Risk stratification of patients with the Brugada syndrome has been an issue of lively debate. It is generally accepted that Brugada syndrome patients presenting with aborted sudden death are at high risk for recurrence and that they should be protected by an implantable cardiac defibrillator (ICD). There is also little argument that a patient with Brugada syndrome presenting with syncope, particularly when the clinical history suggests an arrhythmic syncope (as opposed to typical vasovagal syncope), are at high risk. In contrast, risk stratification of asymptomatic patients has met with considerable debate [11, 15, 66–70]. Several invasive and noninvasive parameters have been proposed for identification of patients at risk of sudden death, including the presence of spontaneous Type 1 ST segment elevation, the characteristics of the S wave [71], wider QRS complexes [72], the presence of late potentials [73] or QRS fragmentation [52, 53] and inducibility of VT/VF using programmed electrical stimulation (PES) [74].

In 1998, Brugada et al. [75] reported that over a 34 month follow-up period, 27 % of previously asymptomatic patients experienced a first ventricular fibrillation or sudden cardiac death. This figure corresponds to an occurrence of life-threatening events of approximately 10 % per year. In 2002, with a mean follow-up of 27  ±  29 months, the same authors [66] reported that 8 % of previously asymptomatic patients had become symptomatic; an occurrence of a life-threatening event of 3.5 % per year. In 2005, Brugada et al. [68] reported that 6 % of asymptomatic patients displayed a first event during a mean follow-up of 42  ±  42 months, corresponding to an event rate of 1.7 % per year. This progressive decline in first event rate in previously asymptomatic patients most likely reflects a reduced severity of phenotypes referred to the Brugada registry in subsequent years. In contrast, Priori et al. in 2002 [67] reported that asymptomatic patients have a cumulative probability of 14 % for developing a cardiac arrest by age 40, corresponding to an natural history incidence of cardiac arrest of 0.35 % per year. In 2005, the same authors reported a first event rate of 3 % (4/132) over a 31 month follow-up period, corresponding to an event rate of 1 % per year [69].

The reason behind the disparity in the data generated by these two groups is not clearly evident. It was suggested by Brugada et al. [68] that the difference may be due to the inclusion by Priori and co-workers of patients with Type 2 and 3 ST segment elevation, which is not considered diagnostic of the Brugada syndrome [7–10]. Priori and co-workers argue that exclusion of Type 2 and 3 from the diagnosis of the syndrome can lead to missed diagnosis of the disease [69]. While this is clearly the case, it may be a rare occurrence, and the exclusion appears justified on the basis that it avoids a large number of false positive diagnoses. As a result of the failure to exclude individuals with Type 2 and 3 ST segment elevation, the European registry may contain many individuals who do not have the syndrome. However, a recent report by Eckardt and co-workers [70] suggests that other factors may be involved. These authors report that 1 out of 123 asymptomatic individuals with a Type 1 ECG (0.8 %) had a first arrhythmic event during a 40  ±  50 month follow-up. This translates into a first event rate of 0.24 % per year, considerably less than the other two registries. Thus, as additional data have become available, it has become clear that the prognosis of asymptomatic patients is associated with much less risk than initially perceived.

The large registry studies agree that Brugada syndrome patients at higher risk for the development of subsequent events are those presenting with a spontaneous Type 1 ST segment elevation or Brugada ECG and/or those with a previous VT/VF or Sudden Cardiac Death (SCD) [70]. The registries also agree that PES inducibility is greatest among patients with previous VT/VF or syncope. Approximately 1/3 of asymptomatic patients are inducible. In the Priori et al. [69] and Eckardt et al. [70] studies inducibility of VT/VF in asymptomatic patients was not associated with risk. The lack of association between inducibility and spontaneous VF in Brugada patients was also reported by a number of smaller studies, such as that of Kanda et al. [76].

In sharp contrast, Brugada et al. [77] found that the risk for developing VT/VF is considerably greater in patients who are inducible during PES, whether or not a Type 1 ST segment elevation was spontaneously present or whether or not they were symptomatic. The reason for the marked disparity in the predictive power of PES inducibility among the different studies is not immediately apparent. The discrepancies may be due to differences in patient characteristics and the use of multiple testing centers with non-standardized or non-comparable stimulation protocols [78]. Additional studies are clearly needed to further define risk stratification strategies for asymptomatic patients.

It is noteworthy that in experimental models of the Brugada syndrome involving the coronary-perfused wedge preparation, polymorphic VT is readily inducible with a single ventricular extrastimulus, but only when applied on the epicardial surface of the wedge. Inducibility is not possible or much more difficult when extra-stimulation is applied to the endocardial surface. The shorter refractory period of epicardium allows extra-stimuli direct access to the vulnerable window across the ventricular wall, thus facilitating the induction of reentry. These relationships suggest that PES applied to the epicardium may provide a more accurate assessment of risk than the current clinical approach in which stimuli are applied to the endocardial surface. In support of this hypothesis, Carlsson et al. reported that a Brugada syndrome patient with recurrent syncope due to polymorphic ventricular tachycardia could not be induced with right ventricular endocardial stimulation. However, epicardial stimulation from a left ventricular site through the coronary sinus led to the development of polymorphic VT [79].

Gehi et al. [80] recently reported the results of a meta-analysis of 30 prospective studies that included 1,545 patients with a Brugada ECG to assess predictors of events. The meta-analysis suggested that a history of syncope or SCD, the presence of a spontaneous Type I Brugada ECG, and male gender predict a more malignant natural history. The findings however did not support the use of a family history of SCD, the presence of an SCN5A gene mutation, or electrophysiologic study to guide the management of patients with a Brugada ECG. A similar meta-analysis by Paul et al. [81] also concluded that the inducibility of VF in asymptomatic patients is of no prognostic value.

Since the publication of the meta-analyses by Gehi et al. and Paul et al., two large multicenter studies from Japan [82] and from Europe (the FINGER study) [83] were published. The Japanese study is important because it included only probands (330 probands of whom 154 were asymptomatic) and the FINGER study was important because the number of asymptomatic patients included (n  =  654) was significantly larger than the number of asymptomatic patients included in the last published series by Brugada (n  =  263) and even larger than the 457 patients number compiled from 15 studies in the meta-analysis by Paul. Both studies used an EPS protocol that included two sites of stimulation [right ventricular apex (RVA) and outflow tract (RVOT)] with up to three extrastimuli, with the FINGER protocol using a minimal coupling interval of 200 ms, whereas the Japanese investigators limited the coupling interval of the extrastimulus only by ventricular refractoriness. This difference in the EPS protocol probably explains why the percentage of asymptomatic individuals with inducible VF was higher in the Japanese study than in FINGER (57 % vs. 37 %). The latter figure is very close to the 34 % inducibility rate reported by Brugada among their asymptomatic individuals.

In Finger, asymptomatic individuals with inducible VF did have more spontaneous arrhythmic events than non-inducible patients, but the event rate was very low for both groups (1.1 vs. 0.4 % event rate per year). Moreover, using multivariate analysis the EPS results were no longer (independent) predictors of outcome. Inducibility of VF was not a predictor of outcome among asymptomatic individuals in the Japanese study.

Makimoto et al. [84] recently reported that inducibility to VF was of prognostic value only when VF was induced with one or two extrastimuli and suggested that triple extrastimulation should be avoided to prevent false-positive results. These results, however, where not confirmed by the prospective PRELUDE study [53]; the induction of VF was of no prognostic value regardless of the protocol of extrastimulation used.

An increase in net repolarizing current, whether secondary to a decrease of inward currents or an increase of outward current, accentuates the action potential notch leading to augmentation of the J wave or appearance of ST segment elevation. A further increase in net repolarizing current can result in partial or complete loss of the action potential dome, leading to a transmural voltage gradient that manifests as accentuation of the J wave or an ST segment elevation [154–156]. In regions of the myocardium exhibiting a prominent I_to, such as the right ventricular epicardium, marked accentuation of the action potential notch leads to a augmentation of the J wave, manifesting as a coved-type ST segment elevation, which is diagnostic of BrS (Fig. 29.3a, b). Because the second action potential upstroke is delayed, epicardium now repolarizes after endocardium, causing inversion of the T wave. Note that although the ECG now displays the typical BrS morphology with a covered type ST segment elevation and negative T wave, no major arrhythmogenic substrates are present. The substrate for reentry, however develops with any additional outward shift of the net current active during the early phase of the action potential. This leads to loss of the action potential dome, thus creating a dispersion of repolarization between epicardium and endocardium as well as within epicardium, between the region where the dome is lost and regions at which it is maintained (Fig. 29.3c). Sodium channel blockers like procainamide, pilsicainide, propafenone, flecainide and disopyramide cause a further outward shift of current flowing during the early phases of the action potential and are thereby effective in inducing or unmasking ST segment elevation in patients with concealed J-wave syndromes [22, 31, 158]. Sodium channel blockers like quinidine, which also inhibits I_to, reduce the magnitude of the J wave and normalize ST segment elevation [154, 159]. Loss of the action potential dome is usually heterogeneous, resulting in marked abbreviation of action potential at some sites but not others. The dome can then propagate from regions at which it is maintained to regions where it is lost, giving rise to a very closely coupled extrasystole via phase 2 reentry (Fig. 29.3d) [3]. The phase 2 reentrant beat is capable of initiating polymorphic ventricular tachycardias (VT) or ventricular fibrillation (Fig. 29.3e, f).

Phase 2 reentry has been shown to occur when right ventricular epicardium is exposed to: (1) K+ channel openers such as pinacidil [160]; (2) sodium channel blockers such as flecainide [3]; (3) increased [Ca²⁺]o [153]; (4) calcium channel blockers such as verapamil; (5) metabolic inhibition [161]; and (6) simulated ischemia [162]. Evidence in support of a phase 2 reentrant mechanism in humans was provided by Thomsen et al. [163, 164].

While most investigations suggest that repolarization abnormalities underlie the pathophysiology of Brugada syndrome, recent studies suggest the possibility of delayed depolarization in the right ventricular outflow tract as a contributing mechanism to ST segment elevation or J waves associated with BrS [165, 166]. The repolarization vs. depolarization hypotheses controversy has been documented as a published debate [167].

Seemingly compelling data in support of delayed conduction in the RVOT as the basis for BrS was recently presented by Nademanee and co-workers [166]. Using an electrogram applied to the epicardial surface of the RVOT, these authors recorded late potentials, in some cases appearing as a continuous fractionated electrogram. This was interpreted as indicating delayed conduction over the anterior aspect of the RVOT epicardium. Catheter ablation over this abnormal region of the RVOT resulted in normalization of the Brugada ECG pattern over a period of up to 3 months and prevented VT/VF, both during electrophysiological studies, as well as spontaneous recurrence of VT/VF episodes. Signal averaged ECG (SAECG) recordings have also demonstrated late potentials in patients with the Brugada syndrome, especially in the anterior wall of the right ventricular outflow tract (RVOT) [168–174].

Although traditionally ascribed to conduction delays secondary to structural defects, in cases of BrS, late potentials of the type described by Nademanee et al. more likely arise from a delayed second upstroke of the epicardial action potential in the RVOT or to a concealed phase 2 reentry [19, 167, 170]. It is noteworthy that wall motion abnormalities have also been detected in BrS patients [175]. Although such contractile abnormalities are commonly considered pathognomonic of structural disease, in the setting of BrS, they could well be the result of loss of the action potential dome in the right ventricular epicardium [170, 176]. Loss of the dome would lead to contractile dysfunction because calcium entry into the cells would be greatly diminished and sarcoplasmic reticulum calcium stores would be depleted.

It has been suggested that the rate-dependence of the ST segment elevation in BrS may be helpful in discriminating between the repolarization and depolarization hypotheses [19]. If the ST segment elevation is due predominantly to delayed conduction in the RVOT, acceleration of the rate would be expected to further aggravate conduction and thus accentuate the ST segment elevation and the RBBB morphology of the ECG. If, on the other hand, ST segment elevation or the BrS sign is secondary to accentuation of the epicardial action potential notch, acceleration of the rate would be expected to normalize the ECG, by reducing the action potential notch and restoring the action potential dome in RV epicardium. This occurs because the transient outward current, which is at the heart of this mechanism, is slow to recover from inactivation and is less available at faster rates.

Although there are relatively few reports of the effects of pacing, most investigators in the field agree that there is a tendency for the ST segment elevation associated with Brugada ECGs to normalize during an increase in heart rate, consistent with the repolarization hypothesis [177–179]. There are however also reports of ST segment elevation or J point elevation with exercise. Amin et al. recently reported J point elevation in BrS patients (both SCN5A+ and SCN5A−) during exercise [180]. The principal difference between studies showing a decrease vs. increase of the J point in response to exercise appears to be the presence of a prominent ST segment elevation at baseline in the former.

Interestingly, in BrS cases in which ST segment elevation is accompanied by notching of the QRS, the latter suggesting major conduction delay in the RVOT, exercise-induced acceleration of rate leads to further fragmentation of the QRS, but to a normalization of the ST segment elevation in all right precordial leads [167]. These findings suggest that the ST segment elevation is due to a repolarization defect and not to the clearly apparent depolarization defect responsible for the fragmentation of the QRS. Fragmentation of the QRS is associated with increased mortality and arrhythmic events in patients with coronary artery disease as well as patients with arrhythmogenic right ventricular cardiomyopathy and Brugada syndrome [181].

Kurita et al. placed monophasic action potential (MAP) electrodes on the epicardial and endocardial surfaces of the right ventricular outflow tract (RVOT) in patients with the Brugada syndrome and demonstrated an accentuated notch in the epicardial response, thus providing direct support for the repolarization hypothesis in humans [182, 183].

Additional support for the repolarization hypothesis derives from the demonstration that quinidine normalizes ST segment elevation and suppresses late potentials recorded in patients with Brugada syndrome [184–186]. These effects of the drug are presumably due to inhibition of I_to leading to reduction of the epicardial action potential notch and normalization of the repolarization heterogeneities. If the ST segment elevation or the late potentials were due to delayed conduction, quinidine-induced I_Na inhibition would be expected to accentuate their appearance.

Although there is no experimental model of BrS based on the depolarization hypothesis, several groups have developed a models of BrS based on the repolarization hypothesis [154, 157, 187–192].

Experimental models displaying major conduction delays have been developed by exposing wedge preparations to global ischemia [193, 194]. Progressive delay in these models leads to a gradual prolongation of the R wave and inversion of the T wave. The ECG at first glance resembles a BrS phenotype, but with closer inspection it is clear that the depolarization hypothesis does not lead to an ST segment elevation, but rather to an R wave prolongation. The marked conduction delay is due to a discontinuity in conduction in the deep subepicardium. Conduction under these conditions is exquisitely sensitive to rate, with acceleration leading to block and inexcitability. This is a common characteristic of ischemia-induced tombstone morphology of the ECG induced by coronary spasm [195], but is not characteristic of BrS A similar phenomenon is observed in right ventricular wedge preparations following exposure to hyperkalemic conditions [196].

Of note, magnetocardiograms recorded from patients with complete RBBB have been shown to generate currents from the RVOT to the upper left chest that are opposite from those recorded in patients with Brugada syndrome [197].

While the available data, both basic and clinical, point to the repolarization hypothesis, i.e., transmural voltage gradients that develop secondary to accentuation of the epicardial notch, at times leading to loss of the action potential dome, as the predominant mechanism underlying the Brugada syndrome ECG signature and arrhythmogenesis, there is no doubt that in some cases, particularly those associated with sodium channel loss of function, conduction slowing may contribute to the development of arrhythmias. There are also likely to be cases in which a conduction defect may predominate [198, 199].

Parasympathetic agonists like acetylcholine facilitate loss of the action potential dome [200] by suppressing I_Ca and/or augmenting potassium current. β(beta)-adrenergic agonists restore the dome by augmenting I_Ca. Sodium channel blockers also facilitate loss of the canine right ventricular action potential dome via a negative shift in the voltage at which phase 1 begins [2, 3]. These findings are consistent with accentuation of ST segment elevation in patients with the Brugada syndrome following vagal maneuvers or Class I antiarrhythmic agents as well as normalization of the ST segment elevation following β(beta) adrenergic agents and phosphodiesterase III inhibitors [4, 5, 201]. Loss of the action potential dome is more readily induced in right vs. left canine ventricular epicardium [127, 161, 202] because of the more prominent I_to-mediated phase 1 in action potentials in this region of the heart. This distinction is believed to be the basis for why the Brugada syndrome is a right ventricular disease.

The electrocardiographic and arrhythmic manifestations of the Brugada syndrome can be induced and modulated by a large number of agents and factors. The Brugada ECG can be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, α adrenergic agonists, β adrenergic blockers, tricyclic or tetracyclic antidepressants, first ­generation antihistaminics (dimenhydrinate), a combination of glucose and insulin, hyperkalemia, hypokalemia, hypercalcemia, and by alcohol and cocaine toxicity (Fig. 29.6) [5, 21, 22, 214–221]. These agents may also induce acquired forms of the Brugada syndrome (Table 29.2). An up-to-date list of agents to avoid in Brugada syndrome can be found at www.BrugadaDrugs.org.

Myocardial infarction or acute ischemia due to vasospasm involving the RVOT mimics ST-segment elevation similar to that seen in Brugada syndrome. This effect is secondary to the depression of I_Ca, inactivation of I_Na and the activation of I_K-ATP during ischemia, and suggests that patients with congenital and possibly acquired forms of Brugada syndrome may be at a higher risk for ischemia-related sudden cardiac death [253, 255]. Although the coexistence of Brugada syndrome and vasospastic angina in the same patient is not rare, Chinushi et al. have failed to observe an enhanced susceptibility to VF nor a proarrhythmic effect of Ca-antagonist in this setting [256].

Hypokalemia has been suggested to be a contributing factor in the high prevalence of Sudden unexpected nocturnal death syndrome (SUDS) in the Northeastern region of Thailand where potassium deficiency is endemic [220, 257]. Serum potassium in the Northeastern population is significantly lower than that of the population in Bangkok, which lies in the central part of Thailand where potassium is abundant in the food. Hypokalemia has been reported to induce VF in a 60 year old man who had asymptomatic Brugada syndrome, without a family history of sudden cardiac death [220]. This patient was initially treated for asthma by steroids, which lowered serum potassium from 3.8 mM on admission to 3.4 and 2.9 mM on the 7th day and 8th day of admission, respectively. Both were associated with unconsciousness. VF was documented during the last episode, which reverted spontaneously to sinus rhythm. Hypokalemia may exert these effects by increasing the chemical gradient for K⁺ and thus the intensity of I_to.

VT/VF and sudden death in the Brugada syndrome usually occur at rest and at night. Circadian variation of sympatho-vagal balance, hormones and other metabolic factors are likely to contribute to this circadian pattern. Bradycardia, due to altered sympatho-vagal balance or other factors, may contribute to arrhythmia initiation [26, 54, 55]. Abnormal ¹²³I-MIBG uptake in 8 (17 %) of the 17 Brugada syndrome patients but none in the control group was demonstrated by Wichter et al. [258]. Segmental reduction of ¹²³I-MIBG in the inferior and the septal left ventricular wall was observed indicating presynaptic sympathetic dysfunction. Of note, imaging of the right ventricle, particularly the RVOT, is difficult with this technique, so that insufficient information is available concerning sympathetic function in the regions known to harbor the arrhythmogenic substrate. Moreover, it remains unclear what role the reduced uptake function plays in the arrhythmogenesis of the Brugada syndrome. If the RVOT is similarly affected, this defect may indeed alter the sympatho-vagal balance in favor of the development of an arrhythmogenic substrate [154, 200].

The Thai Ministry of Public Health Report (1990) found an association between a large meal on the night of death in Sudden unexplained nocturnal death syndrome (SUNDS) patients [257]. Consistent with this observation, a recent study by Nogami et al. found that glucose and insulin could unmask the Brugada ECG [219]. Another possibility is that sudden death in these patients is due to the increased vagal tone produced by the stomach distention. A recent study by Ikeda et al. [24] has shown that a full stomach after a large meal can unmask a Type I ECG, particularly in Brugada syndrome patients at high risks for arrhythmic events, thus suggesting that this technique may be of diagnostic and prognostic value.

Accelerated inactivation of the sodium channel caused by SCN5A mutations associated with the Brugada syndrome has been shown to be accentuated at higher temperatures [94] suggesting that a febrile state may unmask the Brugada syndrome. Indeed, several case reports have emerged recently demonstrating that febrile illness could reveal the Brugada ECG and precipitate VF [23, 95, 96, 259–261]. A report from Keller et al. [262] has identified a missense mutation, F1344S, in SCN5A in a patient with Brugada syndrome and fever-induced VT/VF. Expression of F1344S showed a shift in the voltage-dependence of activation, which was further accentuated at high temperatures mimicking fever. Thus fever may also cause a loss of function in I_Na by accelerating inactivation as well as producing a shift in the voltage-dependence of activation.

Anecdotal data point to hot baths as a possible precipitating factor. Of note, the Northeastern part of Thailand, where the Brugada syndrome is most prevalent, is known for its very hot climate. A study is underway to assess whether this extreme climate influences the prognosis of the disease.

Although the mutation responsible for the Brugada syndrome is equally distributed between the sexes, the clinical phenotype is eight to ten times more prevalent in males than in females. The basis for this sex-related distinction has been shown to be due to a more prominent I_to-mediated action potential notch in the right ventricular (RV) epicardium of males vs. females (Figs. 29.7 and 29.8) [263]. The more prominent I_to causes the end of phase 1 of the RV epicardial action potential to repolarize to more negative potentials in tissues and arterially perfused wedge preparations from males, facilitating loss of the action potential dome and the development of phase 2 reentry and polymorphic VT.

Clinical and basic studies suggest that testosterone plays an important role in ventricular repolarization. Ezaki and co-workers [264] recently demonstrated that ST segment elevation is relatively small and similar in males and females before puberty. After puberty, ST segment elevation in males, but not females, increased dramatically, more so in the right precordial leads and decreased gradually with advancing age. The effect of androgen-deprivation therapy on the ST segment was also evaluated in 21 prostate cancer patients. Androgen-deprivation therapy significantly decreased ST segment elevation. These results suggest that testosterone modulates the early phase of ventricular repolarization and thus ST segment elevation.

The proposed cellular mechanism for the Brugada syndrome is summarized in Fig. 29.9. Available data support the hypothesis that the Brugada syndrome results from amplification of heterogeneities intrinsic to the early phases of the action potential among the different transmural cell types. This amplification is secondary to a rebalancing of currents active during phase 1, including a decrease in I_Na or I_Ca or augmentation of any one of a number of outward currents. ST segment elevation similar to that observed in patients with the Brugada syndrome occurs as a consequence of the accentuation of the action potential notch, eventually leading to loss of the action potential dome in right ventricular ­epicardium, where I_to is most prominent. Loss of the dome gives rise to both a transmural as well as epicardial dispersion of repolarization. The transmural dispersion is responsible for the development of ST segment elevation and the creation of a vulnerable window across the ventricular wall, whereas the epicardial dispersion give to phase 2 reentry which provides the extrasystole that captures the vulnerable window, thus precipitating VT/VF. The VT generated is usually polymorphic, resembling a very rapid form of Torsade de Pointes.