- Email: [email protected]
What is new in Brugada syndrome?
cor et vasa 55 (2013) e525–e532
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/crvasa
Review Article
What is new in Brugada syndrome? Ondrˇej Bolekn, Dan Marek, Milosˇ Ta´borsky´ Department of Internal Medicine – Cardiology, The University Hospital Olomouc, I.P.Pavlova 6, 775 20 Olomouc, Czech Republic
art i cle i nfo
ab st rac t
Article history:
The Brugada syndrome (BrS) and the long QT syndrome are the most frequently diagnosed
Received 28 February 2013
genetically-conditioned arrhythmogenic syndromes. It is a primary disorder of electric cardiac
Received in revised form
activity which is demonstrated by elevation of the ST segment in the right precordial leads
11 September 2013
connected to an increased risk of sudden death in patients without a structural damage of the
Accepted 16 September 2013
heart. In this article, an overview of genetic heterogeneity, pathophysiology, ECG diagnostics
Available online 21 September 2013
and therapy possibilities are discussed, including the innovations of the recent years. A brief
Keywords:
case report of a patient presenting with syncope and ST segment elevation is described.
Brugada syndrome
& 2013 The Czech Society of Cardiology. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Arrhythmia Sudden cardiac death ST-segment elevation Channelopathies
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic heterogeneity and pathophysiology . . . Clinical features. . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential diagnosis. . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case report: syncope in a patient with Brugada ventricular tachycardia . . . . . . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.
................................. ................................. ................................. ................................. ................................. ................................. syndrome with a telemetry-documented ................................. ................................. ................................. .................................
Introduction
The Brugada syndrome (BrS) was named after two Spanish brothers – cardiologists Pedro, Josep Brugara, who is the
........... ........... ........... ........... ........... ........... polymorphic ........... ........... ........... ...........
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. . . . . .
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. . . . . .
. . . . . .
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. 525 . 526 . 527 . 527 . 528 . 528
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specialist in Cardiac Arrhythmias, General Cardiology, Cardiovascular Diseases and Sports Cardiology. The third man on the photo is their brother Ramon Brugada who cooperated with them in many studies and was appointed to be Director
n
Corresponding author. Tel.: þ420 608 829 217. E-mail address: [email protected] (O. Bolek).
0010-8650/$ - see front matter & 2013 The Czech Society of Cardiology. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. http://dx.doi.org/10.1016/j.crvasa.2013.09.003
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cor et vasa 55 (2013) e525–e532
of the Cardiovascular Genetics Center at the University of Girona, Spain (Fig. 1). The syndrome is characterized by abnormal electrocardiogram (ECG) findings and an increased risk of sudden cardiac death (Fig. 2) [1,2]. The Brugada syndrome was first found and reported among survivors who suffered cardiac arrest in 1989 [3]. In 1992, Brugadas described a crucial work dealing with a case-series of 8 patients who died a sudden cardiac death [4,5]. “The syndrome typically manifests during adulthood, with a mean age at the time of sudden death of 41715 years, but it occurs in infants and children also” [6]. BrS is the most common cause of sudden death of young ;Thai men without previously known cardiac disease [5]. Worldwide
Fig. 1 – The three brothers, cardiologists Pedro, Josep and Ramon Brugada (with the consent of Brugada R.).
prevalence of BrS is E1 in 10,000, but it is much higher in Asian countries, reaching 5–10 in 10,000 [6,7].
2.
Genetic heterogeneity and pathophysiology
Approximately 20% of the cases of the Brugada syndrome have been associated with mutations in the gene SCN5A [8] which encoding forming the α-subunit of the cardiac sodium channel (hNav1.5). (Fig. 3) that encodes the sodium ion channel in the cell membranes – the myocytes [9]. A location of this gene is on the short arm of the third chromosome (3p21) [10]. This gene contains mutations which might lead to a loss of the action potential dome of some epicardial areas of the right ventricle, which in turn results in transmural and epicardial dispersion of repolarization. The transmural dispersion is responsible for the ST-segment elevation and also the development of a vulnerable window in the ventricular wall, while the epicardial dispersion of repolarization lies behind the development of phase 2 reentry, which generates a phase 2 reentrant extrasystole. An extrasystole captures the vulnerable window to precipitate ventricular tachycardia and/or fibrillation that often results in sudden cardiac death [11]. So far over 160 mutations in the SCN5A gene have been discovered. Each of them has different ways of functioning and affecting the organism, which explains an expression of this disorder and the varying degrees of penetration [12,13]. Antzelevitch has recently identified mutations in the L-type calcium channel subunits (CACNA1C (A39V and G490R) and CACNB2 (S481L)) which lead to ST elevation and a relatively short QT interval (below 360 ms) [14]. This
Fig. 2 – Brugada syndrome type 1. One of the first ECG strip where Mr. Brugada described Brugada syndrome, courtesy of Dr.Číhalík.
cor et vasa 55 (2013) e525–e532
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H. Liu et al. recently report the study of genetic and functional anomalies of mutations in the TRPM4 gene, which code the transient receptor potential cation channel subfamily M member 4 (hTRPM4), known as melastatin-4, the gene is located on chromosome 19 (19q13.33) [20,21]. It is a calciumactivated nonselective cation channel and has been recently found in families with progressive cardiac conductance disturbances [22]. The results of study suggest that TRPM4 mutations accounts for about 2.7–6% of BrS cases. Surprising is that mutations in TRPM4 not only leads to reduction and loss of current density, but in some cases to increase its effectiveness [20]. The situation is complicated by the fact that TRPM4 is expressed in various tissues and can affect the neuro-hormonal regulation or cardiac development [23,24].
3.
Fig. 3 – Location of the gene SCN5A in the third chromosome. (Freely redrawn according to Dr. Jonas de Jong's picture http:// en.ecgpedia.org/wiki/File:Scn5a.jpg).
mutation is inherited in an autosomal dominant pattern and is more frequently found in males mainly in Asian populations. Ishikawa et al. (in 5/2012) discovered a new pathogenic substrate for BrS. They tested significance of the identified mutations of sarcolemmal membrane–associated protein (SLMAP), which is one of components of T-tubules and sarcoplasmic reticulum. Their right cooperation is necessary for a good contraction of cardiomyocytes [15,16] Abnormalities in these components can cause ventricular arrhythmias [17–19]. The disease-associated SLMAP mutations (they identified 2 SLMAP missense mutations associated with BrS) do not affect the voltage dependence in inactivation or activation profiles, do not biophysically alter the hNav1.5 channel gating, but impaired the cell surface expression of hNav1.5 and reduced the inward sodium current in transfected cells and BrS susceptibility [15].
Clinical features
The complete syndrome is characterized by episodes of fast polymorphic ventricular tachycardia (VT) (Fig. 4) in patients with an electrocardiogram showing a pattern of right bundle branch block and ST segment elevation in leads V1 to V3. If only a short VT occurs, the patient may experience either vertigo or syncope. If the VT is long lasting or ventricular fibrillation (VF) develops, cardiac arrest or sudden death may be a sequelae [25]. In 2012 Jeevaratnam et al. published the results of their study “Frequency distribution analysis of activation times and regional fibrosis in murine Scn5a(þ/ ) hearts: The effects of ageing and sex”. They found a greater occurrence of the bundle branch block in all Scn5a(þ/ ) mice compared to wildtype mice which directly correlated with histomorphometric assessment of regional fibrosis in both septa and free walls, preferentially involving the RV. This was further modified by aging and sex [26]. Priori et al. published an overview of 130 patients with Brugada syndrome and 70 affected family members. Overall, SCN5A mutations were identified in 28 probands; the remaining individuals fulfilled accepted diagnostic ECG criteria. Multivariate Cox regression analysis showed that, after adjusting for sex, a family history of sudden cardiac death, and mutation in SCN5A, the cooccurrence of spontaneous ST segment elevation in the anterior chest leads of a resting 12-lead ECG and a personal history of syncope identified persons at risk for cardiac arrest [27]. Chockalingam showed that fever and vaccination in children may be potential arrhythmia triggers. One of the most common finding on ECG is a conduction delay [28].
4.
Diagnosis
It is possible to diagnose the disease by observing characteristic patterns on an electrocardiogram. BrS has 3 different ECG patterns. Type 1 is characterized by a prominent coved STsegment elevation displaying J wave amplitude or ST-segment elevation Z2 mm or 0.2 mV at its peak followed by a negative T-wave. There is no isoelectric separation. The type 2 is characterizes also by elevation of ST segment, which is descendent, followed by a positive or biphasic T-wave ( a saddle back
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Fig. 4 – Case report: a polymorphic ventricular tachycardia documented on telemetric ECG tracing. configuration). Type 3 is a right precordial ST-segment elevation of o1 mm of saddle back type, coved type, or both [6,13]. According to Brugadas, the pattern that was seen on the ECG suggests persistent ST elevations in the electrocardiographic leads V1–V3 with the appearance of the right bundle branch block (RBBB) with or without the terminal S waves in the lateral leads that are usually associated with a typical RBBB. A prolonged PR interval, suggesting a conduction disturbance in the heart, can also be frequently seen. The electrocardiogram can fluctuate over time, for example—adrenergic stimulation decreases the ST segment elevation, while vagal stimulation worsens it. Second thing is the using of anti-arrhythmic drugs. The administration of class Ia (ajmaline), Ic (flecainide) and III drugs increases the ST segment elevation. ST segment elevation in some patients can be decreased by exercise but it can increase it in others (after exercise when the body temperature has come up). The changes in heart rate caused by atrial pacing are followed by changes in the degree of ST segment elevation. When heart rate drops, ST segment elevation comes up and vice versa. However, it can also occur the other way round [25]. In all patients with unexplained syncope, an electrophysiological testing should be performed with exception of those who were resuscitated for VF. In these patients, ICD implantation as a secondary prevention of sudden death is indicated as a matter of routine [5,6,27]. Genetic testing for the Brugada syndrome is available based on a blood sample analysis. This may help to confirm a diagnosis in patients potentially having the Brugada syndrome, as well as differentiate between relatives who are at risk for the disease and those who are not [13].
5.
Differential diagnosis
The differential diagnosis of Brugada syndrome is very wide, since many disease states may cause ST segment elevation in the right precordial leads in V1–3: an acute myocardial infarction, a right ventricular infarction, an acute myocarditis, an acute pulmonary embolism, the right or left bundle branch block and a left ventricular hypertrophy, the long QT syndrome, a premature depolarization syndrome, hypercalcemia, hyperkalemia, an overdose of tricyclic antidepressants, a cocaine intoxication, vitamin B1 deficiency, a mediastinal tumor compressing outflow tract of the right ventricular, Duchen's muscular dystrophy, Friedreich's ataxia [13,29].
6.
Treatment
Ventricular fibrillation or fast polymorphic ventricular tachycardia is the common cause of death in patients with the Brugada syndrome. These arrhythmias have a sudden onset without any warning. There is no treatment known that could reliably and totally prevent ventricular fibrillation in this syndrome. Implantable cardioverter-defibrillator (ICD) continuously monitors the heart rhythm and can defibrillate an individual should the VF occur. Quinidine, a Class Ia antiarrhythmic drug, has been found to decrease a number of VF episodes and to correct spontaneous ECG alterations, possibly by inhibiting Ito channels [25,30]. On the other hand, some drugs have been found to induce type-1 ECG and/or potentially fatal arrhythmias in the Brugada syndrome patients. Avoiding the use of these drugs, such as propafenone, or using them only under controlled conditions in BrS patients is strictly advised [31]. Beta blockers may be useful [28]. Priori et al. (in 2002) suggested a risk stratification scheme designed to target the use of ICD device in patients with BrS [27]. Some years later (in 2012), they reported the results of the PRogrammed ELectrical stimUlation preDictive valuE registry (PRELUDE), a large cohort of patients prospectively investigated and, where the VT or VF inducibility during programmed electrical stimulation is not predictive of arrhythmic events, on the other side the study affirmed the prognostic value of a spontaneous type I ECG and history of syncope and above that as first in time demonstrated a ventricular effective refractory period o200 ms and QRS fragmentation as independent risk indicators. These results could be basics for a new risk stratification scheme for BrS which could be useful to find the suitable patients for prophylactic implantable cardioverter defibrillator [32].
7. Case report: syncope in a patient with Brugada syndrome with a telemetry-documented polymorphic ventricular tachycardia Male patient, born in 1977, with a history of common children diseases, salmonellosis and allergy (dust, seasonal hay-fever). He was investigated at emergency department because of diarrhea. On ECG, ST segment elevation in V1–3 was
cor et vasa 55 (2013) e525–e532
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Fig. 5 – Case report: 12-lead ECG strip with ST segment elevation in V1–V3.
documented (Fig. 5). This abnormality lead to a suspicion of a heart attack and he was referred to cardiology for coronary angiogram. As the cardioselective markers were negative, the angiogram was not performed. BrS was suspected and the patient was examined when hospitalized at cardiology department and later on in clinics. Complex investigations were made including echo, which came out as normal. Magnetic resonance imaging of the heart was also scheduled. Before it was done, the patient was admitted after syncope when resting at home, with lay and professional cardiopulmonary resuscitation (CPR) performed at home. There were typical Brugada changes on ECG at the time of admission to the hospital (Fig. 6). Echo was repeated, again without any pathological finding. Neurology examination did not reveal any abnormality, as did not a brain CT. On the next day, the patient was resuscitated because of sudden recurrence of unconsciousness with a polymorphic VT documented on telemetric ECG tracing (Fig. 4). On the ECG taken 20 min after the CPR performed at the cardiology department there were again typical BrS features (Fig. 7). According to the abovementioned facts, it was clear that the syncopes were
associated with the Brugada syndrome and uncomplicated implantation of ICD was performed. The ECG changes remained of the same pattern for the rest of the follow up time. The patient was discharged from hospital without antiarrhythmic medication. He experienced 2 adequate ICD shocks during following 7 years and still without any antiarrhythmic medication. Fortunately, he remains without any significant further symptoms.
8.
Conclusion
The Brugada syndrome is a disorder with a high risk of sudden death. Therefore, it is necessary to take it into account especially in connection to differential diagnostics of syncope conditions in younger patients, who also have abnormalities of the ST segment on the ECG and the normal echocardiographic findings. Correctly diagnosed patients with an implanted cardioverter-defibrillator as the only effective form of treatment can lead a full-fledged life with
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Fig. 6 – Case report: 12-lead ECG strip with ST segment elevation in V1–V3 after the professional cardiopulmonary resuscitation.
Fig. 7 – Case report: ECG 20 min after the professional cardiopulmonary resuscitation (CPR) performed at the cardiology department.
a minimized risk of sudden death. Despite a clear indication for ICD use in patients with a history of cardiopulmonary resuscitation for ventricular fibrillation, a pharmacological
testing is recommended in all patients with a lack of clear morphological substrate, as some drugs should be avoided in BrS to decrease number of ICD shocks.
cor et vasa 55 (2013) e525–e532
Acknowledgments This article was kindly supported by Ramon Brugada M.D., who gave consent to the publication of photo of him and his brothers. The leading diagnostic specialist in the Czech Republic in the field of long QT syndrome and Brugada syndrome is MD. Tomáš Novotný Ph.D. with his team from the Department of Cardiology, University Hospital Brno Bohunice, Czech Republic. This department has many years of experience backed by many studies, grants and new discoveries in the field of cardiology. If there is a suspicion of long QT syndrome or other channelopathies, the team may be contacted either by phone 532232980 or email mailto:tomnov@ yahoo.com.
r e f e r e n c e s
[1] K. Nademanee, G. Veerakul, S. Nimmannit, et al., Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men, Circulation 96 (1997) 2595–2600. [2] M. Vatta, R. Dumaine, G. Varghese, et al., Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome, Human Molecular Genetics 11 (2002) 337–345. [3] B. Martini, A. Nava, G. Thiene, et al., Ventricular fibrillation without apparent heart disease: description of six cases, American Heart Journal 118 (1989) 1203–1209. [4] P. Brugada, J. Brugada, Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report, Journal of the American College of Cardiology 20 (1992) 1391–1396. [5] J. Brugada, P. Brugada, R. Brugada, The syndrome of right bundle branch block ST segment elevation in V1 to V3 and sudden death-the Brugada syndrome, Europace 1 (1999) 156–166. [6] C. Antzelevitch, P. Brugada, M. Borggrefe, et al., Brugada syndrome: report of the second consensus conference [Erratum: Circulation 112 (2005) e74], Circulation 111 (2005) 659–670. [7] Y. Miyasaka, H. Tsuji, K. Yamada, et al., Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan, Journal of the American College of Cardiology 38 (2001) 771–774. [8] F. Potet, P. Mabo, G. Le Coq, et al., Novel Brugada SCN5A mutation leading to ST-segment elevation in the inferior or the right precordial leads, Journal of Cardiovascular Electrophysiology 14 (2003) 200–203. [9] M. Chaturvedi, A. Pandey, A. Patel, et al., Brugada syndrome revisited, Journal of Indian Academy of Clinical Medicine 12 (2011) 28–31. [10] P.G. Meregalli, A.A. Wilde, HL. Tan, Pathophysiological mechanisms of Brugada syndrome: depolarisation disorder, repolarisation disorder, or more?, Cardiovascular Research 67 (3) (2005) 367–378. [11] C. Antzelevitch, Late potentials and the Brugada syndrome, Journal of the American College of Cardiology 39 (2002) 1996–1999 〈http://medind.nic.in/jac/t11/i1/jact11i1p28.pdf〉. [12] PL. Hedley, P. Jorgensen, S. Schlamowitz, et al., Brugada syndrome, Human Mutation 30 (2009) 1256–1266.
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[13] R. Brugada, O. Campuzano, P. Brugada, et al., Brugada Syndrome, GeneReviews™ Seattle (WA), Overview of Brugada Syndrome Genetic Testing, University of Washington, Seattle, 1993–2005 Mar 31, PMID: 20301690, 〈www.ncbi.nlm.nih.gov/bookshelf/br.fcgi? book=gene&part=brugada〉 (updated 2012 Aug 16). [14] C. Antzelevitch, Genetic basis of Brugada syndrome, Heart Rhythm 4 (2007) 756–757. [15] T. Ishikawa, A. Sato, Ch.A. Marcou, et al., A novel disease gene for Brugada syndrome sarcolemmal membrane– associated protein gene mutations impair intracellular trafficking of hNav1.5, Circulation: Arrhythmia and Electrophysiology 5 (2012) 1098–1107. [16] F. Brette, C. Orchard, T-tubule function in mammalian cardiac myocytes, Circulation Research 92 (2003) 1182–1192. [17] S.G. Priori, C. Napolitano, N. Tiso, et al., Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia, Circulation 103 (2001) 196–200. [18] N. Tiso, D.A. Stephan, A. Nava, et al., Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2), Human Molecular Genetics 10 (2001) 189–194. [19] H. Lahat, E. Pras, T. Olender, et al., A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel, American Journal of Human Genetics 69 (2001) 1378–1384. [20] H. Liu, S. Chatel, C. Simard, N. Syam, L. Salle, et al., Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel, PLoS ONE 8 (1) (2013) e54131. [21] O. Campuzano, C. Allegue, A. Iglesias, R. Brugada, Genetic basis of Brugada syndrome, Journal of Genetic Syndromes & Gene Therapy 4 (2013) 167. [22] B. Stallmeyer, S. Zumhagen, I. Denjoy, et al., Mutational spectrum in the Ca(2þ)—activated cation channel gene TRPM4 in patients with cardiac conductance disturbances, Human Mutation 33 (1) (2012) 109–117. [23] B. Nilius, G. Owsianik, The transient receptor potential family of ion channels, Genome Biology 12 (2011) 218. [24] I. Mathar, R. Vennekens, M. Meissner, et al., Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice, Journal of Clinical Investigation 120 (2010) 3267–3279. [25] 〈www.brugada.org/about/disease-diagnosis.html〉. [26] K. Jeevaratnam, R. Rewbury, Y. Zhang, et al., Frequency distribution analysis of activation times and regional fibrosis in murine Scn5a(þ/ ) hearts: the effects of ageing and sex, Mechanisms of Ageing and Development 133 (2012) 591–599. [27] S.G. Priori, C. Napolitano, M. Gasparini, et al., Natural history of Brugada syndrome: insights for risk stratification and management, Circulation 105 (2002) 1342–1347. [28] P. Chockalingam, S.A. Clur, JM. Breur, The diagnostic and therapeutic aspects of loss-of-function cardiac sodium channelopathies in children, Heart Rhythm 9 (2012) 1986–1992. [29] S. Krištofová, K. Dvořák, Brugadův syndrom jako příčina náhlého úmrtí, Intervenční a akutní kardiologie 3 (2004) 79–82. [30] B. Belhassen, A. Glick, S. Viskin, et al., Efficacy of quinidine in high-risk patients with Brugada syndrome, Circulation 110 (2004) 1731–1737.
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[31] P.G. Postema, C. Wolpert, AS. Amin, et al., Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org), Heart Rhythm 6 (2009) 1335–1341.
[32] S.G. Priori, M. Gasparini, C. Napolitano, et al., Risk Stratification in Brugada Syndrome Results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) Registry, Journal of the American College of Cardiology 59 (1) (2012) 37–45.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/crvasa
Review Article
What is new in Brugada syndrome? Ondrˇej Bolekn, Dan Marek, Milosˇ Ta´borsky´ Department of Internal Medicine – Cardiology, The University Hospital Olomouc, I.P.Pavlova 6, 775 20 Olomouc, Czech Republic
art i cle i nfo
ab st rac t
Article history:
The Brugada syndrome (BrS) and the long QT syndrome are the most frequently diagnosed
Received 28 February 2013
genetically-conditioned arrhythmogenic syndromes. It is a primary disorder of electric cardiac
Received in revised form
activity which is demonstrated by elevation of the ST segment in the right precordial leads
11 September 2013
connected to an increased risk of sudden death in patients without a structural damage of the
Accepted 16 September 2013
heart. In this article, an overview of genetic heterogeneity, pathophysiology, ECG diagnostics
Available online 21 September 2013
and therapy possibilities are discussed, including the innovations of the recent years. A brief
Keywords:
case report of a patient presenting with syncope and ST segment elevation is described.
Brugada syndrome
& 2013 The Czech Society of Cardiology. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Arrhythmia Sudden cardiac death ST-segment elevation Channelopathies
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic heterogeneity and pathophysiology . . . Clinical features. . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential diagnosis. . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case report: syncope in a patient with Brugada ventricular tachycardia . . . . . . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.
................................. ................................. ................................. ................................. ................................. ................................. syndrome with a telemetry-documented ................................. ................................. ................................. .................................
Introduction
The Brugada syndrome (BrS) was named after two Spanish brothers – cardiologists Pedro, Josep Brugara, who is the
........... ........... ........... ........... ........... ........... polymorphic ........... ........... ........... ...........
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. 525 . 526 . 527 . 527 . 528 . 528
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. 528 . 529 . 531 . 531
specialist in Cardiac Arrhythmias, General Cardiology, Cardiovascular Diseases and Sports Cardiology. The third man on the photo is their brother Ramon Brugada who cooperated with them in many studies and was appointed to be Director
n
Corresponding author. Tel.: þ420 608 829 217. E-mail address: [email protected] (O. Bolek).
0010-8650/$ - see front matter & 2013 The Czech Society of Cardiology. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. http://dx.doi.org/10.1016/j.crvasa.2013.09.003
e526
cor et vasa 55 (2013) e525–e532
of the Cardiovascular Genetics Center at the University of Girona, Spain (Fig. 1). The syndrome is characterized by abnormal electrocardiogram (ECG) findings and an increased risk of sudden cardiac death (Fig. 2) [1,2]. The Brugada syndrome was first found and reported among survivors who suffered cardiac arrest in 1989 [3]. In 1992, Brugadas described a crucial work dealing with a case-series of 8 patients who died a sudden cardiac death [4,5]. “The syndrome typically manifests during adulthood, with a mean age at the time of sudden death of 41715 years, but it occurs in infants and children also” [6]. BrS is the most common cause of sudden death of young ;Thai men without previously known cardiac disease [5]. Worldwide
Fig. 1 – The three brothers, cardiologists Pedro, Josep and Ramon Brugada (with the consent of Brugada R.).
prevalence of BrS is E1 in 10,000, but it is much higher in Asian countries, reaching 5–10 in 10,000 [6,7].
2.
Genetic heterogeneity and pathophysiology
Approximately 20% of the cases of the Brugada syndrome have been associated with mutations in the gene SCN5A [8] which encoding forming the α-subunit of the cardiac sodium channel (hNav1.5). (Fig. 3) that encodes the sodium ion channel in the cell membranes – the myocytes [9]. A location of this gene is on the short arm of the third chromosome (3p21) [10]. This gene contains mutations which might lead to a loss of the action potential dome of some epicardial areas of the right ventricle, which in turn results in transmural and epicardial dispersion of repolarization. The transmural dispersion is responsible for the ST-segment elevation and also the development of a vulnerable window in the ventricular wall, while the epicardial dispersion of repolarization lies behind the development of phase 2 reentry, which generates a phase 2 reentrant extrasystole. An extrasystole captures the vulnerable window to precipitate ventricular tachycardia and/or fibrillation that often results in sudden cardiac death [11]. So far over 160 mutations in the SCN5A gene have been discovered. Each of them has different ways of functioning and affecting the organism, which explains an expression of this disorder and the varying degrees of penetration [12,13]. Antzelevitch has recently identified mutations in the L-type calcium channel subunits (CACNA1C (A39V and G490R) and CACNB2 (S481L)) which lead to ST elevation and a relatively short QT interval (below 360 ms) [14]. This
Fig. 2 – Brugada syndrome type 1. One of the first ECG strip where Mr. Brugada described Brugada syndrome, courtesy of Dr.Číhalík.
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H. Liu et al. recently report the study of genetic and functional anomalies of mutations in the TRPM4 gene, which code the transient receptor potential cation channel subfamily M member 4 (hTRPM4), known as melastatin-4, the gene is located on chromosome 19 (19q13.33) [20,21]. It is a calciumactivated nonselective cation channel and has been recently found in families with progressive cardiac conductance disturbances [22]. The results of study suggest that TRPM4 mutations accounts for about 2.7–6% of BrS cases. Surprising is that mutations in TRPM4 not only leads to reduction and loss of current density, but in some cases to increase its effectiveness [20]. The situation is complicated by the fact that TRPM4 is expressed in various tissues and can affect the neuro-hormonal regulation or cardiac development [23,24].
3.
Fig. 3 – Location of the gene SCN5A in the third chromosome. (Freely redrawn according to Dr. Jonas de Jong's picture http:// en.ecgpedia.org/wiki/File:Scn5a.jpg).
mutation is inherited in an autosomal dominant pattern and is more frequently found in males mainly in Asian populations. Ishikawa et al. (in 5/2012) discovered a new pathogenic substrate for BrS. They tested significance of the identified mutations of sarcolemmal membrane–associated protein (SLMAP), which is one of components of T-tubules and sarcoplasmic reticulum. Their right cooperation is necessary for a good contraction of cardiomyocytes [15,16] Abnormalities in these components can cause ventricular arrhythmias [17–19]. The disease-associated SLMAP mutations (they identified 2 SLMAP missense mutations associated with BrS) do not affect the voltage dependence in inactivation or activation profiles, do not biophysically alter the hNav1.5 channel gating, but impaired the cell surface expression of hNav1.5 and reduced the inward sodium current in transfected cells and BrS susceptibility [15].
Clinical features
The complete syndrome is characterized by episodes of fast polymorphic ventricular tachycardia (VT) (Fig. 4) in patients with an electrocardiogram showing a pattern of right bundle branch block and ST segment elevation in leads V1 to V3. If only a short VT occurs, the patient may experience either vertigo or syncope. If the VT is long lasting or ventricular fibrillation (VF) develops, cardiac arrest or sudden death may be a sequelae [25]. In 2012 Jeevaratnam et al. published the results of their study “Frequency distribution analysis of activation times and regional fibrosis in murine Scn5a(þ/ ) hearts: The effects of ageing and sex”. They found a greater occurrence of the bundle branch block in all Scn5a(þ/ ) mice compared to wildtype mice which directly correlated with histomorphometric assessment of regional fibrosis in both septa and free walls, preferentially involving the RV. This was further modified by aging and sex [26]. Priori et al. published an overview of 130 patients with Brugada syndrome and 70 affected family members. Overall, SCN5A mutations were identified in 28 probands; the remaining individuals fulfilled accepted diagnostic ECG criteria. Multivariate Cox regression analysis showed that, after adjusting for sex, a family history of sudden cardiac death, and mutation in SCN5A, the cooccurrence of spontaneous ST segment elevation in the anterior chest leads of a resting 12-lead ECG and a personal history of syncope identified persons at risk for cardiac arrest [27]. Chockalingam showed that fever and vaccination in children may be potential arrhythmia triggers. One of the most common finding on ECG is a conduction delay [28].
4.
Diagnosis
It is possible to diagnose the disease by observing characteristic patterns on an electrocardiogram. BrS has 3 different ECG patterns. Type 1 is characterized by a prominent coved STsegment elevation displaying J wave amplitude or ST-segment elevation Z2 mm or 0.2 mV at its peak followed by a negative T-wave. There is no isoelectric separation. The type 2 is characterizes also by elevation of ST segment, which is descendent, followed by a positive or biphasic T-wave ( a saddle back
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Fig. 4 – Case report: a polymorphic ventricular tachycardia documented on telemetric ECG tracing. configuration). Type 3 is a right precordial ST-segment elevation of o1 mm of saddle back type, coved type, or both [6,13]. According to Brugadas, the pattern that was seen on the ECG suggests persistent ST elevations in the electrocardiographic leads V1–V3 with the appearance of the right bundle branch block (RBBB) with or without the terminal S waves in the lateral leads that are usually associated with a typical RBBB. A prolonged PR interval, suggesting a conduction disturbance in the heart, can also be frequently seen. The electrocardiogram can fluctuate over time, for example—adrenergic stimulation decreases the ST segment elevation, while vagal stimulation worsens it. Second thing is the using of anti-arrhythmic drugs. The administration of class Ia (ajmaline), Ic (flecainide) and III drugs increases the ST segment elevation. ST segment elevation in some patients can be decreased by exercise but it can increase it in others (after exercise when the body temperature has come up). The changes in heart rate caused by atrial pacing are followed by changes in the degree of ST segment elevation. When heart rate drops, ST segment elevation comes up and vice versa. However, it can also occur the other way round [25]. In all patients with unexplained syncope, an electrophysiological testing should be performed with exception of those who were resuscitated for VF. In these patients, ICD implantation as a secondary prevention of sudden death is indicated as a matter of routine [5,6,27]. Genetic testing for the Brugada syndrome is available based on a blood sample analysis. This may help to confirm a diagnosis in patients potentially having the Brugada syndrome, as well as differentiate between relatives who are at risk for the disease and those who are not [13].
5.
Differential diagnosis
The differential diagnosis of Brugada syndrome is very wide, since many disease states may cause ST segment elevation in the right precordial leads in V1–3: an acute myocardial infarction, a right ventricular infarction, an acute myocarditis, an acute pulmonary embolism, the right or left bundle branch block and a left ventricular hypertrophy, the long QT syndrome, a premature depolarization syndrome, hypercalcemia, hyperkalemia, an overdose of tricyclic antidepressants, a cocaine intoxication, vitamin B1 deficiency, a mediastinal tumor compressing outflow tract of the right ventricular, Duchen's muscular dystrophy, Friedreich's ataxia [13,29].
6.
Treatment
Ventricular fibrillation or fast polymorphic ventricular tachycardia is the common cause of death in patients with the Brugada syndrome. These arrhythmias have a sudden onset without any warning. There is no treatment known that could reliably and totally prevent ventricular fibrillation in this syndrome. Implantable cardioverter-defibrillator (ICD) continuously monitors the heart rhythm and can defibrillate an individual should the VF occur. Quinidine, a Class Ia antiarrhythmic drug, has been found to decrease a number of VF episodes and to correct spontaneous ECG alterations, possibly by inhibiting Ito channels [25,30]. On the other hand, some drugs have been found to induce type-1 ECG and/or potentially fatal arrhythmias in the Brugada syndrome patients. Avoiding the use of these drugs, such as propafenone, or using them only under controlled conditions in BrS patients is strictly advised [31]. Beta blockers may be useful [28]. Priori et al. (in 2002) suggested a risk stratification scheme designed to target the use of ICD device in patients with BrS [27]. Some years later (in 2012), they reported the results of the PRogrammed ELectrical stimUlation preDictive valuE registry (PRELUDE), a large cohort of patients prospectively investigated and, where the VT or VF inducibility during programmed electrical stimulation is not predictive of arrhythmic events, on the other side the study affirmed the prognostic value of a spontaneous type I ECG and history of syncope and above that as first in time demonstrated a ventricular effective refractory period o200 ms and QRS fragmentation as independent risk indicators. These results could be basics for a new risk stratification scheme for BrS which could be useful to find the suitable patients for prophylactic implantable cardioverter defibrillator [32].
7. Case report: syncope in a patient with Brugada syndrome with a telemetry-documented polymorphic ventricular tachycardia Male patient, born in 1977, with a history of common children diseases, salmonellosis and allergy (dust, seasonal hay-fever). He was investigated at emergency department because of diarrhea. On ECG, ST segment elevation in V1–3 was
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Fig. 5 – Case report: 12-lead ECG strip with ST segment elevation in V1–V3.
documented (Fig. 5). This abnormality lead to a suspicion of a heart attack and he was referred to cardiology for coronary angiogram. As the cardioselective markers were negative, the angiogram was not performed. BrS was suspected and the patient was examined when hospitalized at cardiology department and later on in clinics. Complex investigations were made including echo, which came out as normal. Magnetic resonance imaging of the heart was also scheduled. Before it was done, the patient was admitted after syncope when resting at home, with lay and professional cardiopulmonary resuscitation (CPR) performed at home. There were typical Brugada changes on ECG at the time of admission to the hospital (Fig. 6). Echo was repeated, again without any pathological finding. Neurology examination did not reveal any abnormality, as did not a brain CT. On the next day, the patient was resuscitated because of sudden recurrence of unconsciousness with a polymorphic VT documented on telemetric ECG tracing (Fig. 4). On the ECG taken 20 min after the CPR performed at the cardiology department there were again typical BrS features (Fig. 7). According to the abovementioned facts, it was clear that the syncopes were
associated with the Brugada syndrome and uncomplicated implantation of ICD was performed. The ECG changes remained of the same pattern for the rest of the follow up time. The patient was discharged from hospital without antiarrhythmic medication. He experienced 2 adequate ICD shocks during following 7 years and still without any antiarrhythmic medication. Fortunately, he remains without any significant further symptoms.
8.
Conclusion
The Brugada syndrome is a disorder with a high risk of sudden death. Therefore, it is necessary to take it into account especially in connection to differential diagnostics of syncope conditions in younger patients, who also have abnormalities of the ST segment on the ECG and the normal echocardiographic findings. Correctly diagnosed patients with an implanted cardioverter-defibrillator as the only effective form of treatment can lead a full-fledged life with
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Fig. 6 – Case report: 12-lead ECG strip with ST segment elevation in V1–V3 after the professional cardiopulmonary resuscitation.
Fig. 7 – Case report: ECG 20 min after the professional cardiopulmonary resuscitation (CPR) performed at the cardiology department.
a minimized risk of sudden death. Despite a clear indication for ICD use in patients with a history of cardiopulmonary resuscitation for ventricular fibrillation, a pharmacological
testing is recommended in all patients with a lack of clear morphological substrate, as some drugs should be avoided in BrS to decrease number of ICD shocks.
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Acknowledgments This article was kindly supported by Ramon Brugada M.D., who gave consent to the publication of photo of him and his brothers. The leading diagnostic specialist in the Czech Republic in the field of long QT syndrome and Brugada syndrome is MD. Tomáš Novotný Ph.D. with his team from the Department of Cardiology, University Hospital Brno Bohunice, Czech Republic. This department has many years of experience backed by many studies, grants and new discoveries in the field of cardiology. If there is a suspicion of long QT syndrome or other channelopathies, the team may be contacted either by phone 532232980 or email mailto:tomnov@ yahoo.com.
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