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) … SAPHIR Modélisation physiologique integrée multi-organes Integrated, Multi-Organ Physiological Modeling

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

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

4 Plan for this talk 1.Guyton's 'engineering' approach to BP regulation Why regulate blood pressure?Why regulate blood pressure? What are the problems for BP control?What are the problems for BP control? The hierarchy of pressure control systems.The hierarchy of pressure control systems. Relevant principles of Control TheoryRelevant principles of Control Theory Quantitative evaluation of all aspects of BP regulation: the Guyton model(s)Quantitative evaluation of all aspects of BP regulation: the Guyton model(s) 2.Why revive such an old model, and what do we want to do with it? 3.Current state of progress towards implementation of the modular systems modeling environment. 4.What else is needed? (databases, GUI, etc.)

5 Why does the body need to regulate blood pressure? 1. Guyton's 'engineering' approach to BP regulation Why does the body need to regulate blood pressure? 1.To ensure adequate blood flow to each organ autoregulation of individual organs works best with a steady pressure at inputautoregulation 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 HEADSO - the Most important function of BP regulation is to MAINTAIN A STEADY PRESSURE HEAD 2.(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..e.g., in sympathectomized dogs, exercise leads to dramatic fall of BP in the brain.. 3.Adjust BP to bodily needs (sleep, exercise…) 4.Keep BP high enough to supply all organs (>80mmHg), but low enough to avoid damage to the vascular system

6 What are the problems for control? 1. Guyton's 'engineering' approach to BP regulation What are the problems for control? 1.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 volumethis role is assured almost entirely by the kidneys, which control blood volume and extracellular fluid volume 2.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)entirely independent of blood volume changes (too slow) must ensure adequate perfusion of all organs, but esp. the brain and the heartmust 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)depends on controlling strength of the heart, capacity of blood vessels, and total peripheral resistance (TPR) accomplished via nervous control and hormonal signalsaccomplished via nervous control and hormonal signals

7 The hierarchy of pressure control systems. 1. Guyton's 'engineering' approach to BP regulation The hierarchy of pressure control systems. 1. 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"! -- but this simplistic approach is "useless"! 2. The body's approach: a hierarchy of short- and medium-term damping and long-term control short-term (seconds to minutes) short-term (seconds to minutes) cardiovascular reflexes mediated by the nervous systemcardiovascular reflexes mediated by the nervous system intermediate-term (minutes to hours) intermediate-term (minutes to hours) capillary fluid shift from circulation to interstitial fluidcapillary fluid shift from circulation to interstitial fluid delayed compliance of the vasculaturedelayed compliance of the vasculature hormonal controls (angiotensin, vasopressin,..)hormonal controls (angiotensin, vasopressin,..) long-term (hours, days, weeks..) 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!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 The hierarchy of pressure control systems 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 The hierarchy of pressure control systems. 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 Relevant principles of Control Theory 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 Guyton, Coleman, Granger (1972) Ann. Rev. Physiol. kidney muscles circulatory dynamics capillary membrane dynamics thirst ADH control angiotensin control aldosterone control electrolytes & cell water tissue fluids, pressures, gel red cells, viscosity autonomic control pulmonary dynamics local blood flow control oxygen delivery heart rate… heart hypertrophy Project ANR-Biosys — SAPHIR: " a Systems Approach for PHysiological Integration of Renal, cardiac, and respiratory functions " Guyton's modular Systems Model for blood pressure regulation

12 Modular systems-model of blood pressure: Kidney module Guyton, A.C., T.G. Coleman, and H.J. Granger, "Circulation: Overall regulation." Annual Reviews of Physiology, : 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 VIM PA PPC RBF REK NOD VUD CNE AHM AM AUM afferent, efferent, & total resistan ce glomerular filtration volume reabsorption sodium excretion renal blood flow

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

15 The Infinite-Gain feature of the kidney - blood volume - pressure regulator: The acute vs. chronic renal function curves The Infinite-Gain feature of the kidney - 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 the kidney - blood volume - pressure regulator: Shifting the Renal Function Curve… The Infinite-Gain feature of the kidney - 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 J Na too high --> Hypertension

18 Plan for this talk 1.Guyton's 'engineering' approach to BP regulation Why regulate blood pressure?Why regulate blood pressure? What are the problems for control?What are the problems for control? The hierarchy of pressure control systemsThe hierarchy of pressure control systems Relevant principles of Control TheoryRelevant principles of Control Theory Quantitative evaluation of all aspects of BP regulation: the Guyton model(s)Quantitative evaluation of all aspects of BP regulation: the Guyton model(s) 2.Why revive such an old model, and what do we want to do with it? 3.Current state of progress towards implementation of the modular systems modeling environment 4.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 !

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 AQP2-4 UT-A1,A3 AQP1 UT-A2 AQP1 UT-B ROMK1 NKCC2 CaSR AQP2-3 TSC ClC-Ka ENaC