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Physiological regulation in pathogenesis cardiovascular
disease and in general
Stanislav Matoušek, M.D.
Regulated and unregulated variable
Unregulated variable
• Fallen bridge
• Broken leg
Regulated variable
• Cold café
• Hypertension
What are we going to cover?
• 1. Basic terminology of regulation theory• 2. Types of feedback loops in the body (positive,
negative)• 3. Origin of disturbance/disease in regulated system• 4. History of regulated systems and their description• 5. Different types of governors (automated regulators)• 6. Regulation of cardiac output and blood pressure
• heart• vessels• kidney regulator
Regulation or (automatic) control
• if an environmental variable (such as temperature) ....changes and the system can nearly compensate for those changes ...then the system is said to be regulated.– Principia cybernetica web
• Regulation is every process that minimizes difference between the real and the desired (reference) value of the regulated variable.
Zdenek Wunsch, Basics of medical cybernetics (1977) in Czech
Regulation valve of central heating
Open-loop regulation
Feedback regulation
Regulator does not measure output variable (temperature) when it „computes“ the control action to take.
Output signal of the controlled system is measured and fed back for use in the control computation.
The Effect of Feedback
The output error is (5x) smaller then without the feedbackte
mpe
ratu
re/
°C
time / hours
Room temperature regulation
Heater body
Thermo-meter
Heating
Thermostat setting vs. actual temperature
Room temperature
Outside temperature
Set tem-perature
Measured temperature
Hot water valve open/closed
Examples in physiology
Regulation of blood sugar
β cell
β cell
InsulinNormal glycemia
GLUT 4 tissue cell
Glycemia
Glc upta
ke
Regulation in human body
• There are two systems specialized in control and regulation in the body:– endocrine system – nervous system
• Besides these two, every cell and tissue has many local feedback regulated processes
Positive feedback
+
+
faktor XII
faktor XII a
Kalikrein Prekalikrein
++
Rare – amplification of small original „disturbance“; Does not create any equillibrium
Diabetes mellitus
β cells
β cells
InsulinNormal glycemia
GLUT 4 in tissue
Glycemia
Glc entering
cells +
-
Diabetes type I
Diabetes type II
Disease in general
1. Block in the feedback loop
2. Too high a disturbance
3. „Weak actuator“
4. Incorrectly set reference point
20 century
• Maxwell stability criteria
• Problem of long-distance telephoning (use of electronic amplifiers)
• Bell Telephone Laboratories: H. Nyquist (1932) Nyquist criterium of stability
History in biological sciences
• Living organism’s ability to keep life processes in balance and thus confront the disturbances is so apparent that was already noted in Antiquity.
Zdenek Wunschin Basics of Medical Cybernetics
Another important aspect seen as a source of diseases are the organism’s internal imbalances. This idea, while surely correct in its essence, is remarkably trans-cultural.
Stanislav Komarek in Salvation of the Body
Late 18th century and 19th century
Lavoisier: Dynamic balance of known substances in metabolism (oxygen, food compounds, heat) is needed in body
Fredericq (1885): Living organism is a system able to respond to disturbing influence by a compensatory activity that neutralizes or repairs the developing perturbation. The higher the level of the living organism, the more common, more perfect and more complicated these regulatory activities become.
Homeostasis – Walter Cannon
– from the earlier idea of Claude Bernard of milieu interieur, – popularized it in his book The Wisdom of the Body,1932. – Four general features of homeostasis:
• Constancy in an open system, such as our bodies represent, requires mechanisms that act to maintain this constancy.
• Steady-state conditions require that any tendency toward change automatically meets with factors that resist change. An increase in blood sugar results in thirst to dilute the sugar.
• The regulating system - number of cooperating mechanisms acting simultaneously or successively. e.g. Blood sugar is regulated by insulin, glucagons, and other hormones, thirst.
• Homeostasis is the result of organized self-government.
Cybernetics – Norbert Wiener
• 1948 book Cybernetics: Or Control and Communication in the Animal and the Machine.
• The book formalizes the notion of feedback and has gained large influence in many fields: control engineering, computer science, biology, philosophy, sociology and philosophy.
Types of feedback regulators
• The simplest controller is so called proportional (P) controller.
There is always a difference between the reference and actual value.
The difference depends on the size of the disturbance and sensitivity of the feedback mechanism (so called gain)
Integral controllerThis controller can bring the difference between the reference and real value to zero over time.
It is not very fast and has tendency to destabilize the system
Cardiac output and blood pressure depend on:
• Characteristics of the heart:• Contractility• Frequency
• Characteristics (diameter) of the vessels
• Tone of arteriols influences mainly resistence• Tone of veins (or less mid-size arteries)
influences the volume of vascular bed. Volume of the bed is connected to pressure and vascular tone (compliance)
• Volume of circulating blood
Heart
• Autonomous nervous system
• Endocrine system
• Local tissue factors
Heart characteristicsContractilityFrequency
Blood vessels
• Vascular tone– compliance– resistance
Autonomous nervous systemEndocrine systemLocal tissue factors
Volume of circulating blood
• Is given by difference between the intake of salt and water and their output.
• The output is governed by kidney regulator
• Resistance of kidney arteriols
• Kidney filtration and resorption rate
• Renin-angiotensin-aldosteron system
Kidney-fluid mechanism of pressure control
Heart and vessels are regulated by mechanisms that are of a proportional controller type.
Kidney fluid regulator is a integral (I) controller type. (its long term sensitivity/gain is infinity)
= kidneys excrete more fluid until the pressure is set exactly on the equilibrium (reference) value
Why is antihypertensive treatment effective?
• Diuretics
• Beta-blockers
• ACE inhibitors
• Ca++ channel blockers
What did we cover?
• 1. Basic terminology of regulation theory• 2. Types of feedback loops in the body (positive,
negative)• 3. Origin of disturbance/disease in regulated system• 4. History of regulated systems and their description• 5. Different types of governors (automated regulators)• 6. Regulation of cardiac output and blood pressure
• heart• vessels• kidney regulator
Guyton’s model of circulation
• peripheral resistance, heart rate and contractility and vessel tone are primarily regulated variables. They are controlled directly by:
• Autonomous nervous system • Endocrine system• Local tissue factors
• blood pressure, and cardiac output are secondarily (regulated) variables.
They are controlled by • peripheral resistance, • heart rate and • vessel tone
Kidney-fluid mechanism of pressure control
Kidneys excrete more fluids until the pressure is exactly the equilibrium (reference) point.
This is an I (integral) controller
Review
• Regulation• Closed loop = feedback regulation• Same structure of regulatory loops in
engineering and medicine • Stability in regulation is only accomplished by
negative feedback• History of control theory• PID controllers• Blood pressure is determined only by kidney-
fluid mechanism in the long-run (the Integral controller)
Mathematical models and formalization
• Anything that can be quantified in words can also be expressed in formulas (language of mathematics)
• Mathematics gives us powerful methods of deducing correct implications from the underlying statements.
• “Uncritical enthusiasm of mathematical formulation often has the tendency to hide the key meaning nuances of the argumentation taking place behind facade of algebraic symbolism and “certainty””
Wassily Leontief winner of Nobel Prize for economics