How to manage a patient with short QT syndrome? Torino, 27 ottobre2012

Carla Giustetto

Division of University of Torino

QT 260 ms QTc 290 ms QT 280 ms QTc 260 ms Normal T waves Narrow, tall and peaked T waves High incidence of SD

Genetic Background

Two different mutations in KCNH2 (HERG) resulting in the same aminoacid change (N588K) in the S5-P loop region of the cardiac IKr channel

Gain of abbreviation of action potential SQT1 function of duration and IKr refractoriness

Genetic Background SQT1 SQT2 SQT3 SQT4/5 SQT6

QTc 302 ms Overlapping syndromes QTc SQT260 ms syndromes are due to QTc 320 ms dueQTc to reduced Ca+ enhanced K+ current 327 ms currents QTc 329 ms

KCNH2 KCNQ1 CACNA1C KCNJ2 (HERG) CACNB2b CACNA2D1

↑ IKr ↑ IKs ↓ICaL ↑ IK1 ↓ ICaL Genotyped SQTS cases in the EuroShort registry 22 out of 72 patients

18 1 2

1 In the EuroShort Registry genetic mutations were identified in 11 out of 28 (39%) probands who performed the analysis Which is the upper limit of short QT ?

QTc ≤ 340 ms 29 patients

QTc ≤ 360 ms

European short QT Registry Inclusion Criteria

QTc ≤ 340 ms, even ASYMPTOMATIC QTc ≤ 360 ms + or or belonging to families with SQTS

STRESS TEST - QT/HR relation

ms SQTS 1 patients ms control group 440 440 SQTS 1 420 420 400 slope 400 slope 380 -0.5 ± 0.1 380 -1.40 ± 360 360 340 340 0.4 320 320 300 300 280 280 260 260 240 240 220 220 200 200 180 180 40 60 80 100 120 140 160 180 200 220 40 60 80 100 120 140 160 180 200 220 bpm bpm rest QT - peak QT 48.3±14.2 ms 106.7±20.8 ms p<0.0001

European Short QT Registry (Euro-Short) 72 pts

(n = 72)

Males 49 (74%)

Age at observation (y) 34 ±17

Familial SD 47 (65%)

QT (ms) 285 ± 36 29% 43% QTc (ms) ± ± 315 23 [mean HR 76 19] 11% 17% Reason of first clinical observation 42 index patients from European SQT Registry 45% 20 18 16 14 29% 12 10 8 12% 6 7% 7% 4 2

SD/aSD Syncope AF/palp Familial SD Occasional finding Age distribution of Cardiac Events in Males and Females

Males 15 - Females 5

Giustetto et al. JACC 2011; 58: 587-95 THERAPY

16 year- old boy with very short QT interval: QT 248 ms/ QTc 252ms Syncope at 6 months, then completely asymptomatic High incidence of sudden death in the family VF not induced during EPS The dilemma was: what to do with this patient? An ICD was implanted: 17 months thereafter the ICD ICD discharged appropriately during sleep

ICD interrogation may show episodes of rapid nsVT in asymptomatic subjects

M.Z., 58 year old ICD to everyone?

Early/Late complications

Children

3/5 consecutive pts 60% implanted in primary prevention had inappropriate shocks for oversensing 30 ± 26 days after implantation

T wave oversensing = double counting → Causing inappropriate shocks

Technical solutions to reduce T wave oversensing

Maximal R-wave amplitude 10 mv Decay delay “ ” Threshold start Adjusted decay avoids Threshold decay =T 50%-wave R-wave oversensing amplitude 5 mv T-wave oversensing

ICD Linear decay sensing Blanking period EGM wave QRS T Schimpf et al. JCE 2003 Pts with

Late complications Sacher et al. Sarkozy et al. Rosso et al. of ICD in pts with Circ. 2006 EHJ 2007 IMAJ 2008 220 pts 47 pts 59 pts f-up 38±27m f-up 47.5m f-up 45±35m

Lead failure requiring extraction and 19 (8%) 6 (13%) 9 (15%) reimplantation of lead/device Pocket and/or lead infection requiring 3 (1.3%) 1 (2%) lead/device replacement

Pericardial effusion 1 (0.5%) 1 (2%)

Pocket revision 2 (1%) 1 (2%)

Inappropriate shocks (due to: lead failure/dislodgement, T wave 45 (20%) 19 (40%) 14 (24%) oversensing, sinus , supraventricular )

Severe psychological difficulties 2 (1%) 8 (13%) Total device related 62 pts 18 pts 19 pts Complication (28%) (38%) (32%) ICD for everyone?

Early/Late complications Children ICD implant in childhood Issues

High technical complexity due to: small body and size difficult vascular access modifications of the implant owing to growth

Psychosocial distress linked to device discharges (especially if inappropriate)

High rates of leads complications Pts with LQTS

Late complications Etheridge et al. of ICD in children JACC 2007 23 pts, mean age with LQTS 9.4±5.4 y f-up 4.4 ±3.5 Lead failure requiring extraction and 2 (10%) reimplantation of lead/device Pocket and/or lead infection requiring 1 (4%) lead/device replacement

Pericardial effusion

Pocket revision

Inappropriate shocks (due to: lead failure/dislodgement, T wave 4 (17%) oversensing, , supraventricular arrhythmias)

Severe psychological difficulties 13 pts Total device related Complication (48%) THERAPY Drug therapy: may it play a role in the treatment of Short QT patients? BASAL

Short QT Syndrome: Pharmacological Treatment Fiorenzo Gaita, MD; Carla Giustetto, MD; Francesca Bianchi, MD; Rainer Schimpf, MD; Michel Haissaguerre; MD, Leonardo Calò, MD; Ramon Brugada, MD; Charles Antzelevitch, PhD; Martin Borggrefe, MD;QTQT QTChristian 280320 260440 msmsWolpert, ms MD. QTcQTcQTc 260 320266390 msms ms J Am Coll Cardiol 2004; 43: 1494-99

QUINIDINE

Sotalol

N588K mutation in 1000 pA HERG reduces the

affinity of the IKr channel to by 2020--foldfold

4000 pA

Quinidine

N588K mutation in HERG reduces the

affinity of the IKr channel to quinidine by 5.85.8-foldfold

Quinidine also blocks

IKs, Ito, IK1

12 pts with HQ event Rate 0%/ year

Mean f-up 76± 30 months 35 pts without HQ event Rate 4.9%/ year

72 patients from EuroShort Registry

5 dead at observation 72 pts 1 dead for other reasons 1 not in the follow-up 65

15 8 42 SYNCOPE CARDIAC ARREST ASYMPTOMATIC

ICD Hq ICD Hq no ICD Hq no 10 1 3 2 2 7 7 26 ICD+Hq ICD+Hq ICD+Hq 4 1 2 6 occasional finding Follow-- upno familial SQTS or SD -No known genotype ± 2 fast NSVT 1 syncope 1 VF 691 VF 36 months 2 fast NSVT (range 4-129) Rate event: previously symptomatic 3.5%/year, asymptomatic 1.9%/year p=0.3 42 ASYMPTOMATIC pts

2,4% /year in pts without HQ

Log rank p=0.3 42 ASYMPTOMATIC pts: 6 occasional finding

2,4% /year in the “not occasional finding” group

Log rank p=0.5 36 yrs, cyclist. No symptoms QT 350 ms QTc 335 ms Stress test: H.R. 68 H.R. 115 H.R. 150

QT 320 ms QT 280 ms QT 220 ms QTc 340 ms QTc 388 ms QTc 348 ms slope slope SQTS 2 -1.35 control group -1.30±0.3 440 440 420 420 400 400 380 380 360 360 340 340 320 320 300 300 280 280 260 260 240 240 220 220 200 200 180 180 40 60 80 100 120 140 160 180 200 220 40 60 80 100 120 140 160 180 200 220 • no arrhythmias induced at EP study • KCNQ1 V307L mutation (IKs) QT 370 ms Review: Special Report QTc 350 ms Mutation in the KCNQ1 Gene Leading to gain of function of IKs the Short QT-Interval Syndrome abbreviation of action Chloé Bellocq et al, Circulation. 2004;109:2394-2397 potential duration and refractoriness

 SQT2

• discharged on Hydroquinidine 250 mg BID H.R. 55 H.R. 107 H.R. 125

QT 380 ms QT 280 ms QT 265 ms QTc 364 ms QTc 374 ms QTc 380 ms Short QT Syndrome: How to manage a symptomatic patient with SQTS?

In patients with aborted cardiac arrest or syncope, ICD is presently the first-choice therapy Short QT Syndrome: How to menage an asymptomatic patient with SQTS?

Patients with occasional short QT finding should undergo stress test and 24-hour Holter monitoring to study the QT behavior at different heart rates and to better define the diagnosis and, maybe, to guide therapy Short QT Syndrome: How to manage asymptomatic pts?

• As we have not definitive data on predictors of SD yet, ICD should be proposed to adult patients from highly symptomatic families

• Prophylactic treatment with Hydroquinidine should be considered for newborn and children and also for adult patients who refuse ICD implantation EUROPEAN REGISTRY ON SHORT QT SYNDROME “EURO-SHORT” Supported by the European Heart Rhythm Association (EHRA)

Correspondence: Carla Giustetto M.D., Torino, Italy e-mail [email protected] Rainer Schimpf M.D., Mannheim, Germany e-mail: [email protected]