Reentry is a fundamentally different mechanism of arrhythmogenesis than automaticity or triggered activity. The circus movement reentry occurs when an activation wavefront propagates around an anatomical or functional core and reexcites the site of origin. In this type of reentry, all cells take turns recovering from excitation and get ready to be excited again when the next wavefront arrives. In comparison, reflection and phase 2 reentry occur when there are large differences of recovery from one site to another. The site with delayed recovery serves as a virtual electrode that excites its already recovered neighbor, resulting in reentry. A circus movement is not observed. In addition, reentry can also be classified as anatomical and functional, although there is a gray zone in which both functional and anatomical factors are important in determining the characteristics of reentrant excitation.
Circus Movement Reentry Around an Anatomical Obstacle
The ring model is the prototypical example of reentry around an anatomical obstacle. It first emerged as a concept shortly after the turn of the last century when Mayer reported the results of experiments involving the subumbrella tissue of a jellyfish (Sychomedusa cassiopeia).4 The muscular disk did not contract until ringlike cuts were made and pressure and a stimulus applied. This caused the disk to “spring into rapid rhythmical pulsation so regular and sustained as to recall the movement of clockwork.”4 Mayer demonstrated similar circus movement excitation in rings cut from the ventricles of turtle hearts, but he did not consider this to be a plausible mechanism for the development of cardiac arrhythmias. His experiments proved valuable in identifying two fundamental conditions necessary for the initiation and maintenance of circus movement excitation: (1) unidirectional block—the impulse initiating the circulating wave must travel in one direction only; and (2) for the circus movement to continue, the circuit must be long enough to allow each site in the circuit to recover before the return of the circulating wave. G. R. Mines6 was the first to develop the concept of circus movement reentry as a mechanism responsible for cardiac arrhythmias. He confirmed Mayer’s observations and suggested that the recirculating wave could be responsible for clinical cases of tachycardia.124 The clinical importance of reentry was reinforced with the discovery by Kent of an accessory pathway connecting the atrium and ventricle of a human heart,125 and that successful surgical ablation of the accessory pathway results in the cure of the paroxysmal supraventricular tachcardia.126 The following three criteria developed by Mines for identification of circus movement reentry remain in use today:
An area of unidirectional block must exist.
The excitatory wave progresses along a distinct pathway, returning to its point of origin and then following the same path again.
Interruption of the reentrant circuit at any point along its path should terminate the circus movement.
It was recognized that successful reentry could occur only when the impulse was sufficiently delayed in an alternate pathway to allow for expiration of the refractory period in the tissue proximal to the site of unidirectional block. Both conduction velocity and refractoriness determine the success or failure of reentry, and the general rule is that the length of the circuit (path length) must exceed or equal that of the wavelength, the wavelength being defined as the product of the conduction velocity and the refractory period or that part of the path length occupied by the impulse and refractory to reexcitation. The theoretical minimum path length required for development of reentry was therefore dependent on both the conduction velocity and the refractory period. Reduction of conduction velocity127 or APD128 can both significantly reduce the theoretical limit of the path length required for the development of reentry.
Circus Movement Reentry Without an Anatomical Obstacle
That reentry could be initiated without the involvement of anatomical obstacles and that “natural rings are not essential for the maintenance of circus contractions” was first suggested by Garrey in 1914.129 Years later, Allessie and coworkers130 provided direct evidence in support of this hypothesis in experiments in which they induced a tachycardia in isolated preparations of rabbit left atria by applying properly timed premature extra-stimuli. Using multiple intracellular electrodes, they showed that although the basic beats elicited by stimuli applied near the center of the tissue spread normally throughout the preparation, premature impulses propagate only in the direction of shorter refractory periods. An arc of block thus develops around which the impulse is able to circulate and reexcite its site of origin. Recordings near the center of the circus movement showed only subthreshold responses. The authors proposed the term leading circle to explain their observation.7 They argued that the functionally refractory region that develops at the vortex of the circulating wavefront prevents the centripetal waves from short circuiting the circus movement and thus serves to maintain the reentry. The authors also proposed that the refractory core was maintained by centripetal wavelets that collide with each other. Because the head of the circulating wavefront usually travels on relatively refractory tissue, a fully excitable gap of tissue may not be present; unlike other forms of reentry, the leading circle model may not be readily influenced by extraneous impulses initiated in areas outside the reentrant circuit and thus may not be easily entrained. Although leading circle reentry was for a time widely accepted as a mechanism of functional reentry, there is significant conceptual limitation to this model of reentry. For example, the centripetal wavelet was difficult to demonstrate either by experimental studies with high-resolution mapping or with computer simulation studies.
First introduced by Wiener and Rosenblueth in 1946,131 the concept of spiral waves (rotors) has attracted a great deal of interest. Originally used to describe reentry around an anatomic obstacle, the term spiral wave reentry was later adopted to describe circulating waves in the absence of an anatomic obstacle.11,78,132,133 Because the concept of spiral waves of excitation is a well-described phenomenon in many excitable media,132 the application of the spiral waves of excitation to cardiac tissues is met with great enthusiasm. Spiral wave theory has advanced our understanding of the mechanisms responsible for the functional form of reentry. Although leading circle and spiral wave reentry are considered by some to be similar, a number of distinctions have been suggested. The curvature of the spiral wave is the key to the formation of the core.134 The curvature of the wave forms a region of high impedance mismatch (source-sink mismatch), where the current provided by the reentering wavefront (source) is insufficient to charge the capacity and thus excite a larger volume of tissue ahead (sink). The ability of impulse propagation to succeed depends critically on the ability of source current generated by already activated cells to excite the cells ahead that have not yet been activated, generally referred to as the sink. When the source current generated by a few cells is required to activate a large number of cells in the sink, the dilution of the current may lead to conduction failure or block. A prominent curvature of the spiral wave is generally encountered following a wave break, where the wavefront meets the wavetail and a large curvature (and short action potential) is present. As a result of a very small source in part related to a short action potential (wavefront and wavetail meets), the broken end of the wave moves most slowly. Figure 79–8 shows the formation of the spiral wave by wavefront interaction with the refractory tail of a previous activation.135 This three-dimensional computer simulation study reproduced the wavebreak observed in the optical mapping studies of VF in swine ventricle.136 The wavebreak occurs when the wavefront encountered the refractory tail of a previous activation, inducing two spiral waves (panel A). A three-dimensional view of the scroll wave is shown in panel B. Panel C is a close-up of the wavebreak. Note that the newly formed wavebreak has a very high curvature. As curvature decreases along the more distal parts of the spiral, propagation speed increases. The high curvature prevents the wave from propagating in the direction of wavebreak. The wavefront (red) then circles around the wavebreak site to form circus movement. In three dimensions, there are two new scroll waves formed by these interactions. Another difference between the leading circle and spiral wave is the state of the core; in the former, the core is refractory because of repetitive centripetal wavelet that invades the core. In the latter, the core remains unexcited because the source-sink mismatch prevents the propagation of the wavefront into the core.137
Three-dimensional simulation of wavebreak by a wavefront running into the trailing edge of refractoriness. A. Surface activation patterns (red = wavefront, green = waveback) at the times indicated. The white arrows indicate the region where this mechanism of wavebreak occurs. B. Corresponding scroll wavefronts in the tissue (red = rising membrane voltage). C. Blowup of the region of wave break on the upper surface (near the white arrows in A). Residual refractoriness (green) was left over by a previous wavefront, and when the next wave (red) encountered this refractory region, wave break occurred, generating two new scroll waves. White arrows point to the new wave breaks. At that site, the curvature of the wave is high and the source-sink ratio is low, preventing the wavefront from propagating. The wavefront (red) then circles around the wavebreak and forms circus movement. Reproduced with permission from Lee MH, Qu Z, Fishbein GA, et al: Patterns of wave break during ventricular fibrillation in isolated swine right ventricle. Am J Physiol Heart Circ Physiol. 2001 Jul;281(1):H253-H265.136
The term spiral wave is usually used to describe reentrant activity in two dimensions. The center of the spiral wave is called the core, and the distribution of the core in three dimensions is referred to as the filament. The three-dimensional form of the spiral wave forms a scroll wave (see Fig. 79–8B). In its simplest form, the scroll wave has a straight filament spanning the ventricular wall (ie, from epicardium to endocardium). Theoretical studies have described three major scroll wave configurations with curved filaments (L-, U-, and O-shaped), although numerous variations of these three-dimensional filaments in space and time are assumed to exist during cardiac arrhythmias.
Spiral wave activity has been used to explain the electrocardiographic patterns observed during monomorphic and polymorphic cardiac arrhythmias as well as during fibrillation. Monomorphic VT results when the spiral wave is anchored and not able to drift within the ventricular myocardium. In contrast, a meandering or drifting spiral wave causes polymorphic VT/VF-like activity.138,139 VF seems to be the most complex representation of rotating spiral waves in the heart. VF is often preceded by VT. One of the theories suggests that VF develops when a single spiral wave responsible for VT breaks up, leading to the development of multiple spirals that are continuously extinguished and re-created.140
Stability of Circus Movement Reentry
The stability of reentry is critical to the understanding of the electrocardiographic manifestations of arrhythmias. If only a single stable reentrant wavefront is present, the electrocardiogram is likely to show consistent beat-to-beat QRS morphology (such as during monomorphic VT) or consistent beat-to-beat P-wave morphology (such as during cavotricuspid isthmus–dependent atrial flutter). However, if the reentrant circuit either meanders or breaks down into multiple reentrant circuits, then the electrocardiographic manifestation becomes polymorphic or fibrillatory. Many different factors independently determine the stability of the circus movement reentry.138,139,140
Size of the Anatomical Obstacle
Although circus movement reentry can be conveniently classified as anatomical and functional, there is a gray zone in which the features of these two mechanisms are both present. Ikeda et al141 performed a study in isolated superfused canine atria. The authors punched holes with 2- to 10-mm diameters in the center of the tissue. Figure 79–9 shows the effects of a central hole (anatomical obstacle) on reentrant wavefronts (spiral waves). In the absence of a lesion (see Fig. 79–9A), the induced single (functional) reentrant wavefront, in the form of a spiral wave, meandered irregularly from one site to another before terminating at the tissue border. Holes with 2- to 4-mm diameters (see Fig. 79–9B) had no effect on meandering. However, when the hole diameters were increased to 6 to 10 mm (see Fig. 79–9C), the tip of the spiral wave attached to the holes, and reentry became stationary. This model shows that a critically sized anatomic obstacle converts a nonstationary meandering reentrant wavefront to a stationary one. This electrical activation changed from irregular “fibrillation-like” activity into regular monomorphic activity. However, there was no abrupt transition from functional reentry to anatomical reentry. Rather, with a small anatomical obstacle, the reentrant wavefront exhibits the characteristics of both functional and anatomical reentry. Many previous studies showed that functional reentrant wavefronts tend to have a very short life span and are frequently unstable in whole hearts. For example, electrically induced reentry in the ventricles usually has a life span averaging a few seconds in the whole heart.9,142 Under normal conditions, it is unlikely for the initial reentrant wavefronts to persist and continue to serve as the source of rapid excitation to induce sustained ventricular arrhythmia. To induce sustained arrhythmia in the whole heart, these initial spiral waves will need to break down and induce multiple spiral waves to induce VF or to anchor to a large anatomical barrier to induce VT.
Functional and anatomical reentry in isolated superfused canine right atrium. Reentry was induced by electrical stimulation. The red dots represent activation wavefront. The color then changed every 10 milliseconds from yellow to green to light blue and purple before becoming black (background color). A. Reentry without a functional obstacle. The reentrant wavefronts (spiral waves) meandered in the preparation. Bipolar electrogram showed irregular activations. B. Reentry after a 4-mm-diameter hole was created in the middle of the preparation (white circle). There is less meandering, and the activation cycle length was irregular but slower. C. The effects of a 10-mm central hole on reentrant wavefront. The reentry is no longer meandering, and the bipolar electrogram showed regular activations consistent with sustained monomorphic tachycardia. Reproduced with permission from Ikeda T, Yashima M, Uchida T, Hough D, Fishbein MC, Mandel WJ, Chen PS, Karagueuzian HS. Attachment of meandering reentrant wave fronts to anatomic obstacles in the atrium. Role of the obstacle size. Circ Res. 1997 Nov;81(5):753-764.141
Figure-eight reentry was first described by El-Sherif and coworkers in the surviving epicardial layer overlying infarction produced by occlusion of the left anterior descending artery in canine hearts in the late 1980s.143,144 The same patterns of activation can also be induced by creating artificial anatomical obstacles in the ventricles145 or during functional reentry induced by a single premature ventricular stimulation.9 In the figure-eight model, the reentrant beat produces a wavefront that circulates in both directions around a long line of conduction block (Fig. 79–10) rejoining on the distal side of the block. The wavefront then breaks through the arc of block to reexcite the tissue proximal to the block. The reentrant activation continues as two circulating wavefronts that travel in clockwise and counterclockwise directions around the two arcs in a pretzel-like configuration. The diameter of the reentrant circuit in the ventricle can be as small as a few millimeters or as large as a several centimeters. When the line of block is short and functional, the reentrant circuits are unstable and the figure-eight pattern may soon terminate.142 However, more sustained figure-eight reentry can be induced when large anatomical obstacles are present in the preparation.145
Figure-of-eight model of reentry. Isochronal activation map during monomorphic reentrant ventricular tachycardia occurring in the surviving epicardial layer overlying an infarction. Recordings were obtained from the epicardial surface of a canine heart 4 days after ligation of the left anterior descending coronary artery. Activation isochrones are drawn at 20-millisecond intervals. The reentrant circuit has a characteristic figure-of-eight activation pattern. Two circulating wavefronts advance in clockwise and counterclockwise directions, respectively, around two zones (arcs) of conduction block (heavy solid lines). The epicardial surface is depicted as if the ventricles were unfolded following a cut from the crux to the apex. A three-dimensional diagrammatic illustration of the ventricular activation pattern during the reentrant tachycardia is shown in the lower panel. END, endocardium; EPI, epicardium; LV, left ventricle; RV, right ventricle. Reproduced with permission from El-Sherif N. Reentry revisited. Pacing Clin Electrophysiol. 1988 Sep;11(9):1358-68.
A second factor that determines the stability of circus movement reentry is the tissue size. As first documented by Garrey,129 a critical mass must be present for VF to be sustained. If the tissue mass reduces to below that critical mass, VF invariably terminates. Kim et al146 induced VF in isolated and perfused swine right ventricular free wall. The tissue mass was then progressively reduced by sequential cutting. The critical mass to sustain VF in this preparation was around 20 g. As tissue mass was decreased, the number of wavefronts decreased, the life span of reentrant wavefronts increased, and the cycle length, diastolic interval, and duration of action potential lengthened. When the mass is small enough, the remaining wavefront might anchor to the papillary muscle and convert VF to VT.147 Figure 79–11 shows typical examples of activation patterns after progressive tissue mass reduction. In addition, the APD progressively lengthened and the average activation rate progressively reduced with the tissue size reduction. There was a parallel decrease in the dynamical complexity of VF as measured by Kolmogorov entropy and Poincaré plots. A period of quasiperiodicity became more evident before the conversion from VF (chaos) to a more regular arrhythmia (periodicity). Therefore, reducing tissue size is antifibrillatory. It causes a decrease in the number of wavefronts in VF by tissue mass reduction, which causes a transition from chaotic to periodic dynamics via the quasiperiodic route.147 This observation might explain the ameliorative effects of the Maze procedure in the setting of AF.148,149
Effects of tissue mass reduction on reentrant wavefronts in ventricular fibrillation. A. An isolated perfused swine right ventricle preparation. B. The patterns of activation in the right ventricle at baseline and after first, second, and third cuts. C. The average number of wavefronts after each cut in six different preparations. After third cut, a single reentrant wavefront (spiral wave) is present. Reproduced with permission from Kim YH, Garfinkel A, Ikeda T, et al: Spatiotemporal complexity of ventricular fibrillation revealed by tissue mass reduction in isolated swine right ventricle. Further evidence for the quasiperiodic route to chaos hypothesis. J Clin Invest. 1997 Nov 15;100(10):2486-2500.146
Action Potential Duration Restitution and Effective Refractory Period
A third important factor in determining the stability of circus movement reentry is the APD restitution properties of the cardiac tissue. The APD restitution describes the relationship between APD and the preceding diastolic interval. The slope of APD restitution in theory determines the stability of cardiac activation.150,151 When the slope is less than 1.0, repeated pacing of the system will induce APD alternans and dynamic instability, leading to fibrillation. However, flattening the restitution might be an antifibrillatory strategy.152 Figure 79–12 illustrates this concept with the help of computer simulation and a rabbit heart experiment. Panel A shows APD shortening and APD alternans as pacing cycle length decreases. Panel B shows two different APD restitution curves; one with slope > 1 (solid line) and one with slope < 1 (dashed line, obtained with 50% block of the calcium current). Panels C and D are results of computer simulation studies, whereas panels E and F are actual experimental data from a Langendorff-perfused rabbit heart. Flattening of the restitution curves in both simulation studies and in rabbit hearts resulted in the conversion of VF to VT.
Action potential duration (APD) restitution and stability of reentrant. A. APD shortening and APD alternans as pacing cycle length (PCL) decreases (computer simulation). Diastolic interval (DI) is measured from the end of the preceding action potential to the onset of phase 0 of the present action potential. As shown in these examples, the shorter the preceding DI, the shorter is the APD. B. APD restitution curves with slope > 1 (solid line) or < 1 (dashed line, obtained with 50% block of the calcium current). C and D. Spiral wave behavior several seconds after initiating a spiral wave in homogeneous two-dimensional tissue. All cells are identical, with either a steep (C) or shallow (D) APD restitution slope. E and F. Optically measured surface voltage maps in an intact Langendorff rabbit heart before (E) and after (F) partially blocking the L-type calcium current with D600 (0.5 mg/mL) to flatten the APD restitution slope to > 1. In E, multiple wavefronts move in a complex ventricular fibrillation (VF) pattern. In F, VF has converted to ventricular tachycardia, manifested as a stable double-armed rotor. Reproduced with permission from Weiss JN, Qu Z, Chen PS, Lin SF, Karagueuzian HS, Hayashi H, Garfinkel A, Karma A. The dynamics of cardiac fibrillation. Circulation. 2005 Aug 23;112(8):1232-1240.
In normal hearts, atrial effective refractory period (ERP) approximates APD at 70% repolarization in atria and at 90% repolarization in the ventricle (APD70-90).153,154 Abbreviation of ERP is associated with increased susceptibility for development of reentry. In experimental models of AF, without cardiovascular disease, abbreviation of atrial ERP, secondary to pharmacologic interventions or sustained rapid atrial activation, is associated with a significant increase in AF vulnerability.15,130,155,156 In structurally remodeled atria or following exposure to sodium channel blockers, ERP can outlast APD70-90 secondary to reduced excitability, leading to development of postrepolarization refractoriness. Prolongation of ERP, whether by prolongation of APD or development of postrepolarization refractoriness, can terminate and/or prevent the development of reentry and is an effective treatment for paroxysmal AF.157
In addition to APD restitution, the conduction velocity restitution is also an important factor that determines the stability of the reentrant wavefronts.158,159 Figure 79–13 shows the primary findings of those studies. At baseline, the activation rate was fast, and the dominant frequency of VF was around 16 Hz. D600 flattened the APD restitution curve and converted baseline fast (type I) VF to VT. Further increasing the D600 concentration to 2.5 or 5.0 mg/L converted VT to slow (type II) VF with an average dominant frequency around 11 Hz. Because high concentrations of D600 block Na channels as well as Ca channels, the authors hypothesized that reduced excitability might underlie type II VF, which was not driven by steep APD restitution, but was a result of broad conduction velocity restitution. Whereas steep APD restitution drives wave instability by making the waveback sensitive to small changes in diastolic interval, conduction velocity can drive wave instability by making the wavefront sensitive to small changes in diastolic interval, especially if structural and electrophysiologic heterogeneities are present.
Two types of ventricular fibrillation (VF). A. Phase maps of type 1 VF, which is characterized by a steep action potential duration (APD) restitution but narrow conduction velocity (CV) restitution curve. B. Type 2 VF, with a single meandering mother rotor (white circle) that is meandering on the epicardium. This type of VF is characterized by flat APD restitution (which prevents spiral breakup) and broad CV restitution (which facilitates wavebreak). C. Electrograms corresponding to types 1 and 2 VF. Note that there is a period of monomorphic ventricular tachycardia between types 1 and 2 VF. LAD, left anterior descending artery. Reproduced with permission from Wu TJ, Lin SF, Weiss JN, Ting CT, Chen PS. Two types of ventricular fibrillation in isolated rabbit hearts: Importance of excitability and action potential duration restitution. Circulation. 2002 Oct 1;106(14):1859-1866.158
Electrical activation and calcium dynamics are closely coupled. However, the coupling between the two can be variable, which results in an additional complex dynamics that affect the APD restitution and the stability of the reentrant wavefronts.151 Whereas voltage-Cai coupling is generally positive (ie, a longer APD produces a larger Cai transient), Cai-voltage coupling can be either positive or negative. Positive Cai-voltage coupling refers to the mode in which a larger Cai transient produces a longer APD. This occurs when the large Cai transient enhances net inward current during the action potential plateau by potentiating inward INCX to a greater extent than it reduces the ICa,L (by facilitating Ca-induced inactivation). However, negative Ca-voltage coupling refers to the mode in which a larger Cai transient causes a shorter APD. This occurs when the reduction in ICa,L predominates over the increased INCX. In addition to complex coupling, the cardiac Ca handling has its own dynamics. It is possible to have a large discrepancy between the Cai transient duration and the APD in pathologic conditions. The dynamic Vm-Cai coupling underlies the development of arrhythmogenic discordant alternans during rapid ventricular activation160,161 and increases the probability that an ectopic beat will induce reentrant excitations.151 This dynamic coupling could also affect the stability of the spiral waves and contribute to the degeneration of VT into VF.162,163,164
Reentry may also occur without circus movement. One noncircus movement reentry is reflected reentry (or reflection). The concept of reflection was first suggested by studies of the propagation characteristics of slow action potential responses in K+-depolarized Purkinje fibers.165 In strands of Purkinje fiber, Wit and coworkers demonstrated a phenomenon similar to that observed by Schmitt and Erlanger in which slow anterograde conduction of the impulse was at times followed by a retrograde wavefront that produced a “return extrasystole.”165,166 They proposed that the nonstimulated impulse was caused by circuitous reentry at the level of the syncytial interconnections, made possible by longitudinal dissociation of the bundle, as the most likely explanation for the phenomenon but also suggested the possibility of reflection. Direct evidence in support of reflection as a mechanism of arrhythmogenesis was provided by Antzelevitch and coworkers in the early 1980s.167,168 A number of models of reflection have been developed. The first of these involves use of ion-free isotonic sucrose solution to create a narrow (1.5-2 mm) central inexcitable zone (gap) in unbranched Purkinje fibers mounted in a three-chamber tissue bath (Fig. 79–14).169 In the sucrose-gap model, stimulation of the proximal segment elicits an action potential that propagates to the proximal border of the sucrose gap. Active propagation across the sucrose gap is not possible because of the ion-depleted extracellular milieu, but local circuit current continues to flow through the intercellular low resistance pathways (an Ag/AgCl extracellular shunt pathway is provided). This local circuit or electrotonic current, very much reduced on emerging from the gap, gradually discharges the capacity of the distal tissue, thus giving rise to a depolarization that manifests as a either a subthreshold response (last distal response) or a foot potential that brings the distal excitable tissue to its threshold potential (Fig. 79–15).170 Active impulse propagation stops and then resumes after a delay that can be as long as several hundred milliseconds. When anterograde (proximal to distal) transmission time is sufficiently delayed to permit recovery of refractoriness at the proximal end, electrotonic transmission of the impulse in the retrograde direction is able to reexcite the proximal tissue, thus generating a closely coupled reflected reentry. Reflection therefore results from the to-and-fro electrotonically mediated transmission of the impulse across the same inexcitable segment; neither longitudinal dissociation nor circus movement needs to be invoked to explain the phenomenon.
Delayed transmission and reflection across an inexcitable gap created by superfusion of the central segment of a Purkinje fiber with an ion-free isotonic sucrose solution. The two traces were recorded from proximal (P) and distal (D) active segments. P–D conduction time (indicated in the upper portion of the figure, in milliseconds) increased progressively with a 4:3 Wenckebach periodicity. The third stimulated proximal response was followed by a reflection. Reproduced wtih permission from Antzelevitch C: Clinical application of new concepts of parasystole, reflection, and tachycardia. Cardiol Clin. 1983 Feb;1(1):39-50.169
Discontinuous conduction (B) and conduction block (A) in a Purkinje strand with a central inexcitable zone (C). The schematic illustration is based on transmembrane recordings obtained from canine Purkinje fiber–sucrose gap preparations. An action potential elicited by stimulation of the proximal (P) side of the preparation conducts normally up to the border of the inexcitable zone. Active propagation of the impulse stops at this point, but local circuit current generated by the proximal segment continues to flow through the preparation encountering a cumulative resistance (successive gap junctions). Transmembrane recordings from the first few inexcitable cells show a response not very different from the action potentials recorded in the neighboring excitable cells, despite the fact that no ions may be moving across the membrane of these cells. The responses recorded in the inexcitable region are the electrotonic images of activity generated in the proximal excitable segment. The resistive-capacitive properties of the tissue lead to an exponential decline in the amplitude of the transmembrane potential recorded along the length of the inexcitable segment and to a slowing of the rate of change of voltage as a function of time. If, as in panel B, the electrotonic current is sufficient to bring the distal excitable tissue to its threshold potential, an action potential is generated after a step delay imposed by the slow discharge of the capacity of the distal (D) membrane by the electrotonic current (foot-potential). Active conduction of the impulse therefore stops at the proximal border of the inexcitable zone and resumes at the distal border after a step delay that can range from a few to tens or hundreds of milliseconds. Modified with permission from Antzelevitch C, Rosen MR, Janse MJ, et al: Electrotonus and reflection. Cardiac Electrophysiology: A Textbook. Mount Kisco, NY: Futura Publishing Company, Inc; 1990.
A second model of reflection involved the creation of an inexcitable zone permitting delayed conduction by superfusion of a central segment of a Purkinje bundle with a solution designed to mimic the extracellular milieu at a site of ischemia.168 The gap was shown to be largely comprised of an inexcitable cable across which conduction of impulses was electrotonically mediated. Reflected reentry has been demonstrated in isolated atrial and ventricular myocardial tissues as well.171,172,173 Reflection has also been demonstrated in Purkinje fibers in which a functionally inexcitable zone is created by focal depolarization of the preparation with long duration constant current pulses.174 Reflection is also observed in isolated canine Purkinje fibers homogeneously depressed with high K+ solution as well as in branched preparations of normal Purkinje fibers.175
Another reentrant mechanism that does not depend on circus movement and can appear to be of focal origin is phase 2 reentry. Phase 2 reentry occurs when the dome of the action potential, most commonly epicardial, propagates from sites at which it is maintained to sites at which it is abolished, causing local reexcitation of the epicardium and the generation of a closely coupled extrasystole. Accentuated spatial dispersion of repolarization is needed for phase 2 reentry to occur.
Spatial Dispersion of Repolarization
Studies conducted over the past 25 years have established that ventricular myocardium is not homogeneous but is comprised of at least three electrophysiologically and functionally distinct cell types: epicardial, M, and endocardial cells.176,177 These three principal ventricular myocardial cell types differ with respect to phase 1 and phase 3 repolarization characteristics (Fig. 79–16). Ventricular epicardial and M, but not endocardial, cells generally display a prominent phase 1, because of a large 4-aminopyridine–sensitive transient outward current (Ito), giving the action potential a spike and dome or notched configuration. These regional differences in Ito, first suggested based on action potential data,178 have now been directly demonstrated in ventricular myocytes from a wide variety of species including canine,179 feline,180 guinea pig,181 swine,182 rabbit,183 and humans.184,185 Differences in the magnitude of the action potential notch and corresponding differences in Ito have also been described between right and left ventricular epicardium.186 Similar interventricular differences in Ito have also been described for canine ventricular M cells.187 This distinction is thought to form the basis for why the Brugada syndrome, a channelopathy-mediated form of sudden death, is a right ventricular disease.
Action potential characteristics recorded from epicardial, M, and endocardial regions of the canine left ventricle.
Recent optical mapping studies using normal and failing human ventricles confirmed the presence of M-cell islands in the midmyocardial layer.84,188,189 These M-cell islands are characterized by long APDs. A large APD gradient is present between the APD within the island and the surrounding myocardium. Apamin, a specific SK current blocker, prolonged APDs in the surrounding myocardium to a greater extent than within the M-cell island.84 Because apamin is a highly specific blocker of IKAS,84 these findings suggest a highly heterogeneous transmural distribution of the IKAS. The IKAS deficiency may contribute to the long APD of the M cells.
Between the surface epicardial and endocardial layers are transitional and M cells. M cells are distinguished by the ability of their action potential to prolong disproportionately relative to the action potential of other ventricular myocardial cells in response to a slowing of rate and/or in response to APD-prolonging agents.176,190,191 In the dog, the ionic basis for these features of the M cell include the presence of a smaller slowly activating delayed rectifier current (IKs),83 a larger late sodium current (late INa),89 and a larger Na-Ca exchange current (INCX).192 In the canine heart, the rapidly activating delayed rectifier (IKr) and inward rectifier (IK1) currents are similar in the three transmural cell types. Transmural and apical-basal differences in the density of IKr channels have been described in the ferret heart.193 Amplification of transmural heterogeneities normally present in the early and late phases of the action potential can lead to the development of a variety of arrhythmias, including Brugada, early repolarization, long QT, and short QT syndromes as well as catecholaminergic VT. The genetic mutations associated with these inherited channelopathies are listed in Table 79–2. Their resulting gain or loss of function underlies the development of the arrhythmogenic substrate and triggers.
TABLE 79–2.Genetic Disorders Causing Cardiac Arrhythmias in the Absence of Structural Heart Disease (Primary Electrical Disease) ||Download (.pdf) TABLE 79–2. Genetic Disorders Causing Cardiac Arrhythmias in the Absence of Structural Heart Disease (Primary Electrical Disease)
| ||Disorder ||Rhythm ||Inheritance ||Locus ||Ion Channel ||Gene |
|LQTS (RW) ||LQT1 ||TdP ||AD ||11p15 ||↓IKs ||KCNQ1, KvLQT1 |
| ||LQT2 ||TdP ||AD ||7q35 ||↓IKr ||KCNH2, HERG |
| ||LQT3 ||TdP ||AD ||3p21 ||↑INa-L ||SCN5A, Nav1.5 |
| ||LQT4 ||TdP ||AD ||4q25 || ||ANKB, ANK2 |
| ||LQT5 ||TdP ||AD ||21q22 ||↓IKs ||KCNE1, minK |
| ||LQT6 ||TdP ||AD ||21q22 ||↓IKr ||KCNE2, MiRP1 |
| ||LQT7 ||TdP ||AD ||17q23 ||↓IK1 ||KCNJ2, Kir 2.1 |
| ||LQT8 ||TdP ||AD ||6q8A ||↑ICa ||CACNA1C, CaV1.2 |
| ||LQT9 ||TdP ||AD ||3p25 ||↑INa-L ||CAV3, caveolin-3 |
| ||LQT10 ||TdP ||AD ||11q23.3 ||↑INa-L ||SCN4B, Navb4 |
| ||LQT11 ||TdP ||AD ||7q21-q22 ||↓IKs ||AKAP9, Yotiao |
| ||LQT12 ||TdP ||AD ||20q11.2 ||↑INa-L ||SNTA1, α1-syntrophin |
| ||LQT13 ||TdP ||AD ||11q24.3 ||(IK-ACh ||KCNJ5, Kir3.4 |
| ||LQT14 ||TdP ||AD ||14q32.11 ||↑ICa ||CALM1, calmodulin1 |
| ||LQT15 ||TdP ||AD ||2p21.3-p21.1 ||↑ICa ||CALM2, calmodulin2 |
| ||LQT16 ||AVB ||UN ||19q13 ||UN ||CALM3, calmodulin2 |
|LQTS (JLN) || ||TdP ||AR ||11p15 ||↓IKs ||KCNQ1, KvLQT1 |
| || || || ||21q22 ||↓IKs ||KCNE1, minK |
|BrS ||BrS1 ||PVT ||AD ||3p21 ||↓INa ||SCN5A, NaV1.5 |
| ||BrS2 ||PVT ||AD ||3p24 ||↓INa ||GPD1L |
| ||BrS3 ||PVT ||AD ||12p13.3 ||↓ICa ||CACNA1C, CaV1.2 |
| ||BrS4 ||PVT ||AD ||10p12.33 ||↓ICa ||CACNB2b, Cavβ2b |
| ||BrS5 ||PVT ||AD ||19q13.1 ||↓INa ||SCN1B, NaVβ1 |
| ||BrS6 ||PVT ||AD ||11q13-q14 ||↓ICa ||KCNE3, MiRP2 |
| ||BrS7 ||PVT ||AD ||11q23.3 ||↓INa ||SCN3B, Navb3 |
| ||BrS8 ||PVT ||AD ||12p11.23 ||↑IK-ATP ||KCNJ8, Kir6.1 |
| ||BrS9 ||PVT ||AD ||7q21.11 ||↓ICa ||CACNA2D1, Cavα2δ1 |
| ||BrS10 ||PVT ||AD ||1p13.2 ||↑Ito ||KCND3, Kv4.3 |
| ||BrS11 ||PVT ||AD ||17p13.1 ||↓INa ||RANGRF, MOG1 |
| ||BrS12 ||PVT ||AD ||3p21.2-p14.3 ||↓INa ||SLMAP |
| ||BrS13 ||PVT ||AD ||12p12.1 ||↑IK-ATP ||ABCC9, SUR2A |
| ||BrS14 ||PVT ||AD ||11q23 ||↓INa ||SCN2B, Navß2 |
| ||BrS15 ||PVT ||AD ||12p11 ||↓INa ||PKP2, plakophillin2 |
| ||BrS16 ||PVT ||AD ||3q28 ||↓INa ||FGF12, FHAF1 |
| ||BrS17 ||PVT ||AD ||3p22.2 ||↓INa ||SCN10A, Nav1.8 |
| ||BrS18 ||PVT ||AD ||6q ||↑INa ||HEY2 (transcriptional factor) |
|ERS ||ERS1 ||PVT ||AD ||12p11.23 ||↑IK-ATP ||KCNJ8, Kir6.1 |
| ||ERS2 ||PVT ||AD ||12p13.3 ||↓ICa ||CACNA1C, Cav1.2 |
| ||ERS3 ||PVT ||AD ||10p12.33 ||↓ICa ||CACNB2b, Cavß2b |
| ||ERS4 ||PVT ||AD ||7q21.11 ||↓ICa ||CACNA2D1, Cavα2δ1 |
| ||ERS5 ||PVT ||AD ||12p12.1 ||↑IK-ATP ||ABCC9, SUR2A |
| ||ERS6 ||PVT ||AD ||3p21 ||↓INa ||SCN5A, Nav1.5 |
| ||ERS7 ||PVT ||AD ||3p22.2 ||↓INa ||SCN10A, Nav1.8 |
|SQTS ||SQT1 ||VT/VF ||AD ||7q35 ||↑IKr ||KCNH2, HERG |
| ||SQT2 || ||AD ||11p15 ||↑IKs ||KCNQ1, KvLQT1 |
| ||SQT3 || ||AD ||17q23.1-q24.2 ||↑IK1 ||KCNJ2, Kir2.1 |
| ||SQT4 || ||AD ||12p13.3 ||↓ICa ||CACNA1C, CaV1.2 |
| ||SQT5 || ||AD ||10p12.33 ||↓ICa ||CACNB2b, Cavβ2b |
| ||SQT6 || ||AD || ||↓ICa ||CACNA2D1, Cavα2δ1 |
|CPVT ||CPVT1 ||VT ||AD ||1q42-q43 || ||RYR2, ryanodine receptor 2 |
| ||CPVT2 ||VT ||AR ||1p13-q21 || ||CASQ2, calsequestrin 2 |
| ||CPVT3 ||VT ||AR ||6q22.31 || ||TRDN, triadin |
| ||CPVT4 ||VT ||AD ||14q32.11 ||↑ICa ||CALM1, calmodulin1 |
J-Wave Syndrome and Phase 2 Reentry
The J-Wave Syndromes and Phase 2 Reentry
The appearance of prominent electrocardiographic J waves has long been associated with hypothermia194,195,196 and hypercalcemia,197,198 and more recently with life-threatening ventricular arrhythmias.199 Under these circumstances, the accentuated J wave is often so broad as to appear as an ST-segment elevation, as in cases of Brugada syndrome (BrS). A normal J wave in humans typically appears as a J-point elevation, with much of the J wave buried inside the QRS. An early repolarization (ER) pattern in the ECG, characterized by a distinct J wave, J-point elevation, and a notch or slur of the terminal part of the QRS with and without an ST-segment elevation, has traditionally been viewed as benign.200,201 In 2000, this view was challenged202 based on experimental data showing that this ECG manifestation predisposes to the development of polymorphic VT and VF in coronary-perfused wedge preparations.1,202,203,204 This hypothesis was validated by seminal studies of Haïssaguerre et al,205 Nam et al,206 and Rosso et al.207 These formative studies, coupled with many additional case-control and population-based studies, have provided clinical evidence for an increased risk for development of life-threatening arrhythmic events and sudden cardiac death (SCD) among patients presenting with an ER pattern, referred to as early repolarization syndrome (ERS).
An expert consensus statement recently published by MacFarlane and coworkers208 has provided recommendations for measurement and reporting of ER and J waves. The taskforce recommends that peak of an end QRS notch and/or the onset of an end QRS slur be designated as Jp and that Jp should exceed 0.1 mV in two or more contiguous inferior and/or lateral leads of a standard 12-lead electrocardiogram for ER to be present.208 It was further recommended that the start of the end QRS notch or J wave be designated as Jo and the termination as Jt.
BrS and ERS are both associated with vulnerability to development of polymorphic VT and VF leading to SCD1,205,206,209 in young adults and occasionally to sudden infant death syndrome.210,211,212 The region generally most affected in ERS is the inferior region of the left ventricle, and in BrS, it is the anterior right ventricular outflow tract.205,207,213,214,215,216,217 BrS is characterized by accentuated J waves, appearing as a coved-type ST-segment elevation in the right precordial leads, V1-V3, whereas ERS is characterized by J waves, Jo elevation, notch or slur of the terminal part of the QRS, and ST-segment or Jt elevation in the lateral (type I), inferolateral (type II), or inferolateral plus anterior or right ventricular leads (type III).199 ER pattern is often encountered in healthy individuals, particularly in young black individuals and athletes. ER pattern is also observed in acquired conditions, including hypothermia and ischemia.1,218,219
Mechanisms Underlying Electrocardiographic and Arrhythmic Manifestations of Brugada Syndrome and Early Repolarization Syndrome
The J-wave syndromes are so named because they involve accentuation of the electrocardiographic J wave.199 The J wave is thought to be inscribed as a consequence of transmural differences in the manifestation of the action potential notch between epicardium and endocardium secondary to heterogeneous transmural distribution of the transient outward current (Ito).220
The ionic and cellular mechanisms underlying J-wave syndromes have been the subject of some controversy.221,222 Two central hypotheses have been advanced to explain BrS: (1) The repolarization hypothesis maintains that an outward shift in the balance of currents in right ventricular epicardium leads to repolarization abnormalities that give rise to phase 2 reentry and the generation of closely coupled premature beats capable of precipitating VT/VF; and (2) the depolarization hypothesis suggests that slow conduction in the right ventricular outflow tract (RVOT) and other regions of the right ventricle, secondary to structural defects including fibrosis and reduced Cx43, leading to discontinuities in conduction, plays a key role in the development of the electrocardiographic (ECG) and arrhythmic manifestations of the syndrome. These theories are not mutually exclusive and may indeed be synergistic.
Apparently compelling evidence in support of the depolarization hypothesis was advanced by Nademanee et al223 showing that radiofrequency ablation of epicardial sites displaying fractionated bipolar electrograms and late potentials in the RVOT of patients with BrS reduces the ECG and arrhythmic manifestations of the syndrome. Similar results have been reported by Brugada et al224 and in a case report published by Sacher and coworkers.225 Sacher et al225 also observed that accentuation of the Brugada ECG by ajmaline was associated with increasing area of low-voltage and fragmented electrogram activity and a more prominent ST-segment elevation.224 These authors concluded that the late potential and fractionated electrogram activity are caused by conduction delays within the RVOT and that ablation of the sites of slow conduction is the basis for the ameliorative effect of ablation therapy.223,224,225
A direct test of this hypothesis by Szél and coworkers226 provided evidence for an alternative explanation. Using an experimental model of BrS, they showed that low-voltage fractionated electrogram activity nearly identical to that observed by Nademanee et al223 in the RVOT of BrS patients develops as a result of desynchronization in the appearance of the second action potential upstroke, secondary to accentuation of the epicardial action potential notch and not to slow or delayed conduction (Fig. 79–17). They also showed that high-frequency late potentials develop in the right ventricular epicardium as a result of concealed phase 2 reentry and not as a result of delayed conduction as generally presumed.226
New interpretation of fractionated electrogram (EG) activity and late potentials. Desynchrony in the appearance of the epicardial action potential second upstroke gives rise to fractionated epicardial EG activity, and concealed phase 2 reentry gives rise to high-frequency late potentials in the setting of Brugada syndrome (BrS). A. Shown are right precordial lead recordings and unipolar and bipolar EGs from the right ventricular outflow tract (RVOT) of a BrS patient. B. Electrocardiogram (ECG), action potentials from endocardium (Endo) and two epicardial (Epi) sites, and a bipolar epicardial EG (Bipolar EG) all simultaneously recorded from a coronary-perfused right ventricular wedge preparation treated with the Ito agonist NS5806 (5 μM) and the calcium channel blocker verapamil (2 μM) to induce the Brugada phenotype. Basic cycle length = 1000 milliseconds. C. Bipolar EGs recorded from the epicardial and endocardial surfaces of the RVOT in a patient with BrS. The epicardial EG displays fractionated electrogram activity as well as a high-frequency late potential (130 milliseconds delay). D. Bipolar EGs recorded from the epicardium and endocardium of a coronary-perfused wedge model of BrS, together with action potential recordings from an endocardial and two epicardial sites and a transmural ECG. Slow or delayed conduction was never observed. A and B, reproduced with permission from Nademanee K, Veerakul G, Chandanamattha P, et al: Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation. 2011 Mar 29;123(12):1270-1279. C and D, reproduced with permission from Szél T, Antzelevitch C, et al: Abnormal repolarization as the basis for late potentials and fractionated electrograms recorded from epicardium in experimental models of Brugada syndrome. J Am Coll Cardiol. 2014 May 20;63(19):2037-2045.
In another series of studies, Patocskai et al227 targeted these regions of fractionated low-voltage electrogram activity and late potentials as a result of abnormal repolarization for ablation. Ablation of the right ventricular epicardium reduced the manifestation of J waves and ST-segment elevation and abolished all arrhythmic activity, a result identical to that obtained by Nademanee and coworkers (Fig. 79–18). They concluded that ablation ameliorates the BrS phenotype not by eliminating regions of delayed conduction but rather by eliminating the epicardial cells responsible for the repolarization abnormalities that give rise to phase 2 reentry and VT/VF.1,227
Radiofrequency ablation of the epicardial surface abolishes the Brugada syndrome (BrS) electrocardiogram (ECG) and suppresses arrhythmogenesis in coronary-perfused canine right ventricular wedge model of BrS. Transmembrane action potentials (APs) were simultaneously recorded from one endocardial (Endo) and two epicardial (Epi) sites together with epicardial bipolar electrograms (EGs) and a transmural pseudo-ECG. The epicardial bipolar EGs were recorded at 10- to 1000-Hz bandwidth (black trace) and were simultaneously band-pass filtered at 30 to 200 Hz, 50 to 200 Hz, and 100 to 200 Hz (green traces). Column 1: Control. Column 2: Recorded 45 minutes after the addition of the Ito agonist NS5806 (4 μM) to the coronary perfusate. Column 3: Recorded 45 minutes after the concentration of NS5806 was raised to 8 μM. High- and low-frequency late potentials (LPs) are apparent in the EG recordings resulting from progressive delay in the appearance of the second upstroke of the Epi AP secondary to accentuation of the AP notch. Column 4: Recorded 15 minutes after the addition of the ICa blocker verapamil (1 μM) to the coronary perfusate. Column 5: Recorded after 40 minutes of exposure to verapamil (1 μM). Loss of the AP dome at Epi1 but not Epi2 gives rise to a phase 2 reentrant beat, which precipitates polymorphic ventricular tachycardia. Column 6: Recorded 2 hours after radiofrequency ablation of the epicardial surface and 1 hour after reintroduction of the provocative agents to the perfusate (in the same concentration as before ablation). APs are now recorded from the deep subepicardium-midmyocardium (Mid1, Mid2) instead of the epicardial surface. Ablation markedly suppressed the BrS phenotype and abolished all arrhythmic activity by destroying the cells exhibiting the pronounced repolarization abnormalities. Slow or delayed conduction was not observed at any phase. Reproduced with permission from Patocskai B, Antzelevitch C: Novel Therapeutic Strategies for the Management of Ventricular Arrhythmias Associated with the Brugada Syndrome. Expert Opin Orphan Drugs. 2015;3(6):633-651.227
In an attempt to create an in vivo model of BrS, Park et al228 genetically engineered Yucatan minipigs to heterozygously express a nonsense mutation in SCN5A (E558X), which was originally identified in a child with BrS. Atrial myocytes isolated from the SCN5AE558X/+ pigs showed a loss of function of INa, and the minipigs displayed conduction abnormalities consisting of prolongation of the P wave, QRS complex, and PR interval. A BrS phenotype was never observed, not even after the administration of flecainide. These observations are expected as a result of the lack of Ito in the pig, which is a prerequisite for the development of the repolarization abnormalities associated with BrS. These observations were argued to provide strong evidence against the depolarization hypothesis and for the repolarization hypothesis.227
Additional evidence in support of the repolarization hypothesis derives from the observation that monophasic action potentials recorded from the epicardial and endocardial surfaces of the RVOT of a patient with BrS are nearly identical to transmembrane action potentials recorded from the epicardial and endocardial surfaces of the wedge model of BrS.229,230 In both cases, the action potential displays a prominent accentuation of the notch in epicardium, but not endocardium, without any major transmural conduction delays.
Zhang et al231 recently conducted noninvasive ECG imaging of 25 patients with BrS and 6 patients with right bundle branch block. The authors reported both slow discontinuous conduction and steep dispersion of repolarization in the RVOT of patients with BrS. ECG imaging was able to differentiate between BrS and right bundle branch block. Interestingly, in studying the response to an increase in rate, they found increased fractionation of the electrogram but reduced ST-segment elevation, again suggesting that conduction impairment was not the principal cause of the BrS ECG.
Using an experimental model of ERS, Koncz et al215 recently provided evidence that the ECG and arrhythmic manifestations of ERS are similar to those of BrS. They reported that accentuation of transmural gradients in the left ventricular wall are responsible for the repolarization abnormalities underlying ERS, giving rise to J-point elevation, distinct J waves, or slurring of the terminal part of the QRS. The repolarization defect was accentuated by cholinergic agonists and reduced by quinidine, isoproterenol, cilostazol, and milrinone, accounting for the ability of these agents to reverse the repolarization abnormalities responsible for ERS.215,232 Higher levels of Ito in the inferior left ventricle were shown to underlie the greater vulnerability of the inferior left ventricular wall to VT/VF.215
Using ECG imaging, Rudy and coworkers233 provided additional evidence in support of the repolarization abnormalities by identifying abnormally short activation-recovery intervals in the inferior and lateral regions of the left ventricle and a marked dispersion of repolarization. Recent ECG image mapping studies performed in an ERS patient during VF demonstrated VF rotors anchored in the inferolateral left ventricular wall.234
Similarities and Differences Between Brugada Syndrome and Early Repolarization Syndrome
ERS and BrS display several phenotypic similarities, once again suggesting similar pathophysiologic mechanisms.203,220,235,236,237 In both syndromes, (1) males strongly predominate238,239; (2) patients may be totally asymptomatic until presenting with sudden cardiac arrest; (3) the highest incidence of VF or SCD occurs in the third decade of life, perhaps tied to testosterone levels in males240; (4) appearance of accentuated J waves and ST-segment elevation are generally associated with bradycardia or pauses,241,242 explaining why VF in both syndromes often occurs during sleep or at a low level of physical activity243,244; (5) phenotype is associated with mutations or rare variants in the same genes (see Table 9–2); (6) electrical storms and associated J-wave manifestations can be suppressed using β-adrenergic agonists245,246,247,248; and (7) chronic oral pharmacologic therapy using quinidine,249,250 cilostazol,245,247,251,252,253,254,255 denopamine,245,251 and bepridil247 suppresses the development of VT/VF secondary to inhibition of Ito, augmentation of ICa or INa, or both.206,252,256
Differences between the two syndromes include: (1) the region of the heart most affected (RVOT vs inferior left ventricle); (2) greater incidence of late potentials in signal-averaged ECGs in BrS (60%) versus ERS (7%)244; (3) greater inducibility of VF during electrophysiologic study in BrS than in ERS; (4) greater elevation of JO, JP, or Jt (ST-segment elevation) in response to sodium channel blockers in BrS versus ERS; and (5) higher prevalence of AF in BrS versus ERS.257
How Can We Distinguish Between a Depolarization Versus Repolarization Defect?
When notches appear in the rising phase of the R wave, it is well established and accepted that these are a result of conduction defects within the ventricular myocardium.1 When the notch occurs at the terminal portion of the QRS, thus resembling a J wave, it may be a result of either a conduction or repolarization defect.236,258 The response to prematurity or to an increase in rate may be able to differentiate between the two.259 Delayed conduction invariably becomes more exaggerated at faster rates or during premature beats, thus leading to an accentuation of the QRS notch, whereas repolarization defects are usually moderated, resulting in a diminution of the J wave at faster rates. Although typical J waves are usually accentuated with bradycardia or long pauses, the opposite has also been described.260,261 J waves are often seen in young males with no apparent structural heart diseases, whereas intraventricular conduction delay is often observed in older individuals or in cases of postmyocardial infarction or cardiomyopathy.258,260 The prognostic value of a fragmented QRS has been demonstrated in BrS,262,263 although fragmentation of the QRS is not associated with increased risk in the absence of cardiac disease.264 Another factor that may aid in the differential diagnosis of J wave versus intraventricular conduction delay–mediated syndromes is gender, since the appearance of J waves is strongly male predominant.
Thoracic Veins as an Arrhythmogenic Structure
Because of the discovery that pulmonary veins are important sources of AF,265 the arrhythmogenic mechanisms of the pulmonary veins and other thoracic veins deserve separate discussion. Although the original report showed that rapid activations in the pulmonary veins are responsible for triggering AF, rapid activations from other thoracic veins, such as the superior vena cava and the vein of Marshall,266,267 are also important for AF to occur and sustain. Both reentrant and non-reentrant mechanisms may underlie the rapid activations within these thoracic veins.268,269 The embryologic development of the pulmonary veins is closely related to the development of the sinus venosus segment of the heart, which are known to be structures that can generate automaticity.270,271,272 Brunton and Fayer273 first demonstrated independent pulmonary vein contractions in rabbits and cats. They also noted that, although both atria subsequently ceased to beat, the pulmonary veins in both lungs continued to pulsate. These seminal observations have two important implications. The first is that the pulmonary vein has contractile muscle fibers. The second is that the pulmonary vein is capable of generating electrical activity independent of the atria. Findings by other investigators are compatible with these results. Masani et al274 showed that node-like cells are present in the myocardial layer of the pulmonary vein of rats. Subsequent studies showed multiple different arrhythmogenic cell types are present in the pulmonary veins. These cell types include periodic-acid Schiff–positive cells,275,276 Purkinje-like cells,277 interstitial Cajal-like cells,278,279 and melanocyte-like cells.280 All of these cells are potentially electrically active and can contribute to the generation of either automaticity or triggered activity.
Cheung281 demonstrated that ouabain infusion or norepinephrine infusion could trigger the onset of repetitive rapid responses from the distal pulmonary vein. Chen et al282,283 performed transmembrane potential recording of isolated canine pulmonary vein myocytes using standard glass microelectrodes. They reported several types of electrical activity within the pulmonary veins, including silent electrical activity, fast response action potentials driven by electrical stimulation, and spontaneous fast or slow response action potentials with or without EADs. The incidence of action potentials with an EAD and of spontaneous tachycardias is much greater in dogs with chronic rapid pacing than in normal dogs. The authors concluded that pulmonary veins have arrhythmogenic ability through spontaneous activities or high-frequency irregular rhythms. Because of the short APD, the pulmonary veins are also prone to the development of late phase 3 EADs and triggered arrhythmias.120,121,284 In addition to increased propensity for automaticity and triggered activity, the complex myocardial fiber orientation in the pulmonary veins and at the pulmonary vein–left atrial junction can cause conduction blocks and facilitate reentrant excitations in that region.275 In addition, increased fibrosis at the pulmonary vein–left atrial junction in heart failure may play an important role in determining the characteristics of the reentrant wavefronts, thereby perpetuate AF.285