Chapter 12

CARDIAC OUTPUT AND VENOUS RETURN AND THEIR

REGULATION

Learning Objectives

After reading this chapter you should be able to:

1. Define Cardiac Output and Venous Return.

2. Define the factors that affect cardiac output.
3. Explain how alteration in these factors change the cardiac output.
4. Describe the effects of changing total peripheral resistance on cardiac output.
5. Describe a cardiac output curve.
6. Describe the factors that alter the cardiac output curve.
7. Distinguish between low cardiac output states and high cardiac output states.
8. Describe a vascular function curve.
9. Explain the concept of mean systemic filling pressure.
10. Explain how changes in blood volume, venomotor tone and peripheral resistance alters
the vascular function curve.
11. Describe the Guyton cross plot.
12. Illustrate how inotropic agents alter the cross plot.
13. Illustrate how changes in blood volume, venomotor tone and TPR alter the cross plot.

Cardiac Output: Volume of blood pumped into the aorta each minute by the heart
or
Volume of blood that flows round the circulation/min

Venous Return: Volume of blood flowing from the veins into the right atrium each
minute

Venous return usually refers to the systemic venous return i.e. blood returning into the
right atrium. Because the right heart’s input must equal its output in the steady state, and
because the cardiac outputs of the right and left hearts are almost exactly the same, the
input to the right heart must equal the output of the left heart. Thus, systemic VR must

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match the systemic CO. (Fluctuations do occur over a few beats, but the Frank-Starling
mechanism ensures that steady state conditions are soon achieved).

Cardiac Output: 4 – 7 L/min (10% less in females)

A more accurate term is cardiac index, since CO increases with increases in surface area.

Cardiac Index: CO/m2 of body surface = ~ 3L/min/m2

Cardiac Output and Metabolic Rate

As the body’s metabolic needs increase (e.g. as in exercise), CO increases. During sleep
metabolic rate falls and CO falls accordingly.

A heavy meal, excitement or stress can increase cardiac output by 20 – 30%. In pregnant
women CO is increased by ~ 40% due largely to an increase in blood volume. In heavy
exercise it can increase 5 fold.

CO is lower in the elderly but this may be a reflection of decreased metabolism.

Factors which affect Cardiac Output

Cardiac Output (CO) = Heart Rate (HR) x Stroke Volume (SV)

An in HR or SV or both will CO; conversely a in HR or SV or both will CO.

Factors which affect Heart Rate

(i) Autonomic Nervous System:

Sympathetic activity: NE acting on β1 receptors: ↑ HR

Epinephrine (adrenal medulla) β1: ↑ HR

Parasympathetic activity: ACh acting on muscarinic (M2) rec: ↓ HR

(ii) Drugs: β1 agonists ↑ HR

M2 antagonists ↑ HR

β1 antagonists ↓ HR
M2 agonists: ↓ HR

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Factors which affect Stroke Volume

1. End Diastolic Volume (EDV): ↑ EDV → ↑ SV

When EDV is increased, the myocardial fibres are stretched, the force (energy) of
contraction is increased and SV increases (Frank – Starling mechanism). The EDV is
regarded as the preload.

Therefore, ↑ preload → ↑ SV

Factors that affect EDV

(a) Venous Return

↑ VR → ↑ EDV

However, VR is dependent on the filling pressure which in the systemic

circulation is the central venous pressure (CVP). The two phrases are used
synonymously. The CVP provides the pressure gradient that drives blood from the
veins to the atria.

↑ CVP → ↑ VR → ↑ EDV → ↑ SV
↓ CVP → ↓ VR → ↓ EDV → ↓ SV

Factors that affect CVP

CVP depends on the total volume of blood in the circulation, and on how
the volume is distributed between the peripheral and central veins. Volume
distribution is also affected by gravity, peripheral venous tone, the skeletal
muscle pump and the respiratory pump.

(1) Blood Volume

↓ Blood volume → ↓ CVP → ↓ EDV → ↓ SV

Hypovolemia due to hemorrhage or dehydration → ↓ CVP

↓ CVP accounts for the ↓ SV which → ↓ MAP
(↓ MAP is characteristic of hemorrhage)

Converse is true: hypervolemia → ↑ CVP

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 (2) Venoconstriction

↑ venomotor tone → ↑ CVP → ↑ EDV → ↑ SV

Venoconstriction increases the pressure within the veins. The pressure

gradient between the veins and the atria is then increased which facilitates
venous return.

Sympathetic activity causes venoconstriction (mainly in skin, kidney and

splanchnic circulations). This displaces blood from the peripheral veins to
the central veins, thereby increasing CVP

(3) Arteriolar vasoconstriction → ↓ VR

Arteriolar vasoconstriction tends to “hold” the blood in the arterial system

and venous return falls.

Arteriolar vasodilation → ↑ VR

Arteriolar vasoconstriction is equivalent to an increase in TPR.

Other factors that influence the CVP include:

(4) Body posture

Upright posture causes venous pooling and ↓ CVP

(5) Muscle pump: ↑ pump → ↑ VR

Rhythmic exercises compresses the deep veins of the limbs and displaces
blood from the peripheral veins to the central veins thus increasing CVP

(6) Respiratory pump

During inspiration, the intrathoracic pressure becomes more negative the

abdominal veins are compressed due to the downward movement of the
diaphragm. This promotes filling of the central thoracic veins, thus
increasing CVP.

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The effect of increasing EDV on the SV and CO is illustrated by the cardiac performance
curves (also known as cardiac (ventricular) function curves or cardiac output curves)
discussed in Chapter 5 “The Heart as a Pump”.

A typical cardiac function curve is illustrated below. Remember that the y-axis can be
any parameter that represents cardiac work (stroke work, stroke volume, cardiac output)
and the x-axis is a parameter that reflects EDV which could be atrial pressure, or EDP.

Figure 1 A typical cardiac function (cardiac output) curve

The above graph shows that as atrial pressure increases cardiac output increases until a
plateau is reached. Increases in atrial pressure lead to increases in EDV which increases
the stretch on the myocardial muscle fibres. This stretch increases the force of contraction
by the Frank – Starling mechanism.

Factors which affect Stroke Volume (cont.)

2. Contractility

A change in contractility is a change in contractile energy of the heart that is not due to
changes in fibre length, but rather to external factors such as sympathetic activity or
drugs. An increase in contractility is called a positive inotropic effect and factors that
increase contractility are positive inotropes. Positve inotropes increase the pumping
ability of the heart thus increasing SV and CO.

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Positive Inotropes: Sympathetic activity ( via NE on β1 receptors)

Drugs: β1 receptor agonists

Digoxin (a cardiac glycoside)

Contractility is reduced in many pathological states e.g. cardiac failure

25 Maximum sympathetic stimulation

20
Cardiac Output (L/min)

15 Normal sympathetic stimulation

10 Zero sympathetic stimulation

-4 0 +4 +8
Right Atrial Pressure (mmHg)

Figure 2 Effects of changes in contractility on the CO (cardiac performance) curve

The effects of changing contractility on the cardiac output curve is illustrated above.
Note that the x-axis is Right Atrial Pressure. These curves represent the function of the
entire heart rather than a single ventricle. RAP and output from the LV are relatively easy
to measure. Remember that because the heart functions as two pumps in series the input
to the RA must equal the input to the LA in the steady state and the systemic VR must
equal the systemic CO.

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Factors which affect stroke volume (cont.)

3. Arterial Pressure: equivalent to afterload

High arterial pressure → ↓ SV

If the pressure in the aorta is high, the ventricular pressure needed to open the aortic
valves is greater, and the heart must work harder to achieve this.

Summary

CO can be changed by altering HR or SV, or both. HR is altered by the autonomic

nervous system. SV volume is influenced by two opposing factors: the force of
contraction and the arterial pressure that must be overcome to expel the blood. A forceful
or energetic contraction produces a larger SV. The energy of contraction is increased by
stretching the myocardial fibres in diastole ( preload) or by increasing the contractility
of the heart ( sympathetic activity). A high arterial pressure ( afterload), opposes
ejection and reduces SV because ejection cannot begin until ventricular pressure has
exceeded aortic pressure. Therefore SV depends on the interplay between diastolic
stretch, contractility and arterial pressure.

Regulation of Cardiac Output and Venous Return

We have discussed the factors that affect CO. The more difficult issue is what is the
primary controller of CO – is it the VR to the heart or the heart itself (as manifest by its
pumping ability i.e. its contractility)?

The general consensus is that under most normal unstressful conditions, CO is controlled
primarily by the factors that determine the CVP (blood volume, venoconstriction and
arteriolar vasoconstriction) and consequently VR. However, whenever the VR becomes
more than the heart can pump (e.g. in stressful situations like exercise and in pathological
conditions), then the contractility of the heart is altered (by sympathetic activity) such
that the CO is matched to the VR.

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Quantitative Analysis of Cardiac Output Regulation
To understand CO regulation especially in more extreme conditions such as exercise,
cardiac failure and circulatory shock a more quantitative analysis is necessary.

We need to distinguish separately the 2 primary factors concerned with CO regulation:

(1) the pumping ability of the heart - represented by the CO curves and (2) the factors that
affect CVP and consequently the VR. These latter factors are represented by the
vascular function curves (also known as the venous return curves).

The CO function curves have already been described earlier in this chapter. Let us now
focus on the vascular function curves which depict the relationship between venous
return and right atrial pressure. They show how changes in right atrial pressure affect
venous return.

Vascular Function Curves

How much blood flows into the heart (i.e. the VR) is determined by the pressure gradient
between the central veins the right atrium. The greater the pressure gradient the larger the
VR. The lower the pressure in the RA the greater the pressure gradient between the veins
and the RA and the greater the VR; and vice versa - as RAP ↑, VR ↓.
VASCULAR FUNCTION CURVE

10
Venous Return (L/min)

8
6
4 Mean Systemic
Filling Pressure
2
(MSFP)
0
-2 0 +2 +4 +6 +8
Right Atrial Pressure (mm Hg)

Figure 3 A typical Vascular Function Curve

A typical vascular function curve is shown above in Figure 3. This graph shows that as
RAP increases VR declines. The slope of this curve is very steep in that a small increase

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in RAP produces a large fall in VR. The steepness is partly due to the fact that veins are
very compliant (distensible). Note that when the RAP is ~ +2 mm Hg, the VR is ~ 5
L/min. When RAP goes below zero, one would have expected the VR to continue
increasing. It does not do this because at these low pressures, the veins collapse and blood
flow to the heart is impeded. When the RAP is ~ +7 mm Hg, the VR is zero i.e. there is
no pressure gradient between the RA and the veins to drive the blood back to the heart.
This pressure is referred to as the mean systemic filling pressure (MSFP).

Let us see how this vascular function curve was originally derived and what the MSFP
really means.

Imagine what would happen if the heart stopped working as a pump and cardiac output
becomes zero (which is what happens during a cardiac arrest). For several seconds after,
the blood would continue to flow from the arteries to the capillaries to the veins because
the arterial pressure would still be greater than the venous pressure. (Remember that
aortic pressure does not fall to zero during diastole because of the potential energy stored
in the elastic recoil of the arterial walls). Eventually blood flow will stop completely and
the pressures in the arteries, capillaries, veins and the RA would be uniform. This is the
mean systemic filling pressure and its value is ~ +7 mm Hg. If a balloon is filled with
water, the pressure inside depends on the volume of the water and the elasticity of the
balloon. Similarly the MSFP is not zero because it depends on the volume of blood in the
vascular system and its overall distensibility. The overall distensibility (or compliance) of
the vascular system depends on the degree of venomotor tone as well as arteriolar tone.

In the next section we are going to see how varying blood volume, venomotor tone
(which is equivalent to venous compliance) and arteriolar resistance (TPR) affects the
MSFP and the shape of the vascular function curve. You will note that all these factors
mentioned above are all the factors that alter venous return

Factors which affect the Vascular Function Curve and the Mean Systemic Filling
Pressure

Blood Volume
Venomotor Tone
Arteriolar Resistance

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Blood Volume

Because the vascular function curve depends on venous return and venous return depends
on the CVP which in turn is influenced by blood volume, changes in blood volume will
alter the vascular function curve. The graph below shows how an increased blood volume
(e.g. following a blood transfusion) or a decrease blood volume (e.g. hemorrhage) alters
the curve and the MSFP.

10 Blood Volume MSFP

Venous Return (L/min)

8 Blood Volume MSFP

Bl
oo
6 d
Vo
lu
Bl m
e MSFP
4 oo
dV
olu
2 me

0
-2 0 2 4 6 8
Right Atrial Pressure (mm Hg) Shift in MSFP

Figure 4 Effects of Changing Blood Volume on the Vascular Function Curve

An increase in blood volume shifts the curve to the right. There is no alteration in the
slope (as long as there is no change in vessel compliance). The MSFP is increased from
+7 to ~ +9 mm Hg. This increase is to be expected since an increase in volume will
increase the CVP and so a greater RAP is needed to stop venous return. A hemorrhage
will have the opposite effects.

Venomotor Tone

Changing the venomotor tone, either by constricting or dilating only the veins is akin to
changing the blood volume. Changing the tone changes the tension in the walls of the
veins which alters the venous pressure. Increasing venomotor tone would increase the
venous pressure which is similar to increasing the blood volume. Venoconstriction has
the same effect as a blood transfusion. Conversely, decreasing the tone, reduces the
pressure and is equivalent to a decrease in blood volume. Venodilation has the same
effect as a hemorrhage. Increasing venomotor tone is also like decreasing venous
compliance and vice versa.

310
Effects of Changing Arteriolar Resistance
Effects of changing TPR on Vascular Function Curve

10 TPR Arteriolar

Venous Return (L/min)

Vasodilation
8

6 Arteriolar
TPR Vasoconstriction
4

2 No change in MSFP
0
-2 0 +2 +4 +6 +8
Right Atrial Pressure (mm Hg)

Figure 5 Effects of Changes in TPR on the Vascular Function Curve

Changing arteriolar tone has a very different effect on the vascular function curve than
changing venomotor tone. Since a much lesser fraction of the blood volume is found in
arteries, as compared to veins, changing arteriolar tone will have little effect on the
MSFP. So, in the diagram above, MSFP is not changed. However, changes in arteriolar
tone can have marked effects on the central venous pressure which is the driving force for
venous return. When arteriolar tone increases and arterioles constrict, blood is “held”
more in the arterial side of the circulation, resulting in less blood flowing into the venous
side. This results in a lowering of the central venous pressure and hence the gradient
between the veins and the right atria is reduced and the vascular function curve is
flattened (slope is not as steep). Conversely, arteriolar dilation facilitates flow of blood
into the veins, increases CVP thus making it easier for blood to flow back into the heart;
hence the slope of the curve becomes steeper.

311
The Guyton Cross Plot: Combining the CO and VF Curves

10

VR or CO (L/min)
8

6 A

0
-2 0 +2 +4 +6
Right Atrial Pressure (mm Hg)

Figure 6 The Guyton Cross Plot: a combination of the CO curve and the vascular
function curve.

In the beginning of this chapter we saw that RAP influences CO as depicted by the
cardiac function (cardiac output) curves. An increase in RAP increases CO by the Frank –
Starling mechanism. (RAP influences EDV). The cardiac function curve has the same
units as the vascular function curve. We can actually put these two curves on the same
graph (see above). The y-axis for the cardiac function curve is CO, and the y-axis for the
vascular function curve is the VR. The x-axis for both is right atrial pressure. For the
cardiac function curve we are looking at how changes in right atrial pressure (via changes
in end diastolic volume) influence stroke volume and cardiac output. For the vascular
function curves we imagine that the heart has stopped pumping and now we are looking
at how increases in right atrial pressure alters venous return. These two curves will
intersect at a particular right atrial pressure. At this point of intersection, the cardiac
output will be equal to the venous return, and we know that CO and VR are equal when
the system is in a steady state. Looking at the graph above, we see that CO = VR (their
value is about 5l/min) at the point where the right atrial pressure is +2 mmHg. (This new
graph is referred to as the Guyton cross plot after the famous American cardiologist).
This is the equilibrium point for the system. So, for a given pumping ability of the heart
(contractility) and a given venous pressure (based on blood volume and venomotor tone)
there is only one atrial pressure where cardiac output equals cardiac input (venous
return). Under normal resting conditions CO and VR equal ~5L/min at a right atrial
pressure of ~ 2 mm Hg.

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We might ask – do the CO and VR depend on RAP or does the RAP depend on the CO
and VR. Both are true – they all depend on each other. There is no absolute dependent or
independent variable in this closed circuit because, in the steady state, VR and CO must
be equal. They can only be equal at the single point where the two curves intersect (point
A) in Figure 6.

Effect of changing cardiovascular parameters on the equilibrium

The only way to produce a permanent change in CO, VR or RAP is to change either the
cardiac function curve and/or the vascular function curve. The Guyton cross plot
provides a useful tool for predicting changes in cardiac output that will occur when these
various cardiovascular parameters that alter the cardiac function curve and the vascular
function curve are altered. Whenever a parameter changes, the system moves to a new
steady state in which the intersection point where the two curves cross will be altered.
The new operating point tells us what the new cardiac output and the new venous return
are in the new steady state.

Changes in cardiac output and venous return can be brought about by :

(i) positive or negative inotropic effects that alter the cardiac function curve
(ii) changes in blood volume or venomotor tone (venous compliance) that alter the
vascular function curve by changing mean systemic filling pressure
(iii) changes in TPR that alter both the cardiac function curve and the vascular
function curve

(i) Inotropic Effects

A positive inotropic agent will cause an increase in contractility for a RAP, and a
negative inotrope decreases contractility.
pe
ro
ot

10
In

Figure 7
e
+v

al
VR or CO (L/min)

8 Effects of a positive and negative

rm ope
No Inot
r
inotrope on cardiac output, venous
6 -ve
return and right atrial pressure.
4

0
-2 0 +2 +4 +6
Right Atrial Pressure (mm Hg)

313
 Digoxin (a positive inotrope) will increase contractility and increase CO for any level
of RAP. Remember that a positive inotrope shifts the cardiac function curve upwards
and to the left. However, changing contractility will not affect the vascular function
curve so that does not change. With the change in the cardiac performance curve,
there is a new intersection point i.e. a new steady state. In this new steady state,
cardiac output is increased and right atrial pressure is decreased. The decrease in
RAP reflects the fact that more blood is ejected from the heart on each beat as a result
of the increased contractility and stroke volume. In fact, this is what happens to an
individual who has heart failure and is taking digoxin.

A negative inotrope decreases contractility and ↓ CO for any level of RAP. The cardiac
function curve shifts downward and to the right. The vascular function curve is
unchanged. In the new steady state, CO is decreased and RAP is increased. RAP is
increased because less blood is ejected from the heart on each beat, due to the decreased
contractility and decreased stroke volume.

(ii) Effects of changing Blood Volume

Changes in blood volume alter mean systemic filling pressure, thereby altering the
vascular function curve.

a) Increasing Blood Volume

Increases in blood volume increases the MSFP. In the new steady state the cardiac and
vascular function curves intersect at a new point at which cardiac output is increased
and right atrial pressure is increased.

10
VR or CO (L/min)

6 Bl
oo
dV
4 olu
Blo me
od
2 Vo
lum
e
0
-2 0 +2 +4 +6
Right Atrial Pressure (mm Hg)
Figure 8

314
Decreases in blood volume (e.g. after a hemorrhage)

The fall in blood volume, decreases the MSFP. There is a parallel shift to the left of the
vascular function curve and in the new steady state, CO is decreased and RAP is
decreased.

(iii) Effects of Changes in TPR

Changes in TPR reflect changes mainly in the degree of constriction of the arterioles.
Such changes alter the extent to which blood is “held” on the arterial side of the
circulation. Thus changes in TPR alter both arterial blood pressure and venous return to
the heart. An increase in TPR by restricting blood flow out of the arterial side produces
an increase in arterial pressure and a decrease in central venous pressure resulting in a
decrease in venous return, thus affecting the vascular function curve. The increased TPR
also increases arterial pressure which is equivalent to the afterload. Increases in afterload
affect the cardiac output curve. Therefore the effects of changing TPR are more
complicated since both curves are altered.

Increasing TPR (arteriolar vasoconstriction)

Increases in TPR cause an increase in arterial pressure by “holding “ blood in the arteries.
This increase in arterial pressure produces an increase in afterload on the heart, which
decreases CO. The cardiac function curve shifts downward as a result of the increased
afterload. The increase in TPR reduces the slope of the vascular function curve but does
not affect the MSFP. The overall effect of an increased TPR is a new steady state where
both both CO ↓ and VR ↓.

10
VR or CO (L/min)

0
-2 0 +2 +4 +6
Right Atrial Pressure (mm Hg)
Figure 9

315
Decreasing TPR (arteriolar vasodilation)

The decreased TPR decreases afterload and causes the cardiac function curve to shift
upward. The decrease TPR facilitates blood flow back to the heart. The curves intersect at
a new steady state point at which both CO ↑ and VR ↑.

10

VR or CO (L/min) 8

0
-2 0 +2 +4 +6
Right Atrial Pressure (mm Hg)

Figure 10

In Figures 9 and 10, the RAP has not changed. However, the effects of decreased TPR on
RAP are not easily predicted because a change in TPR has different effects via the
cardiac and vascular function curves. A ↓ in TPR ↑ CO, which ↓ RAP (more blood is
pumped out of the heart); and a ↓ in TPR increases VR which increases RAP (increased
flow back to the heart). Depending on the relative magnitude of these effects, RAP can be
slightly increased, slightly decreased or unchanged. In the figure, it is shown as
unchanged.

Let us see what happens to the Guyton cross plot in cardiac failure. It should help us
predict what would happen to cardiac output and right atrial pressure.

316
Cardiac Failure

10

VR or CO (L/min)
8

0
-2 0 +2 +4 +6 +8
Right Atrial Pressure (mm Hg)

Figure 11

The graph above shows how cardiac failure affects various parameters. Cardiac failure
causes a reduction in contractility of the heart and so the cardiac output curve is
depressed (shifted downwards and to the right). Cardiac failure also results in
venoconstriction and fluid retention and these would shift the vascular function curve
upwards. Now we see that the cardiac output and venous return at the new set point are
hardly changed; but the right atrial pressure has increased. In fact, these are the
characteristic features of moderate ventricular failure.

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