The determinants of cardiac output Flashcards
The heart has surprisingly little control over CO!
In a classic experiment, Guyton et al. (1957)
effectively replaced the right atria of dogs with
high-output pumps (Figure 7). Reducing the
pumping capacity below normal reduced cardiac
output, as you might expect. However, perhaps
surprisingly, increasing the pumping capacity did
not increase cardiac output:
This experiment illustrates two important
circulatory concepts:
1) The heart is necessary to maintain CO, but
2) The heart does not normally limit CO.
So why can’t an increase in heart pumping capacity
on its own increase CO? The answer is:
The circulation is a closed system.
Imagine a pump entirely within a fluid-filled
balloon. It can move fluid within the balloon, but it
can’t change the average pressure in the balloon,
and it certainly can’t inflate or deflate it. This is a
closed system. The circulation is surprisingly similar,
as shown in Figure 8.
In this simple model, the heart takes blood from the
veins (reducing venous pressure, PV) and puts it in the arteries (increasing arterial pressure, PA). This
pressure gradient then drives flow through our
model system according to the simple relationship:
Q̇ = (PA – PV) / R
(Flow = pressure gradient / resistance)
If the closed system depicted in Figure 8 were made
of rigid tubing, greater pump activity could produce
ever-increasing pressure gradients and hence
flows. However, if the tubing is not rigid – imagine,
perhaps, that it is an odd-shaped balloon – then an
important constraint appears: if PV becomes
negative (with respect to atmospheric pressure)
then the tubing will collapse. Similarly, real veins
collapse when pressure within them drops more
than about 1 or 2 mmHg below atmospheric
pressure.
This is an important result, and provides the
explanation for Figure 7. The heart cannot increase
the arteriovenous pressure gradient (PA-PV) beyond
the point at which PV becomes significantly
negative, because if PV becomes negative, venous
collapse limits venous return and hence cardiac
output. Direct measurement of right atrial pressure
(by inserting a catheter via the jugular vein)
confirms what Figure 7 suggests: a healthy heart
reduces central venous pressure to almost zero,
even at rest. This means that increasing heart rate
or myocardial contractility in isolation – for
example, by stimulating the cardiac sympathetic
nerves or electrically pacing the heart (Figure 9) –
cannot significantly increase cardiac output, unless
venous return is also increased (in this experiment,
accomplished by connecting the aorta to the vena
cava).
Figure 9: changing the heart rate by electrical pacing does not
greatly change cardiac output
This
is because cardiac output is limited by venous return, which
cannot be increased by the actions of the heart alone.
However, creation of an arterio-venous fistula (dashed line)
provides a rapid pathway for blood to return to the heart and
reveals that the heart is capable of producing a greater cardiac
output if venous return is sufficient. Cowley & Guyton, 1971.
if increasing
cardiac pumping capacity is not sufficient to
increase cardiac output, what else is necessary?
Mean systemic filling pressure is the main
determinant of cardiac output.
- The mean pressure determines the
maximum flow rate for a given resistance.
In order to increase PA, the pump must reduce PV.
Yet, PV is normally close to zero and so cannot be
reduced. The solution is to raise the mean pressure
in the whole system. To see how this works, first
imagine that the mean pressure in Figure 8 was zero. This would imply that PV would become
negative as soon as the pump was started, and
prevent any flow of blood. Then, imagine that the
mean pressure in Figure 8 was 10 mmHg. Now, it is
possible for pumping to produce a significant
arterio-venous pressure gradient without collapsing
the veins. The mean pressure determines the
maximum flow rate for a given resistance.
Exlain mean systemic filling pressure (MSFP)
Mean systemic filling pressure (MSFP) is the mean
pressure in the system (equivalently, the pressure
that would eventually exist everywhere in the
system if the heart stopped). Just as with pressure
in a balloon, MSFP can be increased by extra filling
(such as a blood transfusion or drinking isotonic
fluid) or by constricting the filled volume (imagine
standing on a balloon). The latter can be
accomplished in real life by venoconstriction,
because about 65-70% of blood is usually in the
veins. The effects of these manoeuvres are
illustrated by the experiments shown in Figure 10.
Blood volume and mean filling pressure in a real
system
It is now time to apply the principles of the simple
model system discussed above to the real
circulation. However, it is helpful to start by
considering a very unphysiological state – an empty
circulation.
The normal blood volume in an adult mammal is
approximately 70-80 ml/kg of body mass, or about
5 l for a 70 kg person. If this amount of blood is
added to an empty circulation, the first ~80% does
not cause a rise in pressure, because the pressure
stays at zero until the vessel walls begin to stretch.
This is called the unstressed volume of the
circulation: the volume of blood that just fills the
circulation without stretching the vessel walls.
When the last 20% of normal blood volume is
added, the mean pressure in the system will rise.
This extra volume is the stressed volume, and
normally gives rise to a mean pressure of 7 – 10
mmHg in the circulation.
The effect of cardiac activity (regarding to MSFP)
Now, consider what happens when the heart starts
pumping: blood is transferred from the veins to the
arteries.
This changes the venous and arterial
pressures according to their compliance, as shown
in Figure 11. Veins are very compliant in the
physiological range (although they become quite
stiff if very overstretched, as shown by the dashed
line in Figure 11; this can be observed when a
saphenous vein graft is used to replace a blocked
coronary artery.)
This venous compliance ensures
that if the pressure without cardiac activity was 7
mm Hg everywhere, the reduction in venous
pressure with cardiac activity would be relatively
small. In contrast, the movement of blood into the
far less compliant arteries causes a steep rise in
pressure. In the average human, this process
continues until venous pressure is close to zero and
the mean arterial pressure is about 90-95 mmHg.
Notice that this means that when the heart is
working normally, the arteries are more filled, and
the veins less filled, than they would be if the heart
stopped.
This arteriovenous pressure gradient then drives
blood flow from the arteries, via the capillaries, to
the veins. At last, we have a circulation!
maximum arteriovenous pressure gradient is set
by the mean filling pressure implies
1) The heart cannot change the mean
pressure; (since increase heart pumping cannot increase CO)
2) This mean pressure determines the
maximum cardiac output.
How is MSFP controlled (CO)
Mean systemic filling pressure is therefore a critical
determinant of cardiac output.
MSFP is determined by the
volume of blood and the
mean tension in blood vessel walls.
MSFP can be doubled by increasing the blood
volume by 20%, because that doubles the stressed
volume. This also doubles the cardiac output.
Conversely, because only the “last 20%” of the
blood volume actually stretches vessel walls loss of
20% of the circulating volume would be expected to
reduce MSFP (and hence CO) to zero.
Fortunately, the mean tension in the blood vessel
walls can be regulated. About 60% of blood is in the
venules and small veins, and thus venoconstriction
can reduce the capacity of the circulation such that
MSFP can be maintained above zero until about
40% of the circulating volume is lost. This is
accomplished by sympathetic venoconstriction,
which can up to treble MSFP.
Note that venoconstriction does not significantly
influence TPR, which is primarily determined by the
resistance of arterioles. Conversely, arteriolar
constriction increases TPR but does not influence
MSFP, because less than 1% of blood is contained
within the arterioles.
Quantifying cardiac output
The simple form of Darcy’s law states that:
Flow = Pressure gradient / Resistance.
Thus, the arteriovenous pressure difference
produces blood flow:
CO = (ABP – RAP) / TPR
(Cardiac Output, i.e. flow of blood = (Arterial Blood
Pressure – Right Atrial Pressure) / Total Peripheral
Resistance)
The arteriovenous pressure gradient (ABP – RAP) is
created by the action of the heart, but limited by
MSFP.
TPR is a “lumped parameter” that treats all
the resistances of the various vascular pathways as
a single resistance, but is primarily determined by
arteriolar resistances. RAP is usually so small
compared to ABP that it can often be omitted from
the above equation.
Control of cardiac output
The heart is able to
respond to changing physiological need through
intrinsic and extrinsic mechanisms.
Instrinsic regulation of cardiac output – Starling’s
“Law of the Heart”.
Extrinsic:
control of HR and extrinsic
regulation of contractility
Instrinsic regulation of cardiac output – Starling’s
“Law of the Heart”.
A key mechanism responsible for increasing CO
when MSFP increases is the Frank-Starling
mechanism:
Both increases in preload (right atrial pressure) and
afterload (arterial blood pressure) stretch cardiac
muscle. This causes an increase in myocardial
contractile force by at least two mechanisms: first,
stretching cardiac muscle increases the overlap
between myosin and actin filaments, allowing
greater crossbridge formation; second, stretch of
cardiac muscle increases its sensitivity to Ca2+ such
that greater force is produced at any given Ca2+
concentration.
The steep response of the heart to increased RAP
ensures that increased MSFP produces increased
CO. The increase in myocardial contractility with
increased afterload ensures that an increase in TPR
(by generalised arteriolar vasoconstriction) does
not reduce CO, but instead causes an increase in
ABP (by the equation ABP = CO x TPR). This is
supported by evidence from microsphere
experiments: microspheres injected into dogs
blocked many arterioles, more than doubling TPR.
This did not reduce CO, and therefore ABP more
than doubled.
RAP is therefore a key point of control in the
circulation. If CO stayed constant, then an increase
in MSFP would increase RAP. (Why? Because
pressure would increase throughout the
circulation, and the greatest percentage increase
would be at the right atrium, where pressure was
initially lowest.) However, in real life, CO would not
stay constant: we know from Starling’s experiments
that the increased RAP (i.e., increased pre-load) will
increase stroke volume and hence CO (and ABP by
ABP = CO x TPR).
Above (discussion around Figure 8), we saw that
MSFP limits CO. By considering the Starling
mechanism, we can go further: increased MSFP
causes increased CO under normal physiological
conditions. Conversely, decreased MSFP decreases
the maximum CO: this is why blood loss, for
example, decreases blood pressure, and one reason
why exercise is impaired by severe dehydration.
Extrinsic control of cardiac output.
What about heart rate? If heart rate changes in
isolation, then stroke volume drops and cardiac
output barely changes; the heart cannot “pull”
more blood from the venous system. However,
increased heart rate in exercise, for example,
facilitates increased cardiac output by shifting the
curve of CO vs. RAP.
In addition, as we will discuss in a later lecture,
sympathetic stimulation, e.g. during exercise,
enhances Ca2+ entry.
We will look at control of HR and extrinsic
regulation of contractility in the next lecture.
Another way to look at things
Rather than consider the entire circulation, it may
sometimes be helpful to consider the circulation in
two parts: the part in which pressure is above
MSFP, and the part in which pressure is below
MSFP. We can then consider cardiac output and venous return separately (even though they must
be equal):
CO = (ABP – MSFP) / TPR*
VR = (MSFP – RAP) / RvR
Where TPR* is the resistance prior to the “pivotal
point” where pressure = MSFP, and RvR, the
resistance to venous return, is the remaining
resistance. RvR is a bit of an oddity. It is perhaps
best to think of it as a term that reflects the
difficulties blood has in returning to the heart -such
as the fact that capillary pressure in the feet is
insufficient to drive blood more than a meter
upwards to the heart, so that venous return from
the lower legs must wait for voluntary muscle
movements to pump blood back. Thus, RvR can
change, especially in exercise, but it isn’t specifically
regulated. The venous return equation allows us to
consider venous blood flow at different values of RAP (Figure 15).
In isolation, Figure 15 suggests that venous return
drops as RAP increases: this is simply because the
difference between MSFP and RAP gets smaller.
Thus, it also shows the RAP at a venous return of
zero, which is of course the mean systemic filling
pressure. Raising MSFP by increasing circulating
volume or venoconstriction would shift this curve
up. Reducing RvR would increase the slope without
changing MSFP (i.e. it would not change the
intersection of the line with the x-axis).
RAP does not just influence venous return, though.
By the Starling mechanism, increased RAP increases
cardiac output (Figure 13):
The cardiac output and venous return must be the
same, which is where the curves cross (for this
system, at an RAP of 0 mmHg and a CO of 5 l min-1
).
Note that if the RAP was 5 mmHg, CO would
transiently exceed venous return, which would
cause RAP to drop until VR and CO became equal
again.
These curves are helpful because MSFP only shifts
the VR curve, and TPR or changes in myocardial
contractility only shift the CO curve. Figure 14
shows the effects of sympathetic stimulation as an
example.
Sympathetic venoconstriction and stimulation to the heart (beta 1 receptor) on the VR and CO of Guyton’s curve
Figure 14 allows consideration of two effects of
sympathetic stimulation separately. Without any
such stimulation, the system rests at point A (RAP 0
mmHg, CO 5 l min-1
). Sympathetic venoconstriction
increases MSFP and hence shifts the venous return
curve higher at any RAP (as VR = MSFP – RAP). This
upward shift means that, for a moment, VR exceeds
CO, but as this increases RAP, CO increases and the
system settles at point B: raised RAP and raised CO.
If, instead, we had only increased sympathetic
stimulation to the heart, the cardiac output curve would shift to higher outputs at any RAP. However,
as this drives RAP negative, the increase in CO is
minimal, to point C.
Finally, combining the two
effect shifts both curves to overlap at point D: a higher cardiac output with RAP remaining at zero.
These “Guyton curves” can be helpful in considering
the effect of various changes to the circulation. For
example, imagine what would happen with a failing
heart, such that CO was reduced at every RAP: the
crossing point would slide down the VR curve such
that CO would reduce somewhat and RAP would
increase significantly.
However, these curves are simply a model, or a way
of thinking. As discussed above, it is also possible to
think about the circulation in terms of a single
pressure / flow relationship.
