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Physiome and Virtual Heart

Physiome and Virtual Heart. Eun Bo Shim, Ph.D. Department of Mechanical Engineering Kangwon National University. Limitation of Genome Project. Genomic theory : 1) Discovery of the gene related with a specific disease 2) Discovery of the protein related with the gene

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Physiome and Virtual Heart

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  1. Physiome and Virtual Heart Eun Bo Shim, Ph.D. Department of Mechanical Engineering Kangwon National University

  2. Limitation of Genome Project Genomic theory: 1) Discovery of the gene related with a specific disease 2) Discovery of the protein related with the gene 3) Correction or bypassing of the malfunction protein based on its structure & function or Discovery of gene therapy to replace faulty gene Unsuccessful !!!! Reason : fundamental failure to understand biological complexity

  3. Why ? Problem 1: the function of a gene is NOT specified in the DNA language Problem 2: each gene plays roles in MULTIPLE functions Problem 3: each function arises from co-operation of MANY genes Problem 4: function also depends on important properties NOTspecified by genes - properties of water, lipids, self-assembly etc… Problem 5: nature has built-in fail-safe ‘redundancy’ - this ONLY emerges at the functional level

  4. Genome  Proteome (on-going)  Metabolome  …….  Physiome : From Genes to Function Post – Genome Era

  5. What is the Physiome? Bassingthwaighte (1995): Advances in Experimental Medicine and Biology 1995; 382: 331-9 “The Physiome Project is an integrated program whose mission is to archive and disseminate quantitative data and models of the functional behavior of biological molecules, cells, tissues, organs, and organisms.”

  6. Proposed Projects 1.Brain and CNS 2.Heart and cardiovascular system 3.Lungs and respiratory system 4.Kidney and urinary system 5.Musculo-skeletal system 6.Alimentary system 7.Reproductive system 8.Endocrine system 9.Haemolymphoid system 10.Integumental system

  7. Genes Proteins Biophysical models Constitutive laws Organ model Whole body model Genome Protein Physiology Structural Bioeng. Materials Clinical Molecular Biology Physiology Bioengineering Clinical medicine Physiome Bioinformatics Modeling Hierarchies Databases

  8. Molecular & Cell Biology Biochemistry Anatomy Pathophysiology Physiology Bioengineering Computer Science Clinical Research & Trials Drug discovery Physiome

  9. Mathematical Models Level 1 models: Molecular models Level 2 models: Subcellular Markov models Level 3 models: Subcellular ODE models Level 4 models: Tissue and whole organ continuum models Level 5 models: Whole body continuum models Level 6 models: Whole body system models

  10. Physiome Groups • BioNoME (UCSD) • Biology Network of Modeling Efforts; limited activity but good pedigree • funded by Procter and Gamble for 3 years • Cardiome Project (Auckland) • the model and most active group • Microcirculatory Physiome Project (Johns Hopkins) • seems well supported and active • Endotheliome Project • Pulmonary Physiome

  11. Modeling target in the present Physiome in the Heart (Cardiome)  Virtual heart

  12. 가상심장 (Virtual Heart) • An example of Physiome • 컴퓨터 프로그램으로 가상적으로 구현된 심장 • 신약개발에 활용 - 1997 Hoffman-LaRoche사 심장병약 개발 시 활용 • Fusion technology (Physiology+Mechanics+ Cell biology) - Computational biomedical engineering

  13. An example of Physiome • 컴퓨터 프로그램으로 가상적으로 구현된 심장 • 신약개발에 활용 - 1997 Hoffman-LaRoche사 심장병약 개발 시 활용 • Fusion technology (Physiology+Mechanics+ Cell biology) - Computational biomedical engineering Virtual Heart Modeling

  14. Cardiome Project Anatomy Heart model Tissue Structure Tissue properties Cellular properties Drug Discovery Clinical Applications Model Validation

  15. Anatomy • Completed or underway: • Vent. geom. & fibre-sheet structure for dog • Vent. geom. & fibre-sheets for rabbit • Coronary anatomy for pig • Atrial geometry & structure for pig • Cardiac valve structure

  16. Mechanics • Completed or underway: • Material properties - • biaxial tests on dog myocardium • shear testing of pig myocardium • torsion testing of rabbit pap. muscle • ECM structure • Functional studies on gene targetted mice • Infarct modeling • Ventricular aneurysm • Acute ischemia

  17. Activation • Completed or underway: • Ionic current models • Spatial distribution of ion channels • SA, atrial, AV, HIS, Purkinje • Reentrant arrhythmias • Defibrillation studies • Heart failure • Mutations (eg KvLQT1/minK -> IKs -> LQTS) • EC coupling • Needed soon: • Spatial distribution of gap junctions • Drugs -> models -> clinically observable effects • Mutations (eg HERG -> IKr -> LQTS) • Expression profiling in acquired heart disease

  18. Energy Supply & Metabolism • Completed or underway: • Coronary flow • Coronary flow regulation • Metabolism & energetics • Ischemia • Flux balance & kinetic models • Needed soon: • Integration of different parts of metabolic pathway models • with energy supply & demand • Coupling to electrophysiology & generation of reentrant arrhythmias

  19. Databases • Structure and spatial parameters • Material properties • Dynamic behavior • Documentation • Communications and interactions Cell Tissue Organ(ism)

  20. Membrane Transporter Function Cell Electro- physiology Ventricular Anatomy & Mechanics Gene/Protein Expression Ventricular Excitation Heart modeling Generalized Anatomic Database Interface and Analysis Platform Electrophysiological data Models Imaging, Simulation and Electrical Mapping Data Finite Element Modeling Tools Reconstructed Hearts Data Analysis Tools

  21. Membrane Transporter Function& Cell Electrophysiology Models INab INaCa IpCa ICaL ICab Functional Unit { Irel Functional Unit Sarcoplasmic reticulum Iup JSR NSR Ca 2+ Ca 2+ Itr Calsequestrin Troponin/myofilament Ito1 INa IK1 IK INaK • ~50,000 Functional Units (FUs) • Simulate channel gating in each FU stochastically • Couple stochastic simulation with numerical integration of model ODEs

  22. Action potential : diFrancesco – Noble Model

  23. Ideal Procedure Cell electro-physiological model and mechanical processes (Tension generated-sliding filament theory)  Insertion into global cardiac geometry on a cell by cell basis  Impossible approach for now !!!  Approximation needed !!!  Bidomain model Computational Procedure  SA node model  Action potential propagation model (bidomain model)  Cross-bridge model (fading memory theory)  Stress – Strain relation (constitutive equation) : Finite element method  Heart muscle deformation (contraction) Virtual Heart Modeling

  24. Propagation of action potential : Bidomain model

  25. Measurement and Modeling of Whole-Heart Function:Heart Geometry and Fiber Structure Reconstructed by Nielsen et al, University of Auckland Fox and Hutchins (1972). Johns Hopkins Med. J. 130(5): 289-299

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