Michel Haïssaguerre
email: michel.haissaguerre@chu-bordeaux.fr

MD Josselin Duchateau

MD Remi Dubois

PhD Mélèze Hocini

MD Ghassen Cheniti

MD Frederic Sacher

MD Thomas Lavergne

MD Vincent Probst

MD Elodie Surget

MD Ed Vigmond

PhD Nicolas Welte

MD Remi Chauvel

MD Nicolas Derval

MD Thomas Pambrun

MD Pierre Jais

MD Wee Nademanee

MD Olivier Bernus

Prof Michel Haissaguerre

Idiopathic ventricular fibrillation -role of Purkinje system and microstructural myocardial abnormalities

Keywords: Sudden cardiac death, Ventricular fibrillation, unexplained death, J-wave syndromes Abbreviations 3D -Three-dimensional ARVD -Arrhythmogenic Right Ventricular Dysplasia BBB -Bundle Branch Block BrS -Brugad Syndrom CPVT -Catecholaminergic Polymorphic Ventricular Tachycardia Defibrillator IVF -Idiopathic Ventricular Fibrillation LAO -Left Anterior Oblique LAD

Ventricular Fibrillation can be unexplained despite extensive investigations notably in the young.

• The use of high-density electrophysiological mapping detects causes in the great majority of victims. • Microstructural cardiomyopathies are the main causes, likely underlain by multiple pathological processes. • The phenotypic characterization of substrate is critical to develop therapy and interpret genetic results.

Sudden cardiac death (SCD) remains a major health problem in all continents. Estimates vary around 350000 victims per year in the United States or in Europe and are even higher in Southeast Asia. Coronary artery disease and cardiomyopathies are the main causes in older persons [START_REF] Fishman | Sudden cardiac death prediction and prevention: Report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop[END_REF][START_REF] Mozaffarian | Heart Disease and Stroke Statistics-2016 Update -A Report From the[END_REF][START_REF] Murakoshi | Epidemiology of arrhythmias and sudden cardiac death in Asia[END_REF][START_REF] Priori | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death[END_REF][START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary[END_REF][START_REF] Waldmann | Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real world setting: Focus on idiopathic ventricular fibrillation[END_REF]. However, in victims younger than 35 years, a common finding is the absence of structural heart disease at autopsy, which is reported in 29 to 40% of cases in recent population-based studies particularly in young males [START_REF] Eckart | Sudden Death in Young Adults. An Autopsy-Based Series of a Population Undergoing Active Surveillance[END_REF][START_REF] Winkel | Nationwide study of sudden cardiac death in persons aged 1-35 years[END_REF][START_REF] Semsarian | Sudden cardiac death in the young: The molecular autopsy and a practical approach to surviving relatives[END_REF][START_REF] Neilan | Late gadolinium enhancement among survivors of sudden cardiac arrest[END_REF][START_REF] Bagnall | A Prospective Study of Sudden Cardiac Death among Children and Young Adults[END_REF][START_REF] Torkamani | Molecular Autopsy for Sudden Unexpected Death[END_REF]. In the patients surviving after resuscitation maneuvers, ventricular fibrillation (VF) is consistently the lethal heart rhythm disorder identified at the time of event.

Experimental studies have demonstrated that, once initiated, VF is maintained by the continuous formation of reentrant waves, underlain by depolarization or repolarization heterogeneities. In cardiomyopathic post-transplant human hearts, reentry has been shown to self-perpetuate for many cycles by anchoring to a myocardial scar or structural heterogeneity [START_REF] Gray | Spatial and temporal organization during cardiac fibrillation[END_REF][START_REF] Nash | Evidence for multiple mechanisms in human ventricular fibrillation[END_REF][START_REF] Nair | Intramural activation during early human ventricular fibrillation[END_REF].

Over the last 20 years considerable efforts have been devoted to the search for electrocardiographic, structural and genetic anomalies in survivors [START_REF] Fishman | Sudden cardiac death prediction and prevention: Report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop[END_REF][START_REF] Priori | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death[END_REF][START_REF] Neilan | Late gadolinium enhancement among survivors of sudden cardiac arrest[END_REF]. Despite these progresses, unexplained sudden cardiac death defined as no apparent structural heart disease after extensive investigations remains frequent in young adults [START_REF] Viskin | Idiopathic ventricular fibrillation[END_REF][START_REF] Leenhardt | Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias[END_REF][START_REF] Haissaguerre | Mapping and ablation of idiopathic ventricular fibrillation[END_REF][START_REF] Krahn | Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER)[END_REF][START_REF] Obeyesekere | How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, longQT syndrome, and catecholaminergic polymorphic ventricular tachycardia[END_REF][START_REF] Behr | Sudden arrhythmic death syndrome: Familial evaluation identifies inheritable heart disease in the majority of families[END_REF][START_REF] Visser | Idiopathic Ventricular Fibrillation: The Struggle for Definition, Diagnosis, and Follow-Up[END_REF][START_REF] Wilde | Role of the Purkinje system in heritable arrhythmias[END_REF][START_REF] Haïssaguerre | Localized structural alterations underlying a subset of unexplained sudden cardiac death[END_REF][START_REF] Gray | Circ Arrhythm Electrophysiol. Evaluation after sudden death in the young[END_REF]. In this review, we report the current knowledge on idiopathic VF (IVF) defined as VF with no apparent structural or electrical heart disease after extensive investigations (e.g. no apparent phenotype). We will discuss the value of systematic clinical testing for confirmation of IVF diagnosis and exclusion of other causes of SCD. The results of individual phenotypic characterization based on high-density electrophysiological mapping will be analyzed with their implications for genetic interpretation and therapeutic approach.

Criteria identifying Idiopathic ventricular fibrillation

Definition of IVF

The HRS/EHRA/APHRS expert consensus statements on inherited primary arrhythmia syndromes define IVF as a resuscitated VF victim, in whom known cardiac, respiratory, metabolic and toxicological causes have been excluded through clinical investigations [START_REF] Priori | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death[END_REF][START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary[END_REF].

The diagnosis is based on the absence of a substrate for VF by exclusion of ischemic and structural cardiac diseases (ie, arrhythmogenic right ventricular, hypertrophic, and dilated cardiomyopathy, myocarditis, cardiac sarcoidosis, congenital heart disease) and 'primary arrhythmia syndromes' (ie, Brugada Syndrome BrS, catecholaminergic polymorphic ventricular tachycardia CPVT, long QT syndromes LQTS, short-QT syndrome, and early repolarization syndrome ERS). Whether a heart is considered normal depends obviously on the resolution of examinations and their timing relative to the clinical event [START_REF] Basso | Arrhythmic mitral valve prolapse and sudden cardiac death[END_REF][START_REF] Zaya | Provocative testing for coronary reactivity and spasm[END_REF][START_REF] Liang | Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis[END_REF][START_REF] Noda | Malignant entity of idiopathic ventricular fibrillation and polymorphic ventricular tachycardia initiated by premature extrasystoles originating from the right ventricular outflow tract[END_REF][START_REF] Knecht | Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study[END_REF][START_REF] Nogami | Mapping and ablating ventricular premature contractions that trigger ventricular fibrillation: trigger elimination and substrate modification[END_REF][START_REF] Van Herendael | Catheter ablation of ventricular fibrillation: importance of left ventricular outflow tract and papillary muscle triggers[END_REF][START_REF] Santoro | Ventricular fibrillation triggered by PVCs from papillary muscles: clinical features and ablation[END_REF][START_REF] Nakamura | Stevenson WG Substrate Modification For Ablation Of Recurrent Polymorphic Ventricular Tachycardia/Fibrillation[END_REF][START_REF] Viskin | short-coupled" variant of right ventricular outflow ventricular tachycardia: a not-so-benign form of benign ventricular tachycardia?[END_REF][START_REF] Tadros | Yield and pitfalls of ajmaline testing in the evaluation of unexplained cardiac arrest and sudden unexplained death: Singlecenter experience with 482 families[END_REF][START_REF] Cheung | Comparison of ajmaline and procainamide provocation tests in the diagnosis of brugada syndrome[END_REF][START_REF] Potet | Novel Brugada SCN5A mutation leading to ST segment elevation in the inferior or the right precordial leads[END_REF][START_REF] Nademanee | Mapping and Ablation of Ventricular Fibrillation Associated With Early Repolarization Syndrome[END_REF][START_REF] Escande | Malignant Purkinje ectopy induced by Sodium-channel blockers Heart Rhythm Scientific Sessions[END_REF][START_REF] Viskin | The response of the QT interval to the brief tachycardia provoked by standing: A bedside test for diagnosing long QT syndrome[END_REF][START_REF] Churet | Diagnostic reproducibility of epinephrine drug challenge interpretation in suspected long QT syndrome[END_REF][START_REF] Haissaguerre | Distinctive response of arrhythmogenic right ventricular disease to high dose isoproterenol[END_REF][START_REF] Denis | Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy[END_REF][START_REF] Kumar | Coronary spasm during cardiac electrophysiological study following isoproterenol infusion[END_REF].

IVF accounts for 14 to 23% of SCD in young adults. There is a relative paucity of specific recommendations for the clinical management of IVF but recent reviews and new data have become available [START_REF] Priori | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death[END_REF][START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary[END_REF][START_REF] Waldmann | Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real world setting: Focus on idiopathic ventricular fibrillation[END_REF][START_REF] Visser | Idiopathic Ventricular Fibrillation: The Struggle for Definition, Diagnosis, and Follow-Up[END_REF][START_REF] Wilde | Role of the Purkinje system in heritable arrhythmias[END_REF][START_REF] Haïssaguerre | Localized structural alterations underlying a subset of unexplained sudden cardiac death[END_REF][START_REF] Gray | Circ Arrhythm Electrophysiol. Evaluation after sudden death in the young[END_REF].

Systematic clinical testing

Non-cardiac causes of IVF, including accidental, cerebral, or respiratory causes and drug abuse/intoxication or electrolyte abnormality, are easily eliminated by simple investigations; and will not be discussed here.

Figure 1 shows a diagnostic flow chart illustrating the systematic assessment of patients who survived SCD; with each investigation being important for differential diagnosis of IVF.

Electrocardiography-Telemetry:

12-lead ECGs should be performed using standard and high precordial lead position, and include recordings of spontaneous or induced changes in the QRS & J/ST patterns, including circadian changes, post-pause, Valsalva, stress test or pharmacological tests (Figures 1,2).

Exercise test and signal-averaged ECG are recommended.

The 12-lead ECG recordings of PVC patterns (coupling, morphologies) should include the initial days in the intensive care unit, where the PVCs may be considered normal in the context of recent VF and are therefore often under-documented.

The goal is to recognize the site of origin of PVCs, whether they originate from the Purkinje system, the right or left ventricles, whether they are mono-or polymorphic [START_REF] Noda | Malignant entity of idiopathic ventricular fibrillation and polymorphic ventricular tachycardia initiated by premature extrasystoles originating from the right ventricular outflow tract[END_REF][START_REF] Knecht | Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study[END_REF][START_REF] Nogami | Mapping and ablating ventricular premature contractions that trigger ventricular fibrillation: trigger elimination and substrate modification[END_REF][START_REF] Van Herendael | Catheter ablation of ventricular fibrillation: importance of left ventricular outflow tract and papillary muscle triggers[END_REF][START_REF] Santoro | Ventricular fibrillation triggered by PVCs from papillary muscles: clinical features and ablation[END_REF][START_REF] Nakamura | Stevenson WG Substrate Modification For Ablation Of Recurrent Polymorphic Ventricular Tachycardia/Fibrillation[END_REF]. PVCs of ventricular origin have a wider duration and initial slower deflection than Purkinje ectopy.

The presence of frequent PVCs gives a potential indication of an abnormal (concealed) myocardial area, particularly when they do not have the common morphological patterns from right or left outflow tracts; the latter being commonly associated with normal myocardium.

Purkinje ectopy have a narrower QRS duration particularly when they originate from the left Purkinje system (<120ms) where they exhibit a right-bundle-branch block morphology.

Purkinje ectopy from the right Purkinje arborization have a left-bundle-branch block morphology, and a wider QRS duration (130-150ms) but an initially rapid deflection (Figure 3). The narrower left Purkinje ectopy are probably due to the dense left arborization allowing simultaneous capture of a greater part of left ventricle.

Short coupling (R-on-T) PVCs are clearly in favor of Purkinje origin but can also be seen in ventricular origin [START_REF] Haissaguerre | Mapping and ablation of idiopathic ventricular fibrillation[END_REF][START_REF] Viskin | short-coupled" variant of right ventricular outflow ventricular tachycardia: a not-so-benign form of benign ventricular tachycardia?[END_REF]; and vice versa, Purkinje ectopy may have a long coupling interval (> 360ms). It is essential to document the presence of Purkinje ectopy by 12-lead ECG as it can be the unique abnormality underlying VF and it can be treated by catheter ablation.

Structural investigations

Patients classified as having IVF should have no identifiable structural heart disease demonstrated by normal echocardiographic and delayed gadolinium-enhanced magnetic resonance imaging, no detectable coronary artery disease upon coronary angiography or exercise testing. Ergonovine or acetylcholine provocative tests are performed to exclude coronary artery spasm in the context of pain or ST elevation [START_REF] Zaya | Provocative testing for coronary reactivity and spasm[END_REF]. The presence of minor anatomical 'defects-variants' in coronary artery or valve apparatus (mitral valve prolapse) raises however a problem in establishing their implication [START_REF] Basso | Arrhythmic mitral valve prolapse and sudden cardiac death[END_REF]. Ventricular biopsy can be performed in selected cases (suspected myocarditis, sarcoidosis, ARVD). Ideally the biopsy location should be guided by electrogram or imaging abnormality to increase diagnostic yield and potentially provide new insights in IVF [START_REF] Liang | Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis[END_REF].

Pharmacological tests:

Pharmacological tests have the objective to reveal an arrhythmogenic marker like a distinct ECG phenotype or to provoke an arrhythmia in susceptible patients. Their diagnostic value has been specified in prior reports by Krahn et al, and Visser et al [START_REF] Krahn | Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER)[END_REF][START_REF] Visser | Idiopathic Ventricular Fibrillation: The Struggle for Definition, Diagnosis, and Follow-Up[END_REF]. Pharmacological tests have a high yield for their specific diagnostic purpose, but they may also reveal 'unexpected' responses that provide clues for other causes. An abnormal response to a drug test can be the only abnormality detected by the screening protocol. Standard protocols are used for class 1A drugs and catecholamine infusion as described previously [START_REF] Krahn | Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER)[END_REF][START_REF] Obeyesekere | How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, longQT syndrome, and catecholaminergic polymorphic ventricular tachycardia[END_REF][START_REF] Behr | Sudden arrhythmic death syndrome: Familial evaluation identifies inheritable heart disease in the majority of families[END_REF][START_REF] Visser | Idiopathic Ventricular Fibrillation: The Struggle for Definition, Diagnosis, and Follow-Up[END_REF].

Pharmacological testing with infusion of a sodium-channel blocker (ajmaline, pilsicainide, flecainide, or procainamide) are performed to exclude Brugada syndrome. The sensitivity of ajmaline is higher than flecainide or procainamide in diagnosing BrS [START_REF] Visser | Idiopathic Ventricular Fibrillation: The Struggle for Definition, Diagnosis, and Follow-Up[END_REF][START_REF] Gray | Circ Arrhythm Electrophysiol. Evaluation after sudden death in the young[END_REF][START_REF] Tadros | Yield and pitfalls of ajmaline testing in the evaluation of unexplained cardiac arrest and sudden unexplained death: Singlecenter experience with 482 families[END_REF][START_REF] Cheung | Comparison of ajmaline and procainamide provocation tests in the diagnosis of brugada syndrome[END_REF]. In addition, a J-ST elevation may be observed in the sole inferolateral leads (Figure 4A) which appears specific of an abnormal depolarization area in the inferior part of ventricles; such patients often have a SCN5A variant [START_REF] Potet | Novel Brugada SCN5A mutation leading to ST segment elevation in the inferior or the right precordial leads[END_REF][START_REF] Nademanee | Mapping and Ablation of Ventricular Fibrillation Associated With Early Repolarization Syndrome[END_REF]. The use of sodium channel blockers may also produce unexpected responses, revealing specific causes of VF. In a multicenter group of 16 IVF patients, we have observed the induction of R-on-T ectopy mostly from Purkinje tissue, during administration of Na+ blockers (Figure 4B). There was no concomitant BrS or inferior J-point elevation. The provocation of R-on-T ectopy was reproducible in all 9 patients who underwent a repeat test. In 4 patients, the test was the only means to reveal R-on-T ectopy while other patients had also spontaneous episodic ectopy. Four patients developed VF or polymorphic VT during the test. These four patients who had syncope as the only symptom, have received an ICD. A spontaneous VF was then observed in 3 of them (at a follow-up of 28 months) suggesting a high clinical value of the drug-testing response [START_REF] Escande | Malignant Purkinje ectopy induced by Sodium-channel blockers Heart Rhythm Scientific Sessions[END_REF].

Catecholamine infusion tests are performed to exclude stress-or effort-induced VT, or CPVT (the latter in association with genetic testing). Adrenaline is also recommended to confirm the absence of long QT syndrome. However, false-positive tests are frequent in healthy subjects and QT variations and measurements may be of ambiguous interpretation. QTc prolongation provoked by physical (abrupt/brisk standing position) or mental stress appears more specific [START_REF] Visser | Idiopathic Ventricular Fibrillation: The Struggle for Definition, Diagnosis, and Follow-Up[END_REF][START_REF] Gray | Circ Arrhythm Electrophysiol. Evaluation after sudden death in the young[END_REF][START_REF] Viskin | The response of the QT interval to the brief tachycardia provoked by standing: A bedside test for diagnosing long QT syndrome[END_REF][START_REF] Churet | Diagnostic reproducibility of epinephrine drug challenge interpretation in suspected long QT syndrome[END_REF].

Isoproterenol testing has a different impact than adrenaline testing. It may similarly show LQT (Figure 2A) or CPVT but its high beta-agonist action is particularly interesting to reveal the arrhythmogenicity of (discrete or overt) structural heart diseases. We use it in an infusion of 3 minutes at a dose of 45µg/min [START_REF] Haissaguerre | Distinctive response of arrhythmogenic right ventricular disease to high dose isoproterenol[END_REF][START_REF] Denis | Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy[END_REF] which produces a mean peak sinus rate of 152±18/ min ( 85% of theoretical maximum heart rate on exercise). The isoproterenol test has a higher arrhythmogenic power than exercise testing, inducing non-sustained VTs (≥3beats) in 74-85% of ARVD (PVCs dominantly negative in V1) and 42% of dilated cardiomyopathies (PVCs dominantly positive in V1). In contrast non-sustained VTs are induced in only in 2-2.7% of control patients with PVCs and normal hearts at echocardiography [START_REF] Haissaguerre | Distinctive response of arrhythmogenic right ventricular disease to high dose isoproterenol[END_REF][START_REF] Denis | Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy[END_REF]. In IVF patients presumed to be free of structural heart disease, the isoproterenol test has a significant value when it induces repetitive forms of monomorphic or polymorphic PVCs (Figure 5); as this response often indicates the presence of concealed myocardial alterations that will be demonstrated with high-density electrogram mapping (see results below). Such vulnerability to catecholaminergic arrhythmias is also obviously a potential indication for beta-blocker treatment.

In rare cases, the isoproterenol test has been reported to induce ST elevation and coronary spasm [START_REF] Kumar | Coronary spasm during cardiac electrophysiological study following isoproterenol infusion[END_REF]. We have seen 2 such cases initially considered IVF, one of them is shown in figure 2C. The role of strong sympathetic stimulation with parasympathetic nervous system is believed to play a role in the pathogenesis of coronary spasm induction [START_REF] Kumar | Coronary spasm during cardiac electrophysiological study following isoproterenol infusion[END_REF].

Finally, there are other conditions associated with the clinical occurrence of VF as strong vagal drive or dynamic changes in J-wave or QT intervals, for which no surrogate is currently available allowing replicating them in the hospital environment. The development of provocation tests specific for these diverse conditions would be desirable to improve the diagnostic yield of clinical work-up and risk stratification.

Role of Invasive electrophysiological study

As IVF patients meet criteria for ICD implantation, an electrophysiological study for the sole reason of inducing VF is not currently indicated for risk stratification, particularly as the VF inducibility rate is relatively low [START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary[END_REF][START_REF] Krahn | Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER)[END_REF]. Invasive testing has been reported in selected patients to determine whether a specific substrate, such as a monomorphic VT or supraventricular arrhythmia causing hemodynamic collapse, is the cause of VF [START_REF] Blanck | Bundle branch reentrant ventricular tachycardia: Cumulative experience in 48 patients[END_REF][START_REF] Stein | Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients?[END_REF].

However, an electrophysiological study may have an important role for diagnosis of subclinical myocardial alterations when the initial imaging workup is negative, by relying on sole electrophysiological criteria. This has been demonstrated in a recent study combining invasive and non-invasive mapping (Figure 6) which showed that non-invasively detected reentries during VF were often localized in distinct altered areas in patients with IVF [START_REF] Haïssaguerre | Localized structural alterations underlying a subset of unexplained sudden cardiac death[END_REF]. This point will be developed below.

VF induction:

In our practice, electrophysiological study is performed using two 10-electrode catheters positioned on right and left ventricular sides of the septum, and an additional duodecapolar mapping catheter. Standard induction protocol is performed using unipolar pacing from the RV apex then from the LV (near the distal posterior fascicle) using pulse width of 2 ms at 20 mA. The latter is used instead of the conventional 'double diastolic threshold' in order to achieve shorter extra-stimulation coupling intervals and increase the rate of VF inducibility.

Programmed ventricular stimulation is performed using two basic cycle lengths (600, 400 ms) with up to three extra-stimuli until the refractory period was met. During the induction protocol, non-invasive body-surface mapping can be used to detect the ventricular wavefronts during the initial organized VF; and to locate the main driver areas (Figure 6). We use an array of 252 body-surface electrodes combined to computer tomography-based geometry (ECVue™, Medtronic, OH). [START_REF] Haïssaguerre | Localized structural alterations underlying a subset of unexplained sudden cardiac death[END_REF].

Electrogram mapping in sinus rhythm:

A 20-pole catheter with 2mm interelectrode distances is used for endocardial (Pentaray) and epicardial (Pentaray or Lasso) measurements. A transseptal or retro-aortic approach is performed to access the endocardial left ventricle and a subxyphosternal approach to access into the pericardial space. Electro-anatomical mapping of the endocardium and epicardium is performed using magnetic localization (CARTO system, Biosense Webster, CA). The objective is to perform high-density recordings (> 3000 sites in epicardium) and to determine whether electrogram characteristics identify areas of abnormal conduction indicative of localized myocardium alterations. Electrogram criteria abnormalities are identical to those defining fibrotic and cardiomyopathic tissue during mapping of ischemic or dilated cardiomyopathies. Areas of low amplitude electrograms were defined in bipolar (less than 1 mV) and unipolar modes (less than 8.3 and 5.5mV in left and right ventricles respectively).

Because low amplitude electrograms can be due to normal fat tissue on the epicardium, epicardial electrograms were considered abnormal if they harbored fragmented signals with a duration superior to 70ms (onset to offset) or more than 3 components or split/ late potentials [START_REF] Hsia | Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia[END_REF][START_REF] Soejima | Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars[END_REF][START_REF] Cano | Electroanatomic substrate and ablation outcome for suspected epicardial left ventricular tachycardia in non-ischemic cardiomyopathy[END_REF]. It is important to underline that the 70ms criterion is based on prior small-sized population studies using large interelectrode distances. The current use of 2mm-bipoles (or smaller electrodes) improving detection of near-field component, likely requires to adjust reference cutoffs for electrogram mapping, also taking in account other variables influencing signal characteristics [START_REF] Takigawa | Detailed Analysis of the Relation Between Bipolar Electrode Spacing and Far-and Near-Field Electrograms[END_REF][START_REF] Glashan | Zeppenfeld Multisize Electrodes for Substrate Identification in Ischemic Cardiomyopathy -Validation by Integration of Whole Heart Histology JACC[END_REF][START_REF] Ustunkaya | Epicardial Conduction Speed, Electrogram Abnormality, and Computed Tomography Attenuation Associations in Arrhythmogenic Right Ventricular Cardiomyopathy[END_REF].

Patient population -Results of High density mapping

Our experience of IVF includes 172 patients (1994-2019) of whom 64 were referred specifically for VF trigger ablation. VF triggers originated from Purkinje cells in 57 (right ventricle in 29, left ventricle in 22, both in 6) and ventricular myocardium in 7 (RVOT in 5, others in 2). Interestingly in this (Caucasian) patient cohort, there was a strong association between the patient gender and the origin of Purkinje triggers. Right Purkinje ectopy were observed dominantly in male (24/29, 82.7 %) and left Purkinje ectopy in female (19/22, 86%), which was significant (p= 0.001 on chi 2 test).

From this cohort, we will describe in detail the last 50 patients (35 male, 15 female) in whom comprehensive investigations (as shown in Table 1) were systematically performed. They survived the index VF episode at the age of 33±11 years, which was diagnosed as idiopathic VF after the initial evaluation protocol. No patient had any ECG showing short/long QT or Brugada/J -wave pattern. Structural imaging and pharmacological testing were negative. This IVF population had clinical characteristics (male predominance, young age, occurrence at rest) similar to those of wider groups previously published [START_REF] Bagnall | A Prospective Study of Sudden Cardiac Death among Children and Young Adults[END_REF]. Table 1 summarizes the clinical findings in this cohort. The results of high-density electrophysiological studies are detailed below.

Purkinje-related IVF An abnormality affecting the Purkinje system was the unique finding in 10 patients. It was evidenced as either spontaneous ectopy or by repetitive Purkinje activity inducible by programmed stimulation. None of these patients had abnormal myocardial areas upon endocardial-epicardial mapping.

The presence of Purkinje ectopy was documented in 8 patients, by continuous ECG telemetry in the days following VF, with short coupling intervals (falling on the T wave) in 7 and long coupling intervals in 1. Their role in VF initiation was demonstrated in 4 patients. The ectopy originated from the distal left Purkinje system in 4, the right Purkinje system in 3 and both in 1 (Figure 3).

Another Purkinje abnormality was found during programmed stimulation -in 2 of the above patients with Purkinje ectopy and 2 without Purkinje ectopy -resulting in a total of 10 patients (20%) in whom IVF was associated with a Purkinje abnormality. In these 4 patients repetitive activity was consistently inducible within the distal Purkinje network by programmed stimulation; particularly by pacing close to the distal left Purkinje fascicle [START_REF] Haissaguerre | Idiopathic ventricular fibrillation associated with inducible repetitive activity within the distal Purkinje system[END_REF]. The activity consisted in polymorphic VT (median 7 beats, range 3 -17) with all beats preceded by distal Purkinje potentials (Figure 7 A,B). The left bundle branch potential was slower or absent, excluding a bundle branch reentry. Termination of polymorphic VT was preceded by slowing or disappearance of Purkinje potentials (Figure 7 C). In 2 cases, polymorphic Purkinje VT degenerated into VF requiring DC cardioversion. We have considered these inducible activities as abnormal responses, as they have not been reported in a unique study evaluating left ventricular programmed stimulation [START_REF] Mehdirad | Asymetry of retrograde and reentry within the His-Purkinje system: a comparative analysis of left and right ventricular stimulation[END_REF]. Furthermore, short Purkinje coupling intervals (< 160ms) were occasionally recorded between subsequent Purkinje activities, well below the normal refractory period of Purkinje cells.

Microstructural Cardiomyopathic Alterations

Myocardial areas manifesting low amplitude and fractionated electrograms were found in 34/50 (68%) patients; providing electrophysiological evidence of local conduction alteration (Figures 8,9). They were located in the right ventricle in 22/34 (64.7%), the left ventricle in 7/34 (20.6%) or in both ventricles in 5/34(14.7%), and covered a small size representing 5±3% of the total ventricular surface [START_REF] Haïssaguerre | Localized structural alterations underlying a subset of unexplained sudden cardiac death[END_REF]. The comparison of endocardial and epicardial recordings at the same locations showed that the abnormal electrograms were recorded in one side, mostly epicardial, indicating an alteration affecting a part of ventricular wall. The MRI data focusing on the abnormal areas failed to identify any structural abnormalities. All patients were also retested using ajmaline infusion to exclude Brugada syndrome. The term of microstructural alteration refers to this non-transmural lesion and the inability to perceive it by current imaging techniques. In the patients who had VF inducible by programmed stimulation (table 2), the main VF drivers (on non-invasive mapping) were anchored to abnormal myocardial areas in 85% of cases [START_REF] Haïssaguerre | Localized structural alterations underlying a subset of unexplained sudden cardiac death[END_REF] (Figure 6). Finally, it is noteworthy that a subset of patients with microstructural cardiomyopathy (17.6%, table 2) had also Purkinje ectopy as commonly seen in a variety of SHD, where they may act as VF triggers [START_REF] Haissaguerre | Ventricular arrhythmias and the His-Purkinje system[END_REF].

Distinctive factors The results of clinical examinations in patients with or without myocardial abnormality (34 vs 16) were evaluated (Table 1). Patients with myocardial abnormality were dominantly male (29/34 vs 6/16, p< 0.01) and had a wider QRS duration (100 ± 9 vs 86 ± 5ms, p<0.001) after excluding cases with ventricular conduction disturbance (BBB-fascicular block) and even by adjusting for body weight. In addition, they have a trend for a higher incidence of VT runs (≥3beats) during catecholamine testing: 10 of the 11 patients with isoproterenol-induced VT runs had myocardial abnormality (10/34 vs 1/16, p=0.08). Figure 5 shows two examples of non-sustained polymorphic VT appearing on isoproterenol (without ECG/genetic criteria of CPVT/LQT) in whom an area of myocardial abnormality was later found in the epicardium. These preliminary results warrant confirmation in a wider patient population. .

IVF -a spectrum of concealed diseases

The above results show that a systematic set of investigations reveals areas of altered myocardial conduction in 68% of IVF patients. Purkinje abnormality alone (without associated myocardial abnormality) is observed in 20% of patients; a value possibly overestimated by a referral bias. No abnormality could be observed in 12% of patients. These results indicate that extending the phenotypic investigations by endo-epicardial mapping allows identifying a certain or probable cause in the great majority of IVF patients. Such invasive mapping may be performed during the index clinical presentation; it will also address the questions raised by the patient and his family on the tragic event of unexplained VF. It may alternatively be performed in the case of recurrent VF for the prospect of substrate identification and ablation.

The most frequent abnormality is the presence of localized areas of slow conducting myocardium. The abnormal areas were associated with anchoring of reentries during VF on non-invasive mapping, suggesting a pathophysiological link. These abnormal areas likely indicate microstructural alterations of the myocardium due to fibrosis, fatty tissue or inflammatory infiltration, or cellular or intercellular (gap junctions) pathologies. Their incidence as observed here by electrogram mapping, is much higher than that reported in autopsy studies of IVF patients, which relates to the different methods used [START_REF] Bagnall | A Prospective Study of Sudden Cardiac Death among Children and Young Adults[END_REF][START_REF] Gray | Circ Arrhythm Electrophysiol. Evaluation after sudden death in the young[END_REF]. The electrogram patterns that define the abnormality gives no indication on the specific disease, although a more formal characterization may provide useful information in the future.

However, the varying anatomical and transmural location is suggestive of a large spectrum of potential pathologies. The alterations in the epicardial right ventricle are similar to those encountered in Brugada syndrome, or ARVD; those in the posterolateral left ventricle are similar to those encountered in myocarditis, sarcoidosis or genetic or acquired cardiomyopathies [START_REF] Martini | Ventricular fibrillation without apparent structural heart disease[END_REF][START_REF] Nademanee | Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome[END_REF][START_REF] Junttila | Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders[END_REF][START_REF] Kazmirczak | Assessment of the 2017 AHA/ACC/HRS Guideline Recommendations for Implantable Cardioverter-Defibrillator Implantation in Cardiac Sarcoidosis[END_REF][START_REF] Lynge | Sudden cardiac death caused by myocarditis in persons aged 1-49 years: a nationwide study of 14 294 deaths in Denmark[END_REF][START_REF] Kadakia | Sudden cardiac death in nonischemic cardiomyopathy[END_REF][START_REF] Goff | Sudden death related cardiomyopathies -Arrhythmogenic right ventricular cardiomyopathy, arrhythmogenic cardiomyopathy, and exercise-induced cardiomyopathy[END_REF][START_REF] Miles | Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy[END_REF]. A subendocardial alteration may be a damage following coronary spasm. IVF, in these cases, may represent genetically negative or spatially limited forms (negative imaging) of myocardial diseases; or other unknown affections (Central illustration). The results are in keeping with the increasing detection of gene variants associated with myocardial structure, reported in IVF [START_REF] Priori | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death[END_REF][START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary[END_REF][START_REF] Bagnall | A Prospective Study of Sudden Cardiac Death among Children and Young Adults[END_REF][START_REF] Behr | Sudden arrhythmic death syndrome: Familial evaluation identifies inheritable heart disease in the majority of families[END_REF][START_REF] Gray | Circ Arrhythm Electrophysiol. Evaluation after sudden death in the young[END_REF].

The abnormalities affecting the Purkinje system were less frequent. They were evidenced as triggering ectopy or by Purkinje repetitive activity inducible by programmed stimulation.

Purkinje ectopy were documented by ECGs and endocardial mapping; 4 of them having a documented VF initiation. In others the pathogenic role of Purkinje system could only be inferred, as it was the unique apparent abnormality. The ability of inducing Purkinje repetitive activity in 4 patients was considered an abnormal response, as it is rarely observed in our experience of VF inductions and not reported in a prior study [START_REF] Mehdirad | Asymetry of retrograde and reentry within the His-Purkinje system: a comparative analysis of left and right ventricular stimulation[END_REF]. Further investigations are however needed to confirm its significance, and whether it may reveal subclinical Purkinje abnormalities ('Purkinjopathy'). Unfortunately, major limitations are currently present in the clinical capabilities to investigate Purkinje function and structure, which restrict their characterization. Multiple arrhythmic expressions with the phenotype of Purkinje ectopy (short-coupling, CPVT, MCCP) have been previously described and some genetic abnormalities have been reported so far and recently reviewed [START_REF] Wilde | Role of the Purkinje system in heritable arrhythmias[END_REF]. An alteration in intracellular calcium handling is likely key to the genesis of spontaneous ectopy, particularly by triggered activity based on delayed afterdepolarizations. The ability of inducing Purkinje reentrant activity may alternatively be due to altered conduction properties [START_REF] Haissaguerre | Ventricular arrhythmias and the His-Purkinje system[END_REF] which would relate more to sodium current or gap junctional alterations.

Finally, no myocardial or Purkinje abnormality could be evidenced in a minority of IVF patients ('true' idiopathic VF). Unexplained IVF may have resulted from non-detected abnormalities of conduction, or of repolarization (LQT, early repolarization), or undocumented ectopic trigger; possibly associated with transient variables (as fever, hypokaliemia , drugs, SNA variations..). Such causes may be diagnosed later during a recurrent VF episode, or after genetic testing.

High-density electrophysiological mapping can therefore discriminate between the different arrhythmogenic substrates within IVF patients (who have no clinical phenotype); but also within patients who exhibit a same phenotypic expression. In recent studies, the inferolateral J-wave phenotype has been demonstrated to be the expression of distinct mechanisms -either early repolarization or late depolarization -with strong implications in patient management [START_REF] Haissaguerre | Depolarization versus repolarization abnormality underlying inferolateral J wave syndromes-new concepts in sudden cardiac death with apparently normal hearts[END_REF][START_REF] Nademanee | Mapping and Ablation of Ventricular Fibrillation Associated with Early Repolarization Syndrome[END_REF]. In a specific biomedical research program we have the opportunity to perform exvivo human heart investigations in patients who died from VF. Using high-resolution mapping and imaging methods and targeted cellular biology, we could confirm that a mosaic of different mechanisms manifesting a similar clinical phenotype can be responsible for SCD associated with an apparently normal heart [START_REF] Bernus | A Wide Spectrum Of Substrates Underlie Jwave Syndromes In Humans[END_REF]. Pending further investigations, it may be expected that VF substrates will be more precisely characterized and, in combination with deeper genotyping characterization, will be categorized using more appropriate terminology.

Genotypic and phenotypic characterization

In the past, a variety of arrhythmias initially classified as IVF have been secondarily recognized as distinct diseases after genetic testing, in correlation with the phenotype of 12 lead-ECGs at baseline or during arrhythmia. The identification of a genetic disorder is essential for patient care as it has implications for the management of the disease but also for the family of the affected individual. The 2017 consensus statements recommend genetic testing 'for arrhythmia syndromes in young patients (<40 years of age) with unexplained SCD, or unexplained near drowning' [START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary[END_REF]. The yield of genetic testing is reported as higher if a family history of SCD at a young age is present. In addition, familial phenotypic screening should be performed in first degree relatives, as shown by Behr et al (21). This included resting ECG, exercise testing and echocardiography. In selected cases, Holter and signal-averaged ECGs, MRI and pharmacologic testing can be performed [START_REF] Behr | Sudden arrhythmic death syndrome: Familial evaluation identifies inheritable heart disease in the majority of families[END_REF][START_REF] Visser | Idiopathic Ventricular Fibrillation: The Struggle for Definition, Diagnosis, and Follow-Up[END_REF][START_REF] Gray | Circ Arrhythm Electrophysiol. Evaluation after sudden death in the young[END_REF].

In inherited arrhythmia syndromes, the yield for a given phenotype is varying from about 20%

(BrS) to 60% (CPVT) or 75 % (LQT), and several mutations can be associated with a same phenotype [START_REF] Gray | New insights into the genetic basis of inherited arrhythmia syndromes[END_REF][START_REF] Ackerman | Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance issue[END_REF]. In IVF, extensive genetic testing -using whole-exome sequencing and next-generation sequencing approaches -is currently not recommended because of the low yield and high cost. These large data have allowed the detection of a plethora of candidate genes for IVF associated with cardiac electrical function or myocardial structure. However, the results need to be evaluated against the 'genetic background noise', and the task for interpretation of multiple detected variants is challenging [START_REF] Gray | New insights into the genetic basis of inherited arrhythmia syndromes[END_REF][START_REF] Ackerman | Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance issue[END_REF][START_REF] Offerhaus | Epidemiology of inherited arrhythmias[END_REF][START_REF] Gray | Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants[END_REF]. In addition, most novel variants have not been evaluated using functional studies to validate their arrhythmogenic impact. These variants often concern a specific family or geographic region (as the common DPP6 in The Netherlands) which emphasizes the large spectrum of genetic factors involved in IVF and arrhythmic syndromes.

The phenotypic characterization of IVF patients has an important role to establish causality of genetic variants. Microstructural myocardial affections or Purkinje conduction alterations would be more likely associated with mutations in genes coding for the sodium channels, connexins, and structural proteins. Mutations associated with spontaneous Purkinje ectopy, could be more related to calcium handling. However, the heterogeneous nature and pathogenesis of mutations, and the ubiquity of mutated proteins in the heart reduce both the mutation and tissue specificity. Mutations in SCN5A have many clinical expressions.

Mutations in RYR2 have been associated with CPVT perceived as a primary electrical disease, or ARVD manifesting as structural myocardial abnormalities. An example of a complex phenotype is shown in a patient with pathogenic DPP6 mutation. Although this mutation was deemed to selectively increase the Purkinje cell transient outward potassium current, we also observed severe alterations on the right ventricular epicardial myocardium by electrogram mapping (Figure 10). High density mapping allowing deeper phenotypic characterization may possibly show more complex phenotypes than expected in other unexplored electrical syndromes as the LQT or CPVT, with implications for their early detection and therapy.

Despite the complexity in genetic interactions and phenotypic expressions, idiopathic VF and other VF associated with apparently normal hearts can be tentatively classified according to the dominant primary substrate. Depolarization abnormalities associated with uncoupled and delayed electrograms, are the most prevalent affections [START_REF] Hsia | Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia[END_REF][START_REF] Martini | Ventricular fibrillation without apparent structural heart disease[END_REF][START_REF] Coronel | Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study[END_REF]. They can be associated with secondary repolarization changes [START_REF] Hoogendijk | ST segment elevation by current-to-load mismatch: an experimental and computational study[END_REF]. They include BrS where abnormal depolarization is present in RVOT, the subset of inferolateral J-waves with abnormal depolarization in the inferior part of (right or left) ventricles, and the subset of IVF associated with abnormal depolarization in a variety of areas. Repolarization abnormalities include LQT, SQT, and the subset of inferolateral J-waves due to early repolarization [START_REF] Nademanee | Mapping and Ablation of Ventricular Fibrillation Associated with Early Repolarization Syndrome[END_REF]. Excitation abnormalities include IVF due to Purkinje or PVC triggers, or VF due to multiple focal excitations (like CPVT or MPPC); 'accidental' VF due to external 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 depolarization abnormality), the groups share a common type of primary substrate and mode of therapy. The abnormal depolarization electrograms can be diagnosed and targeted for ablation with the same method in BrS, late depolarization J-wave or IVF. The abnormal repolarization group appears more an electrical dysfunction amenable to drug therapy. In the abnormal excitation group, the ablation of abnormal foci enables effective prevention (Central illustration).

Therapy in IVF

ICD

In patients with IVF (or idiopathic polymorphic VT), an ICD implantation is recommended 'if meaningful survival greater than 1 year is expected'. ICD implantation in patients with IVF is justified by the high recurrence rate of ventricular arrhythmias, varying from 11% to 45%.

Drug therapy

The use of pharmacotherapy is to provide a reduction of implantable cardioverterdefibrillators (ICD) interventions or symptomatic relief (frequent PVCs) in patients considered to have no substrate for catheter ablation or reluctant to invasive therapy. Betablockers are indicated in few selected patients notably those with arrhythmias upon stress or effort. Verapamil has an excellent effect on patients with frequent Purkinje triggers and polymorphic VTs; however the short half-life of this medication makes it more consistently efficient for acute therapy using intravenous administration than for long term oral administration [START_REF] Leenhardt | Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias[END_REF][START_REF] Haissaguerre | Mapping and ablation of idiopathic ventricular fibrillation[END_REF]. Quinidine has been also shown to be beneficial in IVF. It results in significant reduction of ICD shocks (from 7.5 ± 12 to 0.9 ± 1.7 over 34 months), and drug interruption is frequently associated with breakthrough events [START_REF] Malhi | Challenge and Impact of Quinidine Access in Sudden Death Syndromes: A National Experience[END_REF]. Further research will be needed to evaluate whether specific IVF substrates as described above would be most receptive to quinidine or other therapies.

Catheter ablation

Catheter ablation is currently recommended 'for patients with recurrent episodes of IVF initiated by PVCs with a consistent QRS morphology'. This statement indicates that the triggers are the main ablation target in consensus recommendations [START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary[END_REF]. The presence of localized depolarization substrate, in a significant part of IVF patients, represent a potential novel target for ablation. In keeping with the success of substrate-based ablations in patients with BrS or overt structural heart diseases, IVF patients displaying microstructural myocardial substrate are likely to benefit from this type of strategy.

Trigger ablation

The technique has been detailed in prior articles including the maneuvers to elicit PVCs that are suppressed with sedation [START_REF] Haissaguerre | Mapping and ablation of idiopathic ventricular fibrillation[END_REF][START_REF] Knecht | Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study[END_REF][START_REF] Nogami | Mapping and ablating ventricular premature contractions that trigger ventricular fibrillation: trigger elimination and substrate modification[END_REF][START_REF] Van Herendael | Catheter ablation of ventricular fibrillation: importance of left ventricular outflow tract and papillary muscle triggers[END_REF]. The site of earliest ventricular activation during spontaneous PVCs is the target of choice. Multi-electrode catheter are useful for mapping over a wide area of ventricular myocardium with higher spatial sampling and resolution. In the absence of ectopy, ablation can target the local Purkinje potentials or the site of best matched morphology (PVCs documented in the ward) by pace-mapping. Lastly, intracardiac echocardiography can be helpful in the complex anatomical regions like the papillary muscles.

Ablation is facilitated by the use of irrigated tip catheters. In most cases, ablation is extended approximately 1-2 cm around the target site, particularly in Purkinje triggers, in order to reach additional foci and to 'prune' the Purkinje arborization to minimize reentries. During ablation, it is common to have exacerbation of the arrhythmia (multiple PVCs leading to polymorphic VT and more rarely to VF) before the eradication of premature beats. The occurrence of QRS widening during ablation indicates potential catheter displacement towards the more proximal conduction system and ablation should be stopped [START_REF] Haissaguerre | Mapping and ablation of idiopathic ventricular fibrillation[END_REF].

Substrate ablation

An irrigated-tip ablation catheter is used with the target of eliminating fragmented electrograms, as described for ventricular tachycardia in structural heart disease or Brugada syndrome [START_REF] Hsia | Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia[END_REF][START_REF] Soejima | Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars[END_REF][START_REF] Nademanee | Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium[END_REF][START_REF] Jais | Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia[END_REF][START_REF] Pappone | Electrical Substrate Elimination in 135 Consecutive Patients With Brugada Syndrome[END_REF][START_REF] Cronin | HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias[END_REF] . RF energy is delivered with a power of 35-45 W and duration varying from 10 to 30 seconds guided by impact on the local electrogram. Radiofrequency lesions are delivered point-by-point at the area covering abnormal electrograms using serial applications. We have reported a mean duration of 18±5 minutes of radiofrequency energy application in our initial series of 12 patients; with 10 patients free of recurrences at a median follow-up of 14 months (24) Besides the usual risks of catheter ablation, the high prevalence of epicardial abnormalities requires specific precautions, notably to avoid damaging the coronary arteries and phrenic nerve, as recently reviewed in consensus documents [START_REF] Pappone | Electrical Substrate Elimination in 135 Consecutive Patients With Brugada Syndrome[END_REF].

Preoperative imaging of these structures can be integrated to perprocedural 3D mapping system and is useful to reduce these risks [START_REF] Berte | Image-guided ablation of scar-related ventricular tachycardia: towards a shorter and more predictable procedure[END_REF]. New ablative energies are emerging which may demonstrate advantages of safety or efficacy upon standard radiofrequency ablation [START_REF] Guandalini | Ventricular Tachycardia Ablation: Past, Present, and Future Perspectives[END_REF]. Central illustration shows the wide spectrum of potential affections underlying sudden cardiac death in apparently normal hearts, with or without the presence of an ECG phenotype.

Although the pathophysiology of these affections is likely a complex mosaic at a cellular scale, the individual substrate when mapped during EP exploration shows abnormalities dominantly affecting depolarization, or repolarization, or excitation.

Population

  Special care should be taken during Purkinje mapping to avoid inadvertent bumping of the right bundle; the left one being much less vulnerable. In patients without clinical PVCs, PVCs can be inducible by pacing maneuvers (atrial or ventricular) and/or drug infusion like Isoproterenol (1-2 mcg/kg/min) or class I drugs. Non-invasive electrocardiographic mapping imaging can be used to indicate the area of interest in patients with rare or polymorphic PVCs.

Fig. 3 -

 3 Fig. 3-Different patterns of Purkinje activity in 4 patients with IVF.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 two different ECG morphologies. C) Purkinje ectopy with long coupling interval in the aftermath of VF, with no VF recurrences after catheter ablation of ectopy D) Spontaneous polymorphic ventricular tachycardia associated with 1-to-1 Purkinje activity.

Fig. 4 -

 4 Fig.4-Uncommon responses to sodium blocker testing. A) ST 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 right ventricle. B) IVF 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 VF.

Fig 5 .

 5 Fig 5. Polymorphic ventricular tachycardia on isoproterenol testing In 2 IVF patients, isoproterenol testing induces non-sustained polymorphic ventricular tachycardia having a relatively slow rate. Premature ventricular beats are dominantly positive (4A) or negative (4B) in V1 lead. In both patients high density electrogram mapping revealed the presence of localized myocardial alterations, in the left (case shown in figure 8) and right ventricles respectively.

Fig 6 .

 6 Fig 6. Co-localisation of VF reentries with the areas of abnormal electrograms. The bodysurface maps in two spontaneous VF episodes show the location of VF reentries by the blue

Fig 7 .Fig. 8 .

 78 Fig 7. Inducible repetitive activity in peripheral Purkinje. A) 12 lead ECG: induction of polymorphic ventricular tachycardia (VT) with programmed stimulation in a 15yr-old girl. Pacing is performed from the left ventricle close to the left posterior Purkinje system. The endocardial recordings are shown in B. B) Recordings with a multipolar catheter along the distal left posterior fascicle shows a more rapid cycle length (mean 202ms, range 156-240) between Purkinje activities (asterisks) than in the left (217ms) or right ventricles (220ms). 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 VF in one instance. C) Another episode of induced polymorphic VT showing that VT termination is clearly preceded by slowing of Purkinje activity (asterisks)

Fig 9 .

 9 Fig 9. Examples of abnormal epicardial electrograms during sinus rhythm in two small areas in the left ventricle. The 2 areas are located in the lateral and inferior left ventricle with the abnormal signals amplified in the inlet; the recording circular catheter is visible on the electro-anatomical activation maps.

Fig 10 .

 10 Fig 10.Complex phenotype in a patient with pathogenic DPP6 mutation. This patient was referred for ablation of VF triggers originating from the right Purkinje system (left panel) .However, epicardial mapping also revealed an extensive damage on the right ventricular epicardial structure shown by voltage mapping (purple indicating ≥ 1mV) and prolonged fragmented electrograms (right panel).

Table legends Table 1 .

 legends1 Clinical results in 50 patients survivors of IVF, with comparison of those with or without myocardial conduction abnormality on high density mapping (n= 34 vs 16). Continuous variables are reported as means±SD and compared with a 2-sided Students't test. Categorical variable are compared with Fisher exact test.

	Figure legends
	Fig.1 Diagnostic flow chart for investigations (in blue) for patients surviving a sudden cardiac
	death; and their results (in yellow). MRI indicates magnetic resonance imaging; SR, sinus
	rhythm; PVCs, premature ventricular contractions; SAECG, signal-averaged
	electrocardiogram; RV, right ventricle; LV left ventricle; and CPVT, catecholaminergic
	polymorphic ventricular tachycardia.
	Fig.2 -Repolarization changes during provocative tests, in patients initially referred for IVF,
	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) was later evidenced. B) Valsalva
	maneuver producing a prominent inferolateral J -wave after a sinus pause . C) Isoproterenol
	testing inducing ST elevation and coronary spasm which was proven during a repeat test with
	coronary angiography.

This work was supported by the National Research Agency (ANR-10-IAHU04-LIRYC) and the European Research Council (SYMPHONY).

Summary

Idiopathic VF is a puzzling diagnosis defined by negativity of current medical investigations. This condition accounts for a significant part of SCD in young adults. Detailed phenotypic investigations demonstrate that a majority of IVF can be elucidated, particularly using endoepicardial mapping, by showing an important role for microstructural myocardial or Purkinje abnormalities. The various locations and patterns of abnormalities strongly suggest that a mosaic of pathologies -acquired or genetically determined-can potentially underlie their genesis.

Further advances in phenotypic investigations and genetic screening will likely allow a more specific characterization of various substrates; a more adequate terminology; and hopefully an early detection of patients at risk for the development of primary prevention.