DISCUSSION
In a preliminary Brazilian long-term follow-up cohort of 138 Brugada
syndrome patients, we did not find any variable with high sensitivity,
specificity and accuracy to predict severe symptoms. Association with
life threatening event might be underpowered due to the low risk profile
of our population. This was the first Brazilian registry of long-term
follow-up of patients with either a spontaneous or drug-induced type-1
Brugada ECG pattern. The overall characteristics of our middle-aged men
population were similar to the usual presentation of BrS in the
literature.17, 18 It is expected that proband, the
first family member to look for medical assistance, might be more
prevalent in the symptomatic group, which was demonstrated in our study
and by other authors.19
Precise definition of spontaneous type-1 ECG pattern is somewhat dubious
and has changed overtime. Curiously, in our study we demonstrated that
symptoms were associated with the spontaneous pattern only if expressed
in standard leads (p=0.004). In our registry, there is a high frequency
of spontaneous type-1 Brugada ECG pattern detected only when using HPL
ECG technique (~70%), which is a maneuver to improve
sensitivity, widely used since 2005. Despite a previous clinical
comparison between with type-1 BrS detection in conventionalversus HPL ECG showed similar risk profile,20Curcio et al observed a decreased risk of arrhythmic events when type-1
Brugada pattern is defined in the HPL.21 An important
limitation to this analysis is defining the real high-risk group, as we
intended to refine in our methods. Traditional international registries
have pointed out the symptomatic group as at higher risk, but syncope
interpretation is challenging as well.22 Therefore,
grouping these patients only with the category of “severe syncope”
might support the high-risk profile of the group.
Many efforts have been conducted to define non-invasive and invasive
markers of risk, and there is a default of reproducibility in large
scale. There is some evidence that RVOTcd is the main mechanism
underlying ventricular arrhythmia in BrS and this conduction abnormality
can be expressed in the 12-lead ECG as AVR sign, deep S wave in lead I
and QRS-f. Several reports showed its association with arrhythmic
events,9,11,23 however when we analyzed these ECG
parameters we found no association with symptoms.
Early repolarization in inferior leads and QRS-f had a low prevalence in
our population, precluding association analysis. Even in the multicenter
Prelude Study, the prevalence of QRS-f was low, although a possible
marker of risk (~8%).10 Differently,
Morita et al pointed out QRS fragmentation as a risk factor for VF in
both symptomatic and asymptomatic patients, while early repolarization
was an important marker of VF risk recurrence. In this cohort they found
a high prevalence of this ECG finding
(~50%).24
Of note, the natural history of patients with BrS has changed over
time.4 Active familiar screening and improvements in
electrocardiographic recognition may contribute to the growing number of
low risk patients. These findings could partially explain the low annual
event rate of our long-term registry as compared to other
groups.10,18
Patients in our study who had SCD as the first event totalized 6.5% of
the overall population. Even in this group, recurrence of LAE during
follow-up was not as remarkable (22.2%) as previously described in
long-term follow-up (nearly 50%).22 The increased
medical diagnosis, and the progressive improvement in survival might
also be consequence of the recently introduced lifestyle change support,
regularly standardized in our Institution (awareness of drugs to be
avoided, exercise orientation, prompt treatment of fever, and regular
visits to reinforce educational measures).1 Comparison
of our profile with larger series is summarized in Table 5.
Few symptomatic patients underwent EPS at our institution and
nevertheless, our rate of inducible VF/VT was similar to the Finger
Brugada registry findings, when comparing symptomatic and asymptomatic
patients (46 vs 37%, p = 0.02).18 Heterogeneity in
the EPS protocol among registries, use of anesthetic drugs or sodium
channel blockers during procedure could be a confounding factor to a
powerful analysis. Lack of inducibility at EPS could be considered a
predictor of low risk in asymptomatic subjects. In our cohort, negative
predictive value in asymptomatic patients achieved 100%, similar to the
observations described by Sieira et al (98.3%).25However, if we combine the groups with and without symptoms, the
negative predictive value drops to 91.8% in our casuistic and is as
high as 97.5% in the FINGER registry.18 On the other
hand, the positive predictive value was low (11.5%), in agreement with
other larger series.25 PRELUDE was a prospective
multicenter study with homogenous enrolment criteria and has shown no
predictive accuracy of sustained VT/VF inducibility by the
EPS.10 The low event rate in this elegant publication
also limited the accuracy and predictive value.
We also analyzed some aspects of the genotype-phenotype association. The
majority of pathogenic variants reported in BrS were located in SCN5A
locus, a gene that encodes the α subunit of the cardiac sodium channel,
which accounts for less than 30% of clinically diagnosed BrS patients.
Although we understand that this prevalence might be reviewed after the
emerging concepts toward variants classification,26 we
found pathogenic or likely pathogenic SCN5A variants in 22% of our
patients, according to the ACMG criteria.16 Despite
recent controversies, SCN5A is still the main gene associated with
BrS.26 Studies were not elucidative to identify new
variants in minor genes.27
SCN5A mutations in BrS cause loss of function of the sodium channel,
resulting in delayed conduction. Slowed and discontinuous conduction has
been found in computer models simulating decreased sodium
current.28 The aVR sign, deep S-wave in lead 1 and
QRS-f might be signals of conduction delay in the right ventricular
anterior wall and these aspects were more frequent in SCN5A carriers in
our registry.13, 29
Besides, patients with SCN5A variants showed a longer HV interval; PR
and QRS also tended to be longer, but they were not statistically
significant. These findings are also in line with data from other
previous reports.29 We could not establish the
association of SCN5A variants and symptoms.
Classical registries did not explore the association of SCN5A variants
with these conduction delay markers, somehow related to risk. One group
showed a higher aVR sign in subjects with H558R polymorphism in
SCN5A.30 However, H558R polymorphism was once related
to better outcomes.31