Specific Aims

• Develop a more up-to-date electrophysiological model of cardiac myocytes.
• Incorporate new Ca transport data on SR Ca uptake, release and Na/Ca exchange.
• Extend the model to include cooperative Ca-dependent contraction and relaxation.
• Implement model in highly accessible computational formats.

New Ca transport version of model. We have updated LabHEART 4.7 model in several ways already. 1. We have further updated ionic currents (e.g. including important characterization and subdivision of transient outward currents, I_to,f & I_to,s; LabHEART 4.9x). 2. We have added the facility that the user can modify the equations that describe the ionic currents and transporters (LabHEART 5.0). 3). We have also overhauled the model (Shannon-model) to include a more appropriate cellular geometry and compartments based on experimental data (including junctional cleft and subsarcolemmal compartments) and used more up-to-date experimentally tested expressions for Ca current, SR Ca release, SR Ca-ATPase and Na/Ca exchange. This major revision is currently being written up for publication and also being ported to a more versatile computational format (from that in which it was developed). 4. We have used this new model to help distinguish the relative importance of 3 factors that contribute to reducing SR Ca content in heart failure: a) reduced SR Ca-ATPase, b) increased Na/Ca exchange function and c) increased diastolic SR Ca leak, each of which we have measured experimentally. This work will be published in Circulation Research in October (Shannon, Pogwizd and Bers).

Extend model to include myofilament properties. 1. In parallel with the above, we have developed a novel cardiac myofilament model that includes realistic representations of the steep cooperative force-[Ca]i relationship, the length-dependence of myofilament activation and the load-dependence of contraction duration. This used local filament nearest-neighbor interactions and Monte Carlo simulations. 2. This work was written up and published as a full paper in the Biophysical Journal (Rice and deTombe). 3. This sort of Monte Carlo simulation is not practical for incorporation into a cellular ion channel-Ca transport model. So, we have developed a novel ODE (ordinary differential equation) version of this model which retains reasonably well the important characteristics. This version should be practical to incorporate into our current ion channel-Ca transport model.

Highly accessible computational formats. This has been an ongoing thrust in all of the above aims. 1. LabHEART 4.7 is the prototype in user friendly version of the model for both teaching and for use by other scientists in the field. The subsequent LabHEART versions have retained this focus (and we have even developed a student tutorial guide). 2. Our work in dovetailing our model for incorporation into McCulloch's whole heart model constitutes another kind of accessibility that is important (but differs from the stand alone LabHEART). 3. Our newer Shannon-model with additional compartments is also currently being developed both ways (flexible for integration in larger scale models, but also for the stand-alone cellular model).

Research Plans
In the final year we will need to complete many of the ongoing modeling efforts, publish manuscript where appropriate and use them in additional ways. Some key aims are to:

• Complete and publish LabHEART 4.9x and 5.0 versions and make them freely available.
• Complete and publish the new Shannon-model, as well as use it to more fully explore how perturbations in conditions (including rate, adrenergic state) alter electrophysiological and Ca handling properties. Additional perturbations are directly related to ongoing studies by Dr. Beverly Lorell's group where changes in expression of Ca transport and ion channels that occur upon cardiac unloading can be more realistically simulated.
• Connect the Shannon-model to the myofilament ODE model to allow the first up-to-date model combining ion channels, Ca transport and contractile elements (in both variants of user friendliness).
• Extend our collaboration with the whole heart modeling efforts of McCulloch's group which will allow more direct studies of the acute affects of cardiac unloading (as in weightlessness) can be explored (and then observed altered cellular expression of transporters and channels) can be superimposed to simulate more long-term systemic compensations.

Collaborations
Our group already included collaboration of investigators at four different institutions with complementary strengths (Bers and Puglisi, Loyola University, Chicago; deTombe and Solaro, University of Illinois, Chicago; Shannon at Rush University, Chicago; and Rice, IBM, New York). This has allowed good progress to be made along all of the specific aims originally proposed. Inter-group collaborative relationships have also developed, especially strongly between our group and that of McCulloch, and that has extended the sphere of expertise and impact of both groups with respect to modeling. Additional interactions between our group and that of Lorell's have brought some of the biological consequences more clearly into view, and minor interactions have occurred with other modeling and experimentally focused teams.

Project Description
NASA Task Book