Randy Thomas (IBISC FRE 2873 CNRS/Univ. Evry) ———————— with —————————

1. SAPHIRModélisation physiologique integrée multi-organesIntegrated, Multi-Organ Physiological Modeling Randy Thomas (IBISC FRE 2873 CNRS/Univ. Evry) ———————— with ————————— Alfredo Hernandez (INSERM U-642. Rennes) Pierre Baconnier (UMR CNRS 5525 TIMC, Grenoble) Patrick Hannaert (Inserm E0324, Poitiers) Jean-Pierre Françoise (Univ. Paris VI, Paris) … http://saphir.physiome.fr/

2. thirst oxygen delivery muscles kidney ADH control local blood flow control angiotensin control capillary membrane dynamics circulatory dynamics aldosterone control autonomic control tissue fluids, pressures, gel electrolytes & cell water pulmonary dynamics red cells, viscosity heart hypertrophy heart rate… SAPHIR:"a Systems Approach for PHysiological Integration of Renal, cardiac, and respiratory functions" Guyton, Coleman, Granger (1972) Ann. Rev. Physiol. Guyton's modular Systems Model for blood pressure regulation

3. SAPHIR (cont.) Na, K, Cl, glucose, urea, blood pH, HCO3, CO2, O2, Ca++, Mg++, mannitol, blood hemoglobin, COP, phosphate, sulfate, NH4+ Ikeda, N., et al., "A model of overall regulation of body fluids". Annals of Biomedical Engineering, 1979. 7:135-166.

4. Plan for this talk • Guyton's 'engineering' approach to BP regulation • Why regulate blood pressure? • What are the problems for BP control? • The hierarchy of pressure control systems. • Relevant principles of Control Theory • Quantitative evaluation of all aspects of BP regulation: the Guyton model(s) • Why revive such an old model, and what do we want to do with it? • Current state of progress towards implementation of the modular systems modeling environment. • What else is needed? (databases, GUI, etc.)

5. 1. Guyton's 'engineering' approach to BP regulationWhy does the body need to regulate blood pressure? • To ensure adequate blood flow to each organ • autoregulation of individual organs works best with a steady pressure at input • SO - the Most important function of BP regulation is to MAINTAIN A STEADY PRESSURE HEAD • (corollary of (1)): avoid interference/competition among the organs for blood supply • e.g., in sympathectomized dogs, exercise leads to dramatic fall of BP in the brain.. • Adjust BP to bodily needs (sleep, exercise…) • Keep BP high enough to supply all organs (>80mmHg), but low enough to avoid damage to the vascular system

6. 1. Guyton's 'engineering' approach to BP regulation What are the problems for control? • Maintain an appropriate long-term baseline level of BP. • this role is assured almost entirely by the kidneys, which control blood volume and extracellular fluid volume • Provide appropriate short-term changes in the circulatory system in the face of the many acute stresses we encounter • entirely independent of blood volume changes (too slow) • must ensure adequate perfusion of all organs, but esp. the brain and the heart • depends on controlling strength of the heart, capacity of blood vessels, and total peripheral resistance (TPR) • accomplished via nervous control and hormonal signals

7. 1. Guyton's 'engineering' approach to BP regulation The hierarchy of pressure control systems. • The two major parameters of BP control: TPR and CO Art. Press. = Cardiac Output X Total Peripheral Resistance + Right atrial pressure -- but this simplistic approach is "useless"! • The body's approach: a hierarchy of short- and medium-term damping and long-term control • short-term (seconds to minutes) • cardiovascular reflexes mediated by the nervous system • intermediate-term (minutes to hours) • capillary fluid shift from circulation to interstitial fluid • delayed compliance of the vasculature • hormonal controls (angiotensin, vasopressin,..) • long-term (hours, days, weeks..) • in response to numerous signals from elsewhere in the body, the kidney manages overall fluid and solute balance, which determines the baseline level of blood pressure … --> with INFINITE GAIN!

8. 1. Guyton's 'engineering' approach to BP regulation The hierarchy of pressure control systems from Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

9. 1. Guyton's 'engineering' approach to BP regulation The hierarchy of pressure control systems. from Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

10. 1. Guyton's 'engineering' approach to BP regulation Relevant principles of Control Theory • Three types of control: • proportional feedback • integral feedback • feed-forward control • Quantitative modeling, using control systems diagrams: Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

11. thirst oxygen delivery muscles kidney ADH control local blood flow control angiotensin control capillary membrane dynamics circulatory dynamics aldosterone control autonomic control tissue fluids, pressures, gel electrolytes & cell water pulmonary dynamics red cells, viscosity heart hypertrophy heart rate… Project ANR-Biosys 2006-2009 — SAPHIR:"a Systems Approach for PHysiological Integration of Renal, cardiac, and respiratory functions" Guyton, Coleman, Granger (1972) Ann. Rev. Physiol. Guyton's modular Systems Model for blood pressure regulation

12. afferent, efferent, & total resistance renal blood flow volume reabsorption glomerular filtration sodium excretion Modular systems-model of blood pressure: Kidney module INPUTS AUM: sympathetic vasoconstrictor effect on arteries VIM: Blood viscosity PA: aortic pressure PPC: plasma COP RBF: Renal Blood Flow REK: percent of normal renal function CNE: third factor effect AHM: ADH multiplier AM: aldosterone multiplier OUTPUTS NOD: rate of renal Na+ excretion VUD: rate of urine output CNE AHM AUM AM VIM PPC REK RBF NOD PA VUD Guyton, A.C., T.G. Coleman, and H.J. Granger, "Circulation: Overall regulation." Annual Reviews of Physiology, 1972. 34:13-44.

13. The Infinite-Gain feature of thekidney - blood volume - pressure regulator:The (acute) renal function curve from Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

14. The Infinite-Gain feature of thekidney - blood volume - pressure regulator:The (acute) renal function curve and Net sodium intake from Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

15. The Infinite-Gain feature of thekidney - blood volume - pressure regulator:The acute vs. chronic renal function curves from Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

16. The Infinite-Gain feature of thekidney - blood volume - pressure regulator:Shifting the Renal Function Curve… from Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

17. Distal Tubule JNa too high --> Hypertension

18. Plan for this talk • Guyton's 'engineering' approach to BP regulation • Why regulate blood pressure? • What are the problems for control? • The hierarchy of pressure control systems • Relevant principles of Control Theory • Quantitative evaluation of all aspects of BP regulation: the Guyton model(s) • Why revive such an old model, and what do we want to do with it? • Current state of progress towards implementation of the modular systems modeling environment • What else is needed? (databases, GUI, etc.)

19. 2. Why revive such an old model, and what do we want to do with it? • Why? - the Physiome… • What? • update it & accomodate current knowledge of genetic polymorphisms involved in hypertension • make it modular, open source, and extensible • hopefully adapt it to be clinically useful

20. 3. Current state of progress • Original Guyton model has been implemented in several environments: • Fortran (from the original code, thanks to Ron White) • C++ (for the Rennes toolbox) • Matlab/Simulink (in progress) • Ikeda model implemented in Berkeley Madonna • Gearing up to merge the two…

21. 4. What else is needed? • Databases of experimental measurements for determination of the parameter values • Ontology development to standardize terminology across multiple disciplines • GUI for running & adjusting the model, and for customizing the modules • Clinical data for validation and benchmarking • Optimization of parameter identification process • …

22. Merci ! http://saphir.physiome.fr/

23. Collaborators/Fellow Activists Europe SRT, Fariza Tahi, Farida Zehraoui + 2 postdocs (Evry) Alfredo Hernandez (Rennes) Pierre Baconnier, Philippe Tracqui (Grenoble) Patrick Hannaert (Poitiers) Jean-Pierre Françoise (Paris) Benjamin Ribba (Lyon) Marie Beurton-Aimar (Bordeaux) -------------------------- Brian Harvey (Dublin), Mathematicians of BCRI (Cork) -------------------------- Niels Holstein-Rathlou (Copenhagen) USA Harold & Anita Layton (Duke) Leon Moore, Ki Chon, Mariano Marcano (SUNY Stony Brook) William Dantzler & Tom Pannabecker (Tucson) Australia/New Zealand Peter Harris, Andrew Lonie, Bill Appelbe + postdocs (Melbourne) Carey Stevens (chez Peter Hunter, Auckland)

24. Several renal transporters implicated in health problems ENaC TSC AQP2-3 ROMK1 NKCC2 CaSR AQP1 UT-B ClC-Ka AQP1 UT-A2 AQP2-4 UT-A1,A3