We hypothesize that slow inactivation of Ca
2+
/calmodulin-dependent kinase II (CaMKII) and its modulatory effect on sarcoplasmic reticulum (SR) Ca
2+
handling are important for various interval–force (I–F) relations, in particular for the beat interval dependency in transient alternans during the decay of post-extrasystolic potentiation. We have developed a mathematical model of a single cardiomyocyte to integrate various I–F relations, including alternans, by incorporating a conceptual CaMKII kinetics model into the SR Ca
2+
handling model. Our model integrates I–F relations, such as the beat interval-dependent twitch force duration, restitution and potentiation, positive staircase phenomenon and alternans. We found that CaMKII affects more or less all I–F relations, and it is a key factor for integration of the various I–F relations in our model. Alternans arises, in the model, out of a steep relation between SR Ca
2+
load and release, owing to SR load-dependent changes in the releasability of Ca
2+
via the ryanodine receptor. Beat interval-dependent CaMKII activity, owing to its kinetic properties and amplifying effect on SR Ca
2+
load dependency of Ca
2+
release, replicated the beat interval dependency of alternans, as observed experimentally. Additionally, our model enabled reproduction of the effects of various interventions on alternans, such as the slowing or accelerating of Ca
2+
release and/or uptake. We conclude that a slow time-dependent factor, represented in the model by CaMKII, is important for the integration of I–F relations, including alternans, and that our model offers a useful tool for further analysis of the roles of integrative Ca
2+
handling in myocardial I–F relations.
RELIABILITY OF 2-OUT-OF-N:G SYSTEMS WITH NHPP FAILURE FLOWS AND FIXED REPAIR TIMES
