Cardiovascular Physiology

A Text and E-Resource for Active Learning

 Cardiovascular Physiology
A Text and E-Resource for Active Learning

Burt B. Hamrell
Emeritus Professor, Department of Molecular Physiology and Biophysics,
College of Medicine, University of Vermont, Burlington, Vermont
CRC Press
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 Contents

Preface vii
Goals ix

SECTION I  CARDIAC ELECTRO­PHYSIOLOGY AND THE ELECTRO­CARDIOGRAM (ECG) 1

1 Ventricular myocyte electrophysiology 3
Resting potential 3
Action potential 5
2 Cardiac electrical activity elsewhere than in ventricular muscle cells 9
Sinoatrial (SA) node 9
Atrial myocytes 11
Atrioventricular (AV) node 12
Bundle of His, bundle branches, and Purkinje myocytes 12
3 Physiological consequences of ionic mechanisms 15
Pacemaker hierarchy and latent pacemakers 15
Conduction velocity 16
Refractory period 17
Influence of extracellular K+ concentration on the transmembrane potential (Vm) of ventricular
and atrial myocytes 19
4 Control of heart rate 21
Parasympathetic 21
Sympathetic 21
5 Electrical properties and cardiac myocyte structure 23
6 Conduction of electrical activity in the heart 25
Gap junction function 25
Conduction sequence in the heart 25
7 Electrocardiogram 29
Overview 29
ECG waves 30
Standard lead system 31
Monitoring leads 35
Frontal plane vectors 35
Mean electrical axis 41
Precordial leads 41
ECG patterns of normal and abnormal heart conduction 42
ECG patterns of abnormal rhythms: Arrhythmias 49
Mechanisms of arrhythmias 52

SECTION II  CARDIOVASCULAR SYSTEM 59

8 How the circulation works 61
Blood pressure 61
Energy 61
Flow 62
v
 Contents

Blood flow types 64

Blood flow velocity in the circulation 67
Clinical significance 67
9 Cardiac cycle, heart sounds, and murmurs 71
The circulation 71
Cardiac valves 71
Atrial and ventricular phases of the cardiac cycle 71
Normal intravascular pressures in people 75
Heart sounds 75
Murmurs during the cardiac cycle 78
10 Ventricular function 83
Preload 83
Contractility 85
Afterload 88
Examples of changes in ventricular function 90
Ejection fraction 91
Passive (diastolic) pressure-volume relation 91
Control of the heart in vivo: A study summary 93
11 Peripheral circulation 95
Mean arterial pressure and pulse pressure 95
Resistance 100
Blood volume distribution 103
12 Circulatory controls 105
Introduction 105
Arterial neural baroreceptors 105
Hormonal controls 109
Chemoreceptors 116
Local metabolic control 116
Autoregulation 117
Arterial blood pressure and salt and water metabolism 119
Veins in circulatory control 119
Blood pressure control, the autonomic nervous system, and heart failure 120
13 Regional blood flow 121
Introduction 121
Cerebral blood flow 121
Coronary blood flow 124
Skeletal muscle blood flow 129
Pulmonary blood flow 130
Renal blood flow 132
Gastrointestinal blood flow 132
Cutaneous blood flow 132
14 Microcirculation 135
Arterioles 135
Capillaries 135
Metarterioles 135
Postcapillary resistance 136
Nature of blood flow in the microcirculation 136

References for additional reading 143

Index 145

vi
 Preface

The current emphasis in medical school teaching is on more active learning experiences in the
basic sciences. Teachers are being asked to tell less and facilitate more active student learning.
Students are being urged to reduce their expectation of being told what to learn and, instead,
to learn how to learn. Hopefully, learning then becomes a lifelong skill. Patients rarely have
symptoms and other findings as described in textbooks, they often respond differently than
uniquely to treatment, and treatment and disease information changes continually. A com-
petent physician cannot remain passive, but must actively pursue learning related to patient
problems. The competent physician continually actively learns and thinks.
Teachers are being urged to enhance their skills developing goals and objectives and struc-
turing student self-learning experiences. Student active learning source material often consists
of traditional resources such as instructor’s notes, textbooks or monographs, or current litera-
ture such as review articles. Used creatively, these materials can stimulate students to learn
how to learn. However, the electronic self-study modules presented here are not the traditional
material for discussion, but a learning resource that excites and engages the student learner.
Today’s student learners have grown up discovering information presented as electronic text,
images, animations, and videos. Fortunately, contemporary cardiovascular medicine is awash
with patient data presented as dynamic images, which can be configured, for instance, as ani-
mations that stimulate students to inform themselves and are optimally presented in an elec-
tronic format.
The electronic self-study modules presented here are active, self-learning, individually-
paced experiences. The text that follows serves as a reference source for the self-study modules.
The self-study modules include references to related parts of the text. The modules also include
frequent opportunities to choose to review concepts. Study question sets are included for self
assessment. The modules are designed to stimulate informal discussion among students and
are a superb vehicle for stimulating discussion in small group sessions. I use them in this way
in my teaching and they are uniformly successful.
The organization of the text and active learning modules follows the sequence of events in
each heartbeat. The electrophysiological basis of activation of the heart and the heart’s electrical
activity as manifest in the electrocardiogram are presented first. Then the discussion proceeds
to cardiac mechanical activity followed by the circulation of blood. The three-part self-study
module on cardiac muscle mechanics should be studied before learning about ventricular func-
tion. Likewise, it is important to learn about the cardiac cycle early on since the terminology
for describing pressures and flow is derived from the phases and events in the cardiac cycle.
The discussion of ventricular function precedes that of the peripheral circulation, circulatory
controls, and regional circulations. The text concludes with a discussion of the microcirculation
with emphasis on the dynamics of transcapillary fluid exchange and edema formation. The text
also refers the reader to relevant self-study module presentations and, as noted above, each
module cues the reader to relevant text material.
The self-study module on the pathophysiology of hypovolemic shock is included as a com-
pelling emergency clinical problem, the discussion of which provides an excellent review of

vii
 Preface

most of cardiovascular physiology. Likewise, the discussion of chronic heart failure following
a myocardial infarction emphasizes the importance of using knowledge of the cardiac cycle,
cardiac muscle function, ventricular function, circulatory controls, and the physiology of the
peripheral circulation to help a patient.

Burt B. Hamrell
Westford, Vermont, 2016

viii
 Goals

SECTION I  CARDIAC ELECTRO­PHYSIOLOGY AND THE

ELECTRO­CARDIOGRAM (ECG)
After studying the self-study modules and referring to the text material you should be able to
discuss and explain the following:
• Characteristics of cardiac action potentials, including how ionic currents contribute to
each phase of the action potential.
• Why a ventricular cardiac action potential has a long duration and refractory period and
how that is an advantage for maintaining normal rhythmicity.
• Locations and ionic mechanisms of pacemaker function, and the role of neural and
humoral influences on pacemaker function.
• Normal sequence of cardiac activation and the role played by specialized muscle cells.
You should be able to discuss and explain the consequences of abnormal conduction at
any point in the sequence.
• Atrioventricular node function and its role in the sequence of conduction. You should
be able to discuss and explain the advantages of normal slow conduction through the
atrioventricular node and what factors determine the speed of conduction.
• Effects of sympathetic and parasympathetic activity on heart rate, conduction, and
cardiac excitation, and the ionic and other cellular mechanisms of these effects.
• Clinical usefulness of an ECG and how the usefulness is related to the use of a standard
electrode configuration, which you should be familiar with.
• Components of an ECG waveform and the relationship of the waves, intervals, and
segments to the simultaneous cellular electrical events occurring in the heart.
• What a dipole and vector are and how dipoles generated by the heart are reflected in the
ECG recording. Be able to discuss and explain ECG waveform configuration.
• Mean electrical axis of the heart and its clinical significance. You should be able to
estimate the direction of the mean electrical axis from frontal ECG lead recordings.
• Normal electrical conduction in the heart and the mechanisms of some conduction
defects and their ECG manifestations.
• Common arrhythmias and the mechanisms of how reentry and triggered activity can
cause arrhythmias.

SECTION II  CARDIOVASCULAR SYSTEM

After studying the self-study modules and referring to the text material you should be able to
discuss and explain the following:
• How the blood normally circulates and some examples of abnormal blood flow. Discuss and
explain streamline and turbulent flow, why they occur and why they are clinically relevant.
ix
 Goals

• Normal cycle of cardiac activity and selected changes from normal.

• Normal and abnormal heart sounds and murmurs.
• Cardiac muscle function, including excitation–contraction coupling and the mechanics
of contraction. You should be able to discuss and explain how resting muscle length
influences force development and shortening, what contractility is and how it influences
cardiac muscle function, and the relationship of cardiac muscle function to ventricular
function.
• Ventricular afterload, preload, and contractility and how they influence ventricular
function. You should be able to discuss and explain ventricular function curves and
pressure–volume loops and how they are used to evaluate ventricular function.
• Ejection fraction and other measures of ventricular function, and some of the
mechanisms of ventricular dysfunction in heart disease.
• Control of cardiac output in normal people and how it might be altered in disease,
including the role of the autonomic nervous system.
• Relationship of cardiac output to body metabolism and the Fick principle.
• Arterial and venous pressures and their determinants, vascular resistance and peripheral
runoff, and how these parameters change normally, such as in dynamic exercise, and in
disease.
• Formulas that are used to assess the relationships among pressure, flow, and resistance in
the systemic and pulmonary circulations and in flow through organs. You should be able
to apply Poiseuille’s law to understand normal and abnormal organ blood flow.
• Local and feedback circulatory control systems and selected abnormalities.
• Characteristics of normal organ blood flow, the function of the microcirculation, and
selected pathophysiology. You should be able to discuss and explain transcapillary fluid
exchange and how it can change with disease, and the function of the lymphatic system.
• Integrated functions of the cardiovascular system as they are manifest in a life-
threatening problem such as hemorrhage with hypovolemic shock.

x
 CARDIAC ELECTRO­
PHYSIOLOGY AND THE
SECTION

I
ELECTRO­CARDIOGRAM
(ECG)

Many drugs act on heart muscle by changing ion movement across the sarcolemma,
the cardiac muscle cell external membrane. This is also true of many drugs that are
not intended to affect the heart, but do so as a “side effect.” Sarcolemmal function
is often altered in heart disease and abnormal heart rhythms, or arrhythmias, can
result. There are genetic cardiac ion channel abnormalities, channelopathies, which
can lead to arrhythmias, including life threatening arrhythmias and sudden death
in young people. Also, drug effects on ion channel function can result in dangerous
arrhythmias. An understanding of cardiac electrophysiology is central to under-
standing cardiac pathophysiology and drug effects on the heart.
 Ventricular myocyte
electrophysiology
1

RESTING POTENTIAL
There are many positive and negative ions in the cell cytoplasm. Also, there are proteins in the
cytoplasm with negative surface charges. Most of the positives and negatives interact as charge
pairs to maintain electroneutrality. If every positive and negative ion were paired, the resting
membrane potential would be zero. However, in resting ventricular muscle cells the electri-
cal potential difference across the membrane, the resting transmembrane potential or resting
potential, is about −80 to −90 mV (Figure 1.1). The negative sign indicates that the inside of
the cell is negative with respect to the outside. The inside of the ventricular myocyte is nega-
tive mostly due to a slight deficit of potassium ions (K+) inside the cell. This is because a small
number of K+ have left through open K+ selective channels. Negative ions cannot accompany
these K+, leaving a small number of negative ions within the myocyte with no positive ion to
associate with. Please note the emphasis on the word “slight.” The key to understanding the
genesis of a transmembrane potential is to realize that movement of very few ions across the
sarcolemma is what is important; there is no measurable change in ion concentration inside or
outside the myocyte. This is presented with animations in the self-study module Cardiac
e
Action Potentials, Part 1: Ventricular and Atrial.
Charge separation by the sarcolemma with fewer positive than negative charges inside the
cell can occur in the resting cardiac myocyte if two conditions are met:
• There are open sarcolemmal ion selective channels, the K1 channels, selective for K+.
These channels are neither voltage nor ligand gated, are continuously open, and can be
called “leak” channels.
• There is a large K+ concentration gradient with the K+ concentration inside much higher
than outside. A concentration gradient is critically important; a significant concentration
change is not an important factor.

Since the K1 channels are selective for K+, no ion can move with K+ through the K1 channel.
The K+ moving out are attracted by the negative polarity of the cell interior and likely remain
on the outside of the sarcolemma. Those negative ions inside the cell that lack a positive ion
to associate with are attracted to the inside of the sarcolemma because of the positive exterior.
Negative ions lining the inner surface of the sarcolemma and positive ions on the outer surface
give rise to an electrical potential difference across the sarcolemma, the across-the-membrane
or transmembrane potential.

3
 Ventricular myocyte electrophysiology

The outward movement of K+ is opposed by the negative voltage that develops inside and
the positive that develops outside the electrical gradient. That is why so few K+ leave the cell.
K+ move out due to the concentration gradient and move in due to the electrical gradient. The
concentration gradient is balanced by the electrical gradient at the K+ equilibrium potential,
which is slightly more negative than the −80 to −90 mV resting potential in ventricular muscle
cells. The K+ equilibrium potential is not reached because the sarcolemma is somewhat perme-
able to other ions, discussed below.
In healthy ventricular muscle cells bathed in an oxygenated interstitial fluid-like solution,
the resting potential is stable (Figure 1.1, top graph, labeled 4) and does not change until an
adequate electrical stimulus is applied to the muscle. This is presented in the self-study
e modules Cardiac Action Potentials, Part 1: Ventricular and Atrial and Part 2: Nodal and
Conduction System Myocytes.

Time (msec)
Membrane potential (mV)

0 100 200 300 400

+20 1 2
0
–20
3
–40 0
–60
–80 4
–100

0
Sodium
current

INa

0
Calcium
current

ICa

ICl
Chloride
current

0
Ito
IK1
IK1
Potassium
current

IK
0

0 100 200 300 400

Time (msec)

Figure 1.1  Ventricular action potential and ionic currents. (From Katz AM. Physiology of the Heart. 2nd ed.
New York: Raven Press; 1992. With permission of Wolters Kluwer, Lippincott Williams & Wilkins.)

4
 Action potential

ACTION POTENTIAL
A ventricular muscle cell action potential develops in response to an adequate electrical stimu-
lus. Adequate refers to an electrical stimulus that moves the transmembrane potential to a less
negative value, less negative than about −65 mV, where fast Na+ channel external gates begin
to open. Once started, a ventricular action potential lasts roughly 250–300 ms—much longer
than a nerve or skeletal muscle action potential. The sequential portions of a cardiac muscle
action potential are labeled with numbers from 0 to 4 (Figure 1.1).

PHASE 0
Phase 0 is the initial rapid depolarization* or upstroke that occurs and initiates an action poten-
tial. As noted above, an adequate stimulus moves the resting potential to a less negative level
that triggers the opening of fast Na+ channels. Ventricular muscle phase 0 is not substantially
different than depolarization in nerve and skeletal muscle.
An adequate stimulus causes voltage gated, ion selective fast Na+ channels to open. The
Na concentration is very low intracellularly, but is high in the extracellular fluid. The opening
+

of Na+ selective channels leads to a rapid influx of a small number of Na+ ions without accom-
panying negative ions. This large sodium current,† I Na, rapidly depolarizes the cell (Figure 1.1).
The transmembrane voltage moves from negative to positive within 1–2 ms and reaches a peak
(Figure 1.1).
L-type Ca 2+ channels are triggered to open during phase 0 when the transmembrane poten-
tial reaches −40 to −50 mV. These Ca2+ channels are slower to open and there are fewer of
them than fast Na+ channels so their contribution to phase 0 is small. The Ca 2+ current plays a
major role during phase 2, discussed below.
Depolarization stops at the peak of phase 0 at about +20 to +30 mV. Depolarization does
not reach the equilibrium potential for Na+ (approximately +70 mV) because the Na+ current
decreases and a K+ current develops.
The Na+ current decreases for two reasons:

• The inside of the cell becomes positive and this reduces the electrical potential driving
force for the inward movement of Na+.
• Depolarization rapidly inactivates Na+ channels.

Both above factors contribute to a cessation of the voltage rise in phase 0.

A K+ current develops for two reasons:
• The inside of a myocyte is positive with respect to the outside at the peak of the action
potential. Like charges repel, so the inside positive “pushes” K+ out of the cell.

* Depolarization indicates movement of the transmembrane potential in a positive direction; repolariza-

tion and hyperpolarization indicate movement in a negative direction.
† In the convention used by electrophysiologists, movement of positive ions into a cell is a negative current.

That is why the Na+ current in Figure 1.1 is shown moving downward. That can be confusing for other
than an electrophysiologist, so I do not use the negative/positive current terminology. Simply read the
graph for the sodium current as showing a rapid increase due to Na+ moving inward followed by a rapid
decrease as Na+ channels deactivate. For the Ca 2+ current there is a slow increase due to Ca 2+ moving
inward, then a slow decrease.

5
 Ventricular myocyte electrophysiology

This alone would repolarize the membrane as I Na decreases, but in addition,

• Phase 0 depolarization causes voltage-gated K+ channels to open.

One such channel is the transiently outward or “to” channel. K+ conductance transiently
increases (Figure 1.1, bottom graph, Ito, a transient outward K+ current). K+ moving out of the
cell is part of the reason phase 0 depolarization ceases at about +20 to +30 mV. Ito also contrib-
utes to repolarization in the next phase, phase 1. “K” channels are opened by phase 0 depolar-
ization. “K” is the name of the channel and is not an abbreviation for potassium; K channels
are distinct from the K1 channels. K channels are slow to organize and contribute little to the
overall K+ current until phases 2 and, particularly 3, discussed in more detail below.

PHASE 1
This is an initial repolarization following phase 0. It partially repolarizes the cell mem-
brane from about +20 mV to just above 0 mV (Figure 1.1). This initial, brief repolarization is
­dependent on:
• Fast Na+ channel inactivation.
• Ito, described above, an outward movement of K+ ions through Kto channels.
• A small transient increase of Cl− conductance triggered by depolarization. The extra­
cellular concentration of Cl− is much greater than inside the myocyte. Cl− moves down its
concentration gradient into the cell through briefly open ion selective Cl− channels.

PHASE 2
After phase 1, repolarization slows dramatically to form phase 2, the plateau phase of the car-
diac, action potential (Figure 1.1). It is a plateau, but not a perfectly flat plateau. During the pla-
teau myocytes gradually repolarize for 100–200 ms. A plateau occurs primarily due to a partial
balance of K+ moving out of and Ca 2+ moving into the myocyte (Figure 1.1).
Ito, a transient outward K+ current, is important during phase 1, but the Ito channels deacti-
vate early in phase 2 (Figure 1.1). The overall K+ current decreases early in phase 2, but does not
disappear. The reason that a small net K+ current persists is related primarily to a persistent K1
channel current and a small contribution from the K channels.
K1 potassium channels, important for the resting potential, are rectified by depolarization.
Rectification refers to a change in K1 channel function induced by depolarization such that K+
ions do not as readily move through the K1 channels. The K1 channels are not closed, but are
altered such that K+ conductance is reduced. The decrease in overall K+ current is due then to
Kto channels deactivating and rectification of K1 channels (Figure 1.1).
Another reason the net K+ current remains above zero during phase 2 is due to the slow
(very slow) to activate K channels opened by depolarization during phase 0. Ventricular myo-
cyte K channels consist of K r and K s components. Individual K r and K s components of the K
channel current are not shown in Figure 1.1. The current due to the K channels takes a long
time to become fully manifest. I K does contribute in a small way to the net K+ current during
phase 2, but will play a key role during phase 3, when I K is fully manifest. Remember, “K” here
is not an abbreviation for potassium, but is the name of the channel.
As noted above, the L-type Ca 2+ channels are voltage gated channels that open in response
to depolarization to about −40 to −50 mV during phase 0. They begin to open during phase 0,

6
 Action potential

but are slower to open than the fast Na+ channels. ICa reaches a maximum early in the plateau
and produces a depolarizing current. The presence of a net K+ current pushes the transmem-
brane potential toward the negative. Ca 2+ moving into the myocyte nudges the transmembrane
potential toward the positive. The net effect of K+ moving out and Ca 2+ moving in is an almost
steady transmembrane potential, the plateau. Inactivation of Ca2+ channels is slower than for
Na+ channels so the fall of the Ca 2+ current is slow (Figure 1.1).
There is an electrogenic Na+-Ca 2+ exchange channel in the sarcolemma in which one Ca 2+
moves out of the myocyte for 3 Na+ in. That is three positive charges in for two out, three
Na+ in for one Ca 2+ out. This is a depolarizing current. Ca 2+ comes in through the L-type Ca 2+
channels with each action potential so this exchange is important for preventing myocyte Ca2+
overload.
In summary, the ionic basis of the plateau is mostly explained by Ca2+ moving in and K+
moving out. Some Na+ ions move in as well.
The plateau portion of the ventricular action potential is important for two major reasons:

• Fast Na+ channels remain inactivated during the plateau. The transmembrane poten-
tial during the plateau hovers at close to 0 mV. Na+ channels remain inactivated at this
trans­membrane voltage and normally another action potential cannot be induced. This
accounts for the long duration of refractoriness in ventricular myocytes. The long dura-
tion of refractoriness prevents extra depolarizations from occurring.
• Intracellular Ca 2+ concentration increases. The small amount of Ca 2+ that enters
through the L-type sarcolemmal channels during the plateau triggers release of
substantial amounts of Ca 2+ from the terminal cisternae of the sarcoplasmic reticulum.
This Ca 2+-induced-Ca 2+-release results in the large increase in cytoplasmic Ca 2+ that
initiates contraction. This small inward movement of Ca 2+ and the significant increase
in internal Ca 2+ concentration due to Ca 2+-induced-Ca 2+-release is an exception to
the rule that during an action potential there are no measurable changes in ionic
concentrations.

As mentioned above, Ca 2+ leaves the myocyte through a sarcolemmal Na+-Ca 2+ exchanger.

Also, there is an active, ATP-energized pump that transports Ca 2+ across the sarcolemma out of
the myocyte. The net result of these processes is that a normal myocyte does not get overloaded
with Ca 2+. The emphasis here is on “normal.” Ca 2+ overload can cause arrhythmias in heart
disease and drug treatments and is covered in a later section on arrhythmias.

PHASE 3
The plateau ends and phase 3 begins with acceleration of repolarization (Figure 1.1). The return
of the transmembrane potential from the plateau to the resting level is phase 3 (Figure 1.1,
upper graph). Phase 3 repolarization is dependent on changes in K+ and Ca 2+ currents.
The overall K+ current increases during phase 3 (Figure 1.1) as the I K (K r and K s) channels
reach full activation. I K is the predominant repolarizing current. Congenital and acquired mal-
function of the K r or K s channel is one cause of life-threatening arrhythmias or sudden death.
One type of clinical problem is called the long QT syndrome and is discussed in a later section
on arrhythmias.
During depolarization, rectification reduced the K1 current. Repolarization reverses rec-
tification and K+ movement through the K1 channels increases. IK1 then contributes to phase 3

7
 Ventricular myocyte electrophysiology

repolarization. Ca 2+ channels gradually inactivate and the inward movement of Ca 2+ decreases,

and this decrease in positive ions moving into the myocyte also contributes to phase 3
repolarization.

PHASE 4
The interval between action potentials, when the membrane potential of a ventricular cell is at
the resting potential, is called phase 4 (Figure 1.1). Phase 4 is stable in ventricular muscle cells
due primarily to a stable I K1.

8
 Cardiac electrical activity
elsewhere than in ventricular

2 muscle cells

To this point, only ventricular muscle cell action potentials have been discussed. But action
potentials differ among the several types of heart muscle myocytes (Figure 2.1).

SINOATRIAL (SA) NODE

SA node cells depolarize in the interval between action potentials (Figure 2.2) and the most
negative voltage level, the maximal diastolic potential (MDP), is −50 to −60 mV as compared
with −80 to −90 mV in ventricular muscle cells. Diastole refers to the interval between heart-
beats. The less negative level in SA node cells than in ventricular muscle cells is partly related
to the limited expression of K1 channels in SA node cells.
Note the slow upward movement of the transmembrane potential during phase 4 from one
bottom arrow to the next in Figure 2.2. This diastolic depolarization between action potentials
during phase 4 is often termed the pacemaker potential. Diastolic depolarization during phase
4 brings the transmembrane potential to threshold and is responsible for repeated, rhythmic
SA node cell action potentials.
The upstroke of the action potential during phase 0 is slow—the rate of rise of voltage rela-
tive to time, dV/dt, is slow (Figures 2.1 and 2.2). Additionally, the peak of phase 0 is at or slightly
above 0 mV, not as high above zero as in ventricular myocytes.

PHASE 0 UPSTROKE (FIGURE 2.1)

Fast Na+ channels that cause the rapid upstroke of a ventricular muscle action potential are
either absent in SA node cells or not functional. Toward the end of diastolic depolarization
(bottom right arrow in Figure 2.2), the transmembrane potential reaches the threshold for the
opening of L-type Ca 2+ channels. The current through these L-type Ca2+ channels, not Na+
channels, produces depolarization during phase 0 in SA node cells. Phase 0 upstroke is slow
with a small amplitude, because:
• L-type Ca 2+ channels have slow kinetics.
• There are relatively few L-type Ca2+ channels in nodal cell sarcolemma.

9
 Cardiac electrical activity elsewhere than in ventricular muscle cells

Aorta

Action potential
SA node
Superior vena cava

Atrial muscle
Sinoatrial node AV node
LAF
Common bundle

Bundle branches
Atrioventricular
Purkinje fibers
node
Ventricular muscle
Bundle of His

Right bundle branch

ECG P T
U
Purkinje system QR S
0.2 0.4 0.6
Left posterior fascicle Time (s)

Figure 2.1  Action potentials throughout the heart. (Adapted from Barrett KE et al. Ganong’s Review of
Medical Physiology, 23rd ed. New York: McGraw-Hill; 2010. With permission of McGraw-Hill.)

PHASES 1 AND 2
There is no clearly identifiable phase 1 or phase 2 in an SA node action potential (Figures 2.1
and 2.2).

PHASE 3
K channels are important here just as in ventricular cells. Repolarization is due primarily to an
increasing I K and a decrease in ICa,L. The Ca2+ current decreases as Ca2+ channels deactivate.
As noted above, the contribution from K1 channels is minimal. The transmembrane potential
reaches the MDP primarily due to an increasing I K and inactivation of ICa,L. Activation of I f by
repolarization, discussed below, contributes to MDP being less negative than in non-nodal
cardiac myocytes.

Phase 0 Phase 3
Voltage

Phase 4

Time

Figure 2.2  Sinoatrial node action potential. Diastolic depolarization (pacemaker potential) occurs
during phase 4 between the two arrows. Phase 0 peaks at about zero volts.

10
 Atrial myocytes

PHASE 4
Four sarcolemmal ionic currents and intracellular Ca 2+ cycling contribute to SA node diastolic
depolarization during phase 4.
• I f is a depolarizing current during phase 4. I f channels support the slow movement
inward of primarily Na+. It is a peculiar ion channel (“f” stands for funny) in that it is
activated by repolarization. Other voltage-gated channels are activated by depolarization.
This channel also is referred to as the HCN channel: hyperpolarization-activated,
cyclic nucleotide gated channel. As noted above, the onset of I f at the end of phase 3
repolarization is one reason why the MDP is less negative than in non-nodal myocytes.
Another reason is the minimal expression of K1 channels in nodal myocytes.
• Three Na+/1 Ca2+ exchange (NCX) contributes to depolarization during phase 4 and
NCX is related to cyclic changes in myocyte myoplasmic Ca 2+ content. As noted above,
phase 0 is due to the opening of L-type Ca 2+ channels. The entry of Ca 2+ into the cell
initiates Ca 2+-induced-Ca 2+-release from the ryanodine-sensitive Ca 2+-release channels
on the terminal cisternae of the sarcoplasmic reticulum (SR).

The increase in myoplasmic Ca 2+ activates the Ca2+ pumps on the longitudinal portion of
the SR. There is a Ca2+-activated ATPase that hydrolyzes ATP and makes energy available to
the pumps. These ATP-powered pumps move Ca2+ out of the myoplasm into the SR longitu-
dinal tubules where the Ca 2+ diffuses to and is stored at high concentrations in the terminal
cisternae. SR function is presented in more detail in the self-study module Clinical Heart
e
Muscle Physiology, Part 1: Activation and Relaxation.
Recent evidence indicates that in SA node cells, the terminal cisternae Ca 2+ concentra-
tion reaches levels high enough to induce the spontaneous release of Ca 2+ from them into the
­myoplasm. This localized Ca 2+ release increases myoplasmic Ca 2+ concentration.
The increase in intracellular Ca2+ and the low intracellular Na+ concentration provide the
driving forces for one Ca2+ moving out of the cell in exchange for three Na+ moving in. Note:
three positive charges (three Na+) moving in and only two positive charges (one Ca 2+) mov-
ing out. 3 Na+ in/1 Ca 2+ out exchange produces a depolarizing current (I NCX ) including during
phase 4. Localized Ca 2+ release increases I NCX, which contributes to diastolic depolarization.
• K channels open during phase 0 and I K is important for repolarization during phase 3.
I K decreases during diastolic depolarization. This reduces the number of K+ leaving the
cell, positive charges stay in the cell, and this also supports phase 4 depolarization.
• ICa,T involves Ca2+ movement through T-type Ca2+ channels. T-type Ca2+ channels open
near the end of diastolic depolarization and contribute a brief, small depolarizing current.
The T-type Ca2+ channels have a lower threshold and smaller conductance than L-type Ca2+
channels. “T” stands for tiny conductance and for transient.

Diastolic depolarization continues until it reaches the threshold for L-type Ca 2+ channels
and another heartbeat is initiated. Nodal action potentials are presented in the self-study
e
­module Cardiac Action Potentials, Part 2: Nodal and Conduction System Myocytes.

ATRIAL MYOCYTES
The resting potential is stable near −80 mV (Figure 2.1). Normally, there is no diastolic depo-
larization. Phase 0 has a rapid upstroke (Figure 2.1) and an overshoot (movement above zero),
11
 Cardiac electrical activity elsewhere than in ventricular muscle cells

much as in ventricular cells. The upstroke is due primarily to the opening of fast Na+ channels.
The plateau slopes downward more than in a ventricular myocyte action potential (Figure 2.1)
because of two factors. K+ conductance during phase 2 and 3 is greater than in ventricular
­myocytes related to a more robust I K. Also, there is a smaller Ca 2+ current during phase 2.
The action potential is shorter than in ventricular or conduction system myocytes (Figure 2.1)
related to a prominent I K as noted above.

ATRIOVENTRICULAR (AV) NODE

The resting potential is slightly less negative (−60 to −40 mV) than in the SA node, but much
less negative than in non-nodal heart tissue. Phase 4 depolarization is present, but is much
slower than in the SA node. The mechanisms for slow diastolic depolarization are likely quali-
tatively like those in the SA node, but with much slower kinetics. The phase 0 upstroke and
peak resemble the corresponding parts of the SA node action potential (Figures 2.1 and 2.2).

IONIC BASIS OF PHASES 0 AND 3

Fast Na+ channels are absent or inactivated, like the SA node. The upstroke of the action poten-
tial is caused by the opening of L-type Ca 2+ channels as in the SA node. Similarly, there is no
identifiable phase 1 or 2. The mechanisms for phase 3 are like that in SA node cells.

PHASE 4 DEPOLARIZATION
The less negative resting potential than in ventricular myocytes and slow diastolic depolar-
ization have mechanisms like those in the SA node. There are no likely major qualitative dif-
ferences from the SA node. Quantitative differences in ionic currents result in much slower
diastolic depolarization in AV node cells than in the SA node. The SA node is the normal pace-
maker of the heart because its diastolic depolarization is faster than that of the AV node. This
is discussed further below.

BUNDLE OF HIS, BUNDLE BRANCHES, AND

PURKINJE MYOCYTES

PHASE 0
Phase 0 has a fast upstroke due to the opening of fast Na+ channels that produce a large I Na,
just as in ven­t ricular muscle. Note: even though Purkinje fibers have pacemaker activity, dis-
cussed below, they have an Na+ action potential.

PHASES 1, 2, AND 3
The mechanisms for phases 1, 2, and 3 are like those in ventricular myocytes. Phase 1 is promi-
nent and there is a long plateau (phase 2) (Figure 2.1).

12
 Bundle of His, bundle branches, and Purkinje myocytes

RESTING POTENTIAL
His and bundle branch cells have stable K1 channel conductance during phase 4 and resemble
atrial and ventricular cells in this respect. The resting potential is between −80 and −90 mV.
The phase 4 transmembrane potential is stable in His and bundle branch fibers.

VERY SLOW DIASTOLIC DEPOLARIZATION

IN PURKINJE MYOCYTES
Purkinje myocytes differ from other conduction system myocytes in that there is diastolic (phase
4) depolarization. The phase 4 diastolic depolarization is very slow. I f channels are present and
a slow increase in an Na+ current through I f channels contributes to the phase 4 depolarization.
I NCX and the opening of T-type Ca 2+ channels also contribute to diastolic depolarization. T-type
Ca 2+ channels are not normally expressed elsewhere in the conduction system or in ventricu-
lar cells. The presence of K1 channels also influences the very slow diastolic depolarization in
Purkinje myocytes. The movement of K+ out of the cell through K1 channels is a repolarizing
current that reduces the net depolarizing influence of I f, I NCX, and ICa-T.
The slight slope of phase 4 in a Purkinje myocyte action potential is not shown in Figure 3.1.
Purkinje myocyte pacemaker activity can keep the ventricles beating, albeit at a very slow rate,
if action potentials from the atria cannot get through to the ventricles (complete heart block,
discussed later).

13
 Physiological consequences of
ionic mechanisms
3

PACEMAKER HIERARCHY AND LATENT PACEMAKERS

SA NODE
This is the normal pacemaker of the heart because diastolic depolarization is faster than in
before AV node cells and much before Purkinje fibers (self-study module Cardiac Action
Potentials, Part 2: Nodal and Conduction System Myocytes). The pacemaker potential in
SA node cells normally reaches threshold before the AV node cells and much before Purkinje
fibers. The normal heart rhythm, driven by the SA node as the pacemaker, is called “normal
sinus rhythm.” The intrinsic frequency of the SA node, in the absence of input from the auto-
nomic nervous system, is about 100 beats/min.

LATENT PACEMAKERS
AV NODE
Cells in the AV node can serve as the heart’s pacemaker if, for instance, the SA node fails (self-
e
study module Cardiac Action Potentials, Part 2: Nodal and Conduction System Myocytes).
The AV node intrinsic rate, i.e., with no autonomic nervous system input, is approximately
40–60 beats/min. If these cells become the pacemaker of the heart, the patient is said to be in
atrioventricular junctional rhythm rather than normal sinus rhythm. “Junctional” refers to the
pacemaker being at the junction of the atria with the ventricular septum. This rhythm can be
diagnosed from an ECG. The AV node is innervated by sympathetic and parasympathetic nerve
fibers, like the SA node.

PURKINJE FIBERS
The intrinsic frequency of Purkinje fibers is about 25–40/min (self-study module Cardiac Action
e
Potentials, Part 2: Nodal and Conduction System Myocytes). Purkinje fibers can become the
ventricular pacemaker when there is complete failure of transmission of action potentials from
the atria to the ventricles. The resulting abnormal heart rhythm is called complete heart block,
complete atrioventricular block, or complete atrioventricular dissociation. In complete heart
block, the ventricles regularly depolarize independent of the atria at the slow frequency likely set
by a Purkinje fiber pacemaker and the atrial rate is separately set by the SA node.
15
 Physiological consequences of ionic mechanisms

CONDUCTION VELOCITY

DEFINITION
Conduction velocity is the time it takes for conduction of phase 0 from one point to another.
Notice the emphasis on “phase 0.” Conduction velocity has the usual units for velocity, dis-
tance/time, usually mm/ms.

DETERMINANTS OF CONDUCTION VELOCITY

RESISTANCE
A cell’s internal resistance is inversely proportional to its diameter—the bigger the diameter,
the lower the resistance. Cardiac cells are connected to each other at their ends. The larger the
cell diameter, the lower the resistance, the faster the transmission of phase 0 along the length
of the cell and, then, from cell to cell. Also, gap junctions lower cell-to-cell resistance and
contribute to fast conduction. Gap junctions are non-selective ion channels embedded in the
end-to-end connections of myocardial cells. They are discussed below.

PHASE 0 AMPLITUDE
A large amplitude phase 0 (again, notice the emphasis on phase 0) produces a large voltage dif-
ference between the cell being activated and the myocyte in phase 4 to which it is connected.
A large amplitude phase 0 is based on movement inward of a larger number of Na+ ions than
when phase 0 amplitude is small. The probability of Na+ ions passing to the next myocyte
through the gap junctions is increased the more Na+ ions enter during phase 0. Thus, the next
myocyte will quickly depolarize to the fast Na+ channel threshold. Similarly, Ca 2+ moves from
myocyte to myocyte through gap junctions in nodal tissues.

PHASE 0 dV/dt (VOLTAGE CHANGE PER UNIT TIME)

A fast upstroke rapidly depolarizes adjacent myocytes. In other words, a fast upstroke rapidly
raises the transmembrane potential during phase 0 toward positive levels and rapidly increases
the potential difference between depolarizing as compared with connected resting myocytes.
The basis of a fast upstroke is the rapid movement inward of Na+ ions. Myocytes that have a
dense fast Na+ channel population in their sarcolemma, such as in the conduction system, have
a large dV/dt. Thus, Na+ ions quickly reach the vicinity of the gap junctions and move through
them to the next cell. A large dV/dt or fast upstroke during phase 0 is associated with fast cell-
to-cell conduction.

CONDUCTION VELOCITY THROUGHOUT THE HEART

Note: Conduction velocity refers only to phase 0, the leading edge of the action potential, propa-
gating from cell to cell.
• His-Purkinje System: In these large diameter cells with a fast phase 0 upstroke and large
phase 0 amplitude, there is very rapid conduction (high conduction velocity), 1–4 mm/ms.
Purkinje fiber phase 0 characteristics are related to the presence in the sarcolemma of a high
density of fast Na+ channels. Purkinje fibers have the fastest conduction velocity in the
16
 Refractory period

heart (self-study module Cardiac Action Potentials, Part 2: Nodal and Conduction e
System Myocytes). Conduction velocity is influenced only by the characteristics
of phase 0. Conduction velocity is not related in any way to phase 4 slow diastolic
depolarization in the Purkinje fibers.
• AV Node: Most AV node cells a small diameter, a slow phase 0 upstroke, small phase 0
amplitude, and relatively few gap junctions (self-study module Cardiac Action e
Potentials, Part 2: Nodal and Conduction System Myocytes). Therefore, conduction
velocity is slow, roughly 0.05 mm/ms. The slowest conduction in the heart occurs here.
• Atrial and Ventricular Muscle: Intermediate cell diameter and phase 0 properties (self-
e
study module Cardiac Action Potentials, Part 1: Ventricular and Atrial) result in
intermediate conduction velocities of about 1 mm/ms. Conduction velocity is significantly
less than in the conduction system.

REFRACTORY PERIOD

VENTRICULAR AND CONDUCTION SYSTEM MYOCYTES

ABSOLUTE REFRACTORY PERIOD (ARP)
In a normal ventricular myocyte, a stimulus cannot cause a conducted action potential during
the ARP (Figure 3.1a). Ventricular myocyte Na+ channels inactivate as the transmembrane
potential approaches 0 volts during phase 0 (self-study module Cardiac Action Potentials,
e
Part 1: Ventricular and Atrial). Sustained depolarization during phase 2 keeps the Na+ chan-
nels inactivated. The transmembrane potential must repolarize for the Na+ channels to reacti-
vate so that a stimulus will produce another conducted action potential.

(a)

0
Voltage (mV)

–80
ARP RRP

(b) 0

ARP RRP
–80

0 100 200 300

Time (ms)

Figure 3.1  Refractory periods. (a) is a representative ventricular or conduction system myocyte action
potential and (b) is a sinoatrial or atrioventricular node action potential. ARP is absolute refractory and
RRP is relative refractory period.

17
 Physiological consequences of ionic mechanisms

The Na+ channels start to reactivate at the middle of phase 3, which is where the ARP ends
(Figure 3.1a). Consequently, normal ventricular myocytes are refractory from phase 0, through
the plateau to the middle of phase 3 (Figure 3.1a).
A long ARP in heart muscle cells is important to ensure that conduction proceeds only
onward from myocyte-to-myocyte. If a myocyte did not become refractory with depolarization,
the action potential, as it traveled from myocyte-to-myocyte, possibly could reverse direction,
circle back to previously depolarized myocytes and induce aberrant action potentials.
Normal conduction in the heart starts at the SA node and proceeds only onward. Conduction
normally never reverses direction. Refractoriness can become abbreviated, for instance, in
damaged myocardium or resulting from drug effects. Conduction then can reverse direction
and induce an extra action potential, something called reentry, and an abnormal heart rhythm
(arrhythmia) is the result. Reentry is discussed later in the arrhythmia section of the discussion
of the ECG (Section I, Chapter 7).

RELATIVE REFRACTORY PERIOD (RRP)

The ventricular myocyte RRP lasts from the middle of phase 3 to phase 4 (Figure 3.1a). During
the brief RRP in ventricular muscle some Na+ channels are available to open whereas others
have not yet recovered from inactivation. In the RRP a stronger than usual stimulus is needed
to open enough Na+ channels to initiate a conducted action potential.

SA AND AV NODE REFRACTORY PERIOD

ARP AND RRP
Definitions of nodal myocyte ARP and RRP are the same as in the ventricle. Note that the com-
bined ARP plus RRP extends well into phase 4 (Figure 3.1b and self-study module Cardiac
e Action Potentials, Part 2: Nodal and Conduction System Myocytes). The duration of ARP
plus RRP, the total duration of refractoriness, in nodal cells is substantially longer than in ven-
tricular muscle cells (Figure 3.1a and b). This is because Ca 2+ channels, rather than Na+ chan-
nels, are responsible for depolarization of SA and AV nodal cells. All the Ca2+ channels must
recover to restore full excitability of nodal cells. Ca 2+ channel recovery kinetics are slow, so
recovery of nodal cells takes a longer time than for the fast Na+ channels in non-nodal heart
tissues.

PROTECTIVE FUNCTION OF LONG AV NODE REFRACTORINESS

An abnormally fast atrial rhythm can develop due to, for instance, disease or drug effects. Many
of the atrial action potentials are likely to find the AV node refractory and do not propagate
through the AV node into the conduction system. This can prevent a rapid abnormal atrial
rhythm from inducing too rapid beating of the ventricles. Excessively rapid beating of the ven-
tricles can limit the time available for ventricular filling and reduce cardiac output. This is
an important clinical issue. Clinically, we think of the AV node as “protecting” the ventricles
from beating too frequently with atrial tachyarrhythmias (fast abnormal atrial rhythms). The
protective function of the atrioventricular node is related to its long total refractoriness. It is not
related to and has nothing to do with the slow conduction through the atrioventricular node.

18
 Influence of extracellular K+ concentration on the transmembrane potential (Vm) of ventricular and atrial myocytes

INFLUENCE OF EXTRACELLULAR K+ CONCENTRATION ON THE

TRANSMEMBRANE POTENTIAL (Vm) OF VENTRICULAR AND
ATRIAL MYOCYTES
Resting Vm is strongly affected by the external K+ concentration. The resting membrane poten-
tial becomes more positive (less negative; depolarized) if extracellular K+ concentration is
increased. This is because:
• K1 channels in resting ventricular, atrial, and conduction system myocytes remain open.
• An increase in external K+ concentration reduces the concentration gradient across the
membrane and movement of K+ from inside to outside is hindered. The net effect is that
more positive charges remain inside and the transmembrane potential shifts toward the
positive. An equilibrium, where the concentration gradient is balanced by the electrical
gradient, occurs at a less negative level. The greater the increase in external K+ the more
the cell will depolarize. The pathophysiology of elevated serum K+ concentration,
hyperkalemia, is discussed in the self-study module Cardiac Action Potentials, e
Part 1: Ventricular and Atrial.

What is the likely effect on the resting transmembrane potential of a normal ventricular
muscle cell if the extracellular Na+ concentration is substantially increased?*

* The opportunity for Na+ to enter a resting ventricular myocyte is extremely limited, so extracellular Na+
concentration has virtually no effect on the resting transmembrane potential.

19
 Control of heart rate

PARASYMPATHETIC
Acetylcholine (ACh) is the neurotransmitter released from postganglionic parasympathetic
nerves ending on sinoatrial (SA) and atrioventricular (AV) node myocytes. There is some para-
sympathetic innervation of atrial myocytes, but sparse parasympathetic innervation of ven-
tricular myocytes.
The chronotropic effect (effect on heart rate) of parasympathetic activity (Figure 4.1) is due
to actions of ACh on SA node myocytes.
• ACh increases K+ conductances and hyperpolarizes the maximum diastolic membrane
potential during phase 4 (Figure 4.1).
• ACh also decreases the activation of If channels (self-study module Cardiac Action
e
Potentials, Part 2: Nodal and Conduction System Myocytes) and because of this phase
4 depolarization starts from more negative levels, has a decreased slope, and takes longer to
reach the threshold for initiating an action potential.
• Finally, ACh inhibits L-type Ca 2+ channels, which slows the intracellular cycling of
Ca 2+. The latter slows diastolic depolarization (Figure 4.1). The inhibition of L-type Ca 2+
channels also raises the nodal action potential threshold.

The net result of the above is that diastolic depolarization starts from a more negative level,
rises more slowly and must rise to a higher threshold to induce an action potential. This combi-
nation of effects results in a longer interval between beats and a reduced heart rate.

SYMPATHETIC
Norepinephrine is the sympathetic neurotransmitter and is released at sympathetic nerve
endings on myocytes. Sympathetic nerves innervate all heart muscle cells. Also, sympathetic
stimulation of the adrenal medulla results in the release of mostly epinephrine and some
­norepinephrine, which circulate as hormones and interact with cardiac myocytes.
Sympathetic stimulation of SA node cells increases the inward ionic currents of the
pacemaker potential (self-study module Cardiac Action Potentials, Part 2: Nodal and
e
Conduction System Myocytes) with a net effect of increasing the rate of diastolic depolariza-
tion (Figure 4.1). The effects are:

21
 Control of heart rate

0
mV
60
Sympathetic
stimulation

0
mV
60
Vagal
stimulation
Time

Figure 4.1  Effect of sympathetic and parasympathetic simulation on sinoatrial node action potentials.
Note the threshold for the onset of phase 0 is lower with sympathetic stimulation and higher with vagal
stimulation. (Modified from Barrett KE et al. Ganong’s Review of Medical Physiology. 23rd ed. New York:
McGraw-Hill; 2010. With permission of McGraw-Hill.)

• Enhanced opening of L-type Ca 2+ and increased Ca 2+-induced-Ca 2+-release and an

increase in I NCX, a depolarizing current. The enhanced L-type Ca 2+ channel opening
lowers the threshold (Figure 4.1).
• Increased opening of I f channels, which increases the slow inward movement of Na+ and
the slope of phase 4.

The combined effect of increases in ICa, I NCX, and I f (self-study module Cardiac Action
e
Potentials, Part 2: Nodal and Conduction System Myocytes) are an increase in the upward
slope of phase 4 (increased rate of diastolic depolarization) and a lower threshold for initiating
phase 0 (Figure 4.1). Heart rate, as a result, increases.
• Sympathetic stimulation also enhances I K, which accelerates phase 3 repolarization. A
larger I K would slow diastolic depolarization and heart rate, but the combined increases
in I NCX and I f are enough to outweigh the enhanced I K.

22
 Electrical properties and cardiac
myocyte structure
5

Cardiac muscle is partially composed of a highly branched network of small, 12 × 100 micron
(µm) myocytes (Figure 5.1). There are several interchangeable names for a cardiac muscle cell:
myocardial or cardiac muscle fiber and myocardial or cardiac myocyte.
Each myocyte is bounded longitudinally by intercalated discs and can branch (Figure 5.1).
The intercalated discs connect myocytes end-to-end (Figure 5.1). Finger-like projections of the
sarcolemma at the ends of myocytes are interlocked to form the intercalated disc. Desmosomes
are dense areas of adherence within the intercalated disc (Figure 5.1). Desmosomes mechani-
cally link myocytes and transmit force from one myocyte to the next. Of great importance
are other specialized dense areas within the intercalated disc, the gap junctions (Figure 5.1),

Intercalated
discs

Desmosome
Intercalated disc
Gap
junction

Figure 5.1  Intercalated discs, gap junctions, and desmosomes.

23
 Electrical properties and cardiac myocyte structure

which have low electrical resistance (Figure 5.1). The gap junctions contain channel-like struc-
tures called connexins that are low resistance pathways from the end of one myocyte to the
next interconnected myocyte. Ions move relatively freely from myocyte to myocyte through
gap junctions. This accounts for the low myocyte-to-myocyte resistance and high conductance
throughout heart muscle tissue.

24
 Conduction of electrical activity
in the heart
6

GAP JUNCTION FUNCTION

MYOCYTE TO MYOCYTE ACTION POTENTIAL MOVEMENT

Ions move freely from myocyte to myocyte through gap junctions. Electrical charges carried
by ions easily move from cardiac muscle cell to cardiac muscle cell and throughout normal
heart muscle tissue. As noted previously, this is the major reason there is low myocyte to
myocyte electrical resistance and high conductance. Gap junction function can change with
disease.

ALL OR NONE
The electrical response of heart muscle is all or none, which means that an adequate stimulus
to one healthy atrial myocyte will result in an action potential that is then transmitted to all the
other atrial myocytes. The same is true in the ventricles. In other words, all or none refers to the
all-inclusive response of heart muscle cells.
All or none does not mean that each myocyte contracts maximally. It does mean that there
are no quiescent cells waiting in reserve to be called upon if the demands on the heart increase.
Each myocyte is a separate cell with its own cell machinery and bounded by a membrane, the
sarcolemma. But the low myocyte-to-myocyte electrical resistance at the gap junctions and
easy myocyte-to-myocyte transmission of action potentials result in the heart behaving as if it
were a syncytium. It is said to act as a functional syncytium.

CONDUCTION SEQUENCE IN THE HEART

Specialized pacemaker and conduction tissue dictate the origin of activity and the sequence of
activation of heart structures (Figure 6.1).

25
 Conduction of electrical activity in the heart

Sinoatrial (SA) Atria Atrioventricular (AV)

node node

Bundle of His or
atrioventricular bundle Conduction
Bundle branches system
Purkinje myocytes
LA Ventricular myocytes
SA node Left side of septum
Apical subendocardium
AV node Endocardial to epicardial layers
Basal myocardium
RA
LV

RV

Figure 6.1  Sequence of electrical activation of the heart. RA, right atrium; LA, left atrium; RV, right
ventricle; LV, left ventricle.

SINOATRIAL NODE
The sinoatrial (SA) node is in the right atrium at its juncture with the superior vena cava
(Figure 6.1). The SA node is the normal pacemaker of the heart (self-study module Cardiac
e
Action Potentials, Part 2: Nodal and Conduction System Myocytes). As noted above,
electrical activity begins here, initiates each heartbeat, and then spreads throughout the
atria.

ATRIAL MUSCLE
Electrical activity is conducted from atrial myocyte to atrial myocyte throughout the right and
left atria primarily via gap junctions.

ATRIOVENTRICULAR NODE
The AV node is in the right atrium at the bottom of the interatrial septum near the opening of
the coronary sinus. It conducts electrical activity from the atria to the bundle of His (Figure 6.1).
Electrical conduction in the AV node, as noted earlier, is very slow.
Slow AV nodal conduction is important. Slow conduction ensures that atrial activation and
contraction are completed before ventricular activation and contraction begin. Atrial contrac-
tion then will occur when the ventricles are still relaxed.
There is a connective tissue structure, the annulus fibrosus (Figure 6.2), that electrically
insulates the atria from the ventricles. The bundle of His or atrioventricular bundle (Figures
6.1 and 6.2), discussed below, penetrates the annulus. The only normal pathway for conduc-
tion of action potentials from the atria to the ventricles begins in the AV nodal tissue and then
continues in the cardiac myocytes of the bundle of His through the connective tissue electrical
barrier (Figure 6.2).

26
 Conduction sequence in the heart

Atria
AV node

Annulus fibrosus
Bundle of His

Ventricles

Figure 6.2  Atrioventricular node, annulus fibrosus, and the bundle of His.

VENTRICULAR CONDUCTION SYSTEM

The ventricular conducting system consists of the bundle of His or atrioventricular bundle, the
bundle branches, and the Purkinje system (Figure 6.1). The AV node merges with the bundle of
His (Figure 6.2), but is not considered part of the conduction system.
At the top of the interventricular septum, the bundle of His divides into the left and right
bundle branches (Figure 6.1) that distribute action potentials to the left and right ventricles,
respectively. The bundle branches continue to branch extensively in the subendocardial layers
of both ventricles. The Purkinje myocytes are the terminal branches of the conduction system
(Figure 6.1).
The conduction system is not nerve tissue. It is made up of myocytes, but they are special-
ized for rapid conduction (self-study module Cardiac Action Potentials, Part 2: Nodal and
e
Conduction System Myocytes). Purkinje myocytes contain large amounts of glycogen and are
resistant to hypoxia.
The His bundle and bundle branches are surrounded by connective tissue sheaths. The con-
nective tissue sheath insulates these conduction system cells from the surrounding ventricular
muscle. Therefore, the first electrical contact with ventricular myocytes is not made until the
Purkinje myocytes merge into ventricular myocytes. Purkinje fibers do not have connective
tissue sheaths.
The sequence of normal ventricular activation (Figure 6.1):
• Left side of the ventricular septum is first, followed by
• Subendocardial myocardium of ventricular apex, then
• Subendocardial myocardium of the ventricles, then
• From inner subendocardial layers out to subepicardial myocardium, and
• Simultaneously from apex to base—left and right ventricular bases are last

Activation proceeds from endocardial, inner layers of the ventricular wall to the outer, sub-
epicardial layers and from the apex of the ventricles toward the base of each ventricle. The
ventricular myocardium attached to the annulus fibrosus is the base. The bases of the right and
left ventricles depolarize last. The last location to depolarize usually is the outflow tract of the
right ventricle, just proximal to the pulmonary valve.

27
 Electrocardiogram

Most tissue consists of mostly salt water, so the electrical activity of the heart conducts through
the body to produce small voltages and current on the body surface. The electrocardiogram
(ECG) is a recording of this surface electrical activity. An ECG provides information on:
• Heart rate and rhythm
• The pattern of electrical activation of the atria and ventricles
• The approximate mass of tissue being activated
• Damage to heart muscle
• Changes in heart muscle electrolyte composition

Willem Einthoven, a Dutch physiologist, produced the first, definitive, clinically useful ECG
recordings at the beginning of the twentieth century. He did this by refining an instrument
called the string galvanometer that recorded small voltage signals. He pioneered the use of the
ECG as a clinical tool and was awarded the 1924 Nobel Prize in Medicine.

OVERVIEW
The ECG is the body surface recording of voltages that result from the moment-by-moment
conduction of action potentials from myocyte to myocyte. ECG waves reflect the electrical
forces produced by the sequential depolarization and repolarization of myocytes. A normal
ECG does not mean that every myocyte generated an action potential or that all the action
potentials generated were normal. The ECG signal is a “summary” external view of the electri-
cal activity at each instant in a heartbeat.
Much of the usefulness of the ECG depends on widely accepted recording standards and
known correlations of ECG findings with underlying pathology. There is not always a precise
electrophysiological explanation for every feature of an ECG signal.
There is no predictable, reliable, independent correlation of ECG findings with heart func-
tion. Someone with a normal ECG can have serious underlying heart disease; someone with
an abnormal ECG can have perfectly normal heart function. An ECG does not provide direct
information about heart function. However, the finding of an abnormal ECG can alert the
physician to the presence of a cardiac abnormality, which may be associated with abnormal
function, but the function would need to be evaluated with other tests than an ECG.

29
 Electrocardiogram

ECG WAVES
During a heartbeat, a series of voltage deflections or waves are recorded. Einthoven named
these the P wave, a sequence of waves called the QRS complex, and the T wave. There are also
intervals and segments. An interval includes at least one wave whereas a segment does not
include a wave.

P WAVE
The P wave (Figure 7.1) is the body surface recording of the sequential depolarization (phase 0)
of atrial myocytes.

PR INTERVAL
The wave of depolarization, phase 0, moves through the atria, atrioventricular node, and bun-
dle of His and the rest of the conduction system during the PR interval (Figure 7.1). It is mea-
sured from the beginning of the P wave to the beginning of ventricular depolarization. Since it
contains a wave, the P wave, it is called an interval. Most of the PR interval is taken up by slow
conduction through the atrioventricular node.
The segment from the end of the P wave to the onset of the QRS, the PQ segment is flat
(Figure 7.1). Is there any myocardial electrical activity during the PQ segment and, if yes, why is
it flat? Phase 0 is sequentially occurring in the cells of the AV node and the conduction system,
during the PQ segment, but the amount of tissue is too small to generate a large enough electri-
cal signal to be detected on the body surface, hence the flat PQ segment.

QRS
The QRS complex is the body surface recording of the sequential depolarization (phase 0)
of ventricular myocytes (Figure 7.1). If there is a negative deflection at the beginning of the
inscription of the ventricular complex it is called a Q wave. Any positive deflection is called an
R wave—if there is a second positive deflection it is called R’. If there is a negative deflection
after an R it is called an S wave. There is no such thing as a positive Q or S nor is there such a
thing as a negative R wave.

QT interval

R
ST segment

T
P

Q S

PR interval 0.2 second

Figure 7.1  ECG waves, intervals, and segments. On the horizontal axis each small division is 1 mm
and is equal to 0.04 second; 0.2 second is contained between pairs of heavy lines. Each millimeter on
the vertical axis is equal to 0.1 mV. PQRST, intervals and segments are discussed in the text.

30
 Standard lead system

ST SEGMENT
This is a quiescent period from the end of the QRS complex to the beginning of the T wave
(Figure 7.1). The ventricular cells all are in phase 2 of the action potential during the ST segment.

T WAVE
The T wave (Figure 7.1) is related to sequential development of phase 3 repolarization in ven-
tricular myocytes. A wave due to repolarization of the atria is usually obscured by the initial
portion of the QRS.

QT INTERVAL
The QT interval is measured from the beginning of the QRS complex to the end of the T wave
(Figure 7.1).

STANDARD LEAD SYSTEM

A clinically effective assessment of electrical activity in the heart can be obtained with 12 views
of the electrical activity, obtained with 12 different skin electrode sampling configurations or
leads. An adhesive electrode containing conductive paste is applied to a previously cleaned area
of the skin on each of the four limbs and at designated locations on the precordium to record
the 12 leads of a standard ECG.
The appearance of the P and T waves and the QRS complex differs from lead to lead. Each
lead provides a unique view of the electrical activity of the heart. This is a topic that will be
taken up after all the leads are introduced below and is also addressed in the self-study e
module The Mean Electrical Axis: A Story of Vectors.
The 12 standard ECG leads are divided into 6 leads that record electrical activity reflected
into the frontal plane of the torso and 6 leads that record electrical activity reflected into the
horizontal plane (Figure 7.2). “Reflected into” and “plane” sound like geometry and it does take
some very simple (extremely simple!) geometry to understand the clinical ECG.
The heart chambers are three-dimensional structures. For instance, as phase 0 moves from
myocyte to myocyte in the atria, starting from the SA node, as phase 0 moves leftward toward
the left atrium, downward toward the AV node, and rightward toward the right wall of the right
atrium. That is not, however, a complete description. The action potentials also are simultane-
ously traversing the anterior and posterior walls of both atria. The ECG is a two-dimensional
recording of the three-dimensional movement of action potentials. That is why the frontal
plane leads record only that portion of the three-dimensional movement of action potentials
that is reflected into (projected onto) the frontal plane.
Multiple leads are recorded in a standard ECG to obtain meaningful two-dimensional elec-
trical views of the sequence of three-dimensional electrical events in the heart.

FRONTAL PLANE LEADS: LIMB LEADS

Picture a plane through the center of the body with the flat surfaces toward the front and rear of
the body (Figure 7.2). The frontal plane leads record electrical activity reflected into that plane.
The six frontal plane leads consist of three bipolar leads and three augmented unipolar leads.
31
 Electrocardiogram

Frontal
plane

Horizontal
plane

Figure 7.2  Frontal and horizontal planes. (From Malmivuo J, Plonsey R. Bioelectromagnetism Principles
and Applications of Bioelectric and Biomagnetic Fields. 1995. by permission of Oxford University Press.)

THREE BIPOLAR LIMB LEADS I, II, AND III

Einthoven developed the bipolar limb leads. He arranged the electrodes for each lead so there
was a predominantly upright QRS. This sounds arbitrary and it is, but it works because every-
one since has used the same lead system (Figure 7.3). The right arm is not inherently negative
and the left positive for lead I. Lead I is recorded by connecting the right arm to the negative
pole of the ECG machine and the left arm to the positive pole (Figure 7.3). The left leg is con-
nected to the positive pole of the ECG machine for leads II and III, but for lead II the right arm
is connected to the negative pole and for lead III the left arm is connected to the negative pole.
Note that the axes for leads I, II, and III all are at 60° to each other and form an equilateral

RA LA
– +

– Lead I axis –
Lea

is
x
II a
d
II a

dIa
xis

Le

+ +

LL

Figure 7.3  Bipolar (Einthoven) limb leads and their axes.

32
 Standard lead system

triangle, called Einthoven’s triangle (Figure 7.3). An axis is the straight line segment connecting
the electrode from one limb to another (Figure 7.3). For instance, the lead I axis is the straight
line segment from the right arm electrode to the left arm electrode (Figure 7.3).

THREE AUGMENTED UNIPOLAR LIMB LEADS aVR, aVL, AND aVF

An augmented unipolar limb lead is recorded with one limb connected to the positive electrical
pole of the ECG machine. The connection to the negative pole of the ECG machine is created
by connecting two other limbs through resistors. Connecting two limbs together in this way
creates leads whose axes bisect each of the 60° angles in Einthoven’s triangle. The resistors
act to increase or augment the amplitude of the recording from the one limb, hence the term
“augmented.” The value of the resistors was chosen through experimentation to result in ECG
wave amplitudes in these leads that can be analyzed with the bipolar, Einthoven leads. The
lead configurations and axes for leads aVR (Figure 7.4), aVL (Figure 7.5), and aVF (Figure 7.6)
are illustrated.
Lead selection and the resistors all are part of the controls and circuitry of an ECG machine.

RA LA
+

Lea
d aV
Ra
xis

LL

Figure 7.4  Lead aVR lead and axis.

RA LA
+

xis
V La
ada
Le

LL

Figure 7.5  Lead aVL lead and axis.

33
 Electrocardiogram

RA LA

Lead aVF axis

LL
+

Figure 7.6  Lead aVF lead and axis.

HORIZONTAL PLANE LEADS: PRECORDIAL LEADS

The horizontal plane is perpendicular to the frontal plane and passes through the body at the
approximate level of the heart (Figure 7.2). The precordial leads also are unipolar leads. The
object of unipolar leads is to record voltage at different points on the body with respect to
an approximation of electrical ground or zero. Electrical ground should not be affected by
other electrical activity in the body, for instance, that of skeletal muscle. A true electrical
ground could be obtained by connecting a wire from the patient to a ground, such as a cold-
water pipe, but this creates the danger of electrocution if the ECG machine ­malfunctions.
Consequently, no point on the body is truly at electrical ground level, but c­ onnecting the
right arm, left arm, and left leg to a common point or central terminal (Figure 7.7) forms an
equivalent or “body” ground or zero reference level. The point of having a central terminal
is that it is little affected by electrical activity other than that of the heart and approximates
a stable, zero reference level. The central terminal lead is connected to the negative pole of
the ECG machine (Figure 7.7).
An exploring electrode is placed in contact with the skin at defined anatomical points
on the front of the chest (Figure 7.7). The exploring electrode is connected to the positive pole
of the ECG machine (Figure 7.7). The image in the upper right of Figure 7.7 is a cross-section of
the chest and one is looking downward at the horizontal cut section with posterior, the spine,
at the top. The exploring electrode attached to the electrode pasted on the skin of the precor-
dium is the positive end of each precordial lead. The negative end of each precordial lead is
the central terminal described above and is in the center of the thorax in the horizontal plane.
The voltage difference between the central terminal and the exploring electrode is recorded
for each precordial lead.
There are six precordial leads, V1 through V6. The precordial leads record the heart’s elec-
trical activity reflected in a horizontal plane through the heart (Figures 7.2 and 7.7). A draw-
ing of a typical recording from V1 and V6 is illustrated (Figure 7.7). The P waves are not
included.

34
 Frontal plane vectors

Spine

V1 V2
V3 V6 V6
V4 V5
V5
V4
V1 V2 V3

Exploring electrode

RA LA

–
LL

Figure 7.7  Precordial leads. The connection of the limbs to the negative terminal of the ECG machine
is the central terminal described in the text. The exploring electrode is replaced by six wires in a modern
ECG machine. Each wire is labeled, V1, V2, and so on, and are each connected to the respective chest
electrodes. The ECG machine then records tracings from each of the six precordial leads.

MONITORING LEADS
It is common to use modified bipolar chest leads to monitor cardiac rhythm in hospitalized
patients. A commonly used electrode configuration is a negative electrode near the right shoul-
der, a positive electrode in the V5 position, and a third reference electrode near the left shoul-
der. Which of the standard leads does this arrangement approximate?*

FRONTAL PLANE VECTORS

Think outside of the myocyte sarcolemma, not inside! An ECG recording is only influenced by
electrical events on the outside of myocytes. In a resting myocyte, during phase 4, the outside of
the myocyte is positive. K+ has moved out through K1 channels and there is a surplus of posi-
tive ions outside of the sarcolemma (Figure 7.8). Na+ moves in during depolarization (Figure
7.8) and at the peak of phase 0 the outside of the cell is negative because of positive charges
moving into the cell (Figure 7.8).
The waves recorded in an ECG are not the result of only positive or only negative
­extracellular  charges. The ECG waves are the result of there being an electrical  potential

* Lead II.

35
 Electrocardiogram

Resting Depolarization Phase 0 peak

Na+ Na+

+ + +
Voltage

– – –

Time

Figure 7.8  External aspect of depolarization of an atrial or ventricular myocyte in the upper images.
The resting myocyte has a surplus of external K+ and is positive outside. With depolarization Na+ moves
in and the outside develops a negative charge as the inside makes the transition from negative to
positive. Internal voltage changes shown in the bottom graphs. At the peak of phase 0 there is a surplus
of negative as compared with positive charges externally.

difference from one part of the atria or ventricles to another. For instance, a P wave is recorded
when part of the atria is negative and part positive. Before atrial depolarization, when the
outside of all the atrial cells are positive, no wave is recorded. Confusing? Think of a battery—­
connect something to only the positive pole and nothing happens, but then c­ onnect a bulb to
the negative and positive pole—current flows through the bulb, a voltage level is ­created, and
the bulb lights. The bulb lighting is analogous to an ECG wave recording. This is presented
e with animation in the self-study module The Mean Electrical Axis: A Story of Vectors.
The SA node normally is the first place where the outside of myocytes becomes negative
as Ca2+ moves inward. There is too little tissue and too small an electrical signal generated by
the SA node to generate a wave in the ECG recording. Then depolarization (phase 0) spreads
sequentially throughout the atria. The myocytes in the portion of the atria that is depolarized
are negative outside and the myocytes in the portion that is not yet depolarized are positive
outside (Figure 7.9). Note that the lower and leftward portions of the atria are not yet depolar-
ized in a “freeze frame” of an instant during atrial depolarization (Figure 7.9).
Since part of the atria is negative and part is positive, the atria behave electrically as a
dipole. There is an upper, rightward, depolarized, negative pole and a lower, leftward, not-yet-­
depolarized, positive pole. Each small black arrow is a vector, the head of which is positive and
the tail is negative (Figure 7.9).
The large white arrow is the mean vector that results if all the individual vectors are factored
together (Figure 7.9). Its direction represents the average direction of the wave of depolariza-
tion at this moment and the length represents the magnitude of the electrical field associated
with the dipole at this moment. This mean vector becomes a useful tool for relating what is
going on electrically on the surface of the myocytes with the ECG body surface recording. This
is explained below and is illustrated with examples of vector analysis in the self-study
e
module The Mean Electrical Axis: A Story of Vectors.
Important: The head of the vector always points toward the positive part of the myocardium
and the tail is always at the negative part. Repolarization and the T wave will be discussed later
36
 Frontal plane vectors

N
SA

Figure 7.9  Vectors during atrial depolarization. SAN is the sinoatrial node. The large white arrow is the
mean vector. Other features are discussed in the text and in the self-study module The Mean Electrical
Axis: A Story of Vectors.

and the same is true—the vector points toward the positive part of the ventricular myocardium
whether during depolarization or repolarization.
As noted above, the frontal plane bisects the body and is parallel to the front and back of
the chest (Figure 7.2). The frontal leads record the portion of electrical activity that is reflected
onto the frontal plane.
An electrical dipole has similarities to a magnetic dipole. A magnet has magnetic lines of
force surrounding it. Likewise, an electrical dipole has electrical lines of force around it with
current flowing from the negative portions of, for instance, atrial myocardium to the positive
portions (Figure 7.9). The body tissues are excellent conductors and the electrical lines of force
penetrate the tissues surrounding the heart all the way to the skin. The ECG records the result-
ing small electrical potential differences on the surface of the body.
The mean vector (Figure 7.9) is an understandable way to represent the magnitude and
direction of an instantaneous electrical force in the heart. But the vector does not remain static.
It changes amplitude and direction as depolarization progresses from myocyte to myocyte.
For instance, in the atria there is no vector in between heartbeats; all the myocytes are positive
outside. SA node depolarization occurs followed by depolarization of adjacent atrial myocytes.
Now there are a few atrial myocytes that are negative outside and all the rest positive, and a
small vector is present. Once half the atrial myocytes are depolarized and negative outside and
the rest are positive outside, the vector will have grown to its maximal amplitude. Beyond the
half-way point (Figure 7.9) the magnitude of the vector decreases. When all the atrial myocytes
are depolarized and negative outside, the vector disappears. If that sequence of vector ampli-
tude changes over time is projected onto a lead, the result is a P wave. The evolution of the mean
vector for atrial depolarization is easier to portray than for the ventricles because the direction
of the atrial mean vector does not change much.
What is meant by “projected” is discussed below. In summary, the amplitude and direction,
positive or negative, of each of the ECG waves reflects the moment-by-moment evolution of the
amplitude and direction of the mean vector for atrial and then ventricular depolarization and
ventricular repolarization. Projections of a mean vector onto ECG leads is a major theme of
the self-study module The Mean Electrical Axis: A Story of Vectors. e
A reverse analysis also works. The mean vector at each moment during a heartbeat can be
constructed from the waves recorded in an ECG.
A review of lead orientation and polarity will be helpful here.
37
 Electrocardiogram

Each ECG lead axis is oriented in a specific direction and samples skin potentials from that
orientation. The orientation of the axes for leads I, II, and III are as follows:
• The axis of lead I is from shoulder to shoulder (Figure 7.3). As described above, a person’s
right arm (RA) is connected to the negative pole of the ECG machine and the left arm
(LA) is connected to the positive pole for Lead I.
• For lead II it is RA negative, left leg (LL) positive, and the lead II axis is at 60° to lead I
(Figure 7.3).
• And in lead III, the LA is negative and LL positive and the lead III axis is 60° to the axes
for leads I and II (Figure 7.3).

These three bipolar leads sense electrical activity in one plane, the frontal plane of the body,
and, as mentioned above, form an equilateral triangle called Einthoven’s triangle (Figure 7.3).
Each angle in the triangle is 60°.
As noted above, when one-half the mass of atrial myocardium is depolarized, the mean
vector is the largest in magnitude, the mean vector is the longest it will be, and the peak of the
P wave is recorded (Figure 7.10). The arrow representing the mean vector can be moved into the
approximate center of Einthoven’s triangle. The orientation and length of the vector must not
change when moved (Figure 7.10). The broken lines drawn from the head and tail of the mean
vector must be perpendicular to the axes they intersect (Figure 7.10). These perpendiculars
project the mean vector onto each axis and the projections are represented by arrows (Figure
7.10). When the head of the projection points toward the positive end of the lead, the ECG wave
is recorded as positive in that lead. In this example, the projection onto all three leads points
toward the positive end of each lead. The P wave is then positive in each of the three leads
(Figure 7.11). Also note that the P wave amplitude is greatest in lead II, smallest in lead III, and
intermediate in lead I (Figure 7.10).
As noted above, once the atria are completely depolarized (not pictured here), with all the
myocytes negative outside, there is no electrical potential difference, no vector, and the end of
the P wave will be at the baseline.
The ECG signal remains at the baseline as the wave of depolarization moves slowly through
the AV node (Figures 7.1, 7.2, and 7.1). The amount of AV node tissue is too small for its depo-
larization to be manifest on the surface of the body. In other words, the magnitude of the vec-
tor for this electrical activity is too small to influence the skin surface recording. There is rapid

Lead I
N
SA

Lead II Lead III

Must be a
right angle

Figure 7.10  Mean vector for atrial depolarization and Einthoven’s triangle. The broken lines from the
head and tail of the vector must be perpendicular to each axis for a valid projection of the vector onto
each lead axis.

38
 Frontal plane vectors

conduction through the bundle of His, the bundle branches, and the Purkinje fibers, but, again,
the amount of tissue is small and no detectable voltage change is recorded on the surface of the
body. The ECG signal is flat, the PQ segment, from the end of the P wave to the beginning of
the ventricular complex (Figure 7.1).
Important: The delay through the AV node ensures that ventricular contraction occurs only
after atrial contraction is complete. As noted earlier, there is then time for atrial contraction to
push a small amount of blood into the relaxed ventricles to finish ventricular filling. As discussed
earlier, slow conduction through the AV node is due primarily to a small phase 0 slope and ampli-
tude and small diameter cells. Also, there are relatively few gap junctions among AV node cells.
After AV node depolarization, the wave of depolarization traverses the His bundle, the bun-
dle branches, and the Purkinje fibers. Normally the first portion of the ventricular myocardium
to be depolarized is the left side of the interventricular septum. This is because the left bundle
branch divides and arborizes early. Thus, depolarized myocytes on the left side of the interven-
tricular septum are negative outside while those on the right side are still positive. The mean
vector then is oriented from left to right (Figure 7.11).
The mean vector during septal depolarization, projected onto leads I and II, points to the
negative end of each of those leads. This results in an initial negative deflection in these leads,
a Q wave. The initial deflection is positive in lead III because the projection of the vector onto
the lead III axis points toward the positive end. Thus, there will not be a Q wave in lead III and
instead there is the beginning of an R wave.
Consider the remainder of the selected instants during ventricular depolarization.
Following septal depolarization, depolarization moves toward the ventricular apex and then
advances from the inner, subendocardial ventricular myocytes to the subepicardial, and at the
same time from the apex to the base of the ventricles (Figure 7.1). Depolarization of the thinner
right ventricle and the apical portions of the left ventricle occur before the remainder of the
left ventricle. Myocytes in those areas are negative outside while those in the remainder of the
thick left ventricle are positive and the mean vector for ventricular depolarization rotates to
point leftward and downward (Figure 7.12). You should be able to reason from Figure 7.12 that
there will be tall, positive deflections in leads I and II and a likely S wave in lead III. The self-
e
study module The Mean Electrical Axis: A Story of Vectors assists you to work through
such an analysis. The direction of the mean vector when half the ventricular myocytes are
depolarized is the mean electrical axis, discussed below.

Lead I
– +

– –

AO
N
SA

LV Lead II Lead III

RV
+ +

Figure 7.11  Mean vector for ventricular septal depolarization. As noted in the text, when the projection
onto a lead points toward the negative end of that lead, a negative deflection is noted in the ECG. In this
case the negative deflection is a Q wave in leads I and II.

39
 Electrocardiogram

Toward the end of ventricular depolarization the vector decreases in magnitude and finally
points leftward and upward, toward the few remaining left ventricular myocytes not yet depo-
larized and still positive outside. Inscription of the QRS waves ends when all the ventricular
­myocytes are depolarized and no vectors remain.
Phase 1 is brief and low magnitude and there is no distinct wave in the ECG recording
related to it. At the beginning of phase 2 the ventricular myocytes are slightly negative outside,
then hover at close to zero voltage before becoming slightly positive when phase 3 begins.
All the ventricular myocytes are close to the same electrical potential level during phase 2.
Consequently, there is no significant electrical potential difference among the ventricular myo-
cytes. There is then no significant vector at this time and the ECG tracing begins a flat period at
the level of or close to the level of the baseline (ST segment, Figure 7.1).
Repolarization of the ventricles occurs as each myocyte undergoes phase 3 of the action
potential. Logic suggests that the first areas to depolarize will repolarize first. The subendocar-
dial myocardium would then repolarize first and the outside of the subendocardial myocytes
would again become positive first. The vector during repolarization would point rightward
and upward (toward the right shoulder) and the T wave would be negative in leads I and II.
However, this logic does not explain what we see on the ECG. The T waves in leads I and II
usually are positive (Figure 7.1). A useful rule-of-thumb is that T wave polarity in a lead likely
will be the same as the net polarity of the preceding QRS complex in the same lead.
The reason logic alone does not work here is because left ventricular subepicardial myo-
cytes depolarize last and repolarize first. The reason for this unexpected but normal sequence
of repolarization is that action potential duration in subepicardial myocytes is significantly
shorter than in the middle and subendocardial myocytes. Repolarization of subepicardial myo-
cytes is early enough so that the wave of repolarization normally is from subepicardium to
subendocardium in the ventricles. The left ventricular subepicardial myocytes are the first to
return to positive outside. Therefore, the mean vector during ventricular repolarization tends
to point leftward and downward, just as for depolarization (Figure 7.12). The direction of the
repolarization mean vector is similar to that for depolarization, but the magnitude is smaller,
probably because repolarization is less well organized. Remember, the head of a vector always
points to the positive area whether during depolarization or repolarization.
Vector analysis of abnormal ST segments is important in patients with ischemic heart
disease. This is illustrated in the self-study module Clinical use of Vector Analysis:
e
Diagnosis of ST Elevation Myocardial Infarction.

Lead I

LV

Lead II Lead III

RV

Figure 7.12  Mean vector with half the ventricular myocytes depolarized. The direction of the mean
vector at this moment is the mean electrical axis. This is discussed in more detail in the self-study
module The Mean Electrical Axis: A Story of Vectors.

40
 Precordial leads

MEAN ELECTRICAL AXIS

The “mean electrical axis” refers to the direction of the vector when half the ventricular myo-
cardium is depolarized. This is when the vector magnitude is maximal. Estimation of the direc-
tion of the mean electrical axis from the amplitudes of the Q, R, and S waves in the frontal
leads is a standard part of the interpretation of a clinical ECG. There is the opportunity to
work through the analysis of the mean electrical axis in the self-study module The Mean e
Electrical Axis: A Story of Vectors.

PRECORDIAL LEADS
The precordial leads, V1 through V6, sample the heart’s electrical signals in a horizontal plane
that is perpendicular to the frontal plane (Figure 7.2). As described earlier, the precordial
signals are obtained with an exploring electrode placed at prescribed locations on the chest
(Figure 7.7). The appearance of the ECG waves and complexes depends on the direction the
wave of depolarization or repolarization is traveling relative to the exploring electrode. It is a
matter of how the exploring electrode “sees” the wave.
When the exploring electrode “sees” the positive side of the wave of depolarization—in
other words, when the wave of depolarization is coming toward the electrode—a positive
deflection is recorded. When the negative side of the wave front is toward the electrode, a nega-
tive deflection is recorded.
Interpret Figures 7.7 and 7.13, as before, as if the body was cut through at the level of the
heart allowing us to look down onto the bottom half of the body. The anatomical position of
the right ventricular (RV) free wall is anterior and rightward and that of the left ventricular (LV)
free wall is posterior and leftward (Figure 7.13).
Note the position of the septum and the ventricles (Figure 7.13). Initial ventricular depo-
larization occurs on the left, posterior side of the septum and the mean vector at that time
points anteriorly and rightward (Figure 7.14). In other words, during septal depolarization the
left, posterior side of the septum is negative and the right, anterior side of the septum is posi-
tive. The positive end of the vector at that time points toward V1 and there is an initial, small

Spine

LV
RV
V6

V5
V4
V1 V2 V3

Figure 7.13  Orientation of precordial leads and V1 and V6 ventricular complexes. This is a transverse
section of the thorax at the level of the heart, viewed from above.

41
 Electrocardiogram

(a) (b)

LV LV

RV RV

Figure 7.14  Early and late ventricular depolarization in the horizontal plane. This is a transverse section
of the ventricles with the right ventricle (RV) rightward and anterior and the left ventricle (LV) leftward and
posterior. The arrow in (a) represents the mean vector during interventricular septal depolarization and in
(b) the arrow is the mean vector later in ventricular depolarization.

positive deflection of the QRS complex, a small R wave, in V1 (Figure 7.13). The R wave is small
because the amount of tissue involved—just a portion of the interventricular septum—is small.
This initial wave of depolarization is moving anteriorly and away from lead V6 (Figures 7.13 and
7.14). Thus, there is an initial, small negative deflection of the QRS complex, a Q wave, in V6
(Figure 7.13).
After initial depolarization of the septum, the wave of depolarization begins to spread
throughout the ventricles, subendocardium to subepicardium. The mass of the left ventricle
is much larger than that of the right ventricle and is leftward and posterior. The larger mass of
the left ventricle takes longer for depolarization to be completed so there are not yet depolar-
ized myocytes, positive outside, in the left ventricular free wall toward the rear. Thus, the later
larger mean vector points leftward and posterior (Figure 7.14), away from V1. This results in the
large S wave in V1 and large R wave in V6 (Figure 7.13). The S wave in V1 and the R wave in V6
are large because of the large amount of tissue involved. The other precordial leads, V2 to V5,
have intermediate patterns.

ECG PATTERNS OF NORMAL AND ABNORMAL HEART

CONDUCTION

NORMAL CONDUCTION WITH NORMAL SINUS RHYTHM

When the cardiac rhythm is normal each P wave is followed at normal intervals by a ventricular
complex and a T wave (Figure 7.15). Also, the rate is not abnormally slow or fast, greater than 60

Lead II

Figure 7.15  Normal conduction and normal sinus rhythm. (Reprinted from Differential Diagnosis of
Arrhythmia, 2nd ed., Davis D, Copyright 1997, with permission from Elsevier.)

42
 ECG patterns of normal and abnormal heart conduction

Lead II Inspiration Expiration

Figure 7.16  Respiratory sinus arrhythmia. (Reprinted from Quick and Accurate 12-Lead ECG
Interpretation, 4th ed., Davis D, Copyright 2005, with permission from Elsevier.)

and less than 100 beats/minute. Less than 60 beats/minute is called bradycardia and greater than
100 beats/min is tachycardia. Since each beat of a normal rhythm starts with depolarization of
the sinoatrial node, the term used is “normal sinus rhythm.”
Heart rate varies from moment to moment in normal people. This normal variation in heart
rate is often linked to nerve action potentials from the lungs to the brain. There are stretch
receptors in the lungs with afferent nerves to cardiovascular control centers in the brain. With
inspiration and stretch of lung tissue, action potentials to the brain increase. Also, brainstem
neurons that control inspiration inhibit cardiac vagal neurons in the medulla. The result is
less parasympathetic outflow from the central nervous system to the sinoatrial node and an
increase in heart rate with inspiration (Figure 7.16). The heart rate decreases during expiration.
This normal variation in heart rate is called respiratory sinus arrhythmia (Figure 7.16). There
are other sinus arrhythmias not discussed here.
Labelling this respiratory sinus arrhythmia is unfortunate since it is normal. It is more pro-
nounced in normal infants and in adults with slow resting heart rates, such as endurance-
trained people. In fact, recent studies indicate that heart rate variation tends to disappear in
heart disease. Heart failure is accompanied by reduced resting heart rate variation for reasons
that have yet to be determined.

ATRIOVENTRICULAR AND INTRAVENTRICULAR CONDUCTION

BLOCKS
Physiological changes, drugs, and disease can adversely affect the AV node or conduction sys-
tem. The result may be varying degrees of impairment of transmission of action potentials from
the atria to the ventricles. Such impairment is called heart block and some of the more common
degrees and types of heart block are illustrated.

FIRST DEGREE ATRIOVENTRICULAR BLOCK

There is prolonged conduction from the atria to the ventricles in first degree heart block (Figure
7.17). The P wave at the arrow starts on a heavy vertical line and the tiny Q wave starts 5.5 divi-
sions later, which equals a PR interval of 0.22 seconds. The PR interval lengthens as heart rate
slows, but normally does not exceed 0.20 sec. Some drugs and inflammation, such as in acute
rheumatic fever, will slow conduction through the atrioventricular node. The lengthening with
heart rate slowing is related to less sympathetic and more parasympathetic input to the AV
node. Both less catecholamine interaction with AV node beta receptors and more acetylcholine
effects on the AV node result in a reduction in I L-Ca and a decrease in the upslope and amplitude
of phase 0. Thus, AV node conduction velocity is reduced.
43
 Electrocardiogram

Lead II

Figure 7.17  First degree atrioventricular block. The duration of the PR interval after the arrow is
0.22 seconds. (Reprinted from Differential Diagnosis of Arrhythmias, 2nd ed., Davis D, Copyright 1997,
with permission from Elsevier.)

There is no functional impairment with first degree atrioventricular block nor is it likely to
progress to a higher degree of block. Some experts are reluctant to call this a block and refer to
this ECG pattern as simply a prolonged PR interval.

SECOND DEGREE ATRIOVENTRICULAR BLOCK

In first degree atrioventricular block every P wave is followed by ventricular depolarization. In
second degree atrioventricular block there are instances where conduction from atria to ven-
tricles fails to occur and a ventricular action potential does not follow a P wave. The cause varies
and can be due to such things as drug toxicity, ischemia, and inflammation affecting some part
of the conduction system. Second degree heart block also can be related to the effects of the
autonomic nervous system on a normal atrioventricular node. There are two types of second
degree atrioventricular block.

Mobitz Type I or Wenckebach atrioventricular block

This is a relatively benign form of atrioventricular block usually involving altered atrioventricu-
lar node physiology. It is likely due to the effects of increased parasympathetic nerve activity
on the AV node. In this type of atrioventricular block there is a progressive increase of the PR
interval until finally a beat occurs with no conduction to and no electrical activity recorded in
the ventricles (Figure 7.18).
In this rhythm strip there is a small amount of upward drift of the baseline, which is a
recording artifact and not due to an abnormality. The P wave at the arrow (Figure 7.18) is the
beginning of a prolonged PR interval, but is followed by conduction to and depolarization of
the ventricles; there is an RS complex followed by a T wave. Then the next four PR intervals
become progressively longer. Finally, the fifth P wave after the P at the arrow is not followed by

Lead III

Figure 7.18  Second degree, Mobitz Type 1, Wenckebach atrioventricular block. (Reprinted from
Differential Diagnosis of Arrhythmias, 2nd ed., Davis D, Copyright 1997, with permission from Elsevier.)

44
 ECG patterns of normal and abnormal heart conduction

Lead III

Figure 7.19  Second degree, Mobitz Type II, atrioventricular block. The arrows point to nonconducted
beats described in the text. (Reprinted from Differential Diagnosis of Arrhythmias, 2nd ed., Davis D,
Copyright 1997, with permission from Elsevier.)

a ventricular complex. There is no conduction from the atria to the ventricles and a “dropped
beat” occurs. After a long pause the sequence likely begins again although the ratio of con-
ducted to nonconducted beats can vary.
Wenckebach tends to occur at a slow heart rate when parasympathetic input to the SA node
predominates. Wenckebach atrioventricular block can occur in normal young people and is
often observed in infants and in endurance athletes. It can be due to conduction system patho­
logy and lead to more serious problems in older patients.

Mobitz Type II atrioventricular block

In this form of second degree heart block there is a sudden failure of conduction from the atria to
the ventricles without preceding PR interval prolongation. The P waves at the arrows in Figure
7.19 are not followed by ventricular depolarization and repolarization. The other P waves are
followed by normal conduction with normal, stable PR intervals (Figure 7.19). There is no pro-
gressive elongation of the PR interval as in Wenckebach, Mobitz type I atrioventricular block.
Mobitz Type II atrioventricular block can occur as a toxic effect of drugs, ischemia, inflam-
mation, and so on. It is likely that the disturbed conduction is related to pathophysiologic or
pathologic changes in the His bundle or other parts of the conduction system rather than physi-
ologic effects on the atrioventricular node. The presence of Mobitz type II atrioventricular block
is a cause for concern because more complete block may appear—every third beat, every second
beat, and so on. This can lead to complete atrioventricular block and associated complications
discussed next.

COMPLETE HEART BLOCK, COMPLETE ATRIOVENTRICULAR BLOCK,

OR COMPLETE ATRIOVENTRICULAR DISSOCIATION (THE MORE
GENERALLY USED TERMS RATHER THAN THIRD-DEGREE HEART
BLOCK)
Damage to the atrioventricular node, bundle of His, or both bundle branches can cause a com-
plete failure of conduction from the atria to the ventricles. In Figure 7.20, arrows mark the loca-
tion of atrial depolarizations occurring at about 100/minute. RST waves are occurring regularly,
but at a much slower rate than the P waves, approximately 44/minute. The atria are depolar-
izing regularly at their own rate and the ventricles are doing the same, but at their own much
slower rate without a fixed relationship to atrial depolarizations. A likely source of ventricular
pacing in this situation are Purkinje fibers. The fourth arrow from the left marks the occurrence
of an R wave likely superimposed on a P wave. Notice that the R wave is taller than the others.
Several of the P waves are superimposed on T waves.
45
 Electrocardiogram

Lead II

Figure 7.20  Complete atrioventricular dissociation or complete heart block. The arrows mark the
occurrence of atrial depolarizations. (Reprinted from Quick and Accurate 12-Lead ECG Interpretation,
4th ed., Davis D, Copyright 2005, with permission from Elsevier.)

BUNDLE BRANCH BLOCKS

A conduction block in the right or left bundle branch leads to changes from normal in all the
ECG leads. The changes from normal in the precordial leads are distinctive and usually used to
characterize right and left bundle branch block.

Complete right bundle branch block (CRBBB)

CRBBB can occur in people who have no clinical evidence of heart disease. In these otherwise
normal people, CRBBB does not predict future heart problems. CRBBB can also occur due to
dysfunction of the right bundle branch related to right ventricular pressure or volume overload
and hypertrophy. Ischemia involving the right bundle branch can result in CRBBB. In the pres-
ence of structural heart disease, CRBBB can progress to complete heart block if the left bundle
or bundle of His also becomes involved.
In CRBBB there is a small R wave in lead V1 and a Q wave in V6 just as in a normal ECG
(Figure 7.21a and b). The R and Q wave are unchanged from normal because the left bundle
branch is functional and depolarization begins, as usual, on the left, posterior side of the inter-
ventricular septum. Again, as in a normal ECG, the R in V1 is followed by a deep S wave due
to the later depolarization of the leftward, posterior left ventricle (Figures 7.13, 7.14, and 7.21b).
This movement of depolarization posteriorly also accounts for the R wave in V6 (Figures 7.13,
7.14, and 7.21b). The left bundle branch conduction system is normal and action potentials
travel rapidly to the left septal and left ventricular myocardium.
The right bundle branch is completely blocked and action potentials cannot be distributed
by the right bundle rapid conduction system. The action potentials reach the right ventricle by
traveling relatively slowly through the right ventricular myocardium. So right ventricular depo-
larization is delayed and appears as a second, wide R’ wave in V1 and a deep, wide S wave in
V6 (Figure 7.21b). The right ventricle is an anterior structure and the late depolarization moves
toward V1 and away from V6. The result is the classic configuration for CRBBB in the precordial
leads: an RSR’ in V1, the mirror image in V6, and a wider than normal ventricular complex
(Figure 7.21b).

Complete left bundle branch block (CLBBB)

CLBBB rarely occurs in the absence of structural heart disease. Any heart disease that results in
left ventricular hypertrophy (aortic valvular disease, high blood pressure, cardiomyopathy, etc.)
can result in CLBBB. Myocardial ischemia due to obstruction of a coronary artery can involve
left bundle myocytes and result in CLBBB.
46
 ECG patterns of normal and abnormal heart conduction

(a)

V1 V6
(b)

Figure 7.21  Complete right bundle branch block. (a) is the normal V1 and V6 and (b) is the
configuration in complete right bundle branch block in V1 and V6. P waves are not shown here and
would be normal. The inverted T wave in V1 in (b) is not characteristic of CRBBB and may not be
present.

In the presence of CLBBB, initial ventricular depolarization occurs on the right, anterior side
of the interventricular septum instead of the left, posterior side. Consequently, there is no R
wave in V1 (Figure 7.22b). Septal activation proceeds from right, anterior to left, posterior and
the vector for septal depolarization persistently points toward V6 and away from V1.
The intact right bundle branch conduction system depolarizes the right ventricle sooner
than the left ventricle. This results initially in depolarized, negative tissue anteriorly and not-
yet-depolarized, positive left ventricular tissue posteriorly. This negative to positive, front to
back orientation results in a deep, wide QS wave in V1 (Figure 7.22b). It is wide because depo-
larization of the left ventricle without the left conduction system proceeds slowly among the
left ventricular myocytes.
The notch in the QS wave (Figure 7.22b) is probably due to the less organized travel of
depolarization through the left ventricular myocardium that can occur in the absence of the
left bundle branch conduction system. A notch and any T wave changes are not always present.
The configuration of ventricular depolarization in V6 is, as usual, the mirror image of that in
V1 (Figure 7.22).
CLBBB can contribute to left ventricular dysfunction in heart failure. A relatively new ther-
apy involves using an implanted power source with wires connected to left ventricular myo-
cardium to “resynchronize” left ventricular activation by inducing a more normal sequence of
ventricular action potentials.

WOLFF–PARKINSON–WHITE OR PREEXCITATION
This is an excellent example of correlation of an ECG pattern with abnormal anatomy. In
Wolff–Parkinson–White (WPW) there are abnormal congenital muscle connections (bundles
of Kent) from the atria to the ventricles, which bridge the annulus fibrosus. Conduction in
47
 Electrocardiogram

(a)

V1 V6

(b)

Figure 7.22  Complete left bundle branch block. (a) is the normal V1 and V6 and (b) is the
configuration in complete left bundle branch block in V1 and V6. P waves are not shown here and would
be normal. Any T wave changes from normal are not diagnostic.

these accessory pathways leads to earlier than normal ventricular activation or preexcitation.
Conduction velocity is higher in the muscular connections than in the AV node, so ventricular
depolarization begins sooner than normal in ventricular tissue and bypasses the normal con-
duction system.
Conduction velocity in ventricular muscle is faster than in the AV node, but is slower than in
the conduction system. Thus, initial ventricular depolarization is slower than normal and gen-
erates a slurred initial portion of ventricular depolarization, the delta wave (Figure 7.23, arrow).
Meanwhile, action potentials slowly travel through the AV node and then enter the conduction
system just as normal. Action potentials are then rapidly distributed by the conduction system
to ventricular myocardium and ventricular depolarization after the delta wave is brisk (Figure
7.23). The later portion of the ventricular complex is narrow (Figure 7.23). The delta wave plus

Lead II

Figure 7.23  Wolff–Parkinson–White or preexcitation. The arrow points to the slurred beginning of
ventricular depolarization, the delta wave, so-called because of its similarity to the first part of the Greek
letter Δ. (Reprinted from Differential Diagnosis of Arrhythmias, 2nd ed., Davis D, Copyright 1997, with
permission from Elsevier.)

48
 ECG patterns of abnormal rhythms: Arrhythmias

the later faster inscription of ventricular depolarization result in a prolonged total QRS dura-
tion, greater than 0.11 seconds.
WPW is diagnosed from the ECG when there is: (1) a short PR interval, (2) a wide QRS, and
(3) a slurred initial QRS complex (delta wave) (Figure 7.23). WPW predisposes individuals to
develop tachycardia. The tachycardias can arise due to reentry, which is discussed below.

ECG PATTERNS OF ABNORMAL RHYTHMS: ARRHYTHMIAS

ATRIAL ARRHYTHMIAS
PREMATURE ATRIAL BEATS
Premature atrial beats can occur in normal hearts, but also can be secondary to the effects of
drugs or disease. In a premature atrial beat the P wave occurs earlier than expected (arrows in
Figure 7.24), but the premature P wave is followed by the usual waveforms of ventricular depo-
larization and repolarization.

LOWER ATRIAL PREMATURE BEAT

The arrow indicates lower atrial premature beat (Figure 7.25). The interval from the preceding P
wave to the inverted P wave at the arrow is shorter than the other P to P intervals (Figure 7.25).
The negative polarity of the P wave in this lead II tracing suggests that it originates in the lower

Lead III

Figure 7.24  Premature atrial beats. The arrows point to the P waves occurring earlier than expected.
(Reprinted from Differential Diagnosis of Arrhythmias, 2nd ed., Davis D, Copyright 1997, with permission
from Elsevier.)

Lead II

Figure 7.25  Lower Atrial Premature Beat. A lower atrial premature beat is indicated by the arrow.
(Reprinted from Differential Diagnosis of Arrhythmias, 2nd ed., Davis D, Copyright 1997, with permission
from Elsevier.)

49
 Electrocardiogram

Lead II

Figure 7.26  Atrial flutter. In this case there are four atrial depolarizations for each ventricular or 4:1
conduction. The atrial depolarizations are called flutter waves. One atrial flutter wave is obscured by
each QRS complex. Conduction to the ventricles is not more frequent because of the long refractoriness
of the atrioventricular node. (Reprinted from Differential Diagnosis of Arrhythmias, 2nd ed., Davis D,
Copyright 1997, with permission from Elsevier.)

part of the atria because atrial depolarization is then likely from the bottom of the atria upward
toward the right. That would result in a mean vector for atrial depolarization pointing toward
the negative end of lead II.

ATRIAL FLUTTER
Atrial flutter typically originates in the right atrium. In atrial flutter, action potentials travel a
circular, usually counterclockwise path in the right atrial myocardium affected by drug toxicity,
disease, or surgical scarring. It is an example of a reentrant arrhythmia (reentry is discussed
later) in that depolarizations follow a circular path and re-excite previously depolarized atrial
myocytes. This repetitive circular loop results in depolarization of the atria at a rate of 220 to
350 per minute (Figure 7.26). The frequency is related to path length, a function of the size of
the atrium, and conduction velocity.
The ventricular rate in the example presented here is 70/minute (Figure 7.26). The frequent
atrial depolarizations create a typical “sawtooth” pattern at a frequency in this example of 280/
minute (Figure 7.26). That corresponds to four atrial depolarizations for every one ventricular
or 4:1 conduction. One atrial depolarization is hidden by the simultaneously occurring ventric-
ular depolarization. Every atrial depolarization is usually not followed by a ventricular depolar-
ization due to the long total refractoriness of the atrioventricular node. This is a great example
of the atrioventricular node protecting the ventricles from beating too rapidly when there is a
rapid atrial arrhythmia. Rarely 1:1 conduction occurs with an excessively rapid ventricular rate.

ATRIAL FIBRILLATION
In atrial fibrillation (Figure 7.27) there is random, chaotic atrial electrical activity. The atrioventric-
ular node is randomly bombarded by action potentials. Some of the atrial action potentials induce
atrioventricular node action potentials, which then conduct to the ventricles. Others find the atrio-
ventricular node refractory. The resulting ventricular depolarizations are irregularly spaced (Figure
7.27). Since the atrial electrical activity is random and chaotic, there is no organized depolarization
wave front in the atria and there are no P waves. Likewise, there is no effective atrial contraction,
although that is not measured by the ECG, but can be measured by other means.
There usually are baseline fluctuations, called fibrillation waves, but no consistent P wave
precedes each ventricular complex (Figure 7.27). Atrial fibrillation can occur, for instance,
whenever there is hypertrophy or dilatation of the atria. Recognition of this arrhythmia should
be relatively easy: no P waves + irregular R-R intervals = atrial fibrillation.
50
 ECG patterns of abnormal rhythms: Arrhythmias

Lead II

Figure 7.27  Atrial fibrillation. The baseline fluctuations are fibrillation waves reflective of the random
chaotic atrial depolarizations. (Reprinted from Quick and Accurate 12-Lead ECG Interpretation, 4th ed.,
Davis D, Copyright 2005, with permission from Elsevier.)

The chaotic atrial electrical activity occurs with a usual frequency of 400 to 600 per minute.
The fact that the ventricular rate does not follow at that high frequency is another example of
how the long total refractoriness of the atrioventricular node is protective.

ABNORMAL VENTRICULAR BEATS

VENTRICULAR PREMATURE BEATS
A ventricular premature beat (Figure 7.28), as the name indicates, is a ventricular beat that
occurs earlier than expected. There is no preceding P wave because the premature ventricular
beat most often originates within a ventricular muscle focus. Note that the wave preceding
each of the two premature ventricular beats (arrows in Figure 7.28) is a T wave related to the
previous sinus beat, not a P wave. A ventricular premature beat originating from a ventricular
muscle focus looks very different (arrows in Figure 7.28) than a normal QRS complex. Its shape
and long duration are related to the slower moving, less organized wave front of ventricular
depolarization when the conduction system is not distributing the action potentials. A ventric-
ular premature beat originating in the conduction system would look very much like the other,
normal ventricular depolarizations, but would be premature and without a preceding P wave.
Occasional, isolated ventricular premature beats can occur normally. They are of concern
when they occur in the presence of heart disease or potentially cardiotoxic drugs.

VENTRICULAR TACHYCARDIA
Three or more ventricular premature beats in succession constitute ventricular tachycardia.
In ventricular tachycardia (Figure 7.29), there is an abnormal pacemaker somewhere in the
ventricular myocardium. Usually, the abnormal pacemaker is an area of damaged and unstable
ventricular muscle. There is no P wave preceding each R wave (Figure 7.29) since the ventricular

Lead II

Figure 7.28  Premature ventricular beats indicated by the arrows. (Reprinted from Differential Diagnosis
of Arrhythmias, 2nd ed., Davis D, Copyright 1997, with permission from Elsevier.)

51
 Electrocardiogram

Lead II

Figure 7.29  Ventricular tachycardia. (Reprinted from Differential Diagnosis of Arrhythmias, 2nd ed.,
Davis D, Copyright 1997, with permission from Elsevier.)

Lead II

Figure 7.30  Ventricular fibrillation. (Reprinted from Differential Diagnosis of Arrhythmias, 2nd ed.,
Davis D, Copyright 1997, with permission from Elsevier.)

depolarizations are arising from ventricular muscle. The atria are depolarizing but the P waves
are mostly obscured by the ventricular waveforms. The ventricular rate may be high enough
to limit the time for ventricular filling, but compromised ventricular filling would have to be
evaluated with other than the ECG. Reduced ventricular filling can result in inadequate ven-
tricular pumping, particularly if there is associated ventricular muscle dysfunction, and circula-
tory collapse with shock may occur. If arterial blood pressure falls significantly with ventricular
tachycardia, perfusion of the coronary vasculature will fall and ventricular tachycardia then can
deteriorate into ventricular fibrillation and death.

VENTRICULAR FIBRILLATION
In ventricular fibrillation (Figure 7.30), ventricular electrical activity is random and chaotic.
There is no organized, sequential wave of depolarization.
There is no direct information from the ECG about function, but there is no effective orga-
nized ventricular contraction and no effective pumping of blood by the heart in ventricular
fibrillation. Obviously, ventricular fibrillation results in death within minutes. Fibrillation
waves, giving the appearance of an undulating baseline (Figure 7.30), can be fine or coarse, just
as in atrial fibrillation.

MECHANISMS OF ARRHYTHMIAS

REENTRY
Most arrhythmias occur due to reentry. One example of reentry involves the junction of
Purkinje fibers with ventricular myocardium. Purkinje myocytes are highly branched. Consider
52
 Mechanisms of arrhythmias

Depolarization
path
Purkinje
myocytes

Zone of
unidirectional
block
A B

Ventricular myocytes

Figure 7.31  Model of unidirectional block in a branched Purkinje fiber. In the zone of unidirectional
block (shaded) the zigzag lines indicate the variable or blocked conduction that can occur. The arrow
exiting at the top of the zone of unidirectional block is shaded to indicate a depolarization emerging from
the zone, which may or may not induce depolarizations in the normal Purkinje myocytes.

a simple model of a region where a Purkinje myocyte branches and joins ventricular muscle
(Figure 7.31). Distal Purkinje branches are susceptible to one-way block, called unidirectional
block (Figure 7.31). This can develop in an area injured, for instance, by hypoxia secondary to
inadequate coronary blood flow.
Depolarizations traverse the Purkinje branches (Figure 7.31) and branch A merges with
normal ventricular myocytes. Depolarization is blocked at the zone of unidirectional block in
branch B (Figure 7.31). Depolarizations can propagate in any path that has myocytes ready to
develop an action potential, since all myocytes are interconnected by gap junctions. Hence
action potentials propagate retrograde in the distal part of branch B (Figure 7.31).
One mechanism for a zone of unidirectional block is that hypoxia can affect the excitabil-
ity and refractoriness of myocytes and the effects of hypoxia can vary among myocytes. The
variably damaged cells in the zone of unidirectional block (Figure 7.31) are temporarily not
capable of being depolarized by the depolarizations moving down branch B (Figure 7.31). The
depolarizations in branch A (Figure 7.31) traverse a long pathway in interconnected normal
Purkinje and ventricular myocytes and eventually propagate retrograde in the distal portion of
branch B (Figure 7.31). The Purkinje myocytes in the distal portion of branch B, past the area
of unidirectional block, are normal, interconnected by gap junctions, have not yet depolarized,
and are not refractory.
Enough time may have passed so that the damaged myocytes in the zone of unidirectional
block have recovered enough so that depolarizations arriving retrograde (Figure 7.31) can
induce action potentials in the unidirectional block zone. The action potentials induced in the
damaged cells in the unidirectional block zone are not normal and can vary among myocytes,
so conduction through the blocked zone is usually slower than normal and varies among the
damaged myocytes (Figure 7.31, wavy line).
Depolarizations that get through the zone of unidirectional block now reenter the proxi-
mal part of branch B (Figure 7.31, shaded arrow). The long circular path and slow retrograde
conduction of the action potential through the unidirectional block area can take enough time
for the normal Purkinje cells to reach the end of the relative refractory period. The retrograde
conduction into the proximal part of branch B (Figure 7.31, shaded arrow) may now produce
depolarizations that again conduct down the normal branch A and begin the cycle again.
53
 Electrocardiogram

Each cycle is transmitted to all other ventricular myocytes through gap junctions and a prema-
ture ventricular beat is generated with each “circle.”
This circular or circus movement can produce, for example, one or more ventricular prema-
ture beats or, if sustained, ventricular tachycardia. Gap junctions facilitate the transmission of
each circular depolarization to all other ventricular cells.
Circus movement also can occur in the absence of an area of unidirectional block. All that is
needed is an area of abnormal cells with variable excitability and refractoriness. As depolariza-
tions make their way in a tortuous, abnormally long pathway among and around these abnor-
mal cells they may find a previously depolarized, but now vulnerable area that can be reexcited.
Reentry can occur in other than Purkinje myocytes. It can occur in ventricular and atrial myo-
cardium, in conduction tissue, and in nodal tissue. Atrial flutter was discussed earlier and is an
arrhythmia involving reentrant, circus movement of depolarization, usually in the right atrium.
Reentry or circus movement is prone to occur in the presence of:
• An abnormally long conduction pathway,
• Decreased conduction velocity, and
• A short absolute refractory period of the normal myocardium.

Locally blocked or abnormally slow conduction can occur in numerous abnormal circum-
stances. For instance, in the presence of coronary artery obstruction there is a lack of supply of
oxygenated blood to a region of the myocardium. Abnormal function in the myocytes in such a
region may result in a zone of unidirectional block or create conditions for an abnormal, long,
tortuous, slow conduction pathway and reentry can result. Inflammatory injury can produce
similar effects.
Some drugs used to treat arrhythmias are designed to prolong the absolute refractory period
to prevent reentry phenomena. If the treatment works, depolarizations will either find myo-
cytes still refractory at the area of unidirectional block or depolarizations exiting a zone of
unidirectional block (Figure 7.31, shaded arrow) will find the normal cells still refractory. Also,
the abnormal conduction pathway can be shortened by maneuvers that increase myocardial
oxygenation, such as opening a blocked coronary artery. Clinical cardiac electrophysiologists
can catheterize a patient, insert catheters with contact electrodes, record electrograms from the
inner surface of a heart chamber, map electrical activity, and locate circus patterns. They then
can use catheters that emit high frequency energy to damage minute amounts of myocardium
in the reentry path and stop the circus movement of depolarization.

TRIGGERED ACTIVITY
Triggered activity refers to a second action potential that occurs during phase 2, 3, or 4 (Figure
7.32). Something abnormal happens during a myocardial action potential that “triggers” a sec-
ond action potential to occur during or immediately after that same action potential.
Triggered activity falls into two broad categories, early and delayed afterdepolarizations
(Figure 7.32). Early triggered ventricular or atrial action potentials occur during phase 2 or 3
(Figure 7.32) at a time when the cell should be refractory. A delayed triggered action potential
occurs early in phase 4, closely following the preceding action potential (Figure 7.32).
Myoplasmic Ca 2+ overload is a feature common to both early and delayed afterdepolar-
izations. Ca 2+ influx during an action potential is an essential step in normal excitation-­
contraction-coupling. The Ca 2+ entering, mostly during phase 2, induces the release of Ca 2+
from sarcoplasmic reticulum terminal cisternae and this Ca 2+-induced-Ca 2+-release leads to
myocyte contraction. But too much cytoplasmic Ca 2+ can be a problem.
54
 Mechanisms of arrhythmias

Voltage

Early Delayed
Time

Figure 7.32  Triggered activity. Early and delayed afterdepolarizations are indicated.

Excessive cytoplasmic Ca2+ results in more than normal Na+ exchange with Ca2+ across the
sarcolemma. As noted earlier, this exchange involves 3 Na+ entering for 1 Ca2+ exiting and is
depolarizing. Also, excessive levels of cytoplasmic Ca 2+ can induce a transient inward move-
ment of Na+, the mechanism for which is not well defined. Increased cytoplasmic Ca 2+ nor-
mally stimulates the sarcoplasmic reticulum to take up Ca 2+, which is a normal mechanism for
relaxation. In the presence of excessive cytoplasmic Ca2+, the sarcoplasmic reticulum becomes
overloaded with Ca 2+ and the terminal cisternae begin to spontaneously release Ca2+ into the
cytoplasm, creating repetitive cycles of Ca2+ release and uptake. Release of Ca2+ into the cyto-
plasm leads to more 3 Na+/1 Ca2+ exchange as noted above.
Cytoplasmic Ca 2+ overload can occur, for example, as a complication of drugs such as digoxin
or in the presence of increased sympathetic activity. Ischemia and hypoxia can change myocyte
metabolism in such a way as to lead to Ca 2+ overload.

EARLY AFTERDEPOLARIZATIONS
Early afterdepolarizations (Figure 7.32) tend to occur with action potential prolongation. A
decrease in heart rate normally is accompanied by prolongation of atrial and ventricular myo-
cyte action potentials, particularly phase 2. Normal prolongation of phase 2 with a low heart
rate derives from effects related to I K.
Phase 2 may be excessively prolonged as heart rate slows. This excessive prolongation can
occur, for instance, due to certain drugs (some antiarrhythmics, antibiotics, antihistamines,
etc.). Some myocardial tissues are more prone to this such as left ventricular mid-­ventricular
myocytes, the M fibers, that normally have longer action potentials than the subepicardial and
subendocardial ventricular fibers.
As noted earlier, L-type Ca 2+ channels begin opening during phase 0 of the ventricular
action potential and they deactivate toward the end of phase 2. Abnormal prolongation of
phase 2 can reactivate L-type Ca2+ channels and produce a depolarizing Ca 2+ current and an
early afterdepolarization. The fast Na+ channels are inactivated during phase 2, but an early
afterdepolarization can progress to a Ca2+ action potential. Once atrial or ventricular myocytes
enter phase 3 and the transmembrane potential reaches −60 to −70 mV, some fast Na+ chan-
nels reactivate and can depolarize and produce a phase 3 early afterdepolarization. If the phase
3 afterdepolarization is large enough, an Na+ action potential can result.
One treatment strategy consists of the insertion of a pacing catheter to increase heart rate.
Phase 2 shortens as heart rate increases. This type of temporary treatment would be appropri-
ate for a hospitalized patient.
55
 Electrocardiogram

DELAYED AFTERDEPOLARIZATIONS
Delayed afterdepolarizations are also induced by high intracellular Ca 2+ concentrations as
described above. One scenario could involve a patient with an acute myocardial infarction,
with the accompanying increased sympathetic response to pain or due to autonomic reflexes.
Ca 2+ overload here is related to the fact that catecholamines increase L-type Ca 2+ channel
opening and prolong how long they are open. More Ca 2+ enters the myocytes. Catecholamines
also enhance Ca 2+ uptake by the sarcoplasmic reticulum. The sarcoplasmic reticulum becomes
overloaded with Ca 2+ and the terminal cisternae begin spontaneously releasing Ca 2+ into the
cytoplasm. In this scenario, heart rate will be fast related to increased sympathetic effects on
the sinoatrial node.
What can be confusing in a patient with bradycardia is that the prolonged time for Ca 2+
entry into myocytes and the resulting cytoplasmic Ca2+ overload, discussed above, may lead to
delayed afterdepolarizations as well as to early afterdepolarizations. Clinical decision-­making
here can be perplexing! Afterdepolarizations can be treated with, for instance, drugs that
­partially block Ca2+ or Na+ movement across the sarcolemma.

LONG QT SYNDROME
Repolarization is delayed and the plateau is abnormally prolonged in this syndrome, which
can be either genetic or acquired. The triggered extra beats that occur in the long QT syndrome
occur in phase 2 or 3. This is a special case of early afterdepolarizations. In the most com-
mon genetic form of this problem there is decreased K channel function and repolarization is
delayed. In a less common genetic defect of fast Na+ channels their function is enhanced such
that they open during phase 2 or 3 of the action potential instead of remaining inactivated. In
the acquired form of the long QT syndrome, similar channel changes are induced by effects of
drugs.
A delay in repolarization results in either a long phase 2 or prolongation of phase 3. In either
case the time from the onset of ventricular depolarization on the ECG to the end of the T wave
is longer than normal (Figure 7.33).
The patient can develop afterdepolarizations that can progress to a multiform, multifocal
ventricular tachycardia called Torsades de Pointes (Figures 7.34 and 7.35). Torsades de Pointes
is a rapid polymorphic, polyphasic ventricular tachycardia. “Torsades de Pointes” refers to the
varying amplitude of the ventricular complexes giving the appearance of their “twisting around
a point” or imaginary baseline, as in a party streamer (Figure 7.34). The danger is that this rapid
ventricular arrhythmia can limit ventricular filling time enough to decrease cardiac output and
arterial pressure. Decreased coronary vascular perfusion and myocardial hypoxia then can lead
to ventricular fibrillation and sudden death.

Normal Long QT

Figure 7.33  Normal and congenital long QT syndrome ECG tracings. The larger R wave in the
abnormal recording is not a significant finding.

56
 Mechanisms of arrhythmias

Figure 7.34  Torsade de Pointes. The top drawing illustrates the variable shape of the ventricular
depolarizations (polymorphic) and the frequency (polyphasic). A twisted party streamer is depicted in
the middle of the figure. The lower tracing illustrates the undulating pattern of the ECG waves that led
the authors who originally reported this arrhythmia to describe it as twisting around a point, similar to a
twisted paper party streamer.

Figure 7.35  Torsades de Pointes. (From Goldberger AL. Clinical Electrocardiography. 7th ed.
Philadelphia: Mosby Elsevier; 2006. [16–18, p. 199]).

Clinicians need to be aware of drugs that prolong myocardial action potentials, and if a drug
prolongs the QT interval treatment must be carefully monitored. Identification and treatment
of genetically affected individuals is important to prevent sudden death. There are age and
gender differences in the manifestations of the genetic syndrome that should be taken into
consideration. Clinical research continues, but treatments that are being studied include the
use of β blocking drugs, left cardiac sympathetic denervation, and implantation of a cardio-
verter defibrillator.

57
SECTION CARDIOVASCULAR

II
SYSTEM

About 5 liters of blood per minute circulate around your body even when you are
resting. In other words, 5 one-liter soft drink bottles full of blood moved every 60
seconds! During exercise that amount can increase to 20 liters per minute or more!
Moved from where to where? At any given moment, most of the blood in your body,
60% to 70%, resides in the veins. A major function of the heart is to receive blood
at low pressure from the venous compartment, transport it through the lungs, and
increase the pressure as the blood is ejected into the arterial conduits. The blood
then flows from the high pressure arterial side of the circulation back to the low
pressure venous side, and so on, continuously in a circle, just as demonstrated first
by William Harvey in the seventeenth century.
What does the above have to do with the pathophysiology of heart disease? Just
this—the body’s demand for nutrition supplied by blood flow continues unabated
when ventricular function becomes abnormal. Overall body metabolism persists,
the demand of the body for oxygen continues, and the body’s feedback mechanisms
strive to maintain blood flow into the microcirculation for gas and other exchange.
The feedback mechanisms act mostly via the autonomic nerves to the heart, blood
vessels, and adrenal gland. Quite simply, the body has no mechanisms to rest a
weakening heart. There is a continuing drive to produce cardiac output adequate for
body metabolism. Moreover, this drive continues in the presence of abnormal heart
valves or heart muscle pathology. These continuing demands on the abnormal heart
lead to ventricular dysfunction, adverse myocardial myocyte remodeling, and the
symptoms we diagnose as heart disease.
As you can understand from the above, one cannot diagnose and treat heart
disease without understanding how the normal circulation works, including some
of the simple physics of circulating fluid, how the heart pumps blood, and the char-
acteristics of the peripheral circulation, controls in the circulation, individual organ
circulation, and the microcirculation.
 How the circulation works

BLOOD PRESSURE
A little physics is useful here. Pressure can be measured as the height of a column of fluid con-
nected to a pressurized “container,” such as a blood vessel (Figure 8.1). Use of the height of a
fluid column is based on pressure = ρgh; ρ is fluid density, g is acceleration due to gravity, and
h is the height of the fluid column.
The density, ρ, of a fluid such as mercury or water and the acceleration due to gravity, g, are
known and constant, so pressure can be expressed simply as the height (h) of a column of liq-
uid. Two basic types of pressure measuring devices are illustrated (Figure 8.1a and b).

ENERGY
Most of the energy in the circulation ultimately derives from the hydrolysis of ATP in heart
muscle and conversion of high energy phosphate bonds by sarcomeres into heart muscle
work. Work is done by heart muscle on blood contained within the heart and that work is
transformed into two types of energy: pressure potential energy and energy related to move-
ment, kinetic energy. A third type of energy is not derived from heart muscle function. It is
derived from the effects of gravity on blood in the circulation. Energy in the circulation will
be defined first and then flow will be discussed, including a discussion of gravity’s effects on
the circulation.
Total fluid energy is defined as follows:

Total Energy = Pressure Potential Energy + Kinetic Energy + Gravitational Potential Energy

W   =  P  +  (ρv2)/2 + ρgh

P, pressure potential energy, develops due to the work done on the blood in the ventricle by
the contracting heart muscle myocytes during systole. Contracting ventricular muscle squeezes
blood within the ventricular chambers, which cannot decrease in volume because the valves
are all closed. Blood, like water or saline, is incompressible at in vivo pressures. Pressure builds
up in the blood in the ventricular chambers and when the pressure reaches the pressure level
in the pulmonary artery and aorta, the respective valves are pushed open. The ventricles then

61
 How the circulation works

(a) (b)

Connection to an
artery or vein

Mercury Pressure
transducer

Figure 8.1  Blood pressure measuring devices. (a) Mercury-filled U-tube; (b) electronic pressure
transducer. Pressure is measured in a hospital catheterization laboratory or intensive care unit with
electronic pressure transducers as in (b) The tubing from an artery or vein (b) is filled with sterile saline.
Blood pressure within, for instance, an artery pushes against the saline column in the tubing and the
pressure is transmitted to the pressure transducer (b). A pressure transducer (b) transforms pressure into
voltage that is easily displayed and measured (b). Direct connection to a mercury-filled system (a) has
been used in the past, but is avoided because of concerns about mercury toxicity. Most clinical pressure
measurement devices are spring-loaded or electronic sphygmomanometers. They are smaller and more
convenient to use than a fluid column. Any pressure-measuring device can be called a manometer and
“sphygmo-” refers to pulse. Blood pressure measuring devices are calibrated with a mercury column (a).

push the blood into the great vessels, which already contain pressurized blood. This forces the
vessels to expand and aortic and ­pulmonary artery pressure to increase further.
Kinetic energy, (ρv2)/2, appears because some pressure potential energy is transformed into
movement of the blood through the great vessels; v, velocity, is distance moved per unit time.
Density, ρ, is used to refer all calculations to a unit volume and mass of blood. In a person at
rest, kinetic energy in the circulation relative to the other terms is small, approximately 3% to
5% of total energy, but it increases with, for instance, exercise. The last term, ρgh, appears here
because gravity affects all mass in our world, including the mass of blood in blood vessels.

FLOW
If there is fluid flow in a system of tubes, the flow will occur from a point of higher total fluid
energy to a point of lower total fluid energy. Water and a simple siphon can be used to illustrate
this (Figure 8.2). In this simple model, there is no pump and the only energy to consider is
gravitational potential energy. In this example, the flow of water is slow (low velocity) so that
kinetic energy in the siphon is negligible.
The flow of fluid from 1 to 3 in Figure 8.2a and b depends only on the difference in total
energy at 1 as compared with that at 3 and not on what happens to the tubing between the two
points. The energy at point 1 is equal to the sum of atmospheric pressure + pressure potential
energy due to the height of water above point 1. The energy at point 3 is equal only to atmo-
spheric pressure. The difference in total energy from 1 to 3 is the pressure potential energy that
moves fluid from 1 to 3.
Note also that at point 2 pressure is either higher (Figure 8.2a) or lower (Figure 8.2b) than
at 1 or 3. However, it is the pressure potential energy difference between entry and exit points that
determines flow in a siphon and not on the position of the fluid column in between.
62
 Flow

(a) (b)
2

1 1 3
3

Figure 8.2  Siphon. The numbered locations and Fluid flow in a siphon is discussed in the text.

The siphon model is pertinent for the circulation because in the circulation the key energy
term is pressure potential energy. As noted above, this energy derives from ATP split in ven-
tricular myocyte sarcomeres. They develop force that produces ventricular pressure by squeez-
ing on the blood within the ventricles. By splitting sarcomere crossbridge ATP and converting
chemical into mechanical energy, the ventricles generate blood pressure and force a volume of
blood into the aorta and pulmonary artery. That raises aortic and pulmonary artery blood pres-
sure and blood then flows down a pressure gradient from the aorta, through the organ tissues,
on to the veins and then the right atrium, and from the pulmonary artery through the lungs to
the left atrium, just as in a siphon.
Consider the left ventricle and the peripheral circulation. Flow in the circulation acts like a
siphon. As described in the preceding paragraph, the left ventricle generates blood pressure in
the aorta. Blood pressure in the right atrium is very low. The difference in blood pressure from
the aorta to the right atrium is large and the aorta is connected to the right atrium by blood ves-
sel “tubing” that is filled with blood. Flow occurs from the aorta, through the organ blood ves-
sels, to the right atrium. The same reasoning can be used to explain flow from the pulmonary
artery, through the lungs, to the left atrium.
Blood has mass and is influenced by gravitational forces. This is true for both the arterial
and venous parts of the circulation. In a standing person, venous blood pressure in the foot
is higher than in the right atrium and arterial blood pressure in the foot is higher than in the
aortic arch. Both pressures are higher due to the weight of the column of blood above the foot.
But the physiological effects of gravity acting on the blood are most evident on the venous side
of the circulation due to veins being much more compliant than arteries.
When a person is standing, gravity acting on the venous blood column results in an increase
in venous blood pressure in the lower as compared with the upper body. The venous walls are
compliant, the walls stretch easily and a significant volume of blood shifts from the upper to
the lower body with standing. Gravity also increases blood pressure in the arteries of the lower
body with standing, but arteries have relatively stiff walls that do not stretch as easily and there
is no significant shift of arterial blood volume with standing. There is a presentation of some
effects of gravity on the circulation in the self-study module Transcapillary Exchange: e
Starling Principle of Fluid Movement Across a Capillary Wall.
The high compliance of the veins accounts for the fact that about two-thirds of the circu-
lating blood volume resides in the venous system. As blood flows into the highly compliant
venous system, the walls of the veins are stretched and the volume is then large. The systemic
venous system is characterized by low blood pressure and large blood volume.
All the above brings us to some important concepts: (1) Blood moves through the circulation
because of a pressure potential energy difference; the predominant energy difference from the
63
 How the circulation works

aorta to the right atrium and from the pulmonary artery to the left atrium is the difference in
pressure. (2) There is a significant shift of venous blood volume with postural changes.
Blood flow occurring because of pressure difference, like a siphon, is summarized in this
formula:

P1 − P2
Q=
R

Q is blood flow per unit time and R is vascular resistance. When considering the entire systemic
circulation, Q is the same as cardiac output (CO), the volume of blood pumped per unit time, P1
is mean aortic pressure and P2 is mean right atrial pressure. Resistance in the systemic circula-
tion resides mostly in the arterioles and is discussed in Chapter 11, Peripheral circulation. In the
pulmonary circulation Q, again, is the cardiac output and the pressures of interest would be the
mean pulmonary artery pressure, P1, and the mean left atrial pressure, P2.

BLOOD FLOW TYPES

LAMINAR FLOW
In Figure 8.3, the fluid column is flowing from left to right through the aorta. Blood pres-
sure increase is generated by left ventricular contraction. Fluid in the center of the column is
moving most rapidly. It is as if there are extremely thin concentric, onion-skin-like layers of
fluid rubbing against each other with the central layer flowing the fastest (longest arrow in
Figure 8.3) and the layer in contact with the wall not moving. When layered or laminar flow
is present there is a velocity gradient from fast at the center to slow near the wall. Laminar
flow is also called streamlined flow. The velocity wave front, the line joining the arrowheads,
is parabolic (Figure 8.3).
Laminar or streamline flow exists because the internal rubbing mentioned above produces
shear forces related to internal viscosity and results in an orderly, layered arrangement of flow
velocity. Laminar flow is orderly and silent.
The most numerous formed elements of blood, the red blood cells, are nudged toward the
center of the moving fluid column by the shear forces (Figure 8.3). There is a high concentration
of red blood cells in blood, 4 to 5 million RBCs/µL, and their rubbing and bumping each other
is a major contributor to normal blood viscosity.
The self-study module Cardiac Cycle: Heart Sounds and Murmurs contains a demon-
e
stration of laminar flow and presents its importance for clinical medicine.

Aorta

From left To periphery

ventricle

Figure 8.3  Laminar flow. Normal laminar or streamline flow in the aorta from left to right. Left
ventricular contraction increases aortic blood pressure and flow occurs due to the higher pressure
potential energy in the aorta than in the right atrium.

64
 Blood flow types

TURBULENT FLOW
In the self-study module Cardiac Cycle: Heart Sounds and Murmurs, there is a video
e
demonstration of laminar and turbulent flow. An insoluble black dye is injected into the
center of a stream of clear fluid flowing in a glass tube. The fluid flow rate is controlled and at
the onset fluid flow is laminar or streamlined, with the black dye particles staying neatly in
the center of the flowing fluid, like red blood cells in the aorta (Figure 8.3). Then, fluid flow
velocity is gradually increased and when a critical velocity is reached the flow becomes turbu-
lent. Turbulent flow is chaotic and disorganized rather than laminar and the black dye spreads
throughout the cross-section of the tube due to the whorls and eddies of turbulence.
Once turbulence appears, some of the energy that would have produced an increase in
forward flow now appears instead as chaotic whorls and eddies in the fluid column. This is
dramatically demonstrated in the video in the self-study module Cardiac Cycle: Heart e
Sounds and Murmurs. In simple terms, when velocity, kinetic energy, reaches a high enough
level to overcome the cohesive forces of internal fluid viscosity, organized laminar or stream-
lined flow changes to disorganized, chaotic, potentially noisy and less efficient turbulent flow.
In the self-study module Cardiac Cycle: Heart Sounds and Murmurs, there is a pre-
e
sentation of the effect of adding a constriction in the tube in which fluid is flowing. The
pressure upstream of the constriction must be increased to keep the amount of fluid flowing per
unit time through the constriction the same as before the constriction occurred. The amount of
fluid flowing per unit time is unchanged, but velocity through the constriction is higher. This
is discussed below.
Osborne Reynolds, a nineteenth century Irish engineer, first did the experiment with fluid
flowing in a glass tube, described above. Reynolds showed that average velocity, tube diam-
eter, and the viscosity and density of a liquid are crucial factors determining when turbulence
appears. The Reynolds equation is

v Dρ
Re =
η

where

Re = Reynolds dimensionless number

v = Mean velocity, the velocity of forward fluid flow in cm/sec, averaged across the cross-
section of laminar flow
D = Vessel diameter
ρ = Density of blood
η = Viscosity

Turbulence in the circulation appears when Re increases and stays high. Re must increase
to approximately 2000 for turbulence to appear, but the actual value is influenced by the pres-
ence of pulsatile flow. Also, blood is a complex fluid and its viscosity varies with velocity. Blood
viscosity is reduced at higher velocities because red blood cells tend to line up in the center of
the stream and there is less rubbing and bumping of cells across the velocity wave front. Blood
vessel architecture also influences the occurrence of turbulence, which is more likely to occur
at branch points.
Laminar or streamline flow is well organized and it is silent. Turbulence is chaotic and noisy.
The high velocity jet exiting a narrowing can result in turbulence. The turbulence occurs imme-
diately downstream of the narrow area. One may be able to hear the noise with a stethoscope.
65
 How the circulation works

Such noise from a narrowed heart valve is called a “murmur” and from a narrowed artery or
vein it is called a “bruit.” There are animated demonstrations of turbulence with heart
e
valve narrowing in the self-study module Cardiac Cycle: Heart Sounds and Murmurs.
There is another formula to consider that makes the Reynolds relationship clinically useful.
The formula for velocity is

Q
v=
A

As noted above, v is the mean velocity of forward flow averaged over the flow wave front. A,
the cross-sectional area of a valve orifice or a blood vessel, is calculated with the usual πr2, and
Q is the volume of blood flow per unit time. If this formula does not make immediate sense, try
it with the accompanying units:

 cm  Q(cm 3 /sec)
v  =
 sec  A(cm 2 )

Notice that the units on the right side of the equation reduce to cm/sec, the units for linear
velocity, and is then the same as the left side.
Both D and v are in the numerator in the Reynolds formula and A, area, is πr2 or π(D/2)2.
Logic might lead one to conclude that as D decreases, for instance as an aortic valve narrows, v
will increase and, therefore, Re will not change. But Re does increase in the presence of a narrow
aortic valve and may increase enough that turbulence occurs in the aortic root (ascending aorta
above the valve). The reason Re increases in this instance is that v is inversely related to r2, so v
is an exponential function of r or D (2r) (Figure 8.4). When D decreases enough so that veloc-
ity rises significantly (Figure 8.4), Re can increase enough for turbulence and noise to appear.
The above suggests that with minimal narrowing of a heart valve, turbulence may be absent or
minimal and a murmur will not be audible and that is the case.

2500 Q = 10 L/min

2000
Velocity (cm/s)

1500
Q = 5 L/min

1000
Q = 3 L/min

500

0
0 0.5 1 1.5 2 2.5
Diameter (cm)

Figure 8.4  Velocity at a range of aortic valve areas and at three levels of cardiac output (Q). Normal
aortic valve area is about 3 cm2 with a diameter of about 2 cm.

66
 Clinical significance

Also, note the curves shift downward with decreasing Q (Figure 8.4). In a patient with, for
instance, progressive aortic valve narrowing, cardiac output (Q) at rest will eventually decrease
either due to severely compromised left ventricular heart muscle function or to the extremely
high left ventricular pressure load. The patient will, of course, be severely disabled once Q is no
longer adequate to meet the metabolic needs of the body at rest. As Q falls, velocity also falls
(Figure 8.4). Re may decrease enough so that turbulence lessens or disappears. In other words,
late in the natural history of aortic valve narrowing, left ventricular function may be compro-
mised enough that Q at rest is low and there may be little or no murmur. This emphasizes the
fact that when applying a formula like v = (Q/A) in a clinical situation one must have informa-
tion about two of the variables to draw conclusions about the third. Learn more about this in
e
the self-study module Cardiac Cycle: Heart Sounds and Murmurs.

BLOOD FLOW VELOCITY IN THE CIRCULATION

This formula was used above to assess velocity through a narrow orifice, such as a narrow heart
valve or a partial obstruction of a blood vessel:

Q
v=
A

Velocity of blood flow, v, relative to the amount of blood flow per unit time, Q, becomes
important to consider when analyzing blood flow velocity throughout the body. Normal blood
flow, cardiac output (Q), throughout the body at rest averages about 6 L/min in adults. The total
cross-sectional area of the systemic capillary bed, the sum of πr2 of all the individual capillaries,
is the largest cross-sectional area in the systemic circulation, when compared with the aorta and
its branches, the vena cavae and its branches, and so on (Figure 8.5). The circulation is a closed
system, there are no alternative pathways for blood flow so the entire 6 L/min flows through the
systemic capillary bed. The total 6 L/min of blood flow is divided among the millions of capil-
laries. Consequently, the blood flow and velocity are low in each capillary. The area (A) of the
systemic capillary bed is the largest and the velocity of flow in this region is the smallest in the
systemic circulation (Figure 8.5). Obviously, this is advantageous for gas and other exchange in
the capillary beds. All the above comments also apply to the pulmonary circulation (Figure 8.5).

CLINICAL SIGNIFICANCE
The two formulas, Re and v = (Q/A), are important to consider when murmurs or bruits occur
in the circulation of a patient. For instance, Re increases and turbulence can occur with the
­following changes in the circulatory system.

DIAMETER DECREASES
Narrowing of an artery, vein, or heart valve.

Q AND v INCREASE
The maternal circulating blood volume increases during pregnancy as total body metab-
olism increases with growth of the fetus. Maternal blood volume reaches a maximum at
67
 How the circulation works

(a)

es
eri

ns
art

vei
ary e
l
le

le
ric
m

ary
tric

tric
Lef trium

Lef ium
Rig atriu
Pu vent
Ve aries

ies
s
ole

on

on
en

en
Ve les
es

lar

t r
lm
tv

tv
ht

lm
l
eri
ta

ta
ht
eri

pil

pil
nu
ins
Rig
Art
Lef

Pu

Lef
Art

Ca

Ca
1
Lungs

(b) 2
4000

3500

3000
Cross-sectional area (cm2)

2500

2000

1500

1000 6 cm2
4 cm2
500

(c) 3
20
Velocity (cm/sec)

15

10
0.03 cm/sec
5

0
Location

Figure 8.5  Cross-sectional area and velocity at locations in the circulation. Locations are illustrated at
the top (a). Total cross-sectional area is in (b). Additionally, velocity of blood flow is in (c). The enormous
total cross-sectional area in the systemic and pulmonary capillaries results in very low velocity, since
velocity (v) is inversely related to cross-sectional area (A): v = (Q/A). Q is total flow or cardiac output,
which is the same at all locations in the circulation. (Reprinted from Medical Physiology, 2nd ed., Boron
WF, Copyright 2009, with permission from Elsevier.)

68
 Clinical significance

28–32 weeks of pregnancy. Cardiac output rises in parallel with the increasing blood vol-
ume. More blood volume increases ventricular filling and cardiac output (Q) (discussed
below in Chapter 10, Ventricular function). The increase in Q increases v (v = Q/A) and if
there is enough of an increase, Re increases to a level that results in turbulence. It is not
unusual to hear a murmur that then disappears weeks after delivery when maternal cardiac
output returns to pre-­pregnancy levels.

LEAKING HEART VALVE

If Q and v through a leaking valve or defect is great enough, turbulence and a murmur can
result.

DECREASED VISCOSITY (η)

If anemia is severe enough to decrease η enough, the increased Reynolds number can result in
turbulence in many blood vessels. There are likely to be multiple bruits and a systolic murmur.
Density of the blood, ρ, does not change significantly with various alterations of blood and
changes in ρ are not likely to contribute to the development of turbulence in clinical problems.

69
 Cardiac cycle, heart sounds,
and murmurs
9

THE CIRCULATION
The right atrium (RA) receives blood low in oxygen from the vena cavae and delivers blood to
the right ventricle (RV) (Figure 9.1). The RV pumps blood into the pulmonary artery (PA). The
left atrium (LA) receives oxygenated blood from the pulmonary veins and blood then flows into
the left ventricle (LV). The LV pumps blood into the aorta (Ao) (Figure 9.1).

CARDIAC VALVES
The atrioventricular valves are the tricuspid and mitral valves. The tricuspid valve allows one-
way flow from the RA to the RV and the mitral valve from the LA to the LV. The semilunar
valves are the pulmonic and aortic valves. The pulmonic valve allows only one-way flow from
the RV to the PA and the aortic valve from the LV to the Ao.
All four valves open when pressure on the upstream* side begins to exceed pressure on the
downstream side. The atrioventricular valves close when ventricular pressure increases and
ventricular blood is thrust back toward the atrioventricular valve. The semilunar valves close
when forward flow in the pulmonary artery and aorta ceases and begins to reverse as the ven-
tricles begin to relax.

ATRIAL AND VENTRICULAR PHASES OF THE CARDIAC CYCLE

Left-sided events are depicted in Figures 9.2 and 9.3. Pressures in the right heart chambers are
normally much lower than in the left. Other than pressure levels, the timing and characteris-
tics of events in the right heart are like those in the left heart. The following description of the
cardiac cycle will start at the end of diastole when atrial depolarization occurs.

ATRIAL SYSTOLE AT THE END OF DIASTOLE

“Systole” is derived from a Greek word for contraction. After the sinoatrial (SA) node depolar-
izes, depolarization then spreads throughout the atrial musculature and atrial wall contraction

* Think of the bloodstream as a river. For instance, upstream from the mitral valve are the left atrium,
pulmonary veins, and so on. The left ventricle, aorta, and so on are downstream from the mitral valve.

71
 Cardiac cycle, heart sounds, and murmurs

Figure 9.1  The circulation.

occurs. The tricuspid and mitral valves have been open all through filling and remain open
(Figure 9.2). Atrial muscle contraction (Figure 9.2, atrial systole) increases blood pressure in the
atria, in the veins entering the atria, and in the ventricles. Note the left atrial “a” pressure wave
in Figure 9.3. A similar “a” wave occurs in the right atrium.
Right and left atrial systole occur at the end of ventricular filling (Figure 9.2). Atrial systole
results in a small push of blood from the atria into the ventricles called the atrial “kick.” The
contribution of the atrial kick to ventricular filling is small, but becomes more significant:

Ejection
Atrial Isovolumetric
systole contraction Early rapid Late slow
Ao
LA

LV

Later slow Early rapid Isovolumetric

relaxation
Filling

Figure 9.2  Cardiac cycle events in the left heart. Filling, after early rapid and later slow filling,
concludes with atrial systole and the atrial kick. This is discussed in the text.

72
 Atrial and ventricular phases of the cardiac cycle

3
2 Aorta

Pressure→
Left
Left ventricle
1 atrium
4
a c v

S1 S2
Time →

Figure 9.3  Cardiac cycle. Mitral valve closes after 1, aortic valve opens at 2, aortic valve closes at 3,
and mitral valve opens at 4. S1 is the first heart sound and S2 the second.

• When heart rate is high and time for ventricular filling is short, such as in exercise.
• In a patient in severe heart failure, where the extra ventricular filling becomes important
for adequate ventricular function.

ISOVOLUMETRIC CONTRACTION
Depolarization spreads over the atria and then is delayed in the atrioventricular node. Next
it enters the bundle of His and the bundle branches, then spreads throughout the ventricles.
Ventricular muscle contraction begins and force develops in the ventricular wall. The contract-
ing ventricular wall squeezes the blood within the left ventricular chamber. Blood pressure
within the ventricles starts to increase as ventricular blood is thrust back toward the atrioven-
tricular valves. The tricuspid and mitral valve leaflets are pushed close (Figure 9.2, isovolumet-
ric contraction and 1 in Figure 9.3).
After the mitral valve closes, left ventricular pressure continues to increase (Figures 9.2 and
9.3, from 1 to 2). The mitral valve closes immediately after 1 and the aortic valve will not be
pushed open until 2 (Figure 9.3). The left ventricular pressure increase from 1 to 2 (Figure 9.3)
is termed isovolumetric because the mitral and aortic valves are closed, blood in the ventricles
cannot move, and ventricular volume remains constant. The same occurs in the right ventricle
at close to the same time.
The “c” wave in the left atrial pressure tracing (Figure 9.3) during isovolumetric contraction
is related to a small amount of bulging of the closed mitral valve into the blood-filled left atrial
cavity. The bulging is due to the isovolumetric left ventricular pressure increase causing slight
ballooning of the closed mitral valve. A similar c wave occurs in the right atrial pressure trac-
ing for the same reason. There is ballooning of the closed atrioventricular valves. They do not
normally open at this time.

EJECTION
When ventricular pressure rises to and begins to exceed that in the aorta and pulmonary artery,
the semilunar valves open (Figure 9.2, early rapid ejection; 2 in Figure 9.3). Rapid ejection of
blood from the ventricles into the pulmonary artery and aorta begins. Ventricular volume rap-
idly decreases.
Blood flow out of the ventricles is initially rapid (Figure 9.2, early rapid ejection). Left ventric-
ular and aortic pressure rise to a maximal level (Figure 9.3). Pressure increases simultaneously in
73
 Cardiac cycle, heart sounds, and murmurs

the left ventricle and the aorta (Figure 9.3) because the aortic valve is open. The amount of blood
ejected from the left ventricle into the aorta during early rapid ejection exceeds the amount leav-
ing the arterial system through the arterioles (peripheral runoff). The aortic volume increases,
the proximal aortic wall is stretched, and aortic and left ventricular pressures increase.
Aortic and left ventricular pressures then simultaneously fall from their maximum (Figure
9.3) for two reasons:
• Left ventricular ejection begins to decline (Figure 9.2, later slow ejection). Left ventricular
ejection slows because of relaxation of the ventricular myocytes. Relaxation is related to
Ca2+ uptake by the sarcoplasmic reticulum. This is presented in the self-study module
e
Clinical Heart Muscle Physiology, Part 1: Activation and Relaxation.
• Blood is leaving the aorta and its branches, flowing through the arterioles (peripheral
runoff) and entering the capillary beds around the body. During later slower ejection,
the amount of peripheral runoff exceeds the amount ejected into the aorta by the left
ventricle. Aortic blood volume decreases, the proximal aortic walls are less stretched, and
aortic and left ventricular pressures fall (Figure 9.3).

Similar events are occurring in the right ventricle and pulmonary artery.
Ventricular relaxation continues. Ventricular ejection further slows (Figure 9.2, late slow ejec-
tion) and finally ceases. The column of blood in the aorta immediately proximal to the aortic valve
momentarily moves back toward the aortic valve. This part of the aorta is called the aortic root and
the movement of the aortic root blood column back toward the valve is brief. It is brief because the
moment the blood column moves back toward the valve, the aortic valve promptly closes (Figure
9.2, transition from late slow ejection to isovolumic relaxation and Figure 9.3, valve closure occurs
at point 3). Similarly, pulmonary artery flow reverses and the pulmonary valve closes.
When the aortic valve closes, the column of blood in the aortic root bounces against the
closed valve. The aortic root blood column, the aortic valve, and the aortic root wall vibrate. The
vibrations are manifest in the aortic pressure tracing as a notch and rebound (Figure 9.3, notch
in the aortic pressure tracing at point 3). This notch is called the dicrotic notch or incisura. There
is a similar notch in a pulmonary artery pressure tracing.

ISOVOLUMETRIC RELAXATION
Isovolumetric relaxation begins as soon as the pulmonary and aortic valves close (Figure 9.2,
isovolumetric relaxation and Figure 9.3, from point 3 to 4). The atrioventricular valves remain
shut because ventricular pressures are still higher than atrial pressures (Figure 9.2, isovolu-
metric relaxation). All the valves are now shut. Ventricular muscle relaxation continues and
intraventricular pressures decrease (Figure 9.3, left ventricular pressure decrease from 3 to 4).

DIASTOLIC FILLING
The tricuspid and mitral valves open (Figure 9.2, early rapid filling and Figure 9.3 at point 4) as
soon as ventricular pressure drops to and then below the level of atrial pressure. The pulmo-
nary and aortic valves remain shut (Figure 9.2).
The atria have been isolated from the ventricles and filling during isovolumetric contraction,
ejection, and isovolumetric relaxation. The atrioventricular valves remain shut throughout ven-
tricular ejection because ventricular pressure is higher than atrial pressure. Pulmonary artery
mean pressure is higher than left atrial mean pressure during this time and the left atrial wall is
compliant. Blood flows through the pulmonary circulation much like a siphon from pulmonary
74
 Heart sounds

artery to left atrium and left atrial filling results in a rise in atrial pressure called the v wave
(Figure 9.3). Aorta to right atrium blood flow occurs for similar reasons and right atrial filling
also results in a v wave.
At the conclusion of isovolumetric relaxation, the atria are engorged with blood and their
walls are stretched (Figure 9.2). When the atrioventricular valves open, ventricular filling is
initially very rapid (Figure 9.2, early rapid filling). This is a passive transfer of blood from atria
to ventricles driven by elastic forces in the atrial walls—no muscle contraction is involved. The
filling is aided by rapid ventricular relaxation continuing during the beginning of the diastolic
filling period—note the decrease in ventricular pressure after 4 in Figure 9.3. The ventricles
develop a small amount of suction at this time that aids filling. The initial increase in ventricu-
lar volume is rapid and about 80% of ventricular filling occurs during early rapid filling.
After early rapid ventricular filling, the heart functions as if composed of two chambers, a
right and left. The right atrium and ventricle fill from the vena cavae and the left atrium and
ventricle fill from the pulmonary veins. Filling is now slower than initial rapid filling and filling
lasts until the onset of the next cardiac cycle (Figures 9.2 and 9.3 from point 4 to point 1).
As noted above, about 80% of ventricular filling occurs during early rapid filling. Another 5%
of filling occurs during later slow filling until atrial systole. Atrial kick contributes the remain-
ing, approximately 15% of filling. The diastolic filling period then consists of three phases: early
rapid filling, slower filling and atrial kick.

NORMAL INTRAVASCULAR PRESSURES IN PEOPLE

Pressure (mm Hg)

Location Average value Normal range

Right atrium 3 (mean) 2–7 (mean)
Right ventricle peak systolic 25 15–30
 End-diastolic 4 1–7
Pulmonary artery peak systolic 25 15–30
 Diastolic 9 4–12
Left atrium 8 (mean) 2–12 (mean)
Left ventricle peak systolic 130 90–140
 End-diastolic 8 5–12
Aorta systolic 130 90–140
 Diastolic 85 60–90

HEART SOUNDS

FIRST HEART SOUND, S1

S1 is low in frequency and occurs through most of isovolumetric contraction (Figure 9.3). At the
onset of ventricular contraction, blood in the ventricles is pushed toward the atrioventricular
valves. The atrioventricular valves are pushed closed and this results in the first prominent
component of S1, mitral and tricuspid valve closure. The vibrating valves, oscillations in the
blood in the ventricles, and vibrations of the ventricular wall all contribute to the long low
frequency S1.
75
 Cardiac cycle, heart sounds, and murmurs

SECOND HEART SOUND, S2

As noted earlier, the aortic valve closes at the end of ejection when the column of blood in the
aortic root begins to move back toward the valve. Similar events occur in the pulmonary artery
and pulmonary valve. Vibrations occur in the taut valve leaflets, the vessel wall adjacent to the
valve, and in the suddenly decelerating blood column. These oscillations result in the notch
and rebound in pressure recordings from the aorta or pulmonary artery, the dicrotic notch or
incisura, that is coincident with S2 and is discussed above (Figure 9.3, point 3).
S2 is higher in frequency than the first sound, in other words, it is “snappier.” Normally,
pulmonary valve closure (P2) is later than aortic valve closure (A2). The delay of P2 increases
during inspiration (Figure 9.4). This “splitting” of the second sound into an aortic component
followed by a pulmonary artery component is audible during normal inspiration. The splitting
is not pictured in Figure 9.3.
The inspiratory S2 split occurs because intrathoracic pressure drops further below atmospheric
during inspiration. The intrathoracic pressure is the pressure inside the chest, but outside the
lungs, heart, and intrathoracic blood vessels. This decrease in pressure below atmospheric pres-
sure (suction) outside the heart and intrathoracic blood vessels affects these structures because
their size depends on the pressure difference across their walls, the inside minus the external
pressure. This pressure difference is called the transmural pressure, Pt. As an example, Pt for the
pulmonary artery is blood pressure within the pulmonary artery minus the pressure within the
thorax external to the pulmonary artery, the intrathoracic pressure. This fits with the definition of
Pt as the pressure internal to a hollow structure (Pi) minus the external pressure (Pe).

Pt = Pi − Pe

Consider the pulmonary artery and its major branches external to the lung, the extrapul-
monic pulmonary arterial vessels. Intrathoracic pressure is the Pe and blood pressure inside the
extrapulmonic pulmonary arteries is Pi. As intrathoracic pressure (Pe) decreases with inspira-
tion, Pi does not significantly change and Pt increases. The result is an increase in diameter of
the extrapulmonic pulmonary arterial vessels. This increases the capacity (capacitance, Figure
9.5) of extrapulmonic pulmonary arterial blood vessels. This increased pulmonary arterial
capacity in inspiration permits forward blood flow in the pulmonary artery to last longer than
in expiration. Think of this as “more room” for blood flow. During inspiration the duration of
pulmonary artery blood flow is longer, the reversal of blood flow in the pulmonary artery is
delayed, pulmonary valve closure is delayed, and P2 occurs later (Figures 9.4 and 9.5).
More room or capacity in the extrapulmonic pulmonary arteries during inspiration suggests
there is more blood in those vessels during inspiration and there is. The intrathoracic negative

A2 P2

Inspiration

Expiration

A2 P2
Time

Figure 9.4  Bar diagram of second heart sound splitting. A2 refers to the aortic component and P2 to
the pulmonic component of S2.

76
 Heart sounds

↓ Intrathoracic pressure
below atmospheric (suction)

↑ Pulmonary artery ↑ Pulmonary venous

capacitance capacitance
↑ RA/RV filling
↓ LA/LV filling

↑ RV stroke volume ↓ LV stroke volume

Delayed pulmonary
valve closure Earlier aortic valve closure

Delayed P2 Earlier A2

S2 splitting

Figure 9.5  Second heart sound splitting mechanisms. RA = right atrium, RV = right ventricle, LA = left
atrium, LV = left ventricle, P2 = pulmonic component of the second heart sound (S2), and A2 = aortic
component of S2.

pressure or suction created during inspiration is the Pe, the intrathoracic pressure external to
the right heart structures, including the thoracic portion of the cavae, right atrium, and right
ventricle. The increased Pt in those structures draws systemic venous blood into the right heart
during inspiration. Right ventricular filling and stroke volume increase (Figure 9.5). The normal
splitting of S2 then is the interplay of changes in extrapulmonic pulmonary arterial capacitance
with changes in right heart filling and stroke volume (Figure 9.5).
Another result of the decrease below atmospheric pressure in the thorax during inspiration is
an increase in extrapulmonic pulmonary venous capacitance (Figure 9.5). The pulmonary veins
external to the lungs are thin-walled and very compliant. They hold more blood during inspira-
tion and less blood then flows to the left atrium and ventricle (Figure 9.5). Left ventricular filling
is reduced, stroke volume is less, ejection ends earlier, aortic valve closure is earlier (Figure 9.5),
and A2 occurs slightly earlier. The delay in pulmonary valve closure during inspiration contrib-
utes much more to S2 splitting than the earlier closure of the aortic valve (Figure 9.4).

THIRD HEART SOUND, S3

During early rapid ventricular filling (Figure 9.2), a low pitched third heart sound may be heard in
normal young people, below the age of 30–40 years (Figure 9.6). The likely mechanisms include
vibrations in the ventricular wall related to the rapid filling. An S3 can be normal or abnormal.
A third heart sound may be audible at the apex when:
• Blood flow rate and the rate of ventricular filling are high.
 Examples: anemia, fever, or pregnancy.
• Either ventricle is dilated, there is increased ventricular wall stiffness, or both.
  Example: heart disease accompanied by abnormally increased ventricular filling and
ventricular hypertrophy. Obviously, this would be an abnormal S3.
77
 Cardiac cycle, heart sounds, and murmurs

3
2 Aorta

Left

Pressure →
Left ventricle
1 atrium
4
a c v

S3
S1 S2
Time →

Figure 9.6  Third heart sound (S3). S1 and S2 are the first and second heart sounds, respectively.

3
2 Aorta

Left
Pressure→

Left ventricle
1 atrium
4
a c v

S4
S1 S2
Time →

Figure 9.7  Fourth heart sound (S4). S1 and S2 are the first and second heart sounds, respectively.

FOURTH HEART SOUND, S4

A sound can occur coincident with atrial contraction (Figure 9.7) and result from the atrial
“kick” in the presence of a stiffer than normal ventricle. The sound is likely generated by vibra-
tions of the ventricular wall and the blood in the ventricular lumen. Ventricular hypertrophy
with increased ventricular wall stiffness is the typical situation that produces an S4. It is not
heard in normal people.

MURMURS DURING THE CARDIAC CYCLE

Acquired or congenital valvular heart disease occurs when a valve orifice becomes narrowed
(valvular stenosis) or when a valve does not close completely (valvular insufficiency or regur-
gitation). A noise or murmur occurs in the presence of valvular stenosis because of turbulence
immediately downstream of the defect. The turbulence is upstream of a leaking valve. The
location of turbulence with a heart valve defect and other features of murmurs are pre-
e sented in the self-study module Cardiac Cycle: Heart Sounds and Murmurs. The module
includes animations of streamline flow, turbulence, and murmurs.
There are two definitions of systole and diastole. The clinical definition is an outgrowth of
classifying murmurs and began early in the use of stethoscopes. The physiological definition of
78
 Murmurs during the cardiac cycle

systole and diastole is based on more recent hemodynamic measurements and an understand-
ing of myocardial mechanics. The definitions are as follows:

1. Clinical systole consists of the events from S1 to S2 and include isovolumetric contraction
and ejection. Clinical diastole is from S2 to the next S1 and includes isovolumetric
relaxation and the diastolic filling period.
2. Physiological systole consists of events from the closure of the atrioventricular valves to
the valves opening and includes isovolumetric contraction, ejection, and isovolumetric
relaxation. Physiological diastole consists of the diastolic filling period.

Murmurs are named using the clinical definition of systole and diastole and that is what will
be used throughout the following discussion.
The aortic valve will be used for the examples in the following discussion of murmurs.
Murmurs related to defects in the other valves can be analyzed using the principles presented
here. There is a more extensive discussion of murmurs and heart sounds in the self-study
e
module Cardiac Cycle: Heart Sounds and Murmurs.

SYSTOLIC MURMUR
If the aortic valve orifice is narrow (aortic valvular stenosis), turbulence occurs in the root of
the aorta during ejection. If the turbulence generates vibrations with enough energy, the tur-
bulence can be audible as a systolic murmur. The murmur can be recorded (phonocardiogram)
with a microphone placed on the chest (Figure 9.8).
The murmur of aortic valvular stenosis cannot begin until flow starts through the narrowed
aortic valve orifice. The murmur cannot start until ejection begins at the end of isovolumetric
contraction. S1 is heard during isovolumetric contraction and should be audible and normal
since the murmur does not start until the end of isovolumetric contraction. The murmur should
end toward the end of ejection when flow out of the left ventricle into the aorta slows. With
slower flow during later, slower ejection, there is reduced velocity and turbulence. The second
heart sound should be audible. Similar reasoning can be used for the murmur of pulmonary
valvular stenosis. There is a complete presentation of the characteristics of this type of
e
murmur in the self-study module Cardiac Cycle: Heart Sounds and Murmurs.

Left ventricle

Aorta
Pressure→

Left atrium

ESM
S1 S2
Time →

Figure 9.8  Left ventricular and atrial pressure, aortic pressure, and the phonocardiogram in aortic
valvular stenosis. S1 is the first heart sound and S2 the second. ESM = ejection systolic murmur.

79
 Cardiac cycle, heart sounds, and murmurs

A systolic murmur can be present without a defect of the heart or great vessels (see section
on turbulent flow in Chapter 8, How the Circulation Works). Such a so-called “innocent” or
“flow” or “physiologic” murmur is typically systolic.

DIASTOLIC MURMUR
If the aortic valve does not close tightly, blood will leak into the ventricle from the aorta during
isovolumetric relaxation at the onset of diastole. The murmur of aortic valvular insufficiency
(also called aortic valvular regurgitation) begins with A2 and lasts through a portion of diastole
(Figure 9.9). A2 may be diminished or absent when the valve deformity limits aortic valve leaf-
let movement. P2 is often obscured by the murmur.
Note: With the diastolic murmur of aortic valvular insufficiency, the turbulence is in the left
ventricle immediately upstream of the aortic valve. An ejection systolic murmur (Figure 9.9)
may be present if the aortic valvular insufficiency is severe enough. It is likely due to the large
diastolic filling of the left ventricle from the regurgitant flow plus the usual filling from the left
atrium. The left ventricular wall is stretched more and there is a large total stroke volume. The
large flow out of the left ventricle during ejection results in high velocity and increases Re. If Re
increases enough there will be systolic ejection turbulence.
Here is how to figure out when in the cardiac cycle a murmur will likely occur for a specific
valve defect. For example, consider mitral valvular stenosis (narrowing of the mitral valve ori-
fice). This is a defect in which the valve does not fully open. The steps to define the timing of
the murmur are
• First, have clearly in mind when in the cardiac cycle the valve is supposed to be fully
open or completely closed. The mitral valve should be fully open during the entire
diastolic filling period, but in mitral valvular stenosis, the mitral valve cannot fully open.
• Second, pinpoint the part of the cardiac cycle where the valve malfunction will be
manifest. The mitral valve is supposed to open fully at the end of isovolumetric relaxation
and the beginning of filling of the left ventricle. It is supposed to stay open throughout
the diastolic filling period.

Aorta
Pressure→

Left
ventricle
Left
atrium

ESM DM
S1 S2
Time →

Figure 9.9  Left ventricular and atrial pressure, aortic pressure, and the phonocardiogram in aortic
valvular insufficiency/regurgitation. S1 is the first heart sound. S2 is the second heart sound and is
obscured by the diastolic murmur, DM. ESM = ejection systolic murmur.

80
 Murmurs during the cardiac cycle

• Obviously, flow through the mitral valve orifice normally occurs when it is open. If it is
narrow and cannot fully open, that is when a murmur will occur. Therefore, the murmur
of mitral stenosis can be present all through the diastolic filling period. The murmur
must end with S1. Closure of the mitral valve ends flow across the valve and the murmur.

There is a detailed presentation of mitral valvular stenosis and other valve defects in
e
the self-study module Cardiac Cycle: Hearts Sounds and Murmurs.

81
 Ventricular function

10

Ventricular function is best understood after studying heart muscle function. Preload, con-
tractility, and afterload are the major determinants of ventricular function and are functional
parameters based on ventricular myocyte mechanical properties. The accompanying three-
part self-study module, Clinical Cardiac Muscle Physiology, explores heart muscle e
physiology and is designed to facilitate the study of ventricular function. You will be at a
disadvantage if you do not do the module before considering ventricular function.

PRELOAD

CHANGES IN VENTRICULAR FILLING

The volume of ventricular ejection, the stroke volume, is partly determined by the amount of
preceding diastolic filling. The meaning of the relationship in Figure 10.1 is that the more a
ventricle fills, the more it ejects. Ventricular filling stretches ventricular wall myocytes. With
less filling, stroke volume is less and with increased filling, stroke volume increases. This is the
Frank–Starling law of the heart. The law is another way of stating that the length of ventricular
wall myocytes at the end of filling, the preload, is one major determinant of ventricular func-
tion. An increase in ventricular end-diastolic volume is accompanied by an increase in resting
myocyte length and resting sarcomere length. Preload and the effect of resting myocyte
length on cardiac muscle function is presented in the self-study module Clinical Heart e
Muscle Physiology, Part 2: Muscle Mechanics Made Easy.
Stroke volume (SV) (Figure 10.1) and cardiac output (CO) are relatively simple measures
of ventricular performance used in the following discussion. Stroke volume is the amount of
blood ejected by a ventricle during a single cardiac cycle. Cardiac output is the amount of blood
pumped by the heart per minute and is the product of the stroke volume (amount ejected per
cardiac cycle) and the heart rate (cardiac cycles per minute).

 mL blood   mL blood   beats 

CO  = SV  × HR 
 min   beat   min 

Representative factors that result in increased or decreased ventricular filling and end-­
diastolic volume are noted below the horizontal axis in Figure 10.1. The amount of ventricu-
lar filling sets the end-diastolic volume and length of ventricular wall myocytes. Ventricular
83
 Ventricular function

Stroke volume
Diastolic End-diastolic volume Skeletal
filling muscle pump
Total blood Intrapericardial
volume pressure
Body Intrathoracic Venous
position pressure tone

Figure 10.1  Frank–Starling law of the heart. A representative sample of influences on end-diastolic
volume are arrayed below the horizontal axis.

filling and the Frank–Starling law are important in the normal heart for beat-by-beat regulation
of stroke volume and for accommodation of the ventricles to the amount of circulating blood
volume.
Reduced total blood volume becomes clinically important, for instance, in dehydration or
blood loss. Changes in ventricular filling due to changes in intrathoracic pressure during normal
respiration were presented earlier in the discussion of S2 splitting (Chapter 9, Cardiac cycle, heart
sounds and murmurs). Stroke volume varies with respiration, but is the same in the two ventricles
when averaged over multiple respiratory cycles. The skeletal muscle pump refers to the intermit-
tent compression of lower extremity deep veins with cyclic muscle contraction during walking or
running. The lower extremity deep veins are surrounded by muscle and have valves. Compression
of the veins moves venous blood toward the heart through the valves that are pushed open. With
relaxation, the venous blood starts to move backward, but the valves close. Thus, with lower
extremity rhythmic exercise deep venous blood is pumped toward the right atrium.
The pericardial sac normally contains a small amount of serous fluid under negligible pres-
sure for lubrication of the sac internal surfaces. If, for example, pericardial inflammation, peri-
carditis, results in excess sac fluid accumulation, sac pressure can increase to an extent that limits
ventricular filling. Even the normal pericardial sac acts to prevent excessive ventricular filling.
Body position influences end-diastolic volume because of the effects of gravity. In upright
­posture, there is a shift of venous blood to the lower body and reduced ventricular end-­
diastolic volume. This is discussed in the section on arterial neural baroreceptors in Chapter 12,
Circulatory Controls. The effects of gravity on the circulation are presented in the self-
e
study module Transcapillary Fluid Exchange.

PRESSURE-VOLUME LOOP
Ventricular pressure and volume during the cardiac cycle can be plotted to create a pressure-
volume loop (Figure 10.2). Pressure-volume loops are useful to evaluate ventricular function
and the area of the loop is a measure of ventricular work.
The end of the diastolic filling period and closure of the mitral valve is at point A in the
cardiac cycle (Figure 10.2). The end-diastolic pressure is low in a normal ventricle and the vol-
ume is large so A in the pressure-volume loop figure is at a high volume, low pressure point
(Figure 10.2). Pressure rises from A to B without a change in volume during the isovolumetric
84
 Contractility

C D
B Aorta

C
Pressure→

Left
ventricle D
A (aortic valve

Pressure →
E B
closes)
a c v (aortic valve
SV opens)

Time → E (mitral valve

opens) A
(mitral valve
LV volume

closes)
EDV
Volume →

ESV

Figure 10.2  Construction of a pressure-volume loop. EDV is end-diastolic volume and ESV is end-
systolic volume. SV is stroke volume.

contraction phase of the cardiac cycle (Figure 10.2). At B, the aortic valve opens and ventricular
ejection occurs from B to D as left ventricular pressure rises to a maximum at C.
The aortic valve closes at D and the isovolumetric relaxation phase of the cardiac cycle, D to
E, begins. At E, the mitral valve opens (Figure 10.2) and ventricular filling proceeds from E to A.
Ventricular relaxation finishes with a further drop in pressure after E. (Figure 10.2). The hori-
zontal distance in the pressure-volume loop from point A to D (Figure 10.2) is the stroke volume.
A ventricular pressure-volume loop changes with an increase in preload based on the Frank–
Starling law of the heart discussed earlier (Figure 10.1). An increase in ventricular volume from
A to A′ stretches ventricular wall sarcomeres, improves function, and increases stroke volume
(Figure 10.3). D shifts to the right to D′ with more filling and to D″ with additional filling. The
stroke volume as measured by the horizontal distance from A to D increases to A′ to D′ and
further increases to A″ to D″.
The end-systolic pressure-volume points D, D′, and D″ define a linear relationship, the end-
systolic pressure volume relationship (ESPVR) (Figure 10.3). The slope of the ESPVR defines
an inotropic state or level of contractility. The fact that D, D′, and D″ all fall on the same ESPVR
indicates contractility has not been changed by changes in filling. In this example, stroke vol-
ume increased due to an increase in filling, not an increase in contractility. The ESPVR inter-
sects the horizontal axis at close to zero, which is beyond the left edge of the graph.
Contractility is presented in the self-study module Clinical Heart Muscle Physiology,
e
Part 3: Cardiac Contractility.

CONTRACTILITY

VENTRICULAR FUNCTION CURVES

Ventricular function cannot be explained in all circumstances with one Starling curve. For
instance, changes in sympathetic stimulation can change ventricular function without a change
85
 Ventricular function

End-systolic
pressure volume
relation

Ventricular pressure (mm Hg)

C″
D″ C′
D′ C
D
B B′ B″

A A′ A″
E E′ E″

Ventricular volume (mL)

Figure 10.3  Pressure volume loops and end-systolic pressure-volume relation with changes in
ventricular filling. As described in the text and shown in Figure 10.2, stroke volume (SV) is the horizontal
distance from A to D. SV is increased as end-diastolic volume increases to A′ and A″.

in end-diastolic volume. A change in function without a change in end-diastolic volume only

can happen with shift to a different Starling or ventricular function curve (Figure 10.4).
Sympathetic stimulation of heart muscle occurs in two ways:

• Release of norepinephrine at cardiac sympathetic nerve endings.

• Mostly epinephrine and some norepinephrine released from the adrenal medulla, borne
by the bloodstream to the coronary circulation and carried in the coronary blood to the
cardiac myocytes.

Neurotransmitter and hormonal catecholamines interact with β receptors on the surface of

myocytes. This interaction with myocyte β receptors initiates a cascade of intracellular events
that results in an increase in the myocardial contractile state. The effects involve increased
inward Ca 2+ movement through sarcolemmal L-type Ca2+ channels, cAMP and increased

Circulating
catecholamines
Sympathetic
nerves
Force-
frequency
Stroke volume

Intrinsic
depression
Anoxia
acidosis
Drugs
Loss of
myocardium
End-diastolic volume

Figure 10.4  A family of ventricular function curves. Some of the influences on ventricular contractility
are listed.

86
 Contractility

Ca 2+-induced release of Ca 2+ from the sarcoplasmic reticulum terminal cisternae. The resulting
increase in ventricular function can occur with no change in end-diastolic volume and cannot
be explained by a single ventricular function curve.
Each curve in Figure 10.4 characterizes the relationship of end-diastolic volume with ven-
tricular performance for a contractile or inotropic state of ventricular myocardium. A normal
ventricle moves among the curves mostly due to moment-to-moment changes in ventricular
muscle contractile or inotropic state secondary to more or less sympathetic stimulation. As dis-
cussed earlier, the level of function along one curve is determined by the amount of ventricular
filling, the end-diastolic volume.
Some factors that increase or decrease contractility or the inotropic state are noted in
Figure 10.4. Force-frequency in Figure 10.4 refers to treppe, discussed in the self-study
module Clinical Cardiac Muscle Physiology Part 3. Cardiac Contractility. The effects of
force-­frequency (heart rate) on ventricular contractility are small relative to the effects of
sympathetic stimulation and circulating catecholamines. Catecholamine effects on con-
tractility are also discussed in the Clinical Cardiac Muscle Physiology Part 3 module. e
Intrinsic depression refers to depressed contractility that occurs in some types of ventricular
dysfunction. Myocardial infarction resulting from lack of coronary blood flow to a portion
of a ventricle is the most common example of loss of myocardium mentioned in Figure 10.4.
Myocardial infarction and resulting ventricular dysfunction is discussed in the self-
e
study module Myocardial Infarction and Chronic Heart Failure. Many drugs depress
contractility, including certain anesthetic agents. There are also drugs that increase contrac-
tility. Anoxia and acidosis are obvious examples of changes in the chemical environment of
myocytes that can adversely affect their function.

PRESSURE-VOLUME LOOP AND CONTRACTILITY

An increase in contractility is expected to result in more ventricular force development and
faster and more myocyte shortening. The ventricle should empty more and develop more
pressure.
As an example, suppose sympathetic stimulation of a ventricle increases. Remember, every
cardiac myocyte is innervated by sympathetic nerves. The increased sympathetic stimulation
results in an increase in myocyte contractility. Function shifts to a higher ventricular func-
tion curve and stroke volume likely increases (Figure 10.4). Note the leftward shift of the

C′
Ventricular pressure →

C
D′
D
B

A
E′ E

Ventricular volume →

Figure 10.5  Ventricular pressure-volume loops with increased contractility. Points A and B are the
same for both loops. The broken line loop resulted after an increase in contractility.

87
 Ventricular function

end-systolic pressure-volume point D leftward to D’ onto a new, steeper ESPVR (Figure 10.5).
The ESPVRs in Figure 10.5 intersect the horizontal axis at close to zero off the left side of the
graph, just as in Figure 10.3.
This type of ESPVR shift is one measure of an increase in ventricular contractility. Stroke
volume is increased as evidenced by the increase in the horizontal distance AD to AD’. In this
portrayal, there is no change in end-diastolic volume, A.
The end-systolic pressure-volume point D has shifted to D’ on a new steeper end-systolic
pressure-volume relation, an indication of an increase in contractility (Figure 10.5). Here the
stroke volume has increased due to an increase in contractility, but with no change in the extent
of ventricular filling (preload).

AFTERLOAD
The afterload is the load on a ventricle during contraction. It is called “afterload” because it
is the load on the ventricles after contraction begins. A precise measure of ventricular after-
load involves measuring ventricular wall stress or force, since wall force is what myocytes
must work with during pressure development and shortening. Intraventricular pressure and
chamber radius must be measured to estimate wall stress. Fortunately, aortic pressure is
more easily measured and serves as an index of the level of afterload for the left ventricle and
for the right ventricle it is pulmonary artery pressure.
Normal left ventricular afterload increases with increases in aortic systolic blood pressure.
For instance, afterload increases with a reflex increase in peripheral vascular resistance with
skin vasoconstriction in cold ambient temperatures. Aortic systolic pressure increases and a
sequence of events occurs in a normal heart that mostly preserves left ventricular stroke vol-
ume (Figure 10.6):
• The increased load on left ventricular myocytes causes them to shorten less and more
slowly in the first few beats after aortic pressure increases. The effects of load on
e myocyte shortening is presented in the self-study module Clinical Cardiac Muscle
Physiology, Part 2: Muscle Mechanics Made Easy.
• Stroke volume decreases in those first few beats. This is not shown in Figure 10.6.
• More blood remains in the left ventricle at the end of ejection. In other words, end-
systolic volume increases.

Excessive Ao
Normal pressure
Stroke volume →

Decreased
contractility

Aortic systolic pressure →

Figure 10.6  Stroke volume response to changes in aortic systolic pressure in normal ventricles and
with decreased contractility. Ao = aortic.

88
 Afterload

• The usual amount of filling of the left ventricle adds to the increased blood left in the
ventricle (the increased end-systolic volume) and the end-diastolic volume increases.
• The resultant increase in end-diastolic volume returns the stroke volume almost to where
it was before aortic pressure increased.

In summary then, the steady state response to an increase in afterload in a normal left
ventricle is an increase in both end-diastolic and end-systolic volume, with a slight decrease
in steady state stroke volume (Figure 10.6). In a normal ventricle, the stroke volume is close to
unchanged when aortic pressure changes (Figure 10.6).
The preservation of steady state stroke volume when ventricular afterload increases can be
described using pressure-volume loops (Figure 10.7). The horizontal distance A′ to D′ is slightly
less than that for A to D. End-diastolic volume increased from A to A′ as did end-systolic vol-
ume from D to D′. ESPVR does not shift so the response to the increased afterload is not due to
a change in contractility, but rather to more filling. Normally stroke volume decreases very little
with pressure increases up to an aortic systolic blood pressure of approximately 170 mm Hg.
Stroke volume will decrease with an extreme, acute increase in aortic systolic blood pressure
(Figure 10.6, excessive Ao pressure). These excessively high levels are not likely to occur in a
normal person who is not exercising.
A diseased heart with depressed contractility functioning on a lower ventricular function
curve (Figure 10.4) responds abnormally to an increase in afterload. The increase in end-
systolic volume is larger than normal relative to the increase in end-diastolic volume and
steady state stroke volume decreases (Figure 10.6). The reason for this is that the diseased
myocytes respond less to stretch (increased end-diastolic volume) than normal. Ventricular
steady state stroke volume decreases with increases in afterload when contractility is
decreased (Figure 10.6).
Many patients with heart failure have increased peripheral vascular resistance and increased
left ventricular afterload. Current treatment of this type of heart failure includes medications
that reduce peripheral vascular resistance to unload the left ventricle. This type of treatment

End-systolic
pressure volume
relation

C′
Ventricular pressure →

D′ C
D B′
B

A A′
E E′

Ventricular volume →

Figure 10.7  Pressure-volume loops with an increase in afterload. The broken line loop resulted after an
increase in afterload.

89
 Ventricular function

has been shown to reduce mortality and, in some instances, results in the return of ventricular
muscle structure and function toward normal.

EXAMPLES OF CHANGES IN VENTRICULAR FUNCTION

DYNAMIC EXERCISE
As the intensity of dynamic exercise, such as running, increases, cardiac sympathetic nervous
activity increases. Ventricular muscle contractile state increases based on at least three simul-
taneous stimuli:
• Increased amounts of norepinephrine released at myocardial β receptors due to more
action potentials along the cardiac sympathetic nerves (Figure 10.4, sympathetic nerves).
• More plasma epinephrine and some norepinephrine released from the adrenal medulla
secondary to sympathetic stimulation of the adrenal gland (Figure 10.4, circulating
catecholamines).
• A higher heart rate directly affects heart muscle function through the force-frequency
relationship (Figure 10.4). This is the least important of these three factors.

Ventricular function moves to higher ventricular function curves than at rest (Figure 10.4).
The end-systolic pressure-volume relation shifts leftward and is steeper (Figure 10.5). Cardiac
output is greater than at rest—more blood is flowing around the body per unit time than at rest.
There are other factors to consider:
• As heart rate increases, each cardiac cycle shortens and the diastolic filling period
shortens the most. With a shorter diastolic filling period there is less time for ventricular
filling.
• Simultaneously, the increased amount of blood flowing around the body per minute
results in more venous return to the right and left atrium per minute.
• Also, there is sympathetic stimulation of large veins like the inferior vena cava, which
activates caval venous smooth muscle, reduces venous compliance, and enhances return
of blood to the right atrium and ventricle. Sympathetic stimulation of myocardial cells
enhances relaxation and facilitates ventricular filling. The effects of catecholamines
e on heart muscle function is presented in the three-part self-study module Clinical
Heart Muscle Physiology.
• The skeletal muscle pump enhances venous return (Figure 10.1).
• Finally, during inspiration, the diaphragm moves down and increases abdominal
pressure, including pressure on the inferior vena cava and its tributaries. The veins in
the lower body have valves opening toward the heart, so venous blood cannot move
backward. The increase in abdominal pressure pushes venous blood toward the right
atrium. The increased frequency and amplitude of respiratory movements during exercise
increases these effects on the veins.

The net effect of the above during exercise is variable. Measurements in humans during
upright exercise show an initial rise in end-diastolic volume from rest to low level exercise,
but then end-diastolic volume remains steady with further increases in exercise intensity. The
steady end-diastolic volume during higher levels of upright exercise may result from the com-
bination of less time for ventricular filling plus more blood returning per unit time. Ventricular

90
 Passive (diastolic) pressure-volume relation

function continues to increase at the higher levels of exercise, not due to more filling, but due to
increases in ventricular contractility and heart rate.
In other words, cardiac output increases with upright endurance exercise due to an initial
increase in ventricular filling and a continuing increase in heart rate and the contractile state
due to increased sympathetic stimulation.

CHANGES IN POSTURE
The amount of right ventricular filling increases with lying down as venous blood becomes
evenly distributed throughout the body; there is now more venous blood in the thorax than
during standing. The end-diastolic volume of both ventricles increases and the ventricles move
to the right on the ventricular function curve on which they are functioning. There is baro-
reflex withdrawal of sympathetic stimulation of the heart and the parasympathetic nervous
system becomes predominant (the carotid baroreflex is discussed in a later section Chapter 12,
Circulatory Controls). The heart rate slows. Ventricular contractile state decreases, mostly due
to less sympathetic stimulation of myocytes, and ventricular function moves to lower curves.
Summary: Moment-to-moment adjustments in ventricular function with, for instance,
exercise or changes in posture depend on a combination of changes in the contractile state of
­ventricular heart muscle and the end-diastolic volume (preload).

EJECTION FRACTION
Normally, each ventricle empties until it is slightly less than half full. A normal ventricle ejects
about 60% of the EDV in a beat, an ejection fraction of 0.6. Below 0.45 (some say 0.50) is consid-
ered lower than normal. The ejection fraction (EF) is a clinically important measurement and
is the amount ejected by a ventricle (stroke volume; SV) relative to what was in the ventricle
before ejection (end-diastolic volume; EDV).

SV
EF =
EDV

Stroke volume is end-diastolic volume minus end-systolic volume (SV = EDV − ESV). End-
systolic volume, as mentioned before, is the volume of blood in a ventricle at the end of ejection.
EF can be measured non-invasively, for instance, with echocardiography.

PASSIVE (DIASTOLIC) PRESSURE-VOLUME RELATION

During diastole, the ventricle behaves like a passive compliant bag, much like a balloon. As a
normal resting ventricle fills with blood, ventricular pressure increases, but to a small extent.
Consider an experiment with a normal relaxed left ventricle. There are no contractions. A
syringe is used to fill the left ventricle to various volumes (Figure 10.8). Left ventricular passive
pressure is measured at each left ventricular passive volume. Left ventricular pressure versus
left ventricular volume is plotted (Figure 10.8). Again, note that this is in a noncontracting,
relaxed heart. Why does the pressure go up with an increase in volume of the noncontracting
left ventricle?

91
 Ventricular function

Left ventricular pressure Left ventricular volume

Figure 10.8  Passive/resting ventricular pressure-volume relation. A resting ventricle is filled to various
volumes and the resting ventricular pressure is measured.

The data in Figure 10.8 are from a relaxed left ventricle. Ventricular muscle is not active,
so the rise in pressure cannot be due to sarcomere activity. The sarcomeres are relaxed, the
crossbridges are not attached to actin sites, and thick and thin filaments slide freely past each
other. The rise in pressure is partly due to stretch of connective tissue. The connective tissue
in the ventricles consists of an elaborate weave of fine connective tissue fibers that surrounds
and is attached to heart muscle cells and blood vessels (Figure 10.9). There are filamentous,
elastic, noncontractile protein structural elements in the sarcomeres, particularly titin, that
are stretched when sarcomere length increases. Myocardial resting force is generated both by
stretch of extracellular connective tissue and intracellular, sarcomeric proteins such as titin.
The relative contribution of each is currently being investigated. Resting or passive force in
e cardiac muscle and the role of connective tissue and titin is presented in the self-study
module Clinical Heart Muscle Physiology, Part 2: Muscle Mechanics Made Easy.

Figure 10.9  An electron micrograph of normal primate ventricular myocardium. M points to a myocyte
and T is a collagen fiber. W indicates the collagen weave that surrounds every myocyte. There are
collagen fibrils, not shown here, that attach the weave to myocyte sarcolemma.

92
 Control of the heart in vivo: A study summary

Myocardial connective tissue and titin remodeling can occur in heart disease. The result is
an increase above normal in myocardial stiffness and altered ventricular filling in many types
of heart disease. This is presented in the self-study module Myocardial Infarction and e
Chronic Heart Failure.

CONTROL OF THE HEART IN VIVO: A STUDY SUMMARY

• Cardiac Output

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

(CO, Q, or F) = (SV)×(HR)
(L/min or mL/min) = (mL/beat)×(beats/min)

Figure 10.10 provides a review summary of factors that influence ventricular function.

Cardiac Stroke Heart

= ×
output volume rate

Contractile state of the

myocardium; rate and
End-diastolic—End-systolic volume extent of cardiac muscle
shortening (force-velocity
relationship)
Transmural Ventricular Peripheral
and
pressure compliance vascular
(Pi - Pe) resistance

Venous Autonomic nervous system

return Venous compliance
(stiffer [less compliant] large veins due to sympathetic
stimulation of venous smooth muscle results in less
Posture venous capacitance and increased venous return to the
Skeletal muscle right ventricle)
pump

Figure 10.10  A study summary of the control of the heart in vivo.

93
 Peripheral circulation

11

MEAN ARTERIAL PRESSURE AND PULSE PRESSURE

Pulse pressure is peak arterial systolic blood pressure minus arterial diastolic blood pressure
(Figure 11.1). Arterial blood pressure rises to a peak, the systolic pressure, and then falls to a
minimum, the diastolic pressure. So, which is the pressure that relates to the pressure potential
energy discussed in the earlier section, in Chapter 8, How the Circulation Works? The mean
arterial pressure is what is important when considering the function of the circulation as a
siphon. Pulse and mean pressure are illustrated in Figure 11.1 and defined below.
Left ventricular systolic ejection thrusts blood into the blood-filled aorta. The left ventricular
volume decreases and the proximal aorta swells. Aortic pressure and volume reach a maximum
and then decrease (self-study module Cardiac Cycle: Heart Sounds and Murmurs). These e
pressure and volume changes will be discussed in more detail below.
A reasonable value for aortic systolic blood pressure is 122 mm Hg and for aortic diastolic
blood pressure is 80 mm Hg. The pulse pressure is the difference between the two pressures, in
this example 42 mm Hg. The mean arterial pressure in the proximal aorta is not the arithmetic
mean pressure. Mean in this case refers to the average pressure over time, including systole and
diastole, and can be determined as the integral of the pressure wave. The following estimate of
mean pressure is easy to calculate and is clinically useful:

Pulse Pressure
Mean Aortic Blood Pressure = Diastolic Blood Pressure +
3

In the example used here, mean aortic blood pressure = 80 + (42/3) = 94 mm Hg.

Mean pressure is determined primarily by three factors:
• One is cardiac output and its components, stroke volume, and heart rate.
• Another is the rate with which blood leaves the aorta and its branches through the
arteriolar resistance and proceeds on to the capillary bed. Blood leaving the aorta and its
branches is called “peripheral runoff.”
• A third factor is the stiffness of the aorta. Stiffness refers to the extent to which aortic
blood pressure passively increases when the aortic volume increases.

During a steady state, with stable cardiac output, total peripheral runoff per unit time must
equal cardiac output. If left ventricular output increases to a higher steady level, the output will

95
 Peripheral circulation

Systolic

Pressure →
Mean

Diastolic

Time →

Figure 11.1  Aortic pulse and mean blood pressure. Mean arterial blood pressure is discussed in the
text. Diastolic blood pressure here refers to pressure in the aorta, not in the left ventricle. Aortic systolic
blood pressure is measured at the peak of pressure development.

transiently exceed peripheral runoff and aortic volume and mean aortic pressure will increase.
As you would expect with a siphon, increased mean arterial pressure results in increased run-
off. A new steady state is attained with a higher cardiac output, a higher mean aortic pressure,
and more runoff. For a given increase in cardiac output, the amount of increase of the mean
aortic pressure depends on aortic stiffness.

AORTIC STIFFNESS
As noted above, when the aortic wall is stiff a given increase in aortic volume will result in a
bigger increase in mean aortic pressure than when the wall of the aorta is less stiff. Stiffness can
be measured in an aortic segment, such as might be obtained at autopsy (Figure 11.2).
In Figure 11.2, a segment of aorta was removed at autopsy from various age people. Each
aortic segment was attached at one end to a syringe and at the other to a pressure gauge (Figure
11.2). Then each aortic segment was filled to various volumes with saline. The resulting pres-
sure inside the aortic segment at each volume was plotted against the volume (Figure 11.2).
In this experiment, external pressure, Pe, is atmospheric and remains constant. Inside pres-
sure (Pi) increased as saline was injected and transmural pressure (Pt) (Pt = Pi − Pe) increased.

Old Middle age Young

150
Pressure (mm Hg)

100

50

Volume (mL)

Syringe Aortic Pressure

segment gauge

Figure 11.2  Pressure-volume relation in aortic segments from young, middle age, and old people.

96
 Mean arterial pressure and pulse pressure

Pt increases because, as vessel radius increases in response to fluid injection, circumference

increases. The connective tissue fibers in the vessel wall are stretched, wall force increases, and
pressure inside (Pi) rises. The vertical axis, pressure, is Pi (Figure 11.2).
Stiffness of the aorta and other large blood vessels vary with, for example, age. Less volume
is needed in the aorta of an old person to reach, for example, a pressure of 90 mm Hg than for
someone who is middle age or young (Figure 11.2). This means the aorta is less distensible, less
compliant or stiffer in the old person than in the younger person. The explanation is that con-
nective tissue gets stiffer with age. Also note throughout the physiologic mean pressure range
(approximately 70–105 mm Hg) the relationship of pressure with volume is close to linear in
younger people and becomes more steeply upsloping with increasing age. This again is a mani-
festation of the normal aorta getting stiffer with age.
At a given cardiac output and peripheral runoff, the steady state blood volume and stretch of
the aorta in an older person might result in a higher aortic blood pressure, particularly systolic
blood pressure than in a younger person. Why systolic? Because aortic volume is maximal at
peak systolic blood pressure.

RELATIONSHIP OF PRESSURE, FLOW, AND RESISTANCE

P1 − P2
Q=
R

Q is blood flow per unit time and R is vascular resistance. In the overall systemic circulation Q
is the same as cardiac output (CO), P1 is mean aortic blood pressure, and P2 is mean right atrial
blood pressure. In the pulmonary circulation, the pressures of interest would be the mean pul-
monary artery blood pressure and the mean left atrial blood pressure.
Resistance in the systemic circulation resides mostly in the arterioles and is discussed below.
Resistance influences peripheral runoff. High resistance impedes runoff and low resistance
results in an increase in runoff. Below there is a discussion of why changes in runoff due to
changes in resistance can be transient.

DETERMINANTS OF PULSE PRESSURE

The aorta and its branches constitute a confined system with the aortic valve at its proximal end
and peripheral vascular resistance and peripheral runoff at the other end. The left ventricular
ejection of blood into the aorta is rapid during the initial part of ejection. This initial rapid left
ventricular ejection exceeds peripheral runoff. Therefore, aortic volume increases, the aortic
wall is stretched, and aortic blood pressure increases to the peak aortic pressure, the aortic
systolic pressure.
Aortic pressure falls after the peak because:
• Left ventricular myocardial relaxation becomes more manifest, slowing the rate of ejection
of blood into the aorta. There is no further release of Ca2+ from the terminal cisternae in
ventricular myocytes and Ca2+ uptake by the longitudinal portion of the sarcoplasmic
reticulum is proceeding. Activation of contraction and relaxation are presented in
e
detail in the three-part self-study module Clinical Heart Muscle Physiology.
• Peripheral runoff begins to exceed the amount of blood ejected by the left ventricle and
aortic volume begins to fall. Aortic pressure falls as aortic volume decreases (Figure 11.2).
97
 Peripheral circulation

As you know from the earlier section on the cardiac cycle (Chapter 9, Cardiac Cycle, Heart
Sounds and Murmurs), at the end of ejection the left ventricle is not able to sustain forward
flow because of the extant of myocardial relaxation. The column of blood in the aortic root
momentarily moves backward toward the aortic valve and the valve closes. Once the aortic
valve closes the aorta is then sealed at its ventricular end. But at the other end of the arterial
system peripheral runoff continues. Blood exits from the arterial system into the capillary bed
through the arterioles and aortic blood pressure falls. The fall in aortic blood pressure continues
until the next cardiac cycle results in aortic valve opening and ventricular ejection. The lowest
level the aortic blood pressure gets to, at the instant before the aortic valve opens, is the aortic
diastolic blood pressure (Figure 11.3, point 2 and Figure 11.1).
The increase of aortic blood pressure after the aortic valve opens results from early rapid
left ventricular ejection. About 80% of the stroke volume is ejected during early rapid ejection.
The blood pressure increase starts from the aortic diastolic blood pressure level when the aortic
valve opens and reaches the peak aortic and ventricular systolic level. This rise from diastolic to
peak systolic blood pressure is the pulse pressure, as described above.
From the above it should be obvious that the peak aortic systolic pressure is strongly depen-
dent on stroke volume. Also, the aortic diastolic blood pressure is directly dependent on the
amount of peripheral runoff. Since peripheral vascular resistance is a major determinant of the
amount of peripheral runoff, peripheral vascular resistance also strongly influences the level of
aortic diastolic blood pressure.
Finally, for any given amount of stroke volume, pulse pressure will be greater the stiffer the
aorta. This corresponds to what is stated above about aortic stiffness. A given volume incre-
ment added to a stiffer aorta will result in a greater pressure increase than in a less stiff aorta
(Figure 11.2).
Note: The thrust of blood into the aorta from the left ventricle during ejection generates a
pressure wave that starts from the aortic root and travels throughout the arterial system. The
pressure wave can be palpated peripherally, for instance, over the radial artery at the wrist.
All the above comments also apply to the right ventricle and pulmonary artery, but the blood
pressure levels are much lower due to the very low pulmonary vascular resistance and relatively
compliant (low stiffness) pulmonary artery wall.

EXAMPLES OF PULSE PRESSURE CHANGES

With a slow heart rate, there is a longer time for peripheral runoff between heartbeats. With
more time for peripheral runoff more blood can leave the aorta and aortic diastolic blood
pressure decreases. The slower heart rate also results in more time for ventricular filling and
an increase in end-diastolic volume, and stroke volume increases. The rise in stroke volume
increases systolic blood pressure. There is then a tendency for a larger pulse pressure when
heart rate is slow. Mean pressure may not significantly change. For instance, say that peak
aortic systolic blood pressure before a decrease in heart rate is 122 mm Hg and diastolic is
80 mm Hg. The mean blood pressure is 80 + (42/3) = 94 mm Hg. After the increase in heart
rate the values might be 133/70 mm Hg with a mean of 70 + (63/3) = 91 mm Hg. The mean
arterial pressure does not significantly change in this example.
Consider another simplified example. Aortic systolic, pulse, and mean blood pressures
increase with an increase in stroke volume. An increase in stroke volume as an isolated event is
not likely, but this simplified scenario is useful as a learning tool. In this example neither heart
rate nor peripheral vascular resistance change. An increase in mean arterial blood pressure will
increase steady state peripheral runoff. The increase in peripheral runoff in combination with
98
 Mean arterial pressure and pulse pressure

140
Pressure (mm Hg)

100

60
Time

Figure 11.3  Aortic blood pressure changes with dynamic exercise. The horizontal line represents
mean blood pressure at 93 mm Hg.

the increase in stroke volume and aortic systolic blood pressure at a constant heart rate result in
almost no change in the aortic diastolic pressure. With no change in heart rate the time avail-
able for runoff is unchanged. The aorta starts from a higher volume and systolic pressure, but
there is no increase in time for runoff and the diastolic pressure is slightly greater or unchanged.
Figure 11.3 illustrates another change in pulse pressure. In this case, stroke volume and heart
rate increase whereas peripheral vascular resistance (another term for this is systemic vascular
resistance) decreases. Aortic systolic blood pressure increases and aortic diastolic blood pres-
sure decreases, but without a change in mean blood pressure. This latter response occurs in, for
instance, upright dynamic exercise, such as jogging on a treadmill, and is analyzed in detail in
Figure 11.4. Heart rate and stroke volume increase due to increased sympathetic nerve activity
to the heart. The heart rate increase is also related to decreased parasympathetic nerve activity
to the sinoatrial node. The decrease in peripheral vascular resistance is primarily the result of
arteriolar vasodilatation in working skeletal muscles, an effect of local metabolic control, which
is discussed later (Chapter 12, Circulatory Controls).
The next example is what occurs with an increase in peripheral vascular resistance (Figure
11.5). The initial response to an increase in peripheral vascular resistance is a decrease in periph-
eral runoff and an increase in aortic volume, stiffness, and diastolic and mean blood pressures
(Figure 11.5). Since the circulation behaves as a siphon, the increase in mean aortic blood pres-
sure brings peripheral runoff back toward what it originally was. The increase in aortic stiffness
(Figure 11.5) refers to the increase in aortic volume causing a shift onto a steeper portion of an
aortic pressure, volume relation (Figure 11.2). Aortic systolic blood pressure also increases. Left
ventricular stroke volume (not mentioned in Figure 11.5) is little affected by the increased left
ventricular afterload, which is explained in Chapter 10, Ventricular Function, Afterload.

↑ Arterial
↑ Stroke systolic
volume pressure
↑ Heart Pulse pressure ↑
Upright
rate
dynamic Mean pressure
exercise unchanged
↓ Peripheral ↓ Arterial
vascular diastolic
resistance pressure

Figure 11.4  Factors that result in an aortic pulse pressure increase and a stable aortic mean blood
pressure with dynamic exercise.

99
 Peripheral circulation

↑ Peripheral ↓ Peripheral ↑ Aortic ↑ Aortic

vascular resistance runoff volume stiffness
↑ Peripheral
runoff
↑ Arterial
↑ Arterial diastolic
mean pressure pressure

Figure 11.5  Responses to an increase in peripheral vascular resistance.

RESISTANCE
The following formula relating pressure, flow, and resistance was discussed earlier:

P1 − P2
Q=
R

By rearranging this formula, resistance to liquid flowing in a tube can be defined by the
­following ratio:

Pressure Drop from Point 1 to 2 P1 − P2

Resistance to Flow (R) = =
Total Flow from Point 1 to 2 Q

There are several factors that influence resistance, including the cross-sectional area of the
tube, the length of the tube (L), and the viscosity (η) of the fluid flowing in the tube.

8 ηL
R=
πr 4

The radius, r, π and 8 appear as part of the mathematical derivation. Substitution of the for-
mula for R into the first equation results in a relationship called Poiseuille’s law. Poiseuille, a
French physician and physicist, made empirical observations of fluid flow in tubes that eventually
were related mathematically to Newton’s observa­tions and calculations regarding laminar flow.

POISEUILLE’S LAW

π( P1 − P2 )r 4
Q=
8ηL

where
Q = Flow rate in volume/unit time
r = Blood vessel radius
P1 = Mean pressure of the fluid upstream from the location in the blood vessel where this
law is being applied
P2 = Downstream mean pressure
L = Length of blood vessel between the two points where the pressures are measured
η = Viscosity
π
= Constant related to integrating flow over the total cross-section of a blood vessel
8
100
 Resistance

VARIABLES IN POISEUILLE’S LAW

• η: It is hardly surprising that η, viscosity, is in the denominator. The “stickier” or
“thicker” a fluid, the slower it will flow in response to a given pressure difference; for
instance, flow of ketchup versus wine.
 Red blood cells (RBCs) make up a large part of blood volume and the viscosity of blood
is strongly dependent on the RBC content of blood. Normally, RBCs make up about
40% of the volume of blood and the viscosity of blood, its internal viscosity, is about 4
times that of water. The rubbing and bumping of RBCs is the main contributor to the
internal viscous forces of blood. If the number of RBCs increases, viscosity increases. In
anemia, viscosity is less than normal and that is one reason why Q is greater than normal
in anemia (and why murmurs may occur—see the earlier discussion of turbulence in
Chapter 8, How the Circulation Works).
 The viscosity of blood also depends to some degree on the velocity of blood flow. At
extremely low flow rates blood cells tend to stack up in columns and rub more against
each other, and apparent viscosity is greater than at high flow rates. This type of
“sludging” is important to consider when someone is in shock due to low blood flow. At
higher flow rates blood cells tend to migrate to the center of the moving column of blood
where energy and velocity is greatest, but they are randomly distributed within that
center region. This leaves a “lubricating” layer of cell-free plasma near the vessel wall,
and viscosity is less than at lower flow rates.
• (P1 − P2 ): Pressure potential energy generated by myocardial work. Discussed previously
in Chapter 8, How the Circulation Works.
• r4: The radius (r) is of critical importance. Note that flow varies directly with the fourth
power of the radius. With blood vessel obstruction, without other changes, flow will
decrease relative to the fourth power of the decrease in the radius. If blood vessel radius
decreases by 1/2, blood flow will decrease 16-fold, assuming other variables do not
change.
• L: L, vessel length, does not acutely change. The exception to this is the stretch of lung
intra-alveolar blood vessels during deep inspiration.

REGIONAL CHARACTERISTICS OF ARTERIAL BLOOD PRESSURE

The mean pressure in the aorta and its major branches is much higher than in the capillary bed
(Figure 11.6). A steep pressure decrease occurs in the region of the circulation made up of small
muscular arteries with a diameter <100 µm and arterioles (Figure 11.6). The fall in mean pres-
sure is particularly steep starting with an arteriolar diameter of 50 µm. The location of the sharp
fall in mean blood pressure indicates the site of most resistance in the systemic circulation—the
small muscular arteries and arterioles.
Arterioles are characterized by a large ratio of muscular wall thickness to the small lumen
diameter. Contraction or relaxation of arteriolar smooth muscle results in changes in arteriolar
lumen radius and, therefore, in resistance. Arterioles are innervated by autonomic nerves in
some organs, are sensitive to interstitial chemical changes in some organs, or have smooth mus-
cle myocytes that are stretch-activated in some organs. Combinations of these controlling influ-
ences are discussed below in a section on circulatory controls (Chapter 12, Criculatory Controls).
Parasympathetic nerve action potentials induce vasodilation in a few organs, for instance, the
surface blood vessels of the brain. Elsewhere they have limited effects on controlling blood flow.
101
 Peripheral circulation

Blood vessel diameter (µm)

100 25 20 100
200 50 10 8 50
100

75

Pressure (mm Hg)

50 Mean blood pressure

25

Capillaries
0
Aorta Arterial Small muscular Venules to veins
branches arteries and
arterioles

Figure 11.6  Mean blood pressure at locations in the circulation.

SERIES VASCULAR RESISTANCE

Arterioles are the major resistance vessel in the systemic circulation and there are arterioles
in every organ. In some organs, the kidney and the gut for instance, there is more than one
set of arterioles and in these organs the resistances are in series. Resistances (R) in series are
additive:

Rt = R1 + R 2 + R 3 + …

Rt is total resistance and is illustrated in Figure 11.7c.

PARALLEL VASCULAR RESISTANCE

The reciprocal of resistances in parallel are additive.

(1/Rt) = (1/R1) + (1/R 2) + …

Notice that the more resistances added in parallel, the less the total resistance, Rt. This may
seem counterintuitive at first. Each blood vessel added does have resistance, but it also adds
another conduit for fluid flow (Figure 11.7b). Most organs are parallel to each other in the
peripheral circulation. Adding resistances R 2 and R 3 in parallel with R1 in Figure 11.7b adds
multiple parallel paths, reduces total resistance, and increases flow.

VASCULAR CONDUCTANCE
The reciprocal of resistance is conductance, C = (1/R). Series resistances are additive as noted
above, Rt = R1 + R 2 + R 3, and conductance equals 1/Rt. The more the series resistance the
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 Blood volume distribution

(a) (b) (c)

Figure 11.7  Resistances. Single resistance in (a), three parallel resistances in (b), and two series
resistances in (c). The volume in each bottom container accumulates over the same amount of time;
flow rate is greatest in b, least in c, and intermediate in a.

greater the value for Rt and the lower the conductance. Compare the fluid flow in c with a
in Figure 11.7. The reciprocals of parallel resistances are additive and the more the number
of parallel resistances, the lower the overall resistance, Rt. As Rt falls, conductance increases.
Compare the fluid flow in b with a in Figure 11.7.

IN VIVO RESISTANCES
The branches of the aorta are parallel to each other. Compare, for instance, the renal arteries
with the arteries to the extremities and the gastrointestinal tract. With this parallel arrange-
ment vasoconstriction and reduced blood flow (conductance) in one organ can occur with mini-
mal effects on total resistance or systemic blood flow. What often happens is that increased
resistance and reduced blood flow in one organ can be accompanied by reduced resistance and
increased blood flow elsewhere. For instance, in upright dynamic exercise, such as on a station-
ary bicycle, blood flow to skeletal muscles and the heart increases while it decreases to the gut
and kidney.

BLOOD VOLUME DISTRIBUTION

Distribution of blood volume as well as sites of resistance is a function of the geometry and
structure of the circulation. In a resting person, approximately 2/3 of the circulating blood is in
the venous side of the circulation. The veins are thin-walled with a modest amount of smooth
muscle and easily expand. They are well suited to accommodate a large volume of blood. The
venous portion of the peripheral circulation is characterized by high volume and low pressure.

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 Circulatory controls

12

INTRODUCTION
There are multiple levels of control operating simultaneously in the circulation. It is not unusual
in biological systems to have multiple control mechanisms acting to maintain an internal
steady state. The discussion here treats each control system individually, but keep in mind
they all operate together to harmonize cardiovascular function to maintain a normal internal
environment.
Rapid control of blood pressure is accomplished in large part by baroreceptors and the
central nervous system reflexes they are part of. Another term for baroreceptor is “pressure
receptor” or pressoreceptor. The efferent part of this reflex system occurs over sympathetic and
parasympathetic nerves. These neural reflexes are essential for rapid responses to changes in
blood pressure. Neural reflexes quickly stabilize blood pressure levels that are dependent over
the long term on blood volume. Blood volume is strongly influenced by hormonal control of salt
and water excretion, another type of circulatory control. Hormonal control of salt and water
excretion is a slower type of baroreflex control system and also responds to changes in blood
osmolality.

ARTERIAL NEURAL BARORECEPTORS

The major neural baroreceptors are the carotid sinuses bilaterally and the aortic arch.

STRUCTURE
CAROTID SINUS
The carotid sinus is located at the junction of the internal and common carotid arteries (Figure
12.1). There are two key features of the carotid sinus wall that make the sinus a good blood
pressure sensor. The wall is very distensible (highly compliant) and there is an extensively
branched matrix of stretch-activated nerve endings embedded in the wall. Action potentials
generated by stretch of the nerve matrix travel along the carotid sinus nerves bilaterally to the
medulla oblongata. The medulla contains integrating centers.

105
 Circulatory controls

Carotid body External

carotid
artery

Carotid
Internal sinus
carotid artery

Common
carotid artery
Left
common
carotid artery Aortic
body

Left Innominate
subclavian artery
artery

Aortic
body

Aortic arch
(viewed from behind)

Figure 12.1  Two major baroreceptor regions located at the X’s. (From Barrett KE et al. Ganong’s
Review of Medical Physiology, 23rd ed. New York, NY: McGraw-Hill; 2010. With permission of
McGraw-Hill.)

AORTIC ARCH
A matrix of stretch-activated nerve endings is embedded in the wall of the aortic arch, like that
in the carotid sinus (Figure 12.1). The function of the two arterial baroreceptor areas is similar.
The carotid sinus baroreceptor has been more thoroughly studied and will be discussed here.

FUNCTION OF THE CAROTID SINUS BARORECEPTOR

CLINICAL CASE
A clinical case emphasizes the importance of understanding neural baroreceptor function:
A 77-year-old man recently began treatment with beta1 blocking and vasodilating drugs for heart
failure. In the last few days he has had increasing difficulty with dizziness and blurred vision when
changing posture from lying or sitting to standing upright. These symptoms are worse when first
standing in the morning. His blood pressure while sitting is 118/72 mm Hg and after standing, resting
for less than 3 minutes his blood pressure is 92/60 mm Hg. A decrease in systolic blood pressure
within 3 minutes of changing from sitting to standing is normally <20 mm Hg systolic and <10 mm Hg
diastolic.
What is the physiological basis of this problem and how should it be treated? The answers are
dependent on an understanding of the neural baroreflex.

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 Arterial neural baroreceptors

Arterial pressure
decrease Baroreceptor Baroreceptor
Maintained stretch firing rate
Brain
Sympathetic activity

Parasympathetic activity

α1-adrenergic β1-adrenergic Muscarinic

receptor activation receptor activation receptor activation

Systemic vascular Force of Heart rate

resistance contraction

Stroke volume

Cardiac output

Figure 12.2  Flow diagram of the response of the carotid sinus baroreceptor reflex to a decrease in
arterial blood pressure. The flow starts at the upper right with an “arterial pressure decrease” and the
negative feedback loop concludes back at the upper right with arterial pressure increased to maintain a
blood pressure adequate for organ function.

An arterial blood pressure decrease (Figure 12.2, arterial pressure decrease) results in less
expansion of the carotid sinus and less stretch of its wall (↓ baroreceptor stretch) and the embed-
ded nerves. Less stretch of the nerves results in less action potentials (↓ baroreceptor firing rate)
along the carotid sinus afferent nerves to cardiovascular centers in the medulla. Medullary
centers in the brain integrate this incoming information and the result is more action potentials
along sympathetic and less along parasympathetic nerves (Figure 12.2).
Less stretch of the carotid sinus leads to more sympathetic nerve activity—potentially con-
fusing until you consider the following. All the cardiovascular control systems are operating
all the time. They do not turn on when needed and then turn off. The carotid sinus wall is
always stretched by arterial blood pressure and there are continuous carotid sinus nerve action
potentials, the frequency of which increase with more stretch of the sinus and decrease with
less stretch. Carotid sinus nerve action potentials act to inhibit the sympathetic nerve output
from the medullary cardiovascular centers. When blood pressure falls and there is less stretch
of the carotid sinus wall and less carotid sinus nerve action potentials to the medulla there is
less suppression of the sympathetic nerve output and increased action potentials in the sym-
pathetic nerves to the heart and blood vessels. The converse is true of the parasympathetic
system. Basal carotid sinus nerve activity maintains activation of parasympathetic nerve cell
bodies in the medulla and reduced carotid sinus nerve activity results in less activation and less
parasympathetic nerve activity.
The result of more sympathetic activity and less parasympathetic activity is illustrated in
Figure 12.2. Start at the upper left of Figure 12.2 with a decrease in arterial blood pressure.
A common example of a normal decrease in arterial blood pressure is a change of posture
from lying to standing. The effects of gravity result in a significant shift of venous blood to the
lower body with standing, estimated at 800–1000 mL. The venous volume shift substantially
reduces thoracic blood volume (Figure 12.3). The right atrium and ventricle fill less (decreased
right atrial mean pressure in Figure 12.3) and stroke volume decreases (Figure 12.3) (this is a
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 Circulatory controls

SBP
130
Arterial 110
blood pressure MBP
90
(mm Hg)
70
DBP
6
Right atrial
mean pressure
(mm Hg) 0
6
Cardiac output
5
(1/min)
4
100
Stroke volume
(ml)
50
Central 1.2
blood volume 1.0
(1) 0.8
90
Heart rate 80
(beats/min) 70
60
1.5
Splanchnic ( )
renal ( )
1.0
blood flow
(1/min) 0
0 2 4 6 8 10
Time (min)

Figure 12.3  Hemodynamic effects of posture change and the skeletal muscle pump. SBP is systolic
arterial blood pressure, DBP is diastolic arterial blood pressure, and MBP is mean arterial blood
pressure. The figures at the top indicate a transition from supine to standing and then standing with leg
contractions. Other details are discussed in the text. (From Rowell LB. Human Circulation Regulation
during Physical Stress, 1986, by permission of Oxford University Press.)

good time to review the earlier material on Frank–Starling law of the heart). After a few heart-
beats, the same happens in the left atrium and ventricle. Reduced left ventricular stroke volume
results in a decrease in arterial systolic pressure (SBP in Figure 12.3 with standing) and less
stretch of the carotid sinus (Figure 12.2). The result is a decrease in action potential generation
in the carotid sinus nerve endings with a decrease in action potential frequency over those
nerves to the brain (Figure 12.2). Figure 12.2 outlines the reflex loop.
Note that the reflex loops act to maintain mean arterial blood pressure (MBP in Figure 12.3).
Normal resting standing arterial systolic blood pressure is less than what it was when lying
down due to the reduced stroke volume (Figure 12.3) and arterial diastolic blood pressure is
increased (DBP in Figure 12.3) due to peripheral vasoconstriction. The peripheral vasocon-
striction is a result of more sympathetic activity to peripheral arteriolar smooth muscle alpha
receptors (Figure 12.2). Reduced splanchnic and renal blood flow (Figure 12.3) is a result of the
vasoconstriction.

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 Hormonal controls

As noted above, the carotid (and aortic) baroreceptor is a rapid, nervous, millisecond
response control system. One cannot stand up and remain upright free of symptoms unless
this rapid response system works properly. The carotid baroreceptor compensates for the effects
of gravity on the cardiovascular system, but gravity does not go away. All the time one is stand-
ing gravity acts to shift venous blood to the lower body. There is increased sympathetic input
to venous alpha receptors that stiffens the wall of the veins and helps to move venous blood
toward the right atrium, but a reduced ventricular end-diastolic volume and stroke volume per-
sist all the time one is standing as compared with lying down or sitting. Central blood volume
remains reduced during standing as compared with lying down despite the stiffening of the
veins (Figure 12.3).
Figure 12.3 also nicely illustrates the effects of the skeletal muscle pump during stand-
ing. At the 8-minute time mark (top arrow, right vertical line) the upright individual began
contracting and relaxing leg muscles without walking. As described before, contraction of leg
muscles squeezes the deep veins between muscle bundles. These veins have valves. Venous
blood is pushed toward the heart with leg muscle contraction and cannot flow back when
the valves close with leg muscle relaxation. The repeated cycle of contraction and relaxation
pumps blood toward the heart. Note the return of all the parameters back to the levels when
the individual was lying supine. This would be a good time to revisit earlier notes on ventricu-
lar function and the Frank–Starling law of the heart where the skeletal muscle pump is also
discussed.

CLINICAL CASE REVISITED

As you will recall, the 77-year-old man recently began treatment with beta1 blocking and vasodilating
drugs for heart failure and he is now having difficulty with dizziness and blurred vision when changing
posture from lying or sitting to standing upright. His blood pressure decreases more than normal with
changing posture from sitting to standing. The blood pressure decrease is enough to limit brain blood
flow. I hope it is obvious the beta1 blocking and vasodilating drugs are interfering excessively with the
patient’s neural baroreflex response. The medications are appropriate for heart failure therapy, but the
doses or drugs will have to be changed to reduce the patient’s problem with postural low arterial blood
pressure or orthostatic hypotension.

If for some reason arterial blood pressure increases and remains chronically elevated, such as
in the disease “high blood pressure (hypertension),” the baroreceptors adapt and control blood
pressure at the new higher level.

HORMONAL CONTROLS

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS)

RAAS is involved in slower, longer term control of blood pressure than the neural barore-
ceptor system, but both act together to maintain steady state blood pressure levels. A major
feature of RAAS is the control of extracellular fluid volume and thereby the long-term con-
trol of vascular volume and arterial blood pressure. There is a detailed presentation of
RAAS, including animated illustrations, in the self-study module the Pathophysiology e
of Hypovolemic Shock.

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 Circulatory controls

Renin is a proteolytic enzyme secreted into the bloodstream by kidney specialized afferent
arteriolar myocytes, the juxtaglomerular cells (Figure 12.4). Juxtaglomerular cells are special-
ized for renin production and secretion in response to several stimuli:
• One stimulus is less stretch of the wall of the kidney afferent arterioles. Less stretch
occurs, for instance, when perfusion of the kidney decreases due to a drop in arterial
pressure with standing (Figure 12.3). The reduced aortic and renal artery blood pressure
results in less afferent arteriolar distention and less stretch of the juxtaglomerular cells in
the arteriolar wall (Figure 12.4a). The juxtaglomerular cells then secrete more renin into
the bloodstream (Figure 12.4a). This is another example of a baroreflex, but here it is part
of a hormonal response.
• Renin release is also increased by sympathetic stimulation of adrenergic receptors on
juxtaglomerular cells (Figure 12.4b). Part of the carotid baroreceptor response to changing
from lying down to standing is an increase in sympathetic stimulation including of the
juxtaglomerular cells (Figure 12.4b).
• Low plasma NaCl results in less Na+ filtered in the glomerulus and decreased NaCl in the
filtrate reaching the area of the macula densa (Figure 12.4c). There can be a reduction in
glomerular filtration with a decrease in arterial pressure and this also reduces Na+ in the
filtrate that reaches the macula densa (Figure 12.4c). In the presence of reduced Na+, macular
densa cells stimulate JG cells to produce and release more renin.

The above also works in the reverse. Renin release decreases with more stretch of afferent
arteriolar juxtaglomerular cells, with less sympathetic stimulation or with increased plasma
sodium chloride. In other words, the system works “both ways” to control extracellular volume
and arterial blood pressure.
If, for instance, fluid intake is reduced, extracellular fluid volume decreases. Blood pressure
falls and renal arterial perfusion is reduced. There is then less stretch of the kidney afferent
arterioles and the juxtaglomerular cells (Figure 12.4a). Also, there is more sympathetic stimu-
lation of the juxtaglomerular cells due to the response of the neural baroreceptor reflex. Renin
release is increased (Figure 12.4b). Angiotensinogen, constantly produced and released into
the bloodstream by the liver, is enzymatically cleaved by circulating renin to produce angio-
tensin I, a mostly inactive precursor of angiotensin II (Figure 12.5). Vascular endothelial cells
produce angiotensin converting enzyme (ACE). ACE converts angiotensin I into angiotensin
II (Figure 12.5).
Angiotensin II is a potent direct vasoconstrictor and also stimulates the release of antidi-
uretic hormone from the posterior pituitary and acts on the brain to induce thirst. It is prob-
ably angiotensin III, a derivative of II, that has this latter action on hypothalamic centers.
Angiotensin II also directly stimulates the production and release of aldosterone from the adre-
nal cortex. Aldosterone increases distal tubular and collecting duct sodium reabsorption and
water is reabsorbed with sodium.
There are other actions of angiotensin II that are clinically important. It enhances cardiac
contractility by increasing Ca 2+ entry during the cardiac muscle cell action potential plateau.
Also, angiotensin II facilitates norepinephrine release at sympathetic nerve endings, which
increases vascular responsiveness to catecholamines. Angiotensin converting enzyme inhibi-
tors are now being used, for instance, as part of the treatment of some types of heart fail-
ure. There is excessive RAAS activity in heart failure and blocking the action of angiotensin II
reduces morbidity and mortality.

110
 Hormonal controls

(a) Less JG cell stretch,

more renin produced by
the JG cells and
secreted into the blood

Arterial systolic blood

pressure decreases and Specialized smooth muscle cells, the
the afferent arteriole juxtaglomerular (JG) cells, in the wall of the
is less distended afferent arteriole are stretched less
(b)
More renin produced by
sympathetic stimulated
JG cells and secreted
into the blood

Increased sympathetic activity

to juxtaglomerular cells
Sympathetic
nerve
Baroreflex-related increased
sympathetic activity when
blood pressure decreases
(c)

Decreased arterial pressure results in less glomerular

capillary blood pressure, reduced glomerular filtration,
and less NaCl reaching the macular densa cells

Figure 12.4  Renin-angiotensin-aldosterone-system (RAAS) anatomy and physiology. There are

three mechanisms for renin release. (a) illustrates release related to the amount of stretch of the
juxtaglomerular (JG) cells. (b) shows how sympathetic innervation of the JG cells influences renin
release. Macula densa cells (c) are sensitive to the amount of Na+ in the kidney tubule filtrate and with
less Na+ induce the JG cells to produce and release more renin C.

111
 Circulatory controls

Liver

Angiotensinogen

Renin

Angiotensin I

ACE

Angiotensin II

Figure 12.5  Actions of renin and angiotensin converting enzyme (ACE).

ANTIDIURETIC HORMONE (ADH) OR VASOPRESSIN

ADH is synthesized in the hypothalamus and then diffuses along neuronal axons in the pitu-
itary stalk to where it is stored in and available for release from the posterior pituitary gland.
The primary stimulus for release of ADH from the posterior pituitary is an increase in plasma
osmolality. In dehydration, for instance, plasma osmolality increases; this is sensed by hypo-
thalamic osmoreceptors and ADH release increases. ADH release from the posterior pituitary
gland also increases in response to a large decrease in blood volume, such as in hemorrhage.
e This is presented in the self-study module The Pathophysiology of Hypovolemic Shock.
ADH has two major actions. It acts on the kidneys to increase water reabsorption in the
distal tubule. This is its major action in normal people. If there is a large enough decrease in
circulating blood volume, such as in hemorrhage, enough ADH may be released so that blood
levels are high enough to result in vasoconstriction. Hence the name “vasopressin.” This is
e
discussed further in the self-study module The Pathophysiology of Hypovolemic Shock.

ATRIAL AND BRAIN NATRIURETIC PEPTIDES

Atrial natriuretic peptide (ANP) is produced by atrial cells. Brain natriuretic peptide (BNP) is
produced by ventricular cells. BNP was first discovered in pig brain tissue, hence the name.
Subsequently, the primary source was found to be from cardiac ventricular myocardium. BNP
is also produced by the atria, but in smaller amounts than in the ventricles because of the
smaller atrial muscle mass. ANP and BNP are released into the blood and act as hormones.
C-type natriuretic peptide (CNP) is produced in endothelial cells and mostly acts locally in a
paracrine or autocrine manner on vascular smooth muscle.
Release of ANP and BNP into the bloodstream is triggered by increases in atrial and ven-
tricular wall tension due either to chamber distention or increased chamber pressure or a com-
bination of both. The hormonal actions of ANP and BNP can be divided into those that occur
in a normal person and actions that become important in, for instance, heart disease.
Consider, for example, a change in posture in a normal person from standing to lying. There
is a redistribution of venous blood volume so that atrial and ventricular filling increase and wall

112
 Hormonal controls

tension increases. More ANP and BNP are produced and secreted into the bloodstream. They
relax vascular smooth muscle and result in peripheral arteriolar vasodilation, which modulates
the rise in arterial blood pressure related to increased left ventricular stroke volume with lying
down. ANP and BNP also decrease kidney reabsorption of Na+ resulting in more Na+ and water
excretion. The change in posture from standing to lying increases atrial and ventricular filling
and ANP and BNP natriuresis acts to reduce plasma volume and atrial and ventricular filling.
This is another example of negative feedback circulatory control. ANP and BNP also inhibit
renin secretion and aldosterone production, an effect that also will relax arterioles and enhance
kidney salt and water excretion.
The actions of ANP and BNP become important in, for example, heart disease. For example,
increased left ventricular pressure and wall tension in aortic valvular stenosis results in left
ventricular hypertrophy and a stiffer chamber with increased filling pressures. The increased
filling pressures result in an increase in left atrial pressure and wall tension. More than normal
amounts of ANF and BNF are produced and released into the bloodstream.
Patients with aortic valvular stenosis and left ventricular hypertrophy eventually develop
heart failure that is characterized by myocardial and vascular remodeling, and myocardial
apoptosis and fibrosis. Relatively recent findings show that ANP and BNP act to reduce these
adverse myocardial and vascular changes in heart failure. The clinical use of these benefi-
cial effects of ANP and BNP is currently being investigated. The action of natriuretic pep-
tides, particularly ANP, is terminated by enzymatic degradation by neprilysin. Neprilysin
is produced in vascular endothelial cells and the tubular cells of the kidney. Clinical testing
of neprilysin inhibitors have been carried out recently and show promise for heart failure
treatment.
In addition to their physiologic actions, ANP and BNP blood level increases have diagnostic
and prognostic significance. Increased blood levels of the natriuretic peptides are diagnostic of
hemodynamic overload, ventricular dysfunction, and heart failure. Blood levels of these pep-
tides are used to assess prognosis and to monitor therapy.
CNP primarily acts in a paracrine and autocrine manner and has little hormonal and natri-
uretic action, but is still classified as a natriuretic peptide.

VASCULAR ENDOTHELIAL FACTORS

The endothelial cell lining of the vasculature previously was thought to be a single cell layer
functioning only as a smooth liner and passive filter. This is now known to be incorrect.
Endothelial cells are metabolically active and produce vasoactive substances that act mostly
as paracrine hormones. These vasoactive substances are produced by the endothelial cells and
diffuse through the vessel wall to act on the local vascular smooth muscle. Endothelial cell
vasoactive substances act locally to relax vascular smooth muscle in normal arterial resistance
vessels. They also prevent clotting (Figure 12.6).

NO
Nitric oxide (NO) plays a prominent role in vasodilation of larger arterial resistance vessels
and in veins. NO acts through cGMP to decrease smooth muscle cytosolic Ca2+ and relax local
vascular smooth muscle (Figure 12.6). There is continual, basal release of NO from endothe-
lial cells stimulated by the continual shear stress of blood flow. Once released it is quickly
inactivated and its continuing action depends on continual release. Blood flow rubbing on the

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 Circulatory controls

NO Inhibit platelet adhesion

Normal Vasodilatation
endothelial Prostacyclin Prevent leukocyte adhesion
cells Normal t-PA:PAI-1
EDHF

Figure 12.6  Endothelial cell factors produced in and released from normal endothelial cells.

luminal surface of endothelial cells (shear forces) stimulates them to produce and release NO.
NO production and release increase when flow into resistance vessels increases. Thus, more
blood flow is accommodated by vasodilation to match vessel lumen size with flow. Venous
endothelial cells also produce NO.
Production and release of NO is also stimulated by products of clotting such as thrombin,
serotonin, and ADP produced by aggregating platelets, and other chemicals such as bradykinin
and histamine. NO, in turn, inhibits the clotting cascade and reduces the likelihood of com-
pleted clot formation and lumen obstruction (Figure 12.6).
NO production and release is stimulated by acetylcholine. Parasympathetic nerves are
found in the outer layers of blood vessel walls, but some acetylcholine can diffuse through the
wall and affect the endothelium.

PROSTACYCLIN
Prostacyclin is also released in arterial resistance vessels by shear stress related to blood flow.
It relaxes local vascular smooth muscle and prevents clotting. Prostacyclin analogues are used
clinically to relax pulmonary vascular smooth muscle in patients with abnormally high pul-
monary vascular resistance and elevated pulmonary artery blood pressure (a clinical condition
known as pulmonary hypertension).

ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTORS (EDHF)

EDHF opens smooth muscle sarcolemma Ca 2+-activated K+ channels. This makes it easier
for K+ to leave the smooth muscle cells. The smooth muscle cells become hyperpolarized
and less likely to depolarize and contract. EDHF secretion is increased by shear forces, but
it also mediates the vasodilatory effects of bradykinin on vascular smooth muscle. There
are several EDHFs and one is hydrogen peroxide. EDHF seems to play a bigger role in the
smaller arterioles whereas NO is more important in the small muscular arteries and larger
arterioles.
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 Hormonal controls

EFFECTS ON BLOOD CLOTTING

Endothelial cells produce and release tissue plasminogen activator (t-PA) and plasminogen-
activator inhibitor type 1 (PAI-1) (Figure 12.5). A normal ratio is important for normal fibrino-
lysis to prevent inappropriate clot formation.

DYSFUNCTIONAL ENDOTHELIUM
Reduced production and release of NO is characteristic of dysfunctional endothelium (Figure
12.7). Less NO release from endothelial cells tips the balance of endothelial control toward
vascular smooth muscle contraction and clot formation. Abnormalities of endothelial function
can be found in, for instance, the endothelium overlying atherosclerotic plaques and in hyper-
cholesterolemia in the absence of discrete atheroma and obstruction. Changes in endothelial
cell function are proving to be important in the pathogenesis of atherosclerotic coronary and
cerebral vascular disease and in heart failure.

ENDOTHELINS
There are several endothelin isoforms produced by vascular endothelial cells and other tissues.
Interaction of endothelin with receptors on vascular smooth muscle results in sustained con-
traction. Its synthesis and release is induced by several stimuli including angiotensin II, norepi-
nephrine, and inflammatory cytokines, and it plays a role in the generalized vasoconstriction in
some pathological states, such as heart failure. Endothelins play a much smaller role in normal
resistance vessels other than to contribute to vessel tone.
One of the endothelin isoforms interacts with receptors on endothelial cells. It is pro-
duced by endothelial cells and affects local endothelial cell function. This isoform enhances
NO p ­ roduction and favors vasodilation. So endothelin actions can favor vasoconstriction and
vasodilation—this is a good example of dual competitive actions that are not uncommon in

↓ NO
Dysfunctional ↑ Endothelins
endothelial cells ↓ t-PA:PAI-1
↑ Monocyte/macrophage adhesion

Figure 12.7  Abnormal endothelial cell function.

115
 Circulatory controls

circulatory control. Which wins out, vascular smooth muscle relaxation or contraction? That
depends on the net effect of multiple factors. For instance, the combination of an excessive
increase in circulating catecholamines and angiotensin II and increased release of endothelin
from vascular endothelial cells (Figure 12.7) in heart failure results in vasoconstriction.

THROMBOXANE
Thromboxane is produced primarily by platelet aggregation. Vascular endothelial cell damage,
for instance, in the region of an atherosclerotic plaque can result in changes in endothelial
cell function that attract blood platelets and induce them to produce thromboxane, a potent
vasoconstrictor. As noted above, abnormal endothelial cells overlying an atherosclerotic plaque
produce less vasodilators, such as nitric oxide and prostacyclins, relative to endothelin. The ten-
dency toward vasoconstriction increases the obstruction produced by the plaque and further
reduces blood flow and organ blood supply.
Thromboxane can play a role in the vasoconstriction associated with such pathologic states
as atherosclerosis, pulmonary hypertension, heart failure, and kidney failure.

CLOTTING
Abnormal endothelial cells produce a lower t-PA:PAI-1 ratio (Figure 12.7). There is less blood
fibrinolytic activity and a greater tendency toward thrombosis.

CHEMORECEPTORS
It is doubtful whether the normal circulation is under any influence of chemoreceptors.
Chemoreceptors do play a key role in regulation of normal respiration.
Chemoreceptor control of the circulation can become important in some abnormalities. For
instance, with severe enough hemorrhage to result in a major drop in blood pressure, blood
flow decreases in chemoreceptors, for instance, in the aortic and carotid bodies* (Figure 12.1).
PO2 and pH then decrease and PCO2 increases in chemoreceptor interstitial tissue. These local
changes in the chemoreceptor interstitium generate more action potentials over afferent nerves
from the chemoreceptor to medullary vasoconstrictor centers. Increased sympathetic outflow
from the vasoconstrictor centers to α-receptors around the body then contributes to the gener-
alized vasoconstriction that characterizes severe hemorrhage. This is a body survival mecha-
nism to maintain central blood pressure and blood flow to the brain and heart in the face of
severe hemorrhage or other causes of a major abnormal drop in blood pressure.
Central respiratory control centers are also affected in the above scenario. Increased fre-
quency of respiration, tachypnea, accompanies severe hemorrhage.

LOCAL METABOLIC CONTROL

Most organs have local metabolic control of blood flow. An increase in organ work
and metabolism results in changes in the organ’s interstitium that causes arteriolar

* Do not confuse the carotid bodies, chemoreceptor organs, with the carotid sinus baroreceptors (Figure 14.1).

116
 Autoregulation

vasodilatation. Increased organ work and metabolism results in the following changes in
the interstitium:
• ↑ Adenosine
• ↑ K+
• ↑ Lactic acid
• ↓ PO2 (more O2 taken up by the organ cells)
• ↑ PCO2
• ↓ pH (↑CO2 plus interstitial H 2O = H 2CO3, carbonic acid; also, there can be increases in
interstitial lactic acid)

Arterioles are embedded within the interstitium of organs and their smooth muscle is
affected by interstitial chemical constituents. The changes in interstitial constituents, described
above, cause arteriolar smooth muscle relaxation and vasodilation.
An increase in organ work results in increased cell metabolism. Cell oxygen consumption
increases and there is a fall in intracellular and interstitial PO2. More ATP is split in a harder
working cell and AMP, an ATP breakdown product, diffuses out of the cell. Enzymes in the
interstitial fluid act on AMP to produce adenosine. Lactic acid is released from harder working
cells as is CO2 and interstitial pH decreases. Remember, the interstitium contains water and
CO2 + H 2O ↔ H 2CO3, carbonic acid. Repeated action potentials result in more K+ in the inter-
stitial fluid from K+ efflux with repeated repolarization. Decreased interstitial O2 and pH and
increased adenosine and K+ have a combined effect of inducing relaxation of arteriolar smooth
muscle and increasing organ blood flow. The harder the organ works, the more relaxed the
arterioles become and the more blood flow increases.
An increase in organ blood flow brings more O2 to the harder working tissue. Also, the
increased blood flow carries away some of the interstitial PCO2, lactic acid, and adenosine, and
thereby, increases interstitial pH. Some of the K+, adenosine, and any other vasodilatory factors
that may be present are carried away in the increased blood flow. The result is that blood flow
increases to a steady state level that is appropriate for the level of organ work. When organ work
decreases, the above changes are reversed and organ blood flow decreases to settle at a new,
lower steady state level.
Note, this is local feedback control and does not involve hormones or nerves. Local metabolic
control is important, for example, in the brain, heart, and skeletal muscle. It is also present in the gut.
There is a good deal of uncertainty about the relative importance of each of the factors noted
above in metabolic control. For instance, adenosine appears to play an important role when isch-
emia occurs. Ischemia, a reduction in blood flow below normal levels, does result in increased
adenosine in ischemic tissue interstitium and adenosine does then induce vasodilation that miti-
gates some of the ischemia problem. However, evidence for adenosine playing a role in normal
metabolic control is not consistent. Clearly, blood flow increases when work increases in an
organ with local metabolic control, but the precise mechanisms remain to be worked out.

AUTOREGULATION
According to Poiseuille’s law, the amount of blood flow is partly dependent on the difference of
downstream mean pressure ( P2 ) from upstream mean pressure ( P1 ):

π( P1 − P2 )r 4
Q=
8 Lη

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 Circulatory controls

Blood flow →
40 80 120 160 mm Hg
Mean arterial pressure, P1 →

Figure 12.8  Autoregulation of organ blood flow. Steady state blood flow is plotted.

If downstream venous pressure ( P1 ) does not change, then flow in an organ, Q, will increase
with an increase in upstream, arterial mean pressure ( P2 ). This will be true assuming nothing
else changes in Poiseuille’s law. However, when “autoregulation” is present, something else
does change.
First, consider blood flow to an organ, such as the brain, whose circulation does manifest
autoregulation. In this example, nothing has been done to alter vascular smooth muscle func-
tion in the organ (Figure 12.8). Blood flow increases with an increase in mean arterial pressure,
P1, but only at very low pressures (Figure 12.8). Above approximately 60 mmHg mean arterial
blood pressure there is little change in steady state blood flow (Figure 12.8).
An acute increase in mean arterial pressure does induce a transient increase in cerebral
blood flow, not shown in Figure 12.8. But more blood entering the arterioles dilates them and
stretches their walls. The arterioles in organs with autoregulation have smooth myocytes that
are activated by stretch. Stretch of the arteriolar wall smooth muscle cells opens L-type Ca 2+
channels and the smooth muscle contractions, vessel radius decreases and flow then decreases
back close to where it was before. Steady state blood flow is little changed (Figure 12.8). In the
context of Poiseuille’s law, P1 increases, resulting in an increase in Q and arteriolar r4, followed
by arteriolar smooth muscle contraction, a decrease in r4, and a return of Q toward its original
level (Figure 12.8).
The transient rise in flow is not illustrated in Figure 12.2—the graph shows only steady state
blood flow. This is one mechanism that explains, in the face of changing mean arterial pressure,
the constancy of blood flow called autoregulation that is present in some organs.
Also, the transient initial increase in cerebral blood flow caused by an increase in mean
arterial pressure increases cerebral interstitial PO2 and washes away interstitial PCO2. The
transient increase in blood flow carries away adenosine, H+, and K+ that may be present. This
vasodilator washout reduces arteriolar dilation and, with arteriolar smooth muscle stretch acti-
vation, nudges cerebral blood flow back toward where it had been prior to the increase in mean
arterial pressure.
The vasodilator washout and myogenic mechanisms are both important. Caution! The fact
that there is a chemical mechanism at work in autoregulation does not mean autoregulation
is the same as local metabolic control. Local metabolic control matches blood flow to organ
metabolism. Autoregulation acts to maintain constancy of flow. Brain, heart, kidney, and skel-
etal muscle are examples of organs with autoregulation.
Next, consider blood flow to the brain in an experiment where the arteriolar smooth muscle
has been paralyzed with a drug. Now blood flow changes directly with mean arterial pressure.
Autoregulation has been eliminated. This type of experiment highlights the importance of the
myogenic mechanism of autoregulation.
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 Veins in circulatory control

Autoregulation also works with a fall in arterial mean blood pressure. Cerebral blood flow
decreases transiently when arterial pressure decreases. The transiently reduced cerebral blood
flow results in less stretch of the arteriolar walls. With less stretch vascular smooth myocytes
relax and r4 increases. Flow then increases to close to what it was before arterial pressure
decreased. Likewise, with less flow there is less vasodilator washout of adenosine, CO2, K+, and
lactic acid.
Autoregulation is not a reflex. There are no nerves or hormones involved. It is local control
of organ blood flow inherent in blood vessel smooth muscle stretch activation and related to
vasodilator washout from the interstitium.

ARTERIAL BLOOD PRESSURE AND SALT AND WATER

METABOLISM
Arterial blood pressure is partially dependent on the amount of blood in the aorta. That is why
stroke volume, vessel elasticity, and peripheral resistance are among the important determi-
nants of blood pressure. Also of importance is the total volume and distribution of blood in
the circulation. For instance, if total blood volume increases, the following sequence can occur:
• ↑ Total blood volume
• ↑ Aorta radius and circumference
• ↑ Stretch of the aorta
• ↑ Aorta wall tension
• ↑ Aortic blood pressure

The most common cardiovascular disease in the United States and many other countries is
high blood pressure or hypertension. The etiology in most patients is unknown and the patho-
physiology may not be the same in all patients. Some of the patients do have abnormalities
in salt and water metabolism whereby total body sodium and water are greater than normal.
Na+ and the water accompanying it are distributed within the extracellular space, throughout
the intravascular and interstitial compartments. The severity of high blood pressure in these
patients is linked to their sodium intake. In these patients and in most other patients with high
blood pressure, blood pressure is lowered to some degree by drugs that induce the kidneys to
excrete sodium and water.
In summary, salt and water metabolism is important in the long-term control of systemic
blood pressure levels. Although the mechanisms are complex, the important factors are clear
and include the volume of the aorta (radius, circumference, and wall stretch) and aortic wall
elasticity.

VEINS IN CIRCULATORY CONTROL

Veins are very distensible (compliant); consequently about 2/3 of circulating blood volume is
in the venous part of the circulation. Blood flowing into veins easily distends the veins and
increases their volume. The sympathetic nervous system is the primary controller of venous
tone in some parts of the circulation, for instance, the kidney and splanchnic regions.
Increased lower body venous tone due to sympathetic stimulation of vascular alpha recep-
tors enhances the return of blood to the right atrium during the baroreflex response to standing
and helps to partially overcome the effects of gravity.
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 Circulatory controls

BLOOD PRESSURE CONTROL, THE AUTONOMIC NERVOUS

SYSTEM, AND HEART FAILURE
Abnormalities in blood pressure control have been demonstrated in patients with heart failure.
When compared with normal, the increase in heart rate with upright tilt is blunted. In some
heart failure patients there is a significant drop in blood pressure as compared with normal
during upright tilt. The mechanisms are not totally clear. One factor may be a down-regulation
of myocardial beta receptors and reduced norepinephrine synthesis in cardiac sympathetic
nerve endings in heart failure.
Heart failure, even in the early stages, is accompanied by increases above normal in cir-
culating norepinephrine and sometimes epinephrine as well. Increased sympathetic activity
accounts for higher heart rates in heart failure patients. The renin-angiotensin-aldosterone sys-
tem is activated by increased sympathetic activity. More sympathetic activity and more angio-
tensin II lead to widespread vasoconstriction, a hallmark of heart failure.
There is evidence that catecholamines and angiotensin II influences on myocardial myo-
cytes enhance development of myocardial hypertrophy and proliferation of embryonic pro-
teins. These cellular and molecular changes are called adverse remodeling. There is then a
vicious cycle of reduced ventricular function in heart failure leading to more proliferation of
abnormal myocyte proteins leading to more compromise of function. Beta blocking agents and
angiotensin converting enzyme inhibitors or angiotensin II receptor blocking drugs are used in
heart failure treatment, in large part to reduce deleterious myocardial remodeling.
Pathophysiological changes in neural and hormonal control systems in heart failure
e
are illustrated in the self-study module Myocardial Infarction and Chronic Heart Failure.

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 Regional blood flow

13

INTRODUCTION
The control of blood flow to regions varies. There is perhaps no better illustration of this than
dynamic exercise on a stationary bicycle or treadmill. Splanchnic and renal blood flow decrease
with such exercise simultaneous with a substantial increase in coronary and skeletal muscle
blood flow, and cerebral blood flow hardly changes at all. Regional blood flow also can alter
with disease. It is apparent that it is essential to understand regional controls of blood flow.

CEREBRAL BLOOD FLOW

There are four arteries that deliver almost all the blood to the brain: bilateral internal carotid
and vertebral arteries. The two vertebral arteries join to form the basilar artery. There is a minor
contribution from the anterior spinal artery. Venous outflow is via the internal jugular and
vertebral veins.

REGULATION OF CEREBRAL BLOOD FLOW: POISEUILLE’S LAW

Factors that determine cerebral blood flow are noted in Figure 13.1. These factors are the vari-
ables in Poiseuille’s law. L, length, of brain blood vessels does not change except with matura-
tion. There is the additional factor of intracranial pressure that will be discussed.

ARTERIOLAR RADIUS
The sympathetic nervous system plays a small role in normal control of the cerebral ­vasculature.
For instance, there are few α receptors on cerebral arteries or arterioles and sympathetic-
induced vasoconstriction is minimal. Cerebral arteries are innervated by vasodilating peri-
vascular C-fiber nerves and parasympathetic nerves that play a role in the pathophysiology of
migraine headaches, but have a limited role in controlling cerebral blood flow.
Cerebral blood flow is influenced by the PCO2 of arterial blood (Figure 13.2). CO2 is lipid
soluble and readily diffuses across brain capillaries. An increase in arterial PCO2 decreases the
gradient across the capillary wall for CO2 diffusion out of the brain, brain interstitial fluid PCO2
increases, and pH decreases (Figure 13.2). Arterioles in the brain, as in all organs, are embedded
within the brain interstitial tissue and the arteriolar smooth muscle is sensitive to ­interstitial
fluid pH (Figure 13.2). PCO2 combines with interstitial water to form H2CO3 (Figure 13.2). The
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 Regional blood flow

π(P1 – P2)r4
Q=
8ηL
Intracranial Cranium
pressure
Brain, spinal
cord, and
Local spinal fluid
constriction
r4 and dilation of
cerebral
arterioles

P1 Mean arterial pressure

at brain level
η Viscosity of blood
Mean venous pressure Vertebral
P2 column
at brain level

Figure 13.1  Factors important in brain blood flow. (Adapted from Barrett KE et al. Ganong’s Review of
Medical Physiology, 23rd ed. New York, NY: McGraw-Hill; 2010. With permission of McGraw-Hill.)

lower brain tissue pH results in relaxa­t ion of arteriolar smooth muscle, vasodilatation (Figure
13.1, increase in r4), and more cerebral blood flow (Figure 13.2).
The converse of the above occurs if arterial PCO2 decreas­es. For instance, if one were to breathe
in and out deeply and rapidly enough to blow off more CO2 than is produced in the body, arterial
PCO2 decreases. A decrease in arterial PCO2 due to rapid breathing is defined as hyperventila-
tion. The decrease in arterial PCO2 increases the concentration gradient across the capillary wall
from the brain interstitium to the blood and more PCO2 leaves the brain (Figure 13.2). This results
in interstitial brain alkalosis, cerebral arteriolar con­striction, and a decrease in cerebral blood flow
(Figure 13.2). Dizziness and syncope due to decreased cerebral blood flow can occur.
Note: The level of blood pH has negligible effects on brain blood flow because H+ and OH−
ions in the blood do not readily cross the capillary walls in the brain. The blood–brain barrier
is discussed below.

MEAN ARTERIAL PRESSURE

Cerebral hypoxia due to inadequate cerebral blood flow develops below a mean arterial blood
pressure of 60 mm Hg. There is autoregulation of cerebral blood flow that operates above this
arterial blood pressure level, as discussed above.

Capillaries
[HCO3–]
pH = pK + log
[H2CO3]

PCO2

Interstitium

PCO2 pH dilatation
PCO2 pH constriction Arteriole

Figure 13.2  Influence of arterial PCO2 and brain interstitial pH on brain blood flow.

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 Cerebral blood flow

MEAN VENOUS PRESSURE

BLOOD VISCOSITY
Mean venous pressure and blood viscosity have been discussed earlier in Chapter 8, How the
Circulation Works and in Chapter 11, Peripheral Circulation, Poiseuille’s law.

REGULATION OF CEREBRAL BLOOD FLOW: INTRACRANIAL

PRESSURE
The adult central nervous system lies within a rigid container, the skull and vertebral
­column (Figure 13.1). The brain, spinal cord, cerebrospinal fluid, and cerebral vessels nor-
mally fi
­ ll this rigid container. Since the total capacity is fixed, any increase in the volume of
any component within the central nervous system must result in an increase in intracranial
pressure and compression of other components. An increase in intracranial pressure con-
stitutes an increase in external pressure on the central nervous system blood vessels. An
increase in intracranial pressure squeezes the intracranial blood vessels and reduces their
radius.
One complication of a brain tumor is increased intracranial pressure. As the tumor grows,
intracranial pressure increases. Arterial inflow to the brain is reduced because of the increased
intracranial pressure and decreased blood vessel radius (r4) (Figure 13.1). The decrease in r4
constitutes an increase in cerebral vascular resistance. Therefore, inadequate cerebral blood
flow (cerebral ischemia) can be an added problem in such a patient.

CHANGES IN CEREBRAL BLOOD FLOW

Blood PCO2 is tightly regulated by the respiratory system and normally remains constant
even during mild to moderate exercise. The constant blood PCO2 and autoregulation result
in mostly constant brain blood flow. Overall brain metabolism is for the most part con-
stant and changes little with the transition, for instance, from intense mental activity to
relaxation.
But there is a change in local brain blood flow with local activity. Increases in local
blood flow come about because of more brain nerve cell activity and local metabolic con-
trol. Also, as elsewhere in the circulation, endothelial vasoactive factors partly control the
vasculature.
Brain astrocytes surround and communicate with neurons, and have a role in neuronal
metabolism. The end-feet of astrocytes contact neuronal cell bodies and arterioles and release
neurotransmitter substances that are vasoactive, such as NO. This is another mechanism for
linking local increases in neuronal activity with local vasodilation.

SUMMARY OF CEREBRAL BLOOD FLOW REGULATION

Arterial blood levels Brain circulation

↑PCO2 Vasodilatation
↓PCO2 Vasoconstriction
↑ or ↓ pH (pH here is arterial blood pH, not brain Minor effects (H+ and OH− do not easily cross
interstitial pH) the blood–brain barrier, discussed below)

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 Regional blood flow

Local metabolic control—brain cell release of lactic acid, K+, CO2, and adenosine. Also,
astrocytes and local vasoactive substances play a role.
The autonomic nervous system innervates larger cerebral arteries, but has a minor influence
on the control of cerebral blood flow.
Autoregulation is important.

BLOOD–BRAIN BARRIER
Endothelial cell junctions in most of the adult brain capillaries are tight and have few if any
pores. Diffusion between blood and the brain interstitium is very limited in most of the brain
tissue. Astrocytes, surround the cerebral blood vessels and play a role in limiting diffusion
between the brain interstitium and blood.
As is true in capillaries elsewhere, lipid soluble materials (O2, CO2, ethanol, and anesthetics) dis-
solve through the endothelial wall. Diffusion rates and transport mechanisms in brain capillaries
are different from capillaries in other parts of the circulation. Catecholamines do not readily pass
the barrier and brain blood vessel endothelium contains monoamine oxidase that breaks down cat-
echolamines. As noted below, there is a carrier system for glucose in the capillary membrane. Other
materials (heavy metals, antibiotics) pass the barrier with difficulty compared with capillary beds in
other parts of the body. Consideration of the blood–brain barrier becomes important, for example,
when selecting drugs to treat a brain infection or if a toxin is present in the bloodstream.
Some fetal red blood cells normally cross the placenta into the maternal blood stream. If
an Rh– mother has an Rh+ baby, the maternal blood develops antibodies that diffuse across
the placenta and destroy the baby’s red blood cells. Hemoglobin released from the damaged
fetal red blood cells is metabolized by the fetal liver and results in a rise in blood levels of bile
pigments. The newborn immature blood–brain barrier does allow bile pigments to pass across
into the brain. The bile pigments cross the immature blood–brain barrier and can cause brain
damage. Brain damage of this type is not a problem in adult liver disease or hemolytic anemia
because there is full development of the adult blood–brain barrier to bile pigments.

BRAIN METABOLISM
Glucose is the major energy source for the brain and there is a carrier-mediated transfer of
glucose across the blood–brain barrier. A major complication of hypoglycemia, such as with
excessive insulin in a diabetic, is brain cell dysfunction and convulsions.

LYMPHATIC DRAINAGE
The role of lymphatic drainage of brain tissue is being investigated. Cerebral lymphatic drain-
age is limited. Cerebral spinal fluid does equilibrate with blood via capillaries in some loca-
tions in the arachnoid sinuses and there may be lymphatic vessels originating in arachnoid
tissue.

CORONARY BLOOD FLOW

ANATOMY
The two main coronary arteries arise from the sinus of Valsalva of the anterior right and left
aortic valve cusps (Figure 13.3). Coronary artery orifices are patent through­out the cardiac cycle
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 Coronary blood flow

Aorta

Right coronary Left coronary

artery artery

Right
atrium

Coronary
sinus at
opening into
right atrium

Figure 13.3  Coronary artery anatomy.

because a small amount of normal turbulence at the cusps during ejection keeps the aortic
valve leaflets from flattening against the sinus walls.
The main arteries and their major branches are on the surface of the ventricles. Branches emerge
at right angles to these main vessels and penetrate the ventricular wall. The right-angle branches
arborize into small arteries, arterioles, and so on, all within the ventricular muscular wall.

CORONARY BLOOD FLOW AND FLOW DEPENDENT OXYGEN

SUPPLY
At rest, aortic blood O2 content is about 20 mL O2/100 mL blood. Pulmonary artery blood O2
content is typically about 15 mL/100 mL blood. Therefore, the tissues of the entire body extract
from the systemic circulation about 5 mL O2/100 mL blood. In contrast, the O2 content of coro-
nary sinus venous blood in a normal heart is 5 mL O2/100 mL blood. Coronary sinus blood
flow is the major venous effluent from the left ventricle. The left ventricular myocardium then
extracts about 15 mL O2/100 mL blood or roughly 3 times the O2 extraction per unit of blood as
compared with the rest of the body. Even in a normal heart in a resting individual, most of the
oxygen is being extracted from blood passing through the coronary circulation. This fact leads
to an extremely important clinical concept:

An increase in coronary blood flow is the major way the oxygen supply to heart muscle can
be increased. The capacity for increasing O2 extraction from coronary blood flow is very
limited.

This is what is meant by a flow-dependent oxygen supply. For instance, consider a patient
who has a partially obstructed coronary artery and you will appreciate the problem that can
arise when more myocardial O2 is needed, such as during exercise. The partial obstruction can
limit the increase in coronary blood flow during exercise. Since O2 extraction is close to maxi-
mum before exercise begins, extraction of more oxygen from the coronary blood flow during
exercise is limited. The result may be failure to supply enough of an increase in coronary blood
flow to supply the increased O2 demand of the exercising heart.
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 Regional blood flow

CONTROL OF CORONARY BLOOD FLOW

The amount of coronary blood flow is determined primarily by local metabolic control. A
change in cardiac work, due to an increase in heart rate, pressure development, or both is the
major driver of metabolic change and coronary blood flow.
Sympathetic and to some extent parasympathetic nerves innervate coronary arterioles.
Sympathetic stimulation of beta receptors on arterioles contributes about 25% of the total arte-
riolar vasodilation during exercise or stress, the rest being due to local metabolic control. There
also is sympathetic stimulation of alpha receptors on larger coronary arteries. The resulting
activation of medium and large size coronary artery smooth muscle reduces their expansion
with increased flow and enhances forward blood movement. Nervous influences also probably
play a role in maintaining basal arteriolar smooth muscle tone.
Secondary to, for instance, excitement or exercise, the rate of firing of action poten-
tials increases along sympathetic nerves to the sinus node and ventricular muscle. Heart
rate increases as does the rate and extent of force development and shortening of heart
muscle fibers. Stroke volume increases. Systolic blood pressure increases. Myocardial work
increases because heart rate increases and systolic ventricular pressure is higher. Myocardial
metabolism increases and coronary blood flow increases primarily because of local meta-
bolic control.
It is increased cardiac work and an associated increase in myocardial oxygen consumption
brought on by sympathetic stimulation that brings about approximately 75% of the coronary
arteriolar dilatation and increased coronary blood flow. Direct nervous control of the coronary
vasculature accounts for the remaining 25%.

CORONARY BLOOD FLOW, WORK RELATIONSHIP

If ventricular pressure or wall tension increases, myocardial metabolism increases and blood
flow increases due primarily to local metabolic control. Anything that increases the amount of
myocardial pres­sure work will increase myocardial metabolism, significantly dilate coronary
arterioles, and increase the amount of coronary blood flow. Coronary blood flow is then linked
to the myocardial need for O2 via local metabolic control.

MAJOR DETERMINANTS OF MYOCARDIAL OXYGEN

CONSUMPTION
The major determinants of coronary blood flow are those factors that strongly influence systolic
wall tension (tension is force per unit length) per unit time:
• Intraventricular pressure development: Ventricular pressure development is a major
determinant of myocardial oxygen consumption.
• Ventricular size and configuration (law of Laplace): Ventricular wall tension during systole is
a major determinant of myocardial O2 consumption. Systolic wall tension is the force in
the ventricular wall produced by the myocytes. Wall tension is directly related to pressure
via the law of Laplace, P = (T/r). This simplified version of the formula can be rearranged
to T = Pr. In a dilated ventricle (large r) the amount of ventricular wall tension (T)
to produce a given intraventricular pressure is greater than in a ventricle that is not
dilated. This becomes important in a patient with, for instance, heart failure or dilated
cardiomyopathy. The version of Laplace’s law applied to a ventricle is
126
 Coronary blood flow

Pr
T=
2h

   The h is wall thickness. In, for instance, hypertrophy resulting from aortic valvular
stenosis, left ventricular pressure, P, increases, but so does wall thickness, h. Since
there is more muscle tissue, pressure development is shared by more muscle and wall
tension is less than it would otherwise be. The increase in h helps to minimize the
increase in T. As the aortic valve narrows and left ventricular pressure, P, continues to
climb, T does increase despite h increasing and myocardial O2 demands increase. One
complication of aortic valvular stenosis is exercise-induced ischemia due to demand for
O2 exceeding supply.
• Heart rate: No surprise here—every heartbeat consumes O2 and O2 consumption
increases as heart rate increases.
• Contractility: An increase in contractility is accompanied by more vigorous ventricular
contraction with a likely increase in pulmonary artery and aortic pressure. The ventricles
work harder and require more O2.

MINOR DETERMINANTS OF MYOCARDIAL OXYGEN

CONSUMPTION
There are several minor determinants of myocardial oxygen con­sumption that play less of a role
in determining coronary blood flow:
• Stroke volume: Stroke volume production occurs due to ventricular wall myocyte
shortening, but consumes relatively little O2 in addition to that producing force
development.
• Activation energy: ATP used in depolarization and excitation-contraction coupling is in
this category and is a relatively small quantity.

AUTOREGULATION
There is autoregulation in the coronary vasculature. Autoregulation becomes particularly
important when blood pressure falls in the coronary vasculature distal to a coronary artery
obstruction. The fall in blood pressure reduces wall stretch, the coronary arteriolar smooth
muscle relaxes, and the radius increases. Autoregulation then partially offsets the reduction of
flow distal to the obstruction.

CORONARY BLOOD FLOW AND THE CARDIAC CYCLE

SYSTOLE
Coronary arterial inflow varies during the cardiac cycle, particularly in the left ventricle
(Figure 13.4). Intramyocardial coronary arterial vessels are squeezed by contracting myocar-
dium during systole. Reduction of vessel radius and the attendant increase in coronary vascular
resistance results in reduced coronary arterial inflow during systole (shaded portion of graph
in Figure 13.4). Aortic pressure is high enough during left ventricular ejection to drive some
blood through the elevated coronary vascular resistance. The variations in blood flow are less
pronounced in the lower pressure, thinner-walled right ventricle (Figure 13.4).
127
 Regional blood flow

pressure (mm Hg)

120 Aorta

Aortic blood
100
80

Left coronary
artery

Coronary arterial
inflow (mL/min)
Right coronary
artery

Time

Figure 13.4  Variations in coronary arterial inflow during the cardiac cycle.

DIASTOLE
Most coronary artery inflow occurs during diastole (Figure 13.4) when the myocardium is relaxed.
This is particularly true in the left ventricle because of the greater variation in pressure levels and
wall tension than in the right ventricle. When heart rate increases in exercise, the duration of
diastole decreases much more than the duration of systole. The time available for coronary arte-
rial inflow decreases. This is not a problem for a normal person because the extent of coronary
arteriolar vasodilation caused by the increased cardiac work and local metabolic control results in
adequate coronary blood flow.
Tachycardia occurring in a patient with coronary artery narrowing or with an abnormally
increased demand for coronary blood flow, like a patient with aortic stenosis, can result in inad-
equate coronary blood flow relative to the metabolic demands of the heart.

VENOUS OUTFLOW
Venous outflow increases during systole. Ventricular muscle contraction squeezes veins and pro-
pels venous blood through the coronary sinus and other veins. There is much less squeeze during
diastole and veins fill before the next systole. Venous outflow is not included in Figure 13.4.

ENDOTHELIAL VASOACTIVE FACTORS

Control of coronary blood flow related to endothelial vasoactive factors is important. Changes
in coronary blood vessel endothelial cell function are proving to be important in understanding
coronary heart disease.

CLINICAL CASE
An 85-year-old man has been having gradually increasing difficulty with shortness of breath with exertion
over the past 6 months. Also, he has experienced pressure-like anterior chest pain in the last week with
climbing a flight of stairs. On several occasions in the past 5 years he has been told of having a heart mur-
mur and there is a systolic ejection murmur present (discussed earlier in Chapter 9, Cardiac Cycle, Heart
Sounds and Murmurs [Figure 9.8]). What is the heart murmur due to? What is the etiology of the chest pain?

128
 Skeletal muscle blood flow

This patient has aortic valvular stenosis, which is presented in the self-study module
e
Cardiac Cycle: Heart Sounds and Murmurs. His left ventricle is likely hypertrophied and more
muscle requires more O2. Also, left ventricular blood pressure and wall tension, major determinants of
myocardial O2 demand, are higher than normal and increase further with exercise. The chest pain is
likely related to exertional myocardial ischemia. Myocardial work during his exertion increases myocar-
dial O2 consumption enough to exceed O2 delivery by the coronary blood flow. Of course, his doctors
will have to exclude the presence of any coronary artery partial obstructions.

SKELETAL MUSCLE BLOOD FLOW

ANATOMICAL AND MECHANICAL CONSIDERATIONS

Skeletal muscle arterial blood inflow decreases during contraction as arterial branches
between muscle bundles are squeezed. In exercise, such as jogging, leg skeletal muscles alter-
nately contract and relax with the rhythmic movement of the legs. Arterial inflow decreases
during contraction and increases with relaxation. During such exercise, overall skeletal mus-
cle blood flow increases due to the extent of arteriolar vasodilatation brought about by local
metabolic control.
Skeletal muscle contraction squeezes veins within the muscle bundles. Valves in the
veins in the lower extremities open toward the right atrium and prevent reflux back toward
the muscle when the muscle relaxes. The rhythmic contraction and relaxation of leg skeletal
muscles acts as a pump, the skeletal muscle pump discussed earlier (Chapter 10, Ventricular
Function). The venous vascular bed fills from the arterial side during relaxation and during
muscle contraction blood in the veins is pushed toward the heart. The direction is one-
way due to the venous valves. This skeletal muscle pump phenomenon becomes important
for venous return to the right atrium during upright dynamic exercise such as running or
bicycling.

SKELETAL MUSCLE BLOOD FLOW CONTROL

LOCAL METABOLIC CONTROL
Arterioles in working, contracting skeletal muscles are predominately under local metabolic
control rather than autonomic nervous system control.

SYMPATHETIC EFFECTS
Arterioles in resting skeletal muscle are under the direct control of the sympathetic nervous
system and circulating catecholamines. Constriction of resting skeletal muscle arterioles is part
of the baroreceptor mechanism that is important in maintaining blood pressure when standing
upright at rest. This vasoconstriction is due to release of norepinephrine at sympathetic nerves
ending on arteriolar myocyte α receptors. Resting skeletal muscle blood flow is reduced during
intense sympa­thetic stimulation such as in a patient with advanced heart failure or hypovole-
mic shock due to blood loss.
Beta adrenergic receptors (β2) are present in skeletal muscle arterioles. Arterioles dilate in
response to low levels of circulating epinephrine as a balance to the α receptor activity. This
type of vasodilation may be important in low level exercise. During higher levels of exercise
local metabolic control predominates.
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 Regional blood flow

OXYGEN DELIVERY
Interstitial pH drops and temperature rises due to the metabolic activity of mechanically active
muscle. Increased acidic metabolites such as lactate and CO2 contribute to a decrease in inter-
stitial fluid pH. Lactic acid enters the blood and results in a drop in arterial pH during moderate
to heavy exercise.
The heat of muscle work warms blood as it circulates through a muscle. Also, core body
temperature rises after about 5 minutes of a sustained bout of dynamic exercise. Gradually, all
blood in the body is warmed and the temperature of arterial blood entering working muscles
increases.
Drop in blood pH and rise in blood temperature result in an increase in blood PO2 at any
given level of O2 saturation. At any given level of saturation, warmed acidic hemoglobin more
readily releases O2. This assists in O2 delivery to working muscles.

AUTOREGULATION
Autoregulation is present in resting skeletal muscle. Autoregulation is overridden by metabolic
factors during muscle mechanical activity.

PULMONARY BLOOD FLOW

Pulmonary vascular resistance normally is less than a tenth of systemic vascular resistance.
Pulmonary arterioles are shorter and have less smooth muscle than in the systemic c­ irculation.
Pulmonary vascular resistance is less localized than in the systemic circulation. Resistance
is distributed among the small arteries, arterioles, and the microvasculature, including the
venules. Also, the pulmonary vasculature is exposed to a low level of external pressure because
of the spongy lung tissue and negative (below atmospheric) intrathoracic pressure.

CHARACTERISTICS OF PULMONARY BLOOD FLOW

There is very little extravascular support. Lung tissue is spongy. Small pulmonary arteries,
arterioles, capillaries, and venules form a meshwork within the alveolar walls. They are intra-
pulmonic. The larger Pulmonary arteries and veins are largely free of surrounding pulmonary
tissue. They are extrapulmonic. As noted above, external pressure on all these vessels is low
because intrathoracic pressure is below atmospheric.
In a resting person, during inspiration, external pressure on the extrapulmonic arteries and
veins decreases further. However, intrapulmonic vessels are “squeezed” by expanding alveoli,
the radius of these vessels decreases and pulmonary vascular resistance rises, although it is still
far less than systemic vascular resistance.
With very deep inspiration in a resting person, intrapulmonary blood vessels are stretched.
L increases and r decreases, which acts to impede blood flow. Remember:

π( P1 − P2 )r 4
F or Q =
8 ηL

Local control of pulmonary blood flow is predominantly related to alveolar air PO2. In regions
where alveolar air PO2 is low the local arterioles constrict. The site of this vasoco­n­striction is
130
 Pulmonary blood flow

in precapillary sphincters and arterioles­. If in an experiment alveolar air PO2 is reduced and
pulmonary artery blood PO2 is increased, pulmonary vasoconstriction does occur. Therefore,
the primary factor controlling pulmonary arteriolar caliber appears to be the alveolar air PO2
rather than pulmonary artery blood PO2.
There is controversy regarding the factors mediating vasoconstriction resulting from a drop
in alveolar air PO2. Histamine, angiotensin, and catecholamines all have been implicated, but
a specific mediator is not known. A drop in alveolar air PO2 does result in decreased pH of the
local lung tissue. Lung tissue acidosis causes vasoconstriction, not dilatation, as is the case in
other parts of the circulation.
Finally, hypoxia inhibits a K+ current in pulmonary vascular smooth muscle. The result-
ing depolarization of the smooth muscle cells opens Ca 2+ channels and the influx of Ca 2+
induces contraction and vasoconstriction. Experimental evidence is not completely satisfactory
for any one explanation of the mechanism whereby alveolar air hypoxia induces pulmonary
vasoconstriction.
It may seem disadvantageous for flow to decrease with alveolar hypoxia. However, consider
a situation in which a bronchial branch is obstructed. That segment of the lung is not aerated
and alveolar PO2 falls. Vasoconstriction in that segment diverts blood away from the poorly
ventilated alveoli to better aerated alveoli with normal PO2 levels and thereby preserves the
relationship of ventilation with perfusion.
There are sympathetic and parasympathetic nerve fibers to the lung, and there are α and
β receptors on small artery and arteriolar smooth muscle cells. However, the influence of the
autonomic nervous system on the pulmonary vasculature is minimal. Although sympathetic
nerve activity increases in, for instance, exercise, the overwhelming response in the pulmonary
circulation is passive dilatation and reduced vascular resistance in exercise. There are major
autonomic influences on bronchial smooth muscle, which will not be discussed here.
Endothelial vasoactive factors play a critical role here as in the coronary and other circula-
tions. Angiotensin II can cause some vasoconstriction in small arteries and arterioles in the lung.

CHANGES WITH POSTURE AND DYNAMIC EXERCISE

In upright posture, blood pressure in the apical vasculature is lower than in the base due to
gravitational, hydrostatic effects. Transmural pressure (pressure inside the blood vessel minus
pressure outside) is low in the apical vasculature, the blood vessel radius is then small and vas-
cular resistance is high. Thus, in the upright posture there is a vertical gradation of blood flow
in the lung, lowest in the apex and highest in the base.
There is a modest increase in pulmonary artery mean pressure during upright dynamic
exer­cise, even with large increases in cardiac output (CO). Therefore, pulmonary vascular resis-
tance must have decreased conco­m itant with the increase in pulmonary blood flow. Remember:

P1 − P2
CO =
R
P1 is mean pulmonary artery and P2 is mean left atrial blood pressure. If P1 increases less than
expected with the increase in CO, then R, pulmonary vascular resistance, must have decreased.
There are several mechanisms for the decrease in pulmonary vascular resistance during
dynamic exercise.
As pulmonary blood flow increases, pressure increases within the pulmonary blood ves-
sels. Any increase in intravascular pulmonary arterial pressure results in an increase in blood
vessel radius. Pulmonary blood vessel smooth muscle is not stretch activated and there is no
131
 Regional blood flow

autoregulation. Therefore, the increase in radius reduces resistance and blunts the tendency for
pulmonary artery pressure to increase.
As described above, in an upright resting person perfusion of blood vessels in the lung apices is
reduced because of the effects of gravity. During upright exercise the modest increase in pressure
in the pulmonary vasculature is enough to overcome some of the effects of gravity and increase
apical lung blood flow. Blood vessels in the lung apices not fully opened at rest are further opened
by the increased pulmonary arterial blood pressure. There is then recruitment of parallel blood
vessels during upright exercise and that contributes to reduced pulmonary vascular resistance.

RENAL BLOOD FLOW

There are two sets of arterioles in series. The first set of arterioles, the pre-glomerular or affer-
ent arterioles, control blood flow into the capillary network of the glomeruli. The second set,
the efferent arterioles, control blood flow into the rest of the kidney capillaries. All the kidney
arteriolar myocytes are richly innervated by sympathetic fibers. Afferent arteriole myocytes are
innervated by sympathetic nerves ending on α-receptors. Sympathetic stimulation results in
vasoconstriction and can lead to a reduction in overall renal blood flow. Constriction of post-
glo­merular arterioles during sympathetic stimulation will tend to raise glomerular hydrostatic
pressure and enhance glomerular filtration.
Kidney arterioles manifest autoregulation. There is relatively constant renal blood flow (RBF)
with arterial mean blood pressure levels of 70 to 170 mm Hg and glomerular filtration rate stays
constant over this range. This tendency for stability of renal blood flow contributes to optimizing
renal function. In addition to the mechanisms of autoregulation described earlier, in the kidney
there is tubuloglomerular feedback. An increase in kidney blood flow and glomerular capillary
blood pressure transiently result in more glomerular filtration. More water and Na+ are filtered,
travel through the renal tubules, and the increased tubular Na+ is sensed by the macula densa.
This leads to vasoconstriction of the afferent arteriole and a return of blood flow and filtration
close to their original levels. The combination of tubuloglomerular feedback and stretch activa-
tion of vascular smooth muscle maintains stability of renal blood flow and glomerular filtration.
The renin-angiotensin system and the participation of the kidney in control of the circula-
tion is discussed in Chapter 12, Circulatory Controls.

GASTROINTESTINAL BLOOD FLOW

The spleen-to-liver and gut-to-liver vasculature are examples of sets of arterioles and capil-
laries in series, as in the kidney. Autoregulation is not a prominent feature, but control by the
sympathetic nervous system is. Arteriolar myocytes have α-receptors and vasoconstriction is
a prominent feature of sympa­thetic activity, such as during dynamic exercise. Vasodila­tation
occurs in response to local metabolic activity, as with digestion. Vasodilatation in response to
vagal stimulation is probably indirectly due to increased gut activity.

CUTANEOUS BLOOD FLOW

Cutaneous blood flow plays an essential role in the regulation of body temperature as well as in
skin nutrition. Cutaneous blood flow most involved in body temperature control is in the skin
in exposed parts of the body.
132
 Cutaneous blood flow

EXPOSURE TO A COLD ENVIRONMENT

Cold ambient temperatures result in cutane­ous vasoconstriction due to a combination of three
mechanisms.
• There is a direct effect of skin cooling on vascular smooth muscle. A moderate decrease
in skin vascular smooth muscle temperature results in vasoconstriction.
• A second mechanism involves a nerve reflex. There is evidence for a nervous reflex from
the skin to the hypothalamus via not well-defined afferent pathways. Efferent pathways
from the hypothalamus result in sympathetic mediated vasoconstriction of arteriovenous
anastomoses or metarterioles (Figure 13.5).
• Finally, a third mechanism is related to cooled venous blood returning from cooled
skin. The cooled venous blood decreases the temperature of blood in the circulation.
The hypo­thalamus has extremely sensitive temperature receptors and an extensive
vasculature. A fraction of a degree change in blood temperature can be sensed by the
hypothalamic temperature sensitive cells. The efferent pathway from the hypothalamus
is over sympathetic nerves to α-receptors, particularly those innervating metarterioles
(Figure 13.5, metarterioles, also called arteriovenous anastomoses). Vasoconstriction
in the skin diverts blood away from the body surface, reduces heart loss, and acts to
maintain a stable core body temperature in a cold ambient environment.

EXPOSURE TO A WARM ENVIRONMENT

Warm ambient temperatures result in cutaneous vasodilatation due to three mechanisms.
• There is a direct effect of skin warming on vascular smooth muscle. Warmed skin
arteriolar smooth muscle is less responsive to norepinephrine-induced contraction. Also,
there is more NO activity in warmed skin arterioles.
• A second mechanism involves decreased sympathetic vasoconstrictor activity.
Warmer blood returning from the periphery raises circulating blood temperature. The
hypothalamus is perfused with warmer blood and this induces a reduction in h­ ypo­thala­mic
output over sympathetic nerves to arteriovenous anastomoses (Figure 13.5). The decreased

Conduction-convection
Radiation Evaporation

Heat loss

°C Epidermis
Dermal papilla
Heat
Capillary loop Heat
(venous limb)
Venous plexus Dermis
Arteriovenous
anastomosis Vein Arteriole

Figure 13.5  Cutaneous blood flow and temperature control. The vessels labeled “arteriovenous
anastomosis” are metarterioles or thoroughfare channels. They are muscular vessels going from
arteriole to venule. (From Levick JR. An Introduction to Cardiovascular Physiology, 5th ed. London,
England: Hodder Arnold; 2011. With permission of Taylor and Francis.)

133
 Regional blood flow

sympathetic activity to α-receptors results in passive arteriovenous dilatation and more

skin blood flow.
• In the third mechanism there is increased nervous input to the hypothalamus from
temperature sensors in the skin. This results in increased sympathetic cholinergic
stimulation of sweat glands. Sweat gland activity results in sweat secreted onto the skin
surface and the production of substances that diffuse into the skin interstitium. These
substances act on interstitial fluid proteins to produce vasodilators. Bradykinin may be
one such vasodilator.

Increased skin blood flow enhances heat loss by bringing warm blood to the body surface.
Heat is then lost through radiation and conduction/convection. Evaporation of sweat on the
skin surface also increases heat loss.

134
 Microcirculation

14

The microcirculation consists of the arteriolar inflow to the capillary network, the capillary
network and the venous outflow (Figure 14.1). Arterioles and venules have smooth muscle.
Capillaries (Figure 14.1) consist of only endothelial cells.

ARTERIOLES
Blood flow from the arterial supply of an organ to its capillary bed is determined by the amount
of constriction or dilatation of the small muscular arteries and arterioles. All tissues have arte-
rioles (Figure 14.1). Some also have precapillary sphincters. Each precapillary sphincter is a
circle of smooth muscle that surrounds the origin of a capillary from an arteriole (not pictured
in Figure 14.1). These sphincters participate with arterioles in the control of blood entering the
capillaries. When either an arteriole or a precapillary sphincter constricts, blood flow and pres-
sure fall in the downstream capillaries. When they dilate, capillary blood flow and pressure
increase.

CAPILLARIES
A capillary wall consists of a single layer of endothelial cells. Exchange is facilitated by the very
high surface area to volume ratio in the capillary bed. Also, there is no muscle or connective
tissue in capillary walls, the wall is thin and diffusion in and out is facilitated.
There are pores between adjacent endothelial cells in most of the microvasculature. Such
pores are mostly small or absent in the adult cerebral circulation where a blood–brain barrier is
present. Glomerular capillaries in the kidney act to filter the blood and their pores are promi-
nent and highly specialized.

METARTERIOLES
Metarterioles are shunt vessels. Other names are “thoroughfare channel” and “arteriovenous
anastomosis.” They are present in certain specialized areas. As discussed above (Chapter 13,
Regional Blood Flow), parts of the skin microcirculation are particularly rich in metarterioles.
The increase in heat loss through the skin in response to an increase in ambient temperature is
135
 Microcirculation

Arteriole Venule

Capillaries

Lymphatic sac
and lymphatic
capillary

Figure 14.1  The microcirculation and lymphatics. (The superimposed illustration of a lymphatic vessel
is from Levick JR. An Introduction to Cardiovascular Physiology, 5th ed. London, England: Hodder
Arnold; 2011. With permission of Taylor & Francis Group.)

due largely to a reflex increase in cutaneous metarteriole blood flow (Figure 13.5 in Chapter 13,
Regional Blood Flow, cutaneous blood flow). The increased cutaneous metarteriolar flow brings
more blood to the body surface to facilitate heat loss. This flow is non-nutritional. It bypasses
the capillary bed and shunts blood from the arterial to the venous side of the circulation. There
is reflex metarteriolar constriction on exposure to cold ambient temperatures.

POSTCAPILLARY RESISTANCE
When venules (Figure 14.1) constrict, resistance to flow out of a capillary bed increases and
capillary hydrostatic pressure and capillary filtration in­c rease. Blood pressure in the kidney
glomerular capillaries is partly dependent on the series resistance offered by the efferent
arterioles.
The venous portion of the circulation accommodates a large blood volume—normally 60%
to 70% of total blood volume resides there. Veins are thin-walled and relatively compliant and,
as discussed earlier, readily expand as blood flows into them. The venous portion of the circula-
tion characteristically has a large volume and low blood pressure.

NATURE OF BLOOD FLOW IN THE MICROCIRCULATION

NOT LAMINAR OR TURBULENT

Capillary blood flow is not laminar. Red blood cells (RBCs) move in single file because of
the dimension of RBCs relative to the average capillary diameter: 8 µm vessel diameter and
2 × 8 µm RBCs. The biconcave RBCs must fold and slide through the capillary lumen. This
minimizes diffusion distance from RBC to the interstitium. The flow is intermittent and depen-
dent on arteriolar or precapillary sphincter control. There is no possibility for flow to be stream-
lined or turbulent as RBCs move in a single file with intervening plasma columns.
136
 Nature of blood flow in the microcirculation

INTERMITTENT
When capillary blood flow is observed directly, such as in the mesenteric vessels of a frog or rat,
it is seen to be intermittent. Blood flow in any one capillary can proceed forward, stop or reverse
direction, and move slow or fast. Arteriolar control fluctuates in response, for instance, to local
changes in metabolism. For example, in ventricular myocardium, the extent of constriction or
relaxation of an arteriole is related to the metabolism of the myocytes that surround it.

SLOW
As discussed earlier, capillaries are the most numerous of blood vessels in the body. The flow
of blood in each capillary is the slowest in the circulation. This is because the total cardiac
output is divided among many millions of capillaries. Slow flow is optimal for diffusion and
exchange.

FORCES DETERMINING TRANSCAPILLARY EXCHANGE

There is a complete presentation of transcapillary fluid movement in the self-study
module Transcapillary Fluid Exchange: Starling Principle of Fluid Movement across e
a Capillary Wall.
• Capillary blood pressure: The blood pressure within a capillary, Pc, also called the hydro-
static pressure, is an important determi­nant of fluid transudation (Figure 14.2). As noted
above, capillary blood pressure is determined by the combined effects of arteriolar and
precapillary sphincter smooth muscle activity, mean venous pressure, and venular smooth
muscle activity. A high ratio of postcapillary to precapillary resistance favors an increase
in capillary blood pressure and more capillary filtration.
  If arteriolar and precapillary sphincter smooth muscle is relaxed and precapillary
resistance is low, flow into and pressure within the capillaries will be greater than when
precapillary resistance is high. An increase in postcapillary venular resistance will
increase capillary blood pressure as will a rise in mean venous pressure.
• Plasma effective osmotic pressure: This is a force that pulls water into a capillary and is
measured in mm Hg. Plasma effective osmotic pressure (πp) (Figure 14.2), also referred

Pc Pi
Pc
30 mm Hg –3 mm Hg
10 mm Hg

πi
πp
8 mm Hg
28 mm Hg

Net filtration pressure = (Pc – Pi) – σ(πp – πi)

Figure 14.2  Capillary with forces important for transcapillary exchange.

137
 Microcirculation

to as the oncotic pressure, is related mostly to the osmotic pressure of plasma proteins as
follows:

  mm Hg
Albumin 20
Globulin 5
Fibrinogen 1

  Notice that total osmotic pressure is not used here. Total osmotic pressure is attribut-
able mostly to Na+ and its associated anions and is close to 300 mosm/100 mL, which
converts to over 5000 mm Hg. However, ions freely diffuse back and forth through the
capillary wall, with accompanying water, and have no effect on net water movement. Ions
are not normally “effective” in producing net movement of water as they freely move
across the capillary wall.
  Albumen has a small molecular size compared with the other plasma proteins, but it
contributes the largest number of particles among the blood proteins. Osmotic pressure
is strongly related to the number of insoluble particles in a liquid.
• Interstitial fluid pressure: Interstitial fluid pressure, Pi, normally is very low and in many
areas of the body is below atmospheric pressure (Figure 14.2), such as in the lung and
skin. Pi can increase when capillary permeability increases and produces tissue edema,
such as in an allergic reaction or an insect bite. Interstitial fluid accumulation in the
presence of lymphatic blockade is another example of increased interstitial fluid pressure.
• Interstitial fluid effective osmotic pressure: Interstitial fluid effective osmotic pressure, πi
(Figure 14.2), is related, in part, to plasma proteins that have leaked out of the capillary
and into the interstitium. Interstitial space ground substance (hyaluronic acid, chondroi-
tin SO4, etc.) and compounds like lactate also contribute to πi.

STARLING FORMULATION OF TRANSCAPILLARY FLUID

MOVEMENT

• Forces moving fluid out of a capillary: Capillary blood pressure (Pc) is a force that pushes
fluid out of a capillary into the interstitium (Figure 14.2). A simple analogy can be made
to simple filtration, for instance, in making filter coffee. Pouring more water into the filter
increases the fluid level above the filter membrane and enhances the drip rate.
  Interstitial fluid effective osmotic pressure (πi) is a force that pulls fluid out of a
capillary (Figure 14.2). This is because interstitial tissue proteins cannot cross into
capillary blood. The tissue proteins occupy space that would otherwise be occupied by
H 2O. This reduces water activity in the interstitium and draws water to it. A simple way
of remembering this is that osmotic pressure is a sucking force that pulls water to it. πi is
normally a very small force.
  Negative interstitial fluid pressure (Pi) in, for instance, skin pulls water out of the
capillary and into the interstitium (Figure 14.2). This is typically a very small magnitude
force, but it does favor water movement out of a capillary. When Pi is positive it is a force
moving water into a capillary.
• Forces moving fluid into a capillary: Plasma effective osmotic pressure (πp) is, as noted
above, a force related to plasma proteins, primarily albumin, which reduce plasma water

138
 Nature of blood flow in the microcirculation

activity. They reduce water activity because they cannot diffuse out of the capillary and
take up space in the blood that would otherwise be occupied by H 2O. This force pulls
H 2O into the capillary. Again, a simple way of remembering this is that this is a sucking
force pulling water into the capillary from the interstitium.
  If Pi is positive it will act to push fluid into a capillary and if arterial blood pressure is
low enough, Pc can decrease enough to favor net movement of water into the capillary.
The effect of blood loss, low arterial blood pressure, and low Pc on transcapillary
fluid exchange is presented in the self-study module The Pathophysiology of e
Hypovolemic Shock.
• Net fluid movement across a capillary wall: The net fluid movement across a capillary wall
is expressed as the net filtration pressure and is a balance of all four pushing and pulling
forces that influence transcapillary exchange:

Net Filtration Pressure = ( Pc − Pi ) − σ(πp − πi )

  This is a formula developed by Ernest Starling. Sigma (σ) is the reflection coefficient.
If no albumin diffused through the capillary wall and escaped into the interstitium σ
would equal 1.0. In other words, all the albumin trying to diffuse out of the capillary
is “reflected” back into the capillary blood at the capillary wall. Proteins are large
and have difficulty diffusing through a capillary wall and in most capillaries σ
approximates 0.9.
  Damage to capillaries due, for instance, to bacterial toxins and inflammation,
can increase capillary permeability. Capillary permeability increases in an area of
inflammation and σ decreases. Depending on the severity of the damage, water,
electrolytes, proteins, and cells can diffuse out of damaged capillaries. This is seen, for
instance, in vasogenic shock.
• Change along a capillary: There is resistance to flow in capillaries, but it is small as
evidenced by the small fall in pressure as blood flows through a capillary (Figure 14.2). But
there is enough resistance to result in Pc falling as blood flows from the arterial to venous
end of a capillary (See Figure 11.6 in Chapter 11, Peripheral Circulation). Note in Figure 14.2
the fall in Pc along the length of the capillary. There can be subtle changes in πp along
the capillary length, not shown in Figure 14.2, but such changes are usually small. The
net filtration pressure falls along a capillary as Pc falls and reabsorption predominates at
the venous end of many capillaries. For instance, in Figure 14.2 consider the net filtration
pressure (NFP) at the arteriolar and venous ends of the capillary:

Arteriolar end NFP = ( 30 − (−3 )) − 0.9( 28 − 8 ) = +15 mm Hg

Venous end NFP = (10 − (−3 )) − 0.9( 28 − 2 ) = −5 mm Hg

  A negative net filtration pressure indicates a net movement of water into the capillary.
In most capillary beds, there is a net loss of water, as there is here. Significant edema
does not occur partly because the lymphatic system moves interstitial water back into the
vascular compartment.
  The self-study module Transcapillary Fluid Exchange: Starling Principle of Fluid
Movement across a Capillary Wall contains clinical examples of edema formation e
and explanations of changes in net filtration pressure in clinical problems.

139
 Microcirculation

Also, there is an example of a change in net filtration pressure in a clinical problem

presented in the self-study module The Pathophysiology of Hypovolemic Shock.

LYMPH AND LYMPHATICS

Normal lymph fluid is made up of capillary fluid transudate and large molecules including
proteins and fats. Lymphatics begin as blind permeable endothelial sacs (blind sac = bag
with only one opening) (Figures 14.1 and 14.3). Substances enter between the overlapping
endothelial cells of the sac wall that act as flap valves (Figure 14.3). Larger lymphatic ves-
sels have valves to ensure unidirectional flow toward the thorax (Figure 14.3). Most of the
lymphatic flow collects into the thoracic duct, which empties into the left subclavian vein
(Figure 14.3).
The lymphatic blind sac walls are made of endothelial cells that overlap and act like valves
(Figure 14.3). Substances that diffuse into a sac move from the sac through the lymphatic ves-
sels (Figure 14.3). Lymphatic fluid is propelled by at least two forces. Pulsations of smooth
muscle in the lymphatic vessel walls in combination with valves (Figure 14.3) moves fluid for-
ward. Also, the thoracic duct empties into the left subclavian vein, which is in the thorax. The
subatmospheric pressure (suction) of the thorax facilitates lymph movement.
There are filaments attached to the sac endothelial cells (Figure 14.3). These anchoring fila-
ments are attached to the surrounding interstitial structures. Tissue movement, such as limb
movement and respiration, tugs on the filaments and pulls apart the overlapping endothelial
cells allowing fluid and proteins, for instance, to enter the sacs.
Lymph flow rate is low and occurs primarily because of net fluid transudation from the
capillary bed and uptake of the fluid by the lymphatics. Moving tissues, such as the lungs, gut,
heart, and skeletal muscle, rhythmically squeeze lymphatics, which further facilitates fluid flow
through the valves toward the thoracic duct. The flow rate is low, but total daily lymph flow
is substantial and important for maintaining normal circulating blood volume. The brain has
minimal lymphatic drainage.

DIFFUSION
Random movement of molecules and ions results in their eventual even dispersion throughout
a solution. Whenever a concentration difference occurs, there is a net movement toward the
area of lower concentration until equilibrium is restored.

Endothelial One-way Smooth muscle

flap valve valve

Systemic
vein
Blind sac Lymphatic vessels

Anchoring filaments

Figure 14.3  Lymphatic blind sac and lymphatic capillary structure. (From Levick JR. An Introduction
to Cardiovascular Physiology, 5th ed. London, England: Hodder Arnold; 2011. With permission of Taylor
and Francis Group.)

140
 Nature of blood flow in the microcirculation

Fick’s law of diffusion:

dn  dc 
= −DA  
dt  dx 

where
t = Time
n = Amount of substance transported
D = Free diffusion constant
A = Transverse cross-sectional area of the tissue available for diffusion
(dc)/(dx) = Concentration difference per unit distance

Each molecule or compound has a characteristic diffusion constant, D.

The radius of a substance or molecule must be small compared with pore size for diffusion
through the capillary wall. Lipid soluble substances dissolve through the capillary wall.
Once across a capillary wall, molecules must diffuse through the interstitial space to reach
cells. Fick’s law of diffu­sion emphasizes the importance of concentration gradient, surface area,
and distance for diffusion of a substance from and to the capillaries. For instance, working
muscle consumes O2 and muscle interstitial PO2 decreases. PO2 of blood entering the capillary
is high. There is then a large dc/dx for O2 from the blood to the muscle interstitium and muscle
cell, and dn/dt is enhanced.

141
 References for additional reading

Barrett KE et al. Ganong’s Review of Medical Physiology, 23rd ed. New York: McGraw-Hill; 2010.
Boron WF. Medical Physiology, 2nd ed. Philadelphia: Elsevier; 2009.
Davis D. Quick and Accurate 12-Lead ECG Interpretation, 4th ed. Philadelphia: Elsevier; 2005.
Davis D. Differential Diagnosis of Arrhythmia, 2nd ed. Philadelphia: Elsevier; 1997.
Goldberger AL. Clinical Electrocardiography. 7th ed. Philadelphia: Mosby Elsevier; 2006,
(16–18, p. 199).
Goldberger AL, Goldberger ZD, Shvilkin A. Goldberger’s Clinical Electrocardiography, 9th ed.
Philadelphia, PA: Elsevier; 2018.
Levick JR. An Introduction to Cardiovascular Physiology, 5th ed. London, England: Hodder
Arnold; 2011.
Katz AM. Physiology of the Heart. 2nd ed. New York: Raven Press; 1992.
Malmivuo J, Plonsey R. Bioelectromagnetism Principles and Applications of Bioelectric and
Biomagnetic Fields. 1995.
Rowell LB. Human Circulation Regulation during Physical Stress, Oxford: Oxford University
Press; 1986.
Zipes DP, Jalife J. Cardiac Electrophysiology from Bench to Bedside. 6th ed. Philadelphia, PA:
Elsevier; 2014.

143
 Index

Absolute refractory period (ARP), 17–18 Arterial blood pressure, 95, 101, 119; see also Mean
ACE, see Angiotensin converting enzyme arterial blood pressure
Acetylcholine (ACh), 21 coronary vasculature perfusion, 52
ACh, see Acetylcholine decrease in, 107
Acidic metabolites, 130 mean, 95–99, 122
Acquired or congenital valvular heart regional characteristics of, 101
disease, 78 Arterial neural baroreceptors, 105; see also
ADH, see Antidiuretic hormone Circulatory controls
Adult central nervous system, 123 aortic arch, 106
Adverse remodeling, 120 carotid sinus, 105, 106–109
Afterdepolarizations, 54, 55, 56 structure, 105
Afterload, 88–90; see also Ventricular function Arterioles, 101, 117, 129, 135
Angiotensin converting enzyme (ACE), 110; radius, 121–122
see also Circulatory controls vasodilation, 113
actions of, 112 Arteriovenous anastomosis, see Metarterioles
Annulus fibrosus, 27 Astrocytes, 123
ANP, see Atrial natriuretic peptide Atrial arrhythmias, 49
Antidiuretic hormone (ADH), 112 premature atrial beats, 49–50
Aortic arch, 106 Atrial fibrillation, 50–51
Aortic blood pressure Atrial flutter, 50
exercise and, 99 Atrial myocytes, 11–12
pulse and, 96 Atrial natriuretic peptide (ANP), 112–113; see also
Aortic root, 74 Circulatory controls
Aortic stiffness, 96–97 Atrial premature beat, lower, 49–50
Aortic valvular insufficiency, 78, 80 Atrial tachyarrhythmias, 18
Aortic valvular regurgitation, see Aortic valvular Atrioventricular conduction blocks, 43
insufficiency dissociation, 45
ARP, see Absolute refractory period first degree, 43–45
Arrhythmia, 18 second degree, 44
atrial, 49–50 Atrioventricular node (AV node), 12, 27; see also
Ca 2+ influx, 54 Cardiac electrical activity; Sinoatrial node
delayed afterdepolarizations, 56 latent pacemakers, 15
early afterdepolarizations, 55 refractory period, 18
long QT syndrome, 56 Autonomic nervous system, 120; see also
mechanisms of, 52–57 Circulatory controls
reentry, 52–54 Autoregulation, 117–119; see also Circulatory
respiratory sinus, 42–43 controls
Torsades de Pointes, 56, 57 in coronary vasculature, 127
triggered activity, 54–55 in resting skeletal muscle, 130
unidirectional block, 53 AV node, see Atrioventricular node

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Baroreceptor, 105 Cardiac contractility, 85; see also Cardiac electrical

arterial neural, 105–109 activity; Cardiac muscle; Ventricular
regions located at X’s, 106 function
Beta adrenergic receptors, 129 drugs on, 87
Bipolar limb leads, 32–33 pressure-volume loop and, 87–88
Blood–brain barrier, 124; see also Cerebral sympathetic stimulation of heart muscle, 86
blood flow ventricular function curves, 85–87
Blood clotting and vascular endothelial Cardiac cycle, 71, 73
factors, 114 atrial and ventricular phases of, 71
Blood flow, 62–64; see also Circulation; Regional atrial systole at end of diastole, 71
blood flow coronary blood flow and, 127–128
autoregulation of, 117–119 diastolic filling, 74–75
capillary, 136, 137 ejection, 73–74
intermittent, 137 events in left heart, 72
laminar flow, 64 intravascular pressures, 75
local metabolic control of, 116–117 isovolumetric contraction, 73
siphon model, 63 isovolumetric relaxation, 74
and temperature control, 133 murmurs during, 78–81
turbulent flow, 65 v wave, 75
types, 64–67 Cardiac electrical activity, 9, 13; see also Ventricular
velocity at cardiac output, 66 myocyte electrophysiology
velocity in circulation, 67 atrial myocytes, 11–12
Blood pressure, 61; see also Circulation atrioventricular node, 12
aortic pulse and, 96 bundle branches, 12–13
control, 105, 120 bundle of HIS, 12–13
high, 109 Purkinje myocytes, 13
at locations in circulation, 102 sinoatrial node, 9–11
measuring devices, 62 Cardiac muscle, 23; see also Cardiac contractility
Blood viscosity, 64, 65 cell, 23
Blood volume distribution, 103 desmosomes, 23
BNP, see Brain natriuretic peptide gap junctions, 23, 24
Brain; see also Cerebral blood flow intercalated discs, 23
astrocytes, 123 sequential portions of, 4, 5
blood flow factors, 122 Cardiac muscle fiber, see Cardiac muscle—cell
metabolism, 124 Cardiac myocyte, see Cardiac muscle—cell
tumor, 123 Cardiac output (CO), 64, 83
Brain natriuretic peptide (BNP), 112–113; see also Cardiac valves, 71
Circulatory controls Carotid sinus, 105; see also Arterial neural
Bruit, 66 baroreceptors
Bundle branch, 12–13 baroreceptor function, 106
blocks, 46 baroreceptor reflex response to arterial
Bundle of HIS, 12–13, 27 pressure, 107
hemodynamic effects of posture change, 108
Capillary, 135 Carotid sinus, 105, 106–109
blood flow, 136, 137 Cell cytoplasm, 3
blood pressure, 137, 138 Cerebral arteries, 121
transcapillary exchange, 137–138 Cerebral blood flow, 121; see also Circulation;
transcapillary fluid movement, 137, 138–140 Blood flow

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arteriolar radius, 121–122 Conduction; see also Ionic mechanisms,

blood–brain barrier, 124 physiological consequences of
blood viscosity, 64, 65, 123 sequence in heart, 25
brain metabolism, 124 with sinus rhythm, normal, 42
cerebral hypoxia, 122 system myocytes, 17
changes in, 123 velocity, 16–17
factors in brain blood flow, 122 Congenital valvular heart disease, 78
intracranial pressure, 123 Contractility, 85–88
lymphatic drainage, 124 Coronary artery, 124–125
mean arterial pressure, 122 Coronary blood flow, 124; see also Blood flow
mean venous pressure, 122, 123, 137 autoregulation, 127
regulation of, 121, 123 and cardiac cycle, 127
Cerebral hypoxia, 122 clinical case, 128–129
Chemoreceptors, 116; see also Circulatory controls control of, 126
Circular movement, see Circus movement coronary arteries, 124–125
Circulation, 59, 61, 71, 72; see also Blood flow; diastole, 128
Microcirculation; Peripheral circulation endothelial vasoactive factors, 128
blood flow types, 64–67 myocardial oxygen consumption, 126–127
blood pressure, 61 and oxygen supply, 125
blood pressure measuring devices, 62 sinus blood flow, 125
clinical significance, 67–69 systole, 127
energy, 61–62 vasculature perfusion, 52
flow, 62–64 venous outflow, 128
pressure potential energy difference, 62 work relationship, 126
siphon model, 63 Coronary sinus blood flow, 125
velocity, 67 Coronary vasculature perfusion, 52
Circulatory controls, 105 CRBBB, see Complete right bundle branch block
arterial blood pressure, 119 C-type natriuretic peptide (CNP), 112
arterial neural baroreceptors, 105–109 Cutaneous blood flow, 132; see also Blood flow
autonomic nervous system, 120 and cold environment, 133
autoregulation, 117–119 and temperature control, 133
blood pressure control, 120 and warm environment, 133–134
chemoreceptors, 116
heart failure, 120 DBP, see Diastolic blood pressure
hormonal controls, 109–116 Depolarization, 5
local metabolic control, 116–117 of atrial or ventricular myocyte, 36
salt and water metabolism, 119 in horizontal plane, 42
veins in, 119 vectors during atrial, 37
Circus movement, 54 Desmosomes, 23
CLBBB, see Complete left bundle branch block Diastole, 9, 78, 91, 128
Clotting, 116 Diastolic blood pressure (DBP), 108
CNP, see C-type natriuretic peptide Diastolic filling, 74–75
CO, see Cardiac output Diastolic murmur, 80–81
Cold environment, exposure to, 133 Dicrotic notch, 74
Complete left bundle branch block (CLBBB), Diffusion, 140–141
46–47, 48 Drugs, 55
Complete right bundle branch block action mechanism, 1
(CRBBB), 46 contractility, 87

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Drugs (Continued) lead aVR lead and axis, 33

effects on ion channel function, 1 mean electrical axis, 41
in preventing reentry, 54 mechanisms of arrhythmias, 52–57
in prolonging myocardial action potentials, 57 monitoring leads, 35
side effect, 1 normal conduction with normal sinus rhythm, 42
Dynamic exercise, 90, 99 patterns of abnormal rhythms, 49–52
Dysfunctional endothelium, 115; see also patterns of heart conduction, 42–49
Circulatory controls precordial leads, 35, 41–42
abnormal endothelial cell function, 115 precordial leads and V1 and V6 ventricular
endothelins, 115 complexes, 41
thromboxane, 116 P wave, 30
QRS complex, 30
ECG, see Electrocardiogram QT interval, 31
EDHF, see Endothelium-derived hyperpolarizing respiratory sinus arrhythmia, 42–43
factors second degree atrioventricular block, 44–45
EDV, see End-diastolic volume signal, 29
EF, see Ejection fraction standard lead system, 31–35
Einthoven’s triangle, 38 ST segment, 31
Ejection fraction (EF), 91 T wave, 30, 31
Electrical activation sequence in heart, 26 unipolar limb lead, 33
Electrical activity in heart, 25 ventricular depolarization, 42
annulus fibrosus, 27 ventricular fibrillation, 52
atrioventricular node, 27 ventricular premature beats, 51
bundle of His, 27 ventricular tachycardia, 51–52
conduction sequence in heart, 25 waves, 30–31
conduction system myocytes, 17 Wolff–Parkinson–White, 47–49
gap junction function, 25 End-diastolic volume (EDV), 91
sequence of, 26 Endothelial cell, 113
ventricular conducting system, 27 dysfunctional, 115–116
Electrocardiogram (ECG), 29 junctions, 124
abnormal ventricular beats, 51 Endothelial vasoactive factors, 128
atrial arrhythmias, 49–50 Endothelins, 115
atrial fibrillation, 50–51 Endothelium-derived hyperpolarizing factors
atrial flutter, 50 (EDHF), 114
atrioventricular and intraventricular End-systolic pressure volume relationship
conduction blocks, 43 (ESPVR), 85
bipolar limb leads, 32–33 ESPVR, see End-systolic pressure volume
bundle branch blocks, 46 relationship
CLBBB, 46–47, 48 Exercise and aortic blood pressure, 99
complete heart block, 45
CRBBB, 46 Feedback mechanisms, 59
first degree atrioventricular block, 43–44 First heart sound, 75
frontal and horizontal planes, 32 Fourth heart sound, 78
frontal plane leads, 31 Frank–Starling law of the heart, 83, 84; see also
frontal plane vectors, 35–40 Ventricular function
horizontal plane leads, 34 Frontal plane vectors, 35; see also Mean vector
lead aVF lead and axis, 34 during atrial depolarization, 37
lead aVL lead and axis, 33 myocyte depolarization, 36

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Gap junctions, 23, 24 Ions

function, 25 in cell cytoplasm, 3
Gastrointestinal blood flow, 132; see also movement in gap junctions, 24, 25
Blood flow Isovolumetric contraction, 73
Isovolumetric relaxation, 74
Heart; see also Circulatory controls
complete block, 45 Juxtaglomerular cells, 110
conduction patterns, 42–49
failure, 120 LA, see Left arm; Left atrium
in vivo control of, 93 Laminar flow, 64; see also Blood flow
sympathetic stimulation of muscle, 86 Latent pacemakers, 15; see also Ionic mechanisms,
Heart rate control, 21 physiological consequences of
parasympathetic activity, 21 Left arm (LA), 38
SA node action potential simulation, 22 Left atrium (LA), 71
sympathetic activity, 21–22 Left leg (LL), 38
Heart sounds, 75 Left ventricle (LV), 41, 71
first, 75 LL, see Left leg
fourth, 78 Local metabolic control, 116–117; see also
second, 76–77 Circulatory controls
third, 77, 78 Long QT syndrome, 56
transmural pressure, 76 LV, see Left ventricle
High blood pressure, 109 Lymphatic blind sac, 140
Hormonal control of circulation, 109; see also Lymphatic capillary structure, 140
Circulatory controls Lymphatic drainage, 124
antidiuretic hormone, 112 Lymph flow rate, 140
atrial and brain natriuretic peptides, 112–113 Lymph fluid, 140
clotting, 116
dysfunctional endothelium, 115–116 Maximal diastolic potential (MDP), 9
renin-angiotensin-aldosterone system, MBP, see Mean arterial blood pressure
109–112 MDP, see Maximal diastolic potential
vascular endothelial factors, 113–115 Mean aortic blood pressure, 95; see also Peripheral
Hydrostatic pressure, see Capillary—blood circulation
pressure Mean arterial blood pressure (MBP), 108
Hypertension, see High blood pressure Mean vector, 37; see also Frontal plane vectors
for atrial depolarization and Einthoven’s
Incisura, see Dicrotic notch triangle, 38
Intercalated discs, 23 with depolarized ventricular myocytes, 40
Intermittent blood flow, 137 for ventricular septal depolarization, 39
Interstitial fluid effective osmotic pressure, 138 Mean venous pressure, 122, 123, 137
Intracranial pressure, 123 Metabolic control of circulation, 116–117
Intravascular pressures, normal, 75 Metarterioles, 135–136
Ionic mechanisms, physiological consequences Microcirculation, 135; see also Blood flow;
of, 15 Circulation
conduction velocity, 16–17 arterioles, 135
K+ effect on transmembrane potential, 19 capillaries, 135
latent pacemakers, 15 capillary blood flow, 136, 137
pacemaker hierarchy, 15 diffusion, 140–141
refractory period, 17–18 intermittent blood flow, 137

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Microcirculation (Continued) Parasympathetic activity, 21

lymphatic blind sac and lymphatic capillary Parasympathetic nerve action potentials, 101
structure, 140 Peripheral arteriolar vasodilation, 113
and lymphatics, 136, 140 Peripheral circulation, 95; see also Circulation
metarterioles, 135–136 aortic pulse and blood pressure, 96
microcirculation and lymphatics, 136 aortic stiffness, 96–97
nature of blood flow in, 136 blood volume distribution, 103
net filtration pressure, 139 exercise and aortic blood pressure, 99
postcapillary resistance, 136 mean arterial pressure, 95–99
starling formulation of transcapillary fluid pulse pressure, 95–99
movement, 138–140 relationship of pressure, flow, and
transcapillary exchange, 137–138 resistance, 97
transcapillary fluid movement, 137 resistance, 100–103
Monitoring leads, 35 responses to vascular resistance, 100
Moving tissues, 140 Peripheral runoff, 95
Murmur, 78; see also Cardiac cycle Plasma effective osmotic pressure, 137, 138–139
diastolic, 80–81 Plasminogen-activator inhibitor type 1 (PAI-1), 115
systolic, 79–80 Poiseuille’s law, 100, 117; see also Pulse pressure;
Myocardial muscle fiber, see Cardiac muscle—cell Resistance
Myocardial myocyte, see Cardiac muscle—cell variables in, 101
Myocardial oxygen consumption determinants, Postcapillary resistance, 136
126–127 Precordial leads, 35, 41–42
Myocardial resting force, 92 Preexcitation, see Wolff–Parkinson–White
Myocardium, primate ventricular, 92 Preload, 83–85
Myocyte, 25 Premature atrial beats, 49–50
Myoplasmic Ca 2+ overload, 54 Pressoreceptor, see Baroreceptor
Pressure, 61
Na+/Ca 2+ exchange (NCX), 11 receptor, see Baroreceptor
Natriuretic peptides, 112–113 -volume loop, 84–85
NCX, see Na+/Ca 2+ exchange -volume relation, 91–93
Negative interstitial fluid pressure, 138 Primate ventricular myocardium, 92
Neprilysin, 113 Prostacyclin, 114
Net filtration pressure (NFP), 139 Pulmonary artery (PA), 71
Neural reflexes, 105 Pulmonary blood flow, 130; see also Blood flow
NFP, see Net filtration pressure characteristics, 130–131
Nitric oxide (NO), 113–114 posture and exercise effect, 131–132
NO, see Nitric oxide Pulse pressure, 95–99; see also Peripheral
Noise, see Murmur circulation; Poiseuille’s law
Norepinephrine, 21 changes in, 98–100
Normal intravascular pressures in people, 75 determinants of, 97–98
Normal sinus rhythm, 15 mean arterial pressure and, 95–96
Purkinje myocytes, 13
PA, see Pulmonary artery cardiac electrical activity, 13
Pacemaker latent pacemakers, 15
hierarchy, 15 P wave, 30
latent, 15
potential, 9, 10 QRS complex, 30
PAI-1, see Plasminogen-activator inhibitor type 1 QT interval, 31

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RA, see Right arm; Right atrium Right atrium (RA), 71

RAAS, see Renin-angiotensin-aldosterone system Right ventricle (RV), 41, 71
RBCs, see Red blood cells RRP, see Relative refractory period
RBF, see Renal blood flow RV, see Right ventricle
Rectification, 6
Red blood cells (RBCs), 101, 136 Salt and water metabolism, 119
Reentry, 18 SA node, see Sinoatrial node
Refractory period, 17; see also Ionic mechanisms, Sarcolemma, charge separation by, 3
physiological consequences of Sarcoplasmic reticulum (SR), 11
absolute, 17–18 SBP, see Systolic blood pressure
reentry, 18 Second heart sound, 76–77
relative, 18 Sigma, 139
SA and AV node, 18 Single resistance, 103
ventricular and conduction system Sinoatrial node (SA node), 9; see also Cardiac
myocytes, 17 electrical activity
Regional blood flow, 121; see also Blood flow action potential, 10, 22
cerebral blood flow, 121–124 normal sinus rhythm, 15
coronary blood flow, 124–129 pacemaker potential, 9, 10, 15
cutaneous blood flow, 132–134 phase 0 upstroke, 9
gastrointestinal blood flow, 132 phase 1 and phase 2, 10
pulmonary blood flow, 130–132 phase 3, 10
renal blood flow, 132 phase 4, 11
skeletal muscle blood flow, 129–130 refractory period, 18
Regurgitation, see Valvular insufficiency repolarization, 10
Relative refractory period (RRP), 18 sympathetic stimulation of, 21
Renal blood flow (RBF), 132; see also Blood flow Sinus rhythm, normal, 15
Renin, 110 Siphon model, 63; see also Circulation
actions of, 112 Skeletal muscle blood flow, 129; see also Blood
Renin-angiotensin-aldosterone system (RAAS), flow
109–112 anatomical and mechanical considerations, 129
Repolarization of ventricles, 40 autoregulation, 130
Resistance to flow, 100; see also Peripheral control, 129
circulation oxygen delivery, 130
in vivo resistances, 103 sympathetic effects, 129
mean blood pressure at locations in Skeletal muscle pump, 84
circulation, 102 SR, see Sarcoplasmic reticulum
parallel vascular resistance, 102 Standard lead system, 31–35
Poiseuille’s law, 100–101 Starling formulation of transcapillary fluid
regional characteristics of arterial blood movement, 138–140
pressure, 101 Stiffness, 95
series vascular resistance, 102 Streamlined flow, see Laminar flow
single resistance, 103 Stroke volume (SV), 83, 84, 91
three parallel resistances, 103 ST segment, 31
two series resistances, 103 SV, see Stroke volume
vascular conductance, 102–103 Sympathetic activity, 21–22
Respiratory sinus arrhythmia, 42–43 Sympathetic nervous system, 119, 121
Rhythm patterns, abnormal, 49–52 Sympathetic stimulation of heart muscle, 86
Right arm (RA), 38 Systole, 71, 78, 127

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Systolic blood pressure (SBP), 108 Ventricular filling, 83–84; see also Ventricular
Systolic murmur, 79–80 function
Ventricular function, 83, 85–87
Temperature control, 133 afterload, 88–90
Thoroughfare channel, see Metarterioles changes in, 90–91
Thromboxane, 116 changes in posture, 91
Tissue plasminogen activator (t-PA), 115 changes in ventricular filling, 83–84
Torsades de Pointes, 56, 57 contractility, 85–88
t-PA, see Tissue plasminogen activator control of heart in vivo, 93
Transcapillary exchange, 137–138 curves, 85–87
Transcapillary fluid movement, 137 ejection fraction, 91
starling formulation of, 138–140 exercise, 90–91
Transmural pressure, 76, 131 Frank–Starling law of the heart, 83, 84
Tumor, brain, 123 myocardial resting force, 92
Turbulent flow, 65; see also Blood flow passive pressure-volume relation, 91–93
T wave, 30, 31 passive/resting ventricular pressure-volume
relation, 92
Unidirectional block, 53 preload, 83–85
Unipolar limb lead, 33 pressure-volume loop, 84–85
primate ventricular myocardium, 92
Valvular heart disease, 78 Ventricular muscle cell action potential, 5
Valvular insufficiency, 78, 80 adequate, 5
Valvular stenosis, 78 negative current, 5
Vascular conductance, 102–103 phase 0, 5–6
Vascular endothelial factors, 113; see also phase 1, 6, 8
Circulatory controls phase 2, 6–7
effects on blood clotting, 114 phase 3, 7–8
endothelium-derived hyperpolarizing plateau portion of, 7
factors, 114 rectification, 6
nitric oxide, 113–114 Ventricular myocyte electrophysiology, 3; see also
prostacyclin, 114 Cardiac electrical activity
Vascular resistance, 102 action potential, 5–8
three parallel resistances, 103 charge separation by sarcolemma, 3
two series resistances, 103 negative ions, 3
Vasodilators, 116; see also Vascular endothelial factors resting potential, 3–4
Vasopressin, see Antidiuretic hormone ventricular action potential and ionic
Vectors during atrial depolarization, 37 currents, 4
Veins, 119; see also Circulatory controls Ventricular premature beats, 51
Venous outflow, 128 Ventricular pressure, 91
Venous pressure, mean, 122, 123, 137 Ventricular septal depolarization, 39
Ventricular beats, abnormal, 51 Ventricular tachycardia, 51–52
Ventricular complexes, V1 and V6, 41 Venules, 135, 136; see also Arterioles
Ventricular conducting system, 27; see also v wave, 75; see also Cardiac cycle
Electrical activity in heart
Ventricular depolarization in horizontal plane, 42 Warm environment, exposure to, 133–134
Ventricular fibrillation, 52 Wolff–Parkinson–White (WPW), 47–49

152