Clinical arrhythmias occur on the basis of one the following electrophysiologic mechanisms:
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Automaticity
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Reentry
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Micro-reentry
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Macro-reentry
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Small-diameter macro-reentrant circuits (rotors)
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Large-diameter macro-reentrant circuits
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Although all reentry is abnormal, automaticity is essential for certain critical components of normal cardiac activation. For example, the sinoatrial (SA) node functions by virtue of the fact that its cells are capable of spontaneously generating an electrical impulse on the basis of normal automaticity. However, the transmembrane action potentials of pacemaker cells and normal myocytes are different, which explains why the pacemaker cells generate spontaneous electrical impulses and normal myocytes do not.
Normal Automaticity
Normal Contractile Myocytes
When normal myocardial cells are at rest, there is an electrical differential across the cellular membrane of approximately 90 millivolts that is traditionally expressed as–90 mV because the outside of the cell membrane is negatively charged relative to the inside of the cell. This resting membrane potential (RMP) is maintained primarily by the potassium channel IK1, which is an inward potassium current that keeps the RMP from becoming too negative ( Fig. 4.1 ). It is time independent, which means that it reacts instantaneously to changes in the RMP so that above the RMP, the IK1 channel becomes an outward potassium current. In phase 0 when the fast inward sodium current is activated, IK1 decreases to zero. When the RMP reaches its peak voltage, an inward current calcium channel is activated that is responsible for the plateau of phase 2. At the same time, the outward current potassium channel starts to bring down the voltage toward the RMP. As the voltage decreases, IK1, the sodium–potassium (Na + /K + ) pump and the sodium-calcium (Na + /Ca 2+ ) exchanger are activated and reestablish the RMP to normal resting levels.
Normal transmembrane action potential in nonpacemaker myocytes. Ca ++ , Calcium; ( in ), flow from outside the cell to inside the cell; K + , potassium; Na + , sodium; (out), flow from inside the cell to outside the cell. See text for further discussion.
Anything that causes the RMP to increase to the threshold level of approximately–60 mV results in sudden depolarization of that individual myocyte (i.e., it results in an instantaneous reversal of the charge on the outside of the cell from negative to positive). When the transmembrane potential again drops below the threshold potential of–60 mV, the cell is capable of being depolarized again. Sudden cellular depolarization of a myocyte can be caused by a variety of external stimuli such as a change in autonomic neural input or a mechanical external stimulus such as trauma or pacing.
Pacemaker Cells
The cellular electrophysiology of pacemaker cells differs from that of normal contractile myocytes by possessing the characteristic of spontaneous phase 4 depolarization ( Fig. 4.2 ). This critical trait of pacemaker cells is possible for several reasons:
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Pacemaker cells do not have an IK1 channel, which is one of the reasons that spontaneous phase 4 depolarization can occur.
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In pacemaker cells, nonspecific cation channels produce an inward current that further contribute to spontaneous phase 4 depolarization.
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In pacemaker cells, the action potential is produced by the calcium current, but they do not have the fast sodium current seen in nonpacemaker myocytes.
Normal action potential of a pacemaker myocyte emphasizing normal phase 4 depolarization. See text for further discussion.
Factors that decrease the heart rate, including drugs such as beta-blockers, do so by decreasing the slope of phase 4 depolarization of pacemaker cells, thereby lengthening the time between heartbeats ( Fig. 4.3 ). Humoral agents, neural stimuli, and drugs such as isoproterenol that increase the heart rate do so by increasing the slope of the phase 4 depolarization, thereby shortening the time between heartbeats.
Most stimulants and antiarrhythmic medications, as well as neurological events, change the heart rate by altering the slope of phase 4 depolarization. See text for further discussion.
Depolarization of a single cell causes immediate depolarization of adjacent myocardial cells, and the resultant electrical “wavefront” propagates away from this site in all directions. If multiple electrodes are arrayed around this region of the heart, the site where the original cell first depolarized appears to be a single spot or “focus” on an activation time map. Thus during normal sinus rhythm, the sinus impulse appears to originate from a single site.
Normal Wavefront Propagation and Complex Fragmented Atrial Electrograms
Cardiac myocytes are coupled by intercalated disks that are traversed by gap junctions between adjacent myocytes ( Fig. 4.4 ). Gap junctions are tiny “pores” between cells that allow current to flow between a depolarized cell and one that is in the phase 4 resting state. As the current from the depolarized cell passes through the gap junction, it increases the voltage of the resting cell enough to trigger the inward sodium channel (INa) to cause its depolarization and thus propagate the electrical wavefront.
Left upper panel , Diagrammatic illustration of myofibrils showing that the individual myocytes are connected by intercalated disks. Right upper panel , Photomicrograph of myofibrils showing the intercalated disks. Lower panels : Diagrammatic illustration of the details of adjacent myofibrils showing how gap junctions span the connecting intercalated disk between the myofibrils and conducts electrical current from one to the other.
Electrical activity propagates across the atrial myocardium in “waves” characterized by a leading edge of depolarization where billions of individual cells are undergoing simultaneous depolarization ( Fig. 4.5 ). When these cells are depolarized, they cannot be further depolarized for a certain period of time, the so-called effective refractory period (ERP). Allessie and coworkers have referred to the distance between the leading edge and trailing edge of a wavefront as the “wavelength” of propagating electrical activity. Their formula for calculating the wavelength of a given propagating wavefront is as follows:
Diagrammatic illustration of an electrical wavefront propagating across atrial myocardium from right to left. The leading edge of the wavefront is where the cells are simultaneously depolarizing (“phase 0” of the action potentials) and the trailing edge is where they are repolarizing. The distance between the two is the effective refractory period of the atrial tissue at this site. ERP, Effective refractory period.
For example, if a particular site in the atrium has a conduction velocity of 1 mm/ms and an ERP of 200 mm as in Fig. 4.5 , a potential reentrant circuit in this area would require a path length of 200 mm or 20 cm.
The wavelength of a propagating impulse is critical because it determines how large an area of the atrium is necessary for reentry to occur (i.e., it determines the smallest that a reentrant circuit can be in this region of the atrium). In the example given, it means that a potential reentrant pathway of at least 200 mm (20 cm) is needed to sustain a reentrant circuit. Although such reentrant circuits are traditionally illustrated as perfect circles (see later) for clarity’s sake, in reality they can be very circuitous and even out of plane. However, they can only form and sustain themselves in contiguous areas of the atrium that are large enough to allow a wavefront with a given wavelength to circle back and reenter the same area where it began. This concept is fundamentally different from Moe’s hypothesis of “multiple wandering wavelets” as the basis of atrial fibrillation (AF; see Chapter 5 ).
Abnormal Repolarization
Under abnormal conditions such as ischemia, scarring, or inflammation, the earliest measurable electrophysiologic abnormality is frequently an aggravation in the disparity between the repolarization times of individual cells or individual clusters of cells within a small region of the heart. The electrophysiological terms used to describe this pathological condition, which is highly arrhythmogenic in all cardiac tissues, have been changed many times over the years, and the lack of a single descriptive term has led to much confusion. These terms, which all refer to the same electrophysiologic abnormality, include nonuniform recovery, dispersion of refractoriness, inhomogeneity of repolarization, and inhomogeneity of recovery . In this situation, the trailing edge of repolarization of a wavefront is much more ragged and less well defined. Abnormal repolarization is one of the fundamental essentials for the genesis and perpetuation of arrhythmias.
Abnormal Depolarization and Complex Fragmented Atrial Electrogram Sites
Arrhythmogenic tissue can also be characterized by desynchronized activation , a term that describes the nonsimultaneous depolarization of individual cells or clusters of cells in the same region of the heart. In this case, the leading edge of a wavefront may become more ragged and actually leave behind islets of tissue where the electrical activity is delayed so long that the surrounding cells have time to repolarize before the depolarization of all the cells in the isolated islet has been completed ( Fig. 4.6 ). Electrical conduction within such an isolated islet is characterized by slow local conduction and micro-reentry that is confined to that islet because the surrounding tissue is refractory. On local electrograms, this appears as complex fragmented atrial electrograms (CFAEs). The primary wave continues to propagate, and as the trailing repolarization edge clears the area, the confined electrical activity quickly escapes and causes a premature atrial beat ( Fig. 4.7 ). These so-called CFAE spots at various local sites within the atrium have been proposed as drivers that are capable of sustaining AF that should be ablated. However, the systematic ablation of hundreds of these CFAE spots per patient has had no discernible benefit when done in conjunction with catheter ablation of AF.
An example of “desynchronized activation” caused by slow conduction in a small islet of atrial tissue. Such an islet of inhomogeneous scar, fat, or ischemia contains atrial myocytes that were not depolarized by the initial wavefront. The tissue around this nondepolarized islet is refractory so that any electrical activity in this area of slow conduction is effectively “trapped” throughout the refractory period of the wavefront. Local electrograms during that time show continuous fractionated electrical electrograms or (CFAEs).
After the original electrical wave passes through and the surrounding atrial myocardium becomes repolarized, the “trapped” electrical activity in the abnormal isolated islet escapes, causing a premature atrial beat. Such continuous fractionated electrical electrogram (CFAE) spots are likely the basis of some extrapulmonary vein atrial triggers that induce atrial fibrillation (AF). However, CFAE spots are not capable of sustaining AF.
Although it is clear that these CFAE spots do not act as “drivers” that sustain AF, it is possible that they might act as “triggers” that induce AF. We demonstrated many years ago that such isolated focal sites of abnormal conduction and micro-reentry located in the ischemic border zone surrounding myocardial infarctions ( Fig. 4.8 ) lead to continuous fractionated electrical activity and were responsible for the development of premature ventricular beats that could trigger ventricular tachycardia ( Fig. 4.9 ). , Thus although it is possible that CFAE sites might occasionally act as extrapulmonary vein triggers that induce AF, there is nothing to suggest that they are involved in sustaining AF. In addition, recording CFAE is critically dependent on the recording technique. CFAE can result from the recording electrodes “seeing” multiple wavefronts in the nearby regions, and if the area is being recorded in a bipolar mode, both electrodes can be recording potentials individually. The farther the bipolar electrodes are apart, the more likely that double potential and multiple deflections will be recorded. During AF these events occur all over the atria and necessarily in the most critical areas of interest. For these reasons, it is likely that most CFAE sites represent false positive targets for ablation coming from areas of slow conduction or block that have nothing to do with the induction, and certainly not the maintenance, of AF. Thus it is no surprise that their ablation has little efficacy in the treatment of patients with AF.
Mechanism of complex desynchronization and slow propagation in an area of myocardial ischemia. In this schematic, the white areas represent severely depressed (unexcitable) myocardium. The stippled areas represent less severely depressed, nonhomogeneously excitable myocardium. The area of wavy lines represents normally excited myocardium in the absolute refractory period. (A) The more coarsely distributed nonhomogeneity results in fewer spikes of larger amplitude and a shorter duration of the activity than in B. (B) The more finely distributed nonhomogeneity of depressed excitability results in more complex and effectively longer pathways. The greater degree of asynchronous excitation in B results in a larger number of spikes of smaller amplitude and a markedly prolonged duration of the circuitous activity confined to this region. The activity is confined by the absolute refractory state of the surrounding myocardium, which has previously been excited by the normally propagated wavefront through this region. In this example, there is interplay between the duration of persistent desynchronized activity and the duration of the recovery period of the surrounding myocardium, a factor which determines whether reentrant premature ventricular contractions are generated or not. LV, Left ventricular.
(Reproduced from Boineau JP, Cox JL. Slow ventricular activation in acute myocardial infarction—a source of re-entrant premature ventricular contractions. Circulation. 1973;48:702-713.)
(A) Continuous fractionated electrical activity (CFAE) recorded during normal sinus rhythm (NSR) in the ischemic border zone surrounding myocardial infarctions that were associated with the induction of ventricular tachycardia. The blue box shows local site of fractionated electrical activity. Note that the earliest normal activation during sinus rhythm is at electrodes 5 at 6 (blue line), but the fractionated electrical activity begins simultaneously in electrodes 9, 10, and 11. (B) Local recordings from the same electrodes show that the site of origin of the ventricular tachycardia is at sites 10 and 11 (red box), confirming the association between the local fractionated electrical activity and the development of ventricular tachycardia.
Clinical Presentation of Automatic Arrhythmias
Automatic Atrial Tachycardia
The most common clinical arrhythmias that occur on the basis of automaticity are the “automatic atrial tachycardias.” These tachycardias are usually caused by abnormally rapid spontaneous phase 4 depolarization of one or more abnormal cells in a small localized site in the atrium ( Fig. 4.10 ). Automatic left atrial tachycardias usually arise from a single site that can be located anywhere in the left atrium, and they typically remain fixed in one position ( Fig. 4.11 ). They also occasionally occur as a result of congenital “cell rests” located near the left superior pulmonary vein orifice in the mirror-image position of the SA node in the right atrium. Automatic left atrial tachycardia is typically quite regular. It is exceedingly rare for an automatic left atrial tachycardia to have multiple sites of origin. Thus if a left atrial focus can be mapped precisely, it is quite amenable to being ablated either by surgical or catheter-based techniques. If an automatic left atrial focus cannot be located precisely by mapping techniques, either the general region of the automatic focus (e.g., the pulmonary vein orifices) or the entire left atrium can be surgically isolated from the rest of the heart.
