the increased stimulation frequency, producing rising, rather than falling, amplitude of the myoplasmic [Ca²⁺] transients. However, the local control model also suggests that the reduction of the L-type Ca²⁺ current, with an increase in pacing frequency due to Ca²⁺-dependent inactivation, also plays a role in the negative slope of the FFR. In the simulations, the peak Ca²⁺ transient in the FFR correlated with the highest numbers of SR Ca²⁺ sparks: the larger average amplitudes of those sparks, and the longer duration of the Ca²⁺ sparks.