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POINT OF VIEWSection Editor: Yoram Rudy, Ph.D.

Basic Electrophysiology of the Pulmonary Veins and Their Rolein Atrial Fibrillation: Precipitators, Perpetuators, and Perplexers

STANLEY NATTEL, M.D.

From the Department of Medicine and Research Center, Montreal Heart Institute and University of Montreal, Department ofPharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

Introduction

The role of the pulmonary veins (PVs) in atrial fibrilla-tion (AF) exploded into the widespread consciousness of themedical community with the groundbreaking demonstrationof their importance by Haissaguerre’s group in 1997.1 Manysubsequent clinical investigators confirmed these findings,and the PVs of AF patients now are regularly succumbing tothe onslaughts of a host of torments in the (generally fruitful)attempt to suppress AF.

As good practitioners, we have rapidly pursued the howof PV ablation, and we have a bit more slowly begun to ad-dress the why of the important role of PVs in AF. BeforeHaissaguerre’s work, we knew very little (and possibly caredeven less) about the electrical activity of PVs. Over the pastfew years, there has been extensive investigation of PV elec-trical function in normal animals and in animal models of AF.In combination with clinical investigations, the results haveprovided us with some hints about why the PVs are importantin AF, but they have posed a host of new questions. The aimof this article is to synthesize the available information aboutthe potential basic mechanisms of PV involvement in AF andto derive from this synthesis some directions that need to betaken to resolve the major outstanding issues.

Basic Electrical Properties of PVs

In 1876, Brunton and Fayrer2 described the ability (albeitunusual) of the PVs and inferior vena cava to continue to pul-sate independently of the cardiac chambers of dead cats, andreferred to similar observations by Haller published in 1757.In 1972, Spach et al.3 showed that cardiac tissue extends for2 to 4 cm onto the thoracic veins and conducts electricalimpulses, and they found that in a case of AF the PVs fibril-lated while the right atrium and superior vena cava showedan atrial tachycardia at 210/min. In 1980, Donald Cheung4

showed that action potentials could be recorded from a car-diac muscle layer around the PV sleeves, but only a stableresting potential could be recorded from the smooth musclecell layer. PV cardiac cell activity tended to follow that of the

J Cardiovasc Electrophysiol, Vol. 14, pp. 1372-1375, December 2003.

Address for correspondence: Stanley Nattel, M.D., Montreal Heart InstituteResearch Center, 5000 Belanger Street E, Montreal H1T 1C8 Canada. Fax:514-376-1355; E-mail: nattel@icm.umontreal.ca

doi: 10.1046/j.1540-8167.2003.03445.x

atria, sometimes showing slow spontaneous automaticity andmore often being quiescent when not stimulated. In the pres-ence of digitalis toxicity, PV activity became enhanced andcould drive the atria.5 These appear to be the only studies onPV activity before Haissaguerre’s demonstration of the roleof PVs in AF. Over the past few years, a number of poten-tial basic arrhythmogenic mechanisms have been identifiedin PVs. Three basic hypotheses of PV arrhythmogenicity, andthe evidence for them, are as follows.

Normal PV Cells Show Arrhythmogenic Focal Activity,Which is Enhanced by Pathologic States

Chen et al.6 performed a pioneering series of studies inwhich they isolated canine and rabbit PVs and studied theirelectrical properties. They initially recorded very rapid andlow-amplitude spiking activity of unknown mechanism in PVtissue beyond the end of the cardiomyocyte sleeve. This ac-tivity was not generally coupled to atrial activity, and its sig-nificance remains unknown. In a subsequent series of studies,Chen et al.7-9 showed that isolated PV cardiomyocytes fromnormal dogs and rabbits can manifest prominent automatic-ity, as well as arrhythmogenic afterdepolarizations, which areenhanced by putative atrial profibrillatory maneuvers such asseveral weeks of atrial tachypacing or several hours of invitro exposure to triiodothyronine. The precise mechanismsunderlying the arrhythmogenic activities of normal PV cellswere not elucidated.

PV Cells Are Normal Under Baseline ConditionsBut Are Differentially Susceptible to FocalArrhythmogenic Interventions

In contrast to the observations of Chen et al., severalgroups have been unable to detect abnormal automaticityor enhanced pacemaker activity in normal PV cardiomy-ocytes.10-12 However, when AF is induced in the face ofsustained electrically maintained atrial tachycardia13,14 or ex-perimental heart failure,15 rapid, apparently focal PV activityemerges that is not seen when AF is induced acutely in nor-mal hearts. The precise mechanism of this rapid activity andits role in AF maintenance are unclear, but PV activity oftenis more rapid than, and in some cases clearly independent of,invading left atrial wavefronts.

Honjo et al.12 showed that upon infusion of ryanodine(0.5-2 µM), an inhibitor of sarcoplasmic reticulum Ca2+ re-lease channel function, rabbit atrial preparations show a shiftof the pacemaker focus from the sinus node to the PV, and

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repetitive activity is induced by burst pacing in the PV butnot in the right or left atrial appendage. This activity is sup-pressed by inhibitors of sarcoplasmic reticulum Ca2+ uptake,of Na+/Ca2+ exchange, and of Ca2+-dependent Cl− current,and is enhanced by adrenergic stimulation, compatible witha mechanism related to Ca2+-sensitive inward currents. Ac-tivity of this type was not seen in the absence of ryanodine.

Finally, atrial distention is known to be associated withAF. A recent study applied optical mapping in a sheep modelof stretch-related AF.16 At normal atrial filling pressures, PVactivity during AF was slower than that of the atria; however,when atrial pressure was increased above 10 cm H20, the PV-left atrial junction region showed the fastest local activity andwavefronts emanated predominantly from the PV region.

The PVs Are a Privileged Site for Atrial Reentry

Several lines of evidence suggest that the PVs may bea privileged site for intra-atrial reentry. There are abruptchanges in fiber orientation near the PV ostia, resulting inmarked conduction delays during premature and rapid stim-ulation,10 in part because of segmental PV muscular discon-nection and narrowing.17 In addition, the cellular propertiesof PV cardiomyocytes favor the occurrence of reentry, withshorter action potentials10,18 and smaller phase 0 upstrokevelocities18,19 compared to the left atrium. The shorter PVaction potentials appear to be due to a combination of smallerinward L-type Ca2+ current and larger outward rapid and slowdelayed-rectifier K+ currents, whereas the smaller phase 0upstroke velocity is due to reduced inward-rectifier K+ cur-rent, which depolarizes the resting potential and thereby in-activates Na+ channels.18 These cellular properties would beexpected to translate into abbreviated refractoriness and re-duced source current for conduction, which in conjunctionwith source-sink mismatches due to abrupt changes in fiberorientation would be expected to produce substantial con-duction delays (particularly with premature or excessivelyrapid activation). Both abbreviated refractoriness and slowedconduction are expected to favor the occurrence of reentry.Indeed, optical mapping studies have revealed preferentialreentry occurring in the PV region.16,19

Properties of PVs in Humans and Relationshipto Arrhythmias

The PVs are an important source of ectopic beats thatinitiate AF in many patients, and electrical potentials canbe recorded from PVs generating premature ectopy severalcentimeters distal to the atrial junction.20 PVs have been re-ported to have shorter refractory periods than the left atrium,21

with arrhythmogenic PVs showing particularly short refrac-tory periods, decremental conduction, and inducibility of AFduring rapid pacing.22 PVs that are disconnected from theatria can show paroxysmal tachyarrhythmias with fibrilla-tory appearance,23 and PV tachycardias can occur in burstsor more continuously, with the cycle length of bursting ac-tivity being shorter.24 Although PV bursting appears to playa role in AF maintenance, this bursting behavior in turn de-pends on atrial input and largely disappears when PVs aredisconnected from the left atrium.25 Thus, there is evidencefor a dynamic interplay between left atrial and PV activity.

What Basic Studies of PV Electrophysiology HaveTaught Us: Insights and Limitations

Figure 1 synthesizes the potential arrhythmogenic proper-ties of the PV cardiomyocyte sleeve that have emerged frombasic studies. Normal PVs under normal physiologic condi-tions do not appear to generate significant ectopic activity.The PVs are sensitive to the induction of Ca2+-dependenttriggered activity, with the trigger potentially consisting offactors promoting Ca2+ overload and/or ectopy arising viaanother mechanism. In addition, the PVs have a substrate fa-vorable for reentry, on the basis of their refractoriness andconduction properties. Triggered activity arising in PVs mayin turn itself act as a trigger on the favorable substrate toinitiate PV reentry. Repetitive PV activity due to either reen-try or triggered activity would give rise to PV tachycardiasor conceivably, if there is sufficient dissociation among PVpathways, local fibrillatory activity. Understanding the PVcontribution to AF requires a consideration of not only PV ac-tivity but also of its interaction with atrial electrophysiology.PV tachyarrhythmias could produce AF directly by activatingthe atria more rapidly than all regions can follow (fibrillatoryconduction) or by engaging an appropriate atrial substrate toinitiate multiple circuit atrial reentry. PV tachycardias alsocould contribute to the production of an atrial reentrant sub-strate by inducing atrial tachycardia remodeling. Finally, AFmay produce positive feedback on PV activity by potentiatingPV triggered activity.

Figure 1. Schematic representation of potential mechanisms of pulmonaryvein (PV) activity indicated by basic research data that presently are avail-able. Evidence has been presented that suggests favorable substrates for trig-gered activity and reentry in PVs. These substrates are indicated by boxes;primary arrhythmia mechanisms of enhanced automaticity, triggered activ-ity, and reentry are indicated by ovals. In addition to PV mechanisms, theinteractions among these mechanisms and atrial activity must be considered.APD = action potential duration; ERP = effective refractory period; ICa =Ca2+ current; IK1 = inward rectifier K+ current; IKr = rapid delayed recti-fier current; IKs = slow delayed rectifier current; RMP = resting membranepotential; Vmax = slope of phase 0 upstroke of the action potential (an indexof Na+ current).

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Figure 2. Relationship between intravascular ultrasound images and intracardiac recordings from a nonarrhythmogenic (left) and an arrhythmogenicpulmonary vein (right) in a patient with atrial fibrillation. The smooth-contoured right inferior pulmonary vein PV (RIPV) shows no evidence of thickening(A). The left lower pulmonary vein (LLPV) has a crescent-shaped area of thickening (B, arrow). Panels C and D are the intracardiac tracings taken while themapping catheter is in each of the two veins. In the RIPV, the recordings from the PV show only far-field atrial signals (C). Panel D illustrates high-amplitudeand high-frequency potentials recorded from the LLPV, as well as an initiation of atrial fibrillation from this vein (arrow). The luminal artifact is from theguidewire used with the intravascular ultrasound catheter. CS = coronary sinus; (d) = distal; Eso = esophageal lead; (m) = mid; (p) = proximal; RA =right atrium. (Reproduced with permission from Guerra PG, Thibault B, Dubuc M, Talajic M, Roy D, Crepeau J, Nattel S, Tardif JC: Identification of atrialtissue in pulmonary veins using intravascular ultrasound. J Am Soc Echocardiogr 2003; 16:982–987.)

These limited insights leave many questions unanswered.What is the mechanism for the sensitivity of PVs to Ca2+-dependent arrhythmias? What role do they play in PV tachy-cardias that seem to occur with experimental AF and con-gestive heart failure? How often does reentry occur withinPVs? Can a structure as small as a PV support more than onesimultaneous reentrant circuit? If not, how can fibrillatoryactivity be recorded from a PV? What are the specific bio-chemical, ion channel, and histopathologic properties of PVmyocardial sleeves that differentiate them from atrial tissue?Does the smooth muscle cell layer in the PVs play any rolein modulating their electrical properties and function?

Clinically, PVs appear to be involved in both the initia-tion and maintenance of AF. Ca2+-dependent triggered au-tomaticity and reentry, suggested by experimental studies tooccur in PVs, are a reasonable paradigm for clinical PV ac-tivity, but persuasive evidence for their involvement in clin-ical AF is lacking. There is one very important limitation ofexperimental studies of PV electrophysiology that may beinsufficiently considered. Experimental studies of PV activ-ity are obtained in normal animals or animals manipulatedto have pathologies associated with AF in humans. However,the role of PVs in clinical AF is most prominent in parox-ysmal AF occurring in the absence of significant underly-ing heart disease. The PV pathophysiology in such patientsmay have little to do with the substrate in normal subjects,human or otherwise. For example, intravascular ultrasoundstudies have revealed abnormal, crescentic tissue structuresin the walls of arrhythmogenic PVs with demonstrable PVpotentials (Fig. 2).26 This pathology, which may represent

unusually large or electrically unique myocardial fascicles inPV walls, may be totally absent from the experimental ani-mals used for electrophysiologic research. In addition, thereis reason to believe that PVs may contribute to AF in a varietyof ways, which may differ in different patients and clinicalsettings. Thus, in addition to the many questions that remainto be addressed in experimental models, there is no doubt thatextensive careful clinical investigation is needed to clarify theelectrical properties of normal and arrhythmic PVs in a vari-ety of clinical situations in humans. Ultimately, informationfrom both basic and clinical research will be needed to gain afull understanding of the fascinating and frustrating questionof why the PVs are so important in AF.

Acknowledgments: The author thanks France Theriault for secretarial helpwith the manuscript, and Drs. Peter Guerra and Laurent Macle for helpfuldiscussions during preparation of the manuscript.

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