Systems Biology talk July Systems Biology of the Heart Richard Clayton

Systems Biology talk July Ventricular fibrillation

Systems Biology talk July 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, 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

Systems Biology talk July 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.

Systems Biology talk July 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.

Systems Biology talk July 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.

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

Systems Biology talk July 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).

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

Systems Biology talk July  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