Regulation of Cardiac Output

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					                              Regulation of Cardiac Output

I.   Conceptual model of the circulation
     A.    The heart
           1.     In the isolated heart, as characterized by the heart-lung preparation, the
                  output is a function of the filling pressure (atrial pressure, end diastolic
           2.     In considering the heart in the intact circulation the right atrial pressure
                  (central venous pressure) provides the most convenient measure of filling
                  pressure (or preload).
            3.     The right atrial pressure is the filling pressure of the right heart. Given the
                   low resistance in the pulmonary circuit the Starling relation ensures that an
                   increase in right atrial pressure will cause an increase in the output of both
                   right and left ventricles.
            4.     However, to pump a given amount of blood the less compliant left
                   ventricle requires a greater filling pressure than the right ventricle. Thus in
                   the intact circulation left atrial pressure is generally 5-6 mmHg higher than
                   right atrial pressure (Fig. 1).

            Fig. 1
                                         Right ventricle
                      Cardiac 10
                      output, 8
                      L/min    6                                      Left ventricle
                                       -10       -5 0 5 10 15                    20
                                                  Atrial pressure, mmHg

            5.     We can then draw a family of cardiac output curves which depict cardiac
                   output as a function of right atrial pressure under different conditions of
                   contractile state and heart rate (Fig. 2).

Fig. 2                                                                                          rate
     Cardiac 12
     output, 8
     L/min                                                                                     150
              2                    Increased sympathetic
              0                        stimulation
                    -6 -4 -2 0 2 4 6 8 10             -6 -4 -2 0 2 4 6 8 10
                    12                               12
                                    Right atrial pressure, mmHg

             6.     For any contractile state (or heart rate) the cardiac output varies with the
                    right atrial pressure; conversely, with a fixed right atrial pressure the
                    output varies with the contractile state or heart rate.
             7.     The downward shift of the curve at very high heart rates is a result of the
                    severe reduction of the diastolic filling time.
    B.       The peripheral circulation
             1.     The cardiac output curve indicates the potential of the heart to pump blood
                    at a given level of neurohumoral stimulation. At a given heart rate and/or
                    contractile state the cardiac output will vary with the right atrial pressure.
             2.     In the intact circulation the flow into the right atrium is determined by the
                    pressure gradient between the peripheral circulation and the right atrium
                    and the resistance to the flow of blood in the peripheral circulation (Fig.

         Fig. 3

                                                                       Venous pressure
                                                                      gradient = Pv-RAP

II.   The venous return curve
      A.     Experimental basis
             1.     Consider an experimental animal in which the heart is replaced by a
                    mechanical pump in which the pump output can be controlled (Fig. 4).

       Fig. 4

            Veins                                                                             Arteries

        Cv=Vv/Pv                                                                            Ca=Va/Pa

                                                Peripheral resistance

            2.       If the flow is set at different values, starting at zero, and the pressure in the
                     great veins (central venous pressure, right atrial pressure) is measured at
                     different flow rates then one can generate a venous return curve (Fig. 5).

         Fig. 5               2000
                    Venous                                     Venous return curve
                     return,                                        of dog


                                       -4 -2    0     2     4     6   8 10
                                      10 10  Right atrial pressure, mmHg
            3.       At zero flow the pressures are the same throughout the vascular system.
                     The pressure at zero flow is termed the mean circulatory pressure (MCP).

              4.     The value of the mean circulatory pressure is determined by the blood
                     volume and vascular compliance (mainly venous compliance).
              5.     If the pump rate is set at any value above zero, blood will be moved from
                     the venous to the arterial compartment and the central venous pressure will
                     decrease (and arterial pressure increase) as pump output increases.
              6.     The resulting relationship between central venous pressure (right atrial
                     pressure) and flow defines the venous return curve.
              7.     This curve describes the flow properties of the vascular system. It is
                     independent of the properties of the pump.
       B.     Properties of the venous return curve
              1.     Since the venous compliance is ~20x arterial compliance the pressure at
                     zero flow (mean circulatory pressure) is much closer to normal venous
                     pressure than to arterial pressure.
              2.     In the dog the mean circulatory pressure is 7-8 mmHg (we will assume
                     that it has a similar value in the human).
              3.     The effective driving force for venous return is the difference between the
                     mean circulatory pressure (MCP) and the right atrial pressure (RAP).
              4.     As the term (MCP-RAP) increases the venous return increases until RAP
                     falls below atmosphere pressure, at which point venous return is constant.
              5.     The constancy of the venous return at subatmospheric right atrial pressure
                     is due to the tendency of the great veins carrying blood back to the right
                     atrium to flatten and collapse when the pressure inside the veins is less
                     than the external pressure.
III.   Coupling of the heart to the vascular system
       A.     The steady state cardiac output
              1.     Under steady state conditions the output of the heart is equal to the flow
                     through the peripheral circulation (or, cardiac output must equal venous
              2.     The right atrial pressure is both the filling pressure of the right heart and
                     the outlet pressure of the systemic circulation.
              3.     In the intact circulation there can be only a single cardiac output and right
                     atrial pressure at any given moment.
              4.     These values are obtained by plotting both cardiac output and venous
                     return curves on the same right atrial pressure axis (Fig. 6). The point of
                     intersection defines the actual cardiac output and right atrial pressure.

        5.       Using the combined curves it is then possible to analyze how the heart and
                 the peripheral vasculature interact to determine the cardiac output.

     Fig. 6              12
                 Cardiac 8                                  Operating point
                 output, 6
                 L/min 4
                                   -4    -2 0 2 4 6 8 10                         12
                                          Right atrial pressure, mmHg

B.      Mean circulatory pressure and cardiac output
        1.    A change in mean circulatory pressure (MCP) produces a corresponding
              shift in the entire venous return curve (Fig. 7).

 Fig. 7               14
                      12                            MCP increased
              Cardiac 8
              output, 6
               L/min 4
                       0      MCP decreased
                              -4    -2 0 2 4 6 8 10                        12
                                     Right atrial pressure, mmHg

        2.       The MCP is a function of blood volume and vascular compliance; an
                 increase in MCP could be brought about by a) an increase in blood
                 volume, b) a decrease in compliance, or c) a compressive force on veins
                 exerted by contracting skeletal muscles (this is equivalent to an decrease in
                 venous compliance).

        3.     Drawing the cardiac output curve on the same graph, it is seen that the
               cardiac output will increase as a consequence of the Starling relationship
               (Fig. 8).
               a. The increase in MCP increases the driving force for venous return.
               b. The greater flow of blood into the heart will increase the filling
                   pressure (RAP) until the heart reaches a new steady state where
                   cardiac output is equal to venous return.

     Fig. 8
                 10                                  MCP increased,
         Cardiac 8                                   CO increased
         output, 6
          L/min 4
                          -4       -2 0 2 4 6 8 10                    12
                                    Right atrial pressure, mmHg
C.      Blood volume and mean circulatory pressure (Fig. 9)
        1.     MCP increases as an approximately linear function of blood volume.
        2.     The ratio, blood volume/MCP, is the vascular compliance.
        3.     The unstressed volume of the circulation (MCP = 0) is about 25% less
               than the actual blood volume.
Fig. 9                 12
                        6            Unstressed
                        4            volume
                               0     1   2 3 4 5 6                7
                                         Blood volume, L
D.      Compliance and mean circulatory pressure
        1.    Most of the vascular compliance (and hence most of the blood volume) is
              localized in the veins.

        2.     The venous compliance is determined by the level of activation of smooth
               muscle in the walls of the veins.
        3.     Venous smooth muscle activity is mainly under the control of the
               sympathetic nervous system.
 E.     Resistance and cardiac output
        1.     The slope of the venous return curve is inversely related to the resistance
               to the flow of blood through the peripheral circulation.
        2.     Thus for a given MCP and RAP (pressure gradient for venous return) the
               flow will increase as the resistance decreases (Fig. 10).

      Fig. 10
                                                          R decreased
              Cardiac 8
              output, 6
              L/min 4
                       0        R increased
                                -4    -2 0 2 4 6 8 10                        12
                                       Right atrial pressure, mmHg
F.      The arteriovenous fistula: a model to illustrate resistance effects
        1.     An arteriovenous fistula is a direct communicating channel between an
               adjacent artery and vein. It is a low resistance shunt which causes a large
               decrease in the total peripheral resistance.
        2.     Associated with the presence of an arteriovenous fistula is a significant
               elevation of the resting cardiac output.
        3.     Consider an experimental animal with an artificial shunt connecting the
                abdominal aorta and vena cava (Fig. 11).
        4.      Sudden opening of the shunt causes an immediate increase in the cardiac
                output with only a small decrease in mean arterial pressure (MAP = CO x
                R; CO, R). The arterial blood can “short circuit” the main sites of
                resistance, allowing for a more rapid venous return and an increase in right
                atrial pressure.

            5.     Thus, an acute change in resistance can bring about a significant change in
                   cardiac output, independent of any change in heart rate, contractile state, or
                   vascular compliance.

                             120                 Open fistula            Close fistula
          Mean arterial
          pressure, mmHg 100
Fig. 11
                 Flow,      1500
                 cc/min     1000
                            500                                                            Fistula
                              0                                                             flow

                                        0            15            30              45
                                                            Time, sec

     G.     Physiological determinants of resistance
            1.     Resistance is determined by a combination of neural and local metabolic
                   factors acting on pre-capillary resistance vessels.
            2.     The relative contributions of neural (mainly the sympathetic adrenergic
                   system) and metabolic factors varies with different tissues.
            3.     For some tissues (skin) neural control is dominant. In others (heart, brain)
                   metabolic control is dominant.
            4.     In skeletal muscle resistance is determined by both neural and metabolic
                   signals. At rest neural control is dominant. In the exercising muscle local
                   metabolic signals (see later section) cause relaxation of arteriolar smooth
                   muscle with a resultant decrease in total peripheral resistance.
            5.     It is through local metabolic signals acting on adjacent resistance vessels
                   that oxygen delivery (cardiac output) is adjusted to meet oxygen demand.

H.     The role of the heart in regulation of cardiac output
       1.     The role of the heart in controlling cardiac output is limited by the nature
              of the coupling of the heart to the vascular system.
       2.     The requirement that the steady state cardiac output must be at the point of
              intersection of the cardiac output and venous return curves places a
              constraint on the ability of the heart alone, through changes in rate and
              contractility, to alter cardiac output.
       3.     As an example, in the normal cardiovascular system(in a resting subject), a
              selective increase in heart rate by means of pacemaker stimulation will
              have little effect on cardiac output (Fig. 12).
                     16          Increase HR
     Fig. 12 Cardiac 14
             output, 12
              L/min 10
                                -4    -2 0 2 4 6 8 10                        12
                                     Right atrial pressure, mmHg
      4.      In this case the right atrial pressure was close to zero and as the heart
              started to increase its pumping rate it caused a collapse of the great veins,
              thereby preventing any further increase in venous return (and cardiac
       5.     On the other hand if there had been an increase in MCP and/or a decrease
              in resistance (as there is in exercise), then an increase in heart rate would
              be effective in further increasing the cardiac output (Fig. 13).
       6.     The heart plays largely a "permissive" role in the regulation of cardiac
              output. The effect of a given change in heart rate or contractile state on
              cardiac output will depend on the conditions which exist in the peripheral
              circulation (compliance, resistance).

   Fig. 13                                                       HR increased
                    Cardiac 14
                    output, 12
                                                                 R decreased
                     L/min 10
                             6                                    MCP
                             4                                    increased
                                     -4    -2 0 2 4 6 8 10                12
                                          Right atrial pressure, mmHg

Suggested Reading
Berne, R.M. and Levy, M.N. Principles of Physiology, chap. 24.


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