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The best cardiovascular review available for the USMLE®, exam review, and course work
Cardiovascular Physiology, Ninth Edition is a concise and enjoyable way for you to gain a fundamental knowledge of the basic operating principles of the intact cardiovascular system and how those principles apply to clinical medicine. Succinct but thorough, it focuses on the facts and concepts you must know to get a solid “big picture” overview of how the cardiovascular system operates in normal and abnormal situations. No other text will prove more valuable in enhancing your ability to evaluate the myriad new information you will be exposed to throughout your career, than Cardiovascular Physiology.
There is no faster or more effective way to learn how the key principles of cardiovascular function apply to common and pathological challenges than this engagingly written, time-proven guide. Medical students will find it to be an outstanding review for the USMLE® Step 1 and experienced clinicians will find it be a valuable clinical refresher.
Features• NEW! Increased focus on cardiovascular energetics• “Perspectives” section in each chapter that identify important, currently unresolved issues • Clarifies the details of physiologic mechanisms and their role in pathologic states• Links cardiovascular physiology to diagnosis and treatment• Summarizes key concepts at the end of each chapter• Highlights must-know information with chapter objectives• Reinforces learning with study questions at the end of each chapter
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Chapter 1   Overview of the Cardiovascular System
Evolution and Homeostatic Role of the Cardiovascular System
Overall Design of the Cardiovascular System
The Basic Physics of Blood Flow
Material Transport by Blood Flow
The Heart
The Vasculature

Chapter 2   Characteristics of Cardiac Muscle Cells
Electrical Activity of Cardiac Muscle Cells
Mechanical Activity of the Heart
Relating Cardiac Muscle Cell Mechanics to Ventricular Function

Chapter 3   The Heart Pump
Cardiac Cycle
Determinants of Cardiac Output
Influences on Stroke Volume
Summary of Determinants of Cardiac Output
Summary of Sympathetic Neural Influences on Cardiac Function

Cardiac Energetics

Chapter 4   Measurements of Cardiac Function
Measurement of Mechanical Function
Measurement of Cardiac Excitation—The Electrocardiogram

Chapter 5   Cardiac Abnormalities
Electrical Abnormalities and Arrhythmias
Cardiac Valve Abnormalities

Chapter 6   The Peripheral Vascular System
Transcapillary Transport
Resistance and Flow in Networks of Vessels
Normal Conditions in the Peripheral Vasculature
Measurement of Arterial Pressure
Determinants of Arterial Pressure

Chapter 7   Vascular Control
Vascular Smooth Muscle
Control of Arteriolar Tone
Control of Venous Tone
Summary of Primary Vascular Control Mechanisms
Vascular Control in Specific Organs

Chapter 8   Hemodynamic Interactions
Key System Components
Central Venous Pressure: An Indicator of Circulatory Status


Chapter 9   Regulation of Arterial Pressure
Short-Term Regulation of Arterial Pressure
Long-Term Regulation of Arterial Pressure

Chapter 10   Cardiovascular Responses to Physiological Stresses
Primary Disturbances and Compensatory Responses
Effect of Respiratory Activity
Effect of Gravity
Effect of Exercise
Normal Cardiovascular Adaptations

Chapter 11   Cardiovascular Function in Pathological Situations
Circulatory Shock
Cardiac Disturbances

Answers to Study Questions

Appendix A

Appendix B

Appendix C

Appendix D

Appendix E



In this our final edition as primary authors of this text, we have continued
our penchant of focusing on the big picture of how and why the
cardiovascular system operates as it does. Our firm belief is that to
evaluate the importance and consequences of specific details it is essential
to appreciate where they fit in the big picture. The core idea is for students
not to get lost in the forest for the trees. The same approach will serve
practitioners well throughout their careers as they evaluate new
information as it arises.

The cardiovascular system is a circular interconnection of many
individual components—each with its own rules of operation that must be
followed. But in the intact system, the individual components are forced to
interact with each other. A change in the operation of any one component
has repercussions throughout the system. Understanding such interactions
is essential to developing a big picture of how the intact system behaves.
Only then can one fully understand all the consequences of malfunctions
in particular components and/or particular clinical interventions.

This ninth edition includes some recent, new findings as well as a
newly added emphasis on cardiovascular energetics. The latter is a result
of our recent realization that maximizing energy efficiency to limit the
workload on the heart is an important part of the overall plan.

As always, we express sincere thanks to our families for their continual
support of our efforts, and to our mentors, colleagues, and students for all
they have taught us over the years. Also, these authors would like to thank
each other for the uncountable but fruitful hours we have spent arguing
about how the cardiovascular system operates from our own (and often
very different perspectives).

David E. Mohrman, PhD 
Lois Jane Heller, PhD

Overview of the Cardiovascular
System 1


The student understands the homeostatic role of the cardiovascular
system, the basic principles of cardiovascular transport, and the
basic structure and function of the components of the system:
     Defines homeostasis.
     Identifies the major body fluid compartments and states the

approximate volume of each.
     Lists 3 conditions, provided by the cardiovascular system, that

are essential for regulating the composition of interstitial fluid
(i.e., the internal environment).

     Predicts the relative changes in flow through a tube caused by
changes in tube length, tube radius, fluid viscosity, and pressure

     Uses the Fick principle to describe convective transport of
substances through the CV system and to calculate a tissue’s rate
of utilization (or production) of a substance.

     Identifies the chambers and valves of the heart and describes the
pathway of blood flow through the heart.

     Defines cardiac output and identifies its 2 determinants.
     Describes the site of initiation and pathway of action potential

propagation in the heart.
     States the relationship between ventricular filling and cardiac

output (the Starling law of the heart) and describes its importance
in the control of cardiac output.

     Identifies the distribution of sympathetic and parasympathetic
nerves in the heart and lists the basic effects of these nerves on the

     Lists the 5 factors essential to proper ventricular pumping action.
     Lists the major different types of vessels in a vascular bed and

describes the morphological differences among them.
     Describes the basics and functions of the different vessel types.
     Identifies the major mechanisms in vascular resistance control

and blood flow distribution.
     Describes the basic composition of the fluid and cellular portions

of blood.

All living organisms require outside energy sources to survive. Indeed,
Darwin deduced his evolutionary concepts largely on observations of
external adaptations that evolved in different organisms to exploit
particular unique sources of “food” energy. Clearly one strong
evolutionary force has been to maximize the ability to obtain outside

In the big picture of “survival of the fittest,” equally important to
obtaining outside energy is making efficient use of it once it is obtained.
Therefore, we contend that developing energy-efficient mechanisms to
accomplish all internal tasks necessary for successful life has also been a
strong evolutionary force and probably applies to all “internal” processes.

In this text, we focus on how the design and operation of the human
cardiovascular system has evolved to accomplish its essential tasks with a
minimum of energy expenditure.

 A 19th-century French physiologist, Claude Bernard (1813–1878),
first recognized that all higher organisms actively and constantly strive to
prevent the external environment from upsetting the conditions necessary
for life within the organism. Thus, the temperature, oxygen concentration,
pH, ionic composition, osmolarity, and many other important variables of
our internal environment are closely controlled. This process of
maintaining the “constancy” of our internal environment has come to be
known as homeostasis. To aid in this task, an elaborate material transport
network, the cardiovascular system, has evolved.

Three compartments of watery fluids, known collectively as the total
body water, account for approximately 60% of body weight in a normal

adult. This water is distributed among the intracellular, interstitial, and
plasma compartments, as indicated in Figure 1–1. Note that about two-
thirds of our body water is contained within cells and communicates with
the interstitial fluid across the plasma membranes of cells. Of the fluid that
is outside cells (i.e., extracellular fluid), only a small amount, the plasma
volume, circulates within the cardiovascular system. Total circulating
blood volume is larger than that of blood plasma, as indicated in Figure 1–
1, because blood also contains suspended blood cells that collectively
occupy approximately 40% of its volume. However, it is the circulating
plasma that directly interacts with the interstitial fluid of body organs
across the walls of the capillary vessels.

 The interstitial fluid is the immediate environment of individual cells.
(It is the “internal environment” referred to by Bernard.) These cells must
draw their nutrients from and release their products into the interstitial
fluid. The interstitial fluid cannot, however, be considered a large reservoir
for nutrients or a large sink for metabolic products, because its volume is
less than half that of the cells that it serves. The well-being of individual
cells therefore depends heavily on the homeostatic mechanisms that
regulate the composition of the interstitial fluid. This task is accomplished
by continuously exposing the interstitial fluid to “fresh” circulating plasma

Figure 1–1. Major body fluid compartments with average volumes indicated for a normal 70-kg
adult human. Total body water is approximately 60% of body weight.

As blood passes through capillaries, solutes exchange between plasma
and interstitial fluid by the process of diffusion. The net result of
transcapillary diffusion is always that the interstitial fluid tends to take on
the composition of the incoming blood. If, for example, potassium ion
concentration in the interstitium of a particular skeletal muscle was higher
than that in the plasma entering the muscle, then potassium would diffuse
into the blood as it passes through the muscle’s capillaries. Because this
removes potassium from the interstitial fluid, its potassium ion
concentration would decrease. It would stop decreasing when the net
movement of potassium into capillaries no longer occurs, that is, when the
concentration of the interstitial fluid reaches that of incoming plasma.

Three conditions are essential for this circulatory mechanism to
effectively control the composition of the interstitial fluid: (1) there must
be adequate blood flow through the tissue capillaries; (2) the chemical
composition of the incoming (or arterial) blood must be controlled to be
that which is optimal in the interstitial fluid; and (3) diffusion distances
between plasma and tissue cells must be short. Figure 1–1 shows how the
cardiovascular transport system operates to accomplish these tasks.
Diffusional transport within tissues occurs over extremely small distances
because no cell in the body is located farther than approximately 10 μm
from a capillary. Over such microscopic distances, diffusion is a very rapid
process that can move huge quantities of material. Diffusion, however, is a
very poor mechanism for moving substances from the capillaries of an
organ, such as the lungs, to the capillaries of another organ that may be 1
m or more distant. Consequently, substances are transported between
organs by the process of convection, by which the substances easily move
along with blood flow because they are either dissolved or contained
within blood. The relative distances involved in cardiovascular transport
are not well illustrated in Figure 1–1. If the figure was drawn to scale, with
1 inch representing the distance from capillaries to cells within a calf
muscle, then the capillaries in the lungs would have to be located about 15
miles away!

The overall functional arrangement of the cardiovascular system is
illustrated in Figure 1–2. Because a functional rather than an anatomical
viewpoint is expressed in this figure, the role of heart appears in 3 places:
as the right heart pump, as the left heart pump, and as the heart muscle
tissue. It is common practice to view the cardiovascular system as (1) the
pulmonary circulation, composed of the right heart pump and the lungs,
and (2) the systemic circulation, in which the left heart pump supplies
blood to the systemic organs (all structures except the gas exchange
portion of the lungs). The pulmonary and systemic circulations are
arranged in series, that is, one after the other. Consequently, both the right
and left hearts must pump an identical volume of blood per minute. This
amount is called the cardiac output.

As indicated in Figure 1–2, most systemic organs are functionally
arranged in parallel (i.e., side by side) within the cardiovascular system.

There are 2 important consequences of this parallel arrangement. First,
nearly all systemic organs receive blood of identical composition—that
which has just left the lungs and is known as arterial blood. Second, the
flow through any one of the systemic organs can be controlled
independently of the flow through the other organs. Thus, for example, the
cardiovascular response to whole-body exercise can involve increased
blood flow through some organs, decreased blood flow through others, and
unchanged blood flow through yet others.

Many of the organs in the body help perform the task of continually
reconditioning the blood circulating in the cardiovascular system. Key
roles are played by organs, such as the lungs, that communicate with the
external environment. As is evident from the arrangement shown in Figure
1–2, any blood that has just passed through a systemic organ returns to the
right heart and is pumped through the lungs, where oxygen and carbon
dioxide are exchanged. Thus, the blood’s gas composition is always
reconditioned immediately after leaving a systemic organ.

Figure 1–2. Cardiovascular circuitry, indicating the percentage distribution of cardiac output to
various organ systems in a resting individual.

Like the lungs, many of the systemic organs also serve to recondition
the composition of blood, although the flow circuitry precludes their doing
so each time the blood completes a single circuit. The kidneys, for
example, continually adjust the electrolyte composition of the blood
passing through them. Because the blood conditioned by the kidneys
mixes freely with all the circulating blood and because electrolytes and
water freely pass through most capillary walls, the kidneys control the
electrolyte balance of the entire internal environment. To achieve this, it is
necessary that a given unit of blood pass often through the kidneys. In fact,
the kidneys normally receive about one-fifth of the cardiac output under

resting conditions. This greatly exceeds the amount of flow that is
necessary to supply the nutrient needs of the renal tissue. This situation is
common to organs that have a blood-conditioning function.

Blood-conditioning organs can also withstand, at least temporarily,
severe reduction of blood flow. Skin, for example, can easily tolerate a
large reduction in blood flow when it is necessary to conserve body heat.
Most of the large abdominal organs also fall into this category. The reason
is simply that because of their blood-conditioning functions, their normal
blood flow is far in excess of that necessary to maintain their basal
metabolic needs.

The brain, heart muscle, and skeletal muscles typify organs in which
blood flows solely to supply the metabolic needs of the tissue. They do not
recondition the blood for the benefit of any other organ. Normally, the
blood flow to the brain and the heart muscle is only slightly greater than
that required for their metabolism; hence, they do not tolerate blood flow
interruptions well. Unconsciousness can occur within a few seconds after
stoppage of cerebral flow, and permanent brain damage can occur in as
little as 4 minutes without flow. Similarly, the heart muscle ( myocardium)
normally consumes approximately 75% of the oxygen supplied to it, and
the heart’s pumping ability begins to deteriorate within beats of a coronary
flow interruption. As we shall see later, the task of providing adequate
blood flow to the brain and the heart muscle receives a high priority in the
overall operation of the cardiovascular system.

Cardiac muscle must do physical work to move blood through the
circulatory system. Note in Figure 1–2 that the cardiac muscle itself
requires only about 3% of all the blood it is pumping to sustain its own
operation. The clear implication is that the heart has evolved into a very
efficient pump.

Within any given tissue, the blood flow required to maintain local
homeostasis is directly related to its current cellular metabolic rate. Under
challenges of daily life, metabolic activity of many individual organs can
change dramatically from situation to situation. For example, metabolic
rate of maximally active skeletal muscle can be 50 times that of its inactive
(resting) rate. Thus, it is essential for the cardiovascular system to rapidly
adapt to ever-changing needs in the body. As far as the heart is concerned,
the bottom line is how much blood flow it must produce in different
situations regardless of where that total flow is directed. Cardiac output in
a resting human adult is about 5 to 6 L/min (80 gallons/h, 2000
gallons/day!) and can increase to 3 to 4 times that amount during maximal
exercise. Presumably, the cardiovascular system has evolved to efficiently

operate over that range.

One of the most important keys to comprehending how the cardiovascular
system operates is to have a thorough understanding of the relationship
among the physical factors that determine the rate of fluid flow through a
tubular vessel.

 The tube depicted in Figure 1–3 might represent a segment of any
vessel in the body. It has a certain length ( L) and a certain internal radius (
r) through which blood flows. Fluid flows through the tube only when the
pressures in the fluid at the inlet and outlet ends ( P i and P o) are unequal,
that is, when there is a pressure difference (Δ P) between the ends.
Pressure differences supply the driving force for flow. Because friction
develops between the moving fluid and the stationary walls of a tube,
vessels tend to resist fluid movement through them. This vascular
resistance is a measure of how difficult it is to make fluid flow through the
tube, that is, how much of a pressure difference it takes to cause a certain
flow. The all-important relationship among flow, pressure difference, and
resistance is described by the basic flow equation as follows:


where  = flow rate (volume/time), Δ P = pressure difference (mm Hg
1), and R = resistance to flow (mm Hg × time/volume).

Figure 1–3. Factors influencing fluid flow through a tube.

The basic flow equation may be applied not only to a single tube but
also to complex networks of tubes, for example, the vascular bed of an
organ or the entire systemic system. The flow through the brain, for
example, is determined by the difference in pressure between cerebral
arteries and veins divided by the overall resistance to flow through the
vessels in the cerebral vascular bed. It should be evident from the basic
flow equation that there are only 2 ways in which blood flow through any
organ can be changed: (1) by changing the pressure difference across its
vascular bed or (2) by changing its vascular resistance. Most often, it is
changes in an organ’s vascular resistance that cause the flow through the
organ to change.

From the work of the French physician Jean Leonard Marie Poiseuille
(1799–1869), who performed experiments on fluid flow through small
glass capillary tubes, it is known that the resistance to flow through a
cylindrical tube depends on several factors, including the radius and length
of the tube and the viscosity of the fluid flowing through it. These factors
influence resistance to flow as follows:

where r = inside radius of the tube, L = tube length, and η = fluid

Note especially that the internal radius of the tube is raised to the
fourth power in this equation. Thus, even small changes in the internal
radius of a tube have a huge influence on its resistance to flow. For
example, halving the inside radius of a tube will increase its resistance to
flow by 16-fold.

The preceding 2 equations may be combined into one expression
known as the Poiseuille equation, which includes all the terms that

influence flow through a cylindrical vessel:

Again, note that flow occurs only when a pressure difference exists. (If
Δ P = 0, then flow = 0.) It is not surprising then that arterial blood pressure
is an extremely important and carefully regulated cardiovascular variable.
Also note once again that for any given pressure difference, tube radius
has a very large influence on the flow through a tube. It is logical,
therefore, that organ blood flows are regulated primarily through changes
in the radii of vessels within organs. Although vessel length and blood
viscosity are factors that influence vascular resistance, they are not
variables that can be easily manipulated for the purpose of moment-to-
moment control of blood flow.

In regard to the overall cardiovascular system, as depicted in Figures
1–1 and 1–2, one can conclude that blood flows through the vessels within
an organ only because a pressure difference exists between the blood in the
arteries supplying the organ and the veins draining it. The primary job of
the heart pump is to keep the pressure within arteries higher than that
within veins. Normally, the average pressure in systemic arteries is
approximately 100 mm Hg, and the average pressure in systemic veins is
approximately 0 mm Hg.

Therefore, because the pressure difference (Δ P) is nearly identical
across all systemic organs, cardiac output is distributed among the various
systemic organs, primarily on the basis of their individual resistances to
flow. Because blood preferentially flows along paths of least resistance,
organs with relatively low resistance naturally receive relatively high flow.

 Substances are carried between organs within the cardiovascular

system by the process of convective transport, the simple process of being
swept along with the flow of the blood in which they are contained. The
rate at which a substance (X) is transported by this process depends solely
on the concentration of the substance in the blood and the blood flow rate.

where  = rate of transport of X (mass/time),  = blood flow rate
(volume/time), and [ X] = concentration of X in blood (mass/volume).

It is evident from the preceding equation that only 2 methods are
available for altering the rate at which a substance is carried to an organ:
(1) a change in the blood flow rate through the organ or (2) a change in the
arterial blood concentration of the substance. The preceding equation
might be used, for example, to calculate how much oxygen is carried to a
certain skeletal muscle each minute. Note, however, that this calculation
would not indicate whether the muscle actually used the oxygen carried to

The Fick Principle
 One can extend the convective transport principle to calculate the rate

at which a substance is being removed from (or added to) the blood as it
passes through an organ. To do so, one must simultaneously consider the
rate at which the substance is entering the organ in the arterial blood and
the rate at which the substance is leaving the organ in the venous blood.
The basic logic is simple. For example, if something goes into an organ in
arterial blood and does not come out on the other side in venous blood, it
must have left the blood and entered the tissue within the organ. This
concept is referred to as the Fick principle (Adolf Fick, a German
physician, 1829–1901) and may be formally stated as follows:

where  tc = transcapillary efflux rate of X,  = blood flow rate, and [
X] a,v = arterial and venous concentrations of X.

The Fick principle is useful because it offers a practical method to
deduce a tissue’s steady-state rate of consumption (or production) of any
substance. To understand why this is so, one further step in logic is
necessary. Consider, for example, what possibly can happen to a substance
that enters a tissue from the blood. It can either (1) increase the
concentration of itself within the tissue or (2) be metabolized (i.e.,
converted into something else) within the tissue. A steady state implies a

stable situation wherein nothing (including the substance’s tissue
concentration) is changing with time. Therefore, in the steady state, the
rate of the substance’s loss from blood within a tissue must equal its rate of
metabolism within that tissue.


Pumping Action
The heart lies in the center of the thoracic cavity and is suspended by its
attachments to the great vessels within a thin fibrous sac called the
pericardium. A small amount of fluid in the sac lubricates the surface of
the heart and allows it to move freely during contraction and relaxation.
Blood flow through all organs is passive and occurs only because arterial
pressure is kept higher than venous pressure by the pumping action of the
heart. The right heart pump provides the energy necessary to move blood
through the pulmonary vessels, and the left heart pump provides the
energy to move blood through the systemic organs.

The pathway of blood flow through the chambers of the heart is
indicated in Figure 1–4. Venous blood returns from the systemic organs to
the right atrium via the superior and inferior venae cavae. This “venous”
blood is deficient in oxygen because it has just passed through systemic
organs that all extract oxygen from blood for their metabolism. It then
passes through the tricuspid valve into the right ventricle and from there it
is pumped through the pulmonic valve into the pulmonary circulation via
the pulmonary arteries. Within the capillaries of the lung, blood is
“reoxygenated” by exposure to oxygen-rich inspired air. Oxygenated
pulmonary venous blood flows in pulmonary veins to the left atrium and
passes through the mitral valve into the left ventricle. From there it is
pumped through the aortic valve into the aorta to be distributed to the
systemic organs.

Figure 1–4. Pathway of blood flow through the heart.

 Although the gross anatomy of the right heart pump is somewhat
different from that of the left heart pump, the pumping principles are
identical. Each pump consists of a ventricle, which is a closed chamber
surrounded by a muscular wall, as illustrated in Figure 1–5. The valves are
structurally designed to allow flow in only one direction and passively
open and close in response to the direction of the pressure differences
across them. Ventricular pumping action occurs because the volume of the
intraventricular chamber is cyclically changed by rhythmic and
synchronized contraction and relaxation of the individual cardiac muscle
cells that lie in a circumferential orientation within the ventricular wall. 2

When the ventricular muscle cells are contracting, they generate a
circumferential tension in the ventricular walls that causes the pressure
within the chamber to increase. As soon as the ventricular pressure
exceeds the pressure in the pulmonary artery (right pump) or aorta (left

pump), blood is forced out of the chamber through the outlet valve, as
shown in Figure 1–5. This phase of the cardiac cycle during which the
ventricular muscle cells are contracting is called systole. Because the
pressure is higher in the ventricle than in the atrium during systole, the
inlet or atrioventricular (AV) valve is closed. When the ventricular muscle
cells relax, the pressure in the ventricle falls below that in the atrium, the
AV valve opens, and the ventricle refills with blood, as shown on the right
side in Figure 1–5. This portion of the cardiac cycle is called diastole. The
outlet valve is closed during diastole because arterial pressure is greater
than intraventricular pressure. After the period of diastolic filling, the
systolic phase of a new cardiac cycle is initiated.

Figure 1–5. Ventricular pumping action.

 The amount of blood pumped per minute from each ventricle (the
cardiac output, CO) is determined by the volume of blood ejected per beat
(the stroke volume, SV) and the number of heartbeats per minute (the heart
rate, HR) as follows:

It should be evident from this relationship that all influences on cardiac
output must act through changes in either the heart rate or the stroke

An important implication of the above is that the volume of blood that
the ventricle pumps with each heartbeat (i.e., the stroke volume, SV) must
equal the blood volume inside the ventricle at the end of diastole ( end-
diastolic volume, EDV) minus ventricular volume at the end of systole (
end-systolic volume, ESV). That is,


Thus, stroke volume can only be changed by changes in EDV and/or
ESV. The implication for the bigger picture is that cardiac output can only
be changed by changes in HR, EDV, and/or ESV.

Cardiac Excitation
Efficient pumping action of the heart requires a precise coordination of the
contraction of millions of individual cardiac muscle cells. Contraction of
each cell is triggered when an electrical excitatory impulse ( action
potential) sweeps over its membrane. Proper coordination of the
contractile activity of the individual cardiac muscle cells is achieved
primarily by the conduction of action potentials from one cell to the next
via gap junctions that connect all cells of the heart into a functional
syncytium (i.e., acting as one synchronous unit). In addition, muscle cells
in certain areas of the heart are specifically adapted to control the
frequency of cardiac excitation, the pathway of conduction, and the rate of
the impulse propagation through various regions of the heart. The major
components of this specialized excitation and conduction system are
shown in Figure 1–6. These include the sinoatrial node (SA node), the
atrioventricular node (AV node), the bundle of His, and the right and left
bundle branches made up of specialized cells called Purkinje fibers.

The SA node contains specialized cells that normally function as the
heart’s pacemaker and initiate the action potential that is conducted
through the heart. The AV node contains slowly conducting cells that
normally function to create a slight delay between atrial contraction and
ventricular contraction. The Purkinje fibers are specialized for rapid
conduction and ensure that all ventricular cells contract at nearly the same
instant. The overall message is that HR is normally controlled by the
electrical activity of the SA nodal cells. The rest of the conduction system

ensures that all the rest of the cells in the heart follow along in proper
lockstep for efficient pumping action.

Figure 1–6. Electrical conduction system of the heart.

Control of Cardiac Output

 Although the heart can inherently beat on its own, cardiac function
can be influenced profoundly by neural inputs from both the sympathetic
and parasympathetic divisions of the autonomic nervous system. These
inputs allow us to modify cardiac pumping as is appropriate to meet
changing homeostatic needs of the body. All portions of the heart are
richly innervated by adrenergic sympathetic fibers. When active, these
sympathetic nerves release norepinephrine (noradrenaline) on cardiac
cells. Norepinephrine interacts with β 1-adrenergic receptors on cardiac

muscle cells to increase the heart rate, increase the action potential
conduction velocity, and increase the force of contraction and rates of
contraction and relaxation. Overall, sympathetic activation acts to increase
cardiac pumping.

Cholinergic parasympathetic nerve fibers travel to the heart via the
vagus nerve and innervate the SA node, the AV node, and the atrial
muscle. When active, these parasympathetic nerves release acetylcholine
on cardiac muscle cells. Acetylcholine interacts with muscarinic receptors
on cardiac muscle cells to decrease the heart rate (SA node) and decrease
the action potential conduction velocity (AV node). Parasympathetic
nerves may also act to decrease the force of contraction of atrial (not
ventricular) muscle cells. Overall, parasympathetic activation acts to
decrease cardiac pumping. Usually, an increase in parasympathetic nerve
activity is accompanied by a decrease in sympathetic nerve activity, and
vice versa.

 One of the most fundamental causes of variations in stroke volume

was described by William Howell in 1884 and by Otto Frank in 1894 and
formally stated by E. H. Starling in 1918. These investigators
demonstrated that, with other factors being equal, if cardiac filling
increases during diastole, the volume ejected during systole also increases.
As a consequence, and as illustrated in Figure 1–7, stroke volume
increases nearly in proportion to increases in end-diastolic volume. This
phenomenon is commonly referred to as the Starling law of the heart. In a
subsequent chapter, we will describe how the Starling law is a direct
consequence of the intrinsic mechanical properties of cardiac muscle cells.
However, knowing the mechanisms behind the Starling law is not
ultimately as important as appreciating its consequences. The primary
consequence is that stroke volume (and therefore cardiac output) is
strongly influenced by cardiac filling during diastole. Therefore, we shall
later pay particular attention to the factors that affect cardiac filling and
how they participate in the normal regulation of cardiac output.

Figure 1–7. The Starling law of the heart.

Requirements for Effective Operation
For effective efficient ventricular pumping action, the heart must be
functioning properly in 5 basic respects:

1.    The contractions of individual cardiac muscle cells must occur at
regular intervals and be synchronized (not arrhythmic).

2.    The valves must open fully (not stenotic).
3.    The valves must not leak (not insufficient or regurgitant).
4.    The muscle contractions must be forceful (not failing).
5.    The ventricles must fill adequately during diastole.

In the subsequent chapters, we will study in detail how these
requirements are met in the normal heart. Moreover, we will describe how
failures in any of these respects lead to distinctly different, clinically
relevant, pathologies and symptoms.

Blood that is ejected into the aorta by the left heart passes consecutively
through many different types of vessels before it returns to the right heart.
As illustrated in Figure 1–8, the major vessel classifications are arteries,

arterioles, capillaries, venules, and veins. These consecutive vascular
segments are distinguished from one another by differences in their
physical dimensions, morphological characteristics, and function. One
thing that all these vessels have in common is that they are lined with a
contiguous single layer of endothelial cells. In fact, this is true for the
entire circulatory system including the heart chambers and even the valve

Vessel Characteristics
Some representative physical characteristics of these major vessel types
are shown in Figure 1–8. It should be realized, however, that the vascular
bed is a continuum and that the transition from one type of vascular
segment to another does not occur abruptly. The total cross-sectional area
through which blood flows at any particular level in the vascular system is
equal to the sum of the cross-sectional areas of all the individual vessels
arranged in parallel at that level. The number and total cross-sectional area
values presented in Figure 1–8 are estimates for the entire systemic

Arteries are thick-walled vessels that contain, in addition to some
smooth muscle, a large component of elastin and collagen fibers. Primarily
because of the elastin fibers, which can stretch to twice their unloaded
length, arteries can expand under increased pressure to accept and
temporarily store some of the blood ejected by the heart during systole and
then, by passive recoil, supply this blood to the organs downstream during
diastole. The aorta is the largest artery and has an internal (luminal)
diameter of approximately 25 mm. Arterial diameter decreases with each
consecutive branching, and the smallest arteries have diameters of
approximately 0.1 mm. The consecutive arterial branching pattern causes
an exponential increase in arterial numbers. Thus, although individual
vessels get progressively smaller, the total cross-sectional area available
for blood flow within the arterial system increases to several fold that in
the aorta. Arteries are often referred to as conduit vessels because they
have relatively low and unchanging resistance to flow.

Figure 1–8. Structural characteristics of the peripheral vascular system.

 Arterioles are smaller and structured differently than arteries. In
proportion to lumen size, arterioles have much thicker walls with more
smooth muscle and less elastic material than do arteries. Because arterioles
are so muscular, their diameters can be actively changed to regulate the
blood flow through peripheral organs. Despite their minute size, arterioles
are so numerous that in parallel their collective cross-sectional area is
much larger than that at any level in arteries. Arterioles are often referred
to as resistance vessels because of their high and changeable resistance,
which regulates peripheral blood flow through individual organs.

Capillaries are the smallest vessels in the vasculature. In fact, red blood
cells with diameters of 7 μm must deform to pass through them. The
capillary wall consists of a single layer of endothelial cells that separates

the blood from the interstitial fluid by only approximately 1 μm.
Capillaries contain no smooth muscle and thus lack the ability to change
their diameters actively. They are so numerous that the total collective
cross-sectional area of all the capillaries in systemic organs is more than
1000 times that of the root of the aorta. Given that capillaries are
approximately 0.5 mm in length, the total surface area available for
exchange of material between blood and interstitial fluid can be calculated
to exceed 100 m 2. For obvious reasons, capillaries are viewed as the
exchange vessels of the cardiovascular system. In addition to the
transcapillary diffusion of solutes that occurs across these vessel walls,
there can sometimes be net movements of fluid (volume) into and/or out of
capillaries. For example, tissue swelling ( edema) is a result of net fluid
movement from plasma into the interstitial space.

After leaving capillaries, blood is collected in venules and veins and
returned to the heart. Venous vessels have very thin walls in proportion to
their diameters. Their walls contain smooth muscle, and their diameters
can actively change. Because of their thin walls, venous vessels are quite
distensible. Therefore, their diameters change passively in response to
small changes in transmural distending pressure (i.e., the difference
between the internal and external pressures across the vessel wall). Venous
vessels, especially the larger ones, also have one-way valves that prevent
reverse flow. As will be discussed later, these valves are especially
important in the cardiovascular system’s operation during standing and
during exercise. It turns out that peripheral venules and veins normally
contain more than 50% of the total blood volume. Consequently, they are
commonly thought of as the capacitance vessels. More importantly,
changes in venous volume greatly influence cardiac filling and therefore
cardiac pumping. Thus, peripheral veins actually play an extremely
important role in controlling cardiac output.

Control of Blood Vessels
 Blood flow through individual vascular beds is profoundly influenced

by changes in the activity of sympathetic nerves innervating arterioles.
These nerves release norepinephrine at their endings that interacts with α -
adrenergic receptors on the smooth muscle cells to cause contraction and
thus arteriolar constriction. The reduction in arteriolar diameter increases
vascular resistance and decreases blood flow. These neural fibers provide
the most important means of reflex control of vascular resistance and

organ blood flow.
Arteriolar smooth muscle is also very responsive to changes in the

local chemical conditions within an organ that accompany changes in the
metabolic rate of the organ. For reasons to be discussed later, increased
tissue metabolic rate leads to arteriolar dilation and increased tissue blood

Venules and veins are also richly innervated by sympathetic nerves and
constrict when these nerves are activated. The mechanism is the same as
that involved with arterioles. Thus, increased sympathetic nerve activity is
accompanied by decreased venous volume. The importance of this
phenomenon is that venous constriction tends to increase cardiac filling
and therefore cardiac output via the Starling law of the heart.

To the best of our knowledge, there is no important neural or local
metabolic control of either arterial or capillary vessel tone or diameter.

Overall Vascular Function
In essence, the bulk of the vascular system is simply the network of
“pipes” necessary to route blood flow from the heart through capillary
beds in organs throughout the body and then collect it again to return it to
the heart. Because blood is a viscous fluid, there is an unavoidable energy
loss (to heat via fluid friction) as it flows through any vessel. Thus, there is
an energy cost to just distributing the blood throughout the body. This
energy loss as blood moves through the vasculature is important because it
determines how much work the heart must do to produce that flow in the
first place.

There are many possible plumbing schemes (e.g., various
combinations of vessels of different diameters, lengths, and branching
patterns) that could accomplish the goal of distributing blood to capillary
beds throughout the body. However, some would do so with less frictional
energy loss than others. We contend that the vascular system has evolved
to distribute the cardiac output with minimal energy loss in the process.

 Blood is a complex fluid that serves as the medium for transporting

substances between the tissues of the body and performs a host of other
functions as well. Normally, approximately 40% of the volume of whole
blood is occupied by blood cells that are suspended in the watery fluid,

plasma, which accounts for the rest of the volume. The fraction of blood
volume occupied by cells is termed as the hematocrit, a clinically
important parameter.

Hematocrit = Cell volume/Totalblood volume

One of the reasons that a person’s hematocrit is clinically relevant is
that the viscosity of blood increases dramatically with increases in its
hematocrit. Recall that fluid viscosity is one physical factor that affects the
flow through a tube. Other factors equal, the higher the blood viscosity, the
more work the heart has to do to produce any given flow through the

Blood Cells
Blood contains 3 general types of “formed elements”: red cells, white
cells, and platelets (see Appendix A). All are formed in bone marrow from
a common stem cell. Red cells are by far the most abundant. They are
specialized to carry oxygen from the lungs to other tissues by binding
oxygen to hemoglobin, an iron-containing heme protein contained within
red blood cells. Because of the presence of hemoglobin, blood can
transport 40 to 50 times the amount of oxygen that plasma alone could
carry. In addition, the hydrogen ion buffering capacity of hemoglobin is
vitally important to the blood’s capacity to transport carbon dioxide.

A small, but important, fraction of the cells in blood is white cells or
leukocytes. Leukocytes are involved in immune processes. Appendix A
gives more information on the types and function of leukocytes. Platelets
are small cell fragments that are important in the blood-clotting process.

Plasma is the liquid component of blood and, as indicated in Appendix B,
is a complex solution of electrolytes and proteins. Serum is the fluid
obtained from a blood sample after it has been allowed to clot. For all
practical purposes, the composition of serum is identical to that of plasma
except that it contains none of the clotting proteins.

Inorganic electrolytes (inorganic ions such as sodium, potassium,
chloride, and bicarbonate) are the most concentrated solutes in plasma. Of
these, sodium and chloride are by far the most abundant and, therefore, are
primarily responsible for plasma’s normal osmolarity of approximately

300 mOsm/L. To a first approximation, the “stock” of the plasma soup is a
150-mM solution of sodium chloride. Such a solution is called “isotonic
saline” and has many clinical uses as a fluid that is compatible with cells.

Plasma normally contains many different proteins. Most plasma
proteins can be classified as albumins, globulins, or fibrinogen on the basis
of different physical and chemical characteristics used to separate them.
More than 100 distinct plasma proteins have been identified and each
presumably serves some specific function. Many plasma proteins are
involved in blood clotting or immune/defense reactions. Many others are
important carrier proteins for a variety of substances including fatty acids,
iron, copper, vitamin D, and certain hormones.

Proteins do not readily cross capillary walls and, in general, their
plasma concentrations are much higher than their concentrations in the
interstitial fluid. As will be discussed, plasma proteins play an important
osmotic role in transcapillary fluid movement and consequently in the
distribution of extracellular volume between the plasma and interstitial
compartments. Albumin plays an especially strong role in this regard
simply because it is by far the most abundant of the plasma proteins.

Plasma also serves as the vehicle for transporting nutrients and waste
products. Thus, a plasma sample contains many small organic molecules
such as glucose, amino acids, urea, creatinine, and uric acid whose
measured values are useful in clinical diagnosis.

In this first chapter, we have argued that maintaining bodily homeostasis is
the bottom-line task of the cardiovascular system. To maintain
homeostasis in any tissue in any given situation, that tissue must receive a
blood flow through its capillaries that is matched to support the local
current metabolic needs of that tissue. Adequate arterial pressure is
necessary to produce tissue blood flow in the first place but arterial
pressure is only one factor in achieving adequate tissue blood flow.
Constant arterial pressure by itself does not ensure that there will be
homeostasis throughout the body. What constant arterial pressure does do
is allow an individual organ to control its own blood flow by varying the
local resistance to blood flow according to its current metabolic needs.
Moreover, this local control allows any organ to regulate its own flow
without disturbing the flows through other organs. At this juncture we
would also like to draw the reader’s attention to Appendix C, which is a

shorthand compilation of many of the key cardiovascular relationships that
we have and will encounter in due course.

 The primary role of the cardiovascular system is to maintain homeostasis in the

interstitial fluid.

 The physical law that governs cardiovascular operation is that flow through any

segment is equal to pressure difference across that segment divided by its resistance to
flow, that is, . = ∆P/R .

 The rate of transport of a substance within the blood (X) is a function of its

concentration in the blood [X] and the blood flow rate, that is,  = . [X] .

 The heart pumps blood by rhythmically filling and ejecting blood from the ventricular

chambers that are served by passive one-way inlet and outlet valves.

 Cardiac output (CO) is a function of the heart rate (HR) and stroke volume (SV), that

is, CO = HR × SV.

 Changes in heart rate and stroke volume (and therefore cardiac output) can be

accomplished by alterations in ventricular filling and by alterations in autonomic nerve
activity to the heart.

 Blood flow through individual organs is regulated by changes in the diameter of their


 Changes in arteriolar diameter can be accomplished by alterations in sympathetic

nerve activity and by variations in local conditions.

 Blood is a complex suspension of red cells, white cells, and platelets in plasma that is

ideally suited to carry gases, salts, nutrients, and waste molecules throughout the


1–1 .     Which organ in the body always receives the most blood flow?

1–2 .     Whenever skeletal muscle blood flow increases, blood flow to
other organs must decrease. True or false?

1–3 .     When a heart valve does not close properly, a sound called a
“murmur” can often be detected as the valve leaks. Would you
expect a leaky aortic valve to cause a systolic or diastolic murmur?

1–4 .     Slowing of action potential conduction through the AV node will
slow the heart rate. True or false?

1–5 .     Suppose the diameters of the vessels within an organ increase by
10%. Other factors equal, how would this affect the
a. resistance to blood flow through the organ?
b. blood flow through the organ?

1–6 .     The pressure in the aorta is normally about 100 mm Hg, whereas
that in the pulmonary artery is normally about 15 mm Hg. A few of
your fellow students offer the following alterative hypotheses about
why this might be so:
a. The right heart pumps less blood than the left heart.
b. The right heart rate is slower than the left heart rate.
c. The right ventricle is less muscular than the left ventricle.
d. The pulmonary vascular bed has less resistance than the systemic

e. The stroke volume of the right heart is less than that of the left

f. It must be genetics.
Which of their suggestions is (are) correct?

1–7 .     Usually, an individual who has lost a significant amount of blood
is weak and does not reason very clearly. Why would blood loss
have these effects?

1–8 .     What direct cardiovascular consequences would you expect from
an intravenous injection of norepinephrine?

1–9 .     What direct cardiovascular effects would you expect from an
intravenous injection of a drug that stimulates α -adrenergic
receptors but not β -adrenergic receptors?

1–10 .     Individuals with high arterial blood pressure (hypertension) are
often treated with drugs that block β -adrenergic receptors. What is
a rationale for such treatment?

1–11 .     The clinical laboratory reports a serum sodium ion value of 140
mEq/L in a blood sample you have taken from a patient. What does
this tell you about the sodium ion concentration in plasma, in
interstitial fluid, and in intracellular fluid?

1–12 .     Explain how it is that the water flow into your kitchen sink
changes when you turn the handle on its faucet.

1–13 .     A common “side effect” of β -blocker therapy is decreased
exercise tolerance. Why is this not surprising?

1–14 .     You need to determine the correct dose of an IV drug that
distributes only within the extracellular space. Which of the
following values would be the closest estimate of the extracellular
fluid volume of a healthy young adult male weighing 100 kg (220
a. 3 L
b. 5 L
c. 8 L
d. 10 L
e. 20 L

1–15 .     Determine the rate of glucose uptake by an exercising skeletal
muscle (  ) from the following data:

Arterial blood glucose concentration, [G] a = 50 mg/100 mL
Muscle venous blood glucose concentration, [G] v = 30 mg/100
Muscle blood flow  = 60mL/min

1–16 .     The Fick principle implies that doubling the flow through an
organ will necessarily double the organ’s rate of metabolism (or
production) of a substance. True or False?

1–17 .     Five requirements for normal cardiac pumping action were listed
in this chapter. Recall that CO = HR × (EDV − ESV). Use this as a
basis for explaining in detail why a lack of each of the requirements
would adversely affect CO.

1 Although pressure is most correctly expressed in units of force per unit area, it is customary to

express pressures within the cardiovascular system in millimeters of mercury. For example, mean
arterial pressure may be said to be 100 mm Hg because it is same as the pressure existing at the
bottom of a mercury column 100 mm high. All cardiovascular pressures are expressed relative to
atmospheric pressure, which is approximately 760 mm Hg.
2 The basic pumping principle of the heart has a very long evolutionary history. Eons before
mammals evolved, bivalve mollusks were using the same principle to pump water through
themselves to harvest food energy from microscopic organisms living in that water.

Characteristics of Cardiac
Muscle Cells 2


The student understands the ionic basis of the spontaneous electrical
activity of cardiac muscle cells:
     Describes how membrane potentials are created across

semipermeable membranes by transmembrane ion concentration

     Defines equilibrium potential and knows its normal value for
potassium and sodium ions.

     States how membrane potential reflects a membrane’s relative
permeability to various ions.

     Defines resting potential and action potential.
     Describes the characteristics of “fast” and “slow” response

action potentials.
     Identifies the refractory periods of the cardiac cell electrical

     Defines threshold potential and describes the interaction between

ion channel conditions and membrane potential during the
depolarization phase of the action potential.

     Defines pacemaker potential and describes the basis for rhythmic
electrical activity of cardiac cells.

     Names the important ion channels involved in the permeability
alterations during the various phases of the cardiac cycle.

The student knows the normal process of cardiac electrical
     Describes gap junctions and their role in cardiac excitation.
     Describes the normal pathway of action potential conduction

through the heart.

     Indicates the timing at which various areas of the heart are
electrically excited and identifies the characteristic action
potential shapes and conduction velocities in each major part of
the conduction system.

     States the relationship between electrical events of cardiac
excitation and the P, QRS, and T waves, the PR and QT intervals,
and the ST segment of the electrocardiogram.

The student understands the factors that control the heart rate and
action potential conduction in the heart:
     States how diastolic potentials of pacemaker cells can be altered

to produce changes in the heart rate.
     Describes how cardiac sympathetic and parasympathetic nerves

alter the heart rate and conduction of cardiac action potentials.
     Defines the terms chronotropic and dromotropic.
     The student understands the contractile processes of cardiac

muscle cells:
     Lists the subcellular structures responsible for cardiac muscle

cell contraction.
     Defines and describes the excitation–contraction process.
     Defines isometric, isotonic, and afterloaded contractions of the

cardiac muscle.
     Identifies the influence of altered preload on the tension-

producing and shortening capabilities of the cardiac muscle.
     Describes the influence of altered afterload on the shortening

capabilities of the cardiac muscle.
     Defines the terms contractility and inotropic state and describes

the influence of altered contractility on the tension-producing and
shortening capabilities of the cardiac muscle.

     Describes the effect of altered sympathetic neural activity on the
cardiac inotropic state.

     States the relationships between ventricular volume and muscle
length, between intraventricular pressure and muscle tension and
the law of Laplace.

Cardiac muscle cells are responsible for providing the power to drive
blood through the circulatory system. Coordination of their activity
depends on an electrical stimulus that is regularly initiated at an
appropriate rate and reliably conducted through the entire heart.

Mechanical pumping action depends on a robust contraction of the muscle
cells that results in repeating cycles of tension development, shortening,
and relaxation. In addition, mechanisms to adjust the excitation and
contraction characteristics must be available to meet the changing
demands of the circulatory system. This chapter focuses on these electrical
and mechanical properties of cardiac muscle cells that underlie normal
heart function.

In all striated muscle cells, contraction is triggered by a rapid voltage
change called an action potential that occurs on the cell membrane.
Cardiac muscle cell action potentials differ sharply from those of skeletal
muscle cells in 3 important ways that promote synchronous rhythmic
excitation of the heart: (1) they can be self-generating; (2) they are
conducted directly from cell to cell; and (3) they have long duration, which
precludes fusion of individual twitch contractions. To understand these
special electrical properties of the cardiac muscle and how cardiac function
depends on them, the basic electrical properties of excitable cell
membranes must first be examined.

Membrane Potentials
 All cells have an electrical potential (voltage) across their membranes.

Such transmembrane potentials are caused by a separation of electrical
charges across the membrane itself. The only way that the transmembrane
potential can change is for electrical charges to move across (i.e., current
to flow through) the cell membrane.

There are 2 important corollaries to this statement: (1) the rate of
change of transmembrane voltage is directly proportional to the net current
across the membrane; and (2) transmembrane voltage is stable (i.e.,
unchanging) only when there is no net current across the membrane.

Unlike a wire, current across cell membranes is not carried by
electrons but by the movement of ions through the cell membrane. The 3
ions that are the most important determinants of cardiac transmembrane
potentials are sodium (Na +) and calcium (Ca 2 +), which are more
concentrated in the extracellular fluid than they are inside cells, and

potassium (K +), which is more concentrated in intracellular than
extracellular fluid. (See Appendix B for normal values of many
constituents of adult human plasma.) In general, such ions are very
insoluble in lipids. Consequently, they cannot pass into or out of a cell
through the lipid bilayer of the membrane itself. Instead, these ions cross
the membrane only via various protein structures that are embedded in and
span across the lipid cell wall. There are 3 general types of such
transmembrane protein structures that are involved in ion movement
across the cell membrane: (1) ion channels; (2) ion exchangers; and (3) ion
pumps. 1 All are very specific for particular ions. For example, a “sodium
channel” is a transmembrane protein structure that allows only Na + ions to
pass into or out of a cell according to the net electrochemical forces acting
on Na + ions.

The subsequent discussion concentrates on ion channel operation
because ion channels (as opposed to exchangers and pumps) are
responsible for the resting membrane potential and for the rapid changes in
membrane potential that constitute the cardiac cell action potential. Ion
channels are under complex control and can be “opened,” “closed,” or
“inactivated.” The net result of the status of membrane channels to a
particular ion is commonly referred to as the membrane’s permeability to
that ion. For example, “high permeability to sodium” implies that many of
the Na + ion channels are in their open state at that instant. Precise timing
of the status of ion channels accounts for the characteristic membrane
potential changes that occur when cardiac cells are activated.

Figure 2–1 shows how ion concentration differences can generate an
electrical potential across the cell membrane. Consider first, as shown at
the top of this figure, a cell that (1) has K + more concentrated inside the
cell than outside, (2) is permeable only to K + (i.e., only K + channels are
open), and (3) has no initial transmembrane potential. Because of the
concentration difference, K + ions (positive charges) will diffuse out of the
cell. Meanwhile, negative charges, such as protein anions, cannot leave the
cell because the membrane is impermeable to them. Thus, the K + efflux
will make the cytoplasm at the inside surface of the cell membrane more
electrically negative (deficient in positively charged ions) and at the same
time make the interstitial fluid just outside the cell membrane more
electrically positive (rich in positively charged ions). K + ion, being
positively charged, is attracted to regions of electrical negativity.
Therefore, when K + diffuses out of a cell, it creates an electrical potential
across the membrane that tends to attract it back into the cell. There exists

one membrane potential called the potassium equilibrium potential at
which the electrical forces tending to pull K + into the cell exactly balance
the concentration forces tending to drive K + out. When the membrane
potential has this value, there is no net movement of K + across the
membrane. With the normal concentrations of approximately 145 mM K +
inside cells and 4 mM K + in the extracellular fluid, the K + equilibrium
potential is roughly −90 mV (more negative inside than outside by nine-
hundredths of a volt). 2 A membrane that is permeable only to K + will
inherently and rapidly (essentially instantaneously) develop the potassium
equilibrium potential. In addition, membrane potential changes require the
movement of so few ions that concentration differences between the intra-
and extracellular fluid compartments are not significantly affected by the

Figure 2–1. Electrochemical basis of membrane potentials.

As depicted in the bottom half of Figure 2–1, similar reasoning shows
how a membrane permeable only to Na + would have the sodium
equilibrium potential across it. The sodium equilibrium potential is
approximately +70 mV, with the normal extracellular Na + concentration
of 140 mM and intracellular Na + concentration of 10 mM.

Real cell membranes, however, are never permeable to just Na + or just
K +. When a membrane is permeable to both of these ions, the membrane

potential will lie somewhere between the Na + equilibrium potential and
the K + equilibrium potential. Just what membrane potential will exist at
any instant depends on the relative permeability of the membrane to Na +
and K +. The more permeable the membrane is to K + than to Na +, the
closer the membrane potential will be to −90 mV. Conversely, when the
permeability to Na + is high relative to the permeability to K +, the
membrane potential will be closer to +70 mV. 3 A stable membrane
potential that lies between the sodium and potassium equilibrium
potentials implies that there is no net current across the membrane. This
situation may well be the result of opposite but balanced sodium and
potassium currents across the membrane.

Because of low or unchanging permeability or low concentration, roles
played by ions other than Na + and K + in determining membrane potential
are usually minor and often ignored. However, as discussed later, calcium
ions (Ca 2 +) do participate in the cardiac muscle action potential. Like Na
+, Ca 2 + is more concentrated outside cells than inside. The equilibrium
potential for Ca 2 + is approximately +100 mV, and the cell membrane
tends to become more positive on the inside when the membrane’s
permeability to Ca 2 + rises.

Under resting conditions, most heart muscle cells have membrane
potentials that are quite close to the potassium equilibrium potential. Thus,
both electrical and concentration gradients favor the entry of Na + and Ca 2
+ into the resting cell. Left unchecked, this slow leak of Na + and Ca 2 +
into the cell and K + out of the cell would ultimately destroy the
transmembrane potential. However, the very low permeability of the
resting membrane to Na + and Ca 2 + (in combination with a Na +–Ca 2 +
exchanger and an energy-requiring sodium–potassium pump) prevents Na
+ and Ca 2 + from gradually accumulating inside the resting cell. 4 , 5

Cardiac Muscle Cell Action Potentials
 Action potentials of cells from different regions of the heart are not

identical but have varying characteristics that are important to the overall
process of cardiac excitation.

Some cells within a specialized conduction system have the ability to
act as pacemakers and to spontaneously initiate action potentials, whereas
ordinary cardiac muscle cells do not (except under unusual conditions).
Basic membrane electrical features of an ordinary cardiac muscle cell and

a cardiac pacemaker-type cell are shown in Figure 2–2. Action potentials
from these cell types are referred to as “fast-response” and “slow-
response” action potentials, respectively.

Figure 2–2. Time course of membrane potential ( A and B) and ion permeability changes ( C and
D) that occur during “fast-response” ( left) and “slow-response” ( right) action potentials.

 As shown in Figure 2–2A, fast-response action potentials are
characterized by a rapid depolarization (phase 0) with a substantial
overshoot (positive inside voltage), a rapid reversal of the overshoot
potential (phase 1), a long plateau (phase 2), and a repolarization (phase 3)

to a stable, high (i.e., large negative) resting membrane potential (phase 4).
In comparison, the slow-response action potentials are characterized by a
slower initial depolarization phase, a lower amplitude overshoot, a shorter
and less stable plateau phase, and a repolarization to an unstable, slowly
depolarizing “resting” potential ( Figure 2–2B). The unstable resting
potential seen in pacemaker cells with slow-response action potentials is
variously referred to as phase 4 depolarization, diastolic depolarization, or
pacemaker potential. Such cells are usually found in the sinoatrial (SA)
and atrioventricular (AV) nodes.

As indicated at the bottom of Figure 2–2A, cells are in an absolute
refractory state during most of the action potential (i.e., they cannot be
stimulated to fire another action potential). Near the end of the action
potential, the membrane is relatively refractory and can be reexcited only
by a larger-than-normal stimulus. This long refractory state precludes
summated or tetanic contractions from occurring in normal cardiac muscle.
Immediately after the action potential, the membrane is transiently
hyperexcitable and is said to be in a “vulnerable” or “supranormal” period.
Similar alterations in membrane excitability occur during slow action
potentials but are not well characterized at present.

 Recall that the membrane potential of any cell at any given instant
depends on the relative permeability of the cell membrane to specific ions.
As in all excitable cells, cardiac cell action potentials are the result of
large, rapid and transient changes in the ionic permeability of the cell
membrane that are triggered by an initial small, localized depolarization
and then propagated over the entire cell membrane. Figure 2–2C and 2–2D
indicates the changes in the membrane’s permeabilities to K+, Na+, and
Ca2+ that produce the various phases of the fast- and slow-response action
potentials.6 Note that during the resting phase, the membranes of both
types of cells are more permeable to K+ than to Na+ or Ca2+. Therefore,
the membrane potentials are close to the potassium equilibrium potential
(of −90 mV) during this period.

 In pacemaker-type cells, at least 3 mechanisms are thought to
contribute to the slow depolarization of the membrane observed during the
diastolic interval. First, there is a progressive decrease in the membrane’s
permeability to K + during the resting phase. Second, the permeability to
Na + increases slowly. (This gradual increase in the Na +/K + permeability
ratio will cause the membrane potential to move slowly away from the K +
equilibrium potential (−90 mV) in the direction of the Na + equilibrium

potential.) Third, there is a slight increase in the permeability of the
membrane to calcium ions late in diastole, which results in an inward
movement of these positively charged ions and also contributes to the
diastolic depolarization. These permeability changes result in a specific
current that occurs during diastole called the i-funny ( i f) current.

When the membrane potential depolarizes to a certain threshold
potential in either type of cell, major rapid alterations in the permeability
of the membrane to specific ions are triggered. Once initiated, these
permeability changes cannot be stopped and they proceed to completion.

The characteristic rapid rising phase of the fast-response action
potential is a result of a sudden increase in Na + permeability. This
produces what is referred to as the fast inward current of Na + and causes
the membrane potential to move rapidly toward the sodium equilibrium
potential. As indicated in Figure 2–2C, this period of very high sodium
permeability (phase 0) is short-lived. A very brief increase in potassium
permeability then occurs (not shown in Figure 2–2C) that allows a brief
outward-going potassium current ( iTo) and results in a small non-
sustained repolarization after the peak of the action potential (phase 1).
Development and maintenance of a prolonged depolarized plateau state
(phase 2) is accomplished by the interactions of at least 2 separate
processes: (1) a sustained reduction in K + permeability and (2) a slowly
developed and sustained increase in the membrane’s permeability to Ca 2
+. In addition, under certain conditions, the electrogenic action of a Na +–
Ca 2 + exchanger (in which 3 Na + ions move into the cell in exchange for
a single Ca 2 + ion moving out of the cell) may contribute to the
maintenance of the plateau phase of the cardiac action potential.

The initial fast inward current is small (or even absent) in cells that
have slow-response action potentials ( Figure 2–2D). Therefore, the initial
depolarization phase of these action potentials is somewhat slower than
that of the fast-response action potentials and is primarily a result of an
inward movement of Ca 2 + ions. In both types of cells, the membrane is
repolarized (during phase 3) to its original resting potential as the K +
permeability increases to its high resting value and the Ca 2 + and Na +
permeabilities return to their low resting values. These late permeability
changes produce what is referred to as the delayed outward current.

 The overall smoothly graded permeability changes that produce action
potentials are the net result of alterations in each of the many individual
ion channels within the plasma membrane of a single cell. 7 These ion

channels are generally made up of very long polypeptide chains that loop
repeatedly across the cell membrane. These loops form a hollow
conduction channel between the intracellular and extracellular fluids that
are structurally quite specific for a particular ion. These channels can exist
in 1 of 3 conformational states: open, closed, or inactivated. The status of
the channels can be altered by configurational changes in certain subunits
of the molecules within the channel (referred to as “gates” or plugs) so that
when open, ions move down their electrochemical gradient either into or
out of the cell (high permeability) and when closed or inactivated, no ions
can move (low permeability).

The specific mechanisms that control the operation of these channels
during the action potential are not fully understood. Certain types of
channels are called voltage-gated channels (or voltage-operated channels)
because their probability of being open varies with membrane potential.
Another type of channels, called ligand-gated channels (or receptor-
operated channels), are activated by certain neurotransmitters or other
specific signal molecules. Table 2–1 lists a few of the major important
currents and channel types involved in cardiac cell electrical activity. The
number of well-described ion channels in cardiac muscle is rapidly
increasing and abnormalities in these channels (channelopathies) are now
known to be responsible for a variety of excitation abnormalities. Our
oversimplified description of channel function below is an effort to
provide some basic understanding without the many complicating features
of the electrical excitation process.

Table 2–1. Characteristics of Important Cardiac Ion Channels in Order of
Their Participation in an Action Potential

Some of the voltage-gated channels respond to a sudden-onset,
sustained change in membrane potential by only a brief period of
activation. However, changes in membrane potential of slower onset, but
the same magnitude, may fail to activate these channels at all. To explain
such behavior, it is postulated that a given channel has 2 independently
operating “gates”—an activation gate and an inactivation gate—both of
which must be open for the channel as a whole to be open. Both these

gates respond to changes in membrane potential but do so with different
voltage sensitivities and time courses.

  These concepts are illustrated in Figure 2–3. (For simplicity, a

single Na + channel and Ca 2 + channel are shown and K + channels are
ignored). In the resting state, with the membrane polarized to
approximately −80 mV, the activation gate of the fast Na + channel is
closed, but its inactivation gate is open ( Figure 2–3A). With a rapid
depolarization of the membrane to threshold, the Na + channels will be
activated strongly to allow an inrush of positive sodium ions that further
depolarizes the membrane and thus accounts for the rising phase of a
“fast” response action potential, as illustrated in Figure 2–3B. This occurs
because the activation gate responds to membrane depolarization by
opening more quickly than the inactivation gate responds by closing. Thus,
a small initial rapid depolarization to threshold is followed by a brief, but
strong, period of Na + channel activation wherein the activation gate is
open but the inactivation gate is yet to close. Within a few milliseconds,
however, the inactivation gates of the fast sodium channels close and shut
off the inward movement of Na +.

After a brief delay, the large membrane depolarization of the rising
phase of the fast action potential causes the activation gate of the L-type
Ca 2 + channel to open. This permits the slow inward movement of Ca 2 +
ions, which helps maintain the depolarization through the plateau phase of
the action potential ( Figure 2–3C). Ultimately, repolarization occurs
because of both a delayed inactivation of the Ca 2 + channel (by closure of
the inactivation gates) and a delayed opening of K + channels (which are
not shown in Figure 2–3).

The inactivation gates of sodium channels remain closed during the
plateau phase and the remainder of the action potential, effectively
inactivating the Na + channel. This sustained sodium channel inactivation,
combined with activation of calcium channels and the delay in opening of
potassium channels, accounts for the long plateau phase and the long
cardiac refractory period, which lasts until the end of phase 3. With
repolarization, both gates of the sodium channel return to their original
position and the channel is now ready to be reactivated by a subsequent

Multiple factors in addition to membrane voltage can influence the
membrane ionic permeability and normal operation of ion channels. For
example, high intracellular Ca 2 + concentration during systole contributes

to activation of certain K + channels and increases the rate of
repolarization. Sympathetic and parasympathetic neural input can
influence the status of some voltage-gated channels and cause activation or
suppression of other ligand-gated channels. In addition, mechano-gated
and mechano-modultated channels may be activated by myocyte stretch or
myocyte volume changes and can influence membrane permeability to K
+, Na +, and Ca 2 +.

Figure 2–3. A conceptual model of cardiac membrane fast sodium and slow calcium ion channels:
at rest ( A), during the initial phases of the fast-response ( B and C), and the slow-response action
potentials ( D and E). “Activation” gates (m and d) are hatched and “inactivation” gates (h and f)
are stippled.

The slow-response action potential shown in the right half of Figure 2–
3 differs from the fast-response action potential primarily because of the
lack of a strong activation of the fast Na + channel at its onset. This

accounts for the slow rate of rise of the action potential in these cells. The
slow diastolic depolarization that occurs in these pacemaker-type cells is
primarily a result of an inward current ( I funny) flowing through a channel
that is an isoform of the family of nonselective cation hyperpolarization-
activated, cyclic nucleotide-gated (HCN) channels. This channel is
activated at the end of the repolarization phase and promotes a slow
sodium, potassium, and calcium influx that gradually depolarizes the cells
during diastole. This slow diastolic depolarization gives the inactivating h
gates of many of the fast sodium channels time to close before threshold is
even reached ( Figure 2–3D). Thus, in a slow-response action potential,
there is no initial period where all the fast sodium channels of a cell are
essentially open at once. The depolarization beyond threshold during the
rising phase of the action potential in these “pacemaker” cells is slow and
caused primarily by the influx of Ca 2 + through slow L-type channels (
Figure 2–3E).

Although cells in certain areas of the heart typically have fast-type
action potentials and cells in other areas normally have slow-type action
potentials, it is important to recognize that all cardiac cells are potentially
capable of having either type of action potential, depending on their
maximum resting membrane potential and how fast they depolarize to the
threshold potential. As we shall see, rapid depolarization to the threshold
potential is usually an event forced on a cell by the occurrence of an action
potential in an adjacent cell. Slow depolarization to threshold occurs when
a cell itself spontaneously and gradually loses its resting polarization,
which normally happens only in the SA or AV node. A chronic moderate
depolarization of the resting membrane (caused, e.g., by moderately high
extracellular K + concentrations of 5–7 mM) can inactivate the fast
channels (by closing the h gates) without inactivating the slow L-type Ca 2
+ channels. Under these conditions, all cardiac cell action potentials will be
of the slow type. Large, sustained depolarizations (as might be caused by
very high extracellular K + concentration such as more than 8 mM),
however, can inactivate both the fast and slow channels and thus make the
cardiac muscle cells completely inexcitable.

Conduction of Cardiac Action Potentials
 Action potentials are initiated at a local site on a cardiac myocyte and

then conducted over the surface of individual cells. This occurs because
active depolarization in any one area of the membrane produces local

currents that pass through the intracellular and extracellular fluids. These
currents passively depolarize immediately adjacent areas of the membrane
to their voltage thresholds to initiate an action potential at this new site.

In the heart, cardiac muscle cells are branching and connected end-to-
end with neighboring cells at structures called intercalated disks. These
disks contain the following: (1) firm mechanical attachments between
adjacent cell membranes by proteins called adherins in structures called
desmosomes and (2) low-resistance electrical connections between
adjacent cells through channels formed by proteins called connexin in
structures called gap junctions. Figure 2–4 shows schematically how these
gap junctions allow action potential propagation from cell to cell.

Cells B, C, and D are shown in the resting phase with more negative
charges inside than outside. Cell A is shown in the plateau phase of an
action potential and has more positive charges inside than outside. Because
of the gap junctions, electrostatic attraction can cause a local current flow
(ion movement) between the depolarized membrane of active cell A and
the polarized membrane of resting cell B, as indicated by the arrows in the
figure. This ion movement depolarizes the membrane of cell B. Once the
local currents from active cell A depolarize the membrane of cell B near
the gap junction to the threshold level, an action potential will be triggered
at that site and will be conducted over cell B. Because cell B branches (a
common morphological characteristic of cardiac muscle fibers), its action
potential will evoke action potentials on cells C and D. This process is
continued through the entire myocardium. Thus, an action potential
initiated at any site in the myocardium will be conducted from cell to cell
throughout the entire heart.

The speed at which an action potential propagates through a region of
cardiac tissue is called the conduction velocity. The conduction velocity
varies considerably in different areas in the heart and is determined by 3
variables. (1) The diameter of the muscle fiber involved. Thus, conduction
over small-diameter cells in the AV node is significantly slower than
conduction over large-diameter cells in the ventricular Purkinje system. (2)
The intensity of the local depolarizing currents, which are in turn directly
determined by the rate of rise of the action potential. Rapid action potential
depolarization favors rapid conduction to the neighboring segment or cell.
(3) The capacitive and/or resistive properties of the cell membranes, gap
junctions, and cytoplasm. Electrical characteristics of gap junctions can be
influenced by external conditions that promote phosphorylation or
dephosphorylation of the connexin proteins.

Details of the overall consequences of the variable cardiac conduction

rates are shown in Figure 2–5. As noted earlier, specific electrical
adaptations of various cells in the heart are reflected in the characteristic
shape of their action potentials that are shown in the right half of Figure 2–
5. Note that the action potentials shown in Figure 2–5 have been
positioned to indicate the time when the electrical impulse that originates
in the SA node reaches other areas of the heart. Cells of the SA node act as
the heart’s normal pacemaker and determine the heart rate. This is because
the slow spontaneous diastolic depolarization of the membrane is normally
most rapid in SA nodal cells, and therefore, the cells in this region reach
their threshold potential and fire before cells elsewhere.

Figure 2–4. Local currents and cell-to-cell conduction of cardiac muscle cell action potentials.

Figure 2–5. Time records of electrical activity at different sites in the heart wall: single-cell voltage
recordings (traces A to G) and lead II electrocardiogram.

 The action potential initiated by an SA nodal cell first spreads
progressively throughout the branching and interconnected cardiac muscle
cells of the atrial wall. Action potentials from cells in 2 different regions of
the atria are shown in Figure 2–5: one close to the SA node and one more
distant from the SA node. Both cells have similarly shaped fast response-
type action potentials, but their temporal displacement reflects the fact that
it takes some time for the impulse to spread over the atria. As shown in
Figure 2–5, action potential conduction is greatly slowed as it passes
through the AV node. This is because of the small size of the AV nodal
cells and the slow rate of rise of their action potentials. Since the AV node
delays the transfer of the cardiac excitation from the atria to the ventricles,
atrial contraction can contribute to ventricular filling before the ventricles
begin to contract. Note also that AV nodal cells have a faster spontaneous
depolarization during the diastolic period than other cells of the heart
except those of the SA node. For this reason, the AV node is sometimes
referred to as a latent pacemaker, and in many pathological situations, it
(rather than the SA node) controls the heart rhythm. This situation is
referred to as a “nodal” rhythm as distinguished from the normal “sinus”

Because of sharply rising action potentials and other factors, such as
large cell diameters, electrical conduction is extremely rapid in Purkinje
fibers. This allows the Purkinje system to transfer the cardiac impulse to
cells in many areas of the ventricle nearly in unison. Action potentials
from muscle cells in 2 areas of the ventricle are shown in Figure 2–5.
Because of the high conduction velocity in ventricular tissue, there is only
a small discrepancy in their time of onset. Note in Figure 2–5 the
ventricular cells that are the last to depolarize have shorter-duration action
potentials and thus are the first to repolarize. The physiological importance
of this behavior is not clear, but it does have an influence on the
electrocardiograms discussed in Chapter 4.

Electrocardiogram (ECG aka EKG)
Fields of electrical potential caused by the electrical activity of the heart
extend through the extracellular fluid of the body and can be measured
with electrodes placed on the body surface. Electrocardiography provides
a record of how the voltage between 2 points on the body surface changes

with time as a result of the electrical events of the cardiac cycle. At any
instant of the cardiac cycle, the electrocardiogram indicates the net
electrical field that is the summation of many weak electrical fields being
produced by voltage changes occurring on individual cardiac cells at that
instant. When a large number of cells are simultaneously depolarizing or
repolarizing, large voltages are observed on the electrocardiogram.
Because the electrical impulse spreads through the heart tissue in a
consistent pathway, the temporal pattern of voltage change recorded
between 2 points on the body surface is also consistent and repeats itself
with each heart cycle.

The lower trace of Figure 2–5 represents a typical recording of the
voltage changes normally measured between the right arm and the left leg
as the heart goes through 2 cycles of electrical excitation; this record is
called a lead II electrocardiogram and is discussed in detail in Chapter 4.
The major features of an electrocardiogram are indicated on this record
and include the P wave, the PR interval, the QRS complex, the QT interval,
the ST segment, and the T wave. The P wave corresponds to atrial
depolarization; the PR interval to the conduction time through the atria and
AV node; the QRS complex to ventricular depolarization; the ST segment
to the plateau phase of ventricular action potentials; the QT interval to the
total duration of ventricular systole; and the T wave to ventricular
repolarization. (See Chapters 4 and 5 for further information about

Control of Heart Beating Rate
Normal rhythmic contractions of the heart occur because of spontaneous
electrical pacemaker activity (automaticity) of cells in the SA node. The
interval between heartbeats (and thus the heart rate) is determined by how
long it takes the membranes of these pacemaker cells to spontaneously
depolarize during the diastolic interval to the threshold level. The SA
nodal cells fire at a spontaneous or intrinsic rate (≈100 beats/min) in the
absence of any outside influences. Outside influences are required,
however, to increase or decrease automaticity from its intrinsic level.

Figure 2–6. The effect of sympathetic and parasympathetic activity on cardiac pacemaker

 The 2 most important outside influences on automaticity of SA nodal
cells come from the autonomic nervous system. Fibers from both the
sympathetic and parasympathetic divisions of the autonomic system
terminate on cells in the SA node, and these fibers can modify the intrinsic
heart rate. Activating the cardiac sympathetic nerves (increasing cardiac
sympathetic tone) increases the heart rate. Increasing the cardiac
parasympathetic tone slows the heart rate. As shown in Figure 2–6, both
the parasympathetic and sympathetic nerves influence the heart rate by
altering the course of spontaneous diastolic depolarization of the resting
potential in SA pacemaker cells.

Cardiac parasympathetic fibers, which travel to the heart through the
vagus nerves, release the transmitter substance acetylcholine on SA nodal
cells. Acetylcholine increases the permeability of the resting membrane to
K + and decreases the diastolic i f current flowing through the HCN
channels. 8 As indicated in Figure 2–6, these changes have 2 effects on the
resting potential of cardiac pacemaker cells: (1) they cause an initial

hyperpolarization of the resting membrane potential by bringing it closer
to the K + equilibrium potential and (2) they slow the rate of spontaneous
depolarization of the resting membrane. Both of these effects increase the
time between beats by prolonging the time required for the resting
membrane to depolarize to the threshold level. Because there is normally
some continuous tonic activity of cardiac parasympathetic nerves, the
normal resting heart rate is approximately 70 beats/min which is
significantly slower than the intrinsic rate of ~100 beats/min.

Sympathetic nerves release the transmitter substance norepinephrine
on cardiac cells. In addition to other effects discussed later, norepinephrine
acts on SA nodal cells to increase the inward currents ( i f) carried by Na +

and by Ca 2 + through the HCN channels during the diastolic interval. 9
These changes will increase the heart rate by increasing the rate of
diastolic depolarization as shown in Figure 2–6.

In addition to sympathetic and parasympathetic nerves, there are many
(albeit usually less important) factors that can alter the heart rate. These
include a number of ions, circulating hormones, and various drugs as well
as physical influences such as body temperature and atrial wall stretch. All
act by altering the time required for the resting membrane to depolarize to
the threshold potential. An abnormally high concentration of Ca 2 + in the
extracellular fluid, for example, tends to decrease the heart rate by shifting
the threshold potential. Factors that increase the heart rate are said to have
a positive chronotropic effect. Those that decrease the heart rate have a
negative chronotropic effect.

Besides their effect on the heart rate, autonomic fibers also influence
the conduction velocity of action potentials through the heart. Increases in
sympathetic activity increase conduction velocity (have a positive
dromotropic effect), whereas increases in parasympathetic activity
decrease conduction velocity (have a negative dromotropic effect). These
dromotropic effects are primarily a result of autonomic influences on the
initial rate of depolarization of the action potential and/or influences on
conduction characteristics of gap junctions between cardiac cells. These
effects are most notable at the AV node and influence the duration of the
PR interval of the ECG.

Contraction of the cardiac muscle cell is initiated by a membrane action
potential acting on intracellular organelles to evoke tension generation

and/or shortening of the cell. In this section, we describe (1) the
subcellular processes involved in coupling the excitation to the contraction
of the cell (EC coupling) and (2) the mechanical properties of cardiac

 Cardiac Muscle Cell Contractile Apparatus
Basic histological features of cardiac muscle cells are quite similar to those
of skeletal muscle cells. These shared features include:

(1)    An extensive myofibrillar structure made up of parallel
interdigitating thick and thin filaments arranged in serial units called
sarcomeres, which are responsible for the mechanical processes of
shortening and tension development. Proteins making up the thick and
thin filaments are collectively referred to as “contractile proteins.”

The thick filament consists of a protein called myosin, which has a
long straight tail with 2 globular heads each of which contains an
ATP-binding site and an actin-binding site; light chains are loosely
associated with the myosin heads and their phosphorylation may
regulate (or modulate) actin binding.

The thin filament consists of several proteins including actin—2 α-
helical strands of polymerized subunits (g-actin) extending from the Z
lines. Sites along the actin filament interact with the heads of myosin
molecules to make deformable cross-bridges with the thick filaments.
Thin filaments also contain tropomyosin—a regulatory fibrous-type
protein lying in the groove of the actin α-helix, which prevents actin
from interacting with myosin when the muscle is at rest; and troponin
—a regulatory protein consisting of 3 subunits ( troponin C, which
binds calcium ions during activation and initiates the configurational
changes in the regulatory proteins that expose the actin site for cross-
bridge formation; troponin T, which anchors the troponin complex to
tropomyosin; and troponin I, which participates in the inhibition of
actin–myosin interaction at rest).

The giant macromolecule, titin, extends from the Z disk to the M
line in the middle of each sarcomere and provides a continuous
filament network in the sarcomeres extending the length of the cell. It
contributes significantly to the passive stiffness of cardiac muscle
over its normal working range. Phosphorylation of titin can alter the
passive elastic properties of cardiac muscle.

(2)    A complex internal compartmentation of the myocyte cytoplasm by
an intracellular membrane system called the sarcoplasmic reticulum
(SR). This compartment actively sequesters calcium during the resting
phase with the help of the sarco/endoplasmic reticulum Ca 2 +-
ATPase (SERCA) and calcium-binding storage proteins within the
SR, the most abundant of which is calsequestrin.

(3)    Regularly spaced, extensive invaginations of the cell membrane
(sarcolemma), called T tubules. These structures carry the action
potential signal to the inner parts of the cell and appear to be
connected to parts of the SR (“junctional” SR) by dense strands

There are some morphological features that are unique to cardiac
muscle cells. The most obvious of these is the large number of
mitochondria in the cytoplasm that provide the oxidative phosphorylation
pathways needed to ensure a ready supply of adenosine triphosphate
(ATP) to meet the very high metabolic needs of the cardiac muscle.
Students are encouraged to consult current histological references for
specific cellular morphological details.

Figure 2–7. Excitation–contraction coupling, sarcomere shortening, and relaxation.

Excitation–Contraction Coupling
 Muscle action potentials trigger mechanical contraction through a

process called excitation–contraction coupling, which is illustrated in
Figure 2–7. The major event of excitation–contraction coupling is a
dramatic rise in the intracellular free Ca 2 + concentration. The “resting”
intracellular free Ca 2 + concentration is less than 0.1 μM. In contrast,
during maximum activation of the contractile apparatus, the intracellular
free Ca 2 + concentration may reach nearly 1.0 μM. When the wave of
depolarization passes over the muscle cell membrane and down the T
tubules, Ca 2 + is released from the SR into the intracellular fluid.

As indicated on the left side of Figure 2–7, the specific trigger for this
release appears to be the entry of calcium into the cell via the L-type
calcium channels in the t-tubules and an increase in Ca 2 + concentration
just under the sarcolemma of the t-tubular system. Unlike the skeletal
muscle, this highly localized increase in calcium is essential for triggering

the major release of calcium from the SR. This calcium-induced calcium
release is a result of opening calcium-sensitive release channels (RyR2) on
the junctional SR. 10 Although the amount of Ca 2 + that enters the cell
during a single action potential is quite small compared with that released
from the SR, it is essential not only for triggering the SR calcium release
but also for maintaining adequate levels of Ca 2 + in the intracellular stores
over the long run.

When the intracellular free Ca 2 + concentration is high (>1.0 μM),
links called cross-bridges form between the thick and thin filaments found
within the muscle. Sarcomere units, as depicted in the lower part of Figure
2–7, are joined end-to-end at Z lines to form myofibrils, which run the
length of the muscle cell. During contraction, thick and thin filaments slide
past one another to shorten each sarcomere and thus the muscle as a whole.
The cross-bridges form when the regularly spaced myosin heads from
thick filaments attach to regularly spaced sites on the actin molecules in
the thin filaments. Subsequent deformation of the bridges pulls actin
molecules toward the center of the sarcomere resulting in sarcomere (and
muscle) shortening. This actin–myosin interaction requires energy from
ATP. In resting muscles, the attachment of myosin to the actin sites is
inhibited by troponin and tropomyosin. Calcium causes muscle contraction
by interacting with troponin C to cause a configurational change that
removes the inhibition of the actin sites on the thin filament. Because a
single cross-bridge is a very short structure, gross muscle shortening and
tension development requires that cross-bridges repetitively form, produce
incremental movement between the myofilaments, detach, and form again
at a new actin site, and so on in a cyclic manner.

There are several processes that participate in the reduction of
intracellular Ca 2 + that terminates the contraction. These processes are
illustrated on the right side of Figure 2–7. Approximately 80% of this
transient calcium increase is actively taken back up into the SR by the
action of sarco/endoplasmic reticular calcium ATPase (SERCA) pumps
located in the longitudinal part of the SR. 11 About 20% of the calcium is
extruded from the cell into the extracellular fluid either via the Na +–Ca 2 +
exchanger located in the sarcolemma 12 or via sarcolemmal Ca 2 +-ATPase

Excitation–contraction coupling in the cardiac muscle differs from that
in the skeletal muscle in that it may be modulated, th