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

CPVT Long QT syndrome ACTION POTENTIAL-ION CHANNELS-INHERITED 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 KCNQ1 (LQT1) 11p15.5 IKs α subunit (KvLQT1, Kv7.1) KCNH2 (LQT2) 7q35-36 IKr potassium channel α subunit (HERG, Kv11.1) SCN5A (LQT3) 3p21-p24 Cardiac α subunit (Nav1.5)

AKAP9 7q21-q22 Yotiao ANK2 4q25-q27 Ankyrin B CACNA1C 12p13.3 Voltage gated L-type (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