CARDIAC ELECTROPHYSIOLOGY

Medical Physiology – MD 2
ALL SAINTS UNIVERSITY SCHOOL OF MEDICINE
DR. MARIE AFFANA
 Introduction
Cardiac electrophysiology includes all of the processes involved in the electrical activation of the
heart:
- Cardiac action potentials
- Conduction of action potentials along specialized conducting tissues
- Excitability and refractory periods;
- Modulating effects of the autonomic nervous system on heart rate, conduction velocity, and
excitability; and the electrocardiogram (ECG).

Ultimately, the function of the heart is to pump blood through the vasculature. To serve as a
pump, the ventricles must be electrically activated and then contract. In cardiac muscle, electrical
activation is the cardiac action potential, which normally originates in the sinoatrial (SA) node.
The action potentials initiated in the SA node then are conducted to the entire myocardium in a
specific, timed sequence. Contraction follows, also in a specific sequence. “Sequence” is
especially critical because the atria must be activated and contract before the ventricles, and the
ventricles must contract from apex to base for efficient ejection of blood.
Origin and Spread of Excitation within the Heart
The heart consists of two kinds of muscle cells: contractile
cells and conducting cells.

• Contractile cells constitute the majority of atrial and

ventricular tissues and are the working cells of the heart.
Action potentials in contractile cells lead to contraction
and generation of force or pressure.

• Conducting cells constitute the tissues of the SA node, the

atrial internodal tracts, the AV node, the bundle of His,
and the Purkinje system. Conducting cells are specialized
muscle cells that do not contribute significantly to
generation of force; instead, they function to rapidly
spread action potentials over the entire myocardium.
Another feature of the specialized conducting tissues is
their capacity to generate action potentials spontaneously.
Schematic diagram showing the sequence of activation of the myocardium

1. SA node. Normally, the action

potential of the heart is initiated in the
specialized tissue of the SA node, which
serves as the pacemaker. After the
action potential is initiated in the SA
node, there is a specific sequence and
timing for the conduction of action
potentials to the rest of the heart.

2. Atrial internodal tracts and

atria. The action potential spreads from
the SA node to the right and left atria
via the atrial internodal tracts.
Simultaneously, the action potential is
conducted to the AV node.
 Schematic diagram showing the sequence of activation of the myocardium

3. AV node. Conduction velocity

through the AV node is considerably
slower than in the other cardiac
tissues. Slow conduction through the
AV node ensures that the ventricles
have sufficient time to fill with blood
before they are activated and
contract. Increases in conduction
velocity of the AV node can lead to
decreased ventricular filling and
decreased stroke volume and cardiac
output.
Schematic diagram showing the sequence of activation of the myocardium

4. Bundle of His, Purkinje system, and

ventricles. From the AV node, the action
potential enters the specialized conducting
system of the ventricles. The action potential is
first conducted to the bundle of His through the
common bundle. It then invades the left and
right bundle branches and then the smaller
bundles of the Purkinje system. Conduction
through the His-Purkinje system is extremely
fast, and it rapidly distributes the action
potential to the ventricles. The action potential
also spreads from one ventricular muscle cell to
the next, via low-resistance pathways between
the cells. Rapid conduction of the action
potential throughout the ventricles is essential
and allows for efficient contraction and ejection
of blood.
 Schematic diagram showing the sequence of activation of the myocardium

The term normal sinus rhythm has a

specific meaning. It means that the
pattern and timing of the electrical
activation of the heart are normal. To
qualify as normal sinus rhythm, the
following three criteria must be met:

• (1) The action potential must originate

in the SA node.
• (2) The SA nodal impulses must occur
regularly at a rate of 60 to 100
impulses per minute.
• (3) The activation of the myocardium
must occur in the correct sequence
and with the correct timing and delays.
Comparison of Action Potentials in Cardiac Tissues
Cardiac action potentials in the ventricle, atrium, and sinoatrial node. A–C
Action potential in the Ventricular tissue
Action potential in the Ventricular tissue
 Action potential in the Ventricular tissue
Phase 0, upstroke: This is a phase of rapid
depolarization caused by a transient increase in
Na+ conductance (gNa), produced by depolarization-
induced opening of activation gates on the
Na+ channels. When gNa increases, there is an inward
Na+ current (influx of Na+ into the cell), or INa, which
drives the membrane potential toward the
Na+ equilibrium potential of approximately +65 mV.

The membrane potential does not quite reach the

Na+ equilibrium potential because, as in nerve, the
inactivation gates on the Na+ channels close in
response to depolarization (albeit more slowly than the
activation gates open). Thus, the Na+ channels open
briefly and then close. At the peak of the upstroke, the
membrane potential is depolarized to a value of about
+20 mV.
 Action potential in the Ventricular tissue
Phase 1, initial repolarization: Phase 1 in ventricular, atrial,
and Purkinje fibers is a brief period of repolarization, which
immediately follows the upstroke. Recall that, for
repolarization to occur, there must be a net outward
current. There are two explanations for the occurrence of
the net outward current during phase

1. First, the inactivation gates on the Na+ channels close in

response to depolarization. When these gates close,
gNa decreases and the inward Na+ current (which
caused the upstroke) ceases.
2. There is an outward K+ current, caused by the large
driving force on K+ ions: At the peak of the
upstroke, both the chemical and the electrical driving
forces favor K+ movement out of the cell (the
intracellular K+ concentration is higher than extracellular
K+ concentration, and the cell interior is electrically
positive). Because the K+ conductance (gK) is high,
K+ flows out of the cell, down this steep electrochemical
gradient.
 Action potential in the Ventricular tissue
Phase 2, plateau: During the plateau, there is a long period (150 to
200 msec) of relatively stable, depolarized membrane
potential, particularly in ventricular and Purkinje fibers. (In atrial
fibers, the plateau is shorter than in ventricular fibers.)

There is an increase in Ca2+ conductance (gCa), which results in

an inward Ca2+ current. Inward Ca2+ current is also called slow
inward current, reflecting the slower kinetics of these channels
(compared with the fast Na+ channels of the upstroke).

The Ca2+ channels that open during the plateau are L-type
channels and are inhibited by the Ca2+ channel blockers nifedipine,
diltiazem, and verapamil.

To balance the inward Ca2+ current, there is an outward

K+ current, driven by the electrochemical driving force on K+ ions
(as described for phase 1). Thus, during the plateau, the inward
Ca2+ current is balanced by the outward K+ current, the net current
is zero, and the membrane potential remains at a stable
depolarized value.
 Action potential in the Ventricular tissue
The significance of the inward
Ca2+ current extends beyond its effect
on membrane potential. This
Ca2+ entry during the plateau of the
action potential initiates the release
of more Ca2+ from intracellular stores
for excitation-contraction coupling.
This process of so-called Ca2+-induced
Ca2+release is discussed in the section
on cardiac muscle contraction.
 Action potential in the Ventricular tissue
Phase 3, repolarization: begins gradually at the
end of phase 2, and then there is rapid
repolarization to the resting membrane potential
during phase 3.

During phase 3, repolarization results from a

combination of a decrease in gCa (previously
increased during the plateau) and an increase in
gK (to even higher levels than at rest).

At the end of phase 3, the outward K+ current is

reduced because repolarization brings the
membrane potential closer to the K+ equilibrium
potential, thus decreasing the driving force on K+.
 Action potential in the Ventricular tissue
Phase 4, resting membrane potential, or
electrical diastole: The membrane potential fully
repolarizes during phase 3 and returns to the
resting level of approximately −85 mV. During
phase 4, the membrane potential is stable again,
and inward and outward currents are equal.

The resting membrane potential approaches, but

does not fully reach, the K+ equilibrium potential,
reflecting the high resting conductance to K+. The
K+ channels, and the resulting K+ current,
responsible for phase 4 are different from those
responsible for repolarization in phase 3. In
phase 4, the K+ conductance is called gK1 and
the K+ current is called, accordingly, IK1.
RECAP
Action potential in the Conducting tissue
Action potential in the Conducting tissue
The following features of the action potential
of the SA node are different from those in
atria, ventricles, and Purkinje fibers:

(1)The SA node exhibits automaticity; that is,

it can spontaneously generate action
potentials without neural input.
(2)It has an unstable resting membrane
potential, in direct contrast to cells in
atrial, ventricular, and Purkinje fibers.
(3)It has no sustained plateau.
 Action potential in the Conducting tissue
Phase 0, upstroke: Phase 0 (as in the other cardiac
cells) is the upstroke of the action potential. Note that
the upstroke is not as rapid or as steep as in the
other types of cardiac tissues.

The ionic basis for the upstroke in the SA node differs

as well: In the other myocardial cells, the upstroke is
the result of an increase in gNa and an inward
Na+ current.

In the SA nodal cells, the upstroke is the result of

an increase in gCa and an inward Ca2+ current carried
primarily by L-type Ca2+ channels.

There are also T-type Ca2+ channels in SA node, which

carry part of the inward Ca2+ current of the upstroke.
 Action potential in the Conducting tissue
Phase 3, repolarization: As in the
other myocardial tissues,
repolarization in the SA node is due to
an increase in gK. Because the
electrochemical driving forces on
K+ are large (both chemical and
electrical driving forces favor K+ leaving
the cell), there is an outward
K+ current, which repolarizes the
membrane potential.
 Action potential in the Conducting tissue
Phase 4, spontaneous depolarization or
pacemaker potential. Phase 4 is the longest
portion of the SA node action potential. This
phase accounts for the automaticity of SA nodal
cells (the ability to spontaneously generate
action potentials without neural input).

During phase 4, the most negative value of the

membrane potential (called the maximum
diastolic potential) is approximately −65 mV, but
the membrane potential does not remain at this
value. Rather, there is a slow depolarization,
produced by the opening of Na+ channels and
an inward Na+ current called If.
 Action potential in the Conducting tissue
The “f,” which stands for funny, denotes that
this Na+ current differs from the fast
Na+ current responsible for the upstroke in
ventricular cells.

If is turned on by repolarization from the

preceding action potential, thus ensuring
that each action potential in the SA node will
be followed by another action potential.

Once If and slow depolarization bring the

membrane potential to threshold, the T-type
Ca2+ channels are opened for the upstroke.
 Action potential in the Conducting tissue
The rate of phase 4 depolarization
sets the heart rate. If the rate of phase
4 depolarization increases, threshold is
reached more quickly, the SA node will
fire more action potentials per time,
and heart rate will increase.
Conversely, if the rate of phase 4
depolarization decreases, threshold is
reached more slowly, the SA node will
fire fewer action potentials per time,
and heart rate will decrease.
RECAP
 Latent Pacemakers
The cells in the SA node are not the only myocardial cells with intrinsic automaticity;
other cells, called latent pacemakers, also have the capacity for spontaneous phase 4
depolarization. Latent pacemakers include the cells of the AV node, bundle of His, and
Purkinje fibers. Although each of these cells has the potential for automaticity, it
normally is not expressed.

The rule is that the pacemaker with the fastest rate of phase 4 depolarization controls
the heart rate. Normally, the SA node has the fastest rate of phase 4 depolarization,
and therefore, it sets the heart rate.

Additionally, of all myocardial cells, the SA nodal cells have the shortest action potential
duration (i.e., the shortest refractory periods). Therefore, SA nodal cells recover faster
and are ready to fire another action potential before the other cell types are ready.
Firing Rate of Sinoatrial Node and Latent Pacemakers in the Heart
 Conduction Velocity
• It is the speed at which action
potentials are propagated
within the tissue.
• The units for conduction
velocity are meters per second
(m/sec).
• Conduction velocity is not the
same in all myocardial tissues:
It is slowest in the AV node
(0.01 to 0.05 m/sec) and
fastest in the Purkinje fibers (2
to 4 m/sec)
 Mechanism of Propagation of Cardiac Action Potential
Action potentials at one site generate local currents at adjacent sites; the adjacent
sites are depolarized to threshold as a result of this local current flow and fire action
potentials themselves. This local current flow is the result of the inward current of the
upstroke of the action potential.

Conduction velocity depends on:

- The size of the inward current during the upstroke of the action potential. The
larger the inward current, the more rapidly local currents will spread to adjacent
sites and depolarize them to threshold.

- The cable properties of the myocardial fibers. These cable properties are
determined by cell membrane resistance (Rm) and internal resistance (Ri). For
example, in myocardial tissue, Ri is particularly low because of low-resistance
connections between the cells called gap junctions. Thus, myocardial tissue is
especially well suited to fast conduction.
 Excitability and Refractory Periods

Excitability is the capacity of

myocardial cells to generate action
potentials in response to inward,
depolarizing current.

Strictly speaking, excitability is the

amount of inward current required to
bring a myocardial cell to the threshold
potential.

The excitability of a myocardial cell

varies over the course of the action
potential, and these changes in
excitability are reflected in the
refractory periods.
 Excitability and Refractory Periods
Absolute refractory period: For most of
the duration of the action potential, the
ventricular cell is completely refractory to
fire another action potential. No matter
how large a stimulus (i.e., inward current)
might be applied, the cell is incapable of
generating a second action potential
during the absolute refractory period
(ARP), because most of the Na+ channels
are closed.

The absolute refractory period includes the

upstroke, the entire plateau, and a
portion of the repolarization. This period
concludes when the cell has repolarized to
approximately −50 mV.
 Excitability and Refractory Periods
Effective refractory period: The effective
refractory period (ERP) includes, and is
slightly longer than, the absolute refractory
period.

At the end of the effective refractory period,

the Na+ channels start to recover (i.e.,
become available to carry inward current).

The distinction between the absolute and

effective refractory periods is that absolute
means absolutely no stimulus is large
enough to generate another action
potential; effective means that a conducted
action potential cannot be generated (i.e.,
there is not enough inward current to
conduct to the next site).
 Excitability and Refractory Periods
Relative refractory period: The relative
refractory period (RRP) begins at the end
of the absolute refractory period and
continues until the cell membrane has
almost fully repolarized.

During the relative refractory period, even

more Na+ channels have recovered and it is
possible to generate a second action
potential, although a greater-than-normal
stimulus is required.

If a second action potential is generated

during the relative refractory period, it will
have an abnormal configuration and a
shortened plateau phase.
 Excitability and Refractory Periods
Supranormal period: The supranormal period
(SNP) follows the relative refractory period. It
begins when the membrane potential is −70 mV
and continues until the membrane is fully
repolarized back to −85 mV.

As the name suggests, the cell is more excitable

than normal during this period. In other words,
less inward current is required to depolarize the
cell to the threshold potential.

The physiologic explanation for this increased

excitability is that the Na+ channels are
recovered (i.e., the inactivation gates are open
again), and because the membrane potential is
closer to threshold than it is at rest, it is easier
to fire an action potential than when the cell
membrane is at the resting membrane
potential.
 Autonomic Effects on the Heart and Blood Vessels

AV, Atrioventricular; EDRF, endothelial-derived relaxing factor; M, muscarinic.

Effect of sympathetic and
parasympathetic stimulation on the SA
node action potential

A. The normal firing pattern of the SA

node is shown.
B. Sympathetic stimulation increases the
rate of phase 4 depolarization and
increases the frequency of action
potentials.
C. Parasympathetic stimulation
decreases the rate of phase 4
depolarization and hyperpolarizes the
maximum diastolic potential to decrease
the frequency of action potentials.
 Effect of sympathetic and parasympathetic stimulation on the SA node
action potential
Positive chronotropic effects are increases in heart rate.
The most important example is that of stimulation of the sympathetic nervous system.

Norepinephrine, released from sympathetic nerve fibers, activates β1 receptors in the SA

node. These β1 receptors are coupled to adenylyl cyclase through a Gs protein. Activation
of β1 receptors in the SA node produces an increase in If, which increases the rate of phase
4 depolarization.

In addition, there is an increase in ICa, which means there are more functional
Ca2+ channels and thus less depolarization is required to reach threshold (i.e., threshold
potential decreases).

Increasing the rate of phase 4 depolarization and decreasing the threshold potential
means that the SA node is depolarized to threshold potential more frequently and, as a
consequence, fires more action potentials per unit time (i.e., increased heart rate).
 Effect of sympathetic and parasympathetic stimulation on the SA node
action potential
Negative chronotropic effects are decreases in heart rate. The most important example is
that of stimulation of the parasympathetic nervous system. Acetylcholine (ACh), released
from parasympathetic nerve fibers, activates muscarinic (M2) receptors in the SA node.
Activation of muscarinic receptors in the SA node has two effects that combine to produce a
decrease in heart rate.

First, these muscarinic receptors are coupled to a type of Gi protein called GK that inhibits
adenylyl cyclase and produces a decrease in If. A decrease in If decreases the rate of phase
4 depolarization. Second, Gk directly increases the conductance of a K+ channel called K+-
ACh and increases an outward K+ current (similar to IK1) called IK-ACh.

Enhancing this outward K+ current hyperpolarizes the maximum diastolic potential so that
the SA nodal cells are further from threshold potential. In addition, there is a decrease in
ICa, which means there are fewer functional Ca2+ channels and thus more depolarization is
required to reach threshold (i.e., threshold potential increases).
 Effect of sympathetic and parasympathetic stimulation on the SA node
action potential
In sum, the parasympathetic nervous system decreases heart
rate through three effects on the SA node:
(1)slowing the rate of phase 4 depolarization,
(2)hyperpolarizing the maximum diastolic potential so that
more inward current is required to reach threshold
potential
(3)Increasing the threshold potential. As a result, the SA
node is depolarized to threshold less frequently and fires
fewer action potentials per unit time (i.e., decreased heart
rate)
 Clinical Physiology: Sinus Bradycardia
DESCRIPTION OF CASE. A 72-year-old woman with hypertension is being treated with propranolol, a β-
adrenergic blocking agent. She has experienced several episodes of light-headedness and syncope (fainting).
An ECG shows sinus bradycardia: normal, regular P waves, followed by normal QRS complexes; however, the
frequency of P waves is decreased, at 45/min. The physician tapers off and eventually discontinues the
propranolol and then changes the woman’s medication to a different class of antihypertensive drugs. Upon
discontinuation of propranolol, a repeat ECG shows a normal sinus rhythm with a frequency of P waves of
80/min.

EXPLANATION OF CASE. The heart rate is given by the frequency of P waves. During treatment with
propranolol, her heart rate was only 45 beats/min. The presence of P waves on the ECG indicates that the
heart is being activated in the SA node, which is the normal pacemaker. However, the frequency of
depolarization of the SA node is much lower than normal because she is being treated with propranolol, a β-
adrenergic blocking agent. Recall that β-adrenergic agonists increase the rate of phase 4 depolarization in the
SA node by increasing If. β-Adrenergic antagonists, therefore, will decrease phase 4 depolarization and
decrease the frequency at which the SA nodal cells fire action potentials.

TREATMENT. The woman’s sinus bradycardia was an adverse effect of propranolol therapy. When propranolol
was discontinued, her heart rate returned to normal.
 Autonomic Effects on Conduction Velocity in the Atrioventricular Node
The effects of the autonomic nervous system on conduction velocity are called dromotropic effects.

The most important physiologic effects of the autonomic nervous system on conduction velocity are those on the AV node,
which, in effect, alter the rate at which action potentials are conducted from the atria to the ventricles.

Stimulation of the sympathetic nervous system produces an increase in conduction velocity through the AV node
(positive dromotropic effect), which increases the rate at which action potentials are conducted from the atria to the
ventricles. The mechanism of the sympathetic effect is increased ICa, which is responsible for the upstroke of the action
potential in the AV node (as it is in the SA node). Thus, increased ICa means increased inward current and increased
conduction velocity. In a supportive role, the increased ICa shortens the ERP so that the AV nodal cells recover earlier from
inactivation and can conduct the increased firing rate.

Stimulation of the parasympathetic nervous system produces a decrease in conduction velocity through the AV node
(negative dromotropic effect), which decreases the rate at which action potentials are conducted from the atria to the
ventricles. The mechanism of the parasympathetic effect is a combination of decreased ICa (decreased inward current)
and increased IK-ACh (increased outward K+ current, which further reduces net inward current). Additionally, the ERP of AV
nodal cells is prolonged. If conduction velocity through the AV node is slowed sufficiently (e.g., by increased
parasympathetic activity or by damage to the AV node), some action potentials may not be conducted at all from the atria
to the ventricles, producing heart block. The degree of heart block may vary: In the milder forms, conduction of action
potentials from atria to ventricles is simply slowed; in more severe cases, action potentials may not be conducted to the
ventricles at all.