Cardiac Output

Introduction

In this lesson we will learn about the cardiac output. We will discuss the importance of cardiac
output in regards to tissue perfusion. We will discuss how cardiac output is measured as well as
the major factors affecting it.

Lesson learning outcomes

By the end of this lesson, you will be able to:

1. Explain what cardiac output is and state how it is calculated

2. State the major factors which determine cardiac output

3. Explain the importance of heart rate in cardiac output

4. Explain the importance of stroke volume in cardiac output

5. Explain what is venous return and how it is affected by systemic filing pressure

Cardiac Output

Maintaining and regulating cardiac output, which is usually proportional to the tissues' need for
oxygen and other nutrients, is one of the circulatory system's most intricate functions. This is
also the quantity of blood that flows through the circulatory system and is responsible for
transporting substances to and from the tissues. Cardiac output is an essential part of the
circulatory function. It is the volume of blood ejected by each ventricle in 1 minute. It Has 2
components which are: Heart rate & Stroke volume

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

• Heart rate is the number of beats/min which is about 72 beats per minute
 • Stroke volume is the volume of blood pumped out by a ventricle with each contraction
and is about 70ml

The average cardiac output is about 5-6 L/min. As such, the entire blood supply passes through
the heart in about 1min. This can increase during exercise upwards to 25L/min in trained
athletes. Some blood is left in the heart after ventricular contraction and this is known as the
end systolic volume. At rest the heart pumps only 4 to 6 liters of blood per minute. In times of
severe exercise, the amount the heart pumps may go up by three to seven times this amount.
The amount pumped out by the heart per minute is controlled by

(1) An intrinsic cardiac regulation of pumping in response to changes in volume of blood

flowing into the heart and
(2) Regulation of the heart rate and strength of contraction of the heart by the autonomic
nervous system

Measurement of Cardiac output

Measurement of cardiac output makes possible an evaluation of respiratory exchange, i.e., the
delivery of oxygen to the tissues. The cardiac output represents the volume of blood that is
delivered to the body, and is therefore an important factor in the determination of the
effectiveness of the heart to deliver blood to the rest of the body, (i.e., determining heart
failure, inadequate circulation, etc).

Can be measured via the direct Fick method or the indicator dilution method.

Fick method

It utilizes the principle that a substance being taken up by an organ is delivered to that organ
via arterial blood. Once the organ has taken up the substance, what remains of the substance is
left in the veins. Calculating the difference in concentrations of the substance between the
arteries and veins and having knowledge of the blood flow, then the cardiac output can be
calculated. The assumption here is that the only source of the substance is the arterial blood.
One of the major substances is O2 and the difference in arterial and venous O2 concentration
can be used to calculate CO. The arterial O2 can be easily measured from a sample obtained
from any convenient artery. A sample of venous blood in the pulmonary artery is obtained by
means of a cardiac catheter. The procedure involves to insert a long catheter through a forearm
vein and to guide its tip into the heart with the aid of a fluoroscope. A catheter can also be
inserted through the right atrium and ventricle into the small branches of the pulmonary artery.

Output of left ventricle = O2 consumption per minute/(Arterial O2) – (Venous 02)

Factors affecting cardiac output

 Heart rate
 Venous return
 Force of contraction
 Peripheral resistance
HEART RATE

Intrinsic Control

The heart rate is established by the SA node

Extrinsic Control.

The Sino atrial node and AV nodes are innervated by the autonomic nervous system (ANS). The
ANS innervation affects the membrane's permeability to Ca+2, Na+, and Cl+ to make
depolarization more or less difficult.

1. Parasympathetic Division

Innervation via the Vagus Nerve which innervates both the SA & AV nodes. It is responsible for
a decrease in heart rate by slowing the depolarization to threshold. There is no significant
ventricle vagal innervation. It also increases AV nodal delay thus prolonging the transmission of
impulses to the ventricles making the delay even longer than the usual AV nodal delay. The
neurotransmitter is acetylcholine via muscarinic receptors
This intrinsic regulation of heart pumping is known as the Frank-Starling Mechanism. This
mechanism states that the greater the heart muscle is stretched during filling, the greater is the
force of contraction and the greater the quantity of blood pumped into the aorta. It can also be
stated that within physiologic limits, in a normal heart, the heart pumps all the blood that
returns to it by the way of the veins.

2. Sympathetic Division

The sympathetic system innervates the atria (including SA & AV nodes), and richly innervate
the ventricles as well. It results in increase in the rate of depolarization to threshold in the SA
node and reduces AV nodal delay. The neurotransmitter involved here is norepinephrine via β1
receptors

3. Hormones

Hormones can affect heart rate as well. Epinephrine released by the adrenal medulla affects the
heart rate just as the sympathetic division. Emotional states affect the ANS & hormone release
as well.

4. Ionic balance

An increase in the influx of Ca+2 & Na+ increases the rate of depolarization of the SA node thus
resulting in increased heart rate.

An increase in the efflux of K+ and a decrease in the influx of Ca+2 hyperpolarizes the cell with
resultant decrease in heart rate

5. Drugs

Sympathomimetics

Drugs mimicking the effect of sympathetic nervous stimulation will result in effects similar to
sympathetic division – increase in heart rate

Parasympathomimetics
Drugs mimicking the effect of parasympathetic nervous stimulation will result in effects similar
to parasympathetic stimulation – decrease in heart rate

Sympathetic and Parasympathetic blocking agents

Reverse the effects of sympathetic and parasympathetic respectively

7. Physical Factors:

 Age
Heart rate decreases over lifetime

 Gender: Heart rate is normally higher in females as compared to males

 Exercise
Heart rate increases during exercise (explained later). Conditioned athletes have lower resting
heart rate and this is because they have a more efficient heart

 Body temperature
Diffusion and enzyme activity is slower at lower temperatures with resultant decrease in heart
rate while the reverse is the case.

Stroke volume

Stroke volume is the amount of blood pushed out of the heart upon contraction.

End-diastolic volume is the amount of blood that fills in the heart after relaxation and just
before the next contraction.

End-diastolic pressure (preload) is the pressure present before a contraction. It indicates the
extent of cardiac muscle stretching and determines the force at which the blood can be pushed
out during contraction.

Myocardial contractility is the ability of the heart muscle to push out blood upon contraction. It
is essentially the strength of the heart muscle to produce force.
Systolic aortic pressure is the pressure of the blood that is pushed out of the heart which will
be at its greatest immediately after the blood leaves the heart and enters the aorta.

Stroke volume and systolic aortic pressure is a combination of end-diastolic volume, end-
diastolic pressure and myocardial contractility.

If any of the above factors are affected or impaired, the cardiac output can be reduced. This
means that the sufficient blood will not be circulated throughout the body at a pressure that
will maintain a healthy circulation and perfusion.

Maintaining and regulating cardiac output, which is usually proportional to the tissues' need for
oxygen and other nutrients, is one of the circulatory system's most intricate functions.

Measurement of cardiac output makes possible an evaluation of respiratory exchange, i.e., the
delivery of oxygen to the tissues. The cardiac output represents the volume of blood that is
delivered to the body, and is therefore an important factor in the determination of the
effectiveness of the heart to deliver blood to the rest of the body, (i.e., determining heart
failure, inadequate circulation, etc).

Venous return

Venous return

This is the quantity of blood flowing from the veins in to the right atrium per minute. The
relationship of venous return and cardiac output is that they must be equal to each other in a
normal heart with the exceptions of a few heartbeats when blood is temporary stored in or
removed from the heart and lungs. The cardiac output will be determined by several factors
such as the body size, age, the basic level of body metabolism and exercise.

Cardiac Index

Cardiac output increase proportionately with body surface area. Cardiac index is stated as the
Cardiac Output per square meter of body surface area. In a normal human being with a weight
of 70kg:-

Body Surface Area (BSA) = 1.7 square meters

C.I = 3L/min/m2 of BSA

Age

Cardiac index rises with age up to 10 years (> 4L/min/m2) and then declines to about
2.4L/min/m2 of BSA at age 80 yrs. Declining CI is indicative of declining activity with age

Regulation of Cardiac output

Primer control is venous return and not the heart itself. It is controlled by peripheral factors of
the circulation that determine venous return. This is because the heart has an built in-
mechanism that pumps automatically all the blood that flows in to the right atrium from the
veins.

When there is increased quantities of blood flow into the heart, this stretches the walls of the
heart chambers. The result is that the cardiac muscles contract with increased force. They
empty extra blood entered from the systemic circulation. Therefore the blood that flows into
the heart is automatically pumped without delay into the aorta and flows again through the
circulation. This is the Frank – Starling law of the heart which states that in a healthy heart with
normal cardiac output, the amount of blood that is pumped out of the heart (stroke volume)
should return in full (end diastolic volume). The greater the volume of blood that leaves the
heart, the greater the volume that will return and vice versa. If less blood returns that what was
pushed out, then the cardiac output will decrease.

In addition, the stretching the heart results in the stretching of the sinus node in the wall of Rt
atrial wall which will affect rhythm directly resulting in an increase of 10-15% in the heart rate.
This further helps to increase the emptying of ventricles.

Long term CO control varies reciprocally with changes of total peripheral resistance

CO = Arterial pressure/Total peripheral resistance

Venous return

Three principal factors

Affect VR to the heart from the systemic circulation

Right atrial pressure

Right atrial pressure exerts a backward force on the veins which impedes flow of blood from
the veins in to the right atrium. When the right atrial pressure is equal to 7mmHg venous return
decreases to zero. Both arterial and venous pressures come to equilibrium when all flow in the
systemic circulation ceases at pressure of 7mmHg which is Mean Systemic Filling Pressure (Psf).
When Rt atrial pressure < 0mmHg further increase in VR ceases. When Rt atrial pressure falls to
-2mmHg and even more negative VR reaches a plateau
Plateau is caused by the collapse of the veins entering the chest. This is caused by sucking effect
of the negative Rt atrial pressure.

Mean circulatory filling pressure & its effect on venous return

When blood flow in the circulation ceases for a few second after heart pumping has been
stopped, the pressures every where in the circulation becomes equal. This pressure is called the
Mean Circulatory Filling Pressure

The effect of blood on Mean circulatory filling pressure

The greater the volume of blood in the circulation the greater is the mean circulatory filling
pressure. This is because extra blood volume stretches the walls of the vasculature. At 4000mL
the MCFP is close to zero. This is the unstressed volume of circulation. At 5000mL the mean
circulatory filling pressure is the normal value of 7mm Hg. At higher volume the pressure
increases linearly.

The effect of sympathetic stimulation on Mean circulatory filling pressure

Sympathetic stimulation increases the mean systemic filling pressure since it decreases the
capacity of CVS by constricting all the systemic blood vessels, larger pulmonary blood vessels &

chambers of the heart. Thus, the capacity of the system decreases so that at each level of the
blood volume the MSFP is increased. Conversely complete inhibition of the SNS relaxes both
the blood vessels and the heart decreasing the MSFP
The mean systemic filling pressure & its relationship to the mean circulatory filling pressure

The mean systemic filing pressure is slightly different from the mean circulatory filling pressure

It is the pressure measured everywhere in the systemic circulation after blood flow has been
stopped by clamping large blood vessels at the heart. This that pressures in the systemic
circulation can be measured independently from those in the pulmonary circulation. The MSFP
will be almost equal to MCFP because pulmonary circulation has less than an eight the
capacitance of the systemic circulation and only about a tenth as much as blood volume

Mean systemic filling pressure and Venous Return

Degree of filling of the systemic circulation is measured by mean systemic filling pressure. This
is the pressure measured everywhere in the systemic circulation when there is no flow of
blood. It forces blood towards the heart. The greater the mean systemic filling pressure, the
greater the tightness with which the circulatory system is filled with blood and the more the
venous return curve shift upward and to the right. Conversely, the opposite is true. This implies
that the greater the system is filled the easier it is for blood to flow in to the heart and the less
the filling, the more difficult it is for blood to flow in to the heart.
Pressure gradient for venous return

When Rt atrial pressure = mean systemic filling pressure, no different exists between the
peripheral vessels and the right atrium. As such, no blood flow from peripheral vessels to the Rt
atrium will occur. However, flow increases proportionately when Rt atrial pressure falls
progressively lower than the mean systemic filling pressure. Thus the greater the difference
between the mean systemic filling pressure and the Rt atrial pressure (pressure gradient for
venous return) the greater the venous return becomes

Resistance to venous return

Resistance to blood flow between the peripheral vessels and the right atrium mostly occurs in
the veins. Some occurs in the arterioles and small arteries as well. When the resistance in the
veins increases, blood begins to be dammed up, mainly in the veins themselves. However, the
venous pressure rises very little because the veins are highly distensible. This rise in pressure is
not very effective in overcoming the resistance and blood flow in to the right atrium decreases
drastically. Conversely, when arteriolar and small artery resistance increase, blood accumulates
in the arteries which have a capacitance only about 1/30 as great as that of the veins. Thus,
even a slight accumulation of blood in the arteries causes the pressure to increase greatly as
compared to case in veins. And this high pressure does overcome much of the increased
resistance. Mathematically resistance to venous return is determined two thirds by the venous
resistance and about a third by the arteriolar and small artery resistance.
Resistance to venous return (RVR)

VR=(MSFP-PRA)/RVR

VR= Venous Return=5L/m

Psf = mean systemic filling pressure= 7mm Hg

PRA = right atrial pressure= 0mm Hg

Therefore RVR =resistance to venous return

= 1.4 mm Hg per liter of blood flow

The Frank Sterling Law of the heart states that in a healthy heart with normal cardiac output,
the amount of blood that is pumped out of the heart (stroke volume) should return in full (end
diastolic volume). The greater the volume of blood that leaves the heart, the greater the
volume that will return and vice versa. If less blood returns that what was pushed out, then the
cardiac output will decrease. It simply states that the heart will pump all the blood that is
brought to it. This will mean that the more the blood coming to the heart, the more the force of
pumping This is an important concept to understand in order to identify the type of heart
failure and identify the cause of reduced cardiac output. The force of ventricular contraction is
directly proportional to initial length of muscle fibers. Starling's law describes the relationship
between end-diastolic volume and stroke volume. It states that the heart will pump out
whatever volume is delivered to it. If the end-diastolic volume doubles then stroke volume will
double. What goes into the heart comes out. Increased heart volume stretches muscles and causes
stronger contraction. In addition to this, stretch increases heart rate as well. It also has direct effect on
sino-atrial node

Preload: This is the degree to which cardiac muscle cells are stretched by the blood entering the
heart chambers. It is the amount of blood at the end of diastole (the period of filing). It is
directly proportional to End Diastolic Volume. (End Diastolic Volume is the amount of blood
remaining in ventricles at the end of diastole). The greater is preload; more is length of muscle
fibers (as per Sterling law). DV is increased by greater venous return. Therefore the more is pre
load, the more is force of myocardial contraction. This means that any factor that increases
venous return (hence EDV) will increase the force of contraction of the myocardium hence a
higher Stroke volume (NOTE- IN A NORMAL HEART). Sympathetic stimulation will constrict the
veins returning pooled venous blood to circulation hence increased SV. Other factors which
favor increased venous such

- Increased muscle pump

- Increased respiratory pump as in exercise

- Increased venous pressure

will all result in increase in EDV hence increased contractility and increased stroke volume
The heart normally pumps the blood returned to it. Therefore, the more blood that is returned
to the heart (venous return) the higher the EDV and therefore the higher the stroke volume.

The extent of cardiac filling is referred to as the “preload. It is called the preload, because it is
the work load imposed on the heart before contraction even begins
Afterload

Increased sympathetic stimulation

Increased sympathetic stimulation (due to fright, anger, etc.) increases the heart rate. It also
increases stroke volume by increasing contractility, which results in more complete ejection of
blood from the heart (lower ESV).

Increased parasympathetic stimulation

Parasympathetic activity increases after a crisis has passed. This reduces heart rate and stroke
volume from their high levels, bringing cardiac output back to normal.

Increased Venous Return

Cardiac muscle fibers are stretched by increased blood volume returning to the heart
(increased venous return and EDV). Increased stretch results in greater force of contraction,
which increases stroke volume.

Slow or fast heart rate

Slow heart rate allows for more time for ventricular filling, increasing EDV and therefore stroke
volume. Extremely rapid heart rate results in low venous return and therefore decreased stroke
volume.

Exercise
Exercise activates the sympathetic nervous system, increasing heart rate, contractility, and
stroke volume. Both the higher heart rate and squeezing action of skeletal muscles on veins
increase venous return, contributing to increased stroke volume

Sudden drop in blood pressure

A sudden drop in blood pressure results in low venous return and therefore decreased stroke
volume. However heart rate increased due to sympathetic activity, and normal cardiac output
is maintained.

Rising blood pressure

Rising blood pressure reduces sympathetic activity, decreasing heart rate. High blood pressure
also increases arterial pressure which ventricles must overcome before semilunar valves open,
increasing ESV and decreasing stroke volume. Reduced cardiac output helps bring blood
pressure down to normal levels.

• Sudden Drop in Blood Volume - A sudden drop in blood volume (eg. due to severe blood loss)
results in low venous return and therefore decreased stroke volume. Sympathetic activity
increases heart rate, maintaining cardiac output.

Excess Calcium - Excess calcium can lead to spastic heart contractions, an undesirable
condition. Calcium also increases stroke volume by enhancing contractility.

Heart Rate: SNS stimulation increases heart rate, PSNS reduces. HR must remain within a range
to achieve adequate perfusion. Cardiac output falls if heart rate is too slow or too fast. Slowing
heart rate beyond a limit has little effect on stroke volume because most ventricular filling
occurs in early diastole anyway, so the extra time at the end adds little. Very rapid heart rate
impinges on filling time, decreasing stroke volume, and hence cardiac output. So extreme
bradycardia or tachycardia require correction (pharmacological or electrical).

Preload
Preload is the degree to which cardiac muscle cells are stretched by the blood entering the
heart chambers. According to the Frank-Starling law of the heart, the more the chamber is
stretched, the greater the force of its contraction. Because end-diastole volume (EDV) is a
measure of how much blood enters the ventricles, the EDV is an indicator of ventricle preload.
Preload is the muscle length prior to contractility, and it is dependent of ventricular filling (or
end diastolic volume.) This value is related to right atrial pressure. The most important
determining factor for preload is venous return.

Afterload

If output resistance is high, a standard contraction will force out less blood than normal.
Starling's law remedies this problem. Higher output resistance overwhelms one beat forcing
some blood to remain in the ventricle; thus, for the next beat the ventricle will be extra full, so
next beat will be more forceful. Afterload is the tension (or the arterial pressure) against which
the ventricle must contract. If arterial pressure increases, afterload also increases. Afterload for
the left ventricle is determined by aortic pressure, afterload for the right ventricle is determined
by pulmonary artery pressure. Afterload is a measure of the pressure that must be generated
by the ventricles to force the semilunar valves open. The greater the afterload, the smaller the
stroke volume. Arteriosclerosis (narrowing of the arteries) and high blood pressure increase
afterload and reduce stroke volume.

The total amount of blood flow circulating through the heart, lungs and all the tissues of the
body represents the cardiac output. Most individual tissues determine their own flow in
proportion to their metabolic rate. The skin is a notable exception where the priority is thermal
rather than metabolic. Renal blood flow and metabolic rate are related but plasma flow
determines metabolic rate rather than metabolic rate determining blood flow. Brain, heart,
skeletal muscle and the splanchnic area all vary their blood flows according to local tissue
metabolic rate. Summation of peripheral blood flows constitutes venous return and hence
cardiac output

How (TPR)Total Peripheral Resistance effects CO

Cardiac output is therefore, largely, determined by the metabolic rate of the peripheral tissues;
the heart ‘from a flow standpoint, plays a “permissive” role and does not regulate its own
output’. This peripheral tissue, largely metabolic, determination of cardiac output has been
known for many years.

Cardiac output regulation

Contractility
Contractility (neural and humoral regulation)

Sympathetic nerve (norepinephrine) or the epinephrine and norepinephrine (adrenal gland)

enhance the strength and the velocity of the cardiac contraction. The change of myocardial
property is independent of the preload. This is contractility and it is important in exerting a long
time influence on the cardiac output. Sympathetic nerve stimulation increases cardiac
contractility. At rest the heart is under sympathetic tone. Noradrenaline enhances calcium
entry into cardiac cells. Parasympathetic stimulation has little effect on contractility due to the
innervation pattern of the heart (very minimal PSNS innervation to ventricles)
Read

1. Read Ganong’s Review.of.Medical.Physiology chapter 31

2. Guyton’s Textbook of Medical Physiology Pages 427-459.

3. Berne and Levy principles of physiology chapter 19

4. Human physiology: the mechanisms of body function by Vander, Arthur J. Chapter 14 , Section
C

5. Medical physiology: a cellular and molecular approach, Chapter 23

References

i) Guyton, A. & Hall, J. E (2016). Textbook of Human physiology, (13th Edition). Elservier
(Philadelphia)
ii) William F. Ganong. (2016). Review of Medical Physiology. (25 th Edition). McGraw Hill (New
York)

iii) Walter F. Boron, Emile L. Boulpaep. (2009). Medical Physiology, A Cellular and Molecular
Approach (2nd Edition). Elsevier (Philadelphia)

iv) Levy, Mathew N. (2008). Berne and Levy Principles of Physiology. (6 th Edition). Elsevier
(Philadelphia)

v) Vander, Arthur J. (2001). Human physiology: the mechanisms of body function. (8 th Edition).
McGraw Hill (Boston)