Idiopathic ventricular fibrillation: the ongoing quest for diagnostic refinement

Abstract

Prior to the recognition of distinct clinical entities, such as Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome, all sudden cardiac arrest (SCA) survivors with ventricular fibrillation (VF) and apparently structurally normal hearts were labelled as idiopathic ventricular fibrillation (IVF). Over the last three decades, the definition of IVF has changed substantially, mostly as result of the identification of the spectrum of SCA-predisposing genetic heart diseases (GHDs), and the molecular evidence, by post-mortem genetic analysis (aka, the molecular autopsy), of cardiac channelopathies as the pathogenic basis for up to 35% of unexplained cases of sudden cardiac death (SCD) in the young. The evolution of the definition of IVF over time has led to a progressively greater awareness of the need for an extensive diagnostic assessment in unexplained SCA survivors. Nevertheless, GHDs are still underdiagnosed among SCA survivors, due to the underuse of pharmacological challenges (i.e. sodium channel blocker test), misrecognition of electrocardiogram (ECG) abnormalities/patterns (i.e. early repolarization pattern or exercise-induced ventricular bigeminy) or errors in the measurement of ECG parameters (e.g. the heart-rate corrected QT interval). In this review, we discuss the epidemiology, diagnostic approaches, and the controversies related to role of the genetic background in unexplained SCA survivors with a default diagnosis of IVF.

Idiopathic ventricular fibrillation, Sudden cardiac death, Sudden cardiac arrest, Genetic heart disease, Genetics, Diagnosis

Introduction

Prior to the recognition of distinct clinical entities, such as Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and long QT syndrome (LQTS), all SCA survivors with ventricular fibrillation (VF) and apparently structurally normal hearts were labelled as idiopathic ventricular fibrillation (IVF). Over the last three decades, the definition of IVF has changed substantially, mostly as result of the identification of the spectrum of SCA-predisposing genetic heart diseases (GHDs), and the molecular evidence, by post-mortem genetic analysis (aka, the molecular autopsy), of cardiac channelopathies as the pathogenic basis for up to 35% of unexplained cases of sudden cardiac death (SCD) in the young.^1–4

The evolution of the definition of IVF over time has led to a progressively greater awareness of the need for an extensive diagnostic assessment in apparently unexplained SCA survivors.⁵ Nevertheless, GHDs are still underdiagnosed among SCA survivors, due to the underuse of pharmacological challenges (i.e. sodium-channel blocker test), misrecognition of electrocardiogram (ECG) abnormalities/patterns [i.e. early repolarization (ER) pattern or exercise-induced ventricular bigeminy] or errors in the measurement of ECG parameters (e.g. the heart-rate corrected QT interval).^1,6–8

In this review, we discuss the epidemiology, diagnostic approaches, and the controversies related to role of the genetic background in unexplained SCA survivors with a default diagnosis of IVF.

Definition and epidemiological aspects of IVF

In 20–35% of autopsies of SCA victims younger than 40 years, no structural cardiac abnormality is identified.^9,10 According to current guidelines, IVF is considered a diagnosis of exclusion.^1,2 2013 HRS/EHRA expert consensus guidelines define IVF as a resuscitated SCA victim, preferably with documentation of VF, in whom cardiac, respiratory, metabolic, and toxicological aetiologies have been excluded through clinical evaluation.¹ Similarly, 2015 ESC guidelines on the management of ventricular arrhythmias consider IVF as an episode of documented VF following which comprehensive clinical evaluation does not identify an underlying cause.²

The prevalence of IVF in unexplained SCA survivors is low and varies among different studies. A prevalence of 8.4% and 10.8% in implantable cardioverter-defibrillator recipients with otherwise normal ECGs was reported in an Asian and Caucasian cohort of SCA survivors, respectively.^11,12 Moreover, Waldmann et al.^12,13 reported a diagnosis of IVF in 6.8% of survivors from out-of-hospital cardiac arrest of cardiac origin presenting with VF as first rhythm, whereas Conte et al. reported a diagnosis of IVF in 1.2% of SCA survivors with a shockable rhythm and completely normal baseline and follow-up ECGs. The discrepancy between the prevalence of negative autopsies among SCA victims and the prevalence of IVF among SCA survivors is likely due to the fact that autopsies series mainly included young subjects and molecular autopsies were performed in a very limited number of cases. Of note, the prevalence of IVF amongst sentinel SCA cases who sought a second opinion evaluation at tertiary medical centres specializing in GHDs appears to be substantially higher. Giudicessi and Ackerman¹⁴ reported the identification of an aetiology in 63% of these cases, while the remaining 37% were classified as IVF. The major factor contributing to difference in prevalence estimates is likely due to the inclusion of patients with SCAs attributable to ischaemic heart disease as well as heterogeneity among centres in the diagnostic evaluations performed to assess patients with unexplained SCA episodes (Table 1). Moreover, IVF prevalence is expected to decline further with technical advances of diagnostic testing and a more extensive diagnostic testing performed throughout centres to rule-out both channelopathic and cardiomyopathic GHDs in the future.

Table 1

Diagnostic assessment of patients with IVF

Study	Number of patients with initial diagnosis of IVF	Exercise testing	CMR	Cardiac CT/coronary angiogram	Ergonovine challenge	Sodium- channel blockers challenge	EPS/cardiac mapping	Endocardial biopsy	Genetic testing	Number of patients with true IVF
Krahn et al.5	63	100%	100%	100%	NP	100%	NR	1.6%	30%	28 (44%)
Sekiguchi et al.17	64	27/64	100%	100%	NR	NR	76%	NR	0%	40 (62%)
Visser et al.34	33	NR	NR	NR	NR	58%	NR	NR	100%	32 (97%)
Leinonen et al.8	76	75%	62%	NR	NR	NR	51%	29%	NR	69 (91%)
Haissaguerre et al.20	24	NR	NR	NR	NR	100%	100%	NR	17/24	24 (100%)
Waldmann et al.13	49	8.2%	81.6%	100%	38.8%	43%	24.5%	0	18.4%	46 (94%)
Giudicessi and Ackerman14	67	88%	73%	86%	NR	27%	61%	6%	73%	67 (100%)
Conte et al.23	245	80%	65%	100%	NR	64%	59%	1.6%	18%	245 (100%)
Frontera et al.25	54	83%	70%	44%	NR	69%	63%	13%	87%	37 (68%)
Cunningham et al.28	46	41%	57%	11%	NR	NP	NR	4%	72%	22 (48%)

CMR, cardiac magnetic resonance; CT, computed tomography; EPS, electrophysiology study; IVF, idiopathic ventricular fibrillation.

In the past, IVF has been associated with the presence in the standard 12-lead ECG of a malignant ER pattern in the inferior and/or lateral leads, which confers a higher risk of further arrhythmic events.¹⁵ Currently, ER syndrome is considered a completely different clinical entity with a peculiar genetic background and prognosis.^1,16

A small proportion of SCA survivors with no evidence of structural heart disease at the time of initial evaluation, have an ECG remaining normal during follow-up evaluations, without documented repolarization abnormalities, atrioventricular (AV) conduction disturbances, or short-coupled premature ventricular complexes (PVCs). Sekiguchi et al.¹⁷ reported a completely normal ECG only in half of patients with IVF. ER pattern was documented in 38% of IVF patients and AV conduction abnormalities in 14% of cases.

The so-called short-coupled torsades de pointes (SC-TdP)/premature ventricular contraction (PVC)-triggered VF is considered currently a subgroup of IVF. PVCs with short coupling R-on-T intervals (<300 ms), mostly originating from the distal Purkinje system, are observed in up to 30% of cases of IVF and a pathogenic role of the Purkinje system in triggering the arrhythmic event has been hypothesized in this subset of patients.^18–20 At this point in time, it remains unclear if SC-TdP/PVC-triggered VF represents a distinct clinical entity or if it represents a final common pathway for a number of as of yet unidentified disorders.

Diagnostic assessment of IVF

Recently, Waldmann et al.¹³ reported on the insufficient rate of comprehensive investigations performed in the real-world setting of unexplained SCA. Among all out-of-hospital SCA survivors in the Paris area, only 16% of patients, who were labelled as IVF, had received a complete workup, including pharmacological testing.

Current guidelines emphasize the importance of multidisciplinary teams with expertise in GHDs in the diagnostic evaluation of all unexplained SCA survivors. However, there is no standardized set of investigations to perform or diagnostic protocols to follow, before a diagnosis of IVF can be established.^1,2 Table 2 includes a list of the minimal studies required per patient before accepting a diagnosis of IVF.

Table 2

List of the minimal studies required per patient before accepting a diagnosis of IVF

Metabolic and toxicological investigations and family history of SCD assessment

Resting 12-lead ECG with high right precordial leads

Bidimensional transthoracic echocardiography

Coronary angiogram (ideally with ergonovine)/cardiac CT scan

Exercise stress test

24 h-Holter monitoring

Cardiac magnetic resonance

Pharmacological challenge with sodium-channel blockers

CT, computed tomography; ECG, electrocardiogram; IVF, idiopathic ventricular fibrillation; SCD, sudden cardiac death.

The Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) showed that use of systematic non-invasive testing including the selective use of drug provocation, advanced cardiac imaging, and genetic testing led to a probable/definitive diagnosis in 56% of unexplained SCA survivors with preserved left ventricular ejection fraction and normal coronary anatomy.⁵ All these patients underwent as initial evaluation signal-averaged ECG, exercise testing, cardiac magnetic resonance (CMR), intravenous adrenaline, and procainamide challenge; while invasive testing (electrophysiology study and myocardial biopsy) and genetic testing were used at discretionary basis. Of patients with an identified aetiology, 69% had a GHD and the other patients presented with an inherited or acquired structural heart disease. Interestingly, 6% of unexplained SCA survivors had coronary spasm.⁵ This observation supports greater attention on the potential role of ergonovine or acetylcholine challenge aimed at provoking coronary spasm during the initial evaluation of an episode of unexplained SCA.

Re-evaluation of the diagnosis in IVF patients is clinically relevant, as it may have significant impact on the assessment of a patient’s prognosis, family screening, and possibly family counselling. It has been reported that repeated assessment of ECG phenotype of those patients with a previously unexplained SCA caused a change in initial diagnosis in 20–30% of cases.^12,21 (Figure 1).

Figure 1

ECG patterns frequently missed/overlooked in patients incorrectly labelled as IVF. Red Arrows indicate: First panel: early repolarization pattern, Second panel: Brugada type 1 ECG Third panel: PVCs/NSVT. ECG, electrocardiogram; IVF, idiopathic ventricular fibrillation.

Matassini et al.²¹ found a total prevalence of 10% of ER pattern among patients enrolled in the CASPER study, at the time of last follow-up, making ER syndrome the second most frequent condition after LQTS, which was present in 13% of cases. Another diagnosis that should be considered carefully (if not done during the initial evaluations) is CPVT.⁸ This has important clinical implications given the high rate of VT/VF events in untreated CPVT patients. Accordingly, an exercise stress test, or if unable to exercise catecholamine provocation test, should be considered strongly for all unexplained SCA survivors.

Although the baseline 12-lead ECG is useful in identifying channelopathies, drug challenge should be considered as crucial evaluation in all unexplained SCA survivors with normal baseline ECGs and in families of unexplained SCA victims. The systematic use of ajmaline challenge with high right precordial leads has been shown to substantially increase the yield of BrS in families of SCA victims.²² Interestingly, in the largest multicentre long-term registry of IVF survivors with persistently normal baseline and follow-up ECGs, only 64% of patients underwent sodium-channel blocker challenge (ajmaline or flecainide) to rule-out BrS during the initial diagnostic assessment.²³ Importantly, for some GHDs, such as BrS, an age-dependent response to sodium-channel blockers has been reported.²⁴ Conte et al.²⁴ reported on the value of repeat ajmaline challenge after puberty, which unmasked BrS in 23% of patients with a previously negative drug test performed during childhood. This observation highlights the potential value of repeating ajmaline test in unexplained SCA paediatric survivors after puberty, if all initial investigations are elusive.

Of note, 1 out of 10 IVF survivors are ≤16 years of age at the time of the arrhythmic event.²⁵ Paediatric IVF survivors represent a population of IVF patients at higher arrhythmic risk. Conte et al.²³ showed that no independent predictors of VF recurrences, other than age below 16 years, could be identified among IVF survivors with completely normal ECGs. Therefore, this age-related category of patients should be evaluated carefully during the diagnostic work-up and all subsequent follow-up evaluations. Indeed, it has been shown that recurrent VF is common in those paediatric patients with IVF developing a definite clinical phenotype during long-term follow-up.²⁵

In children, a lethal ventricular arrhythmia can manifest before the development of an overt channelopathy or cardiomyopathy phenotype.^26,27 Within a referral population enriched for GHDs, the ability of a comprehensive cardiac evaluation, including genetic testing, to elucidate a root cause in non-ischaemic SCA survivors declined with age.¹⁴ The yield of GHDs in paediatric SCA survivors was high accounting for 90% of episodes occurring during the first decade of life and declined precipitously with each subsequent decade of life.¹⁴ In a Canadian cohort of paediatric patients, half of unexplained SCA survivors received a diagnosis after a median of a month from the arrhythmic event. None of them underwent a pharmacological challenge, 40% had an exercise stress test, 57% underwent CMR, while 72% of them had a genetic testing. Differently from adults, where ischaemic cardiovascular disease is a common cause of SCA, paediatric SCA was typically due to arrhythmogenic GHDs, specifically CPVT and LQTS. Diagnosis was based on phenotype in 46% of children and on phenotype and genotype in the other 54%.²⁸

The value of CMR has been reported consistently for detection of the morphological substrate and/or underlying cardiac condition in patients with VT/VF without previously known heart disease.²⁹ However, there are IVF cases with normal findings at CMR displaying abnormalities during cardiac substrate mapping. Haïssaguerre et al.³⁰ recently reported abnormal electrograms in the epicardium in a significant proportion of patients with IVF, investigated with a combination of multi-electrode body surface recording during VF and detailed invasive catheter mapping during sinus rhythm. VF mapping demonstrated re-entrant or focal activities in all patients and VF drivers clustered in different ventricular regions. These areas were correlated with areas of localized myocardial alterations. These findings support the hypothesis that localized structural alterations may underlie a significant subset of unexplained SCA survivors and highlight the role of cardiac mapping in the characterization of the arrhythmogenic substrate of IVF. Moreover, the same group hypothesized a Purkinje electrical pathology as a dominant mechanism for IVF in some patients without myocardial abnormalities revealed by cardiac mapping. In these patients, a high incidence of Purkinje triggers was documented during cardiac EP invasive evaluation.³⁰ Moreover, even in the absence of ECG documentation of short-coupled ectopy, patients with IVF can present with abnormal EP properties of the peripheral Purkinje system, consisting in fragmented, dissociated and inducible repetitive activity.³¹

The genetic background of IVF

Current HRS/EHRA and American Heart Association (AHA)/American College of Cardiology (ACC) guidelines endorse the use of genetic testing in unexplained SCA survivors with a default diagnosis of IVF if there is reasonable clinical suspicion for a underlying SCA/SCD-predisposing GHD (e.g. a specific cardiac channelopathies or cardiomyopathies).^1,32 However, in light of the possibility of unearthing ≥1 ambiguous variant of unknown significance (VUS) in a bona fide channelopathy- or cardiomyopathy-susceptibility gene(s), the 2013 HRS/EHRA guidelines discouraged the use of pan-arrhythmia, pan-cardiac, and exome-based genetic testing in unexplained SCA survivors with a default diagnosis of IVF.¹

Although the utilization of genetic testing in large multicentre series of unexplained SCA survivors with a default diagnosis of IVF is low (i.e. one out-of-five),²³ several groups have published their experiencing with genetic testing in IVF, many with the assistance of exome sequencing (Figure 2). Not surprisingly given the absence of a discernible cardiac phenotype in IVF, the yield of pathogenic/likely pathogenic (P/LP) variants in established SCA-predisposing genes has been relatively low, ranging between 2% and 17% (Figure 2) based largely on (i) the type of genetic test utilized (e.g. disease-specific vs. exome sequencing) and (ii) the stringency of variant adjudication approaches utilized (i.e. pre- and post-2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines).^{8,14,26,33,34}

Figure 2

Yield of genetic testing in IVF. IVF, idiopathic ventricular fibrillation; P/LP, pathogenic/likely pathogenic; VUS, variant of unknown significance.

Unfortunately, despite providing diagnostic clues (e.g. the detection of a CPVT-causative P/LP in RYR2) in a limited number of IVF cases, the widespread utilization of genetic testing in IVF appears more likely to result in potentially harmful diagnostic miscues related to assigning significance prematurely to an otherwise ambiguous VUS. Moreover, because of the absence of a clinical phenotype and the limited availability of data on family members, co-segregation of variants is difficult and cannot be used to inform the diagnosis of the proband. However, the lack of co-segregation may help in underemphasizing the value of a given variant. Within the aforementioned IVF genetic testing series, the prevalence of ≥1 VUS in channelopathy- or cardiomyopathy-susceptibility genes (range 15–26%; Figure 2) far exceeded that of clinically actionable P/LP variants (range 2–17%; Figure 2).^8,14,26,34 Therefore, it comes as little surprise that genetic testing in IVF has been shown already to result in potentially harmful diagnostic miscues, the most egregious of which is the diagnosis (and treatment) of a specific SCA-predisposing GHD (e.g. BrS or LQTS) on the basis of the presence of a VUS alone in the absence of any clinical phenotype in the proband/family to support such a diagnosis.^35,36 As such, if genetic testing is pursued in hopes of finding evidence of an underlying channelopathy or cardiomyopathy, great care must be taken to assure that clinical phenotype in the proband/family is prioritized over genotype, even in instances when the performing lab reports the identification of P/LP. Therefore, whenever possible, we recommend strongly that genetic testing in unexplained SCA survivors be pursued in the context of dedicated Cardiovascular Genomics clinics with both the expertise and means to interpret accurately and re-evaluate continuously genetic testing results.

In addition to the identification of P/LP variants in known channelopathy- and cardiomyopathy-susceptibility that should prompt ordering healthcare professionals to probe deeper for clinical evidence of an underlying channelopathy or cardiomyopathy in an unrecognized, subclinical or pre-cardiomyopathic electrical state, there is evidence to suggest that ‘true’ IVF may have a distinct genetic basis. To date, P/LP variants in CALM1-3-encoded calmodulin, the IRX3-encoded Iroquois homeobox gene family transcription factor, a distinct loss-of-function variant and large duplication involving the RYR2-encoded cardiac calcium release channel, and a promoter haplotype in the DPP6 gene locus on chromosome 7 have been linked to IVF^37–41 (Table 3).

Table 3

IVF genes and their suspected mechanism(s)

Genes	Suspected mechanism(s)	Observed phenotype
CALM1	Dysregulated binding of Calmodulin (CaM) to ion channels with different consequences on ion channel function (altered calcium-sensitive gating, channel assembly, and cell surface expression) and related disturbances in excitability, excitation–contraction coupling and refractoriness	Modest QTc prolongation
IRX3-encoded Iroquois homeobox gene family transcription factor	Attenuation of IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, resulting in functional perturbation in the His-Purkinje system	Short-coupled TdP/PVC-triggered VF
RYR2-encoded cardiac calcium release channel	Suppression-of-function mutation reduces Ca2+ release and leads to gradual Ca2+ overload in the sarcoplasmic reticulum and prolonged release leading to early after-depolarizations	Short-coupled TdP/PVC-triggered VF
Promoter haplotype in the DPP6 gene locus on chromosome 7	Increased DPP6 mRNA levels as consequence of mutations in regulatory sequences of the gene, leading to altered inactivation kinetics of native transient current (Ito) channel complex	Short-coupled TdP/PVC-triggered VF

IVF, idiopathic ventricular fibrillation; PVC, premature ventricular complex; QTc, QT interval; TdP, torsades de pointes.

However, thus far, only the aforementioned DPP6 haplotype has proven to have a diagnostic role in the assessment of unexplained SCA survivors with a default diagnosis of IVF. DPP6 is 20-fold higher in the myocardium of IVF carries compared to controls. Recent functional studies have pointed to a role of this gene in the transient outward current (Ito) in Purkinje fibres, with DPP6 gain-of-function enhancing this current.⁴⁰ According to this evidence, DPP6 testing is recommended currently in all IVF survivors of Dutch ancestry.⁴² The utility of DPP6 haplotype testing outside of areas with a strong Dutch ancestry remains to be seen.

2017 AHA/ACC/HRS Guideline for Management of Patients with Ventricular Arrhythmias recommends further evaluation for GHDs in young patients (<40 years of age) with unexplained SCA, unexplained near drowning, or recurrent exertional syncope, who do not have ischaemic or other structural heart disease, (Ib recommendation).³² Nearly 30% of the victims of swimming-related drowning host a cardiac channel mutation associated with LQT1 and CPVT.⁴³ Moreover, as exertion-related cardiac arrest, particularly in children, may be related to calmodulin/triadin-mediated LQT/CPVT mutations, additional specialized genetic testing may be required.^44,45

Detection of a causative pathogenic variant in IVF survivors enables cascade family screening.¹ Current guidelines support the comprehensive cardiovascular evaluation of potentially at-risk first-degree relatives to rule-out an underlying SCD-predisposing GHD.¹ However, recommendations on the need of specific genetic evaluation in relatives of families with sudden unexplained death syndrome or unexplained cardiac arrest are still lacking. In a large unselected cohort of more than 400 relatives of an autopsy-negative sudden unexplained death syndrome victim, targeted genetic when combined with a clinical evaluation had a low diagnostic yield (18%).⁴⁶ Conversely, diagnostic yield of such approach in families of SCA survivors was four times higher (62%).⁴⁶

Conclusions and future perspectives

Refinement of a diagnosis by exclusion, such as IVF, is a difficult task and warrants further attention by the scientific community. Identifying a cause in survivors from IVF is crucial as it can lead to disease-targeted therapies (novel genotype-specific therapies), inform appropriate family screening, and make rational decisions on the type of pharmacological and invasive treatment.

International guidelines should promote a standardized and systematic approach for patients with IVF and address indications of each available diagnostic test, from non-invasive examinations and cardiac imaging to more advanced investigations including ergonovine challenge, genetic testing, and cardiac mapping procedures.

In the future, exome or genome sequencing of true IVF survivors and his/her parents, use of patient-specific human induced pluripotent stem cell derived cardiomyocyte models, and the use of artificial intelligence-enabled ECGs may shed light on the understanding of the arrhythmogenic substrate of this still controversial condition.

Funding

G.C. has received a research grant (PZ00P3_180055) from the Swiss National Foundation. M.J.A. and J.R.G. are supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. M.J.A. is a consultant for Abbott, Audentes Therapeutics, Biotronik, Boston Scientific, Daiichi Sankyo, Invitae, Medtronic, MyoKardia, and UpToDate. M.J.A. and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Blue Ox Health Corporation, and StemoniX. However, none of these entities were involved in this study in any manner.

Conflict of interest: none declared.