Cellular Physiology and Clinical Manifestations of ......STATE-OF-THE-ART REVIEW Cellular Physiology and Clinical Manifestations of Fascicular Arrhythmias in Normal Hearts Raphael

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STATE-OF-THE-ART REVIEW

Cellular Physiology and ClinicalManifestations of Fascicular Arrhythmiasin Normal Hearts
Raphael K. Sung, MD,a Penelope A. Boyden, PHD,b Melvin Scheinman, MDc
ABSTRACT

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Fascicular ventricular arrhythmias represent a spectrum of ventricular tachycardias dependent on the specialized

conduction system. Although they are more common in structurally abnormal hearts, there is an increasing body of

literature describing their role in normal hearts. In this review, the authors present data from both basic and clinical

research that explore the current understanding of idiopathic fascicular ventricular arrhythmias. Evaluation of the cellular

electrophysiology of the Purkinje cells shows clear evidence of enhanced automaticity and triggered activity as

potential mechanisms of arrhythmias. Perhaps more importantly, heterogeneity in conduction system velocity and

refractoriness of the left ventricular conduction system in animal models are in line with clinical descriptions of re-entrant

fascicular arrhythmias in humans. Further advances in our understanding of the conduction system will help bridge

the current gap between basic science and clinical fascicular arrhythmias. (J Am Coll Cardiol EP 2017;-:-–-)

© 2017 by the American College of Cardiology Foundation.

F ascicular arrhythmias encompass a wide spec-trum of ventricular arrhythmias that aredependent on the specialized conduction

system including the His, right and left bundles,left-sided fascicular bundles, and the extensive sub-endocardial Purkinje network of fibers extendingout from the fascicular bundles. Purkinje-dependentarrhythmias occur in both structurally normal aswell as cardiomyopathic hearts, particularly whenadvanced conduction system disease is present. Forthis review, we focus on idiopathic left fascicularventricular tachycardia (LFVT) limited to structurallynormal hearts.

ANATOMY OF HIS-PURKINJE SYSTEM

The key to understanding the spectrum of fasciculararrhythmias and their mechanisms comes from a

m the aDepartment of Medicine, National Jewish Health, Denver, Color

rsity, New York, New York; and the cDepartment of Medicine, University o

. Scheinman has received honoraria from St. Jude Medical, Boston Scientifi

er authors have reported that they have no relationships relevant to the

nuscript received January 11, 2017; revised manuscript received June 22,

thorough understanding of the His-Purkinje system(HPS) anatomy. The conduction system and itspostulated function were originally described by Dr.Sunao Tawara in 1906, demonstrating trifascicularbranching off of the main left bundle before extend-ing into a complex Purkinje network (1). The CentralIllustration, Part A depicts the original descriptionfrom Tawara, with 3 distinct fascicular bundles (leftanterior fascicle [LAF], left septal fascicle [LSF], andleft posterior fascicle [LPF]) arising from the main leftbundle before extending into a web-like network ofPurkinje fibers.

On the basis of histological evaluation of 20 healthyhuman hearts, Demoulin and Kulbertus (2) revealedthe significant anatomic variations in the morphologyof fascicular branches, with 4 major patterns of LSForganization observed (Figure 1): 1) extension of theLSF from the main left bundle between the angle

ado; bDepartment of Pharmacology, Columbia Uni-

f California San Francisco, San Francisco, California.

c, Biotronik, Medtronic, and Biosense Webster. Both

contents of this paper to disclose.

2017, accepted July 27, 2017.

http://dx.doi.org/10.1016/j.jacep.2017.07.011

ABBR EV I A T I ON S

AND ACRONYMS

LV = left ventricle/ventricular

PVC = premature ventricular

complex

RBB = right bundle branch

RBBB = right bundle branch

block

VT = ventricular tachycardia

Sung et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7

Fascicular Arrhythmias in Normal Hearts - 2 0 1 7 :- –-

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formed by the LAF and LPF; 2) extensiondirectly from the LAF; 3) extension directlyfrom the LPF; and 4) contribution of fibersfrom both LAF and LPF to form either a septalbranch or a septal fiber network (2).

Further evidence for a functional tri-fascicular nature comes from activationmapping confirming presence of 3 earlyendocardial activation sites during sinusrhythm (3,4), as well as newer recognition of

the electrocardiographic (ECG) pattern of LSF blockrepresented by prominent R waves V1/V2, a mildincrease in QRS duration, and loss of septal forces(Online Figure 1) (5,6).

EARLY DEVELOPMENT OF THE HIS

PURKINJE NETWORK

Current research suggests that the HPS is of sub-endocardial origin. Following looping of the embry-onic heart tube, certain gene programs begin toactivate expression of genes encoding connexin (Cx)proteins in developing Purkinje cells (PCs), specif-ically Cx40 and Cx43 (gap junction proteins), as wellas Nav1.5, the cardiac sodium channel. This promotescell-to-cell conduction of PCs at a high rate and allowsfor nondriven electrical activity, such as triggered orspontaneous activity. These changes isolate the HPSfrom working myocardium, allowing its furtherdevelopment (7,8). Studies in birds and mammalshave shown that bundle branches and subendocardiallayer of PCs are formed from the subendocardialtrabeculae of the embryonic hearts (9,10).

To serve their function during cardiac excitation,PCs need to align and become encapsulated to form3-dimensional networks in the subendocardium aswell as free running bundles (which eventuallycombine to form fascicles). Single PC morphology isaltered depending on the nature of this connectivetissue sheath. Most single-canine PCs form acolumnar shape: they are longer and wider thanventricular myocytes, running parallel to each other,with finger-like gap junctions mostly at terminal endswith few side-to-side junctions (Figure 2A). However,our laboratory (Boyden) has observed that in any PCpreparation from normal canine left ventricular (LV)subendocardium, 10% of PCs are pancake-shapedwith gap junctions surrounding the individual cell(Figure 2B). The arrangement of gap junctions in thedifferent cellular forms is well suited for variousfunctions. The columnar, laterally connected PCskeep the conducting wave front spatially uniformwithin the strand, whereas side-to-side junctions ofthe pancake cell provide transverse interconnections,

allowing quick dispersion of the wave front in mul-tiple directions. To our knowledge, there are no re-ports of anisotropic conduction in Purkinje bundlesfrom normal hearts.

Later in development, free running strands extendfrom the bundle branches toward the trabeculatedmyocardium but remain insulated from underlyingmyocardium by connective sheaths. Thus, electricalactivation cannot escape into myocardium (11).Eventually, PCs form electrical junctions with ven-tricular myocytes through Purkinje-muscle junctions.Ventricular activation occurs at these specific sites.Because the Purkinje network must excite a largeventricular mass, a transitional layer of cells serve asa high resistance barrier between myocardium andPCs (12).

Importantly, a propagated premature impulse,occurring close in time to the functional refractoryperiod of the preparation, will travel through tissue invarious stages of repolarization. If the impulse travelsantegrade from the bundle branch to free-wall mus-cle, it will propagate through tissues, where actionpotentials progressively lengthen proximal to the“gate” and progressively shorten distal to the “gate”(13). This “gate” is a property of LV tissues and pro-tects retrograde conduction from ventricularmyocardium up the Purkinje fiber bundles.

PURKINJE CELLULAR ELECTROPHYSIOLOGY

AND REQUIREMENTS FOR RE-ENTRY

Animal models have shown that conduction is notuniform throughout the specialized conduction sys-tem. Mapping of conduction velocity (CV) along theconduction system in normal murine hearts revealedheterogeneity of CV at various parts of the heart,specifically with reduced CV in the midseptum (14).Careful histological examination showed thatalthough there are regional differences in expressionpattern and distribution of gap junction proteins, themost likely cause of significant CV reduction in themidseptum is due to local changes in bundle brancharchitecture. In this region, there is intense branchingof bundle branch fibers, resulting in load mismatchor increased path length (14). In canine hearts, CV isfaster in proximal bundle branch areas than inthe distal network areas. Some have suggested asimilar architecture exists in human hearts (1,15).These variations in delay and CV may serve as thephysiological substrate for fascicular mediatedtachycardias.

Even in normal hearts, unidirectional block,slowed conduction, and differences in refractorinessmay lead to re-entry within the Purkinje network.

CENTRAL ILLUSTRATION Summary of Fascicular Arrhythmias in Normal Hearts

Sung, R.K. et al. J Am Coll Cardiol EP. 2017;-(-):-–-.

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As an example, in canine hearts, PC action potentialduration (APD) decreases progressively from base ofthe heart toward the apex (11). Heterogeneity of APDsand the presence of a slowly conducting prematurestimulus may lead to re-excitation via large macro–re-entrant circuits involving multiple Purkinje bundles.

Small macro–re-entrant circuits may also existwithin the Purkinje fascicles (PFs). Because APD het-erogeneity may not exist within a fascicle, an area ofslowed conduction is required to initiate a functionalblock, creating anatomical re-entry in the fascicle.The mechanism of slowed conduction within the PC ismost likely due to significant changes in sodiumcurrent function. PC sodium current properties per seare unlikely to affect the slowed conduction seen inthe normal PF. Rather, the voltage-dependent prop-erties of the Na channel and the slow phase of ter-minal action potential (AP) repolarization of a PC willaffect sodium channel availability. This phase of APrepolarization is strongly controlled by the IK1 potas-sium channel, which differs in PCs and ventricularcells. In PCs, the outward IK1 current is weak, and anysmall inward current can easily overcome it at restingvoltages (16). This decreases the resting membranepotential thereby reducing the availability of Nachannels for the next AP upstroke. This may result inslowed conduction and/or functional block.

PURKINJE CELLULAR AUTOMATICITY AND

TRIGGERABILITY

Nondriven electrical activity due to enhanced auto-maticity can occur in normal PFs. Similar to sinoatrialnodal cells, PF automaticity is affected by the pres-ence of pacemaker ion channels (e.g., HCN) as well asintracellular Ca2þ cycling. As such, it would be sen-sitive to ryanodine and/or ivabradine (17). Corre-spondingly, one can postulate mechanisms that may

CENTRAL ILLUSTRATION Continued

(A) A reproduction of Tawara’s original drawing (1) depicting the left bu

ventricle. (B) Schema of left ventricular system conduction tissue and fas

FVT is highlighted in red. The wavy line represents abnormal Purkinje tis

Purkinje tissue may be located near the ventricular exit site or more pro

purple, with a similar mechanism as described in the previous text. LSF (o

auxiliary or upper septal fascicle responsible for retrograde conduction w

(RBB), LPF, and/or LAF resulting in a narrow QRS complex. Typical BBR

and retrograde conduction up the left bundle branch (LBB). Last, focal F

off of the LPF, although it may originate off of other fascicles (includin

same focal FVT can trigger ventricular fibrillation (VF), typically arising

ablation characteristics for each arrhythmia type. AVN ¼ atrioventricula

HB ¼ His bundle; ILVT ¼ idiopathic left fascicular ventricular tachycardi

anterior fascicle; PVC ¼ premature ventricular complex.

result in enhanced automaticity similar to that forsinoatrial nodal cells.

In addition to automaticity, triggered activity inPC/PFs can result from both early afterdepolarizations(EADs) and delayed afterdepolarizations (DADs).

EADs occur during the plateau phase of the AP andare enhanced by sympathetic stimulation. PCs aresusceptible to EADs due to their intrinsically longAPDs due to both late Ca2þ and Na currents. Smallalterations in the amplitude of either of these cur-rents can result in EADs. Early afterdepolarizations inmyocytes are not due to spontaneous regional in-creases in [Ca2þ]i or propagating Ca2þ waves. Rather,a change in membrane potential primarily causes theobserved increases in [Ca2þ]i during an EAD. Evi-dence supporting a role for the L-type Ca2þ windowcurrent in drug-induced EADs in sheep Purkinje in-cludes the demonstration of the appropriate voltageand time-dependent properties of the whole-cellL-type Ca2þ current as well as of its single-channelevents (18,19).

DADs occur through propagation of intracellularCa2þ waves during diastole (20). The voltage changeduring a DAD is a consequence of the ionic current(Iti) generated by both cytosolic and sarcoplasmic re-ticulum Ca2þ. Localized intracellular Ca2þ elevationdrives the Na/Ca exchanger in a PC, and as intracel-lular Ca2þ is extruded from the cell via the exchanger,there is a net positive charge resulting in depolari-zation. A single Ca2þ-wave exchanger current is notsufficient to trigger a large DAD, but intracellular Ca2þ

waves can become synchronized to produce moreNa/Ca exchange current, resulting in a larger DAD andpotentially a triggered beat.

Both Purkinje EADs and DADs are sensitive tonondihydropyridine Ca2þ-channel blockers, which,by blocking Ca2þ influx, tend to deplete the sarco-plasmic reticulum Ca2þ stores. They are also sensitive

ndle branch, fascicles, and extensive Purkinje network within the left

cicular ventricular tachycardia (FVT) types. LPF-dependent re-entrant

sue with a critical zone of slow conduction in the antegrade direction.

ximally (see text). LAF-dependent re-entrant FVT is highlighted in

r upper septal) FVT is depicted in dark green and is dependent on the

ith simultaneous antegrade conduction down the right bundle branch

VT is depicted in blue, with antegrade conduction down the RBB

VT is depicted in light green, shown here to arise from Purkinje tissue

g the moderator band of the right ventricle) to a lesser degree. This

along the distal fascicles. The bottom table highlights successful

r node; BBRVT ¼ bundle branch re-entry ventricular tachycardia;

a; LPF ¼ left posterior fascicle; LSF ¼ left septal fascicle. LAF ¼ left

FIGURE 1 Histopathological Examination of Left Fascicular System

Diagrammatic sketches of the left-sided conduction system as observed in 20 normal hearts originally described by Demoulin and Kulbertus (2).

Four major patterns of left septal fascicle are noted, including direct extension from the left bundle branch block between LAF and LPF

(cases 1 to 4), extension from the LAF (cases 5 to 7), extension from the LPF (cases 8 to 14), and arising from contribution from both LAF and

LPF (cases 15 to 20). Reprinted, with permission, from Demoulin and Kulbertus (2).


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to late Naþ-current blockers and Na/Ca exchangerinhibitors. For a more complete review of the exten-sive electrophysiological mechanisms of Purkinje-related arrhythmias, we refer readers to the recentlypublished book, Electrophysiological Foundations ofCardiac Arrhythmias (21).

IDIOPATHIC LEFT FASCICULAR

VENTRICULAR TACHYCARDIA

Re-entrant LFVT (idiopathic left fascicular ventriculartachycardia [ILVT]) is verapamil sensitive (22), occursin patients who are free of structural cardiac disease

FIGURE 2 Variation in PC Morphology

Two varying forms of Purkinje cell (PC) morphology are observed. Columnar-shaped PCs are more common in PC preparations, accounting

for 90% of all cells, forming elongated, parallel strands that efficiently propagate wave fronts in a linear fashion. Pancake-shaped PCs (P)

are wider in shape, designed to disperse the wavefront in multiple directions. Cell sections are stained with AnkyrinG antibody.



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(23), and is most commonly a manifestation of rightbundle branch block (RBBB) and left axis deviation(LAD) (22). This QRS morphology is due to myocardialexit from the left posterior fascicle where the circuit islocated. However, ILVT may present with other ECGpatterns depending on the involved fascicles,including RBBB and right axis deviation from tachy-cardia originating from the left anterior fascicle(24,25), and narrow QRS complex ILVT with retro-grade activation up an abnormal Purkinje fiber alongthe midseptum with simultaneous anterograde acti-vation of the right bundle branch (RBB), left anterior,and left posterior fascicles (26). Early studies docu-mented a macro–re-entrant mechanism by means ofboth atrial and ventricular entrainment (27–29), withinitial studies suggesting a small circuit, because thetachycardia could be ablated at the earliest fascicularpotential recorded at the exit site (30–32). However,subsequent studies identified entrance sites remotefrom the exit site that also resulted in successfulablation, indicating a larger tachycardia circuit(33,34).

Studies using multipolar electrode cathetersinserted into the LV, together with entrainment andresetting responses, clarified the tachycardia circuit.Initially described by Nogami et al. (35), simultaneouspre-systolic potentials (P2) from the left posteriorfascicles as well as mid-diastolic potentials (P1) were

recorded from the LV midseptal area (Figure 3). Dur-ing ventricular tachycardia (VT), there is orthodromicactivation of the diastolic potential P1 and retrogradeactivation of P2 (Figure 3A). In contrast, during sinusrhythm, there is orthodromic activation of the leftposterior fascicle P2 from base to apex, and P1 isobscured by ventricular activation (Figure 3B). DuringVT, P1 and P2 signals merge at the distal recordingsite. Entrainment pacing from P1 during VT results inorthodromic capture of P2 with identical QRS to thatrecorded in VT, with a post-pacing interval similar tothe VT cycle length. Administration of intravenousverapamil results in a pronounced increase in theP2–P1 interval. Ablation at the site of the diastolicpotential results in gradual prolongation of the P2–P1interval prior to VT termination. After VT termina-tion, P1 can now be recorded following each con-ducted QRS again, with a base-to-apex conductingpattern. These findings suggest the involvement ofslowly conducting myocardial tissue between P2 andP1 that makes up the slow zone of the tachycardiacircuit, because conduction along P1 alone would notaccount for the entire diastolic portion of the circuit.Similar considerations appear operative for patientspresenting with a left anterior fascicle pattern. Thered circuit in the Central Illustration, Part B, depictsthe anatomic circuit of LPF-dependent intrafasciculararrhythmia.

FIGURE 3 Intracardiac Recordings From Octapolar Electrode Catheter During ILVT

(A) During VT, a diastolic potential (P1) and a pre-systolic Purkinje potential (P2) were recorded. P1 signals are activated from proximal to distal

electrodes, indicating antegrade activation along the abnormal Purkinje fiber, whereas P2 signals are activated from distal to proximal electrodes,

indicating retrograde activation along the posterior fascicle. A schematic representation of the circuit is shown in the diagram below the intracardiac

recordings. (B) During sinus rhythm, recording at the same site shows only antegrade conduction along P2. P1 signals are absent, likely due to

activation concurrentwith ventricular activation, and are obscured by the larger,myocardial potentials. A schematic representation of the activation

wave front in sinus rhythm is shown in the diagram below the intracardiac recordings. Reprinted, with permission, from Nogami et al. (35).


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Similar to LPF-dependent ILVT, arrhythmias orig-inating from the left anterior fascicle behave simi-larly, with abnormal Purkinje tissue arising out of theleft anterior fascicle (purple circuit in the CentralIllustration, Part B) (25). In a small series of 6 pa-tients, successful ablation was performed at theventricular exit site in the anterolateral wall for 3patients in whom a fused Purkinje potential wasrecorded preceding the QRS complex by 20 to 35 ms(25). The remaining 3 patients had successful ablationmore proximally at the mid-anterior LV septum,where a diastolic Purkinje potential was noted, pre-ceding the QRS by 56 to 66 ms.

Further insights into the mechanism of thistachycardia come from a recent study by Liu et al.(36), who also used a multipolar electrode catheter inthe LV but paced and ablated using another LVcatheter. Similar to the initial study by Nogami et al.(35), this study was able to record both P1 and P2potentials from 64% of patients studied. Using bothentrainment and resetting responses, they found ev-idence supporting the Nogami model (Figure 4). Thiscircuit consisted of ventricular myocardium con-nected to a slow zone of conduction into P1 that inturn merged with the distal portion of the LPF, withevidence of anterograde and retrograde activation

FIGURE 4 Schematic Diagram of the LPF-VT Re-Entry Circuit

The re-entry circuit of left posterior fascicular ventricular tachycardia (LPF-VT) includes ventricular myocardium, a part of the LPF, a P1 fiber,

and a slow conduction zone connecting the ventricular myocardium and proximal P1. (A) In the cases with a recorded P1 and a more

negative His-ventricular (HV) interval during LPF-VT, the P1 fiber is parallel and adjacent to the LPF, and the connection between P1 and

the LPF (P2) is located at a more distal portion of the LPF. (B) In the cases with a recorded P1 and a slightly negative HV interval during LPF-VT,

the P1 fiber is parallel and adjacent to the LPF, and the connection between P1 and the LPF (P2) is located at the middle or proximal

portion of the LPF. (C) In the cases without a recorded P1 and an HV interval that is slightly negative, the P1 fiber may be short in length,

nonparallel to the LPF, or both. AVN ¼ atrioventricular node; His ¼ His-bundle electrogram; LAF ¼ left enterior fascicle; LPF ¼ left posterior

fascicle; LSF ¼ left septal fascicle; RB ¼ right bundle. Reprinted, with permission, from Liu et al. (36).



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of P2. Moreover, they found that the site of the P1–P2merger could be predicted by the H-V interval duringtachycardia, with more negative H-V interval pre-dicting a more distal connection. Although much hasbeen learned about the LPVT circuit, the preciseidentity of the slow conduction zone inserting into P1remains a mystery (36), although the animal modelfindings, described in the previous text, of reducedCV in the midseptum due to extensive Purkinjenetworking and connection to myocardium areappealing as a potential mechanism in humans (14).

The upper septal–dependent (US) form of ILVT isless common than the LPF and LAF dependent formsof ILVT (26,37), accounting for only 6.2% of allverapamil-sensitive ILVTs (26). In the largest series ofUS-ILVT patients from Talib et al. (26), 12 patientswere identified with US-ILVT among a total of 193patients with verapamil-sensitive ILVT in severalJapanese medical centers (26). Multipolar mappingalong the midseptum depicted a similar mechanismas “common” fascicular VT, but with VT circuitmovement in reverse direction. P1 is again seenpreceding P2, but with retrograde activation of P1signals (representing abnormal Purkinje fibersrunning along the midseptum) and antegrade acti-vation of P2 signals. During VT, His signals precededQRS activation, with H-V intervals consistently

shorter than in sinus rhythm, indicating parallelactivation of His and myocardium, with the upperturn around site closer to the His bundle. This allowssufficient time for activation of other fascicular bun-dles including the RBB, resulting in a narrow QRSmorphology during VT. The dark green circuit in theCentral Illustration, Part B depicts the proposed circuitof US-ILVT.

A very rare form of upper septal fascicular VT hasbeen described, utilizing the upper septal fascicle asthe retrograde limb, followed by variable conductiondown RBB, LPF, and LAF either spontaneously orfollowing injury from mapping or ablation resultingin multiform VT morphologies (37). This unique en-tity is different from previously published cases ofILVT, including verapamil (or diltiazem) insensitivityand alternating VT morphology spontaneously due toconduction block or following mechanical injury toone of the fascicles (Online Figure 2; see figure legendfor more details). In these rare cases, successfulablation sites were generally within the proximalportion of the septum between the angle formed bythe LPF and LAF at sites of concealed entrainmentwith earliest pre-systolic potentials (P1) during VT.Care must be taken to avoid injuring the left bundlebranch or His bundle given the proximal location ofablation.


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ABLATION OF ILVT. Despite the absence of all pre-cise elements of the tachycardia circuit, ablation ofILVT can be performed safely and effectively. Abla-tion of the more common forms of ILVT (RBBB withLAD or right axis deviation) involving a macro–re-entrant circuit localized around the LPF and LAF ismost effective at a midseptal site with both P1 and P2signals identified during tachycardia, taking care toavoid ablation at a site that is too proximal and riskatrioventricular block or left bundle branch block (35).The average interval between onset of P1 to onset ofQRS during VT was 60 � 29 ms in a group of 15patients.

For patients in whom P1 cannot be identified,successful ablation can generally be achieved at theearliest ventricular activation site with a fused P2during VT (35). Furthermore, when VT is seen duringbaseline assessment, the HV intervals during sinusrhythm and during tachycardia may be utilized topredict the successful ablation site (38). The earliestfascicular potential to surface ventricular signal (FP-Vinterval) may be predicted by taking the sum of theHV intervals during sinus and during tachycardia anddividing by 2. This effectively predicts the earliest FP-V interval during tachycardia and is identical to theFP-V interval during sinus rhythm (Online Figure 3).After this calculation is made, mapping of fascicular/Purkinje potentials along the fascicle of interest maybe made during sinus rhythm, with targeted ablationwhen the FP-V interval during sinus rhythm matchesthe predicted calculation.

When the tachycardia cannot be induced, creatingan ablation line transecting the midregion of theaffected fascicle is often effective (39).

In the uncommon or upper septal form of ILVT,successful ablation is achieved along the midportionof the ventricular septum, halfway between the His-bundle recording site and the LV apex, where a dia-stolic Purkinje potential (P1) is identified (40). In thisseries of 12 patients with successful US-ILVT ablation,the P1 signal preceded the QRS onset by 55 � 21 ms.

OTHER FASCICULAR TACHYCARDIAS

BUNDLE BRANCH RE-ENTRY VT. Bundle branch re-entry ventricular tachycardia (BBRVT) representsthe prototypical form of interfascicular tachycardia,involving a macro–re-entrant circuit utilizing theright bundle (typically as the antegrade limb) and theleft bundle branch/fascicles as the retrograde limb(see blue circuit in Central Illustration, Part B). Thistypically results in left bundle branch blockmorphology VT, with His bundle signal precedingventricular activation, longer H-V interval during VT

than in sinus rhythm, and H-H interval changesdriving changes in V-V wobble (41).

Although typically occurring in patients with sig-nificant cardiomyopathy and advanced conductionsystem disease, BBRVT has been noted to occur in theabsence of structural heart disease (42–44), but withisolated conduction system disease. Most recently, 6cases of idiopathic BBRVT were identified in patientswith normal biventricular size and function. All pa-tients were noted to have HPS disease, with pro-longed HV at baseline (mean 69.2 ms). Of the 6 cases,2 had both right and left bundle branch block mor-phologies, whereas only left bundle branch blockmorphology VT was induced in 4 patients. All pa-tients had successful ablation targeting the RBB.

Genetic testing was performed on all 6 patients for12 genes previously implicated in conduction systemdisease: SCN5A, SCN10A, SCN1B, TRPM4, GJA1,LMNA, TBX5, NKX2-5, PRKAG2, KCNK3, KCNK17, andHCN4. Of the 6 patients, 3 had mutations identified: 2in SCN5A and 1 in LMNA (44). This represents aninteresting finding that idiopathic BBRVT may be agenetic condition, manifested by isolated conductionsystem disease, and curable with catheter ablation.

FOCAL FASCICULAR TACHYCARDIA

Focal or non–re-entrant LFVT is much less commonthan the macro–re-entrant circuits described in theprevious text. Sporadic cases of focal fasciculartachycardia have been reported with associatedstructural cardiac disease (45,46) as well as in thosewithout cardiac disease (47–49). The most compre-hensive description of focal fascicular tachycardia is areport of 15 cases by Talib et al. (40). This numberaccounted for only 2.8% of patients presenting withidiopathic extrasystoles or VT of all etiologies. Themajority (75%) presented with an RBB and LADpattern. These extrasystoles proved resistant toverapamil. Successful ablation was found at a siteshowing an early, high-frequency fascicular potentialjust before the ectopic beat(s). The light green high-light in the Central Illustration, Part B depicts theconcept that a focal fascicular potential may arisefrom any area of the complex Purkinje network, mostcommonly arising from the LPF.

THE LEFT FASCICULAR CONDUCTING

SYSTEM AND VENTRICULAR FIBRILLATION

Initial studies linking the HPS to ventricular fibrilla-tion (VF) comes from canine infarct models where ar-rhythmias were found to arise from surviving Purkinjetissue in proximity to infarcted myocardium (50,51).

FIGURE 5 Purkinje-Mediated Initiation of Ventricular Fibrillation

(Top) Initiation of ventricular fibrillation during Holter recording. Note that the initiation beat is different from the preceding isolated premature

beat. (Bottom) In the same patient, a run of premature beats originating from the left ventricular (LV) Purkinje system. Each QRS complex is

morphologically different but is preceded by a Purkinje potential (arrow)with a varying conduction time. The same activity is also present during

sinus rhythm with a short conduction time. dist ¼ distal; prox ¼ proximal. Reprinted, with permission, from Haissaguerre et al. (60).



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These arrhythmias were attributed to either abnor-malities in automaticity or triggered rhythms andrelated to disruption of channel function in affectedPurkinje cells (50,52). Furthermore, there is a growingappreciation for the potential role of Purkinje fiber re-entry in VF (53). The prolonged APD of the PC relativeto the ventricular myocardium acts as a gate to preventretrograde activation that may ultimately lead tore-entry (11,54). In certain conditions resulting inmyocardial cellular disruption, unidirectional blockmay be facilitated at the Purkinje-muscle junction,resulting in re-entry and VF initiation (55).

Involvement of the HPS in the geneses of ar-rhythmias has been demonstrated in animals thatreplicate human genetic arrhythmia syndromes butwithout structural cardiac disease. For example,knock-in mice with RYR2 mutations shown to pro-duce a CPVT phenotype in humans display multifocaldischarges from Purkinje tissue in the presence ofcatecholamines (56). In addition, animal modelsmade to replicate the long QT syndrome by adminis-tration of iKr blockers showed runs of torsades depointes ventricular arrhythmias due to EAD-triggeredactivity from Purkinje tissue (57). Finally, a rare breedof German Shepherd dogs with predisposition tosudden cardiac death were shown to have dischargefrom the Purkinje system associated with dispersionof ventricular refractoriness (58).

In humans, Haissaguerre et al. (59,60) were thefirst to report patients with ventricular fibrillationowing to premature ventricular complex (PVC) trig-gers that were mapped to either right or left fasciculartissue in more than 90%, with the remainder origi-nating from myocardium. These patients werefound to have high-density PVCs with morphologyidentical to those documented to trigger VF. Duringsinus rhythm, there was a short interval between thefascicular potential to myocardial activation (11 ms),while the triggering ectopic beat from the same siteshowed a much longer fascicle to ventricular activa-tion time and often associated with re-entry involvingcontiguous Purkinje fibers, resulting in polymorphicVT or VF. These ectopic triggers were non–re-entrantand could not be reliably triggered with isoproterenolor calcium infusions.

ABLATION OF PVC-INDUCED VF

In patients with VF induced by early Purkinje acti-vation, ablation is performed at the earliest activationof the Purkinje potential, typically along the distalportion of the fascicles near the Purkinje-musclejunctions (Figure 5) (60,61). Figure 5 shows likelyEAD-mediated trigger of VF (top panel), with onset ofPVC preceding the T-wave. It must be appreciatedthat more than 1 Purkinje site might act as a


11

trigger. Ablations at these sites may provoke prema-ture ventricular beats as well as runs of poly-morphous VT or even VF. It is important to continueto deliver radiofrequency energy to these sites evenin the presence of ectopy of polymorphous VT. Inaddition, Haissaguerre et al. (55) suggest the appli-cation of additional ablative lesions at contiguoussites to reduce recurrences of arrhythmias (55). Long-term success after ablation has been shown to beexcellent (61); nevertheless, recurrences have beenreported, and it is probably best to advise insertionof a defibrillator even after apparent successfulablation.

It is worth noting that in a separate study evalu-ating PVC-induced VF, 7 of 36 patients had PVCoriginating from the moderator band of the RV (62).Successful ablation was achieved by targeting theearliest Purkinje potential preceding the QRS, withthe majority directed at the free wall insertion of themoderator band (aided by direct intracardiac echo-cardiogram). When PVCs were not inducible, pacemapping was performed during sinus rhythm todirect successful ablation targets (62).

Last, in addition to idiopathic VT, case reports havedescribed Purkinje (fascicle)-mediated PVCs causingpolymorphic VT/VF in both long QT syndrome andcatecholaminergic polymorphic VT (63–65). In thesecases, mapping was performed to identify the earliestPurkinje potential preceding the culprit PVC(s), withPurkinje-QRS interval of the PVC ranging from 18 to35 ms. Purkinje activity also preceded the earliestventricular activation during sinus rhythm, but with avariable Purkinje-QRS interval duration of 5 to 15 ms.

In these medically refractory cases, ablations wereperformed at the site of earliest Purkinje potentialduring PVC, with endpoints of full PVC resolution orabolition of the local Purkinje potential. In all cases,ablation provoked temporary exacerbation of thearrhythmia with increased PVCs and/or polymorphicVT but ultimately resulted in the resolution of clinicalPVCs with good long-term resolution of VT/VF.

CONCLUSIONS

Idiopathic left fascicular arrhythmias encompass awide spectrum of arrhythmias with varying degreesof clinical significance, ranging from minimallysymptomatic extrasystoles to life-threatening VF.Advances in our understanding of the basic science ofHPS highlight cellular mechanisms of enhancedautomaticity, triggered activity, and heterogeneity inconduction system delay and CV that are likelyresponsible for the extensive variety of clinicalfascicular arrhythmias in normal hearts. A preciseunderstanding of the anatomy is also critical forsuccessful ablation of these varied and complexarrhythmias. As we continue to improve our under-standing of both cellular and clinical electrophysi-ology underlying fascicular arrhythmias, we will bewell situated to further tailor management andimprove outcomes for this complex disease.

ADDRESS FOR CORRESPONDENCE: Dr. Raphael K.Sung, Division of Cardiology, National Jewish Health,1400 Jackson Street, J326a, Denver, Colorado 80206.E-mail: [email protected].

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KEY WORDS cellular physiology, fasciculararrhythmias, Purkinje cells, ventriculartachycardia

APPENDIX For supplemental figures, pleasesee the online version of this article.

























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