An evolving reality of Medicine – Part genetic, part acquired Long QT and Brugada syndromes
Ramon Brugada MD, PhD, FACC, FESC Cardiologist, Hospital Josep Trueta Director Clinical Cardiovascular Genetics Center Professor of Medicine, University of Girona Girona, Spain
GENETIC DISEASES ASSOCIATED WITH SUDDEN CARDIAC DEATH
CARDIOMYOPATHIES CHANNELOPATHIES GENETIC DISEASES ASSOCIATED WITH SUDDEN CARDIAC DEATH
Short QT syndrome Brugada syndrome
CPVT Long QT syndrome ACTION POTENTIAL-ION CHANNELS-INHERITED ARRHYTHMIAS LONG QT SYNDROME: DIAGNOSIS BRUGADA SYNDROME: DIAGNOSIS
Type 1 “Coved
Type 2 & 3 “Saddle back”
NON DIAGNOSTIC BRUGADA SYNDROME: DIAGNOSIS BRUGADA SYNDROME: DIAGNOSIS BRUGADA SYNDROME: ST SEGMENT MAY NORMALIZE GENETIC DISEASES ASSOCIATED WITH SUDDEN CARDIAC DEATH
Genetic diseases
Channelopathies Cardiomyopathies 60% 30% 50%
50% 80% 60% 60% LONG QT SYNDROME: GENETIC BASIS
GENE LOCUS PROTEIN KCNQ1 (LQT1) 11p15.5 IKs potassium channel α subunit (KvLQT1, Kv7.1) KCNH2 (LQT2) 7q35-36 IKr potassium channel α subunit (HERG, Kv11.1) SCN5A (LQT3) 3p21-p24 Cardiac sodium channel α subunit (Nav1.5)
AKAP9 7q21-q22 Yotiao ANK2 4q25-q27 Ankyrin B CACNA1C 12p13.3 Voltage gated L-type calcium channel (Cav1.2) CALM1 14q32.11 Calmodulin CALM2 2p21 Calmodulin CAV3 3p25 Caveolin-3 KCNE1 21q22.1 Kv7.1 potassium channel beta subunit (MinK) KCNE2 21q22.1 Kv11.1 potassium channel beta subunit (MiRP1) KCNJ2 (ATS1) 17q23 IK1 potassium channel (Kir2.1) KCNJ5 11q24.3 Potassium inwardly-rectifying channel (Kir3.4) SCN4B 11q23.3 Sodium channel beta 4 subunit SNTA1 20q11.2 Syntrophin-alpha 1 BRUGADA SYNDROME: GENETIC BASIS
GENE LOCUS PROTEIN CACNA1C 12p13.33 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA2D1 7q21.11 Voltage-dependent calcium channel subunit alpha-2/delta-1 CACNB2 10p12.33-p12.31 Voltage-dependent L-type calcium channel subunit beta-2 GPD1L 3p22.3 Glycerol-3-phosphate dehydrogenase 1-like protein HCN4 15q24.1 Potassium/sodium hyperpolarization-activated cyclic channel KCND3 1p13.2 Potassium voltage-gated channel subfamily D member 3 KCNE3 11q13.4 Potassium voltage-gated channel subfamily E member 3 KCNE5 Xq23 Potassium voltage-gated channel subfamily E member 1-like protein KCNJ 12p12.1 ATP-sensitive inward rectifier potassium channel 8 PKP2 12p11.21 Plakophilin-2 RANGRF 17p13.1 Ran guanine nucleotide release factor SCN1B 19q13.11 Sodium channel subunit beta-1 SCN2B 11q23.3 Sodium channel subunit beta-2 SCN3B 11q24.1 Sodium channel subunit beta-3 SCN5A 3p22.2 Sodium channel protein type 5 subunit alpha SLMAP 3p14.3 Sarcolemmal membrane-associated protein TRPM4 19q13.33 Transient receptor potential cation channel subfamily M member 4 INHERITED DISEASES: NEW FORMS OF VARIANTS?
Transcription regulation Epigenetic regulation
http://www.nature.com
http://www.nature.com
Alternative Splicing Structural variants
(Van Duijvenboden et al. 2014) (Bokil et al. 2010) (Crotti et al. 2009)
http://www.nature.com ROLE OF COPY NUMBER VARIATIONS IN INHERITED DISEASES
BRUGADA SYNDROME: Duplication exons 15 to 28 SCN5A
LONG QT SYNDROME: Deletion exons 7 and 8 KCNH2 MECHANISMS UNDERLYING CONGENITAL AND ACQUIRED LQT
Amin et al. EHJ 2015 ACQUIRED LONG QT SYNDROME
WWW.CREDIBLEMEDS.ORG GENETIC PREDISPOSITION
BASAL ECG BUPIVACAINE BUPIVACAINE
GENETICS BASIC ELECTROPHYSIOLOGY
Vernooy K et al., Heart Rhythm 2005 INDUCED BRUGADA-LIKE ECG PATTERN
Circulation 2002;106:2514 Circulation 2005;111:659 39.5°C 36.4°C PROPOFOL-INDUCED BRUGADA-LIKE ECG PATTERN
Vernooy K et al., 2005 LONG QT SYNDROME: MANAGEMENT BRUGADA SYNDROME: MANAGEMENT
COCAINE INTOXICATION
TRICYCLIC INTOXICATION BRUGADA SYNDROME: MANAGEMENT
A B Before RF A After RF After Flecainide C C A D B B C D
E F E F
D E F KEEP YOUR Is ON BRUGADA SYNDROME
• Do not Ignore the ecg. • ECG pattern under an acute Inducer is a medical emergency. • Remember that it may be an Inherited disease. • Consider Inducibility at EPS SUDEP AND CHANNELOPATHIES
KCNH2 c.246T>C SCN5A W1095X DIAGNOSIS BASED ON THE PRESENCE OF A GENETIC MUTATION