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 . 6 , N O . 6 , 2 0 2 0

ª 2 0 2 0 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N

C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

STATE-OF-THE-ART REVIEW

Idiopathic Ventricular FibrillationRole of Purkinje System and MicrostructuralMyocardial Abnormalities

Michel Haïssaguerre, MD,a,b,c Josselin Duchateau, MD,a,b,c Remi Dubois, PHD,a,b,c Mélèze Hocini, MD,a,b,c

Ghassen Cheniti, MD,a,b,c Frederic Sacher, MD,a,b,c Thomas Lavergne, MD,a,b,c Vincent Probst, MD,d

Elodie Surget, MD,a,b,c Ed Vigmond, PHD,a,b,c Nicolas Welte, MD,a,b,c Remi Chauvel, MD,a,b,c Nicolas Derval, MD,a,b,c

Thomas Pambrun, MD,a,b,c Pierre Jais, MD,a,b,c Wee Nademanee, MD,e Olivier Bernus, PHDb,c

ABSTRACT

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Idiopathic ventricular fibrillation is diagnosed in patients who survived a ventricular fibrillation episode without any identifiable

structural or electrical cause after extensive investigations. It is a common cause of sudden death in young adults. The study

reviews the diagnostic value of systematic investigations and the new insights provided by detailed electrophysiological

mapping. Recent studies have shown the high incidence of microstructural cardiomyopathic areas, which act as the substrate of

ventricular fibrillation re-entries. These subclinical alterations require high-density endo- and epicardial mapping to be iden-

tified using electrogram criteria. Small areas are involved and located individually in various sites (mostly epicardial). Their

characteristics suggest a variety of genetic or acquired pathological processes affecting cellular connectivity or tissue structure,

such as cardiomyopathies, myocarditis, or fatty infiltration. Purkinje abnormalities manifesting as triggering ectopy or providing

a substrate for re-entry represent a second important cause. The documentation of ephemeral Purkinje ectopy requires

continuous electrocardiography monitoring for diagnosis. A variety of diseases affecting Purkinje cell function or conduction are

potentially at play in their pathogenesis. Comprehensive investigations can therefore allow the great majority of idiopathic

ventricular fibrillation to ultimately receive diagnoses of a cardiac disease, likely underlain by a mosaic of pathologies. Precise

phenotypic characterization has significant implications for interpretation of genetic variants, the risk assessment, and individual

therapy. Future improvements in imaging or electrophysiological methods may hopefully allow the identification of the sub-

jects at risk and the development of primary prevention strategies. (J Am Coll Cardiol EP 2020;6:591–608) © 2020 The

Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access

article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

S udden cardiac death (SCD) remains a majorhealth problem on all continents. Estimatesvary around 350,000 victims per year in the

United States and in Europe, and are even higher in

N 2405-500X

m the aDepartment of Electrophysiology and Cardiac Stimulation, Centr

nce; bInstitut Hospitalo-Universitaire Electrophysiology and Heart Mod

rdeaux, France; cCardiothoracic Research Center Bordeaux, Université

iversité de Nantes, Nantes, France; and the eCardiology Department, Bum

is work was supported by the National Research Agency (ANR-10-IAH

MPHONY). Dr. Haissaguerre has received research grants from Biosense W

ria and consulting fees from Biosense Webster. Dr. Jais has received speak

.Nademaneehas received research grant support fromMedtronic andBiosen

bster. All other authors have reported that they have no relationships rele

e authors attest they are in compliance with human studies committe

titutions andFood andDrugAdministration guidelines, includingpatient co

JACC: Clinical Electrophysiology author instructions page.

nuscript received December 10, 2019; revised manuscript received March

Southeast Asia. Coronary artery disease and cardio-myopathies are the main causes in older persons(1–6). However, in victims younger than 35 years ofage, a common finding is the absence of structural

https://doi.org/10.1016/j.jacep.2020.03.010

e Hospitalier Universitaire de Bordeaux, Bordeaux,

eling Institute, Centre Hospitalier Universitaire de

de Bordeaux, Bordeaux, France; dThorax Institute,

rungrad International Hospital, Bangkok, Thailand.

U04-LIRYC) and the European Research Council

ebster and Medtronic. Dr. Sacher has received hon-

er fees from Boston Scientific and Biosense Webster.

seWebster; andhas received royalties fromBiosense

vant to the contents of this paper to disclose.

es and animal welfare regulations of the authors’

nsentwhere appropriate. Formore information, visit

24, 2020, accepted March 24, 2020.

HIGHLIGHTS

� VF can be unexplained despite extensiveinvestigations, notably in the young.

� The use of high-density electrophysio-logical mapping detects causes in thegreat majority of victims.

� Microstructural cardiomyopathies are themain causes, likely underlain by multiplepathological processes.

� The phenotypic characterization of sub-strate is critical to develop therapy andinterpret genetic results.

ABBR EV I A T I ON S

AND ACRONYMS

ARVD = arrhythmogenic right

ventricular dysplasia

BrS = Brugada syndrome

CPVT = catecholaminergic

polymorphic ventricular

tachycardia

ECG = electrocardiography

ICD = implantable-cardioverter

defibrillator

IVF = idiopathic ventricular

fibrillation

LV = left ventricular

PVC = premature ventricular

contraction

RV = right ventricular

SCD = sudden cardiac death

VF = ventricular fibrillation

VT = ventricular tachycard

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heart disease at autopsy, which is reported in29% to 40% of cases in recent population-based studies, particularly in young male pa-tients (7–12). In the patients surviving afterresuscitation maneuvers, ventricular fibrilla-tion (VF) is consistently the lethal heartrhythm disorder identified at the time ofevent.

Experimental studies have demonstratedthat, once initiated, VF is maintained by thecontinuous formation of re-entrant waves,underlain by depolarization or repolarizationheterogeneities. In cardiomyopathic post-transplant human hearts, re-entry has beenshown to self-perpetuate for many cycles byanchoring to a myocardial scar or structuralheterogeneity (13–15).

Over the last 20 years, considerable effortshave been devoted to the search for electro-cardiographic, structural, and genetic anom-

alies in survivors (1,4,10). Despite these progresses,unexplained SCD, defined as no apparent structuralheart disease after extensive investigations, remainsfrequent in young adults (16–25). In this review, wereport the current knowledge on idiopathic VF (IVF),defined as VF with no apparent structural or electricalheart disease after extensive investigations (e.g., noapparent phenotype). We discuss the value of sys-tematic clinical testing for confirmation of IVF diag-nosis and exclusion of other causes of SCD. Theresults of individual phenotypic characterizationbased on high-density electrophysiological mappingwill be analyzed, with their implications for geneticinterpretation and therapeutic approach.

CRITERIA IDENTIFYING IVF

DEFINITION OF IVF. The Heart Rhythm Society/Eu-ropean Heart Rhythm Association/Asia Pacific HeartRhythm Society expert consensus statements oninherited primary arrhythmia syndromes define IVFas a resuscitated VF victim who had known cardiac,respiratory, metabolic, and toxicological causes havebeen excluded through clinical investigations (4,5).The diagnosis is based on the absence of a substratefor VF by exclusion of ischemic and structural cardiacdiseases (i.e., arrhythmogenic right ventriculardysplasia [ARVD], hypertrophic and dilated cardio-myopathy, myocarditis, cardiac sarcoidosis, congen-ital heart disease) and “primary arrhythmiasyndromes” (i.e., Brugada syndrome [BrS], catechol-aminergic polymorphic ventricular tachycardia[CPVT], long QT syndrome, short QT syndrome, andearly repolarization syndrome). Whether a heart is

ia

considered normal depends obviously on the resolu-tion of examinations and their timing relative to theclinical event (26–45).

IVF accounts for 14% to 23% of SCD in youngadults. There is a relative paucity of specific recom-mendations for the clinical management of IVF, butrecent reviews and new data have become available(4–6,22–25).

SYSTEMATIC CLINICAL TESTING. Noncardiac causesof IVF, including accidental, cerebral, or respiratorycauses, and drug abuse or intoxication or electrolyteabnormality, are easily eliminated by simple in-vestigations and will not be discussed here.

Figure 1 shows a diagnostic flow chart illustratingthe systematic assessment of patients who survivedSCD, with each investigation being important fordifferential diagnosis of IVF.

Electrocardiography-telemetry. Twelve-lead electrocar-diography (ECG) should be performed using standardand high precordial lead position, and include re-cordings of spontaneous or induced changes in theQRS and J-wave or ST-segment patterns, includingcircadian changes, post-pause, Valsalva, stress test,or pharmacological tests (Figures 1 and 2). Exercisetest and signal-averaged ECG are recommended.

The 12-lead ECG recordings of premature ventric-ular contraction (PVC) patterns (coupling, morphol-ogies) should include the initial days in the intensivecare unit, in which the PVCs may be considerednormal in the context of recent VF and are thereforeoften underdocumented.

The goal is to recognize the site of origin of PVCs,whether they originate from the Purkinje system,right ventricle (RV), or left ventricle (LV), andwhether they are mono-or polymorphic (29–34). PVCsof ventricular origin have a wider duration and initialslower deflection than do Purkinje ectopy. The

FIGURE 1 Flow Chart

Diagnostic flow chart for investigations (blue) for patients surviving a sudden cardiac death and their results (yellow).

CPVT ¼ catecholaminergic polymorphic ventricular tachycardia; LV ¼ left ventricle; MRI ¼ cardiac magnetic resonance; PVC ¼ premature

ventricular contraction; RV ¼ right ventricle; SAECG ¼ signal-averaged electrocardiogram; SR ¼ sinus rhythm.

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presence of frequent PVCs gives a potential indicationof an abnormal (concealed) myocardial area, partic-ularly when they do not have the common morpho-logical patterns from right or left outflow tracts, thelatter being commonly associated with normalmyocardium. Purkinje ectopies have a narrower QRSduration, particularly when they originate from theleft Purkinje system (<120 ms), where they exhibit aright bundle branch block morphology. Purkinjeectopies from the right Purkinje arborization have aleft bundle branch block morphology, and a widerQRS duration (130 to 150 ms) but an initially rapiddeflection (Figure 3). The narrower left Purkinjeectopies are probably due to the dense left arboriza-tion, allowing simultaneous capture of a greater partof the LV.

Short coupling (R-on-T) PVCs are clearly in favor ofPurkinje origin but can also be seen in ventricularorigin (18,35) and vice versa, Purkinje ectopy may

have a long coupling interval (>360 ms). It is essen-tial to document the presence of Purkinje ectopy by12-lead ECG, as it can be the unique abnormalityunderlying VF, and can be treated by catheterablation.Structura l invest igat ions . Patients classified ashaving IVF should have no identifiable structuralheart disease demonstrated by normal echocardio-graphic and delayed gadolinium–enhanced cardiacmagnetic resonance, no detectable coronary arterydisease upon coronary angiography or exercisetesting. Ergonovine or acetylcholine provocative testsare performed to exclude coronary artery spasm inthe context of pain or ST-segment elevation (27).However, the presence of minor anatomical “defects-variants” in coronary artery or valve apparatus (mitralvalve prolapse) raises a problem in establishing theirimplication (26). Ventricular biopsy can be performedin selected cases (suspected myocarditis, sarcoidosis,

FIGURE 2 Repolarization Changes During Provocative Tests, in Patients Initially Referred for Idiopathic Ventricular Fibrillation,

Which Showed Evidence for Other Diagnosis

(A) Isoproterenol testing producing abrupt QT changes (alternans) in a patient with apparently normal QT interval; a KCNQ1 mutation (long QT1

syndrome) was later evidenced. (B) Valsalva maneuver producing a prominent inferolateral J-wave after a sinus pause. (C) Isoproterenol testing

inducing ST-segment elevation and coronary spasm, which was proven during a repeat test with coronary angiography. The arrows indicate the

repolarization change.

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ARVD). Ideally, the biopsy location should be guidedby electrogram or imaging abnormality to increasediagnostic yield and potentially provide new insightsin IVF (28).Pharmacolog ica l tests . Pharmacological tests havethe objective to reveal an arrhythmogenic marker likea distinct ECG phenotype or to provoke an arrhythmiain susceptible patients. Their diagnostic value hasbeen specified in prior reports by Krahn et al. (19) andVisser et al. (22). Pharmacological tests have a highyield for their specific diagnostic purpose, but theymay also reveal “unexpected” responses that provideclues for other causes. An abnormal response to adrug test can be the only abnormality detected by thescreening protocol. Standard protocols are used forClass Ia drugs and catecholamine infusion asdescribed previously (19–22).

Pharmacological testing with infusion of a sodium-channel blocker (ajmaline, pilsicainide, flecainide, orprocainamide) is performed to exclude BrS. Thesensitivity of ajmaline is higher than flecainide or

procainamide in diagnosing BrS (22,25,36,37). Inaddition, a J-point ST-segment elevation may beobserved in the sole inferolateral leads (Figure 4A),which appears specific of an abnormal depolarizationarea in the inferior part of ventricles; such patientsoften have an SCN5A variant (38,39). The use ofsodium-channel blockers may also produce unex-pected responses, revealing specific causes of VF. In amulticenter group of 16 IVF patients, we haveobserved the induction of R-on-T ectopy, mostly fromPurkinje tissue, during administration of Naþblockers (Figure 4B). There was no concomitant BrS orinferior J-point elevation. The provocation of R-on-Tectopy was reproducible in all 9 patients who un-derwent a repeat test. In 4 patients, the test was theonly means to reveal R-on-T ectopy, while other pa-tients had also spontaneous episodic ectopy. Fourpatients developed VF or polymorphic ventriculartachycardia (VT) during the test. These 4 patientswho had syncope as the only symptom received animplantable-cardioverter defibrillator (ICD). A

FIGURE 3 Different Patterns of Purkinje Activity in 4 Patients With Idiopathic Ventricular Fibrillation

(A) Purkinje ectopy from the right Purkinje system, exhibiting a left bundle branch block morphology; note the initially rapid deflection (arrows). (B) Typical Purkinje

ectopy from the left Purkinje system (asterisks) with narrow QRS duration, right bundle branch block morphology, and short coupling intervals. The earliest activity

preceding ectopic beat is found in the distal left posterior fascicle, with different activation sequences associated with the 2 different electrocardiography morphologies.

(C) Purkinje ectopy with long coupling interval in the aftermath of ventricular fibrillation, with no ventricular fibrillation recurrences after catheter ablation of ectopy. (D)

Spontaneous polymorphic ventricular tachycardia associated with 1-to-1 Purkinje activity. LV ¼ left ventricle.

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spontaneous VF was then observed in 3 of them (at afollow-up of 28 months), suggesting a high clinicalvalue of the drug-testing response (40).

Catecholamine infusion tests are performed toexclude stress- or effort-induced VT, or CPVT (thelatter in association with genetic testing). Adrenalineis also recommended to confirm the absence of longQT syndrome. However, false positive tests arefrequent in healthy subjects and QT variations, andmeasurements may be of ambiguous interpretation.QTc prolongation provoked by physical (abrupt orbrisk standing position) or mental stress appearsmore specific (22,25,41,42).

Isoproterenol testing has a different impact thanadrenaline testing. It may similarly show long QT

syndrome (Figure 2A) or CPVT, but its highbeta-agonist action is particularly interesting toreveal the arrhythmogenicity of (discrete or overt)structural heart diseases. We use it in an infusion of3 min at a dose of 45 mg/min (43,44), which producesa mean peak sinus rate of 152 � 18/min (85% oftheoretical maximum heart rate on exercise). Theisoproterenol test has a higher arrhythmogenic powerthan exercise testing, inducing nonsustained VTs ($3beats) in 74% to 85% of ARVD (PVCs dominantlynegative in V1) and 42% of dilated cardiomyopathies(PVCs dominantly positive in V1). In contrast, non-sustained VTs are induced in only in 2% to 2.7% ofcontrol patients with PVCs and normal hearts atechocardiography (43,44). In IVF patients presumed

FIGURE 4 Uncommon Responses to Sodium-Channel Blocker Testing

(A) ST-segment elevation in the inferior leads during ajmaline testing in association with a Brugada syndrome. Mapping showed an abnormal depolarization

area in the inferior part of the right ventricle. (B) Idiopathic ventricular fibrillation patient: the induction of R-on-T ectopy during administration of ajmaline

was the only abnormality found during the systematic assessment. The provocation of R-on-T ectopy was reproducible on a repeated ajmaline test during

electrophysiological study, and proven to originate from left Purkinje tissue. Spontaneous Purkinje ectopy were later documented during a recurrence of

ventricular fibrillation.

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to be free of structural heart disease, the isoproter-enol test has a significant value when it induces re-petitive forms of monomorphic or polymorphic PVCs(Figure 5), as this response often indicates the pres-ence of concealed myocardial alterations that will bedemonstrated with high-density electrogram map-ping (see results detailed subsequently). Suchvulnerability to catecholaminergic arrhythmias is alsoobviously a potential indication for beta-blockertreatment.

In rare cases, the isoproterenol test has been re-ported to induce ST-segment elevation and coronaryspasm (45). We have seen 2 such cases initially

considered IVF, with 1 of them shown in Figure 2C.The role of strong sympathetic stimulation withparasympathetic nervous system is believed to play arole in the pathogenesis of coronary spasm induction(45).

Finally, there are other conditions associated withthe clinical occurrence of VF as strong vagal drive ordynamic changes in J-wave or QT intervals, for whichno test is currently available to reproduce them in thehospital environment. The development of provoca-tion tests specific for these diverse conditions wouldbe desirable to improve the diagnostic yield of clinicalwork-up and risk stratification.

FIGURE 5 Polymorphic Ventricular Tachycardia on Isoproterenol Testing

In 2 idiopathic ventricular fibrillation patients, isoproterenol testing induced nonsustained polymorphic ventricular tachycardia having a relatively slow rate.

Premature ventricular beats are dominantly (A) positive or (B) negative in the V1 lead. In both patients, high-density electrogram mapping revealed the

presence of localized myocardial alterations, in the left (case shown in Figure 9) and right ventricles, respectively. LBBB ¼ left bundle branch block;

RBBB ¼ right bundle branch block

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ROLE OF INVASIVE

ELECTROPHYSIOLOGICAL STUDY

As IVF patients meet criteria for ICD insertion, anelectrophysiological study for the sole reason ofinducing VF is not currently indicated for risk strati-fication, particularly as the VF inducibility rate isrelatively low (5,19). Invasive testing has been re-ported in selected patients to determine whether aspecific substrate, such as a monomorphic VT orsupraventricular arrhythmia causing hemodynamiccollapse, is the cause of VF (46,47).

However, an electrophysiological study may havean important role for diagnosis of subclinicalmyocardial alterations when the initial imaging work-up is negative, by relying on sole electrophysiologicalcriteria. This has been demonstrated in a recent studycombining invasive and noninvasive mapping(Figure 6), which showed that noninvasively detectedre-entries during VF were often localized in distinctaltered areas in patients with IVF (24). This point willbe developed subsequently.

VF INDUCTION. In our practice, electrophysiologicalstudy is performed using 2 10-electrode catheterspositioned on RV and LV sides of the septum, andan additional duodecapolar mapping catheter.Standard induction protocol is performed usingpacing from the RV apex then from the LV (nearthe distal posterior fascicle) using a pulse width of2 ms at 20 mA. The latter is used instead of theconventional “double diastolic threshold” in orderto achieve shorter extrastimulation coupling in-tervals and increase the rate of VF inducibility.Programmed ventricular stimulation is performedusing 2 basic cycle lengths (600 and 400 ms) withup to 3 extrastimuli until the refractory period wasmet. During the induction protocol, noninvasivebody surface mapping can be used to detect theventricular wavefronts during the initial organizedVF, and to locate the main driver areas (Figure 6).We use an array of 252 body surface electrodescombined to computed tomography–based geome-try (ECVUE, Medtronic, Minneapolis, Minnesota)(24).

FIGURE 6 Colocalization of VF Re-Entries With the Areas of Abnormal Electrograms

The body surface maps in 2 spontaneous ventricular fibrillation (VF) episodes show the location of VF re-entries by the blue curves and red

areas, during the initial 4 s of VF. The re-entries are dominant in the anterior right ventricle (RV) (anteroposterior [AP] view) and their location

is reproducible in the inferior RV, and the high septum–left ventricular (LV) outflow tract area; the latter seen in the left anterior oblique (LAO)

view. Low-voltage fragmented electrograms recorded by epicardial electrodes are present during normal sinus rhythm within the white-dotted

contour, in contiguity with the areas of VF re-entries. All other ventricular regions show narrow signals indicating healthy underlying tissue.

LAD ¼ left anterior descending artery.

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ELECTROGRAM MAPPING IN SINUS RHYTHM. A20-pole catheter with 2-mm interelectrode distances isused for endocardial (PENTARAY, Biosense Webster,Diamond Bar, California) and epicardial (PENTARAY orLASSO [Biosense Webster]) measurements. A trans-septal or retroaortic approach is performed to accessthe endocardial LV and a subxyphosternal approach toaccess into the pericardial space. Electroanatomicalmapping of the endocardium and epicardium is per-formed using magnetic localization (CARTO 3 system[Biosense Webster]). The objective is to perform high-density recordings (>3,000 sites in epicardium) and todetermine whether electrogram characteristics iden-tify areas of abnormal conduction indicative of local-ized myocardium alterations. Electrogram criteriaabnormalities are identical to those defining fibroticand cardiomyopathic tissue during mapping ofischemic or dilated cardiomyopathies. Areas of low-amplitude electrograms were defined in bipolar(<1mV) andunipolarmodes (<8.3 and 5.5mV in LV andRV, respectively). Because low-amplitude electro-grams can be due to normal fat tissue on the

epicardium, epicardial electrograms were consideredabnormal if they harbored fragmented signals with aduration superior to 70 ms (onset to offset) or morethan 3 components or split or late potentials (48–50). Itis important to underline that the 70-ms criterion isbased on prior small-sized population studies usinglarge interelectrode distances. The current use of 2-mm bipoles (or smaller electrodes) improving detec-tion of the near-field component likely requiresadjusting reference cutoffs for electrogram mapping,also taking into account other variables influencingsignal characteristics (51–53).

PATIENT POPULATION:

RESULTS OF HIGH-DENSITY MAPPING

Our experience of IVF includes 172 patients (1994 to2019), of whom 64 were referred specifically for VFtrigger ablation. VF triggers originated from Purkinjecells in 57 (RV in 29, LV in 22, both in 6) and ven-tricular myocardium in 7 (RV outflow tract in 5, othersin 2). Interestingly, in this (Caucasian) patient cohort,

TABLE 1 Clinical Results in 50 Patient Survivors of IVF, With Comparison of Those With or Without Myocardial Conduction Abnormality on

High-Density Mapping

Population(N¼ 50)

IVF With LocalizedMyocardial Alteration

(n ¼ 34)

IVF WithoutMyocardial Abnormality

(n ¼ 16)* p Value

Clinical characteristics

Age, yrs 33 � 11 33 � 12 33 � 12 0.968

Male 39 (78) 29 (85) 10 (62.5) 0.11†

Family history of SCD 6 (12) 4 (11) 2 (12.5) 1.00

Activity at index VF (sleep/effort/other) 11/7/32 7/5/22 4/2/10 1.00

12-lead ECG

PR interval, ms 166 � 28 169 � 30 160 � 26 0.335

QRS duration, ms 95 � 10 100 � 9 86 � 5 <0.001†

QT interval, ms 390 � 28 394 � 27 384 � 30 0.325

QTc interval, ms 413 � 31 411 � 27 416 � 37 0.668

Documented Purkinje ectopy 14 (28.0) 6 (17.6) 8 (50.0) NR

VT runs (>3 beats) on isoproterenol 11 (22) 10 (26) 1 (6) 0.080†

Electrophysiological study

Inducible VF 26 (54.1)‡ 19 (55.9)‡ 7 (43.7) 0.37

VF inducibility with 1/2/3 extrastimuli 0/10/16 0/8/11 0/2/5 0.668

Electrogram mapping (epicardial sites) 3,842 � 1,684 4,068 � 1,886 3,357� 1,103 0.282

RV endocardial sites 718 � 599 824 � 692 506 � 289 0.190

LV endocardial sites 970 � 907 995 � 1,051 907 � 489 0.835

Values are mean � SD and n (%). Continuous variables were compared with a 2-sided Student’s t-test. Categorical variables were compared with the Fisher exact test. *Includes8 with documented PK ectopy, 2 with inducible PK activity, and 6 unexplained IVF. †A trend or a significant result (p < 0.05). ‡2 patients refused.

ECG ¼ electrocardiography; IVF ¼ idiopathic ventricular fibrillation; LV ¼ left ventricular; NR ¼ not relevant; PK ¼ Purkinje; RV ¼ right ventricular; SCD ¼ sudden cardiacdeath; VF ¼ ventricular fibrillation.

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there was a strong association between the patientgender and the origin of Purkinje triggers. RightPurkinje ectopy was observed dominantly in men(n ¼ 24 of 29, 82.7%) and left Purkinje ectopy inwomen (n ¼ 19 of 22, 86%), which was significant(p ¼ 0.001 on chi-square test).

From this cohort, we describe in detail the last 50patients (39 men, 11 women) who had comprehensiveinvestigations (as shown in Figure 1) were systemati-cally performed. They survived the index VF episodeat 33 � 11 years of age, which was diagnosed as idio-pathic VF after the initial evaluation protocol. Nopatient had any ECG showing short or long QT syn-drome, BrS, or J-wave pattern. Structural imaging andpharmacological testing were negative. This IVFpopulation had clinical characteristics (male pre-dominance, young age, occurrence at rest) similar tothose of wider groups previously published (11).Table 1 summarizes the clinical findings in this cohort.The results of high-density electrophysiologicalstudies are detailed subsequently.

PURKINJE-RELATED IVF. An abnormality affectingthe Purkinje system was the unique finding in 10patients. It was evidenced as either spontaneousectopy or by repetitive Purkinje activity inducible byprogrammed stimulation. None of these patients had

abnormal myocardial areas upon endocardial-epicardial mapping.

The presence of Purkinje ectopy was documentedin 8 patients, by continuous ECG telemetry in thedays following VF, with short coupling intervals(falling on the T-wave) in 7 and long coupling in-tervals in 1. Their role in VF initiation was demon-strated in 4 patients. The ectopy originated from thedistal left Purkinje system in 4 patients, the rightPurkinje system in 3 patients, and both in 1 patient(Figure 3).

Another Purkinje abnormality was found duringprogrammed stimulation—in 2 of the previous pa-tients with Purkinje ectopy and 2 without Purkinjeectopy—resulting in a total of 10 patients (20%) whohad IVF was associated with a Purkinje abnormality.In these 4 patients, repetitive activity was consis-tently inducible within the distal Purkinje network byprogrammed stimulation, particularly by pacing closeto the distal left Purkinje fascicle (54). The activityconsisted of polymorphic VT (median 7 beats; range 3to 17), with all beats preceded by distal Purkinje po-tentials (Figures 7A and 7B). The left bundle branchpotential was slower or absent, excluding a bundlebranch re-entry. Termination of polymorphic VT waspreceded by slowing or disappearance of Purkinjepotentials (Figure 7C). In 2 cases, polymorphic

FIGURE 7 Inducible Repetitive Activity in Peripheral Purkinje

(A) Twelve-lead electrocardiography: induction of polymorphic ventricular tachycardia (VT) with programmed stimulation in a 15-year-old girl. Pacing is performed from

the left ventricle (LV) close to the left posterior Purkinje system. (B) Endocardial recordings with a multipolar catheter along the distal left posterior fascicle show a more

rapid cycle length (mean 202 ms; range 156 to 240 ms) between Purkinje activities (asterisks) than in the LV (217 ms) or right ventricle (RV) (220 ms). The exact values

are indicated beat to beat. Each ventricular beat is preceded by Purkinje activity, with a progressively longer timing. The induction of polymorphic Purkinje-driven VT was

consistently reproducible, and led to sustained ventricular fibrillation in 1 instance. (C) Another episode of induced polymorphic VT showing that VT termination is clearly

preceded by slowing of Purkinje activity (asterisks). CL ¼ cycle length.

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Purkinje VT degenerated into VF requiring directcurrent cardioversion. We have considered theseinducible activities as abnormal responses, as theyhave not been reported in a unique study evaluatingLV programmed stimulation (55). Furthermore, shortPurkinje coupling intervals (<160 ms) were occa-sionally recorded between subsequent Purkinje ac-tivities, well below the normal refractory period ofPurkinje cells.

MICROSTRUCTURAL CARDIOMYOPATHIC ALTERATIONS.

Myocardial areas manifesting low amplitude andfractionated electrograms were found in 34 of 50

(68%) patients, providing electrophysiological evi-dence of local conduction alteration (Figures 8 and 9).They were located in the RV in 22 of 34 (64.7%) pa-tients, the LV in 7 of 34 (20.6%), or both ventricles in 5of 34 (14.7%), and covered a small size representing 5� 3% of the total ventricular surface (24). The com-parison of endocardial and epicardial recordings atthe same locations showed that the abnormal elec-trograms were recorded in 1 side, mostly epicardial,indicating an alteration affecting a part of ventricularwall. The cardiac magnetic resonance data focusingon the abnormal areas failed to identify any structuralabnormalities. All patients were also retested using

FIGURE 8 Electrocardiography and Examples of Abnormal Epicardial Electrograms During Sinus Rhythm in the RV in 2 Patients With

Idiopathic Ventricular Fibrillation

(A) The abnormal electrograms are present within the black contour of epicardial voltage map in the right ventricular (RV) apex. (B) The

abnormal electrograms are present within 2 areas (black contour) of the epicardial anterior RV. Despite prolonged and late epicardial elec-

trograms, note the absence of late potentials in high-amplification electrocardiography. Both patients were negative for a panel of 31 genes,

including SCN5A and arrhythmogenic RV cardiomyopathy–related genes. The arrows indicate the abnormal electrograms.

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ajmaline infusion to exclude BrS. The term micro-structural alteration refers to this nontransmurallesion and the inability to perceive it by current im-aging techniques. In the patients who had VF induc-ible by programmed stimulation, the main VF drivers(on noninvasive mapping) were anchored toabnormal myocardial areas in 85% of cases (24)(Figure 6). Finally, it is noteworthy that a subset ofpatients with microstructural cardiomyopathy(17.6%) also had Purkinje ectopy, as commonly seenin a variety of structural heart disease (SHD), wherethey may act as VF triggers (56).

DISTINCTIVE FACTORS. The results of clinical ex-aminations in patients with or without myocardialabnormality (34 vs. 16) were evaluated (Table 1).Patients with myocardial abnormality were domi-nantly men (29 of 34 vs. 10 of 16; p ¼ 0.11) and had awider QRS duration (100 � 9 ms vs. 86 � 5 ms;p < 0.001) after excluding cases with ventricularconduction disturbance (bundle branch block orfascicular block), and even after adjusting for bodyweight. In addition, they have a trend for a higher

incidence of VT runs ($3 beats) during catechol-amine testing: 10 of the 11 patients withisoproterenol-induced VT runs had myocardial ab-normality (10 of 34 vs. 1 of 16; p ¼ 0.08). Figure 5shows 2 examples of nonsustained polymorphic VTappearing on isoproterenol (without ECG or geneticcriteria of CPVT or long QT syndrome) who had anarea of myocardial abnormality later found in theepicardium. These preliminary results warrantconfirmation in a wider patient population.

IVF: A SPECTRUM OF CONCEALED DISEASES

The previous results show that a systematic set ofinvestigations reveals areas of altered myocardialconduction in 68% of IVF patients. Purkinje abnor-mality alone (without associated myocardial abnor-mality) is observed in 20% of patients, a valuepossibly overestimated by a referral bias. No abnor-mality could be observed in 12% of patients. Theseresults indicate that extending the phenotypic in-vestigations by endocardial-epicardial mapping

FIGURE 9 Examples of Abnormal Epicardial EGMs During Sinus Rhythm in 2 Small Areas in the LV

The 2 areas are located in the lateral and inferior left ventricle (LV), with the abnormal signals amplified in the inlet; the recording circular

catheter is visible on the electroanatomical activation maps. EGM ¼ electrogram; LAO ¼ left anterior oblique; RV ¼ right ventricular.

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allows identifying a certain or probable cause in thegreat majority of IVF patients. Such invasive mappingmay be performed during the index clinical presen-tation; it will also address the questions raised by thepatient and his family on the tragic event of unex-plained VF. It may alternatively be performed in thecase of recurrent VF for the prospect of substrateidentification and ablation.

The most frequent abnormality is the presence oflocalized areas of slow-conducting myocardium. Theabnormal areas were associated with anchoring of re-entries during VF on noninvasive mapping, suggest-ing a pathophysiological link. These abnormal areaslikely indicate microstructural alterations of themyocardium because of fibrosis, fatty tissue or in-flammatory infiltration, or cellular or intercellular(gap junctions) pathologies. Their incidence asobserved here by electrogram mapping, is muchhigher than that reported in autopsy studies of IVFpatients, which relates to the different methods used(11,25). The electrogram patterns that define the ab-normality give no indication on the specific disease,

although a more formal characterization may provideuseful information in the future. However, the vary-ing anatomical and transmural location is suggestiveof a large spectrum of potential pathologies. The al-terations in the epicardial RV are similar to thoseencountered in BrS, or ARVD; those in the postero-lateral LV are similar to those encountered inmyocarditis, sarcoidosis, or genetic or acquired car-diomyopathies (57–64). A subendocardial alterationmay be a damage after coronary spasm. IVF, in thesecases, may represent genetically negative or spatiallylimited forms (negative imaging) of myocardial dis-eases, or other unknown affections (CentralIllustration). The results are in keeping with theincreasing detection of gene variants associated withmyocardial structure that are reported in IVF(4,5,11,21,25).

The abnormalities affecting the Purkinje systemwere less frequent. They were evidenced as triggeringectopy or by Purkinje repetitive activity inducible byprogrammed stimulation. Purkinje ectopy was docu-mented by ECG and endocardial mapping; 4 of them

CENTRAL ILLUSTRATION The Wide Spectrum of Potential Affections Underlying Sudden Cardiac Death inApparently Normal Hearts, With or Without the Presence of an Electrocardiography Phenotype

Haïssaguerre, M. et al. J Am Coll Cardiol EP. 2020;6(6):591–608.

Although the pathophysiology of these affections is likely a complex mosaic at a cellular scale, the individual substrate when mapped during electrophysiology

exploration shows abnormalities dominantly affecting depolarization, or repolarization, or excitation.

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had a documented VF initiation. In others, the path-ogenic role of Purkinje system could only be inferred,as it was the unique apparent abnormality. The abilityof inducing Purkinje repetitive activity in 4 patientswas considered an abnormal response, as it is rarelyobserved in our experience of VF inductions and notreported in a prior study (55). However, further in-vestigations are needed to confirm its significance,and whether it may reveal subclinical Purkinje ab-normalities (“Purkinjopathy”). Unfortunately, majorlimitations are currently present in the clinical capa-bilities to investigate Purkinje function and structure,which restrict their characterization. Multiplearrhythmic expressions with the phenotype of Pur-kinje ectopy (short-coupling, CPVT, multifocalectopic Purkinje premature contractions [MEPPC])

have been previously described and some geneticabnormalities have been reported so far and wererecently reviewed (23). An alteration in intracellularcalcium handling is likely key to the genesis ofspontaneous ectopy, particularly by triggered activitybased on delayed afterdepolarizations. The ability ofinducing Purkinje re-entrant activity may alterna-tively be due to altered conduction properties (56),which would relate more to sodium current or gapjunctional alterations.

Finally, no myocardial or Purkinje abnormalitycould be evidenced in a minority of IVF patients(“true” idiopathic VF). Unexplained IVF may haveresulted from nondetected abnormalities of conduc-tion, or of repolarization (long QT syndrome, earlyrepolarization), or undocumented ectopic trigger;

FIGURE 10 Complex Phenotype in a Patient With Pathogenic DPP6 Mutation

This patient was referred for ablation of ventricular fibrillation triggers originating from the right Purkinje system (left). However, epicardial

mapping also revealed an extensive damage on the right ventricular (RV) epicardial structure shown by voltage mapping (purple

indicating $1 mV) and prolonged fragmented electrograms (right). ant ¼ anterior; LV ¼ left ventricular.

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possibly associated with transient variables (as fever,hypokalemia, drugs, autonomic neural system [SNA]variations). Such causes may be diagnosed later dur-ing a recurrent VF episode, or after genetic testing.

High-density electrophysiological mapping cantherefore discriminate not only between the differentarrhythmogenic substrates within IVF patients (whohave no clinical phenotype), but also within patientswho exhibit a same phenotypic expression. In recentstudies, the inferolateral J-wave phenotype has beendemonstrated to be the expression of distinct mech-anisms—either early repolarization or late depolari-zation—with strong implications in patientmanagement (39,65,66). In a specific biomedicalresearch program we have the opportunity to performex vivo human heart investigations in patients whodied of VF. Using high-resolution mapping and im-aging methods as well as targeted cellular biology, wecould confirm that a mosaic of different mechanismsmanifesting a similar clinical phenotype can beresponsible for SCD associated with an apparentlynormal heart (67). Pending further investigations, itmay be expected that VF substrates will be moreprecisely characterized and, in combination with

deeper genotyping characterization, will be catego-rized using more appropriate terminology.

GENOTYPIC AND PHENOTYPIC

CHARACTERIZATION

In the past, a variety of arrhythmias initially classifiedas IVF have been secondarily recognized as distinctdiseases after genetic testing, in correlation with thephenotype of 12 lead-ECGs at baseline or duringarrhythmia. The identification of a genetic disorder isessential for patient care as it has implications for themanagement of the disease but also for the family ofthe affected individual. The 2017 consensus state-ments recommend genetic testing “for arrhythmiasyndromes in young patients (<40 years of age) withunexplained SCD, or unexplained near drowning” (5).The yield of genetic testing is reported as higher if afamily history of SCD at a young age is present. Inaddition, familial phenotypic screening should beperformed in first degree relatives, as shown by Behret al. (21). This included resting ECG, exercise testing,and echocardiography. In selected cases, Holter andsignal-averaged ECGs, cardiac magnetic resonance,

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and pharmacologic testing can be performed(21,22,25).

In inherited arrhythmia syndromes, the yield for agiven phenotype varies from about 20% (BrS) to 60%(CPVT) or 75% (long QT syndrome), and several mu-tations can be associated with a same phenotype(68,69). In IVF, extensive genetic testing—usingwhole-exome sequencing and next-generationsequencing approaches—is currently not recom-mended because of the low yield and high cost. Theselarge data have allowed the detection of a plethora ofcandidate genes for IVF associated with cardiacelectrical function or myocardial structure. However,the results need to be evaluated against the “geneticbackground noise,” and the task for interpretation ofmultiple detected variants is challenging (68–71). Inaddition, most novel variants have not been evalu-ated using functional studies to validate theirarrhythmogenic impact. These variants often concerna specific family or geographic region (as the commonDPP6 in the Netherlands), which emphasizes the largespectrum of genetic factors involved in IVF andarrhythmic syndromes.

The phenotypic characterization of IVF patientshas an important role to establish causality of geneticvariants. Microstructural myocardial affections orPurkinje conduction alterations would be more likelyassociated with mutations in genes coding for thesodium channels, connexins, and structural proteins.Mutations associated with spontaneous Purkinjeectopy could be more related to calcium handling.However, the heterogeneous nature and pathogen-esis of mutations, and the ubiquity of mutated pro-teins in the heart, reduce both the mutation andtissue specificity. Mutations in SCN5A have manyclinical expressions. Mutations in RYR2 have beenassociated with CPVT perceived as a primary elec-trical disease, or ARVD manifesting as structuralmyocardial abnormalities. An example of a complexphenotype is shown in a patient with pathogenicDPP6 mutation. Although this mutation was deemedto selectively increase the Purkinje cell transientoutward potassium current, we also observed severealterations on the RV epicardial myocardium byelectrogram mapping (Figure 10). High-density map-ping allowing deeper phenotypic characterizationmay possibly show more complex phenotypes thanexpected in other unexplored electrical syndromes asthe long QT syndrome or CPVT, with implications fortheir early detection and therapy.

Despite the complexity in genetic interactions andphenotypic expressions, idiopathic VF and other VFassociated with apparently normal hearts can betentatively classified according to the dominant

primary substrate. Depolarization/conduction abnor-malities associated with uncoupled and delayedelectrograms are the most prevalent affections(48,57,72). They can be associated with secondaryrepolarization changes (73). They include BrS whereabnormal depolarization is present in the RV outflowtract, the subset of inferolateral J waves withabnormal depolarization in the inferior part of the(right or left) ventricles, and the subset of IVF asso-ciated with abnormal depolarization in a variety ofareas. Repolarization abnormalities include long QTsyndrome, short QT syndrome, and the subset ofinferolateral J waves due to early repolarization (66).Excitation abnormalities include IVF due to Purkinjeor PVC triggers, or VF due to multiple focal excita-tions (e.g., CPVT or MEPPC); “accidental” VF due toexternal excitation (commotion cordis, electrocution)may also be added.

Although mixed conditions are obviously present(as Purkinje trigger and depolarization abnormality,or repolarization changes secondary to depolarizationabnormality), the groups share a common type ofprimary substrate and mode of therapy. Theabnormal depolarization electrograms can be diag-nosed and targeted for ablation with the samemethod in BrS, late depolarization J-wave, or IVF. Theabnormal repolarization group appears more anelectrical dysfunction amenable to drug therapy. Inthe abnormal excitation group, the ablation ofabnormal foci enables effective prevention (CentralIllustration).

THERAPY IN IVF

INSERTABLE CARDIOVERTER-DEFIBRILLATOR. Inpatients with IVF (or idiopathic polymorphic VT), anICD insertion is recommended “if meaningful sur-vival > 1 year is expected.” ICD insertion in patientswith IVF is justified by the high recurrence rate ofventricular arrhythmias, varying from 11% to 45%(74).

DRUG THERAPY. The use of pharmacotherapy is toprovide a reduction of ICD interventions or symp-tomatic relief (frequent PVCs) in patients consideredto have no substrate for catheter ablation or reluctantto invasive therapy. Beta-blockers are indicated infew selected patients notably those with arrhythmiasupon stress or effort. Verapamil has an excellent ef-fect on patients with frequent Purkinje triggers andpolymorphic VTs; however, the short half-life of thismedication makes it more consistently efficient forimmediate therapy using intravenous administrationthan for long-term oral administration (17,18).

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Quinidine has been also shown to be beneficial in IVF.It results in a significant reduction of ICD shocks(from 7.5 � 12 to 0.9 � 1.7 over 34 months), and druginterruption is frequently associated with break-through events (75). Further research will be neededto evaluate whether specific IVF substrates asdescribed previously would be most receptive toquinidine or other therapies.

CATHETER ABLATION. Catheter ablation is currentlyrecommended “for patients with recurrent episodesof IVF initiated by PVCs with a consistent QRSmorphology.” This statement indicates that the trig-gers are the main ablation target in consensus rec-ommendations (5). The presence of localizeddepolarization substrate, in a significant part of IVFpatients, represent a potential novel target for abla-tion. In keeping with the success of substrate-basedablations in patients with BrS or overt structuralheart diseases, IVF patients displaying microstruc-tural myocardial substrate are likely to benefit fromthis type of strategy.Tr igger ab lat ion . The technique has been detailedin prior articles including the maneuvers to elicitPVCs that are suppressed with sedation (18,30–32).The site of earliest ventricular activation duringspontaneous PVCs is the target of choice. Multielec-trode catheters are useful for mapping over a widearea of ventricular myocardium with higher spatialsampling and resolution. Special care should be takenduring Purkinje mapping to avoid inadvertentbumping of the right bundle, with the left 1 beingmuch less vulnerable. In patients without clinicalPVCs, PVCs can be inducible by pacing maneuvers(atrial or ventricular) or drug infusion like isoproter-enol (1 to 2 mg/kg/min) or Class I drugs. Noninvasiveelectrocardiographic mapping imaging can be used toindicate the area of interest in patients with rare orpolymorphic PVCs. In the absence of ectopy, ablationcan target the local Purkinje potentials or the site ofbest matched morphology (PVCs documented in theward) by pace-mapping. Last, intracardiac echocar-diography can be helpful in the complex anatomicalregions like the papillary muscles.

Ablation is facilitated by the use of irrigated tipcatheters. In most cases, ablation is extendedapproximately 1 to 2 cm around the target site,particularly in Purkinje triggers, in order to reachadditional foci and to “prune” the Purkinje arboriza-tion to minimize re-entries. During ablation, it iscommon to have exacerbation of the arrhythmia(multiple PVCs leading to polymorphic VT and, morerarely, to VF) before the eradication of premature

beats. The occurrence of QRS widening during abla-tion indicates potential catheter displacement towardthe more proximal conduction system and ablationshould be stopped (18).Substrate ab lat ion . An irrigated tip ablation cath-eter is used with the target of eliminating fragmentedelectrograms, as described for VT in structural heartdisease or BrS (48,49,76–79). Radiofrequency energyis delivered with a power of 35 to 45 W and durationvarying from 10 to 30 s guided by impact on the localelectrogram. Radiofrequency lesions are deliveredpoint-by-point at the area covering abnormal elec-trograms using serial applications. We have reporteda mean duration of 18 � 5 min of radiofrequency en-ergy application in our initial series of 12 patients,with 10 patients free of recurrences at a medianfollow-up of 14 months (24). Besides the usual risks ofcatheter ablation, the high prevalence of epicardialabnormalities requires specific precautions, notablyto avoid damaging the coronary arteries and phrenicnerve, as recently reviewed in consensus documents(79). Preoperative imaging of these structures can beintegrated to periprocedural 3-dimensional mappingsystem and is useful to reduce these risks (80). Newablative energies are emerging that may demonstrateadvantages of safety or efficacy upon standard radi-ofrequency ablation (81).

SUMMARY

Idiopathic VF is a puzzling diagnosis defined bynegativity of current medical investigations. Thiscondition accounts for a significant part of SCD inyoung adults. Detailed phenotypic investigationsdemonstrate that a majority of IVF can be elucidated,particularly using endocardial-epicardial mapping, byshowing an important role for microstructuralmyocardial or Purkinje abnormalities. The various lo-cations and patterns of abnormalities strongly suggestthat a mosaic of pathologies—acquired or geneticallydetermined—can potentially underlie their genesis.

Further advances in phenotypic investigations andgenetic screening will likely allow a more specificcharacterization of various substrates, a moreadequate terminology, and hopefully, an earlydetection of patients at risk for the development ofprimary prevention.

ADDRESS FOR CORRESPONDENCE: Dr. MichelHaïssaguerre, Institute of Rhythmology and HeartModelling, Hôpital Cardiologique Haut-Leveque, Avenuede Magellan, 33600 Bordeaux-Pessac, France. E-mail:michel.haissaguerre@chu-bordeaux.fr.

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KEY WORDS J-wave syndromes, suddencardiac death, unexplained death, ventricularfibrillation