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Prognostic significance of fever-induced Brugada syndrome
Author’s Accepted Manuscript The Prognostic Significance of Fever-Induced Brugada Syndrome Yuka Mizusawa, Hiroshi Morita, Arnon Adler, Ofer Havakuk, Aurélie Thollet, Philippe Maury, Dao W. Wang, Kui Hong, Estelle Gandjbakhch, Frédéric Sacher, Dan Hu, Ahmad S. Amin, Najim Lahrouchi, Hanno L. Tan, Charles Antzelevitch, Vincent Probst, Sami Viskin, Arthur A.M. Wilde
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S1547-5271(16)30088-1 http://dx.doi.org/10.1016/j.hrthm.2016.03.044 HRTHM6675
To appear in: Heart Rhythm Received date: 29 September 2015 Cite this article as: Yuka Mizusawa, Hiroshi Morita, Arnon Adler, Ofer Havakuk, Aurélie Thollet, Philippe Maury, Dao W. Wang, Kui Hong, Estelle Gandjbakhch, Frédéric Sacher, Dan Hu, Ahmad S. Amin, Najim Lahrouchi, Hanno L. Tan, Charles Antzelevitch, Vincent Probst, Sami Viskin and Arthur A.M. Wilde, The Prognostic Significance of Fever-Induced Brugada Syndrome, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2016.03.044 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The prognostic significance of fever-induced Brugada Syndrome Short title: Fever-induced BrS.
Yuka Mizusawa, MD*, Hiroshi Morita, MD, PhD**, Arnon Adler, MD, PhD†, Ofer Havakuk, MD†, Aurélie Thollet, PhD‡,§, Philippe Maury, MD††, Dao W Wang, MD, PhD‡‡, Kui Hong, MD, PhD§§, Estelle Gandjbakhch, MD, PhD¶,#, Frédéric Sacher, MD, PhD││, Dan Hu, MD, PhD##, Ahmad S. Amin, MD, PhD*, Najim Lahrouchi, MD*, Hanno L. Tan, MD, PhD*, Charles Antzelevitch, PhD###, Vincent Probst, MD, PhD‡,§, Sami Viskin, MD†, Arthur AM Wilde, MD, PhD*,¶¶.
From *Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; **Department of Cardiovascular Medicine, Okayama University of Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; †Department of Cardiology, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; ‡INSERM, UMR1087, Institut du thorax, Université de Nantes, Nantes, France; §CNRS, UMR 6291, Institut du thorax, Université de Nantes, Nantes, France; ††Service de Cardiologie, CHU, Rangueil, Toulouse, France ; ‡‡Department of Medicine, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; §§Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Nanchang, China; ¶UPMC, University Paris 6, INSERM, UMRS956, Institut de Cardiologie(AP-HP), Paris, France; #AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; ││Bordeaux University Hospital, IHU Institut de Rythmologie et Modélisation Cardiaque, Inserm U1045, Université de Bordeaux, Bordeaux, France; ##Masonic Medical Rearch Laboratory, Utica, New York, USA; ###Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA; and ¶¶Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
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Address for correspondence: Arthur AM Wilde, MD, PhD. Heart Failure Research Centre, Department of Clinical and Experimental Cardiology, Academic Medical Centre, University of Amsterdam, PO Box 22700, 110DE, Amsterdam, the Netherlands. Telephone number: +31 20 56 63072 Fax number: +31 20 69 71385 Email: [email protected]
Conflict of interest: none
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Abstract Background: In Brugada syndrome (BrS), spontaneous type1 ECG (S-type1) is an established risk for fatal arrhythmias whereas drug-induced type1 ECG (D-type1) shows a relatively benign prognosis. No study has analyzed the prognosis of fever-induced type1 ECG (F-type1) in a large BrS cohort. Objective: 1) To assess the prognosis of F-type1 in asymptomatic BrS, and 2) compare the effects of fever and drugs on ECG parameters. Methods: One hundred and twelve BrS patients with a documented F-type1 were retrospectively collected. Prognosis was evaluated in 88 asymptomatic patients. In a subgroup (n=52), ECG parameters of multiple ECGs (at baseline[B], during fever[F] and after drug-challenge[D]) were analyzed. Results: Eighty-eight asymptomatic patients had a mean age of 45.8±18.7 years and 71.6% were men. Twenty-one percent had a family history of sudden cardiac death and 26.4% (14/53) carried a pathogenic SCN5A mutation. Drug-challenge was positive in 29 of 36 patients tested (80.6%). The risk of ventricular fibrillation in asymptomatic patients was 0.9%/year (3/88, 43.6±37.4 months). ST elevation in V2 during fever and after drug-challenge was not significantly different (0.41±0.21 ms[F], 0.40±0.30 ms[D], P>0.05). Fever shortened PR compared to baseline, whereas drug-challenge resulted in prolonged PR and QRS (PR: 169±29 ms[B], 148±45 ms[F], 202±35 ms[D]; QRS: 97±18 ms[B], 92±28 ms[F] and 117±21 ms[D]). Conclusion: BrS patients diagnosed with F-type1 are at risk of arrhythmic events. F-type1 appears to occur through a more complex mechanism compared with D-type1.
Key words: Brugada syndrome; fever-induced type1 ECG; drug-induced type1 ECG; prognosis.
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Introduction Brugada syndrome (BrS) is a rare arrhythmic disorder with an increased risk of sudden cardiac death (SCD). The occurrence of the hallmark ECG abnormality (type1 ECG1) varies between individuals and over time, manifesting spontaneously in some, while only occurring during a febrile state or after application of a sodium channel blocking drug (drug-challenge) in others.2 In order to understand the association between type1 ECG and SCD, clinical studies in the last decade have examined the prognostic role of type1 ECG in BrS.3-6 These studies have shown that, in asymptomatic patients, spontaneously manifesting type1 ECG (S-type1) is a risk marker for fatal arrhythmias (0.5-0.8%/year) while the event rate of patients with drug-induced type1 ECG (D-type1) is much lower (00.35%/year).3,4,7-11 The prognosis of fever-induced type1 ECG (F-type1) has not been established. A recent study on 402 febrile individuals and 909 afebrile individuals admitted to the emergency department reported that type1 ECG occurred in eight febrile patients (2%), and only in a single afebrile patient (0.5%).12 The eight patients with F-type1 remained asymptomatic during 30 months follow-up. On the other hand, in BrS, fever has been described as a trigger of ventricular fibrillation (VF) in susceptible patients.13-15 However, only small series have been reported and no study so far has analysed the prognosis of F-type1 in a large BrS cohort. We therefore collected over a hundred BrS patients with documented F-type1, and studied the prognosis of asymptomatic patients with Ftype1. In a subgroup of our cohort, we analyzed ECGs to study whether the effects of fever and drugchallenge on ECG parameters were different.
Methods Study Population One hundred and twelve patients with F-type1 were retrospectively collected from nine referral centres (Netherlands, Japan, Israel, France, USA, China, Fig.1 and 2). Type1 ECG was defined as ST segment elevation with coved type morphology of ≥2 mm in one or more right precordial leads in the 4
4th, 3rd and/or 2nd intercostal space.1 Fever was defined as oral temperature of ≥38°C or axillary temperature ≥37°C. The prognosis was analysed in 88 patients who were asymptomatic when they were diagnosed with BrS. The prognosis of the remaining 24 patients (10 patients with a history of VF and 14 patients with syncope from highly suspected arrhythmic causes) were not analysed because large cohort studies have clearly shown that symptomatic BrS patients have a worse prognosis than asymptomatic BrS.3,4 Clinical characteristics such as age, sex, SCN5A mutation carriership, family history of SCD, body temperature during fever, therapy (implantable cardioverter defibrillator [ICD], pacemaker, quinidine) were also assessed. Structural heart disease was excluded with conventional diagnostic methods including treadmill test, echocardiogram and/or cardiac magnetic resonance imaging. Patients were followed in the outpatient clinic on a regular basis (once every 3-24 months) or whenever clinical circumstances required unscheduled visits. After the first visit to the referral centres, some patients were instructed to take antipyretics when they had fever. At each visit, follow-up data (including ECGs) were collected. All patients provided written informed consent to research, which was approved by the Human Research Ethics Committee in each centre. The effects of fever and drug-challenge on ECG parameters By study design, all patients had at least one ECG showing type1 ECG recorded during fever, documented either at the first visit to a hospital or at follow-up. ECGs (12 leads and V1, V2 in the 3rd and 2nd intercostal space [IC]) at baseline, in the absence of fever, and after drug-challenge were additionally provided when available. Three ECGs (baseline, fever and drug-challenge) were available in total in 52/112 patients, including both symptomatic and asymptomatic patients. ECGs were digitalized and manually measured on a computer screen using ImageJ (http://imagej.nih.gov/ij/) (YM). ECG parameters measured were heart rate (HR), PR interval, QRS duration, QT interval, QTc (Bazett’s formula) in lead II or V5, ST elevation in lead V1 and V2 in the 4th intercostal space, ΔPR(fever) (=PR interval during fever minus PR interval at baseline), ΔPR(drug) (=PR interval after 5
drug minus PR interval at baseline), ΔQRS(fever) (=QRS duration during fever minus QRS duration at baseline), and ΔQRS(drug) (=QRS duration after drug minus QRS duration at baseline). S-type1 was defined as spontaneously manifesting type1 ECG recorded at baseline or at follow-up (but in the absence of fever), F-type1 as type1 ECG during fever, and D- type1 as type1 ECG during drugchallenge. A drug-challenge was terminated before the full dose was given when type1 ECG was evoked or when excessive QRS prolongation or any ventricular arrhythmias were observed. Statistical analysis Statistical analyses were conducted using SPSS Statistics 23.0. Continuous variables are presented as mean±standard deviation and categorical variables as percentage. Paired t-test was used for comparing ECG parameters in three different conditions. P value of <0.05 was considered statistically significant.
Results The clinical characteristics of asymptomatic patients with F-type1 ECG The clinical characteristics of the 88 asymptomatic patients with F-type1 are summarized in Table 1. The mean age was 45.8±18.7 years, and 76.1% (67/88) were men. Eighty-six patients developed fever as outpatients while 2 cases developed fever during hospitalization (one patient in a post-partum period, and one after an electrophysiological study). Body temperature during fever was 38.9±0.8 °C (range 37.0-40.2). In 80/88 patients (90.9%), BrS was diagnosed because of F-type1 ECG (Fig.2). ECG was recorded by chance in 77/80 patients during a diagnostic evaluation of fever and accompanying symptoms (e.g., chest pain, worsening of general condition, conditions necessitating surgery). In a minority of the cases (3/80 patients), positive family history of BrS and/or family history of SCD prompted the physician to record an ECG during fever.
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F-type1 was documented at follow-up in 8/88 patients (Fig.2). One patient was already known with BrS because S-type1 was documented previously in the absence of fever. Five patients showed non-diagnostic BrS ECG at first medical contact, and drug-challenge induced D-type1, confirming the diagnosis BrS. Two patients were referred because of a family history of SCD. BrS was diagnosed either with S-type1 (one patient) or with D-type1 (one patient). On the whole, 18 patients had a family history of SCD (20.5%). A pathogenic mutation in the SCN5A gene was identified in 14/53 patients tested (26.4%). During diagnostic work-up, drugchallenge was additionally performed in some patients who were already diagnosed with BrS by Ftype1 or S-type1. In total, 36 asymptomatic patients underwent drug-challenge; this was positive in 29 patients (80.6%). Drugs used for drug-challenge were ajmaline (1mg/kg, n=24), pilsicainide (1mg/kg, n=7), or flecainide (2mg/kg, n=5). The false-negative rate of drug-challenge (vs. F-type1) was higher with flecainide (20.0%) and ajmaline (20.8%) than with pilsicainide (14.3%). Three patients were treated with ICD, one with quinidine and two with pacemakers because of concomitant sick sinus syndrome. Outcome of asymptomatic patients with F-type1 During a follow-up period of 43.6±37.4 months, three male patients (3.4%) developed arrhythmic events (ICD shock [n=1] and cardiac arrest [n=2]). The risk of VF in asymptomatic patients with F-type1 was 0.9%/year overall (3/88, 43.6±37.4 months), and 1.1%/year in men (3/67, 48.8±41.1 months). Among the three patients, one event occurred during fever. It could not be confirmed whether this was the case in the remaining two patients (Table 2). Effects of fever and drug-challenge on ECG parameters ECGs at baseline, during fever and after drug-challenge were available for analysis in 52/112 patients. ECG parameters were measured and compared between different conditions (Table 3). At baseline, the mean ST segment elevation in the 4th IC was 0.08±0.11 mV in V1, and 0.15±0.15 mV in
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V2. During fever, ST-segment was elevated to 0.26±0.14 mV in V1, and 0.39±0.26 mV in V2. After drug-challenge, ST elevation was 0.18±0.16 mV in V1, and 0.32±0.26 mV in V2. In order to study whether fever-induced and drug-induced ST elevation in the right ventricular outflow tract (RVOT) area was different, we included all available right precordial leads of the 4th 2nd IC for further analysis. The 4th - 2nd IC were analysed in 67.3% (35/52) during drug-challenge, and 15% (8/52) during fever. The maximal coved-type ST elevation (type1 or type3)16 in any right precordial lead was significantly higher during fever (0.41±0.21 mV) or after drug-challenge (0.40±0.30 mV) than at baseline (0.03±0.14 mV, P<0.01, Figure 3), but not significantly different between fever and drug-challenge (P>0.05). However, type1 ECG occurred in different leads during fever or drug-challenge. D-type1 occurred in the 4th IC in 78.0% (32/41 patients with positive drugchallenge), while it occurred only in the 3rd - 2nd IC in 22.0% (9/41). In 41 patients with positive drugchallenge, F-type1 occurred in the 4th IC in 97.6% (40/41), while only one patient required leads in the 3rd - 2nd IC to detect F-type1. There was no positive correlation observed between body temperature and the level of ST elevation, or between body temperature and the difference of ST elevation (ST elevation during fever minus ST elevation at baseline). During fever, HR was significantly faster than at baseline (96±31 bpm vs. 71±13 bpm, P<0.01), while PR (148±45ms) and QT interval (302±85 ms) were shorter than at baseline (169±29 ms and 367±31 ms, respectively, P<0.01). QRS was not significantly different from baseline (92±28 vs. 97±18 ms, P>0.05). Drug-challenge resulted in significantly longer PR (202±35 ms), QRS (117±21 ms), QT (386±37 ms) and QTc (435±30 ms) compared to baseline (P<0.01). In summary, while ST-segment in V1 and V2 were elevated similarly during fever and after drug-challenge, response of PR and QRS to fever and drug-challenge was different. PR and QRS did not prolong in response to fever (ΔPR[fever] -10±16 ms, ΔQRS[fever] 1.7±14 ms). Whereas PR and
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QRS prolonged in response to sodium channel blockers (ΔPR[drug] 34± 23 ms, ΔQRS[drug] 20± 18 ms).
Discussion F-type1 was initially considered an ominous sign because of initial reports from small series of patients who presented with VF during fever.13,14 However, this could represent selection bias, and no study so far has collected a substantial BrS cohort to establish the prognostic value of F-type1. In the present study cohort, the largest of its kind, it was demonstrated that asymptomatic patients with Ftype1 indeed carry a risk of SCD. As expected, the risk of arrhythmic events among patients with Ftype1 was affected by the clinical presentation: the event rate was 3.0%/year in patients with a history of VF, 1.3%/year in patients with a history of syncope (Fig. 2; details are not shown in Results) and 0.9%/year in asymptomatic patients. The event rate in asymptomatic patients seems comparable to the rates reported for initially asymptomatic patients with S-type1 (0.5-0.8%/year) and higher than for asymptomatic D-type1 patients (0-0.35%/year),3,4,7-11 although we realize that our cohort might be still too small to allow such a comparison. Our results seemingly contrasts with a previous study by Adler et al.12, in which no arrhythmic events in 8 individuals incidentally diagnosed with BrS through Ftype1 were reported (follow-up 30 months). Differences in a priori risk may play a role here with a high a priori risk of our BrS cohort, and a low a priori risk in the general population in the study of Adler et al.12 The question remains how much F-type1 itself contributes to arrhythmia risk. In our cohort, because of its retrospective nature, the outcome of F-type1 could have been overestimated due to concealed S-type1 which was simply not detected by chance, even though patients were followed at regular basis in outpatient clinics. On the other hand, the outcome could have been underestimated because some patients were instructed to take antipyretics immediately after a febrile episode. Our study was also limited by the rarity of BrS patients showing F-type1 ECG, and lack of controls without F-type1. To appropriately assess the risk of F-type1, worldwide collaboration to build a large BrS database will be required. 9
In this study, ECGs in three different conditions (baseline, fever and drug-challenge) were compared in a subpopulation of our cohort to find any relevant ECG markers related to fever in BrS. Surprisingly, the effect of fever was different from drug-challenge. Fever affected RVOT focally to elevate ST-segment, but did not prolong PR and QRS as drug-challenge does. One possible explanation is that fever has less sodium channel blocking effect than drugs. RVOT has developmentally lower protein Nav1.5 and connexin43 levels compared to right ventricle or left ventricle, causing lower conduction reserve.17,18 Subtle decrease of the sodium currents may be enough to induce F-type1 while PR and QRS are not affected because of increased conduction reserve. Alternatively, other yet unknown factors related to acute infection or increased temperature are involved in F-type1. Another interesting observation was that F-type1 and D-type1 occurred in different area of RVOT: in the 41 patients who showed both F-type1 and D-type1, F-type1 occurred in the 4th IC in the majority(97.6%), while D-type1 was induced in different area of RVOT (78% in the 4th IC and 22 % in 2nd-3rd IC only). Because of lack of complete recordings of all RVOT leads during fever/drugchallenge, we could not analyse fully the extent of type1 ST-elevation in RVOT. Future studies should adress this issue by using all right precordial leads in the 4th-2nd IC to study the extent of STelevation during fever and mechanisms behind this phenomenon. With regard to discrepant manifestation of type1 BrS ECG during fever and drug-challenge in the same patients, so far in literature, one case report has reported that fever unmasked type1 ECG, while a flecainide test failed to do so.19 In our cohort, only 29 out of 36 asymptomatic patients (80.6 %) tested were positive during drug-challenge. This suggests that drug-challenge may be less sensitive to unmask type1 ECG than fever. It is important to note, however, that these results were influenced by electrode position (in 2nd and 3rd IC), and types and dosage of drugs used for drugchallenge. The higher false-negative rates of drug-challenge (vs. F-type1) with flecainide and ajmaline (compared to pilsicainide) may be determined by different cardiac ion channel blocking effects of these drugs. While pilsicainide is a pure sodium channel blocker, which may evoke a 10
maximum ST elevation, flecainide and ajmaline also block the transient outward potassium current as well as the delayed rectifier potassium current at clinical concentrations.20-22 Aggregated decrease of the potassium currents may counterbalance the decrease in sodium currents by these drugs, and eventually lead to a lower ST elevation. Although this study did not specifically aim at evaluating the sensitivity and specificity of fever or drug-challenge in the context of BrS diagnosis, the discrepant manifestation of F-type1 and D-type1 in the same patients is intriguing and remains to be addressed in future studies.
Limitations Collecting BrS patients with F-type1 was hampered by the rarity of F-type1. To increase the number of cases with F-type1 as much as possible, patients were collected from large referral centres worldwide where BrS patients are advised to visit a medical facility to record at least one ECG during fever before antipyretics are given. Because it is recommended to treat fever immediately with antipyretic agents in all BrS patients1, F-type1 may be missed nowadays. Owing to our strict instructions to treating physicians to record an ECG during fever in BrS patients before any antipyretics use, we were able to collect the largest population so far with F-type1. Therefore, we believe that our findings certainly add clinically relevant insights to patients with BrS and in particular to those with fever-induced BrS. Although the protocol of drug-challenge testing is standardized in general, the types and dosage of sodium channel blocking drugs used were different between centres due to the retrospective nature of this study. Also, the use of electrode placement in the 3rd-2nd IC was different. These factors could play a role in the outcome. Future studies should address if /why fever is indeed more sensitive to unmask type1 ECG compared to sodium channel blockers by collecting a large BrS cohort worldwide with detailed information, including a standardized drug-challenge protocol.
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Conclusions BrS patients diagnosed with F-type1 are at risk of arrhythmic events. F-type1 appears to occur through a more complex mechanism compared with D-type1.
Acknowledgements Y.M., H.T. and A.M. were supported by the Netherlands CardioVascular Research Initiative": the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences. H.M. is affiliated with the endowed department by Japan Medtronic Inc., and was supported by JSPS KAKENHI (24591051 and 15K09082) and by the Ministry of Health, Labor and Welfare of Japan for Clinical Research on Intractable Diseases (H24-033, H26-040). D.W.W. was supported by National Natural Science Foundation of China (project No. 81170159) and by
National Key Basic Research Program of China (973 Program)(No. 2013CB531105). C.A. was supported by NHLBI grant HL HL47678.
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Figure titles and legends Fig. 1. Fever-induced type1 BrS ECG and VF ECGs of a 50-year old man admitted with acute gastroenteritis (body temperature 38.7°C) and repetitive syncopal episodes. During fever, fever-induced type1 BrS ECG with a ventricular extrasystole (A) and successive VF (B) was recorded. When fever subsided, ECG changed to type2 BrS ECG (C).
Fig. 2. Characteristics of diagnostic ECG and events at follow-up Of 112 patients, 95 patients were admitted with F-type1. The remaining 17 patients were already known with BrS (by either S-type1 or D-type1) and showed F-type1 at follow-up. There were 88 asymptomatic patients. Three of them had SCD or VF at follow-up. Two patients with a history of VF and one patient with a history of syncope experienced VF at follow-up. D-type1=drug-induced type1
15
BrS ECG; F-type1=fever-induced type1 BrS ECG; SCD=sudden cardiac death; S-type1=spontaneous type1 BrS ECG; VF=ventricular fibrillation.
Fig.3. Maximal ST-segment elevation at baseline, during fever and after drug-challenge. The maximal coved–type ST-segment elevation (type1 or 3)16 in any right precordial lead was significantly higher during fever (0.41±0.21 mV) and after drug-challenge (0.40±0.30 mV) than at baseline (0.03±0.14 mV, *P<0.01 for baseline vs. fever and baseline vs. drug, P>0.05 for fever vs. drug).
16
Table 1. Clinical characteristics of 88 asymptomatic BrS patients with F-type1.
N=88 Males, n (%)
67 (76.1)
Age, years
45.8±18.7
F-type1, n (%)
88 (100)
at diagnosis
80 (90.9)
at follow-up
8 (9.1)
Body temperature during fever, °C
38.9±0.8
Family history of SCD, n (%)
18 (20.5)
SCN5A mutation carriers, n (%)
14/53 (26.4)
Drug-challenge positive, n (%)
29/36 (80.6)
Treatment, n (%) ICD
3 (3.4)
Quinidine
1 (1.1)
Pacemaker
2 (2.3)
Follow-up, months
43.6±37.4
17
Table 2. Asymptomatic patients with events at follow-up At diagnosis
Fev er,
SCN5 A mutati on
Sympt om
39, M
No sympt om
No
S
P
No
No
47, 2 M
No sympt om
39.0
F
P
No
27, 3 M
No sympt om
38.9
F
P
No
1
Drugchalle nge
Fami ly histo ry of SCD
Ag e, sex
°C
BrS diagno sis
Events at follow-up Total follo wup, Sympt om
°C
Ftyp e1
ICD
VF
37.0 (axilla ry)
Y
141
No
No
SCD
No
NA
10
No
No
SCD
NA
NA
75
Fever, treatm ent
D=drug-induced type1 ECG; F=fever-induced type1 ECG; ICD=implantable cardioverter defibrillator; M=male; NA=not available; P=positive; S=spontaneous type1 ECG; SCD=sudden cardiac death; VF=ventricular fibrillation; Y=yes.
18
mont hs
Table 3. ECG parameters at baseline, during fever and after drug-challenge. Baseline Fever Drug-challenge 71±13 96±31 78±14 HR 169±29 148±45 202±35 PR -10±16 34±23 ΔPR 97±18 92±28 117±21 QRS 0.7±14 20±18 ΔQRS 367±31 302±85 386±37 QT 395±23 380±104 435±30 QTc 0.08±0.11 0.26±0.14 0.18±0.16 ST elevation in V1 0.15±0.15 0.39±0.26 0.32±0.26 ST elevation in V2 ΔPR presents the extent of PR prolongation from PR(Baseline). ΔQRS presents the extent of QRS prolongation from QRS(Baseline). P<0.01 for all paired t-test except QRS(Baseline) vs. QRS(Fever), QTc(Baseline) vs. QTc(Fever) and ST elevation(Fever) vs. ST elevation(Drug-challenge) in V2 (P>0.05).
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Figure 3
0.80
* *
0.70 0.60
mV
0.50 0.40 0.30
0.20
0.03±0.14
0.41±0.21
0.40±0.30
Baseline
Fever
Drug-challenge
0.10 0.00
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PII: DOI: Reference:
www.elsevier.com/locate/buildenv
S1547-5271(16)30088-1 http://dx.doi.org/10.1016/j.hrthm.2016.03.044 HRTHM6675
To appear in: Heart Rhythm Received date: 29 September 2015 Cite this article as: Yuka Mizusawa, Hiroshi Morita, Arnon Adler, Ofer Havakuk, Aurélie Thollet, Philippe Maury, Dao W. Wang, Kui Hong, Estelle Gandjbakhch, Frédéric Sacher, Dan Hu, Ahmad S. Amin, Najim Lahrouchi, Hanno L. Tan, Charles Antzelevitch, Vincent Probst, Sami Viskin and Arthur A.M. Wilde, The Prognostic Significance of Fever-Induced Brugada Syndrome, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2016.03.044 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The prognostic significance of fever-induced Brugada Syndrome Short title: Fever-induced BrS.
Yuka Mizusawa, MD*, Hiroshi Morita, MD, PhD**, Arnon Adler, MD, PhD†, Ofer Havakuk, MD†, Aurélie Thollet, PhD‡,§, Philippe Maury, MD††, Dao W Wang, MD, PhD‡‡, Kui Hong, MD, PhD§§, Estelle Gandjbakhch, MD, PhD¶,#, Frédéric Sacher, MD, PhD││, Dan Hu, MD, PhD##, Ahmad S. Amin, MD, PhD*, Najim Lahrouchi, MD*, Hanno L. Tan, MD, PhD*, Charles Antzelevitch, PhD###, Vincent Probst, MD, PhD‡,§, Sami Viskin, MD†, Arthur AM Wilde, MD, PhD*,¶¶.
From *Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; **Department of Cardiovascular Medicine, Okayama University of Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; †Department of Cardiology, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; ‡INSERM, UMR1087, Institut du thorax, Université de Nantes, Nantes, France; §CNRS, UMR 6291, Institut du thorax, Université de Nantes, Nantes, France; ††Service de Cardiologie, CHU, Rangueil, Toulouse, France ; ‡‡Department of Medicine, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; §§Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Nanchang, China; ¶UPMC, University Paris 6, INSERM, UMRS956, Institut de Cardiologie(AP-HP), Paris, France; #AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; ││Bordeaux University Hospital, IHU Institut de Rythmologie et Modélisation Cardiaque, Inserm U1045, Université de Bordeaux, Bordeaux, France; ##Masonic Medical Rearch Laboratory, Utica, New York, USA; ###Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA; and ¶¶Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
1
Address for correspondence: Arthur AM Wilde, MD, PhD. Heart Failure Research Centre, Department of Clinical and Experimental Cardiology, Academic Medical Centre, University of Amsterdam, PO Box 22700, 110DE, Amsterdam, the Netherlands. Telephone number: +31 20 56 63072 Fax number: +31 20 69 71385 Email: [email protected]
Conflict of interest: none
2
Abstract Background: In Brugada syndrome (BrS), spontaneous type1 ECG (S-type1) is an established risk for fatal arrhythmias whereas drug-induced type1 ECG (D-type1) shows a relatively benign prognosis. No study has analyzed the prognosis of fever-induced type1 ECG (F-type1) in a large BrS cohort. Objective: 1) To assess the prognosis of F-type1 in asymptomatic BrS, and 2) compare the effects of fever and drugs on ECG parameters. Methods: One hundred and twelve BrS patients with a documented F-type1 were retrospectively collected. Prognosis was evaluated in 88 asymptomatic patients. In a subgroup (n=52), ECG parameters of multiple ECGs (at baseline[B], during fever[F] and after drug-challenge[D]) were analyzed. Results: Eighty-eight asymptomatic patients had a mean age of 45.8±18.7 years and 71.6% were men. Twenty-one percent had a family history of sudden cardiac death and 26.4% (14/53) carried a pathogenic SCN5A mutation. Drug-challenge was positive in 29 of 36 patients tested (80.6%). The risk of ventricular fibrillation in asymptomatic patients was 0.9%/year (3/88, 43.6±37.4 months). ST elevation in V2 during fever and after drug-challenge was not significantly different (0.41±0.21 ms[F], 0.40±0.30 ms[D], P>0.05). Fever shortened PR compared to baseline, whereas drug-challenge resulted in prolonged PR and QRS (PR: 169±29 ms[B], 148±45 ms[F], 202±35 ms[D]; QRS: 97±18 ms[B], 92±28 ms[F] and 117±21 ms[D]). Conclusion: BrS patients diagnosed with F-type1 are at risk of arrhythmic events. F-type1 appears to occur through a more complex mechanism compared with D-type1.
Key words: Brugada syndrome; fever-induced type1 ECG; drug-induced type1 ECG; prognosis.
3
Introduction Brugada syndrome (BrS) is a rare arrhythmic disorder with an increased risk of sudden cardiac death (SCD). The occurrence of the hallmark ECG abnormality (type1 ECG1) varies between individuals and over time, manifesting spontaneously in some, while only occurring during a febrile state or after application of a sodium channel blocking drug (drug-challenge) in others.2 In order to understand the association between type1 ECG and SCD, clinical studies in the last decade have examined the prognostic role of type1 ECG in BrS.3-6 These studies have shown that, in asymptomatic patients, spontaneously manifesting type1 ECG (S-type1) is a risk marker for fatal arrhythmias (0.5-0.8%/year) while the event rate of patients with drug-induced type1 ECG (D-type1) is much lower (00.35%/year).3,4,7-11 The prognosis of fever-induced type1 ECG (F-type1) has not been established. A recent study on 402 febrile individuals and 909 afebrile individuals admitted to the emergency department reported that type1 ECG occurred in eight febrile patients (2%), and only in a single afebrile patient (0.5%).12 The eight patients with F-type1 remained asymptomatic during 30 months follow-up. On the other hand, in BrS, fever has been described as a trigger of ventricular fibrillation (VF) in susceptible patients.13-15 However, only small series have been reported and no study so far has analysed the prognosis of F-type1 in a large BrS cohort. We therefore collected over a hundred BrS patients with documented F-type1, and studied the prognosis of asymptomatic patients with Ftype1. In a subgroup of our cohort, we analyzed ECGs to study whether the effects of fever and drugchallenge on ECG parameters were different.
Methods Study Population One hundred and twelve patients with F-type1 were retrospectively collected from nine referral centres (Netherlands, Japan, Israel, France, USA, China, Fig.1 and 2). Type1 ECG was defined as ST segment elevation with coved type morphology of ≥2 mm in one or more right precordial leads in the 4
4th, 3rd and/or 2nd intercostal space.1 Fever was defined as oral temperature of ≥38°C or axillary temperature ≥37°C. The prognosis was analysed in 88 patients who were asymptomatic when they were diagnosed with BrS. The prognosis of the remaining 24 patients (10 patients with a history of VF and 14 patients with syncope from highly suspected arrhythmic causes) were not analysed because large cohort studies have clearly shown that symptomatic BrS patients have a worse prognosis than asymptomatic BrS.3,4 Clinical characteristics such as age, sex, SCN5A mutation carriership, family history of SCD, body temperature during fever, therapy (implantable cardioverter defibrillator [ICD], pacemaker, quinidine) were also assessed. Structural heart disease was excluded with conventional diagnostic methods including treadmill test, echocardiogram and/or cardiac magnetic resonance imaging. Patients were followed in the outpatient clinic on a regular basis (once every 3-24 months) or whenever clinical circumstances required unscheduled visits. After the first visit to the referral centres, some patients were instructed to take antipyretics when they had fever. At each visit, follow-up data (including ECGs) were collected. All patients provided written informed consent to research, which was approved by the Human Research Ethics Committee in each centre. The effects of fever and drug-challenge on ECG parameters By study design, all patients had at least one ECG showing type1 ECG recorded during fever, documented either at the first visit to a hospital or at follow-up. ECGs (12 leads and V1, V2 in the 3rd and 2nd intercostal space [IC]) at baseline, in the absence of fever, and after drug-challenge were additionally provided when available. Three ECGs (baseline, fever and drug-challenge) were available in total in 52/112 patients, including both symptomatic and asymptomatic patients. ECGs were digitalized and manually measured on a computer screen using ImageJ (http://imagej.nih.gov/ij/) (YM). ECG parameters measured were heart rate (HR), PR interval, QRS duration, QT interval, QTc (Bazett’s formula) in lead II or V5, ST elevation in lead V1 and V2 in the 4th intercostal space, ΔPR(fever) (=PR interval during fever minus PR interval at baseline), ΔPR(drug) (=PR interval after 5
drug minus PR interval at baseline), ΔQRS(fever) (=QRS duration during fever minus QRS duration at baseline), and ΔQRS(drug) (=QRS duration after drug minus QRS duration at baseline). S-type1 was defined as spontaneously manifesting type1 ECG recorded at baseline or at follow-up (but in the absence of fever), F-type1 as type1 ECG during fever, and D- type1 as type1 ECG during drugchallenge. A drug-challenge was terminated before the full dose was given when type1 ECG was evoked or when excessive QRS prolongation or any ventricular arrhythmias were observed. Statistical analysis Statistical analyses were conducted using SPSS Statistics 23.0. Continuous variables are presented as mean±standard deviation and categorical variables as percentage. Paired t-test was used for comparing ECG parameters in three different conditions. P value of <0.05 was considered statistically significant.
Results The clinical characteristics of asymptomatic patients with F-type1 ECG The clinical characteristics of the 88 asymptomatic patients with F-type1 are summarized in Table 1. The mean age was 45.8±18.7 years, and 76.1% (67/88) were men. Eighty-six patients developed fever as outpatients while 2 cases developed fever during hospitalization (one patient in a post-partum period, and one after an electrophysiological study). Body temperature during fever was 38.9±0.8 °C (range 37.0-40.2). In 80/88 patients (90.9%), BrS was diagnosed because of F-type1 ECG (Fig.2). ECG was recorded by chance in 77/80 patients during a diagnostic evaluation of fever and accompanying symptoms (e.g., chest pain, worsening of general condition, conditions necessitating surgery). In a minority of the cases (3/80 patients), positive family history of BrS and/or family history of SCD prompted the physician to record an ECG during fever.
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F-type1 was documented at follow-up in 8/88 patients (Fig.2). One patient was already known with BrS because S-type1 was documented previously in the absence of fever. Five patients showed non-diagnostic BrS ECG at first medical contact, and drug-challenge induced D-type1, confirming the diagnosis BrS. Two patients were referred because of a family history of SCD. BrS was diagnosed either with S-type1 (one patient) or with D-type1 (one patient). On the whole, 18 patients had a family history of SCD (20.5%). A pathogenic mutation in the SCN5A gene was identified in 14/53 patients tested (26.4%). During diagnostic work-up, drugchallenge was additionally performed in some patients who were already diagnosed with BrS by Ftype1 or S-type1. In total, 36 asymptomatic patients underwent drug-challenge; this was positive in 29 patients (80.6%). Drugs used for drug-challenge were ajmaline (1mg/kg, n=24), pilsicainide (1mg/kg, n=7), or flecainide (2mg/kg, n=5). The false-negative rate of drug-challenge (vs. F-type1) was higher with flecainide (20.0%) and ajmaline (20.8%) than with pilsicainide (14.3%). Three patients were treated with ICD, one with quinidine and two with pacemakers because of concomitant sick sinus syndrome. Outcome of asymptomatic patients with F-type1 During a follow-up period of 43.6±37.4 months, three male patients (3.4%) developed arrhythmic events (ICD shock [n=1] and cardiac arrest [n=2]). The risk of VF in asymptomatic patients with F-type1 was 0.9%/year overall (3/88, 43.6±37.4 months), and 1.1%/year in men (3/67, 48.8±41.1 months). Among the three patients, one event occurred during fever. It could not be confirmed whether this was the case in the remaining two patients (Table 2). Effects of fever and drug-challenge on ECG parameters ECGs at baseline, during fever and after drug-challenge were available for analysis in 52/112 patients. ECG parameters were measured and compared between different conditions (Table 3). At baseline, the mean ST segment elevation in the 4th IC was 0.08±0.11 mV in V1, and 0.15±0.15 mV in
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V2. During fever, ST-segment was elevated to 0.26±0.14 mV in V1, and 0.39±0.26 mV in V2. After drug-challenge, ST elevation was 0.18±0.16 mV in V1, and 0.32±0.26 mV in V2. In order to study whether fever-induced and drug-induced ST elevation in the right ventricular outflow tract (RVOT) area was different, we included all available right precordial leads of the 4th 2nd IC for further analysis. The 4th - 2nd IC were analysed in 67.3% (35/52) during drug-challenge, and 15% (8/52) during fever. The maximal coved-type ST elevation (type1 or type3)16 in any right precordial lead was significantly higher during fever (0.41±0.21 mV) or after drug-challenge (0.40±0.30 mV) than at baseline (0.03±0.14 mV, P<0.01, Figure 3), but not significantly different between fever and drug-challenge (P>0.05). However, type1 ECG occurred in different leads during fever or drug-challenge. D-type1 occurred in the 4th IC in 78.0% (32/41 patients with positive drugchallenge), while it occurred only in the 3rd - 2nd IC in 22.0% (9/41). In 41 patients with positive drugchallenge, F-type1 occurred in the 4th IC in 97.6% (40/41), while only one patient required leads in the 3rd - 2nd IC to detect F-type1. There was no positive correlation observed between body temperature and the level of ST elevation, or between body temperature and the difference of ST elevation (ST elevation during fever minus ST elevation at baseline). During fever, HR was significantly faster than at baseline (96±31 bpm vs. 71±13 bpm, P<0.01), while PR (148±45ms) and QT interval (302±85 ms) were shorter than at baseline (169±29 ms and 367±31 ms, respectively, P<0.01). QRS was not significantly different from baseline (92±28 vs. 97±18 ms, P>0.05). Drug-challenge resulted in significantly longer PR (202±35 ms), QRS (117±21 ms), QT (386±37 ms) and QTc (435±30 ms) compared to baseline (P<0.01). In summary, while ST-segment in V1 and V2 were elevated similarly during fever and after drug-challenge, response of PR and QRS to fever and drug-challenge was different. PR and QRS did not prolong in response to fever (ΔPR[fever] -10±16 ms, ΔQRS[fever] 1.7±14 ms). Whereas PR and
8
QRS prolonged in response to sodium channel blockers (ΔPR[drug] 34± 23 ms, ΔQRS[drug] 20± 18 ms).
Discussion F-type1 was initially considered an ominous sign because of initial reports from small series of patients who presented with VF during fever.13,14 However, this could represent selection bias, and no study so far has collected a substantial BrS cohort to establish the prognostic value of F-type1. In the present study cohort, the largest of its kind, it was demonstrated that asymptomatic patients with Ftype1 indeed carry a risk of SCD. As expected, the risk of arrhythmic events among patients with Ftype1 was affected by the clinical presentation: the event rate was 3.0%/year in patients with a history of VF, 1.3%/year in patients with a history of syncope (Fig. 2; details are not shown in Results) and 0.9%/year in asymptomatic patients. The event rate in asymptomatic patients seems comparable to the rates reported for initially asymptomatic patients with S-type1 (0.5-0.8%/year) and higher than for asymptomatic D-type1 patients (0-0.35%/year),3,4,7-11 although we realize that our cohort might be still too small to allow such a comparison. Our results seemingly contrasts with a previous study by Adler et al.12, in which no arrhythmic events in 8 individuals incidentally diagnosed with BrS through Ftype1 were reported (follow-up 30 months). Differences in a priori risk may play a role here with a high a priori risk of our BrS cohort, and a low a priori risk in the general population in the study of Adler et al.12 The question remains how much F-type1 itself contributes to arrhythmia risk. In our cohort, because of its retrospective nature, the outcome of F-type1 could have been overestimated due to concealed S-type1 which was simply not detected by chance, even though patients were followed at regular basis in outpatient clinics. On the other hand, the outcome could have been underestimated because some patients were instructed to take antipyretics immediately after a febrile episode. Our study was also limited by the rarity of BrS patients showing F-type1 ECG, and lack of controls without F-type1. To appropriately assess the risk of F-type1, worldwide collaboration to build a large BrS database will be required. 9
In this study, ECGs in three different conditions (baseline, fever and drug-challenge) were compared in a subpopulation of our cohort to find any relevant ECG markers related to fever in BrS. Surprisingly, the effect of fever was different from drug-challenge. Fever affected RVOT focally to elevate ST-segment, but did not prolong PR and QRS as drug-challenge does. One possible explanation is that fever has less sodium channel blocking effect than drugs. RVOT has developmentally lower protein Nav1.5 and connexin43 levels compared to right ventricle or left ventricle, causing lower conduction reserve.17,18 Subtle decrease of the sodium currents may be enough to induce F-type1 while PR and QRS are not affected because of increased conduction reserve. Alternatively, other yet unknown factors related to acute infection or increased temperature are involved in F-type1. Another interesting observation was that F-type1 and D-type1 occurred in different area of RVOT: in the 41 patients who showed both F-type1 and D-type1, F-type1 occurred in the 4th IC in the majority(97.6%), while D-type1 was induced in different area of RVOT (78% in the 4th IC and 22 % in 2nd-3rd IC only). Because of lack of complete recordings of all RVOT leads during fever/drugchallenge, we could not analyse fully the extent of type1 ST-elevation in RVOT. Future studies should adress this issue by using all right precordial leads in the 4th-2nd IC to study the extent of STelevation during fever and mechanisms behind this phenomenon. With regard to discrepant manifestation of type1 BrS ECG during fever and drug-challenge in the same patients, so far in literature, one case report has reported that fever unmasked type1 ECG, while a flecainide test failed to do so.19 In our cohort, only 29 out of 36 asymptomatic patients (80.6 %) tested were positive during drug-challenge. This suggests that drug-challenge may be less sensitive to unmask type1 ECG than fever. It is important to note, however, that these results were influenced by electrode position (in 2nd and 3rd IC), and types and dosage of drugs used for drugchallenge. The higher false-negative rates of drug-challenge (vs. F-type1) with flecainide and ajmaline (compared to pilsicainide) may be determined by different cardiac ion channel blocking effects of these drugs. While pilsicainide is a pure sodium channel blocker, which may evoke a 10
maximum ST elevation, flecainide and ajmaline also block the transient outward potassium current as well as the delayed rectifier potassium current at clinical concentrations.20-22 Aggregated decrease of the potassium currents may counterbalance the decrease in sodium currents by these drugs, and eventually lead to a lower ST elevation. Although this study did not specifically aim at evaluating the sensitivity and specificity of fever or drug-challenge in the context of BrS diagnosis, the discrepant manifestation of F-type1 and D-type1 in the same patients is intriguing and remains to be addressed in future studies.
Limitations Collecting BrS patients with F-type1 was hampered by the rarity of F-type1. To increase the number of cases with F-type1 as much as possible, patients were collected from large referral centres worldwide where BrS patients are advised to visit a medical facility to record at least one ECG during fever before antipyretics are given. Because it is recommended to treat fever immediately with antipyretic agents in all BrS patients1, F-type1 may be missed nowadays. Owing to our strict instructions to treating physicians to record an ECG during fever in BrS patients before any antipyretics use, we were able to collect the largest population so far with F-type1. Therefore, we believe that our findings certainly add clinically relevant insights to patients with BrS and in particular to those with fever-induced BrS. Although the protocol of drug-challenge testing is standardized in general, the types and dosage of sodium channel blocking drugs used were different between centres due to the retrospective nature of this study. Also, the use of electrode placement in the 3rd-2nd IC was different. These factors could play a role in the outcome. Future studies should address if /why fever is indeed more sensitive to unmask type1 ECG compared to sodium channel blockers by collecting a large BrS cohort worldwide with detailed information, including a standardized drug-challenge protocol.
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Conclusions BrS patients diagnosed with F-type1 are at risk of arrhythmic events. F-type1 appears to occur through a more complex mechanism compared with D-type1.
Acknowledgements Y.M., H.T. and A.M. were supported by the Netherlands CardioVascular Research Initiative": the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences. H.M. is affiliated with the endowed department by Japan Medtronic Inc., and was supported by JSPS KAKENHI (24591051 and 15K09082) and by the Ministry of Health, Labor and Welfare of Japan for Clinical Research on Intractable Diseases (H24-033, H26-040). D.W.W. was supported by National Natural Science Foundation of China (project No. 81170159) and by
National Key Basic Research Program of China (973 Program)(No. 2013CB531105). C.A. was supported by NHLBI grant HL HL47678.
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Figure titles and legends Fig. 1. Fever-induced type1 BrS ECG and VF ECGs of a 50-year old man admitted with acute gastroenteritis (body temperature 38.7°C) and repetitive syncopal episodes. During fever, fever-induced type1 BrS ECG with a ventricular extrasystole (A) and successive VF (B) was recorded. When fever subsided, ECG changed to type2 BrS ECG (C).
Fig. 2. Characteristics of diagnostic ECG and events at follow-up Of 112 patients, 95 patients were admitted with F-type1. The remaining 17 patients were already known with BrS (by either S-type1 or D-type1) and showed F-type1 at follow-up. There were 88 asymptomatic patients. Three of them had SCD or VF at follow-up. Two patients with a history of VF and one patient with a history of syncope experienced VF at follow-up. D-type1=drug-induced type1
15
BrS ECG; F-type1=fever-induced type1 BrS ECG; SCD=sudden cardiac death; S-type1=spontaneous type1 BrS ECG; VF=ventricular fibrillation.
Fig.3. Maximal ST-segment elevation at baseline, during fever and after drug-challenge. The maximal coved–type ST-segment elevation (type1 or 3)16 in any right precordial lead was significantly higher during fever (0.41±0.21 mV) and after drug-challenge (0.40±0.30 mV) than at baseline (0.03±0.14 mV, *P<0.01 for baseline vs. fever and baseline vs. drug, P>0.05 for fever vs. drug).
16
Table 1. Clinical characteristics of 88 asymptomatic BrS patients with F-type1.
N=88 Males, n (%)
67 (76.1)
Age, years
45.8±18.7
F-type1, n (%)
88 (100)
at diagnosis
80 (90.9)
at follow-up
8 (9.1)
Body temperature during fever, °C
38.9±0.8
Family history of SCD, n (%)
18 (20.5)
SCN5A mutation carriers, n (%)
14/53 (26.4)
Drug-challenge positive, n (%)
29/36 (80.6)
Treatment, n (%) ICD
3 (3.4)
Quinidine
1 (1.1)
Pacemaker
2 (2.3)
Follow-up, months
43.6±37.4
17
Table 2. Asymptomatic patients with events at follow-up At diagnosis
Fev er,
SCN5 A mutati on
Sympt om
39, M
No sympt om
No
S
P
No
No
47, 2 M
No sympt om
39.0
F
P
No
27, 3 M
No sympt om
38.9
F
P
No
1
Drugchalle nge
Fami ly histo ry of SCD
Ag e, sex
°C
BrS diagno sis
Events at follow-up Total follo wup, Sympt om
°C
Ftyp e1
ICD
VF
37.0 (axilla ry)
Y
141
No
No
SCD
No
NA
10
No
No
SCD
NA
NA
75
Fever, treatm ent
D=drug-induced type1 ECG; F=fever-induced type1 ECG; ICD=implantable cardioverter defibrillator; M=male; NA=not available; P=positive; S=spontaneous type1 ECG; SCD=sudden cardiac death; VF=ventricular fibrillation; Y=yes.
18
mont hs
Table 3. ECG parameters at baseline, during fever and after drug-challenge. Baseline Fever Drug-challenge 71±13 96±31 78±14 HR 169±29 148±45 202±35 PR -10±16 34±23 ΔPR 97±18 92±28 117±21 QRS 0.7±14 20±18 ΔQRS 367±31 302±85 386±37 QT 395±23 380±104 435±30 QTc 0.08±0.11 0.26±0.14 0.18±0.16 ST elevation in V1 0.15±0.15 0.39±0.26 0.32±0.26 ST elevation in V2 ΔPR presents the extent of PR prolongation from PR(Baseline). ΔQRS presents the extent of QRS prolongation from QRS(Baseline). P<0.01 for all paired t-test except QRS(Baseline) vs. QRS(Fever), QTc(Baseline) vs. QTc(Fever) and ST elevation(Fever) vs. ST elevation(Drug-challenge) in V2 (P>0.05).
19
Figure 3
0.80
* *
0.70 0.60
mV
0.50 0.40 0.30
0.20
0.03±0.14
0.41±0.21
0.40±0.30
Baseline
Fever
Drug-challenge
0.10 0.00
20