Key result
A stochastic computational local control model demonstrated that peak Ca2+ transients in the force-frequency relationship correlate with the highest numbers, larger amplitudes, and longer durations of SR Ca2+ sparks.
Why the study?
The study was conducted to gain insight into the mechanisms underlying the force-frequency relationship in cardiac myocytes using a stochastic computational local control model.
A novel computational model of guinea pig ventricular myocytes demonstrates that Ca2+ sparks and L-type Ca2+ current inactivation are key drivers of the cardiac force-frequency relationship.
New RyR2 model enables mechanistic FFR simulation in guinea pig myocytes; leaves open human validation and clinical translation.
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.
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Paudel et al. (2022) studied Guinea pig ventricular cardiomyocyte (computational model). Stochastic computational local control model vs. Previous common pool models was evaluated on Force-frequency relationship and Ca2+ transient characteristics. A stochastic computational local control model demonstrated that peak Ca2+ transients in the force-frequency relationship correlate with the highest numbers, larger amplitudes, and longer durations of SR Ca2+ sparks.
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