The so Called Brugada Syndrome The True History


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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.

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  • Brugada Mutations
    InsAA – failure of channel to express
    Frameshift Mutation-premature stop at 1397 – 4340delA S5-S6 of Domain III – failure to express
    R1432G (also bet S5 and S6 of Domain III) – failure to express
    1795InsD – Brugada and LQT – positive shift of activation curve (negative shift of inactivation) reduced Ina…
    T1620M – positive shift of activation curve and markedly faster inactivation - reduced Ina during phase 1…
    L567Q – accelerated inactivation (small positive shit of activation and negative shift of inactivation - reduced Ina during phase 1.
    A1924T negative shift of activation curve (-9 mV) - cannot explain phenotype
    R1512W negative shift of activation (-5.1 mV) and small negative shift of inactivation (-3.8 mV) curves – cannot explain phenotype
  • The so Called Brugada Syndrome The True History

    1. 1. The “so called” Brugada syndrome The true history! Bortolo Martini M.D. January 2014
    2. 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. 3. What is this syndrome?
    4. 4. First oral presentation of a new “clinicalECG syndrome” at the Italian Association of Cardiology : 1988
    5. 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. 6. This is an ECG and not a syndrome !!!!!!!!!!!!!!!!!!!
    7. 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. 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. 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. 10. The third description! The third description!
    11. 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. 12. A clinico – ECG association (Not an isolated ECG!!!)
    13. 13. A disease with familial involvement, mainly affecting males
    14. 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
    15. 15. 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
    16. 16. 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
    17. 17. 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
    18. 18. Functional Functional syndrome!!! syndrome!!!
    19. 19. Dinamic ST behaviour 30% of pts with ths syndrome. How many healthy subject with the ecg???
    20. 20. 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%
    21. 21. 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!!!)
    22. 22. 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 "
    23. 23. What is the What is the pathopysiology of these pathopysiology of these ECGs?? Two theories ECGs?? Two theories
    24. 24. 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 !!!
    25. 25. 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
    26. 26. 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
    27. 27. 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
    28. 28. 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
    29. 29. 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.
    30. 30. 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
    31. 31. 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
    32. 32. 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.
    33. 33. 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
    34. 34. Last??? Last???
    35. 35. 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 !!!
    36. 36. 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
    37. 37. 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
    38. 38. 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?
    39. 39. Chen et al, Nature 1998
    40. 40. 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
    41. 41. BrugadaBrugadaAntzelevitch Antzelevitch theory theory But !!!! But !!!!
    42. 42. 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 !!!
    43. 43. Ajmaline Test Ajmaline Test proposed by proposed by Brugada, Brugada, should induce should induce aatypical typical functional functional repolarization repolarization abnormality abnormality
    44. 44. 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
    45. 45. 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 !!!
    46. 46. 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 !!
    47. 47. 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 !!
    48. 48. 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
    49. 49.
    50. 50. 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%)
    51. 51. 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??
    52. 52. 1933:death has a functional or anatomic substrate? 2003?
    53. 53. 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
    54. 54. The syndrome of sudden death, RBBB and ST elevation • Nobody has yet the true !!
    55. 55. Andrea Nava and Bortolo Martini Andrea Nava and Bortolo Martini
    56. 56. 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
    57. 57.