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)

…

SAPHIRSAPHIRModélisation physiologique integrée multi-organesModélisation physiologique integrée multi-organes

Integrated, Multi-Organ Physiological ModelingIntegrated, Multi-Organ Physiological Modeling

http://saphir.physiome.fr/

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Guyton, Coleman, Granger (1972) Ann. Rev. Physiol.

kidneymuscles

circulatorydynamics

capillary membranedynamics

thirst

ADHcontrol

angiotensincontrol

aldosteronecontrol

electrolytes& cellwater

tissue fluids, pressures,

gelred cells,viscosity

autonomiccontrol

pulmonarydynamics

local bloodflow

control

oxygendelivery

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

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SAPHIR (cont.)

Ikeda, N., et al., "A model of overall regulation of body fluids". Annals of Biomedical Engineering, 1979. 7:135-166.

Na, K, Cl, glucose, urea, blood pH, HCO3, CO2, O2, Ca++, Mg++, mannitol, blood hemoglobin, COP, phosphate, sulfate, NH4+

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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 Quantitative evaluation of all aspects of BP regulation: the Guyton model(s)regulation: the Guyton model(s)

2.2. Why revive such an old model, and what do we want to Why revive such an old model, and what do we want to do with it?do with it?

3.3. Current state of progress towards implementation of the Current state of progress towards implementation of the modular systems modeling environment.modular systems modeling environment.

4.4. What else is needed? (databases, GUI, etc.)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?Why does the body need to regulate blood pressure?

1.1. To ensure adequate blood flow to each organTo ensure adequate blood flow to each organ

• autoregulation of individual organs works best with a autoregulation of individual organs works best with a steady pressure at inputsteady pressure at input

• SO - the Most important function of BP regulation is to SO - the Most important function of BP regulation is to MAINTAIN A STEADY PRESSURE HEADMAINTAIN A STEADY PRESSURE HEAD

2.2. (corollary of (1)): avoid interference/competition among (corollary of (1)): avoid interference/competition among the organs for blood supplythe organs for blood supply

• e.g., in sympathectomized dogs, exercise leads to e.g., in sympathectomized dogs, exercise leads to dramatic fall of BP in the brain.. dramatic fall of BP in the brain..

3.3. Adjust BP to bodily needs (sleep, exercise…)Adjust BP to bodily needs (sleep, exercise…)

4.4. Keep BP high enough to supply all organs (>80mmHg), Keep BP high enough to supply all organs (>80mmHg), but low enough to avoid damage to the vascular systembut 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? What are the problems for control?

1.1. Maintain an appropriate Maintain an appropriate long-termlong-term baseline level of BP. baseline level of BP.

• this role is assured this role is assured almost entirely by the kidneysalmost entirely by the kidneys, which , which control blood volume and extracellular fluid volumecontrol blood volume and extracellular fluid volume

2.2. Provide appropriate Provide appropriate short-termshort-term changes in the circulatory changes in the circulatory system in the face of the many acute stresses we system in the face of the many acute stresses we encounterencounter

• 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 must ensure adequate perfusion of all organs, but esp. the brain and the heartbrain and the heart

• depends on controlling strength of the heart, capacity of depends on controlling strength of the heart, capacity of blood vessels, and total peripheral resistance (TPR)blood vessels, and total peripheral resistance (TPR)

• accomplished via nervous control and hormonal signalsaccomplished 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 hierarchy of pressure control systems.

1.1. The two major parameters of BP control: The two major parameters of BP control: TPRTPR and and COCO

Art. Press. = Art. Press. = Cardiac OutputCardiac Output X X Total Peripheral ResistanceTotal Peripheral Resistance + Right atrial pressure + Right atrial pressure

-- but this simplistic approach is "useless"!-- but this simplistic approach is "useless"!

2.2. The body's approach: a hierarchy of short- and medium-term The body's approach: a hierarchy of short- and medium-term dampingdamping and long-term and long-term controlcontrol

1.1. short-term (seconds to minutes)short-term (seconds to minutes)

1.1. cardiovascular reflexes mediated by the nervous systemcardiovascular reflexes mediated by the nervous system

2.2. 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..)

1.1. in response to numerous signals from elsewhere in the body, in response to numerous signals from elsewhere in the body, the the kidneykidney manages overall fluid and solute balance, manages overall fluid and solute balance, which determines the which determines the baseline level of blood pressurebaseline level of blood pressure … --> with INFINITE GAIN! … --> with INFINITE GAIN!

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1. Guyton's 'engineering' approach to BP regulation

The hierarchy of pressure control systems 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. 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 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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Guyton, Coleman, Granger (1972) Ann. Rev. Physiol.

kidneymuscles

circulatorydynamics

capillary membranedynamics

thirst

ADHcontrol

angiotensincontrol

aldosteronecontrol

electrolytes& cellwater

tissue fluids, pressures,

gelred cells,viscosity

autonomiccontrol

pulmonarydynamics

local bloodflow

control

oxygendelivery

heart rate…heart

hypertrophy

Project ANR-Biosys 2006-2009 — SAPHIR: "a Systems Approach for PHysiological Integration of Renal, cardiac, and respiratory functions"

Guyton's modular Systems Model for blood pressure regulation

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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, 1972. 34:13-44.

INPUTS

AUM: sympathetic vasoconstrictor effect on arteries

VIM: Blood viscosityPA: aortic pressurePPC: plasma COPRBF: Renal Blood FlowREK: percent of normal renal functionCNE: third factor effectAHM: ADH multiplierAM: aldosterone multiplier

OUTPUTSNOD: rate of renal Na+ excretionVUD: rate of urine output

VIMPA

PPC RBF REKNOD

VUD

CNEAHMAM

AUM

afferent,

efferent, & total

resistance

glomerular filtration

volume reabsorptio

n

sodium excreti

on

renal blood flow

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The The Infinite-GainInfinite-Gain feature of the feature of thekidney - blood volume - pressure regulator:kidney - blood volume - pressure regulator:

The (acute) renal function curveThe (acute) renal function curve

from Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

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from Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.

The Infinite-Gain feature of theThe Infinite-Gain feature of thekidney - blood volume - pressure regulator:kidney - blood volume - pressure regulator:

The (acute) renal function curve and Net sodium intakeThe (acute) renal function curve and Net sodium intake

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The Infinite-Gain feature of theThe Infinite-Gain feature of thekidney - blood volume - pressure regulator:kidney - blood volume - pressure regulator:

The acute vs. chronic renal function curvesThe 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 theThe Infinite-Gain feature of thekidney - blood volume - pressure regulator:kidney - blood volume - pressure regulator:

Shifting the Renal Function Curve…Shifting 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 --> Hypertension

AQP2-4UT-A1,A3

AQP1UT-A2

AQP1UT-B

ROMK1NKCC2CaSR

AQP2-3

TSC

ClC-Ka

ENaC

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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 Quantitative evaluation of all aspects of BP regulation: the Guyton model(s)regulation: the Guyton model(s)

2.2. Why revive such an old model, and what do we want to Why revive such an old model, and what do we want to do with it?do with it?

3.3. Current state of progress towards implementation of the Current state of progress towards implementation of the modular systems modeling environmentmodular systems modeling environment

4.4. What else is needed? (databases, GUI, etc.)What else is needed? (databases, GUI, etc.)

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2. Why revive such an old model, and 2. Why revive such an old model, and what do we want to do with it?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 progress3. 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?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 ActivistsEurope

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)

USAHarold & Anita Layton (Duke)

Leon Moore, Ki Chon, Mariano Marcano (SUNY Stony Brook)William Dantzler & Tom Pannabecker (Tucson)

Australia/New ZealandPeter Harris, Andrew Lonie, Bill Appelbe + postdocs (Melbourne)

Carey Stevens (chez Peter Hunter, Auckland)

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Several renal transporters implicated in health problems

AQP2-4UT-A1,A3

AQP1UT-A2

AQP1UT-B

ROMK1NKCC2CaSR

AQP2-3

TSC

ClC-Ka

ENaC