1. Physiological regulation in pathogenesis cardiovascular disease and in general Stanislav Matoušek, M.D.

2. Regulated and unregulated variable Unregulated variable Fallen bridge Broken leg Regulated variable Cold café Hypertension

3. 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

4. Basic terminology

5. 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

6. 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.

7. Open loop temperature/ °C time / hours

8. Open loop temperature/ °C time / hours

9. Open loop Outside disturbance Error of the output variable temperature/ °C time / hours

10. Feedback temperature/ °C time / hours

11. Feedback temperature/ °C time / hours

12. Feedback temperature/ °C time / hours Outside disturbance Error of the output variable

13. The Effect of Feedback The output error is (5x) smaller then without the feedback temperature/ °C time / hours

14. Open loop vs. closed loop Open loop regulated system: Feedback (=closed loop) regulated system:

15. Feedback in physiology

16. RAAS system

17. General structure of control system

18. 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

19. Examples in physiology Regulation of blood sugar β cell Insulin Normal glycemia GLUT 4 tissue cell Glycemia Glc upta ke

20. Types of feedback in the body (positive, negative)

21. 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

22. Local regulation

23. Systemic regulation

24. Negative feedback PTH Ca ++ + - Keeps the value of the regulated entity close to the equilibrium.

25. Positive feedback + + faktor XII faktor XII a KalikreinPrekalikrein ++ Rare – amplification of small original „disturbance“; Does not create any equillibrium

26. Disturbance/disease in regulated system (body)

27. Diabetes mellitus β cells Insulin Normal glycemia GLUT 4 in tissue Glycemia Glc entering cells + - Diabetes type I Diabetes type II

28. Disease in general 1.Block in the feedback loop 2.Too high a disturbance 3.„Weak actuator“ 4.Incorrectly set reference point

29. History of regulation and feedback control

30. History in engineering Float valve of ancient Greece and Rome.

31. Steam Engine by James Watt

32. James Watt – fly-ball governor 1788

33. System stability

34. 20 century Maxwell stability criteria Problem of long- distance telephoning (use of electronic amplifiers) Bell Telephone Laboratories: H. Nyquist (1932) Nyquist criterium of stability

35. Today

36. 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

37. Ancient Greece Empedocles from Agrigent (504-443 BC)

38. Ancient Rome Galenos

39. Ancient China

40. Late 18 th century and 19 th 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.

41. Homeostasis – Walter Cannon –from the earlier idea of Claude Bernard of milieu interieur,Claude Bernardmilieu 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.blood 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.

42. 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.

43. Advent of computational biology – Arthur Guyton and Thomas Coleman

44. Thomas Coleman and laboratory of biocybernetics of our institute

45. Little intermezzo

46. Reminder of high-school calculus

47. Derivative

48. Important functions

49. Integral

50. Different types of governors / controllers

51. 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)

52. With high sensitivity (gain) of feedback, system might become unstable

53. 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

54. Derivative controller Cannot be used alone. Stabilizes the system

55. PID controller Proportional – integrative – derivative controller

56. Regulation of blood pressure

57. 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

58. Heart Autonomous nervous system Endocrine system Local tissue factors Heart characteristics Contractility Frequency

59. Blood vessels Vascular tone –compliance –resistance Autonomous nervous system Endocrine system Local tissue factors

60. 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

61. 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

62. Kidney-fluid mechanism of pressure control Time Net flow to the system

63. Kidney fluid mechanism of pressure control

64. Increased peripheral resistance is common in hypertensive individuals, but it is not the main cause

65. Why is antihypertensive treatment effective? Diuretics Beta-blockers ACE inhibitors Ca++ channel blockers

66. 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

71. 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

72. 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

75. 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)

76. 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

77. 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