Texas Heart Institute Journal

Fever-Induced Brugada Syndrome in Patients with Malaria Plasmodium Falciparum

--Manuscript Draft--

Manuscript Number:

Full Title: Fever-Induced Brugada Syndrome in Patients with Malaria Plasmodium Falciparum

Article Type: Case Reports/Case Series

Corresponding Author: Jimmy Oi Santoso, MD

Universitas Indonesia
Jakarta, . INDONESIA

Corresponding Author's Institution: Universitas Indonesia

Order of Authors: Ervan Zuhri, MD

Jimmy Oi Santoso, MD

Bambang B. Siswanto

Abstract: Aims

To report a case of 49-year-old man with fever-induced Brugada Syndrome in Malaria

Falciparum.

Case Ilustration

A 49-year-old non-obese man with chief complaint of fever with chilling for 1 day. ECG
on admission revealed ST-segment elevation of >2 mm in lead V1 and V2 with T-wave
inversion and saddleback-shaped ST-T-segment in lead V3 (Figure 1). No history of
syncope or sudden death in the family. The Drike-Drupple blood examination showed
plasmodium falciparum 1-10 paracyte per large visual field in 100 large visual fields. In
emergency department, the patient got syncope, and the doctor did precordial thump
and patient woke up again. Patient got dihydroartemisinin-piperaquine QID, primaquine
TID. Patient was observed in high-care unit.

Discussion

Brugada syndrome (BS) is reported to be responsible for about 4% of all sudden

deaths and about 20% of all sudden deaths in people without structural heart disease.
Fever-induced BS are tought involving the effect of high temperature to reduce sodium
current, accelerated inactivation of sodium channels, and the loss of sodium channels
function augmented by higher temperatures leading to re-entry in phase 2 of action
potential and the development of closely coupled extrasystoles leading to VT/VF
leading sudden death or syncope.

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Appendix

Figure 1. Patient’s electrocardiogram at the time of admission in emergency department (Body’s temperature 38.5 0 Celsius)

Figure 2. ECG pattern when body’s temperature of patient was 37.4 0 Celsius

Figure 3. The mechanism of ECG pattern in BS.2

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Brugada Full Text.docx

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4 CASE REPORT
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7 Fever-Induced Brugada Syndrome in Patients with Malaria Plasmodium Falciparum
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9 Ervan Zuhri, MD 1,2, Jimmy O. Santoso, MD2, Bambang B.Siswanto3
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Department of Emergency and Critical Care, Fak Fak Hospital, West Papua, Indonesia
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Faculty of Medicine, University of Indonesia
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16 National Cardiovascular Center Harapan Kita, Faculty of Medicine Universitas Indonesia
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Author
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22 1. Name : Ervan Zuhri, MD
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24 Affiliation : Department of Emergency and Critical Care, Fak Fak Hospital, West Papua,
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26 Indonesia
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28 2. Name : Jimmy Oi Santoso, MD
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Affiliation : Faculty of Medicine Universitas Indonesia
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33 3. Name : Bambang B. Siswanto, Prof
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35 Affiliation : 3National Cardiovascular Center Harapan Kita, Faculty of Medicine
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37 UniversitasIndonesia
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Corresponding author
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44 Name : Jimmy Oi Santoso, MD
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46 Affiliation : Faculty of Medicine, Universitas Indonesia
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49 Address : Salemba 6, Central Jakarta, DKI Jakarta
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51 Email : santosojimmyoi@gmail.com
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54 Phone : +6287808760190
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 1
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6 Word count
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8 Manuscript without references: 969 words
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11 Abstract: 197 words
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13 Number of figure: 3
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Number of table: 0
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19 ABSTRACT
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21 Aims
22 To report a case of 49-year-old man with fever-induced Brugada Syndrome in Malaria
23 Falciparum.
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Case Ilustration
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26 A 49-year-old non-obese man with chief complaint of fever with chilling for 1 day. ECG on
27 admission revealed ST-segment elevation of >2 mm in lead V1 and V2 with T-wave inversion
28 and saddleback-shaped ST-T-segment in lead V3 (Figure 1). No history of syncope or sudden
29 death in the family. The Drike-Drupple blood examination showed plasmodium falciparum 1-10
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paracyte per large visual field in 100 large visual fields. In emergency department, the patient got
32 syncope, and the doctor did precordial thump and patient woke up again. Patient got
33 dihydroartemisinin-piperaquine QID, primaquine TID. Patient was observed in high-care unit.
34 Discussion
35 Brugada syndrome (BS) is reported to be responsible for about 4% of all sudden deaths and
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37 about 20% of all sudden deaths in people without structural heart disease. Fever-induced BS are
38 tought involving the effect of high temperature to reduce sodium current, accelerated inactivation
39 of sodium channels, and the loss of sodium channels function augmented by higher temperatures
40 leading to re-entry in phase 2 of action potential and the development of closely coupled
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extrasystoles leading to VT/VF leading sudden death or syncope.
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44 INTRODUCTION
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Brugada syndrome (BS) is reported to be responsible for about 4% of all sudden deaths and
47 about 20% of all sudden deaths in people without structural heart disease. BS is characterized by
48 a coved-type ST-segment elevation ≥2 mm in the right precordial leads (BS type I) and a
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50 tendency to develop malignant polymorphic ventricular arythmias that may lead to syncope or
51 cardiac arrest. BS is caused by mutations in the sodium channel. Several experimental studies
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reported that dysfunction of the mutated sodium channel can be temperature sensitive. Fever can
54 unmask or exacerbate the typical BS electrocardiogram (ECG) pattern and trigger ventricular
55 tachycardia (VT) or ventricular fibrillation (VF) leading syncope or cardiac arrest.1-7
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58 CASE ILLUSTRATION
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4 A 49-year-old non-obese man with chief complaint fever with chilling for 1 day, athralgia,
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6 myalgia, headache, and nausea but no vomitting or diarrhea. There was no chest pain or dyspnea.
7 In the history of patient and his family, there was no history of syncope, diabetes mellitus,
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9 hypertension, dyslipidemia, coronary artery disease, or sudden death. He was a smoker and
10 alcoholic man. No drug concumption before. At the time of admission in the emergency room,
11 the blood pressure was 140/80, the heart rate was 98x/minute, the respiratory rate was
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13 20x/minute, and the body’s temperature was 38.50 Celsius. The other physical examination was
14 in normal range. An ECG at the time of admission revealed ST-segment elevation of >2 mm in
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16 lead V1 and V2 with T-wave inversion and saddleback-shaped ST-T-segment in lead V3 (Figure
17 1). The results of laboratory examination show that leucocyte was 6.100/uL, haemoglobin was
18 12.4 g/dL, erythrocyte was 4.96x106/uL, hematochrite was 36%, thrombocyte was 75.000/uL
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20 with negative IgM and IgG Dengue, blood glucose was 90.6 mg/dL, and total cholesterol was 98
21 mg/dL. Drike Drupple blood examination show that there is plasmodium falciparum 1-10
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23 paracyte per large visual field in 100 large visual fields. In emergency department, the patient got
24 syncope, and the doctor did precordial thump. Patient woke up again. Patient got
25 dihydroartemisinin-piperaquine 1x4 tablet for 3 days, primaquine 1x3 tablet for 1 days. Ringer
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27 lactat intravenous fluid, paracetamol drips intravenously 4x500 mg, oxygen 3 liter per minute by
28 nasal canule, and ranitidine 2x50 mg intravenous. Patient was observed in high-care unit.
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DISCUSSION
32 There are three subtypes of BS. Only type 1 ECG pattern was diagnostic of BS, while type 2 and
33 type 3 are not diagnostic. Type 1 of BS was characterized by ST-segment elevation in >1 right
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35 precordial lead either spontaneously or following provocation. Type 1 ECG pattern in
36 conjunction with with one of the following: documented VT/VF, a family history of sudden
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cardiac death at <45 years old, coved-type ECG in family members, inducibilty of VT with
39 programmed stimulation, syncope or nocturnal agonal respiaration.1,2 BS is caused by mutations
40 in the SCN5A gene encoding the α-subunit of the voltage-gated sodium channel Nav1.5. The
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42 mechanism of ECG pattern in BS can be seen in Figure 3.1-7 The inward Na+ current and
43 transient outward K+ current made a normal spike and dome morphology in phase 1 of the
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normal action potential. If Na+ current was weak, the unopposed outward K+ current and Ca+
46 current made accentuation of the action potential notch in the RV epicardium, resulting in
47 accentuated J wave and ST segment elevation associated with the Brugada pattern. Because these
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49 changes occur in the epicardium, but not in the endocardium, they made a transmural voltage
50 gradient. The changes occur just in epicardium because the density of Kalium channel is higher
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in the epicardium than in the endocardium. The reason why ECG pattern of BS occur in the right
53 precordial lead was the high density of Kalium channel in the right ventricle. Also, the reason
54 why ECG pattern of BS occur more common in male than female was the density of Kalium
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56 channel was greater in the male than the female. 1-4
57 Arrhythmias develop because of inhomogeneous repolarization in different areas of the RV
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epicardium leading to re-entry in phase 2 of action potential and the development of closely
60 coupled extrasystoles leading to VT/VF leading sudden death or syncope.1-4
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4 Molecular mechanism underlying fever-induced ventricular arrhythmias leading syncope or
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6 cardiac arrest in patients with BS are not well understood, but some mechanism were proposed.
7 Fever-induced BS are tought involving the effect of high temperature to reduce sodium current,
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9 accelerated inactivation of sodium channels, and the loss of sodium channels function augmented
10 by higher temperatures. Other studies proposed that a high temperature could alter functional
11 expression of other specific genetic mutations.1-5
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15 Conclusion
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17 From this case, we could learn that if we met patient with syncope at febrile state, we should
18 consider Brugada Syndrome as a diagnosis.
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23 REFERENCES
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25 1. Vohra J, Rajagopala S. Update of the Diagnosis and Management of Brugada Syndrome. Heart Lung Circ
26 2015;24(12):1141-8
27 2. Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol 2006; 29(10): 1130-59.
28 3. Keller DI, Rougier JS, Kucera JP, Benammar N, Fressart V, Guicheney P, et al. Brugada syndrome and
29 fever: genetic and molecular characterization of patients carrying SCN5A mutations. Cardiovasc Res
30
31 2005;67:510-9.
32 4. Adler A, Topaz G, Heller K, Zeltser D, Ohayon T, Rozovski U, et al. Fever-induced brugada pattern: how
33 common is it and what does it mean. Heart Rhytm 2013;10:1375-82.
34 5. Khalid N, Chhabra L, Kluger J. Pyrexia-indeuced brugada phenocopy. J Ayub Med Coll Abbottabad 2015;
35 27(1).
36 6. Plunkett A, Hulse JA, Mishra B, Gill J. Variable presentation of brugada syndrome: lessons from three
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38 generations with syncope. BMJ 2003; 326:1078-9.
39 7. Niebla JG, Autonell GS, Fiol M, Luna ABD. Brugada electrocardiographic: reality or fiction? J
40 Electrocardiol 2014; 47:362-3.
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Manuscript Click here to access/download;Manuscript;Cover Letter THJ.doc

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7 Jimmy Oi Santoso
8 Faculty of Medicine, Universitas Indonesia
9 Jalan Salemba Raya 6, Jakarta, Indonesia, 10440
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14 November 13rd 2018
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18 Dear Texas Heart Institute Journal,
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We wish to submit an original research article entitled “Fever-Induced Brugada Syndrome in Patients
22 with Malaria Plasmodium Falciparum” for consideration by Texas Heart Institute Journal.
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24 We confirm that this work is original and has not been published elsewhere, nor is it currently under
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consideration for publication elsewhere.
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28 In this paper, we report a case of Brugada Syndrome Induced by Fever. This is significant because this
29 case is quite rare and has some learning points especially to tropical countries.
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32 Learning point from this case is Brugada syndrome can induced by an infection of Malaria Falciparum.
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34 Fever caused by the infection caused accelerated inactivation of sodium channels, and the loss of
35 sodium channels function augmented by higher temperatures leading to Brugada syndrome. Thus, we
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have to be aware of possibility of Brugada syndrome in patient admitted with syncope at febrile state.
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42 We have no conflicts of interest to disclose.
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Thank you for your consideration of this manuscript.
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47 Sincerely,
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49 Jimmy Oi Santoso, MD
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