Idiopathic Ventricular Fibrillation
2016; Lippincott Williams & Wilkins; Volume: 9; Issue: 5 Linguagem: Inglês
10.1161/circep.115.003817
ISSN1941-3149
AutoresMarloes Visser, Jeroen F. van der Heijden, Pieter A. Doevendans, Peter Loh, Arthur A.M. Wilde, Rutger J. Hassink,
Tópico(s)Ion channel regulation and function
ResumoHomeCirculation: Arrhythmia and ElectrophysiologyVol. 9, No. 5Idiopathic Ventricular Fibrillation Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessResearch ArticlePDF/EPUBIdiopathic Ventricular FibrillationThe Struggle for Definition, Diagnosis, and Follow-Up Marloes Visser, MD, Jeroen F. van der Heijden, MD, PhD, Pieter A. Doevendans, MD, PhD, Peter Loh, MD, PhD, Arthur A. Wilde, MD, PhD and Rutger J. Hassink, MD, PhD Marloes VisserMarloes Visser From the Department of Cardiology, University Medical Center, Utrecht, The Netherlands (M.V., J.F.v.d.H., P.A.D., P.L., R.J.H.); Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands (M.V., R.J.H.); and Department of Clinical and Experimental Cardiology, Heart Centre, AMC, Amsterdam, The Netherlands (A.A.W.). , Jeroen F. van der HeijdenJeroen F. van der Heijden From the Department of Cardiology, University Medical Center, Utrecht, The Netherlands (M.V., J.F.v.d.H., P.A.D., P.L., R.J.H.); Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands (M.V., R.J.H.); and Department of Clinical and Experimental Cardiology, Heart Centre, AMC, Amsterdam, The Netherlands (A.A.W.). , Pieter A. DoevendansPieter A. Doevendans From the Department of Cardiology, University Medical Center, Utrecht, The Netherlands (M.V., J.F.v.d.H., P.A.D., P.L., R.J.H.); Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands (M.V., R.J.H.); and Department of Clinical and Experimental Cardiology, Heart Centre, AMC, Amsterdam, The Netherlands (A.A.W.). , Peter LohPeter Loh From the Department of Cardiology, University Medical Center, Utrecht, The Netherlands (M.V., J.F.v.d.H., P.A.D., P.L., R.J.H.); Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands (M.V., R.J.H.); and Department of Clinical and Experimental Cardiology, Heart Centre, AMC, Amsterdam, The Netherlands (A.A.W.). , Arthur A. WildeArthur A. Wilde From the Department of Cardiology, University Medical Center, Utrecht, The Netherlands (M.V., J.F.v.d.H., P.A.D., P.L., R.J.H.); Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands (M.V., R.J.H.); and Department of Clinical and Experimental Cardiology, Heart Centre, AMC, Amsterdam, The Netherlands (A.A.W.). and Rutger J. HassinkRutger J. Hassink From the Department of Cardiology, University Medical Center, Utrecht, The Netherlands (M.V., J.F.v.d.H., P.A.D., P.L., R.J.H.); Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands (M.V., R.J.H.); and Department of Clinical and Experimental Cardiology, Heart Centre, AMC, Amsterdam, The Netherlands (A.A.W.). Originally published21 Apr 2016https://doi.org/10.1161/CIRCEP.115.003817Circulation: Arrhythmia and Electrophysiology. 2016;9:e003817IntroductionSudden cardiac arrest (SCA) and sudden cardiac death (SCD) are disastrous outcomes of various predominant cardiac diseases. The leading cause of SCA and SCD is coronary artery disease.1 However, SCA/SCD in young patients is mainly caused by congenital disorders of primary arrhythmic or structural origin.2 SCD is defined as death from an unexpected circulatory arrest, usually because of a cardiac arrhythmia occurring within an hour of the onset of symptoms. The definition of SCA is similar, with the addition that a medical intervention (eg, defibrillation) reverses the event.3Idiopathic ventricular fibrillation (IVF) is a rare cause of SCA. Patients with IVF present with a sudden onset of ventricular fibrillation (VF) of unknown origin that is not identified even after extensive diagnostic testing. The exact incidence of IVF is unknown but is declining with the advance of diagnostic testing and the discovery of primary arrhythmia syndromes, such as the Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), long-QT syndrome (LQTS), short-QT syndrome, and early repolarization syndrome (ERS).Although the exact definition of IVF has changed during the years and although new diagnostic tools are available, no specific guidelines have been developed for the definition and diagnosis of IVF, as well as a protocol for exclusion of specific cardiac diseases that cause SCA and SCD. In this review, we discuss the definition of IVF, overlap with other primary arrhythmia syndromes, the diagnosis, and follow-up of patients with IVF.Definition of IVF and Overlap With Other Primary Arrhythmia SyndromesTwo different consensus statements about IVF have been published, and proposed 2 different definitions of IVF. The first is from the 1997 Consensus Statement of the Joint Steering Committees of the Unexplained Cardiac Arrest Registry of Europe and the United States that describes IVF as the terminology that best acknowledges our current inability to identify a causal relationship between the clinical circumstance and the arrhythmia.4 The second and more recent definition is from the 2013 Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society expert consensus statement of inherited primary arrhythmia syndromes and defines IVF as a resuscitated cardiac arrest victim, preferably with documentation of VF, in whom known cardiac, respiratory, metabolic and toxicological causes have been excluded through clinical evaluation.5 In other words, the diagnosis IVF depends on the absence of a substrate for VF and exclusion of specific diseases, including structural cardiac disease (ie, myocarditis, cardiac sarcoidosis, arrhythmogenic right ventricular, hypertrophic, and dilated cardiomyopathy) and primary arrhythmia syndromes (ie, BrS, CPVT, LQTS, short-QT syndrome, and ERS).Most primary arrhythmia disorders were regarded as IVF before they were discovered. For example, BrS was described as IVF in a 1998 Nature article.6 Studies in which careful phenotypic and genetic analysis had been performed showed that these primary arrhythmia syndromes are actually separate disease entities, with a separate pathophysiology.7,8 The differentiation between IVF and other primary arrhythmic syndromes has been facilitated by the advance in genetic testing, for example in CPVT and LQTS patients where the yield of genetic testing is 60% and 75%, respectively.9 In addition, genetic testing has facilitated the detection of causative mutations for IVF, such as the Dutch DPP6-haplotype and CALM1.10,11Early repolarization (ER) is a common electrocardiographic finding that is present in 1% to 5% of the general population.12 ER pattern is defined as J-point elevation of ≥0.1 mV in ≥2 contiguous leads of a standard 12-lead ECG, excluding leads V1–V3, with an end-QRS notch or slur on the downslope of the R wave with an onset above the baseline.5,13 Although ER historically was regarded as a benign finding, multiple studies have shown that ER, and specifically ER in the inferior and lateral leads is associated with an increased risk of VF and SCD.14 ER pattern is differentiated from ERS, that is diagnosed in patients with unexplained VF or polymorphic VT and documented ER, or in SCD victims with a negative autopsy and a previous ECG demonstrating ER.5 Until recently, ERS was regarded as a subentity of IVF. However, ERS has a distinctive phenotype and has shown to have a separate genetic substrate as several candidate genes for a familial inheritance of a malign ER pattern have been identified.15 Therefore, ERS is considered a separate disease entity that is distinct from IVF. If a patient shows ER that does not fulfill the criteria as mentioned above than these abnormalities are not explanatory and the diagnosis IVF remains.Short-coupled ventricular premature beats (VPBs) may elicit Torsades de Pointes (TdP) or immediate VF.16 A subgroup of IVF patients show short-coupled VPBs causing TdP/VF. In these patients, mapping and ablation proved effective to prevent recurrence of short coupled TdP (scTdP)/VF.17,18 The pathogenesis of short-coupled VPBs is largely unknown, although a genetic origin is detected in a limited number of patients with scTdP/VF including the Dutch DPP6-haplotype, a novel RyR mutation that causes scTdP in rest, and a novel IRX3 mutation.10,19,20 Until the pathogenesis is further specified, scTdP/VF remains a subgroup of IVF because no particular phenotype responsible for VF can be detected either on the ECG nor during additional diagnostic testing.Concerning IVF: when do we classify VF as idiopathic? This is a matter of opinion and open for discussion. In fact, here we publish not a consensus document but a personal opinion that incites debate. In our definition of IVF, we have made a distinction between pathogeneses with a clear (sometimes provoked) phenotype, such as LQTS (nonidiopathic) and those without such an obvious phenotype (idiopathic): for example, CALM1 and DPP6 mutations that are still associated with an unclear phenotype. Future research will possibly link these particular mutations to separate disease entities as happened with BrS and other diagnoses (Figure 1).Download figureDownload PowerPointFigure 1. Schematic illustration of the evolution of the diagnosis idiopathic ventricular fibrillation (IVF). In the 2013 Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society expert consensus, statement on the diagnosis of patients with inherited primary arrhythmia syndromes early repolarization syndrome was for the first time mentioned as a separate disease entity.5CALM1 indicates calmodulin 1 gene mutation; CPVT, catecholaminergic polymorphic ventricular tachycardia; and DPP6, Dutch DPP6 risk haplotype associated with sudden cardiac death.Pathophysiological Mechanism of IVF and Overlap With Other Arrhythmia SyndromesThe exact pathogenesis and pathophysiological mechanism of IVF are unknown. We hypothesize that IVF has a heterogeneous pathogenesis that is different for each patient with IVF. First, IVF might have a monogenic origin.10,19,20 Second, the origin could be polygenic. Third, the origin might be multifactorial in which mono- or polygenic mutations need particular environmental and discrete subclinical structural abnormalities, for example minimal electrolyte disturbances such as a mild hypokalemia or development of small areas of fibrotic myocardial tissue, that are currently undetectable with the available diagnostic modalities. The monogenic hypothesis (ie, the hypothesis that the disease is caused by 1 gene mutation) is supported by the detection of several causative mutations in patients with IVF, including DPP6, CALM1, the novel RyR2 mutation, and IRX3.10,11,19,20 The detection of candidate genes for IVF has been accelerated by the advance in genetic testing and the greater availability of new techniques, such as whole-exome or whole-genome sequencing. However, these extensive genetic data need a critical appraisal against the background, genetic noise rate, as many variants of uncertain clinical significance are concurrently detected. In addition, functional studies have to further elucidate the underlying mechanism that translates novel candidate genes into arrhythmogenesis. Although the monogenic hypothesis is supported by the available literature, the polygenic hypothesis (ie, the hypothesis that the disease is caused by ≥2 gene mutations) and the second hit hypothesis (ie, the hypothesis that the disease is the result of accumulated mutations to the cell's DNA) cannot be rejected, as no research has been conducted in these areas.The pathogenic mutations that are described in inherited primary arrhythmia syndromes and IVF cause changes in the cardiac ion channels. This results in altered ion currents disrupting the normal cardiac action potential morphology. Potentially, any change in action potential morphology might lead to enhanced arrhythmogenesis.9The cellular mechanism of short-coupled VPBs and scTdP is dependent on the transient outward potassium (K+) current (also known as Ito) of the His and Purkinje fibers. An increase in Ito causes a deeper phase 1 of the cardiac action potential. Because the Ito only increases in the Purkinje fibers, a strong local repolarization gradient is created with the adjacent ventricular myocardium that results in local ectopy and short-coupled VPBs. VPBs with a short-coupled interval (ie, R-on-T phenomenon) can cause phase 2 reentry and hereby elicit VF.16Differential Diagnosis of Patients With VFVF has an extensive differential diagnosis consisting of many cardiac and noncardiac causes. As the definition of IVF implies, structural cardiac, primary arrhythmic, respiratory, metabolic, and toxicological causes must be excluded before IVF is diagnosed. Because noncardiac causes of VF are usually easily detected by simple laboratory and toxicological assessment, we exclusively discuss the potential cardiac causes of VF. Table 1 shows, if known, an overview of the incidence and prevalence of the diseases in the cardiac differential diagnosis of IVF, the percentage of patients presenting with (aborted) SCD as first manifestation, and event rates of recurrences of VT/VF for each specific disease.Table 1. Differential Diagnosis of IVFDiseaseIncidence/PrevalenceSCD as First Manifestation of DiseaseEvent RateCAD/MIIncidence MI: 785 000/y in the United States21Prevalence CAD: 17.6 million in the United States2120%22Death rate CAD: 287–390/100 000/y for males and 201–277/100 000/y for females21Coronary artery spasmIncidence: unknownPrevalence: unknown2.4% (35/1429)2314% (2/14) of patients with a secondary prophylactic ICD received appropriate ICD therapy (FU 3.2 y)23DCMIncidence: 3.6–7.9/100 000 person-years24Prevalence: 1/270024RarelyUnknownHCMIncidence: 1.4–3.6/100 000 person-years24Prevalence: 1/50025UnknownAnnual death rate SCD 0.7%2635% (44/125) of all HCM-related deaths are sudden and unexpected265%/y ICD discharge rate26 (skewed toward a more severe phenotype)ARVD/CIncidence: unknownPrevalence: 1/50002713%2819% (16/84) of primary prophylactic ICD patients showed recurrence of VF (FU 4.7 y)29BrSIncidence: unknownPrevalence: 50–100/100 0005UnknownEvent rate per year per group of presentation30:Cardiac arrest: 7.5%Syncope: 1.8%Asymptomatic, spontaneous type 1 BrS ECG: 0.8%Total (all patients with BrS): 1.9%LQTSIncidence: unknownPrevalence: 50/100 0005Unknown2% (23/1049) of young athletes with SCD in postmortem studies213% (87/647) of genotyped patients with LQTS 1, 2, or 3 experienced cardiac arrest before the age of 40 years and before initiation of treatment (FU 6.2 y)31CPVTIncidence: unknownPrevalence: 10/100 0005UnknownArrhythmic event rate32:Probands: 21.7 per 1000 person-yearsRelatives with RyR2 mutation: 4.4 per 1000 person-yearsSQTSIncidence: unknownPrevalence: unknown40% (19/47)3316% (10/62) of patients experienced VF (FU 60 mo)33ERSIncidence ERS: unknownPrevalence ER: in normal population: 1% to 5%12in patients with IVF: 7% to 31%34,35100% (presentation with VF or SCD is part of the definition of ERS)UnknownMyocarditisIncidence: unknownPrevalence: unknown16% (17/112)36UnknownCardiac sarcoidosisIncidence: unknownPrevalence: 20–30/100 000 for pulmonary sarcoidosis, of which 5% has cardiac involvement3741% (16/42) of patients with myocardial sarcoidosis confirmed on autopsy presented with SCD38UnknownIVFIncidence: Estimated 4900–47 000 patients/y in the United StatesPrevalence: unknown100%Appropriate ICD therapy in 11% to 43%34,39,40ARVD/C indicates arrhythmogenic right ventricular dysplasia/cardiomyopathy; BrS, Brugada syndrome; CAD, coronary artery disease; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; ER, early repolarization; ERS, early repolarization syndrome; FU, follow-up; HCM, hypertrophic cardiomyopathy; ICD, implantable cardiac defibrillator; IVF, idiopathic ventricular fibrillation; LQTS, long-QT syndrome; MI, myocardial infarction; SQTS, short-QT syndrome; SCD, sudden cardiac death; VF, ventricular fibrillation; and VT, ventricular tachycardia.Diagnosis of IVFThe correct diagnosis of IVF requires extensive diagnostic testing. Routine testing excludes the most common causes of VF. Routine testing usually comprises blood chemistry (cardiac enzymes, electrolytes, and thyroid function), toxicological screening, ECG, chest x-ray, echocardiography, exercise testing, Holter or telemetry monitoring, coronary angiography with or without ventriculography, and magnetic resonance imaging. In young patients ( 30 ms occurred92%86%76%96%Shimizu et al4990 patients (31 LQT1, 23 LQT2, 6 LQT3, and 30 healthy controls)∆QTc ≥35 msLQT190%97%97%91%LQT291%90%88%93%Clur et al5041 children with clinical suspicion of LQTSQTc* cutoff >470 ms in asymptomatic individualsQTc* cutoff >450 m in symptomatic individuals50%61%6%96%Krahn et al51170 patients, including 58% SCA survivors, 21% SCA relatives, 18% SCD relatives, and 4% patients with syncopeAbsolute QT interval prolonged by ≥30 ms40%†84%50%78%Exercise test; LQTSAndrsova et al52105 patients with KCNQ1 or KCNH2 mutationQTc cut-off NR92%93%NRNRSy et al53152 genotyped LQT1 and LQT2 patientsAlgorithm rest QTc+exercise-QTcQTc* cutoff >470 ms in males or >480 ms in femalesExercise-QTc measured at 4-min recovery94%82%NRNRKrahn et al5423 patients (14 LQTS score >4, 9 family members of LQT patients) and 40 healthy controls∆RT >25 ms(∆RT=RT interval at 1 min recovery subtracted from RT interval at a similar heart rate during exercise)73%92%79%90%QTc prolongation provocation by QTc posture test; LQTSAdler et al55108 genotyped LQT1, LQT2, and LQT3 patientsQTc* cutoff >490 ms89%87%NRNRViskin et al5668 patients (31 LQT1, 28 LQT2, 3 LQT3, and 6 unsuccessful genotyped) and 82 healthy controlsMaximal QT-stretching (not further specified)90%86%NRNREpinephrine test; CPVTMarjamaa et al5736 patients (25 RyR carriers, 11 genetically undefined CPVT patients) and 45 healthy unaffected family members≥3 consecutive VPBs or recurrent couplets or sustained bigeminial rhythm and >10 single VPBs per minute28%98%88%75%Exercise test; CPVTHayashi et al5867 genotyped asymptomatic CPVT relativesBigeminal VPBs, VPB couplets, or ventricular tachycardia (≥ 3 of successive VPBs)50%97%NRNRBlich et al5916 CPVT patients with CASQ2 mutation and 36 healthy subjects≥3 consecutive VPBs at peak exercise97%100%94%100%BrS indicates Brugada syndrome; CAG, coronary angiography; CAS, coronary artery spasm; CPVT, catecholaminergic polymorphic ventricular tachycardia; LQT1, long-QT syndrome type 1; LQT2, long-QT syndrome type 2; LQT3, long-QT syndrome type 3; LQTS, long-QT syndrome; QTc, corrected QT interval; NR, not reported; SCA, sudden cardiac arrest; SCD, sudden cardiac death; and VPB, ventricular premature beat.*QTc measured in lead II and V5 using Bazett formula.†Sensitivity calculated with positive exercise test or genetic test as a gold standard.Genetic testing increasingly contributes in diagnosing concealed primary arrhythmia syndromes. The role of extensive genetic testing is, however, controversial in patients with IVF.5 Targeted genetic screening based on phenotype is performed in a limited number of patients with IVF and the yield is heterogeneous. In addition, variants of uncertain clinical significance are frequently detected. Table 3 shows the yield of genetic testing in patients with IVF.Table 3. Yield of Genetic TestingCohortPopulationSelection of Patients for Genetic ScreeningGenes That Were ScreenedYieldDetected Pathogenic MutationsBai et al60175 patients with IVF or a family history of unexplained SCDAll patientsLQTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2BrS: SCN5ACPVT: RyR29% (15/175)NRHerman et al34200 patients with unexplained cardiac arrest with normal ECG, echocardiography, and CAGBasis of phenotype detection after systematic clinical testingLQTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2BrS: SCN5AARVD/C: PKP2, DSPCPVT: RyR28% (13/158)RyR2 (2 patients; CPVT), DSP (2 patients; ARVD/C ), PKP2 (3 patients; ARVD/C ), KCNH2 (1; LQT2), SCN5A (2 patients; BrS and LQT3), LMNA (1 patient; no diagnosis specified, has concurrent RyR2 mutation), KCNQ1 (1 patient; probable diagnosis not specified), TMEM43 (1 patient; ARVD/C )Knecht et al1738 patients with IVF caused by short-coupled VPBsIn patients suspected of channelopathyNR0% (0/14)NoneHaïssaguerre et al1837 patients with IVF caused by short-coupled VPBsIn patients suspected of channelopathy, including 5 patients with a family history of SCDBrS: SCN5ALQTS: KCNH20% (0/12)NoneARVD/C indicates arrhythmogenic cardiomyopathy; BrS, Brugada syndrome; CAG, coronary angiography; CPVT, catecholaminergic polymorphic ventricular tachycardia; IVF, idiopathic ventricular fibrillation; LQT2, long-QT syndrome type 2; NR, not reported; SCD, sudden cardiac death; and VPB, ventricular premature beat.In summary, acetylcholine and ergonovine have a comparable sensitivity in diagnosing coronary artery spasm.43,44 Coronary artery spasm provocation has a potential risk of arrhythmias; however, this risk is acceptable with an overall incidence of ≈5% of arrhythmic complications that can usually be treated adequately.61,62 The value of diagnosing coronary artery spasm and the subsequent medical treatment and prevention of ischemic and important arrhythmic events outweighs, in our opinion, the risks of the test.Of the sodium channel blockers, ajmaline and flecainide show a comparable sensitivity in diagnosing BrS; however, when compared to each other flecainide fails to identify 32% of the patients with BrS.45–47,63 The exact sensitivity of pilsicainide and procainamide is unknown, but all sodium channel blockers are suitable to diagnose BrS. The choice of sodium channel blocker depends on the availability and differs per country.Although epinephrine shows a high sensitivity and specificity in diagnosing LQTS, healthy subjects show a high number of false-positive test results.64 Therefore, the epinephrine test is of no additive value in the regular evaluation of LQTS. A good alternative is the highly sensitive QTc posture test, in which QT prolongation is provoked by brisk standing.55,56 Epinephrine provocation testing is also not suitable for diagnosing CPVT because of the low sensitivity and specificity.57Genetic screening is performed in a limited number of patients, and the yield is heterogeneous.17,18,34,60 We recommend genetic screening in IVF patients with a negative phenotype with a basic panel of SCN5A and the most common LQTS genes (KCNQ1 and KCNH2), as half of the patients with BrS who present with SCA have a concealed phenotype, and ≈25% of genotype-positive LQTS patients have a normal QT-interval.30,65 If a patient presents with exercise- or emotion-induced VF, we recommend additional screening of RyR2 and CALM1. Genetic testing is a matter of debate, and caution is warranted as a negative genetic test result does neither exclude concealed primary arrhythmia syndromes nor a genetic origin of IVF. Although the limited available data on targeted exome sequencing of large gene panels in SCD victims <50 years of age show a yield of 21% to 32%, it is not routinely recommended because the finding of variants of unknown clinical significance may lead to unnecessary treatment and anxiety among patients.66–68Characteristics and Follow-Up of Patients With IVFMultiple studies that focused on IVF have been published; however, data on the diagnosis and follow-up of patients with IVF are limited.17,18,35 Only one study shows the long-term follow-up of 200 patients with an apparently unexplained cardiac arrest and no evident cardiac disease as cause of the cardiac arrest.34 The other available data on the follow-up of patients with IVF are derived from cohort studies, mostly published before the introduction of magnetic resonance imaging, and report largely incomplete diagnostic data (Figure 2). Structural cardiac diseases and primary arrhythmia syndromes were not systematically excluded; therefore, these cohorts are presumably confounded with patients with unrecognized underlying disease. Nevertheless, these are the best available data on the diagnosis and follow-up of patients with IVF. Table 4 shows the characteristics of these cohorts.Table 4. FU of Patients Initially Diagnosed With IVFCohortYear of PublicationNo. of Patients IncludedMean FU (mo)Specific Diagnosis Detected After Additional Diagnostics or During FU; N (%)Patients With IVF; N (%)Male/Female; N (%)/N (%)Mean Age During IVF Event, yICD Implantation; N (%)No. of IVF Patients With Arrhythmia Recurrence; N (%)Herman et al342016200 (134 with initial diagnosis IVF)3.15±2.34 y13(7)119 (90*)73(61)/46(39)NRWhole cohort: 48±14.7111 (93)10 (11)Remme et al6920013777±414(11)33 (89)NR/NRWhole cohort:26(70)/11(30)35±1723 (62)NRWhole cohort: 16 (43)Champagne et al7020052941±2711(38)18 (62)13 (72)/5 (28)42±14All (100)7 (39)Meissner et al7119932830.6028 (100)15 (54)/13 (46)42±14All (100)16 (57)Mewis et al7219981845±29018 (100)9 (50)/9 (50)48±141 (6)2 (11)Crijns et al7319951032010 (100)8 (80)/2 (20)37±111 (10)0 (0)TotalN/A385 (254 with initial diagnosis of IVF)42 mol/L28(11†)226 (94)NR/NR45193 (80)NRFU indicates follow-up; ICD, implantable cardiac defibrillator; IVF, idiopathic ventricular fibrillation; N/A, not applicable; and NR, not reported.*Ninety percent of 134 patients with an initial diagnosis of IVF.†Eleven percent of 254 patients with an initial diagnosis IVF.Download figureDownload PowerPointFigure 2. Performed diagnostic tests and yield. EMB indicates endomyocardial biopsy; EPS, electrophysiological study; and MRI, magnetic resonance imaging.ICD Therapy in Patients With IVFThe only therapeutic option in patients with IVF is secondary prevention with a prophylactic implantable cardiac defibrillator (ICD). ICD implantation in patients with IVF is justified by the high recurrence rate of ventricular arrhythmias, varying from 11% to 45%.34,39,40 A meta-analysis showed recurrences of arrhythmias in 31% of the patients with IVF during a mean follow-up of 5.3 years.40 Another study showed appropriate ICD therapy in 43% in a median follow-up of 8.8 years, but also included patients with ERS.39 A recent study showed a lower rate of appropriate ICD therapy: 11% of patients with IVF received one or multiple appropriate shocks in a mean follow-up of 3.2 years, with a median time to first shock of 2.6 years.34 No predictors for appropriate ICD therapy have been identified in patients with IVF, although patients with ERS show higher recurrence of ventricular arrhythmias.39 The limited available data on inappropriate ICD therapy show a high rate of inappropriate shocks (14% to 44%; mean follow-up, 1.9–8.8 years).34,39,70 The reason for most inappropriate shocks is atrial fibrillation. The limited data on ICD complications show complications in 17% in a mean follow-up of 41±27 months.70Necessity of Follow-Up and Reassessment of DiagnosisToday, only 7% of patients reveal a specific diagnosis during follow-up because of comprehensive advanced testing at time of the index event.34 However, historically almost 30% of patients initially diagnosed with IVF qualify for a specific diagnosis during follow-up. This emphasizes the need for follow-up as in current daily practice many patients were diagnosed with IVF after limited diagnostic testing.69,70The first explanation that many patients qualify for a specific disease is that structural or electric abnormalities were (clinically) absent at time of the index event and developed during follow-up. The second explanation is that the relatively new diagnoses such as BrS were not recognized or described yet at the time of the index event. BrS was first described in 1992, before then patients with BrS were incorrectly regarded as patients with IVF.7 The third explanation is that development of diagnostic techniques have improved the early detection of specific dis
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