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

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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/
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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
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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. 7135-166.
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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.)

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1. Guyton's 'engineering' approach to BP
regulation Why 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
  (gt80mmHg), but low enough to avoid damage to the
  vascular system

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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

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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 --gt with INFINITE GAIN!

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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.
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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.
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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.
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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
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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. 3413-44.
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The Infinite-Gain feature of thekidney - blood
volume - pressure regulatorThe (acute) renal
function curve
from Guyton, A. C. (1980). Circulatory Physiology
III. Arterial Pressure and Hypertension.
Philadelphia, W.B. Saunders.
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The Infinite-Gain feature of thekidney - blood
volume - pressure regulatorThe (acute) renal
function curve and Net sodium intake
from Guyton, A. C. (1980). Circulatory Physiology
III. Arterial Pressure and Hypertension.
Philadelphia, W.B. Saunders.
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The Infinite-Gain feature of thekidney - blood
volume - pressure regulatorThe acute vs.
chronic renal function curves
from Guyton, A. C. (1980). Circulatory Physiology
III. Arterial Pressure and Hypertension.
Philadelphia, W.B. Saunders.
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The Infinite-Gain feature of thekidney - blood
volume - pressure regulatorShifting the Renal
Function Curve
from Guyton, A. C. (1980). Circulatory Physiology
III. Arterial Pressure and Hypertension.
Philadelphia, W.B. Saunders.
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Distal Tubule JNa too high --gt Hypertension
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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.)

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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

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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

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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

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• Merci !

http//saphir.physiome.fr/
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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)
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Several renal transporters implicated in health
problems