Professor Eric Schulze-Bahr

Transcription

1 No CoI. Professor Eric Schulze-Bahr Institute for Genetics of Heart Diseases Department of Cardiology and Angiology University Hospital Münster / Germany

2 ICD therapy in asymptomatic or borderline LQTS patients

3 Primum non nocere Secundum cavere Tertium sanare

4 Cascade Genetic Testing in LQTS Family evaluation is recommended after identification of the proband s (LQTS) gene mutation (e.g., HR/EHRA Expert Statement 2011, UK Position Statement 2008) Subsequently, thorough family investigations identify additional mutation carriers, e.g. - being a-/presymptomatic - having currently no clinical signs of familial disease (i.e., non-penetrance) Identified family members have to get expert medical advice and, often, some psychological aid

5 Cascade Genetic Testing: An Early Detection Tool Family evaluation may unravel additional asymptomatic mutation carriers that are at Low Intermediate High-risk (for a first CE) Family evaluation may unravel additional asymptomatic mutation carriers that have incomplete, but age-dependent penetrance (e.g., Brugada, HCM, ARVC, DCM) > Age-dependency of disease manifestation may require recurrent risk (re-) evaluation

6 ECG of a young female Asymptomatic, National Team Player (Basketball) HR 50/min QT 500 ms QTc 456 ms HR 121/min QT 380 ms QTc 540 ms (100W)

7 Long-life ICD therapy in a female, asymptomatic LQT-1 patient being exposed to high endurance and triggers for many years?!

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9 Risk Evaluation in A-/Presymptomatic LQTS Patients Impact of Family history Impact of a particular LQTS subtype or mutation for individual risk assessment Individual and electrocardiographic parameters and risk > Therapy should be adjusted to the level of risk.

10 455 ms QTc: 398 ms ECG of a father (44 y; asymptomatic)., having a 18-y old daughter with VF during SMS message 629 ms QTc: 547 ms ECG of the proband s sister, 16-y old, asymptomatic. 536 ms QTc: 487 ms 451 ms QTc: 411 ms

11 Does the need of an ICD implantation in an index case (e.g., for secondary prevention of VF) automatically require ICD implants in other relatives (i.e., identical mutation carriers)?!

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13 Impact of LQTS Family History and Individual Disease Severity LQTS-ICD (n=27): 63% CA, 33% syncope during BB Mönnig et al. (2005) Heart Rhythm 2:

14 LQTS and Family History LQTS profiles (QTc, symptomes) of parents (n= 422) and siblings (n= 369) have no influence or no impact on disease severity of LQTS probands (n= 221). Only gender and QTc are determinants 1 QTc > 530ms, female gender and previous syncope are associated with LQTS-related death or CA 2 n=194 (108/86; 21+12y) 36% CE before 40 y 10% CA/SCD Fig: Seth et al. (2007) JACC 49: : Kimbrough et al. (2001) Circulation 104: : Kaufman et al. (2008) Heart Rhythm 5: )

15 Risk Evaluation in A-/Presymptomatic LQTS Patients Impact of Family history Impact of a particular LQTS subtype or mutation for individual risk assessment Individual and electrocardiographic parameters and risk > Therapy should be adjusted to the level of risk.

16 Asymptomatic LQTS Patients: ICD Implantation 2006: ACC/AHA/ESC VT/SCD guidelines Class IIb (Level B) can be considered for prophylaxis in categories possibly associated with higher risk of cardiac arrest such as LQT2 and LQT3 2007: German Cardiac Society ICD guidelines Class IIb (Level C), adopted from : ACC/AHA/HR device guidelines strong family history for SCD or intolerance of a drug... data from genetic analysis becoming increasingly useful for clinical decision making 2010: UK ICD guidelines No ICD indication (events <0.1%/a), adopted from 2006

17 Does a particular LQTS gene mutation represents an indicator to implant an ICD, apart from clinical presentation?!

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19 ??? Proband Clinic+ Genotype+ Clinic- Genotype+ Clinic- Genotype-

20 In consequence, risk prediction upon For a given the majority genotype of or genotyped particular mutation seems LQTS unlikely families for (>400 the to majority. date), we observe significant intrafamilial variability of QTc and/or symptoms that indicates non-uniform (better: individually modified) disease expression.

21 Kaplan-Meier Analysis (580 LQTS Patients, untreated) All Cardiac Events LQT-1: ms ms LQT-2: ms ms LQT-3: ms ms 0.33% events/y (m: 0.33%, f: 0.28%) 0.60% (m: 0.46%, f: 0.82%) 0.56% (m: 0.96%, f: 0.30%) Priori et al. (2003) New Engl. J. Med. ; 348:

22 LQTS Genotypes: Associated with Different Cardiac Risk?! LQT-1 N QTc Localisation ms ms Transmembranous Channel pore Mutation type ms ms Missense Biophysical Dysfunction ms ms Moss et al. (2007) Circ.115: Dominant negative LQT-2 N QTc Localisation ms ms Moss et al. (2002) Circ.105:

23 Loss of Functional HERG Channels: Key Mechanism for LQT-2 (I Kr ) HEK kda: Mature HERG protein 135 kda: Immature HERG protein 28/34 Missense mutations were trafficking-deficient (Western blot: 135 kda) 4/6 Missense mutations (R328C, P347S T436M, R922W) had a wild-type like I Kr Anderson et al. (2006) Circulation 113:

24 Ion Channel Dysfunction Upon Gene Mutations Reduced number of of functional (WT) channels Dysfunctional channels

25 Risk Evaluation in A-/Presymptomatic LQTS Patients Impact of Family history Impact of a particular LQTS subtype or mutation for individual risk assessment or??? Individual and electrocardiographic parameters and risk > Therapy should be adjusted to the level of risk.

26 Kaplan-Meier Analysis (580 LQTS Patients, untreated) <446 ms #468 ms #498 ms >498 ms Priori et al. New Engl. J. Med. 2003; 348:

27 LQTS CE and QTc Kaufman et al. (2008) Heart Rhythm 5:

28 Does every asymptomatic LQTS patient need an ICD?!

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30 Therapy of Asymptomatic LQTS Patients Use beta-blockers (K+-channel LQTS), combine with AA class Ib in LQT-3 (Na+) Perform life-style modification, avoid triggers Avoid low K+ and QT-prolonging drugs (list!) ICDs in asymptomatic patients?! - Selected (minority) use, preferentially females - Reserved for pts. with a long QTc (>500 ms) - Consider when intolerance or refuse of BB - So far: no prospective randomized trial data

31 Risk Evaluation in A-/Presymptomatic LQTS Patients Impact of Family history Impact of a particular LQTS subtype or mutation for individual risk assessment Individual and electrocardiographic parameters and risk > Therapy should be adjusted to the level of risk.

32 Professor Eric Schulze-Bahr Institute for Genetics of Heart Diseases Department of Cardiology and Angiology University Hospital Münster / Germany

33 Risk Evaluation in A-/Presymptomatic LQTS Patients Impact of Family history Impact of a particular LQTS subtype or mutation for individual risk assessment Individual and electrocardiographic parameters and risk Others?!

34 Imaging of Myocardial Innervation Radioactive Tracer Activity Sympathetic System L-Tyrosine NE [ 11 C]HED [ 123 I]MIBG Choline ACh Parasympathetic System NE NE NE Ch ACh NE NE Ch ACh NE NE NE NE ACh ACh ACh [ 11 C]MQNB 1: [ 11 C]-GB67 m2 1: [ 11 C]-CGP MYOCYTE 2: 12177

35 Sympathetic cardiac innervation: 28 symptomatic LQTS pts. (MIBG-SPECT) N: QTc (ms) Syncope/VF 18/10 7/0 5/7 6/3 Abnormal MIBG: Segm. with tracer : Kies et al. (in press) Eur. J. Nucl. Med.

36 MIBG-SPECT and QT Prolongation: 28 symptomatic LQTS pts. N: QTc (ms) Syncope/VF 18/10 7/0 5/7 Abnormal MIBG: 17 (61%) 10 (56%) 7 (70%) Kies et al. (in press) Eur. J. Nucl. Med.