Idiopathic Ventricular Fibrillation
Introduction
Sudden 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.3
Idiopathic 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 Syndromes
Two 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 CALM1.10,11
Early 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).
Figure 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 Syndromes
The 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.9
The 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.16
Differential Diagnosis of Patients With VF
VF 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.
| Disease | Incidence/Prevalence | SCD as First Manifestation of Disease | Event Rate |
|---|---|---|---|
| CAD/MI | Incidence MI: 785 000/y in the United States21Prevalence CAD: 17.6 million in the United States21 | 20%22 | Death rate CAD: 287–390/100 000/y for males and 201–277/100 000/y for females21 |
| Coronary artery spasm | Incidence: unknownPrevalence: unknown | 2.4% (35/1429)23 | 14% (2/14) of patients with a secondary prophylactic ICD received appropriate ICD therapy (FU 3.2 y)23 |
| DCM | Incidence: 3.6–7.9/100 000 person-years24Prevalence: 1/270024 | Rarely | Unknown |
| HCM | Incidence: 1.4–3.6/100 000 person-years24Prevalence: 1/50025 | UnknownAnnual death rate SCD 0.7%2635% (44/125) of all HCM-related deaths are sudden and unexpected26 | 5%/y ICD discharge rate26 (skewed toward a more severe phenotype) |
| ARVD/C | Incidence: unknownPrevalence: 1/500027 | 13%28 | 19% (16/84) of primary prophylactic ICD patients showed recurrence of VF (FU 4.7 y)29 |
| BrS | Incidence: unknownPrevalence: 50–100/100 0005 | Unknown | Event 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% |
| LQTS | Incidence: unknownPrevalence: 50/100 0005 | Unknown2% (23/1049) of young athletes with SCD in postmortem studies2 | 13% (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)31 |
| CPVT | Incidence: unknownPrevalence: 10/100 0005 | Unknown | Arrhythmic event rate32:Probands: 21.7 per 1000 person-yearsRelatives with RyR2 mutation: 4.4 per 1000 person-years |
| SQTS | Incidence: unknownPrevalence: unknown | 40% (19/47)33 | 16% (10/62) of patients experienced VF (FU 60 mo)33 |
| ERS | Incidence ERS: unknownPrevalence ER: in normal population: 1% to 5%12in patients with IVF: 7% to 31%34,35 | 100% (presentation with VF or SCD is part of the definition of ERS) | Unknown |
| Myocarditis | Incidence: unknownPrevalence: unknown | 16% (17/112)36 | Unknown |
| Cardiac sarcoidosis | Incidence: unknownPrevalence: 20–30/100 000 for pulmonary sarcoidosis, of which 5% has cardiac involvement37 | 41% (16/42) of patients with myocardial sarcoidosis confirmed on autopsy presented with SCD38 | Unknown |
| IVF | Incidence: Estimated 4900–47 000 patients/y in the United StatesPrevalence: unknown | 100% | Appropriate ICD therapy in 11% to 43%34,39,40 |
Diagnosis of IVF
The 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 (<45 years) with a low risk for coronary artery disease, coronary CT or MR angiography is an alternative for coronary angiography because the sensitivity, specificity, and especially the negative predictive value are high.41,42 If coronary CT or MR is normal, coronary angiography is not necessary. The mandatory additional diagnostic tests are ergonovine or acetylcholine provocation to exclude coronary artery spasm and administration of a sodium channel blocker (ajmaline, flecainide, procainamide, or pilsicainide) to exclude BrS. Optional additional diagnostic tests are endomyocardial biopsy and electrophysiological testing. In daily practice, the option of additional testing often provokes discussion because the diagnostic value of some additional tests is debatable. Table 2 shows the diagnostic value of the additional provocation tests, specified per disease.
| Cohort | Population | Cut-Off Values | Sensitivity | Specificity | Positive Predictive Value | Negative Predictive Value | |
|---|---|---|---|---|---|---|---|
| Intracoronary acetylcholine; Coronary artery spasm | |||||||
| Okumura et al43 | 70 patients with previous chest pain with total occlusion or severe spasm at CAG | Occlusion or severe spasm at CAG | 90% | 99% | NR | NR | |
| Intravenous ergonovine; Coronary artery spasm | |||||||
| Waters et al44 | 34 patients with CAS (chest pain, relief of chest pain with nitroglycerine and ST elevation on ECG) | ST elevation ≥2 mm on surface ECG | 90% | NR | NR | NR | |
| Ajmaline test; BrS | |||||||
| Veltmann et al45 | 382 genotyped patients (20% SCN5A carrier) | Type 1 Brugada ECG | 76% | 43% | 24% | 88% | |
| Hong et al46 | 104 genotyped patients (35 SCN5A carriers) of which 71 received an ajmaline challenge | Type 1 Brugada ECG | 80% | 94% | 93% | 83% | |
| Flecainide test; BrS | |||||||
| Meregalli et al47 | 110 genotyped patients (35 SCN5A carriers) | Type 1 Brugada ECG | 77% | 80% | 96% | 36% | |
| Epinephrine test; LQTS | |||||||
| Vyas et al48 | 125 genotyped patients (LQT1, 2, and 3) | QTc cut-off NREpinephrine test abnormal if paradoxical QT prolongation >30 ms occurred | 92% | 86% | 76% | 96% | |
| Shimizu et al49 | 90 patients (31 LQT1, 23 LQT2, 6 LQT3, and 30 healthy controls) | ∆QTc ≥35 ms | LQT1 | 90% | 97% | 97% | 91% |
| LQT2 | 91% | 90% | 88% | 93% | |||
| Clur et al50 | 41 children with clinical suspicion of LQTS | QTc* cutoff >470 ms in asymptomatic individualsQTc* cutoff >450 m in symptomatic individuals | 50% | 61% | 6% | 96% | |
| Krahn et al51 | 170 patients, including 58% SCA survivors, 21% SCA relatives, 18% SCD relatives, and 4% patients with syncope | Absolute QT interval prolonged by ≥30 ms | 40%† | 84% | 50% | 78% | |
| Exercise test; LQTS | |||||||
| Andrsova et al52 | 105 patients with KCNQ1 or KCNH2 mutation | QTc cut-off NR | 92% | 93% | NR | NR | |
| Sy et al53 | 152 genotyped LQT1 and LQT2 patients | Algorithm rest QTc+exercise-QTcQTc* cutoff >470 ms in males or >480 ms in femalesExercise-QTc measured at 4-min recovery | 94% | 82% | NR | NR | |
| Krahn et al54 | 23 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; LQTS | |||||||
| Adler et al55 | 108 genotyped LQT1, LQT2, and LQT3 patients | QTc* cutoff >490 ms | 89% | 87% | NR | NR | |
| Viskin et al56 | 68 patients (31 LQT1, 28 LQT2, 3 LQT3, and 6 unsuccessful genotyped) and 82 healthy controls | Maximal QT-stretching (not further specified) | 90% | 86% | NR | NR | |
| Epinephrine test; CPVT | |||||||
| Marjamaa et al57 | 36 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 minute | 28% | 98% | 88% | 75% | |
| Exercise test; CPVT | |||||||
| Hayashi et al58 | 67 genotyped asymptomatic CPVT relatives | Bigeminal VPBs, VPB couplets, or ventricular tachycardia (≥ 3 of successive VPBs) | 50% | 97% | NR | NR | |
| Blich et al59 | 16 CPVT patients with CASQ2 mutation and 36 healthy subjects | ≥3 consecutive VPBs at peak exercise | 97% | 100% | 94% | 100% | |
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.
| Cohort | Population | Selection of Patients for Genetic Screening | Genes That Were Screened | Yield | Detected Pathogenic Mutations |
|---|---|---|---|---|---|
| Bai et al60 | 175 patients with IVF or a family history of unexplained SCD | All patients | LQTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2BrS: SCN5ACPVT: RyR2 | 9% (15/175) | NR |
| Herman et al34 | 200 patients with unexplained cardiac arrest with normal ECG, echocardiography, and CAG | Basis of phenotype detection after systematic clinical testing | LQTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2BrS: SCN5AARVD/C: PKP2, DSPCPVT: RyR2 | 8% (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 al17 | 38 patients with IVF caused by short-coupled VPBs | In patients suspected of channelopathy | NR | 0% (0/14) | None |
| Haïssaguerre et al18 | 37 patients with IVF caused by short-coupled VPBs | In patients suspected of channelopathy, including 5 patients with a family history of SCD | BrS: SCN5ALQTS: KCNH2 | 0% (0/12) | None |
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.57
Genetic 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.66–68
Characteristics and Follow-Up of Patients With IVF
Multiple 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.
| Cohort | Year of Publication | No. of Patients Included | Mean 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, y | ICD Implantation; N (%) | No. of IVF Patients With Arrhythmia Recurrence; N (%) |
|---|---|---|---|---|---|---|---|---|
| Herman et al34 | 2016 | 200 (134 with initial diagnosis IVF) | 3.15±2.34 y | 13(7) | 119 (90*)73(61)/46(39) | NRWhole cohort: 48±14.7 | 111 (93) | 10 (11) |
| Remme et al69 | 2001 | 37 | 77±41 | 4(11) | 33 (89)NR/NRWhole cohort:26(70)/11(30) | 35±17 | 23 (62) | NRWhole cohort: 16 (43) |
| Champagne et al70 | 2005 | 29 | 41±27 | 11(38) | 18 (62)13 (72)/5 (28) | 42±14 | All (100) | 7 (39) |
| Meissner et al71 | 1993 | 28 | 30.6 | 0 | 28 (100)15 (54)/13 (46) | 42±14 | All (100) | 16 (57) |
| Mewis et al72 | 1998 | 18 | 45±29 | 0 | 18 (100)9 (50)/9 (50) | 48±14 | 1 (6) | 2 (11) |
| Crijns et al73 | 1995 | 10 | 32 | 0 | 10 (100)8 (80)/2 (20) | 37±11 | 1 (10) | 0 (0) |
| Total | N/A | 385 (254 with initial diagnosis of IVF) | 42 mol/L | 28(11†) | 226 (94)NR/NR | 45 | 193 (80) | NR |
Figure 2. Performed diagnostic tests and yield. EMB indicates endomyocardial biopsy; EPS, electrophysiological study; and MRI, magnetic resonance imaging.
ICD Therapy in Patients With IVF
The 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.70
Necessity of Follow-Up and Reassessment of Diagnosis
Today, 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.69,70
The 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 diseases. High-resolution imaging modalities such as magnetic resonance imaging have been introduced, enhanced the detection of small structural abnormalities, and facilitated diagnosing early-stage cardiomyopathy. New provocation tests and disease algorithms for concealed primary arrhythmia syndromes have been developed, for example ajmaline provocation for the exclusion of BrS and the 1993 Schwartz criteria for LQTS. Genetic testing has become increasingly available and contributed in the early diagnosis of concealed primary arrhythmia syndromes.
The consensus statements provide no or limited advice on the follow-up of patients with IVF. The only advice on follow-up was provided in the 1997 IVF consensus statement that recommended ECG, Holter monitoring, and echocardiograms to be repeated every year.4 We recommend follow-up of patients with IVF because a third of patients initially diagnosed with IVF reveal a specific disease during follow-up. Diagnosis of a specific disease generally requires lifestyle changes and initiation of pharmacological treatment, for example avoidance of competitive sports in patients with CPVT, HCM, arrhythmogenic right ventricular dysplasia/cardiomyopathy, and LQTS, treatment with β-blockers in CPVT and LQTS patients, specific drug avoidance in patients with LQTS and BrS and prevention or treatment of fever in patients with BrS. Patients incorrectly diagnosed with IVF are deprived of therapy that could prevent recurrence of ventricular arrhythmias. Moreover, detection of inherited disease has implications about family counseling and screening. Family members of patients with inherited disease should undergo phenotypic, and if applicable genetic, screening. Affected family members should receive prophylactic therapy and lifestyle changes if indicated. No particular data are available on the value of screening the family of patients with IVF. We recommend cardiac screening of first degree relatives with ECG, echocardiography, and exercise test. Further cascade family screening is indicated in case either a pathogenic mutation is found (for example DPP6 or CALM1) or a specific diagnosis is revealed.
Guidelines provide limited guidance in the diagnosis and follow-up of patients with IVF; therefore, a protocol is required. A protocol as shown in Figure 3 may be suggested.
Figure 3. Proposed flowchart for the diagnosis and follow-up of patients with idiopathic ventricular fibrillation (IVF).*In young patients (<45 years) without risk factors for coronary artery disease, coronary computed tomography (CT; or MR) angiography is an alternative diagnostic tool to exclude coronary artery disease. The sensitivity is 85% and 99%, respectively, the specificity is 90% and 64%, respectively, the positive predictive value is 91% and 86%, respectively, and the negative predictive value is 83% and 90%, respectively.41,42 Coronary CT angiography has a higher sensitivity compared with magnetic resonance imaging (MRI) in detecting coronary stenosis; therefore, CT is a better alternative for coronary angiography.74 †A proposed acquisition protocol for cardiac MRI is available in the Data Supplement and is based on the arrhythmogenic right ventricular dysplasia/cardiomyopathy protocol. ‡Proposed genetic testing consists of a basic panel of SCN5A, the most common long-QT genes (KCNQ1 and KCNH2), RyR2, and CALM1 in patients with exercise-induced VF. In patients with a negative phenotype, we recommend SCN5A, KCNQ1, and KCNH2 screening. FU indicates follow-up.
Future Perspectives
The incidence of IVF is declining and we expect the number of patients with IVF to decline further. This decline might be explained by the detection of new well-defined primary arrhythmia syndromes, the improvement in high resolution imaging modalities, and the advance in genetic testing. Historically, after limited diagnostic testing all VF patients with an apparently normal heart were diagnosed with IVF, resulting in a heterogeneous and comprehensive group of patients with IVF. Today, IVF is redefined as a rare primary arrhythmia syndrome of unknown, maybe (mono- or poly-) genetic origin that shows different manifestations including scTdP, which however are not explanatory for the arrhythmic event. Genetic testing including the screening of large multigene panels and exome or genome sequencing, followed by functional studies, might redefine IVF even further in the future.
In the present expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes, extensive genetic testing is not recommended in patients with IVF because of the low yield and high costs.5 However, the costs of genetic testing have decreased, resulting in an increase in the feasibility of genetic testing. Consequently, large custom multigene panels have been created and are rapidly replacing targeted genetic screening based on phenotype. However, the yield of these custom multigene panels has yet to be determined. Moreover, an increasing number of variants of uncertain clinical significance are detected. The interpretation and clinical use of these variants of uncertain clinical significance is challenging. Future research, and more specifically functional studies, have to demonstrate the causality between variants of uncertain clinical significance and IVF.
Conclusions
The diagnosis of IVF depends on exclusion of cardiac, respiratory, metabolic, and toxicological causes. Differentiation from structural cardiac disease and other primary arrhythmia syndromes is critical for targeted therapy, follow-up, and family screening. The present expert consensus statements provide limited guidance on the diagnosis and follow-up of patients with IVF. Therefore, we proposed a protocol for the diagnosis and follow-up of IVF. Follow-up is of utmost importance because ≤30% of patients initially diagnosed with IVF qualify for a specific disease during follow-up. Reassessment of diagnosis is, therefore, always necessary in patients with IVF.
Disclosures
None.
Footnotes
References
- 1.
Zipes DP, Wellens HJ. Sudden cardiac death.Circulation. 1998; 98:2334–2351.LinkGoogle Scholar - 2.
Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006.Circulation. 2009; 119:1085–1092. doi: 10.1161/CIRCULATIONAHA.108.804617.LinkGoogle Scholar - 3.
Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL ; American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.Circulation. 2006; 114:e385–e484. doi: 10.1161/CIRCULATIONAHA.106.178233.LinkGoogle Scholar - 4. Consensus Statement of the Joint Steering Committees of the Unexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular Fibrillation Registry of the United States. Survivors of out-of-hospital cardiac arrest with apparently normal heart.Circulation. 97;95:265–272.Google Scholar
- 5.
Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013.Heart Rhythm. 2013; 10:1932–1963. doi: 10.1016/j.hrthm.2013.05.014.CrossrefMedlineGoogle Scholar - 6.
Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O’Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.Nature. 1998; 392:293–296. doi: 10.1038/32675.CrossrefMedlineGoogle Scholar - 7.
Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report.J Am Coll Cardiol. 1992; 20:1391–1396.CrossrefMedlineGoogle Scholar - 8.
Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, DeSimone L, Coltorti F, Bloise R, Keegan R, Cruz Filho FE, Vignati G, Benatar A, DeLogu A. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.Circulation. 2002; 106:69–74.LinkGoogle Scholar - 9.
Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).Heart Rhythm. 2011; 8:1308–1339. doi: 10.1016/j.hrthm.2011.05.020.CrossrefMedlineGoogle Scholar - 10.
Alders M, Koopmann TT, Christiaans I, Postema PG, Beekman L, Tanck MW, Zeppenfeld K, Loh P, Koch KT, Demolombe S, Mannens MM, Bezzina CR, Wilde AA. Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.Am J Hum Genet. 2009; 84:468–476. doi: 10.1016/j.ajhg.2009.02.009.CrossrefMedlineGoogle Scholar - 11.
Marsman RF, Barc J, Beekman L, Alders M, Dooijes D, van den Wijngaard A, Ratbi I, Sefiani A, Bhuiyan ZA, Wilde AA, Bezzina CR. A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence.J Am Coll Cardiol. 2014; 63:259–266. doi: 10.1016/j.jacc.2013.07.091.CrossrefMedlineGoogle Scholar - 12.
Maury P, Rollin A. Prevalence of early repolarisation/J wave patterns in the normal population.J Electrocardiol. 2013; 46:411–416. doi: 10.1016/j.jelectrocard.2013.06.014.CrossrefMedlineGoogle Scholar - 13.
Macfarlane PW, Antzelevitch C, Haissaguerre M, Huikuri HV, Potse M, Rosso R, Sacher F, Tikkanen JT, Wellens H, Yan GX. The early repolarization pattern: a consensus paper.J Am Coll Cardiol. 2015; 66:470–477. doi: 10.1016/j.jacc.2015.05.033.CrossrefMedlineGoogle Scholar - 14.
Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Long-term outcome associated with early repolarization on electrocardiography.N Engl J Med. 2009; 361:2529–2537. doi: 10.1056/NEJMoa0907589.CrossrefMedlineGoogle Scholar - 15.
Medeiros-Domingo A, Tan BH, Crotti L, Tester DJ, Eckhardt L, Cuoretti A, Kroboth SL, Song C, Zhou Q, Kopp D, Schwartz PJ, Makielski JC, Ackerman MJ. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes.Heart Rhythm. 2010; 7:1466–1471. doi: 10.1016/j.hrthm.2010.06.016.CrossrefMedlineGoogle Scholar - 16.
Xiao L, Koopmann TT, Ördög B, Postema PG, Verkerk AO, Iyer V, Sampson KJ, Boink GJ, Mamarbachi MA, Varro A, Jordaens L, Res J, Kass RS, Wilde AA, Bezzina CR, Nattel S. Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation.Circ Res. 2013; 112:1310–1322. doi: 10.1161/CIRCRESAHA.112.300227.LinkGoogle Scholar - 17.
Knecht S, Sacher F, Wright M, Hocini M, Nogami A, Arentz T, Petit B, Franck R, De Chillou C, Lamaison D, Farré J, Lavergne T, Verbeet T, Nault I, Matsuo S, Leroux L, Weerasooriya R, Cauchemez B, Lellouche N, Derval N, Narayan SM, Jaïs P, Clementy J, Haïssaguerre M. Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study.J Am Coll Cardiol. 2009; 54:522–528. doi: 10.1016/j.jacc.2009.03.065.CrossrefMedlineGoogle Scholar - 18.
Haïssaguerre M, Shoda M, Jaïs P, Nogami A, Shah DC, Kautzner J, Arentz T, Kalushe D, Lamaison D, Griffith M, Cruz F, de Paola A, Gaïta F, Hocini M, Garrigue S, Macle L, Weerasooriya R, Clémenty J. Mapping and ablation of idiopathic ventricular fibrillation.Circulation. 2002; 106:962–967.LinkGoogle Scholar - 19.
Cheung JW, Meli AC, Xie W, Mittal S, Reiken S, Wronska A, Xu L, Steinberg JS, Markowitz SM, Iwai S, Lacampagne A, Lerman BB, Marks AR. Short-coupled polymorphic ventricular tachycardia at rest linked to a novel ryanodine receptor (RyR2) mutation: leaky RyR2 channels under non-stress conditions.Int J Cardiol. 2015; 180:228–236. doi: 10.1016/j.ijcard.2014.11.119.CrossrefMedlineGoogle Scholar - 20.
Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, Nogami A, Fukamizu S, Sakurada H, Takahashi Y, Nakamura H, Ishikura T, Koseki H, Arimura T, Kimura A, Hirao K, Isobe M, Shimizu W, Miura N, Furukawa T. Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias [published online ahead of print October 1, 2015].Eur Heart J. pii: ehv449.Google Scholar - 21.
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB ; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: heart disease and stroke statistics–2012 update: a report from the American Heart Association.Circulation. 2012; 125:188–197. doi: 10.1161/CIR.0b013e3182456d46.LinkGoogle Scholar - 22.
O’Doherty M, Tayler DI, Quinn E, Vincent R, Chamberlain DA. Five hundred patients with myocardial infarction monitored within one hour of symptoms.BMJ. (Clin Res Ed). 1983; 286:1405–1408.CrossrefMedlineGoogle Scholar - 23.
Takagi Y, Yasuda S, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H ; Japanese Coronary Spasm Association. Clinical characteristics and long-term prognosis of vasospastic angina patients who survived out-of-hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association.Circ Arrhythm Electrophysiol. 2011; 4:295–302. doi: 10.1161/CIRCEP.110.959809.LinkGoogle Scholar - 24.
Codd MB, Sugrue DD, Gersh BJ, Melton LJ . Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975-1984.Circulation. 1989; 80:564–572.LinkGoogle Scholar - 25.
Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults.Circulation. 1995; 92:785–789.LinkGoogle Scholar - 26.
Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, Graham KJ, Burton DA, Cecchi F. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population.Circulation. 2000; 102:858–864.LinkGoogle Scholar - 27.
Peters S, Trümmel M, Meyners W. Prevalence of right ventricular dysplasia-cardiomyopathy in a non-referral hospital.Int J Cardiol. 2004; 97:499–501. doi: 10.1016/j.ijcard.2003.10.037.CrossrefMedlineGoogle Scholar - 28.
Hulot JS, Jouven X, Empana JP, Frank R, Fontaine G. Natural history and risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy.Circulation. 2004; 110:1879–1884. doi: 10.1161/01.CIR.0000143375.93288.82.LinkGoogle Scholar - 29.
Bhonsale A, James CA, Tichnell C, Murray B, Gagarin D, Philips B, Dalal D, Tedford R, Russell SD, Abraham T, Tandri H, Judge DP, Calkins H. Incidence and predictors of implantable cardioverter-defibrillator therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy undergoing implantable cardioverter-defibrillator implantation for primary prevention.J Am Coll Cardiol. 2011; 58:1485–1496. doi: 10.1016/j.jacc.2011.06.043.CrossrefMedlineGoogle Scholar - 30.
Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, Babuty D, Sacher F, Giustetto C, Schulze-Bahr E, Borggrefe M, Haissaguerre M, Mabo P, Le Marec H, Wolpert C, Wilde AA. Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry.Circulation. 2010; 121:635–643. doi: 10.1161/CIRCULATIONAHA.109.887026.LinkGoogle Scholar - 31.
Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-QT syndrome.N Engl J Med. 2003; 348:1866–1874. doi: 10.1056/NEJMoa022147.CrossrefMedlineGoogle Scholar - 32.
van der Werf C, Nederend I, Hofman N, van Geloven N, Ebink C, Frohn-Mulder IM, Alings AM, Bosker HA, Bracke FA, van den Heuvel F, Waalewijn RA, Bikker H, van Tintelen JP, Bhuiyan ZA, van den Berg MP, Wilde AA. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.Circ Arrhythm Electrophysiol. 2012; 5:748–756. doi: 10.1161/CIRCEP.112.970517.LinkGoogle Scholar - 33.
Mazzanti A, Kanthan A, Monteforte N, Memmi M, Bloise R, Novelli V, Miceli C, O’Rourke S, Borio G, Zienciuk-Krajka A, Curcio A, Surducan AE, Colombo M, Napolitano C, Priori SG. Novel insight into the natural history of short QT syndrome.J Am Coll Cardiol. 2014; 63:1300–1308. doi: 10.1016/j.jacc.2013.09.078.CrossrefMedlineGoogle Scholar - 34.
Herman AR, Cheung C, Gerull B, Simpson CS, Birnie DH, Klein GJ, Champagne J, Healey JS, Gibbs K, Talajic M, Gardner M, Bennett MT, Steinberg C, Janzen M, Gollob MH, Angaran P, Yee R, Leather R, Chakrabarti S, Sanatani S, Chauhan VS, Krahn AD. Outcome of apparently unexplained cardiac arrest: results from investigation and follow-up of the prospective cardiac arrest survivors with preserved ejection fraction registry.Circ Arrhythm Electrophysiol. 2016; 9:e003619. doi: 10.1161/CIRCEP.115.003619.Google Scholar - 35.
Haïssaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, de Roy L, Pasquié JL, Nogami A, Babuty D, Yli-Mayry S, De Chillou C, Scanu P, Mabo P, Matsuo S, Probst V, Le Scouarnec S, Defaye P, Schlaepfer J, Rostock T, Lacroix D, Lamaison D, Lavergne T, Aizawa Y, Englund A, Anselme F, O’Neill M, Hocini M, Lim KT, Knecht S, Veenhuyzen GD, Bordachar P, Chauvin M, Jais P, Coureau G, Chene G, Klein GJ, Clémenty J. Sudden cardiac arrest associated with early repolarization.N Engl J Med. 2008; 358:2016–2023. doi: 10.1056/NEJMoa071968.CrossrefMedlineGoogle Scholar - 36.
Magnani JW, Danik HJ, Dec GW, DiSalvo TG. Survival in biopsy-proven myocarditis: a long-term retrospective analysis of the histopathologic, clinical, and hemodynamic predictors.Am Heart J. 2006; 151:463–470. doi: 10.1016/j.ahj.2005.03.037.CrossrefMedlineGoogle Scholar - 37.
Smedema JP, Snoep G, van Kroonenburgh MP, van Geuns RJ, Dassen WR, Gorgels AP, Crijns HJ. Cardiac involvement in patients with pulmonary sarcoidosis assessed at two university medical centers in the Netherlands.Chest. 2005; 128:30–35. doi: 10.1378/chest.128.1.30.CrossrefMedlineGoogle Scholar - 38.
Matsui Y, Iwai K, Tachibana T, Fruie T, Shigematsu N, Izumi T, Homma AH, Mikami R, Hongo O, Hiraga Y, Yamamoto M. Clinicopathological study of fatal myocardial sarcoidosis.Ann N Y Acad Sci. 1976; 278:455–469.CrossrefMedlineGoogle Scholar - 39.
Siebermair J, Sinner MF, Beckmann BM, Laubender RP, Martens E, Sattler S, Fichtner S, Estner HL, Kaab S, Wakili R. Early repolarization pattern is the strongest predictor of arrhythmia recurrence in patients with idiopathic ventricular fibrillation: results from a single centre long-term follow-up over 20 years†. [published online ahead of print January 11, 2016].Europace. pii: euv301.Google Scholar - 40.
Ozaydin M, Moazzami K, Kalantarian S, Lee H, Mansour M, Ruskin JN. Long-Term Outcome of Patients With Idiopathic Ventricular Fibrillation: A Meta-Analysis.J Cardiovasc Electrophysiol. 2015; 26:1095–1104. doi: 10.1111/jce.12737.CrossrefMedlineGoogle Scholar - 41.
Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Niinuma H, Gottlieb I, Paul N, Clouse ME, Shapiro EP, Hoe J, Lardo AC, Bush DE, de Roos A, Cox C, Brinker J, Lima JA. Diagnostic performance of coronary angiography by 64-row CT.N Engl J Med. 2008; 359:2324–2336. doi: 10.1056/NEJMoa0806576.CrossrefMedlineGoogle Scholar - 42.
Meijboom WB, Meijs MF, Schuijf JD, Cramer MJ, Mollet NR, van Mieghem CA, Nieman K, van Werkhoven JM, Pundziute G, Weustink AC, de Vos AM, Pugliese F, Rensing B, Jukema JW, Bax JJ, Prokop M, Doevendans PA, Hunink MG, Krestin GP, de Feyter PJ. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study.J Am Coll Cardiol. 2008; 52:2135–2144. doi: 10.1016/j.jacc.2008.08.058.CrossrefMedlineGoogle Scholar - 43.
Okumura K, Yasue H, Matsuyama K, Goto K, Miyagi H, Ogawa H, Matsuyama K. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm.J Am Coll Cardiol. 1988; 12:883–888.CrossrefMedlineGoogle Scholar - 44.
Waters DD, Szlachcic J, Bonan R, Miller DD, Dauwe F, Theroux P. Comparative sensitivity of exercise, cold pressor and ergonovine testing in provoking attacks of variant angina in patients with active disease.Circulation. 1983; 67:310–315.LinkGoogle Scholar - 45.
Veltmann C, Wolpert C, Sacher F, Mabo P, Schimpf R, Streitner F, Brade J, Kyndt F, Kuschyk J, Le Marec H, Borggrefe M, Probst V. Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges.Europace. 2009; 11:1345–1352. doi: 10.1093/europace/eup189.CrossrefMedlineGoogle Scholar - 46.
Hong K, Brugada J, Oliva A, Berruezo-Sanchez A, Potenza D, Pollevick GD, Guerchicoff A, Matsuo K, Burashnikov E, Dumaine R, Towbin JA, Nesterenko V, Brugada P, Antzelevitch C, Brugada R. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations.Circulation. 2004; 110:3023–3027. doi: 10.1161/01.CIR.0000144299.17008.07.LinkGoogle Scholar - 47.
Meregalli PG, Ruijter JM, Hofman N, Bezzina CR, Wilde AA, Tan HL. Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome.J Cardiovasc Electrophysiol. 2006; 17:857–864. doi: 10.1111/j.1540-8167.2006.00531.x.CrossrefMedlineGoogle Scholar - 48.
Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response.Circulation. 2006; 113:1385–1392. doi: 10.1161/CIRCULATIONAHA.105.600445.LinkGoogle Scholar - 49.
Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, Suyama K, Aihara N, Sunagawa K, Echigo S, Miyamoto Y, Yoshimasa Y, Nakamura K, Ohe T, Towbin JA, Priori SG, Kamakura S. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome.Heart Rhythm. 2004; 1:276–283. doi: 10.1016/j.hrthm.2004.04.021.CrossrefMedlineGoogle Scholar - 50.
Clur SA, Chockalingam P, Filippini LH, Widyanti AP, Van Cruijsen M, Blom NA, Alders M, Hofman N, Wilde AA. The role of the epinephrine test in the diagnosis and management of children suspected of having congenital long QT syndrome.Pediatr Cardiol. 2010; 31:462–468. doi: 10.1007/s00246-009-9603-2.CrossrefMedlineGoogle Scholar - 51.
Krahn AD, Healey JS, Chauhan VS, Birnie DH, Champagne J, Sanatani S, Ahmad K, Ballantyne E, Gerull B, Yee R, Skanes AC, Gula LJ, Leong-Sit P, Klein GJ, Gollob MH, Simpson CS, Talajic M, Gardner M. Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden death: from the cardiac arrest survivors with preserved Ejection Fraction Registry.Circ Arrhythm Electrophysiol. 2012; 5:933–940. doi: 10.1161/CIRCEP.112.973230.LinkGoogle Scholar - 52.
Andrsova I, Novotny T, Kadlecova J, Bittnerova A, Vit P, Florianova A, Sisakova M, Gaillyova R, Manouskova L, Spinar J. Clinical characteristics of 30 Czech families with long QT syndrome and KCNQ1 and KCNH2 gene mutations: importance of exercise testing.J Electrocardiol. 2012; 45:746–751. doi: 10.1016/j.jelectrocard.2012.05.004.CrossrefMedlineGoogle Scholar - 53.
Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS, Perrin M, Gollob MH, Skanes AC, Yee R, Gula LJ, Leong-Sit P, Viskin S, Klein GJ, Wilde AA, Krahn AD. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands.Circulation. 2011; 124:2187–2194. doi: 10.1161/CIRCULATIONAHA.111.028258.LinkGoogle Scholar - 54.
Krahn AD, Klein GJ, Yee R. Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome?Circulation. 1997; 96:1551–1556.LinkGoogle Scholar - 55.
Adler A, van der Werf C, Postema PG, Rosso R, Bhuiyan ZA, Kalman JM, Vohra JK, Guevara-Valdivia ME, Marquez MF, Halkin A, Benhorin J, Antzelevitch C, Wilde AA, Viskin S. The phenomenon of “QT stunning”: the abnormal QT prolongation provoked by standing persists even as the heart rate returns to normal in patients with long QT syndrome.Heart Rhythm. 2012; 9:901–908. doi: 10.1016/j.hrthm.2012.01.026.CrossrefMedlineGoogle Scholar - 56.
Viskin S, Postema PG, Bhuiyan ZA, Rosso R, Kalman JM, Vohra JK, Guevara-Valdivia ME, Marquez MF, Kogan E, Belhassen B, Glikson M, Strasberg B, Antzelevitch C, Wilde AA. The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome.J Am Coll Cardiol. 2010; 55:1955–1961. doi: 10.1016/j.jacc.2009.12.015.CrossrefMedlineGoogle Scholar - 57.
Marjamaa A, Hiippala A, Arrhenius B, Lahtinen AM, Kontula K, Toivonen L, Happonen JM, Swan H. Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia.J Cardiovasc Electrophysiol. 2012; 23:194–199. doi: 10.1111/j.1540-8167.2011.02188.x.CrossrefMedlineGoogle Scholar - 58.
Hayashi M, Denjoy I, Hayashi M, Extramiana F, Maltret A, Roux-Buisson N, Lupoglazoff JM, Klug D, Maury P, Messali A, Guicheney P, Leenhardt A. The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands.Europace. 2012; 14:1344–1351. doi: 10.1093/europace/eus031.CrossrefMedlineGoogle Scholar - 59.
Blich M, Marai I, Suleiman M, Lorber A, Gepstein L, Boulous M, Khoury A. Electrocardiographic comparison of ventricular premature complexes during exercise test in patients with CPVT and healthy subjects.Pacing Clin Electrophysiol. 2015; 38:398–402. doi: 10.1111/pace.12574.CrossrefMedlineGoogle Scholar - 60.
Bai R, Napolitano C, Bloise R, Monteforte N, Priori SG. Yield of genetic screening in inherited cardiac channelopathies: how to prioritize access to genetic testing.Circ Arrhythm Electrophysiol. 2009; 2:6–15. doi: 10.1161/CIRCEP.108.782888.LinkGoogle Scholar - 61.
Takagi Y, Yasuda S, Takahashi J, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H ; Japanese Coronary Spasm Association. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.Eur Heart J. 2013; 34:258–267. doi: 10.1093/eurheartj/ehs199.CrossrefMedlineGoogle Scholar - 62.
Sueda S, Ochi N, Kawada H, Matsuda S, Hayashi Y, Tsuruoka T, Uraoka T. Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine.Am J Cardiol. 1999; 83:1186–1190.CrossrefMedlineGoogle Scholar - 63.
Wolpert C, Echternach C, Veltmann C, Antzelevitch C, Thomas GP, Spehl S, Streitner F, Kuschyk J, Schimpf R, Haase KK, Borggrefe M. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.Heart Rhythm. 2005; 2:254–260. doi: 10.1016/j.hrthm.2004.11.025.CrossrefMedlineGoogle Scholar - 64.
Magnano AR, Talathoti N, Hallur R, Bloomfield DM, Garan H. Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol in healthy subjects.J Cardiovasc Electrophysiol. 2006; 17:983–989. doi: 10.1111/j.1540-8167.2006.00555.x.CrossrefMedlineGoogle Scholar - 65.
Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C, Platonov PG, Priori SG, Qi M, Schwartz PJ, Shimizu W, Towbin JA, Vincent GM, Wilde AA, Zhang L. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals.J Am Coll Cardiol. 2011; 57:51–59. doi: 10.1016/j.jacc.2010.07.038.CrossrefMedlineGoogle Scholar - 66.
Narula N, Tester DJ, Paulmichl A, Maleszewski JJ, Ackerman MJ. Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series.Pediatr Cardiol. 2015; 36:768–778. doi: 10.1007/s00246-014-1082-4.CrossrefMedlineGoogle Scholar - 67.
Bagnall RD, Das K J, Duflou J, Semsarian C. Exome analysis-based molecular autopsy in cases of sudden unexplained death in the young.Heart Rhythm. 2014; 11:655–662. doi: 10.1016/j.hrthm.2014.01.017.CrossrefMedlineGoogle Scholar - 68.
Nunn LM, Lopes LR, Syrris P, Murphy C, Plagnol V, Firman E, Dalageorgou C, Zorio E, Domingo D, Murday V, Findlay I, Duncan A, Carr-White G, Robert L, Bueser T, Langman C, Fynn SP, Goddard M, White A, Bundgaard H, Ferrero-Miliani L, Wheeldon N, Suvarna SK, O’Beirne A, Lowe MD, McKenna WJ, Elliott PM, Lambiase PD. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing [published online ahead of print October 25, 2015].Europace. pii: euv285.Google Scholar - 69.
Remme CA, Wever EF, Wilde AA, Derksen R, Hauer RN. Diagnosis and long-term follow-up of the Brugada syndrome in patients with idiopathic ventricular fibrillation.Eur Heart J. 2001; 22:400–409. doi: 10.1053/euhj.2000.2366.CrossrefMedlineGoogle Scholar - 70.
Champagne J, Geelen P, Philippon F, Brugada P. Recurrent cardiac events in patients with idiopathic ventricular fibrillation, excluding patients with the Brugada syndrome.BMC Med. 2005; 3:1. doi: 10.1186/1741-7015-3-1.CrossrefMedlineGoogle Scholar - 71.
Meissner MD, Lehmann MH, Steinman RT, Mosteller RD, Akhtar M, Calkins H, Cannom DS, Epstein AE, Fogoros RN, Liem LB. Ventricular fibrillation in patients without significant structural heart disease: a multicenter experience with implantable cardioverter-defibrillator therapy.J Am Coll Cardiol. 1993; 21:1406–1412.CrossrefMedlineGoogle Scholar - 72.
Mewis C, Kühlkamp V, Spyridopoulos I, Bosch RF, Seipel L. Late outcome of survivors of idiopathic ventricular fibrillation.Am J Cardiol. 1998; 81:999–1003.CrossrefMedlineGoogle Scholar - 73.
Crijns HJ, Wiesfeld AC, Posma JL, Lie KI. Favourable outcome in idiopathic ventricular fibrillation with treatment aimed at prevention of high sympathetic tone and suppression of inducible arrhythmias.Br Heart J. 1995; 74:408–412.CrossrefMedlineGoogle Scholar - 74.
Schuijf JD, Bax JJ, Shaw LJ, de Roos A, Lamb HJ, van der Wall EE, Wijns W. Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography.Am Heart J. 2006; 151:404–411. doi: 10.1016/j.ahj.2005.03.022.CrossrefMedlineGoogle Scholar
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.