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Systems Biology of the Heart

Systems Biology of the Heart. Richard Clayton. Ventricular fibrillation. Experimental maps of electrical activity during VF. Davidenko et al, Nature 1992, 355 349-51. First image of a spiral wave in a thin section of sheep heart.

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Systems Biology of the Heart

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  1. Systems Biology of the Heart Richard Clayton Systems Biology talk July 2004

  2. Ventricularfibrillation Systems Biology talk July 2004

  3. Experimental maps of electrical activity during VF Davidenkoet al, Nature 1992, 355 349-51 First image of a spiral wave in a thin section of sheep heart More recent movie of spiral wave in a rabbit heart (Movie from the Living State Physics group, Vanderbilt University, Tenessee) 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 2004

  4. 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 2004

  5. The heart as a system The beating heart: an electromechanical pump A fully integrative cardiac model needs • Cardiac action potential. • Intracellular Ca2+ storage and release. • Coupling of electrical and mechanical activity. • Electrical coupling of cells. • Mechanical coupling of cells. • Anatomy. • Boundaries. Systems Biology talk July 2004

  6. The heart as a system The beating heart: an electromechanical pump A fully integrative cardiac model needs • Cardiac action potential. • Intracellular Ca2+ 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 2004

  7. Cardiac model hierarchy Action potential Voltage + time dependence of ion channel conductances Anatomy Coupling between cells Intracellular calcium handling (storage and release) Systems Biology talk July 2004

  8. Model hierarchy Action potential Voltage + time dependence of ion channel conductances • 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). Anatomy Coupling between cells Intracellular calcium handling (storage and release) Systems Biology talk July 2004

  9. Virtual torso with ECG electrodes Ventricular fibrillation in virtual heart Simulated ECG signal Systems Biology talk July 2004

  10. Analysis • 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. Systems Biology talk July 2004

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