Brugada Syndrome: Do We Know How They Act?
F. NACCARELLA1, C. LIYING2,5, L. SHUZHENG2, S. SDRINGOLAMARANGA3, G. LEPERA1, F. IACHETTI1, G. NACCARELLI4, D. CORRADO6, A. RAMPAZZO6, A. NAVA6, C. FELICANI1, S. DEPADOA1
Introduction
More than 90% of sudden cardiac deaths (SCD) occur in patients with a known or previously unrecognised pre-existing coronary artery disease (CAD) or cardiomyopathy. It has become evident that SCD occurs, with suffi- cient frequency, in patients with an apparently normal heart, and ventricular fibrillation (VF) may represent the first clinical sign of structural heart dis- ease that becomes manifest, only several years later, among survivors.
Different causes of SCD have been documented, mainly by genetic screening and a more accurate clinical evaluation of the group of patients suffering from so-called idiopathic VF (IVF) [1–26].
Brugada syndrome [1, 5, 10, 14–16, 21–25] has been clearly shown to be one of the most frequent causes of SCD in this context, and should be differ- entiated from other clinical conditions or cardiac diseases [7, 13, 19, 20, 22, 26]. The purpose of the present article is: (1) to clarify the ionic alterations and electrophysiological mechanisms, underlying Brugada syndrome; (2) to verify the importance of triggering factors detected by ECG and clinical events; (3) discuss the long-term outcomes of Brugada syndrome patients and their family members.
1Cardiology Department, Azienda USL Città di Bologna, Bologna, Italy;2Cardiology Department, An Zhen Hospital, Beijing, China;3Cardiology Division, Hermann Memorial Hospital, Houston, TX USA; 4NASPE-Heart Rhy thm Association International Fellowship, Bologna, Italy;5Hershey Medical School, Hershey, PA, USA;
6Istituto di Cardiologia, Facoltà di Medicina, Università di Padova, Padua, Italy
From Idiopathic Ventricular Fibrillation to Different Genetically Determined Arrhythmic Syndromes
The 1997 Consensus conference clearly defined the diagnostic requirements, – non-invasive and invasive, mandatory, highly recommended or elective – to evaluate patients surviving a cardiac arrest and their family members. In the wide group of IVF patients, Brugada syndrome is, today, clearly identifi- able [1, 5, 10, 14–16, 21–25]. Importantly, confounding factor/s, that could account for the ECG abnormality or syncope should be carefully excluded, including atypical right bundle-branch block, left ventricular hypertrophy, early repolarisation, acute pericarditis, acute myocardial ischaemia/infarc- tion, pulmonary embolism, Prinzmetal angina, dissecting aortic aneurysm, various central and autonomic nervous system abnormalities, Duchenne muscular dystrophy, thiamine deficiency, hyperkalaemia, hypercalcaemia, ARVDC, pectus excavatum, hypothermia, and mechanical compression of the right ventricular outflow tract (RVOT), such as occurs in mediastinal tumours or haemopericardium [1, 5, 10, 14–16, 21–25].
Brugada syndrome is inherited via an autosomal dominant mode of transmission. The first and only gene to be linked to Brugada syndrome is SCN5A, which encodes the alpha subunits of the sodium-channel. More than 80 mutations in SCN5A have been found, and more than 24 of them result in loss of function due to: failure of the sodium channel to express a shift in the voltage and time dependence of sodium channel current activation, inactiva- tion, or reactivation; entry of the sodium channel into an intermediate state of inactivation from which it recovers more slowly; or accelerated inactiva- tion of the sodium channel [5, 10]. A higher incidence of SCN5A mutations has been reported in familial than in sporadic cases [5, 10, 23–25].
A second locus on chromosome 3, close to but distinct from the SCN5A locus, was recently found and is associated with a relative benign prognosis.
SCN5A mutations account for 18–30% of Brugada syndrome cases, implying that, in the remaining cases, mutations in other genes cause the disease.
Antzelevitch made the most important contribution to the understanding of the ionic changes in Brugada syndrome. Ventricular epicardial and M-cell, but not endocardial cell, action potentials display a large phase 1, due to the presence of a predominant transient outward current (Ito), giving rise to a spike-and-dome or notched configuration of the action potential. Important differences also exist in the magnitude of Itobetween right and left ventricu- lar epicardial and M-cells, with right ventricular cells displaying a much greater Ito. These transmural ion channel distinctions lead to a differential response of the epicardium and endocardium to sodium channel block, IKATP
activation, and hypercalcaemia. Heterogeneous loss of the action potential dome, within epicardium and between epicardium and endocardium, accen-
tuates local epicardial as well as transmural dispersion of repolarisation, thus creating a vulnerable window within the epicardium and across the ventricular wall [5, 6–9, 10].
The ECG J-wave, or Osborn-wave, has long been recognised as pathogno- monic of hypothermia or hypercalcaemia [4, 8]. In fact, the decrease in tem- perature has been shown to accentuate this transmural voltage gradient, thus increasing the amplitude of the J-wave. This effect is due to differences in the Q10for the kinetics of ICaand Ito. A greater cooling induces a more evident slowing of ICaactivation or Itoactivation. Similarly, in Brugada syndrome, IKATP activation or inhibition of INa and ICa are involved, resulting in a markedly abbreviated response in some areas of the epicardium [4–9].
Agents that block Ito, such as quinidine, restore the epicardial action poten- tial and normalise the ST segment. Furthermore, a lower density of Itoin the female heart has been shown. This correlates with a lower propensity of female hearts to develop Brugada syndrome, despite equal transmission of the mutation in both sexes [5, 7].
Conversely, it has been demonstrated that premature inactivation of the sodium channel due to SCN5A mutation is a function of body temperature.
Thus, several authors have suggested that a febrile condition could unmask Brugada syndrome and precipitate serious arrhythmic events [5, 7, 17].
Drugs Affecting STT Pattern and Mimicking Brugada Syndrome
Several drugs are able to induce Brugada-like ECG patterns, and discontinu- ation of these drugs is associated with reversal of the previously observed pattern. Even shortly after a direct current cardioversion, a Brugada-like pat- tern has been observed for several hours. The largest experience has been obtained with sodium channel blockers, which are used also as a provocative test [5, 21], and with psychotropic drugs, mainly tricyclic antidepressants [5, 18], which should be carefully administered and accurately monitored. At present time, it is not known whether some individuals are gene carriers for Brugada syndrome. Thus, the following families of drug should be carefully used:
1. Antiarrhythmic drugs, mainly sodium channel blockers, such as class IC drugs (flecainide, pilsicainide, propafenone), class IA drugs (ajmaline, procainamide, disopyramide, cibenzoline), calcium channel blockers (verapamil), beta-blockers (propranolol mainly, but also the others at toxic doses).
2. Antianginal drugs, such as calcium channel blockers (nifedipine, dilti- azem, etc.), nitrates (isosorbide dinitrate, nitroglycerine), potassium channel openers (nicorandil and other analogues).
3. Psychotropic drugs, such as tricyclic antidepressant (amitriptyline, nor- triptyline, desipramine, clomipramine and analogues), tetracyclic antide- pressant (maprotiline), phenotiazine (perphenazine, cyamemazine), selective serotonin reuptake inhibitors (fluoxetine).
4. Other drugs, such as dimenhydrinate, cocaine, alcohol intoxication.
Factors Triggering of Arrhythmic Events
The ECG manifestations of congenital Brugada syndrome are often con- cealed, but can be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, vagotonic manoeuvres, and several other stimuli. Moreover, alpha-adrenergic agonists, beta-adrenergic blockers, tri- cyclic or tetracyclic antidepressants, a combination of glucose and insulin, hyperkalaemia, hypokalaemia, hypercalcaemia, alone or in combination, can be responsible as triggering factors (TF) of arrhythmic events. Alcohol and cocaine toxicity has been reported as a TF [5]. These agents may also induce acquired forms of Brugada syndrome. Superimposed acute myocardial ischaemia can mimic ST-segment elevation similar to that in Brugada syn- drome. This effect is due to a depression of the calcium channel current (ICa) and activation of the ATP-sensitive potassium channel current (IKATP) during ischaemia. This suggests that patients with congenital and acquired forms of Brugada syndrome are at higher risk for ischaemia-related SCD (5). VF and SCD [5] usually occur at rest, post-exercise, and at night, as confirmed by the circadian pattern of 64 VF episodes in 19 sudden unexplained nocturnal death syndrome (SUNDS) patients treated with ICDs. Circadian variation of sympathovagal balance hormones and other metabolic factors are likely to contribute to this circadian pattern. Bradycardia, resulting from altered auto- nomic balance, drugs, or an association of factors may contribute to the ini- tiation of arrhythmias in these subjects, in whom a myocardial presynaptic sympathetic dysfunction has been demonstrated. Even the RVOT could be similarly affected by a sympathovagal imbalance, as shown by the difficulty in demonstrating local innervation in these areas or by the presence of localised zones of primary or secondary myocardial dysfunction (Figs. 1, 2).
Hypokalaemia has been implicated as a contributing factor in Brugada syndrome, mainly in Asia, specifically Thailand, where potassium deficiency is endemic. Furthermore, it was noted that many SUNDS victims had con- sumed large meals of glutinous (sticky) rice or carbohydrates for dinner before the night of death. In fact, glucose and insulin infusion could unmask the Brugada ECG.
Furthermore, Dumaine and other authors demonstrated that sodium channel inactivation can be observed with both low (< 30°C) and high
Fig. 1.Predisposing factors for ECG and arrhythmic manifestations of Brugada syn- drome (modified from [5])
Fig. 2.Predisposing factors for ECG and arrhythmic manifestations of acquired vs con- genital long QT and other catecholaminergic arrhythmic syndromes (modified from [27])
(> 38°C) temperatures. While in humans severe hypothermia is rare, febrile states are very frequent and could unmask Brugada syndrome and precipi- tate VF. Even hot baths and hot climates, as in North-Eastern Thailand, have been claimed as precipitating factors [5].
Risk Stratification and Outcomes
Risk stratification is still the most important goal of Brugada syndrome researchers worldwide [1–5, 23–26]. Patients initially presenting with abort- ed SD, are at the highest risk for a recurrence (from 69% at 54 ± 54 months of observation of Brugada syndrome symptoms [5] to 26% at 22 ± 24 months, as in our own patient population) [26].
Patients presenting with syncope and a spontaneously appearing type-1 ECG have a recurrence rate of 19% at 26 ± 36 months of follow-up. An 8%
occurrence of cardiac events was observed in initially asy mptomatic patients. Priori presented different data [5] in a less selected patient popula- tion, as did Eckardt recently [23]. Our data are more similar to those of Brugada, since probably a more selected population was followed-up, includ- Table 1.Brugada syndrome: predisposing factors and prognostic outcomes (modified from Behlassen)
Aggravating factors:
Sodium channels blockers (flecainide > ajmaline > procainamide)
Increased vagal tone (night time) or post-exercise, post-emotional, during venous puncture increased vagal tone
Extreme beta-adrenergic blockade
Hypercalcaemia, hypokalaemia and association of:
Gender-related unknown or partially known factors (a more prominent Ito in men vs women
General anaesthesia and surgery Tricyclic antidepressant Other drugs
Fever (accelerated inactivation of sodium channels) Strong family history of sudden death
Coved-type pattern in the rest ECG Syncopal episodes
Racial factor?
Improving factors:
Moderate non-competitive exercise
Beta-adrenergic stimulation (non-clinically useful)
Demonstrated quinidine sulfate administration in any given patient No family history of sudden death
Saddleback-type pattern in the rest ECG
ing many families with a striking evidence of cardiac arrest and SCD occur- ring early in life [25].
Asymptomatic patients, at highest risk are most likely those who show type 1 ECG spontaneously, those with syncope, those with the coved type versus the saddleback type of ST-segment elevation, and those with a family history of cardiac arrest.
Combined ECG markers such as the width of the S-wave and ST-segment elevation magnitude, may be helpful in risk stratification. Other groups showed that combined ST-segment elevation and the presence of late poten- tials could be diagnostically useful, but the value of these combined markers remains to be tested in a prospective fashion. Data from Brugada, Corrado, and our group (Tables 2, 3) suggest that, both among symptomatic and asymptomatic patients, the inducibility of VT/VF during programmed elec- trical stimulation (PES) may forecast risk. However, Priori and Eckardt did not find an association between inducibility and recurrence of VT/VF [5, 23].
These differences could be due to selection bias of isolated cases versus cases with a family distribution and to non-comparable stimulation protocols.
Conclusions
In conclusion, patients at the highest risk are those who already experienced aborted SCD and those with a spontaneously abnormal type 1 ECG, even without syncope but mainly those with true syncope [1, 5, 23, 26].
Men have a 5.5-fold higher risk of SCD than women [1, 5, 23, 25].
Furthermore, recent information confirmed that a negative family history does not exclude the risk of SCD [5], while patients with an evident family distribution of SCD seem to be at higher risk [5, 24, 25].
Many old and new drugs should be avoided in Brugada patients, while patients on these therapies who show a Brugada-like ECG should be careful- ly evaluated and monitored.
Electrolytes imbalance should be monitored and general anaesthesia should be performed under strict control during surgery in these subjects [16].
Vagal manoeuvres, vagal stimuli, and bradycardia itself could be TF of serious events distinct from other arrhythmic syndromes, such as some forms of congenital or acquired long QT syndromes [7]; short QT syndrome [19]; familial polymorphic ventricular tachycardia; catecholaminergic VT with normal QT interval, secondary to cardiac ryanodine receptor-calcium release channel mutations [20, 22]; and arrhythmogenic right ventricular dysplasia (ARVDC) [2]. In all of these conditions, sympathetic tone, alone or in combination with other factors, is considered the most important TF of arrhythmic events (Fig. 2).
Table 2.Comparison ofthe published data ofthe five largest registries worldwide on Brugada syndrome patients and family members:part 1 Brugada et al.Brugada et al.Priori et al.Eckardt et al.Corrado et al.Naccarella et al. Circulation 2002Circulation 2003Circulation 2002Circulation 2005Eur Heart J 2005ECAS 2005 No.(no.men)334 (255)547 (408)200 (152)212 (152)209 (182)200 (152) Index (men) 294130 (110)165 (132)68/ Aborted SCD71022242015 Syncope7312434654125 (12) Asymptomatic190423144123148148 Age at diagnosis,years42 ±1641 ±1541 ±1845 ±638.9 ±1239 ±12 Brugada ECG pattern (%) Spontaneous234 (70)391 (71)90/176 (51)125 (59)126 (60)38 (90) After class I100 (30)156 (29)86 (49)87 (41)83 (40)60 (61) Family history ofSCD (%)180/334 (54)302/547 (55)26/130 (22)60/212 (28)129 (62)37/200 (19) Aborted SCD23 (38)0NA3 (13)NA15/37 (41) Syncope26 (39)NANA16 (25)NA37/200 (19) Asymptomatic131 (72)NANA41 (33)NA22/200 (11) SCN5A (%) Screened index patients MutationNANA1301362829 NANA28 (22)32 (24)6/28 (21)3/29 (10) NAnot available
Table 3.Comparison ofthe published data ofthe five largest registries worldwide on Brugada syndrome patients and family members;part 2 Brugada et al.Brugada et al.Priori et al.Eckardt et al.Corrado et al.Naccarella et al. Circulation 2002Circulation 2003Circulation 2002Circulation 2005Eur Heart J 2005ECAS 2005 Electrophysiological 252408861866857 study,n (%) Inducible130 (52)163 (40)57 (66)93 (50)27 (40)17/57 (30) Aborted SCD44/54 (83)NA18 (82)15/22 (68)19/27 (70)12/17 (71) Syncope41/62(68)NANA40/65 (62)NA3/57 (5) Asymptomatic45/136 (33)NANA38/98 (39)NA28/57 (49) ICD,n (%)NA177 (32)NA113 (53)29 (14)9/12 (75) Follow-up,mo33 ±3924 ±3334 ±4440 ±503.6 ±1.916 ±25 Aborted SCD54 ±54NANA83 ±66NA22 ±24 Syncope26 ±36NANA39 ±37NA26 ±42 Asymptomatic27 ±29NANA34 ±52NA14 ±59 Events during 74 (39)45 (8)139 (4)16 (8)21/57 (37) follow-up,n (%) Aborted SCD44 (62)NANA4 (17)11 (68)15/57 (26) Syncope14 (19)NANA4 (6)2 (1)3/57 (5) Asymptomatic16 (8)NA61 (1)1 2/57 (4) NAnot available
Hypokalaemia resulting from other electrolytic disorders or the use of certain drugs should be carefully controlled.
Stress testing in not useful in Brugada syndrome, unless for arrhythmias occurring in the post-exercise and recovery phases, when vagal tone is pre- dominant or when the imbalance favours parasympathetic over sympathetic tone. Sports activities are not allowed for subjects with clearly diagnosed Brugada syndrome or for those with drug-induced abnormalities after provocative testing, even in asymptomatic subjects. Conversely, stress test and provocative manoeuvres are particularly useful and, sometimes even more useful than PES, in so-called catecholaminergic precipitated ventricu- lar arrhythmias and in other arrhythmic syndromes, such as those men- tioned above.
Twelve-lead 24-h serial Holter monitorings are more useful to assess the spontaneous variability of ST T-segment elevation, in addition to a more prominent ST T-segment elevation (coved) and bradycardia, the occurrence of non-sustained or sustained ventricular arrhythmias, and, not infrequently, atri- al fibrillation or flutter. Concomitant complicating factors which are not suffi- ciently investigated at the time of the event may be difficult to identify later.
Acknowledgements
We thank Valentina Galletti, and Elena Seragnoli for help in preparing this paper and for assembling the figures. We thank Elena Cuomo, Director of the Service of KNOWLEDGE MANAGEMENT of Maggiore Hospital G.Laschi Library, Azienda USL Bologna, Bologna, Italy.
References
1. Anonymous (1997) Survivors of out-of-hospital cardiac arrest with apparently normal heart. Need for definition and standardized clinical evaluation. Consensus statement of the joint Steering Committees of the Unexplained cardiac arrest Registry of Europe and of the Idiopathic ventricular fibrillation Registry of the United States. Circulation 95:265–272
2. Kontny F, Dale J (1990) Self-terminating idiopathic ventricular fibrillation present- ing as syncope: a 40-year follow-up report. J Int Med 227:211–213
3. Fish JM, Di Diego JM, Nesterenko V et al (2004) Epicardial activation of left ven- tricular wall prolongs QT interval and transmural dispersion of repolarization.
Implications for biventricular pacing. Circulation 109:2136–2142
4. Fish JM, Antzelevitch C (2004) Link between hypothermia and the Brugada syn- drome. J Cardiovasc Electrophysiol 15:942–944
5. Antzelevitch C, Brugada P, Borggrefe M et al (2005) Brugada syndrome. Report of the Second Consensus Conference. Circulation 111:659–670
6. Antzelevitch C, Belardinelli L, Zygmunt AC et al (2004) Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhy thmic properties.
Circulation 110:904–910
7. Antzelevitch C, Extramiana F (2004) Amplified transmural dispersion of repolar- ization as the basis for arrhythmogenesis in a canine ventricular-wedge model of short-QT syndrome. Circulation 110:3661–3666
8. Gussak H et al (1995) ECG phenomenon called the J-wave. J Electrocardiol 28:49–58
9. Yan GX, Antzelevitch C (1996) Cellular bases for the electrocardiographic J-wave.
Circulation 93:372–379
10. Fish JM, Antzelevitch C (2003) Cellular and ionic bases for the sex related differ- ence in the manifestation of the Brugada syndrome and progressive conduction disease phenotypes. J Electrocardiol 36:173–179
11. Haverkamp W, Rolf S, Eckardt L et al (2005) Long QT syndrome and Brugada syn- drome. Drugs, ablation or ICD? Herz 30(2):111–118
12. Watanabe H, Chinushi M, Washizuka T et al (2005) Variable electrocardiographic effects of short term quinidine sulphate administration in Brugada syndrome.
Pacing Clin Electrophysiol 28(5):372–377
13. Mohler PJ, Bennett V (2005) Ankyrin-based cardiac arrhythmias: a new class of channelopathies due to loss of cellular targeting. Curr Opin Cardiol 20(3):189–193 14. Rossenbacker T, Carroll SJ, Liu H et al (2004) Novel pore mutation in SCN5A mani-
fests as a spectrum of phenotypes ranging from atrial flutter, conduction diseases and Brugada syndrome to sudden cardiac death. Heart Rhythm 1(5):610–615 15. Ackerman MJ, Splawski I, Makielski JC et al (2004) Spectrum and prevalence of
cardiac sodium channel variance among black, white, Asian and Hispanic individ- uals: implications fpr arrhythmogenic susceptibility and Brugada/long QT syn- drome genetic testing. Heart Rhythm 1(5):600–607
16. Santambrogio LG, Mencherini S, Fuardo M et al (2005) The surgical patients with Brugada sy ndrome: a four cases clinical experience. Anesth Analg 100(5):1263–1266
17. Peng J, Cui YK, Yi SD et al (2005) Fever and Brugada syndrome: report of 21 cases.
Di Yi Jun Yi Da Xue Xue Bao 25(4):432–434
18. Chow BJ, Gollob M, Birnie D (2005) Brugada syndrome precipitated by a tricyclic antidepressant. Heart 91(5):651
19. Gaita F, Giustetto C, Bianchi F et al (2004) Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 43:1494–1499
20. Priori S, Napolitano C, Memmi M et al (2002) Clinical and molecular characteriza- tion of patients with catecholaminergic polymorphic ventricular tachycardia.
Circulation 106:69–74
21. Hong K, Brugada J, Oliva A et al (2004) Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCNA muta- tions. Circulation 110:3023–3027
22. Marks AR (2002) Clinical implications of cardiac ryanodine receptor/calcium release channel mutations linked to sudden cardiac death. Circulation 106:8–10 23. Eckardt L, Probst V, Smits JPP et al (2005) Long-term prognosis of individuals with
right precordial ST-segment-elevation Brugada syndrome. Circulation 111:257–263 24. Hong K, Antzelevitch C, Brugada P et al (2004) Brugada syndrome: 12 years of pro-
gression. Acta Med Okayama 58:255–261
25. Naccarella F, Bresciani B, Lepera G et al (2005) Prospective follow-up of thirteen Brugada patients and of their families (200 members). Non-invasive evaluation and drug tests. Proceedings of the First annual congress of the European cardiac arrhythmia society. Marseille, April 10–12 2005 (in press)
26. Corrado D, Leoni L, Naccarella F et al (2003) Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ven- tricular cardiomyopathy dysplasia. Circulation 108:3084–3091
27. Camm AJ, Malik M, Yap GY (2004) Acquired long QT syndrome. Blackwell Futura Publishing, Philadelphia
