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Electrophysiological Foundations of Cardiac Arrhythmias
A Bridge Between Basic Mechanisms and Clinical Electrophysiology
By Andrew L. Wit, Hein J. Wellens, Mark E. Josephson Cardiotext Publishing, LLC
Copyright © 2017 Andrew L. Wit, Hein J. Wellens, Mark E. Josephson
All rights reserved.
ISBN: 978-1-942909-12-5
CHAPTER 1
BASIC PRINCIPLES OFNORMAL AUTOMATICITY
Normal automaticity is found in the primary pacemaker of the heart, the sinus node, as well as in certain subsidiary or latent pacemakers (the terms are used interchangeably) that can become the pacemaker under special conditions (hence the term, latent) that we will describe later in this chapter. Impulse initiation is a normal property of these latent pacemakers, as it is in the sinus node. The recording of the transmembrane resting potential (often referred to here as simply the membrane potential) and action potentials as well as the membrane currents of individual myocardial cells has provided much of the information necessary for understanding the mechanism by which certain myocardial cells can generate impulses spontaneously by normal automaticity.
The cause of normal automaticity in the sinus node and in latent pacemakers is a spontaneous decline (becoming less negative) in the membrane potential during diastole or phase 4. This decline in membrane potential is referred to as either the pacemaker potential phase 4 depolarization, or spontaneous diastolic depolarization (SDD). Figure 11 illustrates an action potential with a pacemaker potential in a myocardial cell with the property of normal automaticity and compares the automatic cell with a cell without normal automaticity (nonautomatic cell).
Panel A shows a nonautomatic cell with a steady level of resting (diastolic) potential (phase 4) between action potentials (purple arrow). An action potential is initiated only when the cell is excited from an external source (green arrow), e.g., another cell or an applied electrical stimulus. The action potential is comprised of phase 0 (rapid depolarization phase or "upstroke") and phases 1, 2, and 3 (repolarization phases).
Panel B shows a cell with normal automaticity. Spontaneous diastolic depolarization (the pacemaker potential) is that part of the membrane potential labeled "SDD" (black arrow) coinciding with phase 4 of the membrane potential. In Panel B, the membrane potential moves spontaneously in a positive direction from the MDP negative value of –70 mV until it reaches the TP, which is less negative at –60 mV. At this point, the inward depolarizing current (phase 0, red arrow) is activated, and this in turn causes the cell to generate an action potential. Phase 0 is responsible for conduction of the action potential from the pacemaker cell to surrounding cells. These values for the membrane potential vary in different regions of the heart. The MDP in pacemaker cells in general is less negative than the resting potential in nonpacemaker cells. This depolarization of membrane potential during SDD reflects a net inward (depolarizing) current. In actuality, it represents the summation of a number of inward and outward currents with depolarization resulting because inward current dominates.
In later chapters of Part I, we describe the specific ion channels and membrane currents that are involved in the genesis of the pacemaker depolarization, but these details are not necessary at this point for understanding the role of automaticity in causing arrhythmias. The general principles of normal automaticity are organized into 5 subsections. Subsequent chapters use examples of clinical arrhythmias to demonstrate in greater detail how these electrophysiological foundations apply to clinical electrophysiology.
General Principles of Normal Automaticity
• Control of rate of automatic impulse initiation
• Relationship between sinus node and latent pacemakers
• Electrophysiological causes of ectopic automatic arrhythmias
• General ECG characteristics of automatic arrhythmias
• Effects of electrical stimulation and pharmacological agents on normal automaticity
Control of Rate of Automatic Impulse Initiation
The rate of automatic impulse initiation is determined by two major factors: the characteristics of the transmembrane potential and electrical coupling between pacemaker and nonpacemaker cells.
Transmembrane Potential
The rate of impulse initiation by pacemaker cells is controlled by four specific characteristics of the transmembrane potential. Understanding the interplay of these factors is necessary for understanding how automatic arrhythmias occur. The intrinsic rate at which pacemaker cells initiate impulses is determined by the amount of time it takes for the membrane potential to move from its maximal negativity after repolarization to the threshold potential to generate an action potential or impulse. This time to threshold potential is in turn dependent on the interplay of several factors (Figure 1-2) that include:
• The level of the maximum diastolic potential (MDP), which is the maximum negativity attained after repolarization of the action potential. This term is used instead of "resting potential" since the membrane potential in a pacemaker cell does not have a period of rest as it does in a nonpacemaker cell (Figure 1-1, Panel B).
• The level of the threshold potential (TP) for initiation of phase 0 of the action potential.
• The slope of spontaneous diastolic depolarization (SDD), which is the rate of change of phase 4 of the action potential, also referred to as the pacemaker potential. This slope is dependent on the speed of activation and the magnitude of net inward current. Sometimes there may be two different slopes if the rate of change is not constant.
• The action potential duration (APD) from depolarization phase 0 to complete repolarization at the end of phase 3.
These features of the transmembrane potential are under the control of the ion channels, pumps, and exchangers involved in the genesis of the pacemaker potential and action potential, which will be described in detail later in this chapter and also in Chapters 2 and 3. A change in any one of the above parameters caused by changes in the membrane currents will alter the time required for SDD to move the membrane potential from its MDP to the TP, and thereby alter the rate of impulse initiation.
Figure 1-2 illustrates how these parameters control the spontaneous rate. Panel A shows how changes in the slope of the SDD can change the rate of automatic impulse initiation. The red trace shows the initial intrinsic or automatic rate of the pacemaker cell, which is determined by the time required for SDD caused by the pacemaker current(s), to move the membrane potential from the MDP to TP. The blue trace (labeled 1) shows the effect of a decrease in the slope of SDD. This would be caused by a decrease in net inward pacemaker current, resulting in a longer interval between action potentials and a decrease in heart rate because of the longer time required for membrane potential to reach the threshold potential. Modest parasympathetic (vagal) activation is one condition that results in a decreased slope of SDD of sinus node pacemaker cells and slows the heart rate. Some antiarrhythmic drugs also have this effect on latent pacemakers. The green trace (labeled 2) shows the effect of an increase in the slope of SDD. This would be caused by an increase in the net inward pacemaker current, which reduces the time to reach threshold potential and decreases the time between action potentials. Sympathetic activation, which accelerates the heart rate, is an example of this condition.
Figure 1-2, Panel B illustrates how a change in the MDP can change the rate of automatic impulse initiation. If the MDP increases (becomes more negative), going from the nadir of the solid red trace to the blue trace (labeled 1), then the SDD (or pacemaker potential) takes longer to reach threshold potential and the rate of impulse initiation slows. This occurs even though the slope of the SDD is not altered. This condition results from a net increase in outward current during diastole. Strong vagal activation causes this change in sinus pacemaker cells in addition to the decreased slope of SDD, which slows sinus rate. Conversely, a decrease in the MDP (going from red to green trace) decreases the time it takes to go from MDP to TP and increases the rate of impulse initiation. A simultaneous increase in sympathetic activity and decrease in vagal activity can produce this change and increase the sinus rate, although the slope of SDD is also likely to change.
Figure 1-2, Panel C illustrates the effect of changes in TP on the rate of impulse initiation. The TP (dashed lines) is the membrane potential required for initiation of the upstroke (phase 0) of the action potential. It is the value of the membrane potential at which the inward current causing phase 0 becomes regenerative. When the TP is decreased from the red dashed line (associated with the solid red line action potential) to the less negative TP (blue dashed line), then the SDD must proceed for a longer time before an impulse is finally initiated (rapid upstroke, solid blue trace) and the heart rate is slower. Conversely, an increase in TP (from red to more negative green dashed line) accelerates the rate shown by the earlier green action potential.
Don't be confused by this terminology corresponding to negative values in which an increase in "potential" — the difference between the measured value and 0 — is actually more negative, while a decrease in potential is less negative. On the other hand, when the term "threshold" is used by itself, an increase in threshold means "more difficult to excite" while a decrease in threshold means "more excitable." Changes in TP in general (but not always) occur from changes in properties of ion channels responsible for phase 0 of the action potential rather than changes in the currents responsible for the SDD. Some examples of a decrease in TP are the slowing of automatic rate by L-type calcium channel-blocking drugs (verapamil) and the Class IA [Na.sup.+] channel antiarrhythmic drugs (disopyramide). Catecholamines might increase the threshold potential to speed sinus rate.
Figure 1-2, Panel D, shows how changes in the APD can alter the rate of impulse initiation. The APD is controlled in part by the membrane currents that determine the time course for repolarization (phases 1, 2, and 3). SDD begins after completion of action potential repolarization. If APD lengthens (increases), the rate of impulse initiation decreases (compare onset of the second red action potential with the later blue action potential that has a longer time course for repolarization), while a decrease in action potential duration accelerates the rate (compare the earlier onset of the green action potential that has a shorter action potential duration with the later timing of the second red action potential). Changes in APD do not normally apply to the physiological control of rate but may be instrumental in the presence of drugs that alter repolarization, like Class III (amiodarone) and Class IA (disopyramide) antiarrhythmics that prolong the time for repolarization.
Electrical Coupling Between Pacemaker and Nonpacemaker Cells
In addition to the changes discussed in Figure 1-2, electrical coupling between pacemaker and nonpacemaker cells can modulate the pacemaker rate. The way this effect is exerted is diagrammed in Figure 1-3.
The lower part of the figure diagrams two adjacent cells, A and B (yellow cylinder). In Figure 1-3, cell A is a pacemaker cell (action potential is above it) with SDD (black trace) and cell B is a nonpacemaker cell with a more negative membrane potential during phase 4. The broken double dark lines between the two cells represents the adjacent cell membranes (sarcolemmae) of each cell, which abut to form the intercalated disk. In the disks are structures called gap junctions, specialized regions of close interaction between the sarcolemmae of neighboring myocytes in which clusters of transmembrane channels, formed by proteins called connexins, bridge the paired plasma membranes. Because gap-junctional membrane is several orders of magnitude more permeable than nonjunctional plasma membrane, it provides low resistance pathways for electrotonic current flow between myocardial cells, which is important for impulse propagation. (The mechanism for impulse propagation is described in detail in Figure 9-5.) Current flow in the absence of propagation also influences impulse initiation by automaticity.
In Figure 1-3, channels in the gap junctions connect the intracellular spaces of cell A and cell B. Ionic current carried by positively charged ions (cations, to a large extent [Na.sup.+] but also Ca and [K.sup.+]) flows between the two cells in intracellular space through these gap junctional channels (curved black arrow) down an electrical gradient, from a more positive region to a less positive (more negative) region.
During SDD, the membrane potential in the pacemaker cell becomes much less negative than the membrane potential in the adjacent nonpacemaker cell (B). As a result of this potential difference, current (positive charges) flows intracellularly from the pacemaker cell (A) towards the non-pacemaker cell (B) through the gap junction channels (curved black arrows and + signs). It also flows in extracellular space from the nonpacemaker cell at the right (cell B) to the pacemaker cell at the left (cell A), also down the potential gradient (curved green arrow and + symbols). The addition of positive charges outside the membrane of cell A and removal of + charges from the inside of the membrane caused by the current flow push the membrane potential of the pacemaker cell in a negative direction and retard SDD (red arrow shows shift in slope of SDD from black to red trace) in the pacemaker cell.
In summary, coupling of the pacemaker cell to the nonpacemaker cell — which has a more negative membrane potential — by gap junctions reduces the slope of SDD and slows or inhibits pacemaker cell impulse initiation by electrotonic current flow.
The efficacy of the inhibitory effect of electrotonic current flow is dependent on the magnitude of the current, which in turn is influenced by the conductance (ability to pass current) of the gap junctions. One determinant of conductance is the isoform of the connexin protein that forms the gap junction. There are 5 connexin isoforms that form gap junctions in the human heart. The conventional nomenclature for a connexin (Cx) includes a suffix referring to its molecular weight. Some connexin proteins (Cx40 and Cx43) have high conductance, and others (Cx45) have low conductance. Different types of connexins are located in different regions of the heart. In the sinus node, where pacemaker cells are coupled to atrial cells with a more negative membrane potential, it is important that the gap junctions between the two cell types have low conductance, or sinus node pacemaker activity might be silenced (see Figure 2-8). More details on gap junction function are described in later chapters in Part I, since a decrease in coupling caused by changes in gap junctions can enhance automaticity and cause arrhythmias.
Relationship Between Sinus Node and Latent Pacemakers
Cells with normal pacemaker properties occur throughout the heart. There is a hierarchy of pacemaker impulse initiation such that the sinus node is normally the primary pacemaker. With the sinus node functioning normally, other pacemaker sites are effectively "silent." Why does impulse initiation in the normal heart reside in the sinus node and not at one of the ectopic sites, since they also have the property of normal automaticity? Two factors are involved: the hierarchy of pacemakers and overdrive suppression.
Sinus Node as the Primary Pacemaker
The sinus node is the prototype of normal automaticity and the dominant pacemaker in the normal heart. In addition, there are other special regions throughout the heart where myocardial cells have the normal, intrinsic ability to initiate impulses by automaticity. Myocardial cells at these ectopic sites are called latent or subsidiary pacemakers (Figure 1-4).
They include multiple sites in the right and left atria, the atrioventricular (A-V) junction (A-V node and His bundle), and the specialized conducting system of the ventricles (Purkinje system). Pacemaker cells at some of these sites such as the A-V junction and Purkinje system can be identified by a specific histological structure while most pacemaker cells in the atria usually appear the same as the working myocardial cells with typical contractile structure and function. A more detailed description of latent pacemaker cell locations is provided in the sections on the different origins of automatic arrhythmias in Chapters 2 and 3.
The latent pacemakers have membrane currents causing SDD similar in many aspects to the mechanism described for the sinus node in Chapter 2 (Figure 2-9). In general, latent pacemaker sites with normal automaticity have cells with an isoform of a specific gene called the HCN gene (HCN stands for Hyperpolarization-activated Cyclic Nucleotide-gated). This gene controls the expression of a membrane channel that is involved in the genesis of the pacemaker current. Myocardial cells in atria and ventricles classified as "working," i.e., able to perform the contractile functions, do not normally express pacemaker ability, although under pathological conditions, they may express abnormal automaticity (see Chapter 4).
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Excerpted from Electrophysiological Foundations of Cardiac Arrhythmias by Andrew L. Wit, Hein J. Wellens, Mark E. Josephson. Copyright © 2017 Andrew L. Wit, Hein J. Wellens, Mark E. Josephson. Excerpted by permission of Cardiotext Publishing, LLC.
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