systems biology talk july 20041 systems biology of the heart richard clayton
TRANSCRIPT
Systems Biology talk July 2004 1
Systems Biology of the Heart
Richard Clayton
Systems Biology talk July 2004 2
Ventricular fibrillation
Systems Biology talk July 2004 3
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, 355 349-51First 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 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 beating heart: an electromechanical
pump
The heart as a system
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 beating heart: an electromechanical
pump
The heart as a system
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
Intracellular calcium handling
(storage and release)
Coupling between cells
Anatomy
Voltage + time dependence of
ion channel conductances
Action potential
Systems Biology talk July 2004 8
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 2004 90 1000 2000 3000 4000 5000 6000 7000 8000
Time (ms)
Ventricular fibrillation in virtual heart
Virtual torso with ECG electrodes
Simulated ECG signal
Systems Biology talk July 2004 10
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