1. Systems Biology talk July 20041 Systems Biology of the Heart Richard Clayton

2. Systems Biology talk July 20042 Ventricular fibrillation

3. Systems Biology talk July 20043 Experimental maps of electrical activity during VF More recent movie of spiral wave in a rabbit heart (Movie from the Living State Physics group, Vanderbilt University, Tenessee) Davidenko et al, Nature 1992, 355 349-51 First image of a spiral wave in a thin section of sheep heart Experimental work looks at the surface of the heart, but not within the tissue, this is a major justification for modelling

4. Systems Biology talk July 20044 The heart as a system  Heart is an electromechanical pump; electrical activation of heart cells (the action potential) initiates contraction.  Electrical properties of cells are well characterised experimentally.  Mechanical properties of cardiac tissue, and coupling of electrical and mechanical properties are less well understood.

5. Systems Biology talk July 20045 The beating heart: an electromechanical pump The heart as a system A fully integrative cardiac model needs  Cardiac action potential.  Intracellular Ca 2+ storage and release.  Coupling of electrical and mechanical activity.  Electrical coupling of cells.  Mechanical coupling of cells.  Anatomy.  Boundaries.

6. Systems Biology talk July 20046 The beating heart: an electromechanical pump The heart as a system A fully integrative cardiac model needs  Cardiac action potential.  Intracellular Ca 2+ storage and release.  Coupling of electrical and mechanical activity.  Electrical coupling between cells.  Mechanical coupling between cells, and mechanical properties of tissue.  Anatomy.  Boundaries.

7. Systems Biology talk July 20047 Cardiac model hierarchy Intracellular calcium handling (storage and release) Coupling between cells Anatomy Voltage + time dependence of ion channel conductances Action potential

8. Systems Biology talk July 20048 Model hierarchy Intracellular calcium handling (storage and release) Coupling between cells Anatomy Voltage + time dependence of ion channel conductances Action potential  Integrative model, simulates processes at molecular, cell, tissue and organ level.  Can be validated at cell and tissue levels.  Some gene polymorphisms affect ion channel properties. Models can be used to study how mutant ion channels affect function at cell, tissue and organ levels (but we haven’t done organ level simulation yet).

9. Systems Biology talk July 20049 Ventricular fibrillation in virtual heart Virtual torso with ECG electrodes Simulated ECG signal

10. Systems Biology talk July 200410  Successes. Spiral waves in the heart predicted in 1960s, and observed in 1990s. Many experimentalists now see value in modelling.  Failures. Many different cell models available, little consistency between research groups.  Technologies. Continuous (PDE) models of cell to cell coupling. High performance computing (shared and distributed memory).  Expectations. Insights into mechanisms that initiate and sustain fibrillation. Rational drug design.  Education. An appealing subject to teach, and is a good case study for modelling and simulation in physiology. Analysis