so called brugada syndrome the true history
DESCRIPTION
TRANSCRIPT
Stigler’s law
• no scientific discovery is named after its original discoverer.
Stephen M. Stigler is Professor of Statistics at the University of Chicago.
Stephen M. Stigler is Professor of Statistics at the University of Chicago.
What is this syndrome?
First oral presentation of a new “clinical-ECG syndrome” at the Italian
Association of Cardiology : 1988
• 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
Nava-sign
This is an ECG and not a syndrome !!!!!!!!!!!!!!!!!!!
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?
In this article all the typical ECG pattern of the syndrome were described
In this article all the typical ECG pattern of the syndrome were described
Shinzo 1990;22(suppl 2):80Shinzo 1990;22(suppl 2):80
The 2nd paper on the syndrome was published in Japan!The 2nd paper on the syndrome was published in Japan!
The third description!The third description!
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
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
In this article all the ECG patterns of the syndrome were described
The ecg pattern is due to CONDUCTION DELAY AT THE rvot.
Nava 1988
The ecg pattern is due to CONDUCTION DELAY AT THE rvot.
Nava 1988
HV interval in the pts with the syndromeBrugada JACC 1992
HV interval prolongation indicates ORGANIC HEART DISEASE
HV interval prolongation indicates ORGANIC HEART DISEASE
Late potentials (which mean late depolarization abnormality) are often present, and can always be induced with flecainide
Late potentials (which mean late depolarization abnormality) are often present, and can always be induced with flecainide
Functional syndrome!!!
Functional syndrome!!!
Dinamic ST behaviour30% of pts with ths syndrome. How many healthy subject with the ecg???
Prevalence of Nava-sign (coved ECG in V1) inHealthy population.
Reference Totalsujects
Mean age Menexamined
TotalPrev.
Men Prev. WomenPrev.
Miyasaka2001
13929 58 27% 0,12% 0,38% 0,03%
Tohyou1995
4092 46 78% 0,07% 0.09% 0,00%
Viskin2000
592 36 58% 0,00% 0,00% 0,00%
Hermida2000
1000 39 63% 0,10% 0,16% 0,00%
Overall 19613 0,11% 0,23% 0,03%
Mortality at follow up of asymptomatic subjects with Jwave+coved/saddle-back ecg
Suravicz (Editorial) JACC 2001;38:775
Author Number(normal subjects)
Follow up Sudden death
BrugadaJCE 2001;12:7-8 ????????
"unpublished"observations in 239pts/subjects with theBrugada ECG"
3 8%
PrioriCirculation 2000;102:2509
30 1-3 0%
AtarashiAJC 1996;78:581
34 1-3 0%
TakenakaJCE 2001;12:2
11 3-4 0%
MiyasakaJACC 2001;38:771
98 2,6 1%
MatsuoJACC 2001;38:765
32 1-14 22,4%(mean age 57!!!)
PTS with the syndrome of RBB+ST elevation and sudden death
4 9 p a tien tsh ad som e card iac
ab n orm a lit ies p articu la rlyo f th e rig h t ven tric le
b u t, 1 6 o f B ru g ad a se riesh ad "n on sp ec ip h ic ab n orm a lit ies "
2 4 1 h ad n orecog n ized h eart
d isease
Tota l P a tien ts 2 9 2(G IA C 1 9 9 9 ":1 5 7 -7 7 )
What is the pathopysiology of these ECGs?? Two theories
What is the pathopysiology of these ECGs?? Two theories
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 !!!
The Cardiac Pathology of Sudden, Unexplained Nocturnal Death in
Southeast Asian RefugeesKirshner 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
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 a lesion of the conduction tissue both at septal and infundibular level
The ecg may be due to a lesion of the conduction tissue both at septal and infundibular level
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
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
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.
Localized RV morphological anomalyes detected by electron beam C-T represent arrhythmogenic substrates in pts with Brugada
Syndrome.Takagy-Aihara Eur Heart J 2001;22:1032-41
Localized RV morphological anomalyes detected by electron beam C-T 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 e-mail
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.
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
Last???Last???
The experiment of Antzelevitch were devoted to explain the J wave in the Left Ventricle !!!
The experiment of Antzelevitch were devoted to explain the J wave in the Left Ventricle !!!
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
The significance of Jwave+st: science and science fiction
Epicardial in vivo recording does not show absence of epicardial dome (2002)
Epicardial in vivo recording does not show absence of epicardial dome (2002)Experiment
show non-coincident spontaneous epicardial notch and loss of the dome after drug. Note the morphology of ECG leads which rensembles a V6
Experiment show non-coincident spontaneous epicardial notch and loss of the dome after drug. Note the morphology of ECG leads which rensembles a V6
Drawing by Align, transform the experimental V6 in V1, and confirms that if you have J wave, you do not have ST elevation
Drawing by Align, transform the experimental V6 in V1, and confirms that if you have J wave, you do not have ST elevation
Prevalence of SCN5A abnormalities
• Brugada:50%, • Priori:20%, • Breithard: 10%
Does presence of SCNA abnormality exclude organic heart disease?
Does presence of SCNA abnormality exclude organic heart disease?
Chen et al, Nature 1998
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
Brugada-Antzelevitch theory
Brugada-Antzelevitch theory
But !!!!But !!!!
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 !!!
Ajmaline Test proposed by Brugada, should induce a typical functional repolarization abnormality
Ajmaline Test proposed by Brugada, should induce a typical functional repolarization abnormality
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.
The New Frontiers of Arrhythmias. 1992, pag. 353
Brugada J.
The New Frontiers of Arrhythmias. 1992, pag. 353
But Flecainide has effects on depolarization and not on repolarization !
But Flecainide has effects on depolarization and not on repolarization !
Science and science fiction
Experiments with flecainide, do not induce J wave or ST elevation
Experiments with flecainide, do not induce J wave or ST elevation
But drawing can do that !!!
But drawing can do that !!!
Flacainide test induces repolarization or depolarization abnormality?
No late potentials
No late potentials
Induction of late potentials, can be only due to a conduction disturbance and not to repolarizattion abnormality !!
Induction of late potentials, can be only due to a conduction disturbance and not to repolarizattion abnormality !!
Brugada experiment
Circulation 2000;101:510
Brugada experiment
Circulation 2000;101:510
True pt. With the same ecg withourt drugs
True pt. With the same ecg withourt drugs
The ecg is DUE to conduction disturbance and not repolarization abnormality !!
The ecg is DUE to conduction disturbance and not repolarization abnormality !!
Flecainide is speciphic for a functional disorderBrugada, Circulation 2000
• But• This patient has RVC• flecainide test is
positive• Linkage analysis
shows chromosome 14 involvement
Www.brugada.crtia.be
Clinical and genetic Heterogeneity of RBBB and ST_Segment elevation Syndrome.
A prospective evaluation in 52 FamiliesPriori 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%)
Organic and Functional syndromes:differences and similarities
Nava-Martini-Thiene BrugadaClinicalPicture
Sudden death due to VF,in middle aged males
Same
Ecg 1)J wave + coved, saddleor dome ST2)RBBB+LAD+PR>3)Isolate ST abnormality4)Class 1c +
Same
HV interval Not rarely Prolonged SameLate potentials Positive SameRVOT delay Present Not investigatedFamiliarity Present PresentEco, Angio,NMR, electronbeam CT
Often positive for organicheart disease
Always negative.Recent admissionof localizedabnormalities(stunned M)
Biopsy Fibrosis, adiposis “Non speciphic”abnormalities
Necropsy Right VentricularCardiomyopathy+ Hislesion
Never performed
Geneticabnormality
Chromosome 14 ??Chromosome ???
SCN5A??Chromosome 3??
1933:death has a functional or anatomic substrate?
2003?
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
The syndrome of sudden death, RBBB and ST elevation
• Nobody has yet the true !!
Andrea Nava and Bortolo MartiniAndrea Nava and Bortolo Martini
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
