Brugada syndrome is a rare disorder characterized by ST-segment elevation in the right precordial leads of the surface electrocardiogram (ECG) and ventricular tachyarrhythmias, syncope, and sudden cardiac death in patients with structurally normal hearts. The syndrome was first described as a distinct entity by Brugada and Brugada.1 In 1998, the first genetic mutation was reported in the cardiac sodium channel gene SCN5A. Meanwhile, several mutations in this and other genes encoding for cardiac channel proteins have been reported. Therefore, Brugada syndrome is currently considered a primary electrical disease (channelopathy).
However, long before the description of Brugada syndrome as an entity and before the detection of the genetic background of the disease, the role of the autonomic nervous system became evident. In Southeast Asian men, a sudden unexplained nocturnal death syndrome (SUNDS) was reported by different authors under the names of ‘Bangungut’ in the Philippines, ‘Pokkuri’ in Japan, and ‘Lai Tai’ in Thailand.2 Recent evidence proved that SUNDS and Brugada syndrome are phenotypically, genetically, and functionally the same disorder.
Clinical hallmarks of Brugada syndrome and SUNDS are the predominance in men and the occurrence of polymorphic ventricular arrhythmias and sudden cardiac death in the resting state and during sleep when the vagal tone is dominant. The typical ECG changes are variable over time and can be modulated by exercise, vagal stimuli, or pharmacological interventions that interact with the cardiac sodium channel (i.e. ajmaline, flecainide, and procainamide) or with the cardiac autonomic nervous system. For example, ECG signs of Brugada syndrome may be unmasked or intensified by vagal stimulation, parasympathomimetic drugs (i.e. edrophonium), anti-adrenergic drugs (i.e. β-blockers), or α-adrenergic receptor stimulators (i.e. norepinephrine). In contrast, they may be diminished during exercise or isoproterenol infusion.3 Based on these observations, intravenous isoproterenol has also been used in single cases to treat electrical storms with recurrent ventricular tachyarrhythmias and multiple shocks from an implanted cardioverter defibrillator.4,5
Babaee Bigi et al.6 investigated the role of cardiac autonomic neuropathy (CAN) for risk stratification in patients with Brugada syndrome. Four non-invasive tests were performed in 115 patients with a Brugada ECG pattern to assess autonomic function: the Valsalva manoeuvre and beat-to-beat heart rate variation during deep breathing (tests for parasympathetic function) as well as postural fall in the blood pressure and the sustained handgrip test (tests for sympathetic function). The presence of two or more abnormal test results was considered as evidence for the presence of CAN. In 13 of 28 patients (46%) with a type-1 Brugada ECG pattern, CAN was present. All patients with CAN were male. In contrast, CAN was not detected in female patients or those with type-2 or type-3 ECG pattern. Eleven of 13 patients (84%) with CAN had a history of previous cardiac events compared with only two of 15 patients (13%) without CAN. In conclusion, male patients with a type-1 Brugada ECG pattern and the presence of CAN had the highest incidence for a history of arrhythmic events, whereas female gender, type-2 or type-3 ECG patterns, and the absence of CAN indicated a more favourable prognosis. The predominance of males among symptomatic patients with Brugada syndrome was explained by the higher incidence of CAN as a risk factor in males rather than male gender as an independent risk factor per se.
The results from this study confirm previous reports on autonomic dysfunction as an important co-factor in the pathophysiology and arrhythmogenesis of Brugada syndrome. Autonomic imbalance is mainly caused by adrenergic dysfunction, as demonstrated by the predominance of abnormal autonomic tests assessing the sympathetic function.6 This is well in line with the results from our previous pathophysiological investigations with assessment of the cardiac autonomic system in patients with Brugada syndrome using non-invasive radionuclide techniques.7,8 These studies showed an abnormal sympathetic innervation of the heart resulting in a dominance of the parasympathetic tone and subsequent autonomic imbalance. First, we demonstrated regionally impaired adrenergic innervation with the use of [123I]m-iodobenzylguanidine and single-photon emission computed tomography.7 In a subsequent study using quantitative positron emission tomography, adrenergic dysfunction was confirmed by the finding of increased myocardial presynaptic catecholamine recycling (Vd of 11C-hydroxyephedrine), despite preserved post-synaptic β-adrenoceptor density (Bmax of 11C-CGP 12177) in patients with Brugada syndrome.8
Interpreting these results, we hypothesized that a lack of sympathetic drive and preserved parasympathetic stimulation may reduce cAMP production, with a potential impact on protein phosphorylation and spatial heterogeneity of calcium transients, which may be arrhythmogenic.7 The parasympathetic transmitter acetylcholine is known to affect ion currents such as Ito and ICa. These are more prominent in the epicardium compared with the endocardium, explaining the so-called spike-and-dome morphology of the action potential. Autonomic imbalance with reduced adrenergic nerve activity and dominant vagal tone may therefore modulate epicardial ion currents, resulting in a loss of the action potential along with subsequent elevation of the ST segment in the right precordial surface ECG. This mechanism may lead to increased transmural dispersion of refractoriness and subsequently to a higher susceptibility for the onset of ventricular tachyarrhythmias. The autonomic imbalance may be even more intense at times of physiological downregulation of adrenergic activity, which partly explains the propensity for ventricular tachyarrhythmia and sudden death at rest or during sleep.7,8
The findings of the present study by Babaee Bigi et al.6 further support this hypothesis and provide additional evidence for the role of autonomic dysfunction in the pathophysiology and potentially also for risk stratification in Brugada syndrome. An autonomic imbalance unmasks or aggravates the typical ECG signs of Brugada syndrome and may be a relevant co-factor for arrhythmia occurrence and prognosis.
This concept is strongly supported by various publications, indicating a correlation of the presence and extent of ECG abnormalities with the risk of arrhythmic events in patients with Brugada syndrome. A recent study by Mizumaki et al.9 demonstrated a spontaneous augmentation of ST elevation in daily life along with an increase in vagal activity assessed by analysis of heart rate variability on a 24-h Holter ECG. The authors also reported that ST elevation was augmented more in patients with a history of documented or inducible ventricular fibrillation than in those without ventricular tachyarrhythmias under similar vagal tone.9 Further evidence for the role of autonomic dysfunction in Brugada syndrome comes from investigations using large meals as a diagnostic tool (‘full stomach test’).10,11 These studies demonstrated that vagal stimulation induced by a large meal not only augmented characteristic ECG changes diagnostic of Brugada syndrome but also indicated prognostic implications. Patients with a positive full stomach test had a higher incidence of a history of life-threatening events than patients with a negative test result.
In summary, there is increasing and convincing evidence that autonomic dysfunction and imbalance contribute significantly to the pathophysiology, arrhythmogenesis, and prognosis of Brugada syndrome. The results from the present study by Babaee Bigi et al.6 not only confirm previous study results and hypotheses on the role of the autonomic imbalance but also add important and new prognostic information with potential impact on the refinement of risk stratification and treatment algorithms in Brugada syndrome.
At present, however, it remains to be determined which of the proposed autonomic tests or test combinations yield the highest predictive value to identify patients with Brugada syndrome at high risk of sudden death. The results from Babaee Bigi et al.6 and other authors therefore, require validation and confirmation in prospective studies with appropriate patient numbers, long-term follow-up, and clinical endpoints.
Conflict of interest: none declared.
The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.