The syndrome of sudden Death, right bundle branch block and ST elevation was firstly described by A.Nava and B. Martini in 1988-1989, and only five years later by the Brugada Brothers. The ECG pattern is due to a conduction disturbance of the RVOT, caused by fibrofatty substitution of that structure.

1. The “so called” Brugada
syndrome
The true history!
Bortolo Martini M.D.
Bortolo.martini@gmail.com
January 2014

2. Stephen M. Stigler is
Stephen M. Stigler is
Professor of Statistics at
Professor of Statistics at
the University of Chicago.
the University of Chicago.
Stigler’s law
• no scientific
discovery is
named after its
original
discoverer.

3. What is this syndrome?

4. First oral presentation of a new “clinicalECG syndrome” at the Italian
Association of Cardiology : 1988

5. Nava-sign
• This is the first e.c.g.
trace of a patient with
the syndrome (not an
healty men!) published
by Andrea Nava in
Medical literature.
• Mises a Jour
Cardiologiques
1988;17:157-159

6. This is an ECG and not a syndrome !!!!!!!!!!!!!!!!!!!

7. Martini B, Nava A, Thiene G, Buja GF, Canciani B, Scognamiglio R,
Daliento L, Dalla VS: Ventricular fibrillation without apparent heart
disease: description of six cases. A m Heart J 1989, 118:1203-1209
• 1989. The first
complete description
of the syndrome!!!
• Nava-Martini-Thiene
or Brugada syndrome?

8. In this article all the typical ECG pattern of
In this article all the typical ECG pattern of
the syndrome were described
the syndrome were described

9. The 2nd paper on the syndrome was published in Japan!
The 2nd paper on the syndrome was published in Japan!
Shinzo 1990;22(suppl 2):80
Shinzo 1990;22(suppl 2):80

10. The third description!
The third description!

11. What is the syndrome of sudden
death, RBBB and ST elevation?
• A clinico – ECG association (Not an isolated
ECG!!!)
• A disease with familial involvement, mainly
affecting males
• ECG pattern of RBBB (different degrees), and ST
elevation, often dynamic (not only 3 patterns!!),
mostly due to a conduction delay at the RVOT
• Easily inducible VF
• Organic substrate in ALL the cases submitted to
detailed necropsy study

12. A clinico – ECG association (Not an
isolated ECG!!!)

13. A disease with familial involvement,
mainly affecting males

14. ECG pattern of RBBB (different degrees), and ST
elevation, often dynamic (not only 3 patterns!!),
mostly due to a conduction delay at the RVOT
In this article all the ECG patterns of
the syndrome were described

16. The ecg pattern
The ecg pattern
is due to
is due to
CONDUCTION
CONDUCTION
DELAY AT THE
DELAY AT THE
rvot.
rvot.
Nava 1988
Nava 1988

17. HV interval prolongation indicates ORGANIC
HV interval prolongation indicates ORGANIC
HEART DISEASE
HEART DISEASE
HV interval in the pts with the syndrome
Brugada JACC 1992

18. Late potentials (which mean late
Late potentials (which mean late
depolarization abnormality) are often
depolarization abnormality) are often
present, and can always be induced
present, and can always be induced
with flecainide
with flecainide

20. Functional
Functional
syndrome!!!
syndrome!!!

21. Dinamic ST behaviour
30% of pts with ths syndrome. How many healthy subject with the ecg???

22. Prevalence of Nava-sign (coved ECG in V1) in
Healthy population.
Reference Total
sujects
Miyasaka 13929
2001
Tohyou 4092
1995
Viskin
592
2000
Hermida 1000
2000
Overall 19613
Mean age Men
Total
examined Prev.
58
27%
0,12%
Men Prev. Women
Prev.
0,38%
0,03%
46
78%
0,07%
0.09%
0,00%
36
58%
0,00%
0,00%
0,00%
39
63%
0,10%
0,16%
0,00%
0,11%
0,23%
0,03%

23. Mortality at follow up of asymptomatic subjects with
Jwave+coved/saddle-back ecg
Suravicz (Editorial) JACC 2001;38:775
Author
Number
Follow up
Sudden death
3
8%
(normal subjects)
Brugada
JCE 2001;12:7-8
????????
Priori
30
1-3
0%
34
1-3
0%
11
3-4
0%
98
2,6
1%
32
1-14
22,4%
"unpublished"
observations in 239
pts/subjects with the
Brugada ECG"
Circulation 2000;102:2509
Atarashi
AJC 1996;78:581
Takenaka
JCE 2001;12:2
Miyasaka
JACC 2001;38:771
Matsuo
JACC 2001;38:765
(mean age 57!!!)

24. PTS with the syndrome of RBB+ST
elevation and sudden death
T o t a l P a t ie n t s 2 9 2
(G IA C 1 9 9 9 ":1 5 7 -7 7 )
4 9 p a t ie n t s
h a d s o m e c a r d ia c
a b n o r m a lit ie s p a r t ic u la r ly
o f t h e r ig h t v e n t r ic le
241 had no
r e c o g n iz e d h e a r t
d is e a s e
b u t , 1 6 o f B r u g a d a s e r ie s
h a d " n o n s p e c ip h ic a b n o r m a lit ie s "

25. What is the
What is the
pathopysiology of these
pathopysiology of these
ECGs?? Two theories
ECGs?? Two theories

26. The organic theory
• The syndrome is due to a concealed right
ventricular pathology (not the typical right
ventricular cardiomyopathy/dysplasia)
which induces a conduction disturbance at
the septal level (responible for the RBBB
pattern), and infundibular (responsible for
the ST elevation).
• All the cases submitted to autopsy have
organic heart disease !!!

27. The Cardiac Pathology of Sudden,
Unexplained Nocturnal Death in
Southeast Asian Refugees
Kirshner RH JAMA 1986;256:2700
• 18 hearts examined
• 14 had cardiomegaly
• 17 had conduction system
abnormalities:
• 14 persistent fetal
dispersion of AV node or
His
• 13 accessory conduction
fibers
• 1 congenital a-v block

28. Familial Cardiomyopathy Underlies Syndrome of RBBB, ST Segment Elevation and
Sudden Death
Corrado D, Nava A, Buja G, Martini B, Thiene G.
JACC 1996;27:443-8
•
A: atrophy, fibrosis, adiposis
of the RVFW
•
B: severe fibrosis of the
bifurcating His bundle with
sclerotic interruption of right
bundle branch
The ecg may be due to aalesion of the conduction
The ecg may be due to lesion of the conduction
tissue both at septal and infundibular level
tissue both at septal and infundibular level

29. Arrhytmogenic Right Ventricular Cardiomyopathy Underlies Syndrome
of Right Bundle Branch Block, ST-Segment Elevation, and Sudden Death
Tada H. Am J Cardiol 1998;81:519
• a) necropsy study in
pt. 2 shows RVC
• b) histologic specimen
from pt 1, at operation
shows RVC

30. The syndrome of right bundle branch block, persistent ST segment elevation
and sudden cardiac death. Which is the histological substrate?
Morgera T. Eur Heart J 1997;18:1190

32. Right Bundle Branch Block, Right Precordial ST-Segment Elevation, and
Sudden Death in Young People
Domenico Corrado, MD; Cristina Basso, MD, PhD; Gianfranco Buja, MD; Andrea Nava,
MD; Lino Rossi, MD; Gaetano Thiene, MD
Circulation.2001;103:710.
Circulation.2001;103:710.

33. Localized RV morphological anomalyes detected by electron beam CT represent arrhythmogenic substrates in pts with Brugada
Syndrome.
Takagy-Aihara Eur Heart J 2001;22:1032-41

34. Localized RV morphological anomalyes detected by electron beam CT represent arrhythmogenic substrates in pts with Brugada
Syndrome.
Takagy-Aihara Eur Heart J 2001;22:1032-41
• Evidence-based: 81% of 26 pts with the syndrome and
coved or Saddle ST had RV abnormalities, mostly in
RVOT. High correlation between QRS morpology of
ectopic beats and RVWMA.
• Brugada interpretation: “the morphological
abnormalityes are secondary to electrical abnormality:
conduction defect and abnormal repolarization”
Brugada Eur Heart J 2001;22:982-4
• Antzelevitch interpretation: localized stunned
myocardium, which can later become organic lesions
secondary to localized SCN5 abormalities. 2001 Public email

35. The functional theory
• The disorder is due to a functional disorder of
repolarization, genetically determined by SCN5A
abnormalities with produced a notch and absence
of the dome in epicardial layers, wich are
responsible for ventricular reentry arrhythmias.
These ecg abnormalities can be evidentiated by
class 1c drugs
• This theory is based on experimental work on Left
Ventricle
• There is not a single anatomic evidence.

36. Brugada-Antzelevitch-Gussak
theories
•
•
•
•
•
•
1992: “prolonged HV suggest His-Purkinje disease”. “Marked dispersion of
refractory periods or extreme anisotropic conduction
1994: disorder related to “M cells”
1996: IT0 channels involvement
1998 mutations of SCN5A genes inducing eterogenicity in epicardial and
endocardial AP in 50% of pts with the ECG
The available data suggest that the Brugada syndrome is a familial primary
electrical disease caused by a defect in an ion channel gene, resulting in
premature repolarization of some right ventricular epicardial sites.
Gussak,Antzelevitch JACC 1998;33:5-15
“the morphological abnormalityes are secondary to electrical conduction
defect and abnormal repolarization” Brugada Eur Heart J 2001;22:982-4

37. Last???
Last???

38. The experiment
The experiment
of Antzelevitch
of Antzelevitch
were devoted to
were devoted to
explain the JJ
explain the
wave in the Left
wave in the Left
Ventricle !!!
Ventricle !!!

39. Images sometime change to demonstrate an
undemonstrable truth
• A) Original imagine by
Antzelevitch. Note V6.
Circulation1996;93:372
• B) Recent imagine by
Alings. Note that V1 has
substitute V6. Moreover,
when J wave is present ST
elevation disappear and
vice-versa. Circulation
1999;99:666

40. The significance of Jwave+st:
science and science fiction
Experiment
Experiment
show nonshow noncoincident
coincident
spontaneous
spontaneous
epicardial
epicardial
notch and loss
notch and loss
of the dome
of the dome
after drug.
after drug.
Note the
Note the
morphology of
morphology of
ECG leads
ECG leads
which
which
rensembles aa
rensembles
V6
V6
Epicardial in vivo
Epicardial in vivo
recording does
recording does
not show
not show
absence of
absence of
epicardial dome
epicardial dome
(2002)
(2002)
Drawing by
Drawing by
Align, transform
Align, transform
the experimental
the experimental
V6 in V1, and
V6 in V1, and
confirms that if
confirms that if
you have JJwave,
you have wave,
you do not have
you do not have
ST elevation
ST elevation

41. Prevalence of SCN5A
abnormalities
• Brugada:50%,
• Priori:20%,
• Breithard: 10%
Does presence of SCNA
Does presence of SCNA
abnormality exclude organic
abnormality exclude organic
heart disease?
heart disease?

42. Chen et al, Nature 1998

43. Variant of SCN5A Sodium Channel Implicated in Risk of
Cardiac Arrhythmia
Igor Splawski,1* Katherine W. Timothy,2 Michihiro Tateyama,3 Colleen E. Clancy,3 Alka Malhotra,2 Alan H. Beggs,4 Francesco P.
Cappuccio,5 Giuseppe A. Sagnella,6 Robert S. Kass,3 Mark T. Keating1*
Every year, ~450,000 individuals in the United States die suddenly of cardiac
arrhythmia. We identified a variant of the cardiac sodium channel gene SCN5A that is
associated with arrhythmia in African Americans (P = 0.000028) and linked with
arrhythmia risk in an African-American family (P = 0.005). In transfected cells, the
variant allele (Y1102) accelerated channel activation, increasing the likelihood of
abnormal cardiac repolarization and arrhythmia. About 13.2% of African Americans
carry the Y1102 allele. Because Y1102 has a subtle effect on risk, most carriers will
never have an arrhythmia. However, Y1102 may be a useful molecular marker for the
prediction of arrhythmia susceptibility in the context of additional acquired risk factors
such as the use of certain medications.
Science 2002 297: 1252

44. BrugadaBrugadaAntzelevitch
Antzelevitch
theory
theory
But !!!!
But !!!!

45. Flecainide challenge
• This test has been proposed to make a
speciphic diagnosis of the syndrome.
• Despite enthusiasm this has not beeen
confirmed
• Flecainide is retained to induce
repolarization abnormalities, but all the
evidence is that the drug induces a
depolarization disturbance !!!

46. Ajmaline Test
Ajmaline Test
proposed by
proposed by
Brugada,
Brugada,
should induce
should induce
aatypical
typical
functional
functional
repolarization
repolarization
abnormality
abnormality

47. But Flecainide has effects on depolarization
But Flecainide has effects on depolarization
and not on repolarization ! !
and not on repolarization
MECHANISMS OF THE PROARRHYTHMIC
EFFECTS OF FLECAINIDE AND RELATED
ATIARRHYTHMIC DRUGS
• “Class 1C drugs induce a depression in
conduction property of the electrical impulse”
• “This effect is due to a decrease in the number
of Na+ channels available during phase 0”
• “The upstroke of phase 0 is decreased and
conduction velocity is depressed”
Brugada J.
Brugada J.
The New Frontiers of Arrhythmias.
The New Frontiers of Arrhythmias.
1992, pag. 353
1992, pag. 353

48. Science and science fiction
Experiments with
Experiments with
flecainide, do not induce
flecainide, do not induce
JJwave or ST elevation
wave or ST elevation
But drawing can
But drawing can
do that !!!
do that !!!

49. Flacainide test induces repolarization or
depolarization abnormality?
No late
No late
potentials
potentials
Induction of late
Induction of late
potentials, can
potentials, can
be only due to aa
be only due to
conduction
conduction
disturbance and
disturbance and
not to
not to
repolarizattion
repolarizattion
abnormality !!
abnormality !!

50. Brugada
Brugada
experiment
experiment
Circulation
Circulation
2000;101:510
2000;101:510
True pt. With the
True pt. With the
same ecg
same ecg
withourt drugs
withourt drugs
The ecg is DUE to conduction
The ecg is DUE to conduction
disturbance and not repolarization
disturbance and not repolarization
abnormality !!
abnormality !!

51. Flecainide is speciphic for a functional disorder
Brugada, Circulation 2000
• But
• This patient has RVC
• flecainide test is
positive
• Linkage analysis
shows chromosome 14
involvement

52. Www.brugada.crtia.be

53. Clinical and genetic Heterogeneity of RBBB and
ST_Segment elevation Syndrome.
A prospective evaluation in 52 Families
Priori Circulation 2000;102:2509
• 15% prevalence of SCN
% genes abnormalities
• No SD in asymptomatic
• Limited value of PES
(PPV50%, NPV 46%)
• Flecainide challenge
unable to unmask silent
gene carriers (PPV 35%)

54. Organic and Functional syndromes:
differences and similarities
Nava-Martini-Thiene
Clinical
Sudden death due to VF,
Picture
in middle aged males
Ecg
1)J wave + coved, saddle
or dome ST
2)RBBB+LAD+PR>
3)Isolate ST abnormality
4)Class 1c +
HV interval
Not rarely Prolonged
Late potentials Positive
RVOT delay
Present
Familiarity
Present
Eco, Angio,
Often positive for organic
NMR, electron heart disease
beam CT
Biopsy
Fibrosis, adiposis
Necropsy
Right Ventricular
Cardiomyopathy+ His
lesion
Chromosome 14 ??
Chromosome ???
Genetic
abnormality
Brugada
Same
Same
Same
Same
Not investigated
Present
Always negative.
Recent admission
of localized
abnormalities
(stunned M)
“Non speciphic”
abnormalities
Never performed
SCN5A??
Chromosome 3??

55. 1933:death has a functional or
anatomic substrate?
2003?

56. The brugada syndrome. Do we need more than the
12-lead ECG?
J. Farré Eur Heart J 2000-21-264
• The syndrome is a
Clinical-ECG
association.
• The ECG pattern itself is
not speciphic
• Flecainide is not
speciphic
• Syncope may be vagal
• We need research tools
other than the ECG

57. The syndrome of sudden death,
RBBB and ST elevation
• Nobody has yet the true !!

58. Andrea Nava and Bortolo Martini
Andrea Nava and Bortolo Martini

59. New book 2013
•
Chapter 1
•
•
ARARE LETHAL SYNDROME IN SEARCH
OF ITS IDENTITY: SUDDEN DEATH, RIGHT
• BUNDLE BRANCH BLOCK AND ST
• SEGMENT ELEVATION
•
•
Bortolo Martini,1,* Jiashin Wu2 and Andrea Nava3
1Director of the Cardiovascular Unit, Boldrini Hospital, Thiene, Italy
•
2University of South Florida, US
•
3Associate Professor of Cardiology, University of Padua, Italy

60. bortolo.martini@gmail.com