CANALOPATIAS,
MUERTE SUBITA
Y
DAI
Andrés Bodegas
Unidad de Arritmias y Marcapasos
Hospital de Cruces
CANALOPATÍAS
SINDROMES ARRITMICOS PRIMARIOS (Muerte súbita)
 Síndrome
Síndrome QTQT
LargoLargo






Síndrome QT corto
Síndrome Brugada
TV Catecolaminérgica
Síndrome Leenhardt
Fibrilacion Ventricular Idiopática
Síndrome QT Largo - Genes Responsables
ARRITMIA CROMOSOMA
GEN
FRECUENCIA
• QTc normal: 36%
AUTOSOMICO
DOMINANTE
Desencadenante (88%):
QTL1
QTL2
QTL3
Emocion, hiperactividad simpatica
I1p15
KCNQI
7q35
KCNH2
3p21
SCN5A
50%
30-40%
10%
QTL4
QTL5
QTL6
• QTc normal:
4q25 19%
ANK2
Desencadenante:
21q22
KCNEI
Emocion, est. auditivos,
reposo
21q22
KCNE2
Raro
Raro
Raro
QTL7
17
AUTOSOMICO
Raro
• QTc normal: 10%
KCNJ2
RECESIVO
QTL8
I1P15DEPENDIENTE,
KCNQI
Inicio
de las T de
P, PAUSA
es predominante Raro
en el SQTL2 y
Desencadenante:
ausentesueño
o raro en el SQTL1
Reposo,
QTL9
21Q22
KCNQ2
Tan H, et al. Circulation.2006;114:2096 14.XI.06
Raro
Mutant Caveolin-3 Induces Persistent Late Sodium Current and Is Associated
With Long-QT Syndrome
Vatta, Matteo PhD*; Ackerman, Michael J. MD, PhD*; Ye, Bin PhD; Makielski, Jonathan C. MD; Ughanze,
Enoh E. MD; Taylor, Erica W. BS; Tester, David J. BS; Balijepalli, Ravi C. PhD; Foell, Jason D. BS; Li,
Zhaohui PhD; Kamp, Timothy J. MD, PhD; Towbin, Jeffrey A. MD
From the Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston (M.V., E.E.U., E.W.T.,
Z.L., J.A.T.); Departments of Internal Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics,
Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, Minn (M.J.A.,
D.J.T.); and Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison (B.Y., J.C.M.,
R.C.B., J.D.F., T.J.K.). Circulation 2006;:2104 14.XI.2006
Background: Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from
perturbed cardiac repolarization. LQTS, which affects [almost equal to]1 in 3000 persons, is 1 of the most common
causes of autopsy-negative sudden death in the young. Since the sentinel discovery of cardiac channel gene mutations
in LQTS in 1995, hundreds of mutations in 8 LQTS susceptibility genes have been identified. All 8 LQTS genotypes
represent primary cardiac channel defects (ie, ion channelopathy) except LQT4, which is a functional channelopathy
because of mutations in ankyrin-B. Approximately 25% of LQTS remains unexplained pathogenetically. We have
pursued a “final common pathway” hypothesis to elicit novel LQTS-susceptibility genes. With the recent observation
that the LQT3-associated, SCN5A-encoded cardiac sodium channel localizes in caveolae, which are known membrane
microdomains whose major component in the striated muscle is caveolin-3, we hypothesized that mutations in
caveolin-3 may represent a novel pathogenetic mechanism for LQTS.
Methods and Results: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and
direct DNA sequencing, we performed open reading frame/splice site mutational analysis on CAV3 in 905 unrelated
patients referred for LQTS genetic testing. CAV3 mutations were engineered by site-directed mutagenesis and the
molecular phenotype determined by transient heterologous expression into cell lines that stably express the cardiac
sodium channel hNav1.5. We identified 4 novel mutations in CAV3-encoded caveolin-3 that were absent in >1000
control alleles. Electrophysiological analysis of sodium current in HEK293 cells stably expressing hNa v1.5 and
transiently transfected with wild-type and mutant caveolin-3 demonstrated that mutant caveolin-3 results in a 2- to 3fold increase in late sodium current compared with wild-type caveolin-3. Our observations are similar to the increased
late sodium current associated with LQT3-associated SCN5A mutations.
Conclusions: The present study reports the first CAV3 mutations in subjects with LQTS, and we provide functional
data demonstrating a gain-of-function increase in late sodium current.
Conclusions: The present study reports the first CAV3
mutations in subjects with LQTS, and we provide functional
data demonstrating a gain-of-function increase in late sodium
current.
Síndrome QT Largo
ESTRATIFICACION DEL RIESGO

Intervalo QTc
Síndrome QT Largo
ESTRATIFICACION DEL RIESGO
PROBABILIDAD DE 1ºEVENTO ENTRE 10-20 AÑOS (DEPENDIENDO DEL QTc)
1.- La detección de un QTc>500
ms y su seguimiento identifica a
los p. con alto riesgo de eventos
cardiacos.
2.- Es necesario obtener ECG
seriados.
Goldenberg, I. Mathew J. et al. Corrected QT Variability in Serial Electrocardiograms in Long QT Syndrome J Am Coll Cardiol 2006;48:1047 septiembre 2006
Síndrome QT Largo
ESTRATIFICACION DEL RIESGO
Intervalo QTc
 Fenotipo → Sindrome Jervel-Lange-Nielsen

Síndrome QT Largo - Genes Responsables
ARRITMIA CROMOSOMA
GEN
FRECUENCIA
AUTOSOMICO DOMINANTE
QTL1
QTL2
Sindrome
QTL3
I1p15
KCNQI
7q35
KCNH2
Jervell-Lange-Nielsen
3p21
SCN5A
50%
30-40%
10%
QTL4
QTL5
QTL6
4q25
21q22
21q22
ANK2
KCNEI
KCNE2
Raro
Raro
Raro
QTL7
17
AUTOSOMICO
KCNJ2
RECESIVO
Raro
QTL8
QTL9
I1P15
21Q22
KCNQI
KCNQ2
Raro
Raro
ESTRATIFICACION DEL RIESGO
JLNS (n = 44)
Age at last contact (mean ± SD)
Any cardiac event (%)†
20.1 ± 11.4
86*
Age at first cardiac event (mean ± SD)
5.0 ± 7.0*
RWS (n = 2,174)
LQT1 (n = 285)
29.1 ± 12.5
28.8 ± 12.9
46
48
14.2 ± 9.3
12.1 ± 8.9
Fatal/Near-fatal event (%)‡
30*
11
7
Age at first fatal/near-fatal event (mean ± SD)
14.5 ± 9.0
19.3 ± 10.7
24.2 ± 9.6
Syncope (%)
84*
43
47
TdP (%)
17*
7
2
VF (%)
15*
6
3
Aborted cardiac arrest, at anytime (%)
14*
8
5
LQTS-related death (%)
19*
4
2
Noise (%)
7
15
5
Emotions (%)
58*
29
28
Physical activity (%)
62*
40
58
Swimming (%)
38*
17
38
Missed Beta-blocker therapy (%)
22*
5
5
Pregnancy (%)
7
9
5
Sleep (%)
25
16
3
Arousal (%)
13
8
4
Events by type during follow-up
Event factor
Values are given as percentages.
*P < 0.05 for the comparison between the JLNS and the RWS groups. †Defined as first syncope, aborted cardiac arrest, or LQTS-death. ‡Defined as first aborted cardiac
arrest or LQTS-death. JLNS = Jervell and Lange-Nielsen syndrome; LQT1 = type 1 long-QT syndrome; RWS = Romano-Ward syndrome; TdP = torsade de pointes; VF
= ventricular fibrillation.
Goldenberg, I. Moss, A. et al. Clinical Course and Risk Stratification of Patients Affected with the JLN Syndrome. J Cardiovasc Electrophysiol 17 2006 (11), 1161-1168.
Síndrome QT Largo
ESTRATIFICACION DEL RIESGO
RIESGO DE UN PRIMER EVENTO FATAL
Goldenberg, I. Moss, A. et al. Clinical Course and Risk Stratification of Patients Affected with the JLN Syndrome. J Cardiovasc Electrophysiol 17 2006:(11), 1161-1168.
Síndrome QT Largo
ESTRATIFICACION DEL RIESGO
Intervalo QTc
 Fenotipo → Sindrome JLN
 Clínica

Los pacientes resucitados de una PC (MS) tienen un
peor pronóstico, con un riesgo de 12.9 veces mayor.
Moss, A. Zareba, J. et al. Effectiveness and limitations of BBtherapy in congenital long QT syndrome. Circulation 2000;101:960
Síndrome QT Largo
ACC/AHAESC 2006 Guidelines for Management of
Patients With Ventricular Arrhythmias and the
Prevention of Sudden Cardiac Death
Circulation 2006;114:1088 (septiembre 2006)
Recomendaciones CLASE I:
1.
2.
3.
Modificación del estilo de vida (B)
Tratamiento con BB (B)
Implante de DAI en Parada Cardiaca previa (A)
CANALOPATÍAS

Síndrome QT Largo
 Síndrome




QT corto
Síndrome Brugada
TV Catecolaminérgica
Síndrome Leenhardt
Fibrilacion Ventricular Idiopática
Síndrome Clinico
GEN
Consecuencia Functional
Herencia
Long QT1 syndrome
KCNQ1KvLQT1
IKs loss of function
AD
Jervell-Lange-Nielsen
type I
KCNQ1
IKs loss of function
AR
Familial atrial
fibrillation
KCNQ1
IKs gain of function
AD
Short QT syndrome
KCNQ1
IKs gain of function
AD
Long QT5 syndrome
KCNE1 /MinK/
IKs loss of function
AD
Jervell-Lange-Nielsen
type II
KCNE1
IKs loss of function
AR
Long QT2 syndrome
KCNH2 /HERG/
IKr loss of function
AD
Short QT syndrome
KCNH2
IKr gain of function
AD
Long QT6 syndrome
KCNE2 /MiRP1/
IKr loss of function
AD
IK1
Andersen/long QT7
KCNJ2 /Kir2.1/
IK1 loss of function
AD
INa
Long QT3
SCN5A
INa gain of function
AD
Brugada syndrome
SCN5A
INa loss of function
AD
Lenegre/PCCD
SCN5A
INa loss of function
AD
Sick sinus Syndrome
SCN5A
INa loss of function
AR
If
Sick sinus syndrome
HCN4
If loss of function
?
Anchoring
protein
Long QT4 syndrome
ANK2
Ion channel targeting
AD
CPVT1
RyR2
Calcium release
AD
CPVT2
CASQ2
Calcium storage
AR
Proteina
Canalopatías
IKs
IKr
Intracellu
lar Ca+
movement
CANALOPATÍAS


Síndrome QT Largo
Síndrome QT corto
 Síndrome



Brugada
TV Catecolaminérgica
Síndrome Leenhardt
Fibrilacion Ventricular Idiopática
Síndrome Brugada
Indicaciones de DAI (I)
ECG ESPONTANEO TIPO 1
ASINTOMATICO
SINTOMATICO
MS
Hª FAMILIAR DE MS
SINCOPE
Evaluación causa EC
DAI (Clase I)
+
Seguimiento
NO Hª FAMILIAR DE MS
EP justificado (Clase IIa)
EP (Clase IIa)
+
-
DAI (Clase IIa)
Seguimiento
+
DAI (Clase IIa)
Seguimiento
Clase I: Hay consenso general
Clase IIa: Opción válida, sin consenso general, se
Se recomienda EEF (TSV)
apoya en múltiples estudios de grandes pacientes
Clase IIb: Opción válida, sin consenso general, se
apoya en limitado numero de estudios
ANTZELEVITCH,Ch. Brugada Syndrome.PACE;2006;29(10),1130-1159. Octubre 2006
Síndrome Brugada
Indicaciones de DAI (II)
ECG TIPO 1 INDUCIDO CON FARMACOS
ASINTOMATICO
SINTOMATICO
MS
Hª FAMILIAR DE MS
SINCOPE
Evaluación causa EC
(Clase I) DAI (Clase IIa)
+
Seguimiento
NO Hª FAMILIAR DE MS
EP justificado (Clase IIb)
EP (Clase IIb)
+
-
DAI (Clase IIb)
Seguimiento
+
DAI (Clase IIb)
Seguimiento
Clase I: Hay consenso general
Clase IIa: Opción válida, sin consenso general, se
Se recomienda EEF (TSV)
apoya en múltiples estudios de grandes pacientes
Clase IIb: Opción válida, sin consenso general, se
apoya en limitado numero de estudios
ANTZELEVITCH,Ch. Brugada Syndrome.PACE;2006;29(10),1130-1159. Octubre 2006
Síndrome Brugada
ACC/AHAESC 2006 Guidelines for Management of
Patients With Ventricular Arrhythmias and the
Prevention of Sudden Cardiac Death
Circulation 2006;114:1088 (septiembre 2006)
CLASE I: Implante de DAI en pacientes diagnosticados de
Síndrome Brugada y Parada Cardiaca previa (C)
CLASE IIa: Implante de DAI es razonable en pacientes
diagnosticados de Síndrome Brugada con clinica de
Síncope con o sin gen SCN5A (C)
CLASE IIb: La EP puede estratificar el riesgo en pacientes
asintomaticos diagnosticados de Síndrome Brugada con
clinica de Síncope con o sin gen SCN5A (C)
CANALOPATÍAS



Síndrome QT Largo
Síndrome QT corto
Síndrome Brugada
 TV


Catecolaminérgica
Síndrome Leenhardt
Fibrilacion Ventricular Idiopática
TV Catecolaminérgica
►►
Síndrome Clinico
GEN
Consecuencia Functional
Herencia
Long QT1 syndrome
KCNQ1KvLQT1
IKs loss of function
AD
Jervell-Lange-Nielsen
type I
KCNQ1
IKs loss of function
AR
Familial atrial
fibrillation
KCNQ1
IKs gain of function
AD
Short QT syndrome
KCNQ1
IKs gain of function
AD
Long QT5 syndrome
KCNE1 /MinK/
IKs loss of function
AD
Jervell-Lange-Nielsen
type II
KCNE1
IKs loss of function
AR
Long QT2 syndrome
KCNH2 /HERG/
IKr loss of function
AD
Short QT syndrome
KCNH2
IKr gain of function
AD
Long QT6 syndrome
KCNE2 /MiRP1/
IKr loss of function
AD
Andersen/long QT7
KCNJ2 /Kir2.1/
IK1 loss of function
AD
SCN5A
INa gain of function
AD
Brugada syndrome
SCN5A
INa loss of function
AD
Lenegre/PCCD
SCN5A
INa loss of function
AD
Sick sinus Syndrome
SCN5A
INa loss of function
AR
If
Sick sinus syndrome
HCN4
If loss of function
?
Anchoring
protein
Long QT4 syndrome
ANK2
Ion channel targeting
AD
Proteina
Canalopatías
Ejercicio
IKs
IKr
IK1
INa
Long
Ejercicio
►►
QT3
Intracellu CPVT1
RyR2
Calcium release
AD
+
lar
Ca
Sarkozy A, Brugada P, Sudden Cardiac Death and Inherited Arrhythmia Syndromes. J Cardiovasc Electrophysiol 16
CPVT2
CASQ2
Calcium storage
AR
TV Catecolaminérgica
ACC/AHAESC 2006 Guidelines for Management of
Patients With Ventricular Arrhythmias and the
Prevention of Sudden Cardiac Death
Circulation 2006;114:1088 (septiembre 2006)
CLASE I:
 1. BB en presencia de TV documentadas por el estrés
 2. DAI y BB en supervivientes de PC
CLASE IIa:
 1. BB pueden ser efectivos en asintomáticos pero con
diagnóstico genético
 2. DAI y BB con Síncope o TV documentada
CANALOPATÍAS




Síndrome QT Largo
Síndrome QT corto
Síndrome Brugada
TV Catecolaminérgica
 Síndrome

Leenhardt
Fibrilacion Ventricular Idiopática
Síndrome Leenhardt
Síndrome Leenhardt
CANALOPATÍAS





Síndrome QT Largo
Síndrome QT corto
Síndrome Brugada
TV Catecolaminérgica
Síndrome Leenhardt
 Fibrilacion
Ventricular Idiopática
Fibrilación Ventricular Idiopática
Fibrilación Ventricular Idiopática
EPISODIOS DE FV
HORAS/DIA
RECIDIVAS/MESES
SOSTENIDO
NO SOSTENIDO
2
2
1
0
1
El 50% el 1º mes
1º EPISODIO
RECIDIVA
> 50% de las 1º año NO SOSTENIDAS
20.01-22
•
3
3
16.01-18
4
12.01-14
•
8.01-10
4
Recidivas:
4.01-6
5
0-2
5
0
0-12
13-24
25-36
37-48
49-60
•
De 6-20EPISODIOS
horas ocurren
el 90%.
DE FV
DIAS DE LA SEMANA
•
81% de los 1º episodios
•
100% de las Recidivas
5
4
•
Los 1º episodios:
Miercoles, Jueves y Domingo (63%)
3
2
1º EPISODIO
RECIDIVA
Domingo
Sábado
Viernes
Jueves
0
Miércoles
Las Recidivas:
Miercoles, Jueves y Domingo (75%)
Martes
•
Lunes
1
Eguía I, Bodegas A, Arana JI, Barrenetxea JI. (Congreso Nacional de Cardiología: Octubre 2006)
CANALOPATÍAS, MS y DAI
GRACIAS
POR
SU ATENCION