Physiological regulation in
pathogenesis cardiovascular
disease and in general
Stanislav Matoušek, M.D.
Regulated and unregulated
variable
Unregulated variable
• Fallen bridge
Regulated variable
•
Cold café
• Broken leg
•
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
Basic terminology
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
Regulator does not
measure output variable
(temperature) when it
„computes“ the control
action to take.
Feedback regulation
Output signal of the controlled
system is measured and fed back
for use in the control computation.
temperature/ °C
Open loop
time / hours
temperature/ °C
Open loop
time / hours
temperature/ °C
Open loop
Error of the
output variable
Outside
disturbance
time / hours
temperature/ °C
Feedback
time / hours
temperature/ °C
Feedback
time / hours
temperature/ °C
Feedback
Error of the
output variable
Outside
disturbance
time / hours
temperature/ °C
The Effect of Feedback
The output error is
(5x) smaller then
without the feedback
time / hours
Open loop vs. closed loop
Open loop
regulated system:
Feedback
(=closed loop)
regulated system:
Feedback in physiology
RAAS system
General structure of control system
Room temperature regulation
Outside
temperature
Set temperature
Thermostat
setting vs.
actual
temperature
Room
temperature
Hot water
valve
open/closed
Heater
body
Measured
temperature
Heating
Thermometer
Examples in physiology
Regulation of blood sugar
Normal
glycemia
β cell
Insulin
Glycemia
GLUT 4
tissue cell
Glc
upta
ke
β cell
Types of feedback in the body
(positive, negative)
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
Local regulation
Systemic regulation
Negative feedback
Keeps the value of the
regulated entity close to the
equilibrium.
Ca++
-
+
PTH
Positive feedback
Rare – amplification of small
original „disturbance“;
Does not create any equillibrium
Kalikrein
+
Prekalikrein
+
+
faktor
XII
+
faktor
XII a
Disturbance/disease in
regulated system (body)
Diabetes mellitus
Diabetes
type II
Normal
glycemia
β cells
Insulin
-
Glycemia
GLUT 4 in
tissue
Glc
entering
+
cells
β cells
Diabetes
type I
Disease in general
1. Block in the
feedback
loop
2. Too high a
disturbance
3. „Weak
actuator“
4. Incorrectly
set
reference
point
History of regulation and
feedback control
History in engineering
• Float valve of ancient
Greece and Rome.
Steam Engine by James Watt
James Watt – fly-ball governor
1788
System stability
20 century
• Maxwell stability
criteria
• Problem of longdistance telephoning
(use of electronic
amplifiers)
• Bell Telephone
Laboratories: H.
Nyquist (1932)
Nyquist criterium of
stability
Today
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 Wunsch
in 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
Ancient Greece
• Empedocles from Agrigent
(504-443 BC)
Ancient Rome
Galenos
Ancient China
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.
Advent of computational biology –
Arthur Guyton and Thomas Coleman
Thomas Coleman and laboratory of
biocybernetics of our institute
Little intermezzo
Reminder of high-school calculus
Derivative
Important functions
Integral
Different types of governors /
controllers
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)
With high sensitivity (gain) of
feedback, system might become
unstable
Integral controller
This 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
Derivative controller
• Cannot be used alone.
• Stabilizes the system
PID controller
Proportional – integrative
– derivative controller
Regulation of blood pressure
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 characteristics
Contractility
Frequency
Blood vessels
Autonomous nervous
system
Endocrine system
Local tissue factors
• Vascular tone
– compliance
– resistance
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-angiotensinaldosteron 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
Net flow to the system
Kidney-fluid mechanism of
pressure control
Time
Kidney fluid mechanism of
pressure control
Increased
peripheral
resistance is
common
in
hypertensive
individuals,
but it is not
the main
cause
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 kidneyfluid 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
System without feedback –
mathematical formalization
• If we want to mathematically express the
behaviour of a feedback regulated system,
we first need to depict behavior of the
system without feedback