No CoI. Professor Eric Schulze-Bahr Institute for Genetics of Heart Diseases Department of Cardiology and Angiology University Hospital Münster / Germany
ICD therapy in asymptomatic or borderline LQTS patients
Primum non nocere Secundum cavere Tertium sanare
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
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
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)
Long-life ICD therapy in a female, asymptomatic LQT-1 patient being exposed to high endurance and triggers for many years?!
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.
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
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)?!
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: 497-504
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: 1092-1098 1: Kimbrough et al. (2001) Circulation 104: 557-562 2: Kaufman et al. (2008) Heart Rhythm 5: 831-836)
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.
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 2006 2008: 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
Does a particular LQTS gene mutation represents an indicator to implant an ICD, apart from clinical presentation?!
??? Proband Clinic+ Genotype+ Clinic- Genotype+ Clinic- Genotype-
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.
Kaplan-Meier Analysis (580 LQTS Patients, untreated) All Cardiac Events LQT-1: 466 +44 ms 488 +47 ms LQT-2: 490 +49 ms 519 +55 ms LQT-3: 496 +49 ms 523 +55 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: 1866-1874
LQTS Genotypes: Associated with Different Cardiac Risk?! LQT-1 N QTc Localisation 57 485 ms 51 460 ms Transmembranous Channel pore Mutation type 54 481 ms 62 471 ms Missense Biophysical Dysfunction 187 500 ms 169 470 ms Moss et al. (2007) Circ.115: 2482-2487 Dominant negative LQT-2 N QTc Localisation 35 486 ms 166 459 ms Moss et al. (2002) Circ.105: 794-799
Loss of Functional HERG Channels: Key Mechanism for LQT-2 (I Kr ) HEK293 155 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: 365-373
Ion Channel Dysfunction Upon Gene Mutations Reduced number of of functional (WT) channels Dysfunctional channels
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.
Kaplan-Meier Analysis (580 LQTS Patients, untreated) <446 ms #468 ms #498 ms >498 ms Priori et al. New Engl. J. Med. 2003; 348: 1866-1874
LQTS CE and QTc Kaufman et al. (2008) Heart Rhythm 5: 831-836
Does every asymptomatic LQTS patient need an ICD?!
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
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.
Professor Eric Schulze-Bahr Institute for Genetics of Heart Diseases Department of Cardiology and Angiology University Hospital Münster / Germany
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?!
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
Sympathetic cardiac innervation: 28 symptomatic LQTS pts. (MIBG-SPECT) N: 10 28 7 12 9 QTc (ms) 501+69 481+69 508+81 508+54 Syncope/VF 18/10 7/0 5/7 6/3 Abnormal MIBG: 17 5 7 5 Segm. with tracer : 5 6 4 Kies et al. (in press) Eur. J. Nucl. Med.
MIBG-SPECT and QT Prolongation: 28 symptomatic LQTS pts. N: 28 18 10 QTc (ms) 501+69 468 543 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.