1 Introduction to Cardiac Arrhythmias. Electrophysiology of Heart, Action Potential and Membrane ...

36 Pages·2016·1.5 MB·English

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Introduction to Cardiac Arrhythmias. Electrophysiology of Heart,
Action Potential and Membrane Currents

Norbert Jost, PhD

Department of Pharmacology & Pharmacotherapy, Faculty of Medicine,
University of Szeged, Hungary

Correspondence:
Norbert Jost, PhD
Department of Pharmacology & Pharmacotherapy, Faculty of Medicine,
University of Szeged
Dóm tér 12, P.O. Box 427, H-6701 Szeged, Hungary
Tel.: [phone], Fax: [phone]
E-mail: [email protected]

@All rights reserved to Dr. Norbert Jost, associate professor
Department of Pharmacology & Pharmacotherapy, Faculty of
Medicine, University of Szeged, Hungary
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Keywords: cardiac membrane potential, action potential,
electrophysiology, transmembrane ion channels,

List of abbreviations:

AF = atrial fibrillation
APD = action potential duration
AVN = atrioventricular node
cAMP= cyclic adenosine monophosphate
E , E = equilibrium potential for K+ or Na+, respectively
K Na
E = resting membrane potential
M
HVA and LVA = high and low voltage-activated calcium channels,
respectively
I = L-type calcium current
CaL
I = acetylcholine sensitive potassium current
K(ACh)
I = ATP sensitive potassium current
KATP
I = delayed rectifier potassium current;
K
I = rapid component of the delayed rectifier potassium current;
Kr
I = slow component of the delayed rectifier potassium current;
Ks
I = inward rectifier potassium current
K1
I = ultra-rapid component of the delayed rectifier potassium current;
Kur
I = Na+/Ca2+ exchanger current
NCX
I = transient outward potassium current;
to
I = fast sodium current
Na
I = late sodium current
NaL
KV = voltage gated K+ channels
LQT3 = long QT3 syndrome
mRNA= messenger RNA
NaV = voltage gated Na+ channels
Na/K pump= sodium-potassium pump
NCX= sodium-calcium exchanger current
SAN = sinoatrial node
V = membrane potential
m
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Table of contents

Abstract
1. Introduction
2. Cell membrane potentials. Electrical activity in the heart: conduction
system and cardiac action potential
2.1. Equilibrium potentials
2.2. Cardiac conduction system
2.3. The cardiac action potential
3. Transmembrane ion channels in the heart
3.1. Voltage-gated Na+ (NaV) currents
3.2. Voltage-gated Ca2+ (CaV) currents
3.3. Voltage gated K+ (KV) channels
3.3.1. Transient outward KV currents (I )
to
3.3.2. Delayed rectifier KV currents (I )
K
3.3.3. Inward rectifier potassium currents (I )
K1
3.3.3. ATP sensitive potassium currents (I )
KATP
3.3.5. Background potassium channels
3.4. Summary
4. Concluding remarks
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Abstract

Myocytes represent the functional unit of cardiac muscle;
nonetheless, the heart behaves more or less like an electrical syncytium,
whose global activity depends on low resistance coupling between the
myocytes. The term “more or less” is used here intentionally to imply
that, while the activity intrinsic to individual myocytes is affected by
coupling, its features remain recognizable within the context of the whole
heart and are important to determine its function. Electrical changes
within the myocytes plays an important role to initiate the cardiac
contraction. This chapter addresses (a) the electrical activity of individual
myocytes, namely the resting membrane potentials and action potentials;
(b) the way action potentials are conducted throughout the heart to initiate
coordinated contraction of the entire heart; and (c) the transmembrane
ionic currents underlying cardiac action potential.

1. Introduction

The heartbeat arises from organized flow of ionic currents through ion-
specific channels in the cell membrane, through the myoplasm and gap
junctions that connect cells, and through the extracellular space. The
action potential formation results from the opening and closing (gating
mechanism) of several inward and outward ion channels, which are
largely expressed within the sarcolemma of cardiomyocytes. Ion channels
possess distinct genetic, molecular, pharmacologic, and gating properties,
while exhibit heterogeneous expression levels within different cardiac
regions. By gating, ion channels permit ion currents across the
sarcolemma, thereby creating the different repetitive phases of the action
potential, which will be discussed later in detail (e.g., resting phase 
depolarization  repolarization circles). The importance of ion channels
in maintaining normal heart rhythm is reflected by the increased
incidence of arrhythmias in inherited diseases that are associated to
several mutations in genes encoding cardiac ion channels or
pumps/exchangers or their accessory proteins and in acquired diseases
that are associated with changes in ion channel expression levels or gating
properties (e.g., different forms of electrical, structural or contractile
remodelling linked to congestive heart failure, dilated cardiomyopathy,
permanent forms of atrial fibrillation, etc.). To understand the functioning
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of the transmembrane ion currents and their contribution to the cardiac
action potential, it is important to understand the biophysics of the
biological cell membranes, including the ion transports, membrane and
Nernst potentials as well.

2. Cell membrane potentials. Electrical activity in the heart:
conduction system and cardiac action potential

Cardiac cells, similar with the majority of the living cells from the
body, have an electrical potential across the cell membrane. This potential
can be investigated by inserting a microelectrode into the cell and to
determine the electrical potential in millivolts (mV) inside the cell relative
to the outside of the cell. By convention, the outside of the cell is
considered 0 mV. If measurements are taken with a resting ventricular
myocyte, a membrane potential of about –90 mV will be recorded. This
resting membrane potential (E ) is determined by the concentrations of
M
positively and negatively charged ions across the cell membrane, the
relative permeability of the cell membrane to these ions, and the ionic
pumps that transport ions across the cell membrane.

2.1. Equilibrium potentials

Of several others ions present inside and outside of cells, the
concentrations of Na+, K+, Cl-, and Ca2+ are most important in
determining the membrane potential across the cell membrane. Table 1
shows typical concentrations of these ions. Among these ions, K+ is the
most important in determining the resting membrane potential. In a
cardiac cell, the concentration of K+ is relatively high inside (about 140-
150 mM), while it is significantly lower outside (4-4.5 mM) the cell.

Table 1. Ion concentrations inside and outside of resting myocytes

ION INSIDE (mM) Outside (mM)
Na+ 20 145
K+ 150 4
Ca2+ 0.0001 2.5
Cl- 25 140
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Therefore, a strong chemical gradient (concentration difference) exists for
K+ that facilitates the ion diffusion out of the cell. The opposite situation
is found for Na+; its chemical gradient favours an inward diffusion. The
concentration differences across the cell membrane for these and other
ions are determined by the activity of energy-dependent ionic pumps and
the presence of impermeable, negatively charged proteins within the cell
that affect the passive distribution of cations and anions. These
concentrations are approximations and are used to illustrate the concepts
of chemical gradients and membrane resting potential.
To understand how concentration gradients of ions across a cell
membrane affect membrane potential, consider a cell in which K+ is the
only ion other than the large negatively charged proteins inside of the cell.
In this cell, K+ diffuses down its chemical gradient out of the cell because
its concentration is much higher inside than outside the cell. As K+
diffuses out of the cell, it leaves behind negatively charged proteins,
thereby creating a separation of charge and a potential difference across
the membrane (leaving it negative inside the cell).
The membrane potential that is necessary to oppose the movement
of K+ down its concentration gradient is termed the equilibrium potential
for K+ (E ), and is expressed by the Nernst potential. The Nernst potential
K
for K+ at 37°C is as follows:
[K]
E 61log i 96mV
K [K]
o
where the potassium concentration inside [K+] = 150 mM and the
i
potassium concentration outside [K+] = 4 mM. The –61 is derived from
o
RT/zF, in which R is the universal gas constant, z is the number of ion
charges (z=1 for K+; z=2 for divalent ions such as Ca2+), F is Faraday’s
constant, and T is absolute temperature (°K). The equilibrium potential is
the potential difference across the membrane required to maintain the
concentration gradient across the membrane. In other words, the
equilibrium potential for K+ represents the electrical potential necessary
to keep K+ from diffusing down its chemical gradient and out of the cell.
An increase in the outside K+ concentration will reduce the chemical
gradient for diffusion out of the cell, i.e. the membrane potential required
to maintain electrochemical equilibrium would be less negative according
to the Nernst equation. The E for a ventricular myocyte is about –90
M
mV, which is very close to the equilibrium potential for K+. Because the
equilibrium potential for K+ is –96 mV and the resting membrane
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potential is –90 mV, a net driving force (net electrochemical force) acts
on the K+, causing it to diffuse out of the cell. In the case of K+, this net
electrochemical driving force is the E (–90 mV) minus the E (–96 mV),
M K
resulting in +6 mV. Because the resting cell has a finite permeability to
K+ and a small net outward driving force is acting on K+, K+ slowly leaks
outward from the cell.
The sodium ions play a major role in determining the membrane
potential. Because the Na concentration is higher outside the cell, this ion
would diffuse down its chemical gradient into the cell. To prevent this
inward flux of Na, a large positive charge is needed inside the cell
(relative to the outside) to balance out the chemical diffusion forces. This
potential is called the equilibrium potential for Na+ (E ) and is calculated
Na
using the Nernst equation, as follows:
[Na]
E  61log i  52mV
Na [Na]
o
where the sodium concentration inside [Na+] =20 mM and the sodium
i
concentration outside [Na+] =145 mM. The calculated equilibrium
o
potential for sodium indicates that to balance the inward diffusion of Na+
at these intracellular and extracellular concentrations, the cell interior has
to be + 52 mV to prevent Na+ from diffusing into the cell.

2.2. The cardiac conduction system

The conducting system of the heart consists of group of several cardiac
muscle cells and conducting fibres, which are specialized for initiating
impulses and conducting them rapidly through the heart (Figure 1). They
initiate the normal cardiac cycle and coordinate the contractions of
cardiac chambers, first contract both atria, then the ventricles. The
conducting system provides the heart its automatic rhythmic beat. For the
heart to pump efficiently and the systemic and pulmonary circulations to
operate in synchrony, the events in the cardiac cycle must be coordinated.
The cardiac impulse originates in the sinoatrial node (SA node), located
in the right atrium, which is activated first followed by the left atrium.
The general direction of the atrial activation is inferiorly, to the left, and
posteriorly. This causes the atria to contract and pump blood from the
atria to the ventricles; it is recorded on an EKG as a P wave (Figure 1).
The atrial impulse is delayed in the atrioventricular node (AV node) to
allow the ventricular chambers to fill, and is then conducted rapidly
through the ventricles (the bundle of His, the right and left bundles, and
the Purkinje fibres). This causes the ventricles to pump blood out of the
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heart and to the body; it is recorded on an EKG as a QRS complex.
Recovery following the cardiac cycle, or repolarization, follows.

Figure 1. Electrical activity in the myocardium. Schematic
representation of a human heart with illustration of typical action
potential (AP) waveforms recorded in different regions, and their
contribution to surface electrocardiogram.

This is recorded as a T wave on an EKG. On the microscopic level, the
wave of depolarization propagates to adjacent cells via gap junctions
located on the intercalated disk. The heart is a functional syncytium (not
to be confused with a true "syncytium" in which all the cells are fused
together, sharing the same plasma membrane as in skeletal muscle). In a
functional syncytium, electrical impulses propagate freely between cells
in every direction, so that the myocardium functions as a single
contractile unit. This property allows rapid, synchronous depolarization of
the myocardium. While advantageous under normal circumstances, this
property can be detrimental, as it has potential to allow the propagation of
incorrect electrical signals. These gap junctions can close to isolate
damaged or dying tissue, as in a myocardial infarction.
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2.3. The cardiac action potential

The normal mechanical (pump) function of the mammalian heart
depends on proper electrical function [1,2], as reflected in the successive
activation of cells in specialized, "pacemaker" regions of the heart and the
propagation of activity through the ventricles. Myocardial electrical
activity is attributed to the generation of action potentials (AP) in
individual cardiac cells, and the normal coordinated electrical functioning
of the whole heart is readily detected in surface electrocardiograms
(Figure 1). Propagation of the electrical activity and coordination of the
electromechanical functioning of the ventricles strongly depend on
cellular electrical coupling mediated by gap junctions [3]. The generation
of myocardial action potentials reflects the consecutive activation and
inactivation of ion channels that conduct depolarizing, inward (Na+ and
Ca2+), and repolarizing, outward (K+), currents. The waveforms of action
potentials in different regions of the heart are different reflecting to
differences in the expression and/or the properties of the underlying ion
channels. These differences contribute to the normal unidirectional
propagation of excitation through the myocardium and to the generation
of normal cardiac rhythms [4,5,6].
The cardiac electrical cycle has been divided in to five “phases”,
four of them describing the AP contour and one the diastolic interval
(Figures 1 and 2). Phase 0 refers to the autoregenerative depolarization,
which occurs when the excitation threshold is exceeded. Phase 0 is
supported by activation of two inward (depolarizing) currents, I and
Na
I . Membrane depolarization will quickly activate these channels and,
CaL
with a delay of several milliseconds for I and of tens of milliseconds for
Na
I , inactivates them. Thus, membrane depolarization provides both the
CaL
triggering and breaking mechanism for the autoregenerative
depolarization. Although short-lived, I is large and provides most of the
Na
charge influx required for AP propagation (see below). I has a small
CaL
component with fast activation/inactivation (I ) and a larger one with
CaT
slower kinetics (I ). I mediates most of Ca2+ influx required to trigger
CaL CaL
myocyte contraction and may support propagation under conditions in
which I is not expressed or functional (e.g. in the SA node). Phase 0
Na
depolarization also activates K+ currents, which contribute to termination
of this phase and to subsequent repolarization. Among these, the transient
outward current (I ) is fast enough to limit the depolarization rate during
to
phase 0.
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Figure 2. Phases of a typical atrial and ventricular APs and underlying
currents. The numbers refer to the five phases of the action potential. In
each current profile, the horizontal line represents the zero current level;
inward currents are below the line and outward currents are pointing
upward.

Phase 1 is the initial phase of repolarization, mainly supported by
I (the Ca independent I fast component –see section 3.3.1 for details),
to,f to
a potassium current that, similarly to I , is activated and quickly
Na
inactivated by depolarization. Thus, I supports fast repolarization.
to,f
Phase 2, also named “plateau”, is the slow repolarization phase,
which accounts for the peculiar configuration of the cardiac AP. The net
transmembrane current flowing during phase 2 is small and it results from
the algebraic summation of inward and outward components. The
outward one (promoting repolarization) mainly consists of depolarization-
activated K+ currents collectively named “delayed rectifiers” (I ). I is
K K
actually the sum of rapid (I ) and slow (I ) components (and ultra-rapid
Kr Ks
in atria, I ), carried by separate channels with different properties and
Kur
pharmacology [7]. The inward phase 2 currents (opposing repolarization)
are mostly carried by “window” components of I and especially of I ,
Na CaL
which flow when membrane potential (V ) is such that the activated state
m
of these channels is not yet completely offset by the inactivation process.