Dr. Andrew D. McCulloch is developing computational models of cardiac electrical, mechanical and metabolic function that integrate systems models of cellular biophysics in structurally detailed models of organ physiology. The models will be used to predict weightlessness' effects on cardiac performance but also will have applications in cardiovascular science and medicine.
Andrew D. McCulloch, Ph.D.
University of California, San Diego
Project Aims Aim 1: To apply our existing techniques for modeling three-dimensional cardiac mechanics and action potential propagation to develop anatomically detailed three-dimensional dynamic finite element models of regional cardiac electromechanics.
Aim 2: To bridge models and data on cardiac metabolism and cellular dynamics with systems models of coronary flow, central hemodynamics, and cardiovascular regulation.
Aim 3: To develop tools for using available wall motion data from medical imaging in man to validate the mechanoenergetic models and identify myocardial constitutive properties.
Aim 4: To apply new models of geometric and constitutive remodeling in response to chronically altered external loading conditions to develop simulations of long-term cardiac adaptation to microgravity.
Aim 5: To implement the models using modular object-oriented software engineering techniques that allow the models to be readily integrated with others through standard broker architectures for software interoperability.
Aim 6: To collaborate with other prospective projects in the Integrated Human Function Core.
Key Findings/Progress Significant progress has been made coupling cardiac electromechanical models. Two new papers have been accepted applying and extending the a new computational model reported last year (Usyk TP, LeGrice IJ, McCulloch AD. Computational model of three-dimensional cardiac electromechanics. Comput Visual Sci 4(4):249-257, 2002.) in which a model of anisotropic cardiac impulse propagation is coupled to a model of three-dimensional anisotropic ventricular wall mechanics in an anatomically detailed three-dimensional model of the left and right ventricles that also includes a model of the Purkinje fiber network anatomy. In one new paper now in press (Usyk, T. P. and A. D. McCulloch. Relationship between regional shortening and asynchronous electrical activation in a three-dimensional model of ventricular electromechanics (Journal of Cardiovascular Electrophysiology 14 (suppl).) this model has been used to investigate the effects of altered mechanical pacing sequence due to ectopic activation, and showed excellent agreement with published experimental data. In another paper now in press (Usyk, T. P. and A. D. McCulloch. Electromechanical model of cardiac resynchronization in the dilated failing heart with left bundle branch block. J Electrocardiol, 2003.), we tested the ability of the model to predict countermeasure effectiveness, by using it to predict the effects of bi-ventricular pacing for cardiac resynchronization therapy in an experimental model of heart failure with a conduction defect. Again the model predictions showed very good agreement with experimental measurements.
As a result of the NSBRI Exercise workshop in Seattle in September 2002, models of cardiac electromechanics during exercise are focussing on the effects of heart rate, adrenergic stimulation and acidosis. We have developed a new model of adrenergic signaling in the cardiac myocyte that couples to electrophysiology by simulating the effects of β adrenergic receptor stimulation on excitation-contraction coupling mechanisms via phosphorylation of several cellular targets by protein kinase A. This new paper now in press (Saucerman, J. J., L. L. Brunton, A. P. Michailova, A. D. McCulloch. Modeling beta-adrenergic control of cardiac myocyte contractility in silico. J Biol Chem, 2003.) successfully recapitulates major effects of the neurohormonal activation that occurs during exercise on the ventricular myocyte.
A new object-oriented modular version of Continuity that was released during the previous period has been updated. A new release, tentatively named release 6.2 is due for release in the Fall 2003. It has a modular client-server design, very high-level scripting language, a graphical user interface and new three-dimensional viewer. The newest version supports additional computer platforms, especially Linux. It has also been used successfully in classroom teaching.
We have engaged in productive collaborative activities with other members of the Integrated Human Function Core, especially the group of Dr. Bers. As the result of discussions with the Cardiovascular Alterations Team, we have conducted preliminary experiments on changes in restitution dynamics with mechanical loading. This will provide a basis for new computational models of mechanoelectric feedback as a follow-up to our recent report showing how altered mechanical loading slows action potential propagation and prolongs repolarization in the whole heart (Sung D, Mills RW, Schettler J, Narayan SM, Omens JH, McCulloch AD. Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart. J Cardiovasc Electrophysiol 14(7):739-749, 2003.)
Impact These findings of the three-dimensional electromechanical models validate the original premise of the proposal that an integrated cardiac three-dimensional electromechanical model is both computational feasible and physiologically predictive. They also demonstrate the utility of such models for countermeasure design, assessment and validation. This is a fundamental advance that paves the way for the other objectives and applications. By including cell signaling pathways in the cellular models of cardiac excitation-contraction coupling, we will be in a position to simulate the physiological effects of exercise and other stresses that activate the major pathways that respond to neurohormonal signals in the heart.
The new software, Continuity 6.0 provides a problem solving environment for integrative modeling that is general enough for both structurally integrated models that couple from single cell to organ system scales and functionally integrated models that couple electrophysiology, mechanics, metabolism and regulatory processes. The methods are generic and thus applicable to other systems such as soft tissues and muscle.
Proposed Research Plan We will extend the electromechanical models to include more detailed cellular biophysical models of cardiac excitation and contraction whose parameters therefore have greater physiological meaning thus making the models more inherently predictive. These cellular models are developed by our group and the group of Dr. Bers including new models of ionic currents, excitation-contraction coupling, myofilament activation and crossbridge interactions. The integrative whole heart models that contain these improved cellular models will also be used to incorporate the effects of regional cellular heterogeneity in the heart walls. For example, the T-wave of the electrocardiogram may be an important predictor of potentially life-threatening cardiac events in space. The morphology of this waveform is directly influenced by the fact that myocyte repolarizing currents are different as a function of transmural position in the ventricular wall. We have therefore begun a new model in collaboration with Dr. Bers lab that includes three transmural cell layers in the epicardium, M-cell layer and endocardial regions of the ventricular walls. We will also extend the current cellular models model to include the pH regulation of intracellular calcium handling, the regulation of cardiac electrophysiology and contraction by beta adrenergic stimulation, and the effects of magnesium which may offer a potential countermeasure. The next major release of Continuity will include improved facilities for composing and integrating cellular models and for the efficient parallel solution of large-scale whole organ models. Synergistic collaborations with other NSBRI projects will be continued.